CZ278999A3 - 3-Pyperidinyl-4-oxoquinazoline derivatives and pharmaceutical preparations containing thereof - Google Patents

Abstract

3-piperidyl-4-oxoquinazoline derivatives of formula (IIH) wherein R is an amine or a cyclic amine such as dibenzoazepine, each of it is substituted with substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl similarly, n is an integer from 1 to 4, R 3 and R (are independently linked, lower alkyl and the like or a pharmaceutically acceptable salt thereof. Compounds of formula UJ have excellent inhibitory activity against MIP. Such compounds not only inhibit the formation of LDL which is cause arteriosclerotic diseases but also limit TG, cholesterol and 1-lipoproteins, such as LDL, regulate cellular in the blood Lipids through regulation of MIP activity. These can also be used as a new type of preventive or therapeutic agent for hyperlipaemia or arteriosclerotic diseases. In addition, it may be use a pro-preventive or therapeutic agent for pancreatitis, obesity, hypercholesterolemia a hypertriglyceridemia.

Description

3-piperidinyl-4-oxoquinazoline derivatives and pharmaceutical compositions in which they are contained

Technical field

The present invention relates to a novel 3-piperidinyl-4-oxoquinazoline derivative. More particularly, it relates to a pharmaceutical composition comprising a 3-piperidinyl-4-oxoquinazoline derivative having microsomal triglyceride transfer protein (MTP) inhibitory activity or a pharmaceutically acceptable salt thereof.

BACKGROUND OF THE INVENTION

Hyperlipemia, diabetes and hypertension are risk factors in arteriosclerotic disorders such as coronary artery disease. Hyperlipemia refers to a condition in which lipids such as cholesterol are abnormally elevated in the blood. There are three types of hyperlipemia depending on the cause. One is primary lipemia resulting from an inherited abnormality of enzymes and proteins involved in the metabolism of low density lipoproteins (LDL) and lipoprotein receptors. The second is secondary hyperlipemia, which is the result of various diseases or medications. The third is non-genetic hyperlipemia resulting from overeating.

Lipids taken from food are absorbed in the small intestine by bile acids and are excreted into the blood as chylomicrons through the lymphatic vessels. The triglyceride (TG) unit of secreted chylomicron is catabolized to free fatty acids by lipoprotein lipase (LPL), which is found in the capillary wall, which is converted to cholesteryl ester (CE) rich chylomicron residues, which are transferred to the liver via chylomicron residual receptors. In the liver, chylomicron residues and / or free fatty acids are further converted to TG and the like by enzymes such as acyl CoA synthetase (ACS). The resulting products are then combined with apolipoprotein B synthesized on a rough endoplasmic reticulum to form a very low density lipoprotein (VLDL). VLDL moves to the Golgi apparatus and is subject to modification. The modified VLDL is secreted outside the cells, thereby becoming a medium density lipoprotein (IDL) by treatment with LPL. The resulting IDL is converted to LDL by HTGL (hepatitis lipase). Thus, lipids are distributed to peripheral tissues.

It was found that after the formation of chylomicron in the small intestine and VLDL in the liver, proteins having TG and CE-transfer activity were present in the microsomal fractions in the small intestine and liver. In 1985, Wetterau et al. isolate and purify the protein, i. microsomal triglyceride transfer protein (MTP), from microsomal fractions in bovine liver (Wetterau J.R. et al., Chem. Phys. Lipids 38, 205-222 (1985)).

However, MTP was not in the focus of clinical medicine until it was published in 1993 that the cause of abetalipoproteinemia was a defect in MTP. This disease is characterized by an almost absent serum apolipoprotein B, but a missing anomaly in the genes associated with apolipoprotein B. Serum cholesterol is less than 500 mg / L and serum triglycerides are extremely low. Another characteristic of the disease is that apolipoprotein B containing lipoproteins such as chylomicron, VLDL and LDL are completely absent in the blood. These findings indicate that MTP is an essential protein for conjugation of apolipoprotein B with TG and CE, i. for the production of VLDL and chylomicron, and plays an essential role in the secretion of these lipoproteins.

Since lipids are by their nature insoluble in water, they associate in blood with a hydrophilic protein called apolipoprotein and are present as lipoproteins. VLDL, IDL, LDL and chylomicron, which are involved in hyperlipemia, are all lipoproteins.

MTP is present in microsomal fractions in hepatocytes and epithelial cells of the small intestine and is responsible for intracellular transmission of TG and CE. During the synthesis of apolipoprotein B (the liver apolipoprotein B100 and the small intestine apolipoprotein B48), TG and CE associate with the corresponding apolipoproteins by MTP transmission, producing VLDL or chylomicron in the liver and small intestine. As a result, these lipoproteins are secreted outside the cells as VLDL from the liver and as chylomicron from the small intestine. MTP is necessary for assembly of these lipoproteins. Therefore, lipoprotein formation can be inhibited by inhibiting MTP activity, thus preventing the transfer of lipids such as TG to apolipoproteins.

Thus, it is clear that LDL is closely related to the onset of arteriosclerotic disease in general. LDL crosses the blood vessel endothelium and is stored in the intracellular matrix of the blood vessel wall. Oxidative degeneration occurs where a series of lipid peroxide-induced inflammatory reactions are triggered and degenerate proteins cause macrophage and vascular smooth muscle invasion, lipid deposition, cell proliferation and increase in intracellular matrix in blood vessel walls. Then arteriosclerotic lesions arise. Therefore, prevention or treatment of arteriosclerotic diseases by lowering LDL levels can be performed.

As mentioned, lipoproteins such as VLDL and LDL can be prevented by inhibiting MTP activity. Therefore, TG, cholesterol and lipoproteins such as LDL in blood and lipids in cells can be controlled by regulating MTP activity. Compounds having such activity are believed to be novel drugs intended to prevent and treat not only hyperlipemia or arteriosclerotic disease, but also pancreatides, obesity, hypocholesterolemia, hypertriglyceridemia and the like.

Compounds with MTP inhibitory activity have recently been described.

···· ····

For example, in Eur. J. Biochem. 240: 731-720 (1996) discloses 4'-bromo-3'-methylmethaqualone as a compound which is active in inhibiting MTP. However, the literature neither describes nor suggests such compounds as the compounds of the present invention. and

Unexamined Japanese patent application (JP-A) Hei 6-38761 (EP 584446) discloses 2- [1- (3,3-diphenylpropyl) -4-piperidinyl] -2,3-dihydro-3-oxo-1H-isoindole hydrochloride as a compound having MTP inhibitory activity. However, the compounds of the present invention are neither described nor suggested in this publication.

It further discloses JP-A-Hei 7-165712 (US 5595872) as a compound having MTP inhibitory activity,

2- (4-piperidyl) -2,3-dihydro-3-oxo-1H-isoindole compounds such as 2- [1- [2- (5H-dibenzo [a, d] cyclohepten-5-yl) ethyl] - 4-piperidyl] -2,3-dihydro-3-oxo-1H-isoindole and WO 96/26205 discloses isoindole compounds such as 9- [3- [4- (2,3-dihydro-1-oxo-1H-isoindole)]. -2-yl) -1-piperidyl] -propyl] -N-propyl-9H-fluorene-9-carboxamide. However, none of these publications disclose or suggest compounds of such structures as described in the present invention.

WO96 / 40640 discloses tetrahydroisoquinolin-6-yl amide derivatives of biphenyl-2-carboxylic acid such as [2- (1,5a, 6,9,9a, 9b-hexahydro-4H-dibenzofuran-4a-ylmethyl) -1,2,

4'-Trifluoromethylbiphenyl-2-carboxylic acid 3,4-tetrahydroisoquinolin-6-yl] amide as an MTP inhibitor. However, the publication neither describes nor suggests such compounds as the compounds of the present invention.

There are many references to the compounds they have

A 3-piperidyl-4-oxoquinazoline structure similar to the compounds of the present invention.

For example, JP-A-Sho 53-34784 (US 4166117) discloses N-substituted quinazoline compounds such as 1 - [(2,6-dimethylphenoxy) -2-ethyl] -4- [4-oxo [3H] quinazoline-3 -yl] piperidine as compounds having antihypertensive activity. However, the publication does not disclose compounds of such structures as the compounds of the present invention. In addition, the publication neither describes nor suggests that the compounds have MTP inhibitory activity.

JP-A-Hei 8-151377 discloses quinazoline derivatives such as N- (2,6-dichloro-4-nitrophenyl) -4- (1,2,3,4-tetrahydro-1,6-dimethyl-2,4- dioxoquinazolin-3-yl) -1-piperidineacetamide. However, the compounds disclosed in this publication exhibit activity in inhibiting adenosine processing, and it is not disclosed or suggested that the compounds have MTP inhibitory activity.

US 4364954 discloses diphenylpropanamine compounds such as 1- [1- [3- [bis (4-fluorophenyl) amino] propyl] -4-piperidyl] -1,3-dihydro-2H-benzimidazol-2-one. The compounds are described as a therapeutic agent for schizophrenia and not in the present invention as an MTP inhibitor. Moreover, the publication neither describes nor suggests compounds of such structures as the compounds of the present invention.

EP 802188 discloses that heterologous phenylglycinolamides having a 4-oxoquinazoline group are effective against atherosclerotic diseases. However, the publication neither describes nor suggests compounds of such structures as the compounds of the present invention.

SUMMARY OF THE INVENTION

The present inventors have intensively sought compounds of the types already described which have MTP inhibitory activity. As a result, it is somewhat surprising to find that compounds with a 3-piperidyl-4-oxoquinazoline structure having an aminoalkyl group at the 1-position of the piperidyl group exhibit excellent MTP inhibitory activity. Thus, the present invention has been completed.

· '· - ******** ** **

The present invention relates to the 3-piperidyl-4-oxoquinazoline derivatives mentioned in the following (1) to (13) or pharmaceutically acceptable salts thereof, and to the pharmaceutical compositions in which they are contained.

(1) The 3-piperidyl-4-oxoquinazoline derivative of the general formula (I):

wherein R is a radical of formula (II):

Ri —N

R ₂ (II) wherein R 1 and R ₂ are the same or different and represent hydrogen, lower alkyl of 1 to 4 carbon atoms, aralkyl, benzoyl, cycloalkyl of 3 to 7 carbon atoms, aryl or heteroaryl containing 1 to 3 heteroatoms selected nitrogen, sulfur and oxygen (wherein the cycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 3 substituents selected from halo, lower alkyl of 1 to 4 carbon atoms, lower haloalkyl of 1 to 4 carbon atoms, nitro, lower alkoxy of (1-4 carbon atoms, amino, lower alkyl substituted amino of 1 to 4 carbon atoms, hydroxy, phenoxy and sulfo), provided that one of R ₁ and R ₂ is not hydrogen, or of formula (III):

• substituents consisting

selected from 1 to 4 (III) wherein A and B are the same or different and are an aromatic hydrocarbon ring, an aromatic heterocyclic ring containing 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen, a cycloalkane ring of 3 to 7 carbon atoms, or a C 5 -C 7 cycloalkene ring (wherein the aromatic hydrocarbon, aromatic heterocyclic, cycloalkane or cycloalkene ring is optionally substituted with 1 to 3 of halogen, lower alkyl of carbon atoms, lower haloalkyl of 1 to 4 carbon atoms, hydroxyl, nitro, lower (C1 -C4 alkoxy, amino, lower alkyl substituted by C1 -C4 and sulpho), X is a single bond, straight chain alkylene or branched C1 -C4 alkylene, lower alkenylene straight chain or branched alkenylene consists C 2 -C 4 (wherein the lower alkylene or lower alkenylene includes substituent (s) selected from halogen, hydroxyl, nitro, lower alkoxy of 1 to 4 carbon atoms, amino and sulfo), oxygen, sulfur is substituted with lower alkyl an imino group consisting of 1 to 4 -SZ-, -ZS-, -NH-Z-, carbon atoms, carbonyl, -Ο-Z-, -Z-O-,

-NR ₅ -Z-, -Z-NH- or -Z-NR _S - (where Z is a lower alkylene group consisting of 1 to 4 carbon atoms), Y is a single bond, straight chain or branched alkylene 44 44

43 4 4 43 4 4 4 4 4

4 4444 4444

4 4 ·· 999 9,999,999

9 9 9 9 9 9 θ 4444 4444 44 44 * · 4.

C 1-4 alkylene or carbonyl, n is an integer of 1 to 4 and R ₃ to R ₄ are the same or different and represent hydrogen, lower alkyl of 1 to 4 carbon atoms, halogen, lower haloalkyl of 1 to 4 Or a pharmaceutically acceptable salt thereof.

(2) 3-piperidyl-4-oxoquinazoline derivative described in point (1), wherein R is a group of formula (IV): Rí ' —N Ra ' (IV) where R '1 and R' ₂ are the same or different and represent cycloalkyl of 3 to 7 carbon atoms, aryl or

heteroaryl having 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen (wherein the cycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 3 substituents selected from halogen, lower alkyl of 1 to 4 carbon atoms, lower haloalkyl of 1 to 4 carbon atoms , amino, amino substituted by lower alkyl of 1 to 4 carbon atoms, hydroxyl and sulfo) or a group of formula (V):

(V) wherein A 'and B' are the same or different and are an aromatic hydrocarbon ring, an aromatic heterocyclic ring containing 9 9 9 9 9 9 9 9999 9999 9 9 9 999 9 9 ·· 999

9 9 9 9 9

9999 9999 99 99 99 99

up to 3 heteroatoms selected from nitrogen, open and oxygen, cycloalkane ring consisting of 3 to 7 atoms carbon or cycloalkene ring consisting of 5 to 7 atoms carbon (where

the aromatic hydrocarbon, aromatic heterocyclic, cycloalkane or cycloalkene ring is optionally substituted with 1 to substituents selected from halogen, lower alkyl of 1 to 4 carbon atoms, lower haloalkyl of 1 to 4 carbon atoms, hydroxyl, nitro, lower alkoxy of 1 to 4 X 'is a single bond, a straight chain alkylene or a branched alkylene of 1 to 4 carbon atoms, a straight chain alkenylene or a branched alkenylene consisting of 2 to carbon atoms (wherein the lower alkylene or lower alkenylene includes substituent (s) selected from halogen, hydroxyl, nitro, lower alkoxy of 1 to 4 carbon atoms, amino and sulfo), oxygen, sulfur, imino which is substituted ni lower alkyl having 1 to 4 carbon atoms, carbonyl, -O-Z'-, -Ζ´-Ο-,

-S-Z'-, -Ζ'-S-, -NH-Z'-, -NR _5' -Z'-, -Z'-NH- or -Z'-NR ₅ '- (wherein

Z 'is a lower alkylene group having 1 to 4 carbon atoms or carbonyl and R ₅ ' is a lower alkyl having 1 to 4 carbon atoms), Y 'is a single bond, a straight chain alkylene or a branched alkylene having 1 to 4 atoms R ₃ to R ₄ are the same or different and represent hydrogen or lower alkyl consisting of 1 to 4 carbon atoms or a pharmaceutically acceptable salt thereof.

(3) The 3-piperidyl-4-oxoquinazoline derivative described in (2), wherein R is a group of formula (VI):

RT —N

R ₂ ”(VI)

¹⁰ ·· ·· ·· • · · · · · 9 9 9 9 9 · · · 9900 9900 99 99 99 99 9 9 9 9 9 9 9 9 9 9 999 9,999,999 9 9 9 99 99 99 where R _x and R ₂ are same or different and represent cycloalkyl consisting of of 3 to 7 carbon atoms, aryl or

heteroaryl having 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen (wherein the cycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 3 substituents selected from halogen, lower alkyl of 1 to 4 carbon atoms, lower haloalkyl of 1 to 4 carbon atoms (nitro, lower alkoxy of 1 to 4 carbon atoms and hydroxyl) or a group of formula (VII):

(VII) wherein A and B are the same or different and are an aromatic hydrocarbon ring, an aromatic heterocyclic ring containing 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen (wherein the aromatic hydrocarbon or aromatic heterocyclic ring is optionally substituted with 1 to 3 substituents selected halogen, lower alkyl of 1 to 4 carbon atoms, lower haloalkyl of 1 to 4 carbon atoms, nitro, lower alkoxy of 1 to 4 carbon atoms and hydroxyl), X is a single bond, straight chain alkylene or branched alkylene (C 1 -C 4), straight-chain lower alkenylene or branched C 2 -C 4 alkenylene (wherein the lower alkylene or lower alkenylene comprises substituent (s) selected from halogen, hydroxyl and C 1 -C 4 lower alkoxy) ), oxygen, sulfur, imino, which is ex optionally substituted by lower alkyl of 1 to 4 carbon atoms, carbon, carbonyl, -O-Z-, -SZ-, -NH-Z- or -NR ₅ -Z- ( where

Z is a lower alkylene group having 1 to 4 carbon atoms or carbonyl and R ₅ is a lower alkyl having 1 to 4 carbon atoms), and R ₃ to R ₄ are hydrogen or a pharmaceutically acceptable salt thereof.

(4) The 3-piperidyl-4-oxoquinazoline derivative described in (3), wherein R is a group of the formula (VI) wherein R 1 and R ₂ are the same or different and represent cycloalkyl of 3 to 7 carbon atoms, aryl, heteroaryl containing 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen (wherein the cycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 3 substituents selected from halogen, lower alkyl of 1 to 4 carbon atoms, lower haloalkyl of 1 to 4 carbon atoms, nitro, lower alkoxy of 1 to 4 carbon atoms and hydroxyl), or a pharmaceutically acceptable salt thereof.

(5) The 3-piperidyl-4-oxoquinazoline derivative described in (4), wherein R 1 and R ₂ are the same or different and represent phenyl, pyridyl, pirazinyl, pyrimidinyl, thienyl, furyl or pyrrolyl (wherein each of said groups). is optionally substituted with 1 to 3 substituents selected from halogen, lower alkyl of 1 to 4 carbon atoms, lower haloalkyl of 1 to 4 carbon atoms, nitro, lower alkoxy of 1 to 4 carbon atoms and hydroxyl), or a pharmaceutically acceptable thereof salt.

(6) The 3-piperidyl-4-oxoquinazoline derivative described in (5), wherein R is diphenylamine, N-phenyl-N-thienyl, N-phenyl-N-pyridylamine, dipyridylamine, N-phenyl-N-pyrimidylamine (wherein each of said groups is optionally substituted with 1 to 3 substituents selected from halogen, lower alkyl cyclohexyl, pyridazinyl, consisting of 1 to 4 consisting of 1 to 4 carbon atoms, lower haloalkyl carbon atoms, nitro, lower; · 4 4 4 4

4 4 4 4 4 4

0 000 0 00 · 000

(C 1-4 alkoxy group consisting of 1 to 4 carbon atoms and hydroxyl), or a pharmaceutically acceptable salt thereof. ⁽⁷⁾ The 3-piperidyl-4-oxoquinazoline derivative as described in (3) wherein R represents a group of formula (V) wherein A and B are identical or different and represent an aromatic hydrocarbon ring or aromatic heterocyclic ring containing 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen (wherein the aromatic hydrocarbon or aromatic heterocyclic ring is optionally substituted with 1 to 3 substituents selected from halogen, lower alkyl of 1 to 4 carbon atoms, lower haloalkyl of 1 to 4 carbon atoms, nitro, lower X is a single bond, straight chain alkylene or branched alkylene of 1 to 4 carbon atoms, lower straight chain alkenylene or branched alkenylene of 2 to 4 carbon atoms (wherein lower alkylene or lower alkenylene include substituent (s) selected from halogen , hydroxyl and lower alkoxy of 1 to 4 carbon atoms), oxygen, sulfur, imino optionally substituted by lower alkyl of 1 to 4 carbon atoms, carbonyl, -O-Z-, -SZ-, -NH-Z or -NR ₅ -Z- (wherein Z is a lower alkylene group of 1 to 4 carbon atoms or carbonyl and R ₅ is a lower alkyl of 1 to 4 carbon atoms), or a pharmaceutically acceptable salt thereof.

(8) The 3-piperidyl-4-oxoquinazoline derivative described in (7), wherein A and B are the same or different and represent benzene, pyridine, pyrazine, pyrimidine or pyridazine (wherein each optionally substituted with 1 to 3 of halogen, lower alkyl) the ring is selected from said substituents of 1 to 4 carbon atoms, lower haloalkyl of 1 to 4 carbon atoms, nitro, lower alkoxy of 1 to 4 carbon atoms and hydroxyl), or a pharmaceutically acceptable salt thereof.

• 0 0 0 0 0 0 · · 0 0 0 0 0 0 0 0 0 0 0 0 0 • 0 0 0 0 0 0

(9) The 3-piperidyl-4-oxoquinazoline derivative described in (8), wherein R is carbazol-9-yl, phenoxazin-10-yl, phenothiazin-10-yl, acridone- 10-yl, 9,9-dimethylacridan-10-yl, 10,11-dihydro-5H-dibenzo [b, f] azepin-5-yl, 10,11-dihydro-2-hydroxy-5H-dibenzo [b, f] azepin-5-yl, 10,11-dihydro-10-hydroxy-5H-dibenzo [b, f] azepin-5-yl, 5H-dibenzo [b, f] azepin-5-yl,

5,11-dihydrodibenzo [b, e] [1,4] oxazepin-5-yl, 10,11-dihydro-11-oxo-5H-dibenzo [b, e] [1,4] disepepin-5-yl, 11-hydro-10-methyl-11-oxo-5H-dibenzo [b, e] [1,4] disepepin-5-yl, or a pharmaceutically acceptable salt thereof.

(10) The 3-piperidyl-4-oxoquinazoline derivative described in (3), selected from the group consisting of 3- [1- [2- [N- (2-methylphenyl) -N-methylamine] ethyl] piperidine- 4-yl] -3H-quinazolin-4-one; 3- [1- [2- (10,11-dihydro-5H-dibenzo [b, f] azepin-5-yl) ethyl] piperidin-4-yl -3H-quinazolin-4-one,

3- [1- [2- (10,11-Dihydro-10-hydroxy-5H-dibenzo [b, f] azepin-5-yl) ethyl] piperidin-4-yl] -3H-quinazolin-4-one, 3- [1- [2- (10,11-Dihydro-2-hydroxy-5H-dibenzo [b, f] azepin-5-yl) ethyl] piperidin-4-yl] -3H-quinazolin-4-one, 3- [1- [2- (5,11-dihydrodibenzo [b, e] [1,4] oxazepin-5-yl) ethyl] piperidin-4-yl] -3H-quinazolin-4-one, or a pharmaceutically acceptable salt thereof acceptable salt.

(11) A pharmaceutical composition comprising

The 3-piperidyl-4-oxoquinazoline derivative described in (1) to (10), or a pharmaceutically acceptable salt thereof, as active ingredient.

(12) A microsomal triglyceride transfer protein (MTP) inhibitor comprising the 3-piperidyl-4-oxoquinazoline derivative described in (1) to (10) or a pharmaceutically acceptable salt thereof as an active ingredient.

(13) A therapeutic or preventive agent for hyperlipemia or arteriosclerosis comprising the 3-piperidyl-4-oxoquinazoline derivative described in (1) to (10), or a pharmaceutically acceptable salt thereof, as an active ingredient.

• 4

4 4 4

4 4 4

444 4

4 4

4

44

Lower alkyl having 1 to 4 carbon atoms as used herein specifically denotes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc.

Aralkyl refers to alkyl of 1 to 4 carbon atoms substituted with the aryl described below. Specific examples include benzyl, benzhydryl, trityl, phenethyl, 3-phenylpropyl, 2-phenylpropyl, 4-phenylbutyl, naphthylmethyl, 2-naphthylethyl,

4-biphenylmethyl, 3- (4-biphenyl) propyl, etc.

C 3 -C 7 -cycloalkyl specifically refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

Aryl refers to phenyl, naphthyl, biphenyl, etc.

Heteroaryl containing 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen refers to a 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen. Specifically, they are thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isooxazolyl, triazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, etc.

Halogen refers to fluorine, chlorine, bromine, etc.

Lower haloalkyl of 1 to 4 carbon atoms denotes lower alkyl substituted by halogen (s). Specific examples include fluoromethyl, chloromethyl, bromomethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, chloroethyl, difluoroethyl, trifluoroethyl, pentachloroethyl, bromopropyl. dichloropropyl, trifluorobutyl, etc.

Lower alkoxy of 1 to 4 carbon atoms specifically includes methoxy, ethoxy, propoxyl, isopropoxyl, butoxyl, isobutoxyl, sec-butoxyl, tert-butoxyl, and the like.

Amino substituted with a lower alkyl of 1 to 4 carbon atoms refers to an amine that is mono- or disubstituted with a lower alkyl of 1 to 4 carbon atoms. Specific examples include methylamine, ethylamine,

00 0 ··· 0 · 0

Butylamine, isobutylamine, dimethylamine, diethylamine, ethyl acetate, propylamine, sec-butylamine, dipropylamine, isopropylamine, tert-butylamine, diisopropylamine, methylethylamine, methylbutylamine, etc.

Aromatic hydrocarbon ring refers to benzene, naphthalene, etc.

An aromatic heterocyclic ring containing 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen refers to a 5- or 6-membered aromatic heterocyclic ring containing 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen. Specifically, it is thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isooxazole, triazole, pyridine, pyrazine, pyrimidine, pyridazine, etc.

The cycloalkane ring of 3 to 7 carbon atoms specifically includes cyclopropane, cyclohexane, cycloheptane, etc.

A cycloalkane ring consisting specifically includes cyclopentene, cyclohexadiene, cycloheptadiene, etc.

Specifically, the straight-chain or branched-chain lower alkylene of 1-4 carbon atoms includes methylene, ethylene, trimethylene, tetramethylene, propylene, ethylethylene, dimethylmethylene, etc.

Specifically, the straight-chain lower alkenylene or branched lower alkenylene of 2 to 4 carbon atoms includes vinylene, propenylene, butenylene, butadienylene, methylvinylene, ethylvinylene, 3-methylpropylene, etc.

An amino group which is optionally substituted with 1 to 4 carbon atoms refers to an optionally substituted lower alkyl of 1 to 4 carbon atoms. Specifically, they are imine, methylimine, ethylimine, propylimine, isopropylimine, butylimine, isobutylimine, etc.

cyclobutane, cyclopentane, from 5 to 7 cyclohexene, cycloheptene carbon atoms, alkyl consisting of a secondary amine which

9 9 9 9 9 4

9 9 9 9 9

9 9 9 9 999 · 9 · 994

9 9 · · 9 9, ββββ.ββββ ee «« «9 β»

These embodiments are described in more detail below, but are not limited to this description.

Lower C 1 -C 4 alkyl represented by R _x or R ₂ is preferably methyl or ethyl.

The aralkyl represented by R _x or R ₂ is preferably benzyl or benzhydryl.

The cycloalkyl of 3 to 7 carbon atoms represented by R _x or R ₂ is preferably a cycloalkyl of 5 to 7 carbon atoms. Cyclohexyl is particularly preferred.

The aryl represented by R ₁ or R ₂ is preferably phenyl.

The heteroaryl containing 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen represented by R _x or R ₂ is preferably thienyl, furyl, pyrrolyl, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl.

Halogen as a substituent, cycloalkyl, aryl or heteroaryl represented by R _x or R ₂ is preferably fluorine or chlorine.

Lower alkyl having 1-4 carbon atoms as a substituent, cycloalkyl, aryl or heteroaryl represented by R _x or R ₂ is preferably methyl, ethyl, propyl, isopropyl or butyl. Methyl is particularly preferred.

Lower haloalkyl having 1 to 4 carbon atoms as a substituent, cycloalkyl, aryl or heteroaryl represented by R _x or R ₂ is preferably trifluoromethyl.

The lower alkoxy of 1 to 4 carbon atoms as a substituent of cycloalkyl, aryl or heteroaryl represented by R _x or R ₂ is preferably methoxy.

Amino substituted by lower alkyl of 1 to 4 carbon atoms as a substituent of cycloalkyl, aryl or heteroaryl represented by R _x or R ₂ is preferably methylamine, ethylamine, dimethylamine or diethylamine.

Expression optionally substituted with 1 to 3 substituents relative to the cycloalkyl, aryl or heteroaryl represented by R _x

44 44 4 44 44 44 4444 4444 4444 4444 4444 4444 4444 4444 4444 4444 4444 4444 4444

Or R ₂ preferably means that these groups are substituted by 1 to 2 substituents, more preferably by one substituent.

Preferred substituents of cycloalkyl represented by R ₁ or R ₂ are methyl, fluoro, chloro or amine.

Preferred aryl substituents represented by R _x or R ₂ are methyl, ethyl, propyl, isopropyl, butyl, fluoro, chloro, trifluoromethyl, nitro, methoxy or phenoxy. Methyl is particularly preferred.

The substituent of the heteroaryl represented by R _x or R ₂ is methyl.

Combinations of substituents in a group of formula (II) are not particularly limited as long as they fall within the scope of the definition. The compound of formula (II) is preferably dicyclohexylamine, diphenylamine, N-phenyl-N-thienylamine,

N-phenyl-N-pyridylamine or dipyridylamine. Particularly preferred are diphenylamine and dipyridylamine. The substituents R ₁ and R ₂ are as defined above.

The aromatic hydrocarbon ring represented by A or B is preferably benzene.

The aromatic heterocyclic ring containing 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen represented by A or B is preferably pyridine or pyrimidine, with pyridine being particularly preferred.

The cycloalkane ring of 3 to 7 carbon atoms represented by A or B is preferably cyclopentane, cyclohexane or cycloheptane.

The cycloalkane ring of 5 to 7 carbon atoms represented by A or B is preferably cyclopentene, cyclohexene or cycloheptene.

Halogen as a substituent of the aromatic hydrocarbon, aromatic heterocyclic, cycloalkane or cycloalkene ring represented by A or B is preferably fluorine or chlorine.

A lower alkyl having 1 to 4 carbon atoms as a substituent on the aromatic hydrocarbon, aromatic heterocyclic, cycloalkane or cycloalkene ring represented by A or B is preferably methyl or ethyl.

The lower haloalkyl of 1 to 4 carbon atoms as a substituent of the aromatic hydrocarbon, aromatic heterocyclic, cycloalkane or cycloalkene ring represented by A or B is preferably trifluoromethyl.

The lower alkoxy of 1 to 4 carbon atoms as a substituent of the aromatic hydrocarbon, aromatic heterocyclic, cycloalkane or cycloalkene ring represented by A or B is preferably methoxy.

Amino substituted with lower alkyl of 1 to 4 carbon atoms as a substituent of the aromatic hydrocarbon, aromatic heterocyclic, cycloalkane or cycloalkene ring represented by A or B is preferably methylamine, ethylamine, dimethylamine or diethylamine.

The expression optionally substituted with 1 to 3 substituents relative to the aromatic hydrocarbon, aromatic heterocyclic, cycloalkane or cycloalkene ring represented by A or B preferably means that these groups are substituted with 1 to 2 substituents and more preferably one substituent.

The cycloalkane ring substituent represented by A or B is preferably methyl, fluoro, chloro or amine.

The cycloalkene ring substituent represented by A or B is preferably methyl, fluoro, chloro or amine.

The aromatic hydrocarbon ring substituent represented by A or B is preferably methyl, ethyl, fluoro, chloro, trifluoromethyl, nitro, hydroxyl, sulfo or methoxy. Particularly preferred is hydroxyl.

The aromatic heterocyclic ring substituent represented by A or B is preferably methyl or hydroxyl.

ΦΦ · · · φ φ φ φ φ φ φ φ φ φ φ φ φ * * * * * * * φ · »(» · «« «φ · β φ φβ φ9

The straight-chain lower alkylene or branched lower alkylene of 1 to 4 carbon atoms represented by X is preferably methylene, ethylene or dimethylmethylene.

The straight-chain lower alkenylene or branched lower alkenylene of 2 to 4 carbon atoms represented by X is preferably vinylene.

Halogen as a substituent of the lower alkylene or lower alkenylene represented by X is preferably fluorine or chlorine.

The lower alkoxy of 1 to 4 carbon atoms as a substituent of the lower alkylene or lower alkenylene represented by X is preferably methoxy.

The expression optionally substituted with respect to the lower alkylene or lower alkenylene represented by X preferably means that these groups are optionally substituted with one substituent.

The lower alkylene substituent represented by X is fluoro, hydroxyl, methoxy or sulfo.

A preferred lower alkenylene substituent represented by X is fluoro, hydroxyl, methoxy or sulfo.

A preferred amino group which is optionally substituted

lower alkyl consisting of 1 to 3 carbon atoms; 4 atoms carbon represented by X is imine or methylimine. A preferred lower alkylene consisting of 1 to 4 atoms The carbon represented by Z is methylene. A preferred lower alkyl consisting of 1 to 4 carbon atoms

represented by R ₅ is methyl or ethyl. Methyl is particularly preferred.

A preferred straight-chain lower alkylene or branched lower alkylene of 1 to 4 carbon atoms represented by Y is methylene.

The combination of substituents in the group of formula (III) is not particularly limited as long as it falls within the scope of that definition. The group of formula (III) is preferably carbazol-9-yl, phenoxazin-10-yl, phenothiazin-10-yl, acridone-

·· ·· • · ·

-10-yl, 9,9-dimethylacridan-10-yl, 10,11-dihydro-5H-dibenzo [b, f] azepin-5-yl, 5H-dibenzo [b, f] azepin-5-yl, 11,1-dihydrodibenzo [b, e] [1,4] oxazepin-5-yl, 10,11-dihydro-11-oxo-5H-dibenzo [b, e] [1,4] diisepin-5-yl or II -hydro-10-methyl-11-oxo-5H-dibenzo [b, e] [1,4] diisepin-5-yl. Particularly preferred are 10,11-dihydro-5H-dibenzo [b, f] azepin-5-yl or 5,11-dihydrodibenzo [b, e] [1,4] oxazepin-5-yl. Substituents A and B are as defined above.

n is preferably an integer from 2 to 4, with 2 being particularly preferred.

Preferred lower alkyl having 1-4 carbon atoms represented by R ₃ or R ₄ is methyl.

Preferred halogen represented by R ₃ or R ₄ is fluoro or chloro.

Preferred lower haloalkyl having 1 to 4 carbon atoms represented by R ₃ or R ₄ is trifluoromethyl.

R ₃ and R ₄ are most preferably hydrogen.

Any pharmaceutically acceptable salt may be used as long as it forms a non-toxic salt with the compound of formula (I). Examples of such salts include salts with inorganic acids such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, carbonate, bicarbonate and perchlorate, salts with organic acids such as formate, acetate, trifluoroacetate, propionate, oxalate, glycolate, succinate, lactate , maleate, hydroxy maleate, fumarate, adipate, tartrate, malate, citrate, benzoate, cinnamon, ascorbate, salicylate, 2-acetoxybenzoate, nicotinate and isonicotinate, sulfonates such as methanesulfonate, ethanesulfonate, isethionate, benzenesulfonate, benzenesulfonate, benzenesulfonate salts with acidic amino acids such as aspartic acid and glutamic acid, alkali metal salts such as sodium and potassium, salts with organic bases such as trimethylamine, triethylamine, pyridine, picoline, dicyclohexylamine and Ν, Ν'-dibenzylethylenediamine and salts and amino acids such as lysine and arginine.

More particularly, it is preferred that R in the compound of formula (I) is N-phenyl-N- (2-methylphenyl) amine, 10,11-dihydro-5H-dibenzo [b, f] azepin-5-yl, 10,11 -dihydro-2-hydroxy-5H-dibenzo [b, f] azepin-5-yl, 10,11-dihydro-10-hydroxy-5H-dibenzo [b, f] azepin-5-yl, or 5,11-dihydrodibenzo [b, e] - [1,4] oxazepin-5-yl, n is 2 and R ₃ and R ₄ are hydrogen.

The compounds of the present invention are optionally hydrates or solvates. The compounds of the present invention include prodrug compounds and metabolites thereof.

The compounds of the present invention have low toxicity and excellent MTP-inhibitory activity and increase the amount of high density lipoproteins (HDL). Therefore, these compounds are expected to be a novel drug for the treatment or prevention of hyperlipemia or arteriosclerotic diseases.

When the compounds of formula (I) of the present invention or their pharmaceutically acceptable salts are used in a pharmaceutical composition, they can be formulated as tablets, pills, powders, granules, supplements, injections, liquids, capsules, aerosols, beverages, suspensions, emulsions. and syrups, together with acceptable carriers, excipients, disintegrators, stabilizers, buffers, emulsifiers, aromatizers, viscosity-increasing agents, flavors, solvents or other additives such as water, vegetable oil, alcohols such as ethanol or benzyl alcohol, polyethylene glycol, glycerol triacetate gelatin , lactose or sugars such as starches, magnesium stearate, talc, lanolin and petrolatum. The composition may be administered orally, rectally or parenterally.

The compounds of the present invention can be used as medicaments for animals as well as humans.

known pharmacological diluents, extenders, preservatives, colorants, »»

The dosage varies depending on the type and degree of disease, the compounds administered, the route of administration, the age, sex and weight of the patients. For oral administration, the compound of formula (I) is preferably administered to adults daily at a dose of 1 mg to 1000 mg, more preferably 50 mg to 800 mg.

The compounds of the present invention are prepared by the following methods. Of course, the production methods cannot be limited to these.

Step 1

A compound of formula (X) _(R represents an amine protecting group such as benzyl, benzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl, and R ₃ and R ₄ are as defined above) is synthesized by reacting a compound of formula (VIII) (R ₃ and R φ φ φ · · · · φ · · · · · · · φ φ φ φ φ · · · · φφ φφφφ φ ·· ·· ·· ·· are as defined above) with a compound of formula (IX) (R _u is as defined above) using a condensing agent such as l-ethyl-3- (3 -dimethylaminopropyl) carbodiimide (WSOHCl), dicyclohexylcarbodiimide (DCC), diphenylphosphoryl azide (DPPA) or carbonyldiimidazole (CDI), if necessary in the presence of an activating agent such as 1-hydroxybenzotriazole (HOBT), hydroxysuccinimide (HOSu) or -5-norbornene-2,3-dicarboxylic acid (HONB) in organic solution; a solvent such as dimethylformamide, dichloromethane, chloroform, acetonitrile, tetrahydrofuran, dimethylsulfoxide, carbon tetrachloride or toluene, or in a mixture of these solvents, with ice cooling or heating or at a suitable temperature in between.

Step 2

The compound of formula (XI) (R _3, R ₄ and R _n are as defined above) is synthesized by reacting a compound of formula (X) (R _3, R "and R _u are as defined above) in the presence of formic acid, triethyl orthoformate, etc. in an organic solvent such as methanol, ethanol, toluene, tetrahydrofuran, acetic acid or dimethylformamide, or in a mixture of these solvents or in the absence of solvents, with heating.

Step 3

A compound of formula (XII) (R ₃ and R ₄ are as defined above) is synthesized from compound (XI) (R _3, R ₄ and R _n are as defined above) in the presence. acids such as hydrochloric acid, hydrobromic acid, trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid, hydrogen chloride in dioxane, hydrogen chloride in ether, hydrogen chloride in acetic acid or hydrogen bromide in acetic acid, in an organic solvent such as dioxane, ether, dichloromethane, tetrahydrofuran, methanol, ethanol, chloroform, benzene, toluene, ethyl acetate or acetic acid or water or a mixture of these

solvents or in the absence of solvents. Alternatively, a compound of formula (XII) is obtained by subjecting a compound of formula (XI) to catalytic reduction with hydrogen in the presence of a metal catalyst such as palladium on carbon, platinum oxide, Raney nickel, palladium black or palladium hydroxide in an organic solvent such as methanol, ethanol, dimethylformamide, ether, dioxane, tetrahydrofuran, acetic acid or ethyl acetate or water or a mixture of these solvents.

Step 4

A compound of formula (I) (R, R ₃ , R ₄ and n as defined above) is synthesized by reacting a compound of formula (XII) (R ₃ and R ₄ as defined above) with a compound of formula (XIII) (R ₁₂ represents a leaving group such as halogen, methanesulfonyloxy or p-toluenesulfonyloxy and R and n are as defined above) using a base such as potassium carbonate, sodium acetate, sodium hydroxide, potassium hydroxide, sodium carbonate , sodium bicarbonate, triethylamine or pyridine, if necessary in the presence of sodium iodide, etc., in an organic solvent such as methanol, ethanol, tetrahydrofuran, dioxane, dimethoxyethane, ether, diisopropyl ether, acetonitrile, dimethylformamide, toluene, ethyl acetate, chloroform or dichloromethane or water, or in a mixture of these solvents, with ice cooling or with heating or at a suitable temperature in between.

The compound of formula (I) is also synthesized by the following steps.

• ·

Step 5

A compound of formula (XV) (R ₁₃ represents an amine protecting group such as benzyl or benzyloxycarbonyl) is synthesized by reacting a compound of formula (XVI) (R ₁₃ is as defined above) in the presence of Pivalic anhydride, etc. in an organic solvent such as dichloromethane, chloroform, dioxane, tetrahydrofuran, toluene, dimethylformamide or ether, or in a mixture of these solvents, with cooling or heating or at a suitable temperature in between.

Step 6

The compound of formula (XVI) is synthesized by subjecting a compound of formula (XV) (R ₁₃ as defined above) to catalytic reduction with hydrogen in the presence of a metal catalyst such as palladium on carbon, platinum oxide, Raney nickel, palladium in organic ethanol, dimethylformamide, palladium black or hydroxide of a solvent such as methanol, ether, dioxane, tetrahydrofuran, acetic acid or ethyl acetate or water, or a mixture of these solvents.

Step 7

A compound of formula (XVIII) (R ₁₂ and n as defined above) is synthesized by reacting a compound of formula (XVI) with a compound of the formula represented by a leaving group such as formula (XVII) halogen, methanesulfonyloxy

p-toluenesulfonyloxy group and R ₁₂ and n are as defined above) using a base such as potassium carbonate, sodium acetate, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, triethylamine or pyridine, if necessary in the presence of sodium iodide , an organic solvent such as methanol, tetrahydrofuran, dioxane, diisopropyl ether, acetonitrile, ethyl acetate, chloroform or dichloromethane or water or in a mixture of these solvents, with cooling or heating or at a suitable temperature in between.

(Rn ma or dimethoxyethane, dimethylformamide, etc., in ethanol, ether, toluene,

27 Mar: • · • · · • · ···· ···· • · • · • · ·· • · · · · · ··· · ··· · · · • · · ·· ·· · » Step 8 General compound formula (XX) (R a n equivalent i already this definition) synthesizes so that se let it react compound of formula (XVIII) (R12 and n equivalent i already this definition) compound common formulas (XIX) (R corresponds to the already mentioned definition) presence bases such as Yippee

sodium hydride, sodium amide or n-butyllithium, in an organic solvent such as dimethylsulfoxide, dimethylformamide, tetrahydrofuran or ether, or in a mixture of these solvents, with cooling or heating or at a suitable temperature in between.

Step 9

A compound of formula (XXI) (Ran as defined above) is synthesized from a compound of formula (XX) (Ran as defined above) in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, hydrogen chloride in ether, hydrogen chloride in ethyl acetate or hydrogen bromide in dioxane, in an organic solvent such as dichloromethane, chloroform, tetrahydrofuran, ethyl acetate, dioxane, ether or toluene or water or in a mixture of these solvents, with cooling or heating or at a suitable temperature in between.

Step 10

A compound of formula (XXII) (R, R ₃ , R ₄ and n as defined above) is synthesized by reacting a compound of formula (XXI) (Ran as defined above) with a compound of formula (VIII) (R) ₃ and R ₄ are as defined above) using a condensing agent such as WSOHCl, DCC, DPPA or CDI, if necessary in the presence of an activating agent such as HOBT, HOS or HONB in an organic solvent such as dimethylformamide, dichloromethane, chloroform, acetonitrile, tetrahydrofuran, dimethylsulphoxide, carbon tetrachloride or toluene, or in a mixture of these solvents, with ice cooling or heating or at an appropriate temperature in between.

Step 11

A compound of formula (I) (R, R ₃ , R ₄ and n as defined above) is synthesized by reacting a compound of formula (XXII) (R, R ₃ , R ₄ and n already in the presence of formic acid, defining] triethyl orthoformate, etc. in an organic solvent such as methanol, ethanol, toluene, tetrahydrofuran, acetic acid or dimethylformamide, or in a mixture of these solvents or in the absence of solvents, with heating.

The compound of formula (I) is also synthesized as follows.

Step 12 ............— ------ The compound of formula (I) (R, R ₃ , R _{4 and} n are as defined above) is synthesized by reacting the compound of formula (XXI) (Ran is as defined above) with a compound of formula (XXIII) (R ₃ and R ₄ are as defined above) in the presence of triethyl orthoformate, etc. in an organic solvent such as toluene, xylene or benzene or in a mixture of these solvents with heating.

A compound of formula (I) having a hydroxyl or amino group as a substituent is produced by synthesizing the corresponding compound with a protecting group attached as described above and then removing the protecting group by conventional means.

···· ····

The compound of formula (I) obtained in steps 4, 11 or 12 can be converted into a salt by conventional methods after the synthesis of the compound of formula (I). For example, the following step synthesizes the hydrochloride.

step 43 o (CHARR

_H and (XXIV) '

Step 13

A compound of formula (XXIV) (R, R ₃ , R ₄ and n as defined above) is synthesized from a compound of formula (I) (R, R ₃ , R ₄ and n as defined above) in the presence of hydrogen chloride in ether, hydrogen chloride in ethyl acetate, hydrogen chloride in dioxane, etc. in an organic solvent such as chloroform, dichloromethane, ethyl acetate, ethanol, methanol, acetone, toluene, tetrahydrofuran or dioxane or in a mixture of these solvents, with cooling or heating or at a suitable temperature in between.

The compound of formula (XIII) used in step 4 is synthesized by the following steps.

• · · · · · · · · ·

Ο

I c

Step 14

A compound of formula (XXV) (R ₁₄ is halogen and is as defined above) is synthesized by reacting a compound of formula (XXVI) (R ₁₄ and n is as defined above) with a compound of formula (XIX) (R is as defined above) in the presence of a base such as diisopropylethylamine in an organic solvent such as toluene or xylene, or in a mixture of these solvents or without

4 4 4

4 4 ·

4 · 4,444

Ee the presence of solvents under heating. Compounds such as N- (3-bromopropyl) -10,11-dihydro-5H-dibenzo [b, f] azepine can be synthesized by synthesizing compounds such as N- (3-bromopropyl) -5H-dibenzo [b, f] azepine is reduced in a conventional manner.

The compound of formula (XIII) is also synthesized by the following steps.

Step 15

A compound of formula (XXVIII) (R ₁₅ is a hydroxyl protecting group such as acetyl, benzyl or tert.-butyldimethylsilyl and R and n is as defined above) is synthesized by reacting a compound of formula (XIX) (R is already as defined above) with a compound of formula (XXVII) (R ₁₂ , R ₁₅ and n as defined above) in the presence of a base such as sodium hydride, sodium amide or n-butyllithium in an organic solvent such as dimethylsulfoxide, dimethylformamide or tetrahydrofuran; in a mixture of these solvents with cooling or heating or at a suitable temperature in between.

Step 16

In this step, a compound of formula (XXIX) (Ran as defined above) is synthesized by removal of the hydroxyl protecting group, R ₁₅ , by conventional deprotection reaction. For example, if the protecting group is acetyl or benzyl, a compound such as sodium hydroxide, potassium hydroxide, potassium carbonate or sodium carbonate, in an organic solvent, is added to the compound of formula (XXVIII) (R, R ₁₅ and as defined above). such as methanol, ethanol, tetrahydrofuran, dioxane, dimethylformamide or acetonitrile or water, or in a mixture of these solvents with cooling or heating or at a suitable temperature in between. When the protecting group is tert-butyldimethylsilyl, to the compound of formula (XXVIII) is added tetrabutylammonium fluoride, etc., in an organic solvent,

4 '4 4 4 4 4 4 4 4 4 4 9 9 9 999 999 4 9 9 9

99 such as tetrahydrofuran under cooling or heating or at an appropriate temperature in between.

Step 17

A compound of formula (XXX) (R ₁₆ is methanesulfonyl or p-toluenesulfonyl and R and n is as defined above) is synthesized by reacting a compound of formula (XXIX) (Ran as defined above) with a sulfonylating agent such as is methanesulfonyl chloride or p-toluenesulfonyl chloride, in the presence of a base such as triethylamine or pyridine, in an organic solvent such as dichloromethane, chloroform or toluene or in a mixture of these solvents with cooling or heating or at a suitable temperature in between.

A compound of formula (XXV) is also synthesized from a compound of formula (XXIX).

Step 18

The compound of formula (XXV), (R, R ₁₄ n are as defined above) is synthesized such that the compound of formula (XXIX) (Ran are as defined above) is added a halogenating agent such as carbon tetrabromide, carbon tetrachloride, or N bromosuccinimide, together with an adjuvant such as triphenylphosphine, in an organic solvent such as dichloromethane or chloroform or in a mixture of these solvents with cooling or heating or at a suitable temperature in between. Alternatively, the compound is produced by adding a halogenating agent such as thionyl chloride or phosphorus tribromide in an organic solvent such as chloroform or a solvent mixture with cooling or heating or at a suitable temperature in between. In some cases, this compound can be synthesized in the same manner as in Step 17.

The compound of formula (XXIX) is synthesized as follows.

• 0 • 0

0 '0 0

0

0 · 0 · ···· 0 0 · 0 0

Step 19

The compound of formula (XXXII) (m is 0 or an integer from 1 to 3 which is one less than n (for example, if n of the resulting compound is 2, then m is 1) and R and R ₁₅ are as defined above) synthesized by reacting a compound of formula (XIX) (R is as defined above) with a compound of formula (XXXI) (R ₁₄ , R _{15 and} m are as defined above) in the presence of a base such as triethylamine or pyridine in an organic solvent such as chloroform, dichloromethane, toluene, tetrahydrofuran, ethyl acetate or dioxane or in a mixture of these solvents with cooling or heating or at a suitable temperature in between.

Step 20

The compound of formula (XXIX) (Ran is as defined above) is synthesized by adding a reducing agent such as lithium aluminum hydride in an organic solvent to the compound of formula (XXXII) (R, R ₁₅ and m as defined above). such as ether or tetrahydrofuran or in a mixture of these solvents under cooling or heating or at a suitable temperature in between.

The compound of formula (XXIX) is also synthesized by the following procedure.

Step 21

A compound of formula (XXXIV) (R am are as defined above) is synthesized by reacting a compound of formula (XIX) (R is as defined above) with a compound of formula (XXXIII) (R ₁₂ am are as defined above in the presence of a base such as sodium hydride in an organic solvent such as dimethylformamide or dimethyl sulfoxide or in a mixture of these solvents with cooling or heating or at a suitable temperature in between.

(R and m already correspond to the <0 0 0 · «

Step 22

A compound of formula (XXXV) as defined) is synthesized of formula (XXXIV) (R m definition) by adding an oxidizing agent such as ozone in an organic solvent such as tetrahydrofuran, dichloromethane, chloroform, ether, ethyl acetate or methanol or a mixture of these a solvent such as dimethylthioether, zinc in acetic acid, sodium iodide or trimethylphosphite, in an organic solvent such as tetrahydrofuran, dichloromethane, chloroform, ether, ethyl acetate or methanol or a mixture of these solvents under cooling or heating or at a suitable temperature in between. Alternatively, the desired compound is produced by adding to the compound of formula (XXXIV) a mixture of oxidizing agents such as sodium periodate and osmium tetroxide in an organic solvent such as tetrahydrofuran, dichloromethane, chloroform, ether, ethyl acetate or methanol or water or mixtures of these solvents with cooling or heating or at a suitable temperature in between. '

Step 23

A compound of formula (XXIX) (Ran as defined above) is synthesized by adding a reducing agent such as sodium borohydride, sodium cyanotrihydride, lithium aluminum hydride, diisobutyldihydride aluminum to a compound of formula (XXXV) (Rm and as defined above). lithium or lithium borohydride, in an organic solvent such as methanol, ether, tetrahydrofuran, toluene, dichloromethane or chloroform or in a mixture of these solvents with cooling or heating or at a suitable temperature in between.

A compound of formula (XXIX), wherein at least one of

R ₁ or R ₂ is lower alkyl, such as methyl, is synthesized as follows. By way of example, a method for producing the desired compound wherein R ₂ is lower alkyl will be described.

• ta ta · ta · ta · ta · ta · ta · ta · ta · tatata tata · ta · ta · ta · ta · ta ···

R, —NHj (WW)

O

R &lt; 6 &gt; Chax-OR18 (xxxQ

S <vok

O

R, -N-J- (Cty _m -OR ₁₅₎

M (xxxvi)

R / ol 25

R1-N- (CH2) _n -OH-;

R 1 - N - (CH 2) n -OH 14 Z (xxxvii) (XXXVIII)

R 1 -N- (CH 2) _n -OH

R-ie (XXXIX)

Step 24

A compound of formula (XXXVI) (R _*, R ₁₅ am are as defined above) is synthesized by reacting a compound of formula (XXXVI) _(R is as defined above) with a compound of formula (XXXI) (R _u , R _{15 and} m are as defined above) in the presence of a base such as triethylamine or pyridine, in an organic solvent such as dichloromethane, chloroform, toluene, tetrahydrofuran, ethyl acetate or dioxane or in a mixture of these solvents under cooling or heating or at a suitable temperature in between.

Step 25

A compound of formula (XXXVII) (R ₁ and n as defined above) is synthesized by adding a reducing agent such as lithium aluminum hydride or borane complex to a compound of formula (XXXVI) (R _1Z R ₁₅ and m as defined above). tetrahydrofuran, in an organic solvent such as tetrahydrofuran, ether or toluene or &lt; tb >&lt; tb &gt;&lt; tb &gt;

444 4,444 44 «

4444 4444

4 &quot; in a mixture of these solvents with cooling or heating or at a suitable temperature in between.

Step 26 A compound of formula (XXXVIII) (R ₁₇ is hydrogen or lower alkyl such as methyl, and R _{7 and} n are as defined above) is synthesized by reacting a compound of formula (XXXVII) (R ₇ and n already as defined above) with the corresponding carboxylic acid ethyl ester such as ethyl formate or ethyl acetate or an acid halide such as acetyl chloride in an organic solvent such as dichloromethane or chloroform or in a mixture of these solvents or in the absence of solvents with cooling or heating or at a suitable temperature in between.

Step 27

A compound of formula (XXXIX) (R ₁₈ is lower alkyl such as methyl, and R _{3 and} n are as defined above) is synthesized by reacting to a compound of formula (XXXVIII) (R _1Z R ₁₇ and n is as defined above) add a reducing agent such as lithium aluminum hydride or borane-tetrahydrofuran complex in an organic solvent such as tetrahydrofuran with cooling or heating or at a suitable temperature in between.

A compound of formula (XXVIII) wherein at least one of R ₁ or R ₂ is benzyl or benzoyl is synthesized as follows. By way of example, a process for the preparation of the desired compound wherein R ₂ is benzyl or benzoyl will be described.

Η, -Ν-ίΟΗ ^ —OR '- (χΓΤ

R (N-CH) -OR ₁₅ (xu) '

Step 28

The compound of formula (XLI) (R ₂₁ is benzyl or benzoyl and R 1 R ₁₅ and _n are as defined above) is synthesized

44

4 4 · • 4 ♦ »· * 4 4

'. · · · · · · · · · ·

4) by reacting a compound of formula (XL) (R _x , R ₁₅ and _n as defined above) with a corresponding halide such as benzyl bromide or benzyl chloride, in the presence of a base such as sodium hydride, potassium carbonate or triethylamine, in an organic solvent such as dimethylformamide, dichloromethane, dimethylsulfoxide, tetrahydrofuran, toluene or ether, or in a mixture of these solvents with cooling or heating or at a suitable temperature in between.

The compound of formula (I) thus obtained is isolated and purified by known isolation and purification procedures such as sublimation, sublimation under reduced pressure, solvent extraction, crystallization, recrystallization and chromatography.

The best embodiment of the invention

The present invention will be described in more detail below with reference to manufacturing examples, working examples and test examples. However, it cannot be inferred that the present invention is limited to these examples only.

DETAILED DESCRIPTION OF THE INVENTION

Production Example 1

Synthesis of 10,11-dihydro-5H-benzo [b, e] [1,4] diazepin-1-one A mixture of 2-chlorobenzoic acid (15.7 g), 1,2-phenylenediamine (10.8 g,), powdered copper (6.3 g) and chlorobenzene (300 ml) were heated under reflux for 8 hours under argon. After hot filtration, the mixture was allowed to cool to room temperature. After cooling, the mixture was evaporated under reduced pressure to 1/3 of its volume and a solid was gradually crystallized. The solid was filtered, washed with chlorobenzene and methanol and dried to give the title compound (5.89 g, yield 28%) as a dark yellow-green solid.

· · 4 · · 4

-4

44 · 4 · 4 · 4 · 4 · 4 · 9 · 9 44 * 44 · 4 · 4 · 4

4 4 4 4 · 4

4 ««;

: 6, 8 ml),

Production Example 2

Synthesis of 2-methyl-N-phenylaniline

1) A mixture of 2-methylacetanilide (4.5 g), potassium iodobenzene (8.3 g) and copper iodide (574 mg) was stirred overnight at 150 ° C. After cooling the mixture, water and ethyl acetate were added thereto, and the resulting mixture was further stirred. The mixture was then filtered through diatomaceous earth. The filtrate was collected and the aqueous phase was extracted with ethyl acetate. The extract was washed with water and saturated sodium chloride solution and dried over sodium sulfate. The resulting solution was filtered and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (mobile ethyl acetate: hexane = 1: 2.5) to give

2-methyl-N-phenyl-acetanilide (4.96 g, yield 73%) as a light brown oil.

2) The compound (4.51 g) obtained in 1) of this example was dissolved in tetrahydrofuran (80 mL) and potassium tert-butoxide (132.0 mL) and water (0.72 mL) were added. The resulting reaction mixture was stirred for 1.5 hours at 80 ° C. After cooling the mixture, water was added thereto while cooling the phase with an ice bath. After evaporation of tetrahydrofuran, the residue was extracted with ethyl acetate, washed with water and saturated sodium chloride solution and dried over sodium sulfate. The resulting product was filtered, and the filtrate was evaporated under reduced pressure to give the title compound (3.44 g, yield 94%) as an oil.

Production Example 3

Synthesis of N- (2-thienyl) aniline

1) A mixture of acetanilide (6.0 g), 2-iodo-thiophene (18.6 g), cuprous iodide (864 mg) and potassium carbonate (12.2 g) was heated to 150 ° C for 2 hours. After cooling the mixture, water and ethyl acetate were added thereto. The resulting mixture was further stirred and then filtered through celite. The aqueous phase was

* Wash with water and extract with ethyl acetate. The extract was saturated with brine and dried over sodium sulfate. The resulting solution was filtered and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 5) to give N- (2-thienyl) acetanilide (1.77 g, yield 18%) as a light brown solid.

2) To a solution of the compound obtained in 1) of this example (1.77 g) in ethanol (16 mL) was added water (6 mL) and potassium hydroxide (64.6 mL). After cooling, the mixture was extracted with ethyl acetate, washed with water and saturated brine and dried over sodium sulfate. The resulting solution was filtered and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 5) to give the title compound (701 mg, 49% yield) as a violet oil.

Production Example 4

Synthesis of N- (3-pyridyl) aniline

1) Acetanilide (6.0 g) -------- and 3-bromopyridine (14.1 g) were reacted in the same manner as in Example 1 of Production Example 2. Purification by silica gel column chromatography (mobile phase) ethyl acetate: hexane = 1: 1 to 1

1: 2) to give N- (3-pyridyl) -acetanilide (9.52 g, in quantitative yield) as a light red solid.

2) A mixture of the compound (13.4 g) obtained in 1) of this example and 2N hydrochloric acid (130 ml) was heated at 100 ° C for 4 hours. After cooling the mixture, neutralization was carried out with 4N sodium hydroxide, followed by extraction with ethyl acetate and washing with saturated sodium chloride solution. The resulting solution was dried over sodium sulfate and filtered. The filtrate was evaporated under reduced pressure to give the title compound (10.3 g, yield 96%) as a light pink solid.

Production Example 5

Synthesis of N-phenyl-2-propylanilide

1) To a solution of 2-propylaniline in toluene (100 mL) was added acetic anhydride (7.5 mL) and the resulting mixture was stirred for 2 hours at room temperature. The crystals thus precipitated were filtered off and washed with hexane. The filtrate was evaporated under reduced pressure. Hexane was then added and trituration was performed. The resulting crystals were filtered off and washed with hexane. From these crystallizations, 2-propylacetanilide (13.0 g, yield 96%) was obtained as white crystals.

2) The compound (5.3 g) obtained in 1) of this example and iodobenzene (12.4 mL) were reacted in the same manner as in 1) of Production Example 2. Purification by column chromatography on silica gel (mobile phase ethyl acetate: hexane) = 1: 4) to obtain

N-phenyl-2-propylacetanilide (3.15 g, 41% yield) as an amber solid.

3) Using the compound (3.15 g) obtained in 2) of this example, the reaction was carried out in the same manner as in 2) of Production Example 4 to give the title compound (2.63 g in quantitative yield) as a light brown oil. .

Production Example 6

Synthesis of N- (3-thienyl) -aniline

1) Using acetanilide (6.0 g) and 3-bromothiophene (14.5 g), the reaction was carried out in the same manner as in Example 1 of Production Example 2. Subsequent purification by silica gel column chromatography (ethyl acetate: hexane mobile phase) · = 1: 4), N- (3-thienyl) acetanilide (2.43 g, yield% mole) was obtained as a light brown solid.

(2) Using the compound (2.4 g) obtained in (1) of this example, the reaction was carried out in the same manner as in (2) of Production Example 3. Subsequent purification by silica gel column chromatography (ethyl acetate: hexane = 1: 5) to give the title compound (1.64 g, yield 85%) as a brown oil.

Production Example 7

Synthesis of N- (5-pyrimidinyl) aniline

1) Using acetanilide (8.25 g) and 5-bromopyridine, the reaction was carried out in the same manner as in Example 1 of Production Example 2. Subsequent purification by silica gel column chromatography (mobile phase ethyl acetate: hexane = 1: 1 to 3: 1). ), N- (5-pyrimidinyl) acetanilide (7.98 g, yield 61%) was obtained as a pale yellow oil.

2) Using the compound (6.8 g) obtained in item 1) of this example, the reaction was carried out in the same manner as in item 2) of production example 3 to obtain the desired compound 74, 88 g, yield 89%) as light. yellow solid.

Production Example 8

Synthesis of 3-methoxy-N-phenylaniline

1) Using acetanilide (3.7 g) and 3-iodoanisole, the reaction was carried out in the same manner as in Example 1 of Production Example 2. Subsequent purification by silica gel column chromatography (mobile phase ethyl acetate: hexane = 1: 3 to 1): 2) 3-methoxy-N-phenylacetanilide (4.44 g, yield 67%) was obtained as a light brown oil.

2) Using the compound (4.4 g) obtained in item 1) of this example, the reaction was carried out in the same manner as in item 2) of production example 3 to obtain the desired compound (3.0 g, yield). 83% mole) as a light brown solid.

Production example 9

Synthesis of 2-isopropyl-N-phenylaniline

1) Using 2-isopropylaniline (10.0 g), the reaction was carried out in the same manner as in Example 1 of Production Example 5 to give 2-isopropylacetanilide (13.2 g, in quantitative yield) as a light brown solid.

2) Using the compound (5.32 g) obtained in 1) of this example and iodobenzene (5.04 ml), the reaction was carried out in the same manner as in 1) of Production Example 2. Subsequent purification by column chromatography on silica gel (mobile phase ethyl acetate) hexane = 2: 5) to give 2-isopropyl-N-phenylacetanilide (3.8 g, yield 50%) as a light pink solid.

3) Using the compound (3.8 g) obtained in (2) of this example, the reaction was carried out in the same manner as in (2) of Production Example 2 to give the title compound (3.15 g, yield 99%) as light brown oil e.

Production Example 10

Synthesis of 2-butyl-N-phenylaniline

1) Using 2-butylaniline (10.0 g), the reaction was carried out in the same manner as in Example 1 of Production Example 5 to give 2-butylacetanilide (12.0 g, yield 94%) as a white solid.

2) Using the compound (5.7 g) obtained in 1) of this example and iodobenzene (6.8 mL), the reaction was carried out in the same manner as in 1) of Production Example 2. Subsequent purification by column chromatography on silica gel (mobile phase ethyl acetate) : hexane = 1: 5) was obtained was 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 · · · · Βββββββί β se se ··

2-butyl-N-phenylacetanilide (3.65 g, yield 46%) as an amber oil.

3) Using the compound (3.65 g) obtained in step 2) of this example, the reaction was carried out in the same manner as in step 2) of production example 4 to give the title compound (3.07 g in quantitative yield) as a brown oil.

Production example 11

Synthesis of 2-ethyl-N-phenylaniline

1) Using 2-ethylacetanilide (4.9 g) and iodobenzene (12.4 ml), the reaction was carried out in the same manner as in Example 1 of Production Example 2. Subsequent purification by silica gel column chromatography (ethyl acetate: hexane = 1: 3) 2-ethyl-N-phenylacetanilide (4.0 g, yield 56%) was obtained as a brown oil.

. (2) Using the compound (4.0 g) obtained in (1) of this example, the reaction was carried out in the same manner as in (2) of Production Example 4. Subsequent purification by silica gel column chromatography (ethyl acetate: hexane = 1: 35) to give the title compound (3.3 g, yield 95%) as a brown oil.

Production Example 12

Synthesis of 1,1,1'-triphenyldimethylamine hydrochloride To a toluene solution (100 mL) of benzophenone (18.2 g) and benzylamine (11.0 mL) was added a small amount of p-toluenesulfonic acid monohydrate. Water was removed using an azeotropic distillation head. After 11 hours, the reaction solution was evaporated under reduced pressure to give an oily product. Sodium borohydride (3.5 g) was added to a solution of this product in methanol (250 mL) under ice-cooling, and the resulting reaction mixture was stirred overnight at room temperature. Then the reaction mixture was evaporated under reduced pressure, water, ethyl acetate and 2 N acid were added

ΦΦ ΦΦ ΦΦ · · φ φ φ φ φ φ φ · · · φ φ φ φ · · · · · · φ φ φ φ φ φ ee ee hydrochloric acid (100 mL), whereupon crystals precipitated. The resulting crystals were filtered and washed with ethyl acetate and water to give the title compound (14.4 g, yield 46%) as white crystals.

Production Example 13

Synthesis of N-benzyl-N- (2-tert-butyldimethylsilyloxyethyl) amine N, N-dimethylformamide solution (40 mL) of 2-benzylaminoethanol (3 g), tert-butyldimethylsilyl chloride (3.6 g) and imidazole (3.4) g) was stirred for 1 hour at room temperature under a stream of argon. Water (300 mL) was then added to the reaction mixture and the solution was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and filtered. The filtrate was evaporated under reduced pressure and the obtained residue was dried to give the title compound (5.3 g in quantitative yield) as a pale yellow oil.

Production Example 14

Synthesis of 4-chloro-N-pyridyl-2-ylaniline

A mixture of 2-bromo-pyridine (5.1 g), 2-bromopyridine (9.5 g), potassium carbonate (8.3 g) and copper iodide (570 mg) was stirred overnight at 150 ° C. The mixture was allowed to cool and water and ethyl acetate were added. The resulting solution was filtered through diatomaceous earth and the organic layer was separated. Ethyl acetate was added to the aqueous layer to extract and the extract was combined with the organic layer previously obtained. The combined extracts were washed with water, saturated brine, dried over sodium sulfate and filtered. The filtrate was evaporated under reduced pressure. Subsequent purification by silica gel column chromatography (ethyl acetate: hexane = 1: 1) was obtained

4-Chloro-N-pyridyl-2-ylacetanilide (7.3 g, crude product) as a yellow oil.

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2) To the compound (7.3 g) obtained in 1) of this example, 2 N hydrochloric acid (63 ml) was added and the solution was heated to reflux with stirring. After

2.5 N aqueous sodium hydroxide solution was added thereto for 2.5 hours to neutralize the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water, and brine, dried over sodium sulfate, and filtered. The filtrate was evaporated under reduced pressure and ethyl acetate was added to the residue. The solution was recrystallized from hexane to give the title compound (4.0 g, yield 65%) as pale yellow crystals.

Production Example 15

Synthesis of 5,11-dihydrodibenzo [b, e] [1,4] oxazepine

1) Aqueous solution (20 ml) of potassium hydroxide (3.2 g) was added dropwise to an ethanol solution (40 ml) of 2-bromobenzyl bromide (10.0 g) and 2-nitrophenol (6.7 g). The resulting reaction mixture was heated to reflux for 3 hours and then allowed to cool with stirring at room temperature. The crystals thus obtained were filtered, washed with water and dried under reduced pressure at 60 ° C to obtain o-bromobenzyl-o-nitrophenyl ether (11.0 g, yield 89%) as pale yellow crystals.

(2) Isopropanol (160 mL) was added to the compound (11.0 g) obtained in (1) of this example and dissolved at 60 ° C. Hydrochloric acid (7.1 ml) was added followed by iron (30 mg) in six portions. The resulting reaction mixture was heated at reflux for 8 hours and then filtered through celite. The filtrate was washed with isopropanol and evaporated under reduced pressure. The residue was. 2 N aqueous sodium hydroxide solution was added and the resulting neutralized solution was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and filtered.

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The filtrate was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 6) to give o- (o-bromobenzyloxy) aniline (9.9 g in quantitative yield) as a brown oil. .

3) To the compound (9.9 g) obtained in point 2) of this example and sodium formate (4.9 g) was added a formic acid solution (60 ml). The resulting reaction mixture was heated to reflux for 3 hours, allowed to cool to room temperature and poured into water (150 mL) under ice-cooling. After further stirring, the precipitated crystals were filtered off and washed with water. The resulting crystals were dried under reduced pressure at 60 ° C to give (o-bromobenzyloxy) formanilide (9.6 g, 88% yield) as a beige solid.

4) A solution of the compound (9.6 g) obtained in 3) of this example in N, N-dimethylformamide (110 ml), potassium carbonate (8.7 g) and copper powder (710 mg) were stirred at 150 ° C. under a stream of argon. After 3.5 hours, the reaction mixture was filtered while hot. The filtrate was washed with ethanol and evaporated under reduced pressure. The residue thus obtained was dissolved in ethanol (80 ml) and treated with charcoal. After filtration, the filtrate was evaporated and dissolved in ethanol (80 mL). To this solution was added 25% aqueous sodium hydroxide solution (17 ml), expressed as a percentage by weight, and the mixture was heated to boiling under stirring for 1 hour. reflux condenser. The resulting reaction mixture was then evaporated under reduced pressure, water was added to the residue, and the solution was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and filtered. The filtrate was evaporated under reduced pressure, and the residue thus obtained was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 10) and recrystallized from hexane to obtain hexane. The title compound (4.4 g, 71% yield) as a white solid was obtained as the white solid, mp &lt; tb &gt; &lt; tb &gt;

Production Example 16

Synthesis of 3,5-dimethyl-N- (2-pyridyl) aniline

1) Toluene (50 ml) acetic anhydride solution (7.78 ml) was added to a toluene (100 ml) 3,4-dimethylaniline solution (10 ml) under ice-cooling. The resulting solution was stirred at room temperature for 2 hours, evaporated under reduced pressure and dried to give

3,5-dimethylacetanilide (13.3 g, 99% yield) as a light brown solid.

2) Using the compound (4.9 g) obtained in 1) of this example and 2-bromopyridine (9.5 mL), the reaction was carried out in the same manner as in 1) of Production Example 14. Subsequent purification by silica gel column chromatography (mobile) phase ethyl acetate: hexane = 1: 1) was obtained

3,5-dimethyl-N- (2-pyridyl) acetanilide (7.2 g) as a pale yellow oil.

(3) Using the compound (5.7 g) obtained in (2) of this example, the reaction was carried out in the same manner as in (2) of Production Example 14. Subsequent purification by silica gel column chromatography (ethyl acetate: hexane = 1: 3) to give the title compound (4.4 g, yield 75%) as a light brown solid.

Production Example 17

Synthesis of 4-fluoro-N- (2-pyridyl) aniline

1) To a chloroform solution (100 mL) of 4-fluoroaniline (22.3 g) was added triethylamine (31 mL) and acetyl chloride (15 mL) dropwise under ice-cooling. The resulting reaction mixture was stirred at room temperature for 2 hours and evaporated under reduced pressure. The solid so obtained was washed with water, filtered and recrystallized from ethanol-water to give a white solid

Colorless crystals of 4-fluoroacetanilide (25.5 g, yield 83% mole) were obtained.

2) Using the compound (10.7 g) obtained in 1) of this example and 2-bromopyridine (22.2 g), the reaction was carried out in the same manner as in 1) of Production Example 14. Subsequent purification by silica gel column chromatography (mobile) ethyl acetate: hexane phase (1: 2 to 1: 1) gave oily 4-fluoro-N- (2-pyridyl) acetanilide (14.2 g, crude product).

3) Using the compound (14.2 g) obtained in step 2) of this example, the reaction was carried out in the same manner as in step 2) of production example 14. The product thus obtained was recrystallized from ethanol-water and then from ethyl acetate-hexane to give the desired compound (8.9 g, yield 77%) was obtained.

Production Example 18

Synthesis of 4-methyl-N- (2-pyridyl) aniline

1) Using 4-methylacetanilide (4.48 g) and 2-bromopyridine (9.50 g), the reaction was carried out in the same manner as in Example 1 of Production Example 14. Subsequent purification by silica gel column chromatography (ethyl acetate: hexane = 2: 3) gave 4-methyl-N- (2-pyridyl) acetanilide (6.93 g, crude product) as a yellow oil.

(2) Using the compound (6.91 g) obtained in (1) of this example, the reaction was carried out in the same manner as in (2) of Production Example 14. Subsequent purification by silica gel column chromatography (ethyl acetate: hexane: chloroform = 1: 4: 1) to give the title compound (4.69 g, yield 83%) as a white solid.

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Production Example 19

Synthesis of 4-methoxy-N- (2-pyridyl) aniline

1) Using 4-methoxyacetanilide (5.0 g) and 2-bromopyridine (9.5 g), the reaction was carried out in the same manner as in Example 1 of Production Example 14. Subsequent purification by silica gel column chromatography (ethyl acetate: hexane = 1: 1) 4-methoxy-N- (2-pyridyl) acetanilide (7.3 g, crude product) was obtained as a brown oil.

2) Using the compound (7.3 g) obtained in item 1) of this example, the reaction was carried out in the same manner as in item 2) of production example 14. The residue thus obtained was dissolved in ethyl acetate and recrystallized from hexane to give the title compound (3). 1.0 g (50% yield) as pale yellow crystals.

Production Example 20

Synthesis of 3,4-dichloro-N- (2-pyridyl) aniline

1) Using 3,4-dichloroaniline (10.00 g), the reaction was carried out in the same manner as in Example 1 of Production Example 16 to give 3,4-dichloroacetanilide (12.62 g in quantitative yield) as a brown solid. substances.

2) Using the compound (9.50 g) obtained in 1) of this example and 2-bromopyridine (6.12 g), the reaction was carried out in the same manner as in 1) of Production Example 14. Subsequent purification by silica gel column chromatography (mobile) Ethyl acetate: hexane = 2: 3) gave 3,4-dichloro- (2-pyridyl) acetanilide (7.90 g, crude product) as a brown oil.

(3) Using the compound (7.90 g) obtained in (2) of this example, the reaction was carried out in the same manner as in (2) of Production Example 14. Subsequent purification by silica gel column chromatography (ethyl acetate: hexane: chloroform = 1: 7) : 1) was obtained • 0

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Production Example 21

Synthesis of N- (6-methyl-2-pyridyl) aniline

1) Using acetanilide (9.16 g) and 2-chloro-6-methylpyridine (17.3 g), the reaction was carried out in the same manner as in Example 1 of Production Example 14. Subsequent purification by silica gel column chromatography (ethyl acetate: hexane = 1: 1, ethyl acetate) gave N- (6-methyl-2-pyridyl) acetanilide (1.07 g, 7% yield) as a light brown oil.

2) Using the compound (1.3 g) obtained in (1) of this example, the reaction was carried out in the same manner as in (2) of Production Example 14 to give the title compound (956 mg, 90% yield) as a brown oil. .

Production Example 22

Synthesis of 3-trifluoromethyl-N- (2-pyridyl) aniline.1) Using 3-trifluoromethyl acetanilide (6.1 g) and 2-bromopyridine, the reaction was carried out in the same manner as in Example 1 of Production Example 14. Subsequent column purification silica gel chromatography (ethyl acetate: hexane = 1: 1) gave 3-trifluoromethyl-N- (2-pyridyl) acetanilide (4.20 g, yield 50%) as a light brown oil.

(2) Using the compound (4.2 g) obtained in (1) of this example, the reaction was carried out in the same manner as in (2) of Production Example 14. Subsequent purification by silica gel column chromatography (ethyl acetate: hexane = 1: 3) to give the title compound (2.64 g, yield 74%) as a white solid.

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Production Example 23

Synthesis of 3-fluoro-N- (2-pyridyl) aniline

1) Using 3-fluoroacetanilide (4.6 g) and 2-bromopyridine (9.5 g), the reaction was carried out in the same manner as in Example 1 of Production Example 14. Subsequent purification by silica gel column chromatography (ethyl acetate: hexane = 1: 1) 3-fluoro-N- (2-pyridyl) acetanilide (6.9 g, crude product) was obtained as a yellow oil.

(2) Using the compound (6.9 g) obtained in (1) of this example, the reaction was carried out in the same manner as in (2) of Production Example 14. Subsequent purification by silica gel column chromatography (ethyl acetate: hexane = 1: 4) to give the title compound (3.4 g, yield 60%) as white crystals.

Production Example 24

Synthesis of 4-trifluoromethyl-N- (2-pyridyl) aniline

1) Using 4-trifluoromethylacetanilide (6.1 g) and 2-bromopyridine (9.5 g), the reaction was carried out in the same manner as in Example 1 of Production Example 14. Subsequent purification by silica gel column chromatography (ethyl acetate: hexane = 1: 1) afforded 4-trifluoromethyl-N- (2-pyridyl) acetanilide (8.0 g, crude product) as a red oil.

2) Using the compound (8.0 g) obtained in 1) of this example, the reaction was carried out in the same manner as in 2) of the manufacturing process. Example 14. Subsequent purification by silica gel column chromatography (ethyl acetate: hexane = 1: 3) gave the title compound (4.4 g, yield 65%) as white crystals.

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Production Example 25

Synthesis of 3-chloro-N- (2-pyridyl) aniline

1) Using 3-chloroacetanilide (5.09 g) and 2-bromopyridine (9.50 g), the reaction was carried out in the same manner as in Example 1 of Production Example 14. Subsequent purification by silica gel column chromatography (ethyl acetate: hexane = 2: 3) 3-chloro-N- (2-pyridyl) acetanilide (8.08 g, crude product) was obtained as a brown oil.

2) Using the compound (8.00 g) obtained in item 1) of this example, the reaction was carried out in the same manner as in item 2) of production example 14. Subsequent purification by silica gel column chromatography (mobile phase ethyl acetate: hexane: chloroform = 1: 7) 2) gave the title compound (4.82 g, 79% yield) as a white solid.

Production Example 26

Synthesis of 2-fluoro-N- (2-pyridyl) aniline

1) Using 2-fluoroacetanilide (4.6 g) and 2-bromopyridine (9.5 g), the reaction was carried out in the same manner as in 1)

------ production example 14. Subsequent purification by silica gel column chromatography (ethyl acetate: hexane = 1: 1.5 as eluent) gave 2-fluoro-N- (2-pyridyl) acetanilide (5.2 g, crude product) as a red oil.

(2) Using the compound (5.2 g) obtained in (1) of this example, the reaction was carried out in the same manner as in (2) of Production Example 14. Subsequent purification by silica gel column chromatography (mobile phase ethyl acetate: hexane = 1: 5) The title compound (2.0 g, yield 47%) was obtained as white crystals.

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Production Example 27

Synthesis of 2-chloro-N- (2-pyridyl) aniline

1) Using 2-chloroacetanilide (5.1 g) and 2-bromopyridine (9.5 g), the reaction was carried out in the same manner as in Example 1 of Production Example 14. Subsequent purification by silica gel column chromatography (ethyl acetate: hexane = 1: 2 to 1: 1) gave 2-chloro-N- (2-pyridyl) acetanilide (6.9 g, crude product) as a red oil.

(2) Using the compound (6.9 g) obtained in (1) of this example, the reaction was carried out in the same manner as in (2) of Production Example 14. Subsequent purification by silica gel column chromatography (ethyl acetate: hexane = 1: 3) to give the title compound (3.45 g, yield 56%) as white crystals.

Production Example 28

Synthesis of 3,5-difluoro-N- (2-pyridyl) aniline

1) Using 3,5-difluoroaniline (3.8 g), the reaction was carried out in the same manner as in Example 1 of Production Example 16 to give 3,5-difluoroacetanilide (4.86 g, 97% yield) as white solids ----------------------------------------------- --- ----------- 2) Using the compound (4.8 g) obtained in 1) of this example and 2-bromopyridine (8.85 g), the reaction was carried out in the same manner as in 1) of Production Example 14. Subsequent purification by silica gel column chromatography (mobile phase ethyl acetate: hexane = 1: 2 to 1: 1) gave:

3,5-difluoro-N- (2-pyridyl) acetanilide (6.46 g, crude product) as a red oil.

(3) Using the compound (6.4 g) obtained in (2) of this example, the reaction was carried out in the same manner as in (2) of Production Example 14. Subsequent purification by silica gel column chromatography (ethyl acetate: hexane = 1: 3) to give the title compound (3.54 g, yield 61%) as a white solid.

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Production Example 29

Synthesis of 3-fluoro-N-phenylaniline

1) Using 3-fluoroacetanilide (4.6 g) and 2-bromobenzene (9.4 g), the reaction was carried out in the same manner as in Example 1 of Production Example 14. Subsequent purification by silica gel column chromatography (ethyl acetate: hexane = 1: 2) 3-fluoro-N-phenylacetanilide (1.46 g, 21% yield) was obtained as a violet oil.

2) Using the compound (1.46 g) obtained in (1) of this example, the reaction was carried out in the same manner as in (2) of Production Example 14. Subsequent purification by silica gel column chromatography (ethyl acetate: hexane = 1: 6) to give the title compound (1.15 g, yield 96%) as a light brown oil.

Production Example 30

Synthesis of 3-methyl-N- (2-pyridyl) aniline

1) Using 3-methylacetanilide (4.48 g) and 2-bromopyridine (9.49 g), the reaction was carried out in the same manner as in Example 1 of Production Example 14. Subsequent purification by column chromatography of ografi-na-si. The title compound (mobile phase - ethyl acetate: hexane = 1: 1) gave 3-methyl-N- (2-pyridyl) acetanilide (6.87 g, crude product) as a pale yellow oil.

(2) Using the compound (6.8 g) obtained in (1) of this example, the reaction was carried out in the same manner as in (2) of Production Example 14. Subsequent purification by silica gel column chromatography (ethyl acetate: hexane = 1: 3) to give the title compound (4.94 g, yield 89%) as white crystals.

Production Example 31

Synthesis of 3-methoxy-N- (2-pyridyl) aniline

1) Using 3-methoxyaniline (4.93 g), the reaction was carried out in the same manner as in step 1) of Production Example 16, 9H. Aaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaa aaaaa

To give a light brown solid (6.6 g in quantitative yield).

2) Using the 3-methoxyacetanilide (4.96 g) obtained in 1) of this example and 2-bromopyridine (9.49 g), the reaction was carried out in the same manner as in 1) of Production Example 14. Subsequent purification by silica gel column chromatography (ethyl acetate: hexane = 1: 1 to 1: 2) gave 3-methoxy-N- (2-pyridyl) acetanilide (6.6 g, crude product) as a red-brown oil.

(3) Using the compound (6.6 g) obtained in (2) of this example, the reaction was carried out in the same manner as in (2) of Production Example 14. Subsequent purification by silica gel column chromatography (ethyl acetate: hexane = 1: 4 to 1) 3) the title compound (4.77 g, yield 80%) was obtained as a colorless oil.

Production Example 32

Synthesis of 3-fluoro-N- (3-fluorophenyl) aniline

1) Using 3-fluoroacetanilide (3.4 g) and 1-fluoro-3-iodobenzene (10.0 g), the reaction was carried out in the same manner as in (-1) - Production Example-14. Subsequent purification by silica gel column chromatography (ethyl acetate: hexane = 1: 3 as eluent) gave 3-fluoro-N- (3-fluorophenyl) acetanilide (3.08 g, yield 56%) as a brown oil.

2) Using the compound (3.08 g) obtained in (1) of this example, the reaction was carried out in the same manner as in (2) of Production Example 14 to give the title compound as a crude product.

Production Example 33

Synthesis of 2-methyl-N- (2-pyridyl) aniline

1) Using 2-methylacetanilide (4.5 g) and 2-bromopyridine (9.5 g), the reaction was carried out in the same manner as in 1). 999 9 0 9 9 9 9 9 9 • 9 9 9

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9999.9999 99 99 99 99 of Production Example 14. Subsequent purification by silica gel column chromatography (mobile phase ethyl acetate: hexane = 1: 1) afforded 2-methyl-N- (2-pyridyl) acetanilide (6.9 g, crude product) in in the form of a yellow oil.

(2) Using the compound (6.9 g) obtained in (1) of this example, the reaction was carried out in the same manner as in (2) of Production Example 14. Subsequent purification by silica gel column chromatography (ethyl acetate: hexane = 1: 4) to give the title compound (4.0 g, yield 72%) as a white solid.

Production Example 34

Synthesis of 2-methoxy-N- (2-pyridyl) aniline

1) Using 2-methoxyacetanilide (5.0 g) and 2-bromopyridine

79.5 g) was reacted in the same manner as in Example 1 of Production Example 14. Subsequent purification by silica gel column chromatography (ethyl acetate: hexane = 1: 1) gave 2-methoxy-N- (2-pyridyl) acetanilide. (4.3 g, crude product) as a yellow oil.

2) Using the compound (4.3 g) obtained in 1) of this example, the reaction was carried out in the same manner as in 2) -------- of Production Example 14. Subsequent purification by silica gel column chromatography (ethyl acetate mobile phase) hexane = 1: 3.5) to give the title compound (2.4 g, 40% yield) as a white solid.

Production Example 35

Synthesis of 3-nitro-N- (2-pyridyl) aniline

1) Using 3-nitroacetanilide (5.4 g) and 2-bromopyridine (9.49 g) the reaction was carried out in the same manner as in Example 1 of Production Example 14. Subsequent purification by silica gel column chromatography (ethyl acetate: hexane = 1: 1 to ethyl acetate) gave 3-nitro-N- (2-pyridyl) acetanilide (6.64 g, crude product) as a light brown oil.

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2) Using the compound (6.64 g) obtained in item 1) of this example, the reaction was carried out in the same manner as in item 2) of production example 14. Subsequent purification by silica gel column chromatography (ethyl acetate: hexane = 1: 1 to chloroform) ) to give the title compound (3.58 g, yield 55%) as a white solid.

Production Example 36

Synthesis of 2,6-difluoro-N- (2-pyridyl) aniline

1) Using 2,6-difluoroaniline (10 g), the reaction was carried out in the same manner as in 1) of Production Example 16 to give 2,6-difluoroacetanilide (13.6 g in quantitative yield) as a white solid.

2) Using the compound (5.13 g) obtained in 1) of this example and 2-bromopyridine (9.49 g), the reaction was carried out in the same manner as in 1) of Production Example 14. Subsequent purification by silica gel column chromatography ( mobile phase ethyl acetate: hexane = 1: 2 to 1: 1) was obtained

2,6-Difluoro-N- (2-pyridyl) acetanilide (8.0 g, crude product) as a pale yellow oil.

(3) Using the compound (8.0 g) obtained in (2) of this example, the reaction was carried out in the same manner as in (2) of Production Example 14. Subsequent purification by column chromatography on silica gel ( mobile phase ethyl acetate: hexane = 1: 4) to give the title compound (3.68 g, yield 66%) as a white solid.

Production Example 37

Synthesis of 2,3-difluoro-N- (2-pyridyl) aniline

1) Using 2,3-difluoroaniline (10 g), the reaction was carried out in the same manner as in Example 1 of Production Example 16 to give 2,3-difluoroacetanilide (12.6 g, 95% yield) as a white solid substances.

· · · Φ · · · '·' · φ φ · φ ΦΦΦ φ ΦΦΦΦ

2) Using the compound (5.13 g) obtained in 1) of this example and 2-bromopyridine (9.49 g), the reaction was carried out in the same manner as in 1) of Production Example 14. Subsequent purification by silica gel column chromatography (mobile) phase ethyl acetate: hexane = 1: 1) was obtained

2,3-difluoro-N- (2-pyridyl) acetanilide (8.8 g, crude product) as a pale yellow oil.

(3) Using the compound (8.8 g) obtained in (2) of this example, the reaction was carried out in the same manner as in (2) of Production Example 14. Subsequent purification by silica gel column chromatography (ethyl acetate: hexane = 1: 4) to give the title compound (4.80 g, yield 78%) as a white solid.

Production Example 38

Synthesis of 11-hydro-10-methyl-5H-dibenzo [b, e] [1,4] diazepin-11-one

A solution of 10,11-dihydro-5H-dibenzo [b, e] [1,4] diazepin-11-one (2 g) and potassium tert-butoxide (2.35 g) in 1,4-dioxane (25 ml) ) was heated to reflux. After 1 hour, ____ methyl iodide (1.78 mL) was added to this solution without cooling, and the resulting solution was further heated to reflux. After 4 hours the solution was allowed to cool to room temperature and evaporated under reduced pressure. The residue thus obtained was dissolved in chloroform and washed with aqueous sodium hydrogen carbonate solution and then with water and saturated sodium chloride solution, dried over sodium sulfate and filtered. The filtrate was evaporated and the resulting residue was purified by silica gel column chromatography (mobile phase: chloroform: methanol = 100: 1 to 50: 1) to give the title compound (1.14 g, yield 53%) as a light brown-white solid. .

• · ··· ·

• 9 • · · t

Production Example 39

Synthesis of 2-methyl-N- (3-methyl-2-pyridyl) aniline

1) Using 2-methylacetanilide (4.48 g) a

2-bromo-3-methylpyridine (10.3 g) was reacted in the same manner as in Example 1 of Production Example 14. Subsequent purification by silica gel column chromatography (ethyl acetate: hexane = 1: 3) gave 2-methyl- N- (3-methyl-2-pyridyl) acetanilide (7.2 g, crude product) as a light brown oil.

(2) Using the compound (7.2 g) obtained in (1) of this example, the reaction was carried out in the same manner as in (2) of Production Example 14. Subsequent purification by silica gel column chromatography (ethyl acetate: hexane = 1: 5) to give the title compound (3.98 g, yield 67%) as a white solid.

Production Example 40

Synthesis of 2-ethyl-N- (2-pyridyl) aniline

1) Using 2-ethylaniline (10 g), the reaction was carried out in the same manner as in 1) of Production Example 16, whereby

----- 2-Ethylacetanilide (13.2 g, 98% yield) was obtained.

2) Using the compound (4.9 g) obtained in 1) of this example and 2-bromopyridine (9.49 g), the reaction was carried out in the same manner as in 1) of Production Example 14. Subsequent purification by silica gel column chromatography (mobile) phase ethyl acetate: hexane = 1: 2) was obtained

2-ethyl-N- (2-pyridyl) acetanilide (8.34 g, crude product) as a light brown oil.

(3) Using the compound (8.34 g) obtained in (2) of this example, the reaction was carried out in the same manner as in (2) of Production Example 14. Subsequent purification by silica gel column chromatography (ethyl acetate: hexane = 1: 5) to give the title compound (3.28 g, yield 55%) as a white solid.

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Production Example 41

Synthesis of 2-propyl-N- (2-pyridyl) aniline

1) To a chloroform (50 ml) solution of 2-propylaniline (10.5 g) was added dropwise acetyl chloride (5.6 ml) and triethylamine (12.5 ml) under ice-cooling. The reaction solution was stirred for 3 hours at room temperature. The solution was evaporated under reduced pressure and the solid thus obtained was washed with water and filtered. The resulting residue was recrystallized from ethanol-water to give 2-propylacetanilide (11.85 g, yield 86%) as white crystals.

2) Using the compound (10.6 g) obtained in 1) of this Example and 2-bromopyridine (18.9 g), the reaction was carried out in the same manner as in 1) of Production Example 14. Subsequent purification by silica gel column chromatography (mobile) ethyl acetate: hexane = 1: 2) to give 2-propyl-N- (2-pyridyl) acetanilide (14.4 g, crude product) as a yellow oil.

3) Using the compound (14.4 g) obtained in (2) of this example, the reaction was carried out in the same manner as in (2) of Production Example 14. Subsequent purification by column chromatography of silica gel (MBB: ethyl acetate: hexane) = 1: 4) the title compound (10.6 g, 88% yield) was obtained as white crystals.

Production Example 42

Synthesis of 9,10-dihydro-9,9-dimethylacridine

1) A mixture of methyl 2-aminobenzoate (7 g), iodobenzene (3.9 ml), potassium carbonate (6.4 g) and copper powder (0.46 g) was heated at 180 ° C for 17 hours. . The reaction mixture was allowed to cool to room temperature and then ethyl acetate was added. The resulting mixture was stirred and filtered through diatomaceous earth. The filtrate was washed with ethyl acetate and evaporated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (eluent: · ethyl acetate: hexane = 1:30) to obtain methyl

2-Phenylaminobenzoate (7.13 g, 90% yield) as a pale yellow solid.

2) To an ether solution (35 mL) of the compound (7.1 g) obtained in 1) of this example, methyl lithium (89 mL) was added dropwise at -78 ° C under argon, and the resulting reaction mixture was stirred for 3 hours. , 5 hours at room temperature. Ice was added to the reaction mixture and the resulting solution was stirred in an ice bath. Then the solution was extracted with ether, the extract was washed with water and saturated sodium chloride solution, dried over sodium sulfate and filtered. The filtrate was evaporated and dried to give N- [2- (1-hydroxy-1-methylethyl) phenyl] aniline (6.3 g, crude product) as a light brown oil.

3) A solution of the compound (3 g) obtained in 2) of this example in phosphoric acid (60 ml) was stirred at room temperature for 17 hours. Water was then added, the solution was neutralized with sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and filtered.

The filtrate was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate: hexane = 1:30), to give the title compound (123 mg, 4% yield) as a yellow-white solid.

Production Example 43

Synthesis of 4H-3,1-benzoxazin-4-one

1) A toluene (1100 mL) solution of anthranilic acid (205.5 g) and formic acid (170 mL) was heated to reflux for 4.5 hours. The solution was allowed to cool and hexane was added to give rise to crystals. The crystals were filtered off and washed with hexane. The resulting crystals were dried at 110 ° C under reduced pressure to give N-formyl-anthranilic acid (244.0 g, crude product) as white crystals.

2) To the compound (272.8 g) obtained in 1) of this example, triethyl orthoformate (550 mL) was added and the resulting mixture was heated to form a solution. The solution was distilled under normal pressure to remove portions boiling at 75 ° C. Unreacted triethyl orthoformate was removed by evaporation under reduced pressure. The resulting residue was heated under reduced pressure at 140 ° C and the liquid was allowed to cool to give the title compound (148.1 g, 61% yield) as white to pale yellow crystals.

Production Example 44

Synthesis of N- (2-bromoethyl) -10,11-dihydro-10-hydroxy-5H-dibenzo [b, f] azepine

1) To chloroform solution (250 ml)

5H-dibenzo [b, f] azepine (25.0 g) was added acetyl chloride (11.0 mL) under ice-cooling. The resulting solution was heated to reflux for 30 minutes and then allowed to cool. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate. and filtered. The filtrate was evaporated and the obtained residue was recrystallized from ethyl acetate-hexane to give N-acetyl-5H-dibenzo [b, f] azepine (28.6 g, yield 94%) as a white solid.

2) Sodium hypochlorite (150 ml) and silica (10 g) were added to an acetonitrile solution (20 ml) of the compound (7.00 g) obtained in 1) of this example. The resulting mixture was heated to reflux for 2 hours, allowed to cool and filtered. The filtrate was extracted with chloroform. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and dried over sodium sulfate.

evaporated. The residue thus obtained was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2) to give N-acetyl-5H-dibenzo [b, f] azepine-10,11-epoxide (3.45 g, yield). 46%) as a yellow amorphous substance.

3) To a chloroform solution (35 mL) of the compound (3.45 g) obtained in 2) of this example was added lithium iodide (1.86 g) and the solution was heated to reflux for 15 minutes. The solution was allowed to cool and was further washed with 10% aqueous sodium sulfite, water, and saturated sodium chloride solution. The resulting solution was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated and the residue thus obtained was purified by silica gel column chromatography (mobile phase ethyl acetate: hexane = 1: 1) to obtain N-acetyl-10,11-dihydro-10-oxo-5H-dibenzo [b, f] azepine (3.04 g, yield 94%) as a yellow solid.

4) To a tetrahydrofuran solution (20 ml) of the compound (1.01 g) obtained in point 3) of this example was added potassium tert-butoxide (3.1 g) and the solution was stirred for

1.5 hours with heating at 80 ° C. The solution was allowed to cool, poured into water and then extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated and the obtained residue was purified by silica gel column chromatography (mobile phase ethyl acetate: hexane = 1: 5) to obtain 10,11-dihydro-10-oxo-5H-dibenzo [b, f] azepine (624 mg, 69% yield) as a yellow solid.

5) To a chloroform solution (10 mL) of the compound (524 mg) obtained in 4) of this example was added bromoacetyl bromide (478 μΐ) and the reaction mixture was heated to reflux for 30 minutes. The solution was allowed to cool,

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washed with water and saturated sodium chloride solution and dried over anhydrous sodium sulfate. After filtration, the filtrate was evaporated and the obtained residue was purified by silica gel column chromatography (mobile phase ethyl acetate: hexane = 1: 3) to obtain white amorphous N- (2-bromoacetyl) -10,11-dihydro-10-oxo-5H -dibenzo [b, f] azepine (827 mg in quantitative yield).

6) To a tetrahydrofuran solution (10 mL) of the compound (827 mg) obtained in 5) of this example was added BH ₃ -tetrahydrofuran complex (6.6 mL). The resulting solution was stirred for 30 minutes under ice-cooling and then for 1 hour at room temperature. The solution was poured into water and extracted with ethyl acetate. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated and the obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 5) to give a pale yellow amorphous compound to give the title compound (545 mg, 68% yield).

-------- Manufacturing Example 45 --------------------------------------- -------------------------------- Synthesis of N- (2-chloroethyl) -10,11-dihydro-2-hydroxy -5H-dibenzo [b, f] azepine

1) Under a nitrogen atmosphere under ice-cooling, phosphorus pentachloride (20.9 ml) was added dropwise to dimethylformamide anhydride (20.9 ml) and the resulting solution was stirred for 10 minutes at room temperature. While cooling with ice, N- (2-bromoethyl) -10,11-dihydro-5H-dibenzo [b, f] azepine (16.0 g) was added to the reaction mixture, and the resulting reaction mixture was stirred for 20 minutes at 100 ° C. Noc: 2 ° C. The solution was then poured into ice water, neutralized with 2 N aqueous sodium hydroxide solution and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over sodium sulfate, and filtered. The filtrate was evaporated, and the resulting residue was concentrated. Purified by column chromatography on silica gel (mobile phase ethyl acetate: hexane = 1:10 to 1: 5) to give

N- (2-chloroethyl) -2-formyl-10,11-dihydro-5H-dibenzo [b, f] azepine (13.3 g, 88% yield) as a red-yellow oil.

2) To a solution of the compound (12.80 g) obtained in 1) of this example in dichloromethane (130 mL) was added trifluoroacetic acid (12.1 mL). A dichloromethane (60 mL) solution of m-chlorobenzoic acid (14.3 g) was slowly added dropwise to the reaction mixture. The resulting solution was stirred at room temperature for 1.5 hours and neutralized with saturated aqueous sodium bicarbonate solution to separate the organic layer. The aqueous layer was extracted with chloroform. The resulting extract was combined with the previously obtained organic layer. The combined organic layers were washed with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated and the residue thus obtained was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 7 as eluent) to give N- (2-chloroethyl) -2-formyloxy-10,11-dihydro-5H-dibenzo [ b, f] azepine ----- (4.88 g, yield 36% molar) as a colorless oil.

3) To a solution of the compound (4.83 g) obtained in 2) of this example in chloroform (5 mL) with methanol (50 mL) was added sulfuric acid (1 mL) and the resulting solution was stirred for 2 hours at room temperature. . After evaporation, ethyl acetate was added to the residue and the resulting solution was washed with water and saturated sodium chloride solution and dried over anhydrous sodium sulfate. After filtration, the filtrate was evaporated to give N- (2-chloroethyl) -10,11-dihydro-2-hydroxy-5H-dibenzo [b, f] azepine (4.05 g) as pale yellow crude crystals.

The compounds produced in Production Examples 1 to 45 are listed in Tables 1 and 2.

Table 1

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Table 2

Manufacturing example Compound Manufacturing example Compound 1 Manufacturing ! example Compound 2 5 XX H 3 2 χχ. 3 9 010 Me ^H 2 6 3 3 Me 4 0 2 7 Cl 3 4 X x / χ x L -X N N 1 H About me 4 1 jC ^ X 2 8 ÁX H 3 5 XX 4 2 Mťt kb IW? IVK? CQO 2 9 xx 3-6 4 3 what- H F 3 0 χχ 3 7 XX F 4 4 3 1 XX H 1 3 8 ^<ΜΘ H 4 5 OH ^and t

β β ί Φ 99 9 9 9

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9999 99999 99 it φ.φ «6

Example 1

Synthesis of 3- [1- (2- (Ν, N-diphenylamino) ethyl] piperidin-4-yl] -3H-quinazolin-4-one hydrochloride

Step 14) (2-Bromoethyl) diphenylamine (compound of formula (XIII))

1,2-dibromoethane (49 mL) was added to a solution of diphenylamine (4.7 g) in diisopropylethylamine (48.6 mL) and the resulting reaction mixture was heated at reflux for 14 hours at 135 ° C. The solution was allowed to cool to room temperature, the solid was triturated, filtered and washed with toluene. The filtrate was evaporated under reduced pressure and the residue thus obtained was purified by silica gel column chromatography (mobile phase - hexane) to obtain the title compound (2.0 g, yield 26%) as a light yellow oil.

Step 1) 2-Amino-N- (1-ethoxycarbonylpiperidin-4-yl) benzamide (compound of formula (X))

1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (64.9 g) was added to a solution of 2-aminobenzoic acid (42.2 g), ethyl 4-aminopiperidine carboxylate _53-g-1a-1-hydroxy-ybene under ice-cooling. The resulting mixture was stirred overnight at room temperature. The reaction mixture was evaporated, water was added to the residue, and the resulting mixture was stirred at room temperature for ¹ h. The organic layer was washed successively with 10% aqueous citric acid solution, water, saturated sodium bicarbonate solution, water, saturated sodium chloride solution, and dried over sodium sulfate, and the residue was crystallized from ethyl acetate. hexane to give the title compound (64.5 g, 72% yield) as yellow crystals.

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Step 2) 3- (1-ethoxycarbonylpiperidin-4-yl) -3H-quinazolin-4-one

A solution of the compound obtained in step 1) (64.5 g) in formic acid (350 ml) was heated to reflux for 16 hours. The reaction solution was allowed to cool to room temperature, concentrated in vacuo and extracted with chloroform. Saturated aqueous sodium hydrogencarbonate solution was added to the extract, the extract was washed with water and saturated sodium chloride solution, dried over sodium sulfate and evaporated under reduced pressure to give the title compound (60.7 g, yield 91%) as light beige. solids.

Step 3) 3- (piperidin-4-yl) -3H-quinazolin-4-one (compound of formula (XII))

To the compound (60.7 g) obtained in Step 2) was added 25% hydrogen bromide in acetic acid (385 mL), expressed as a percentage by weight, and the resulting reaction mixture was stirred for 18 hours at 60 ° C. Then the reaction mixture was concentrated under reduced pressure, neutralized with 4 N sodium hydroxide and extracted with chloroform. The extract was washed with water and saturated

NaCl solution, dried over sodium sulfate and concentrated in vacuo to give the title compound (40.7 g, 88% yield) as a white powder.

Step 4) 3- [1- [2- (N, N-Diphenylamino) ethyl] piperidin-4-yl] -3 H -quinazolin-4-one (compound of formula (I))

In an acetonitrile solution (14 mL) of the compound (1.6 g) obtained in step 3), the compound (1.9 g) obtained in step 14) and potassium carbonate (1.9 g) were heated at reflux overnight. Water was then added to the reaction mixture and the solution was extracted with chloroform. The extract was washed with water and saturated sodium chloride solution and dried over sodium sulfate. The residue thus obtained was purified by silica gel column chromatography (eluent: ethyl acetate: hexane = 1: 1) to give a 9% yield.

The title compound (1.6 g, yield 55%) was obtained as a white solid.

Step 13) To a chloroform solution (1 mL) of the compound (1 g) obtained in step 4) was added hydrogen chloride in ether (15 mL) under ice-cooling, and the resulting solution was stirred at room temperature for 0.5 hours. The formed crystals were filtered, washed with ether and dried to give the title compound (1.10 g, 94% yield) as white crystals.

Example 2

Synthesis of 3- [1- [2- (5H-dibenzo [b, f] azepin-5-yl) ethyl] piperidin-4-yl] -3H-quinazolin-4-one hydrochloride

Step 14) N- (2-bromoethyl) -5H-dibenzo [b, f] azepine (compound of formula (XIII))

1,2-Dibromoethane was added to a solution of 5H-dibenzo [b, f] azepine (10.0 g) in diisopropylethylamine (100 mL) and the resulting reaction mixture was heated at 130 ° C for 4.5 hours. The solution was allowed to cool to room temperature, filtered and washed with toluene. The filtrate was evaporated and the residue was purified by column chromatography on silica gel (mobile phase - chloroform) to give the title compound (15.0 g, 97% yield) as a yellow solid.

Step 4) 3- [1- [2- (5H-dibenzo [b, f] azepin-5-yl) ethyl] piperidin-4-yl] -3H-quinazolin-4-one (compound of formula (I))

Using the compound (500 mg) obtained in step 14) and the compound (720 mg) obtained in step 3) of Example 1, the reaction was carried out in the same manner as in step 4) of Example 1. The residue thus obtained was purified by silica gel column chromatography ( mobile phase - chloroform: methanol = 40: 1) to give the title compound (888 g, yield 91%) as a yellow solid.

Step 13) Using the compound (888 mg) obtained in step 4), the reaction was carried out in the same manner as in step 13)

of Example 1 to give the title compound (960 mg, quantitative yield) as a pale yellow powder.

Example 3

Synthesis of 3- [1- [2- (N-benzyl-N-phenylamino) ethyl] piperidin-4-yl] -3H-quinazolin-4-one hydrochloride

Step 14) N- (2-Bromoethyl) -N-benzylaniline (compound of formula (XIII))

Using N-benzylaniline (916 mg) and 1,2-dibromoethane (9.39 g), the reaction was carried out in the same manner as in step 14) of Example 1. The residue thus obtained was purified by silica gel column chromatography (ethyl acetate: hexane = 1:40) to give the title compound (1.18 g, 81% yield) as a blue-yellow-white oil.

Step 4) 3- [1- [2- (N-benzyl-N-phenylamino) ethyl] piperidin-4-yl] -3 H -quinazolin-4-one (compound of formula (I))

Using the compound (696 mg) obtained in step 14) and the compound (459 mg) obtained in step 3) of Example 1, the reaction was carried out in the same manner as in step 4) of Example 1.

The residue thus obtained was crystallized from. ethyl acetate, yielding the title compound (678 mg, 71% yield) as light brown acicular crystals.

Step 13) Using the compound (673 mg) obtained in step 4), the reaction was carried out in the same manner as in step 13) of Example 1 to give the title compound (648 mg, yield 89%) as colorless needle crystals.

Example 4

Synthesis of 3- [1- [3- (10,11-dihydro-5H-dibenzo [b, f] azepin-5-yl) propyl] piperidin-4-yl] -3H-quinazolin-4-one

Step 14) N- (3-bromopropyl) -10,11-dihydro-5H-dibenzo [b, f] azepine (compound of formula (XIII)).

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Using 5H-dibenzo [b, f] azepine (5.0 g) a

1,3-dibromopropane (52.2 g) was reacted in the same manner as in step 14) of Example 1. The residue thus obtained was purified by silica gel column chromatography (mobile phase - hexane to chloroform gradient) to obtain the crude product (10). 0 g) as a yellow oil.

.7.5% palladium on carbon (50% hydration, 1.0 g) was added to a solution of the crude product (5.1 g) in tetrahydrofuran (50 ml) and the resulting reaction mixture was stirred at room temperature for 5.5 hours at normal pressure. The reaction mixture was filtered through diatomaceous earth, the filtrate was evaporated and purified by silica gel column chromatography (mobile phase - hexane to chloroform gradient) to give the title compound (4.05 g, yield 99%) as a white solid.

Step 4) Using the compound (759 mg) obtained in step 14) and the compound (500 mg) obtained in step 3) of Example 1, the reaction was carried out in the same manner as in step 4) of Example 1. The residue thus obtained was purified by column chromatography on Silica gel (mobile phase - chloroform: methanol 40: 1).

The obtained product was further crystallized from ethyl acetate-hexane to give the title compound (745 mg, yield 74%) as a white solid.

Example 5

Synthesis of 3- [1- [2- (10,11-dihydro-11-oxo-5H-dibenzo [b, e] [1,4] diazepin-5-yl) ethyl] piperidin-4-yl] -3H hydrochloride -quinazolin-4-one

Step 14) 5- (2-bromoethyl) -10,11-dihydro-5H-dibenzo [b, e] [1,4] diazepin-11-one (compound of formula (XIII))

Using the compound (1.0 g) obtained in Production Example 1 and 1,2-dibromoethane (8.94 g), the reaction was carried out in the same manner as in Step 14) of Example 1. The residue thus obtained

44

4444 4444

44 «

4.4 was purified by silica gel column chromatography (mobile phase - ethyl acetate: hexane = 1: 2) to obtain the title compound (146 mg, yield 9.7%) as a pale yellow-white amorphous substance.

Step 4) 3- [1- [2- (10,11-Dihydro-11-oxo-5H-dibenzo [b, e] [1,4] diazepin-5-yl) ethyl] piperidin-4-yl] - 3H-quinazolin-4-one (compound of formula (I))

In an acetonitrile solution (5 mL) of the compound (240 mg) obtained in step 14), the compound (174 mg) obtained in step 3) of Example 1, potassium carbonate (105 mg) and sodium iodide (117 mg) was heated for 14 hours. reflux. The solution was allowed to cool to room temperature, water was added to the reaction mixture, and the solution was extracted with ethyl acetate. The extract was washed with water and saturated sodium chloride solution and dried over sodium sulfate. The residue thus obtained was purified by silica gel column chromatography (mobile phase - chloroform: methanol = 20: 1) to obtain the title compound (246 mg, yield 70%) as a white solid.

Step 13) Using the compound (240 mg) obtained in step 4), the reaction was carried out in the same manner as in step 13 of Example 1 to give the title compound (238 mg, 91% yield). as a white solid.

Example 6

Synthesis of 3- [1- (4- (N, N-diphenylamino) butyl] piperidin-4-yl] -3H-quinazolin-4-one hydrochloride

Step 15) 4- (N, N-diphenylamine) butyl acetate (compound of formula (XXVIII))

A solution of sodium hydride (1.4 g) in anhydrous dimethylsulfoxide (10 mL) was stirred for 15 minutes at 50 ° C under a stream of argon. Was then added under ice cooling a solution of diphenylamine (3.0 g) in dimethylsulfoxide (15 ml) and the mixture was stirred for 0.5 hours at room φ'φ φφ * · · · φ '· φ Φ ^1' · · Φ: ««:: · · · · · · ί ί ί ί ί ί ί ί ί ί ί · Φφ φφ temperature. 4-Bromobutyl acetate (10.4 g) was then added to the reaction mixture and stirred for 4.5 hours at 60 ° C. Water was then added to the reaction mixture with ice-cooling, and the solution was extracted with ethyl acetate. The extract was washed with water and saturated sodium chloride solution and dried over sodium sulfate. The residue thus obtained was purified by silica gel column chromatography (mobile phase - ethyl acetate: hexane = 1: 10) to obtain the crude product (7.5 g) as a yellow oil.

Step 16) 4- (N, N-diphenylamine) butanol (compound of formula (XXIX))

To a solution of the crude product (7.5 g) obtained in step 15) in methanol (80 mL) was added 1 N sodium hydroxide in water (53 mL) and the resulting reaction mixture was stirred for

2.5 hours at room temperature. The reaction mixture was evaporated, water was added to the residue, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and saturated sodium chloride solution and dried over sodium sulfate. The residue thus obtained was purified by silica gel column chromatography (eluent: ethyl acetate: hexane = 1: 3) to obtain the desired compound ---- (- 3 -, - 6-g -, - yield 84-%). in the form of a colorless oil.

Step 17) 4- (N, N-Diphenylamine) butyl methanesulfonate (compound of formula (XIII))

To a solution of the compound (1.0 g) obtained in step 16) in dichloromethane (15 mL) was added triethylamine (0.69 mL) and methanesulfonyl chloride (0.39 mL) under ice-cooling, and the resulting solution was stirred for 10 min. room temperature. Then the solution was extracted with chloroform, the extract was washed with water and saturated sodium chloride solution and dried over sodium sulfate. The residue thus obtained was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2) to obtain the desired residue.

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compound (1.1 g, yield 86%) as a colorless oil.

Step 4) 3- [1- [2- (N, N-Diphenylamino) butyl] piperidin-4-yl] -3H-quinazolin-4-one (compound of formula (I))

In an acetonitrile solution (6 mL) of the compound (769 mg) obtained in step 17), the compound (460 mg) obtained in step 3) and potassium carbonate (27.6 mg) were heated over. night to reflux. The solution was allowed to cool to room temperature, water was added to the reaction mixture, and the solution was extracted with chloroform. The extract was washed with water and saturated sodium chloride solution and dried over sodium sulfate. The residue thus obtained was purified by silica gel column chromatography (mobile phase - ethyl acetate to ethyl acetate: triethylamine gradient = 100: 1) to obtain the title compound (772 mg, yield 85%) as a white solid.

Step 13) To an ethyl acetate solution (8 mL) of the compound (412 mg) obtained in step 4) was added 4 N hydrogen chloride in ethyl acetate (1 mL), and the resulting solution was stirred at room temperature for 0.5 hours. The formed crystals were filtered off, washed with ethyl acetate and ethanol to give the title compound (443 mg, quantitative yield) as a white powder.

Example 7

Synthesis of 3- [1- [2- [N- (2-methylphenyl) -N-phenylamino] ethyl] piperidin-4-yl] -3H-quinazolin-4-one

Step 15) 2- [N- (2-methylphenyl) -N-phenylamine] ethyl acetate (compound of formula (XXVIII))

To a solution of the compound (3.4 g) obtained in Production Example 2 in anhydrous dimethylsulfoxide (3.5 ml) was added sodium hydride (2.2 g) under argon flow and the resulting solution was stirred for 0.5 hour at room temperature. . 2-Bromobutyl acetate (6.2 g) was then added and the resulting solution was stirred for 9 minutes and then added.

and e e e e a - e a e e e e e a e a a a a a a a aaa aaaa aa aa e ee room temperature for 2 hours. Water was then added to the reaction mixture with ice-cooling, and the solution was extracted with ethyl acetate. The extract was washed with water and saturated sodium chloride solution and dried over sodium sulfate. The residue thus obtained was used directly for the next step.

Step 16) 2- [N- (2-methylphenyl) -N-phenylamine] ethanol (compound of formula (XXIX))

To a solution of the crude product obtained in step 15) in a mixture of methanol (4 mL) with tetrahydrofuran (4 mL) was added 1 N sodium hydroxide in water (8 mL) under ice-cooling, and the resulting reaction mixture was stirred for 4 hours at room temperature. temperature. Then the reaction mixture was evaporated and the residue was extracted with ethyl acetate. The extract was washed with water and saturated sodium chloride solution and dried over sodium sulfate. The residue thus obtained was purified by silica gel column chromatography (mobile phase - ethyl acetate: hexane = 1: 4) to obtain the title compound (1.11 g, yield 22%) as a light yellow oil.

Step 17) 2- [N- (2-methylphenyl) -N-phenylamine) ethyl methanesulfonate (compound of formula (XIII))

- To a solution of the compound (430 mg) obtained in step 16j in dichloromethane (12 mL) was added triethylamine (316 µΐ) and methanesulfonyl chloride (176 µΐ), and the resulting solution was stirred for 3 hours at room temperature. Water was then added to the reaction mixture and the solution was extracted with chloroform. The extract was washed with water and saturated sodium chloride solution and dried over sodium sulfate. The residue thus obtained was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 3) to give the title compound (577 mg, quantitative yield) as a pale yellow oil.

Step 4) In an acetonitrile solution (10 mL) of the compound (577 mg) obtained in step 17), the compound (433 mg) was obtained. 4 <44 4 4 44 444 44 44 In step 3) of Example 1, potassium carbonate (261 mg) and sodium iodide (283 mg) were heated at reflux overnight. The solution was allowed to cool to room temperature, water was added to the reaction mixture, and the solution was extracted with chloroform. The extract was washed with water and saturated sodium chloride solution and dried over sodium sulfate. The residue thus obtained was purified by column chromatography

Silica gel (mobile phase - ethyl acetate: hexane = 2: 1) to give the title compound (540 mg, yield 65%) as a white solid.

Example 8

Synthesis of 3- [1- [2- [N- (2-ethylphenyl) -N-phenylamine] ethyl] piperidin-4-yl] -3H-quinazolin-4-one hydrochloride

Step 13) To a dichloromethane solution (5 mL) of the compound (110 mg) obtained in step 4) of Example 7 was added 4 N hydrogen chloride in ethyl acetate (1 mL) and the resulting solution was stirred at room temperature for 0.5 hours. The resulting crystals were filtered, washed with ethyl acetate and dried under reduced pressure to give the title compound A'ld4 MGP-GET ~ k ^ 9δ Τηδ ^! ^ ATrTíclTJ VE ^- formyl ^ ^ Bite evhe vlatko

Example 9

Synthesis of 3- [1- [2- (1,2,3,4-tetrahydrocarbazol-9-yl) ethyl] piperidin-4-yl] -3H-quinazolin-4-one

Step 15) 2- (1,2,3,4-tetrahydrocarbazol-9-yl) ethyl acetate (compound of formula (XXVIII))

To a solution of 1,2,3,4-tetrahydrocarbazole (2 g) in anhydrous dimethylsulfoxide (25 mL) was added sodium hydride (762 mg) under a stream of argon, and the resulting solution was stirred for 10 minutes at room temperature. 2-Bromoethyl acetate (3.9 g) was then added and the resulting solution was stirred at room temperature for an additional 15 hours. Water (100 mL) was then added to the reaction mixture and the solution was extracted with ethyl acetate. The extract was • 44 44 44

4 4 4 ♦ «» * - 4 4 '4' 4 '

4 4 4 '4 4 4. <4 4 4

4 '4' 4 444 4 44 * 44 4

4 4 4

44444444 44 44 44 44 washed with water and saturated sodium chloride solution and dried over sodium sulfate. The residue thus obtained was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 10) to give the title compound (2.5 g, yield 82%) as a pale yellow oil.

Step

Q / 1 Q * 3 Δ - r ohi zrl in * / - \ V o vTx -I π / λ 1 - Q - * r * 1 \ 4- T-, * l «- \ ff * y _L jc L. ii 0.110 X (compound of formula (XXIX))

To a solution of the compound (2.4 g) obtained in step 15) in a mixture of methanol (15 mL) and tetrahydrofuran (10 mL) was added 1 N sodium hydroxide in water (28 mL) under ice-cooling, and the resulting reaction mixture was stirred for room temperature. Then the reaction was reduced in pressure and the residue was extracted with ethyl acetate. The extract was washed with water and saturated sodium chloride solution and dried over sodium sulfate. The residue thus obtained was purified on silica gel

5), evaporated for 6 hours after column chromatography with ethyl acetate: hexane = 1 compound (1.70 g, yield 85 yellow oil).

(mobile phase to obtain the desired mole%) in the form of light

Step 17) 2- (1,2,3,4-tetrahydrocarbazol-9-yl) ethyl methanesulfonate (compound of formula (XIII))

Using the compound (1.70 g) obtained in step 16), the reaction was carried out in the same manner as in step 17) of Example 6 to give the title compound (1.8 g, yield 78%) as a yellow-white solid.

Step 4) Using the compound (600 mg) obtained in step 17) and the compound (468 mg) obtained in step 3) of Example 1, the reaction was carried out in the same manner as in step 4) of Example 6 to obtain the desired compound (114 mg, 13% yield) as a white solid.

φφ «► ♦ '· φφ. φ φ φ «φ φ φ

Φ φ φ * 9 φ φ, φφ _φ

Φ · · · ΦΦΦ Φ ί φ φ φ • · · · · · φ φ φ φ φ φ φ φ

Example 10

Synthesis of 3- [1- [3- (Ν, N-diphenylamino) propyl] piperidin-4-yl] -3H-quinazolin-4-one hydrochloride

Step 15) O-tert-Butyldimethylsilyl-3- (N, N-diphenylamine) propanol (compound of formula (XXVIII))

A solution of diphenylamine (5 g) in anhydrous dimethylsulfoxide (60 mL) was stirred under argon at room temperature for 10 minutes. O-tert-butyldimethylsilyl-3-bromopropanol (22.4 g) was then added under ice-cooling, and the resulting solution was stirred at room temperature for 15 hours. Water was then added to the reaction mixture and the solution was extracted with ethyl acetate. The extract was washed with water and saturated sodium chloride solution and dried over sodium sulfate. The residue thus obtained was purified by silica gel column chromatography (mobile phase - ethyl acetate: hexane = 1:50) to obtain the crude product (16 g) as a pale yellow oil.

Step 16) 3- (N, N-Diphenylamine) Propanol (Compound of Formula (XXIX))

To a solution of the crude product (5 g) obtained in step 15) in tetrahydrofuran (45 mL) was added tetrabutylammonium fluoride in tetrahydrofuran (1 mL / 1.30 mL) under ice-cooling, and the resulting reaction mixture was stirred for 2.5 hours at room temperature. temperature. Water was then added to the reaction mixture and the solution was extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution and dried over sodium sulfate. The residue thus obtained was purified by silica gel column chromatography (eluent - ethyl acetate: hexane = 1: 4) to obtain the crude product (960 mg) as a light blue oil.

Step 17) 3- (N, N-Diphenylamine) Propyl Methanesulfonate (Compound of Formula (XIII))

Using the compound (950 mg) obtained in step 16), the reaction was carried out in the same manner as in step 17) of Example 6. The residue thus obtained was purified by column chromatography to & gt ^; '· ·> · «

9 .9 9 9 ‘9 9

9999 9999 99 99 94 silica gel (mobile phase - ethyl acetate: hexane = 1: 3) to give the crude product (450 mg) as a colorless oil.

Step 4) 3- [1- [3- (Ν, Ν-Diphenylamino) propyl] piperidin-4-yl] -3H-quinazolin-4-one

Using the compound (450 mg) obtained in step 17) and the compound (337 mg) obtained in step 3) of Example 1, the reaction was carried out in the same manner as in step 4) of Example 6. Subsequent purification by silica gel column chromatography (mobile phase - ethyl acetate): triethylamine - 80: 1) to give the title compound (510 mg, 79% yield) as a white solid.

Step 13) Using the compound (500 mg) obtained in step 4), the reaction was carried out in the same manner as in step 13) of Example 1 to give the title compound (540 mg, quantitative yield) as a white solid.

Examples 11 to 22

The compounds listed in Tables 6 to 10 were obtained in the same manner as in Example 1, Example 6 and Example 7.

—Example 23 ----------------------------------------------- ----------------------------------- ^- ----------- Synthesis of hydrochloride 3 - [1- [2- [N- (3-Chloro-phenyl) -N-phenylamino] -ethyl] -piperidin-4-yl] -3H-quinazolin-4-one

Step 15) 2- [N- (3-chlorophenyl) -N-phenylamine] ethyl acetate (compound of formula (XXVIII))

Using 3-chloro-N-phenylalanine (2.5 g) a

2-bromoethyl acetate (6.1 g) was reacted in the same manner as in step 15 of Example 6. The residue thus obtained was used directly in the next step.

Step 16) 2- [N- (3-chlorophenyl) -N-phenylamine] ethanol (compound of formula (XXIX))

Using the crude product obtained in step 15), the reaction was carried out in the same manner as in step 16) of Example 6. The residue thus obtained was purified by column chromatography to &gt; 4. · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · Silica gel (mobile phase - ethyl acetate: hexane = 1: 8) to give the title compound (847 mg, 28% yield). molar) in the form of an orange oil.

Step 18) N- (2-Bromoethyl) -N-phenyl-3-chloroaniline (compound of formula (XIII))

To a solution of the compound (847 mg) obtained in step 16) in dichloromethane was added triphenylphosphine (1.08 g) and carbon tetrachloride (1.36 g) under ice-cooling, and the resulting solution was stirred for 1 hour at room temperature. The residue thus obtained was purified by silica gel column chromatography (eluent - ethyl acetate: hexane = 1:50) to obtain the title compound (1.06 g, quantitative yield) as a green oil.

Step 4) 3- [1- [2- [N- (3-Chloro-phenyl) -N-phenylamino] -ethyl] -piperidin-4-yl] -3H-quinazolin-4-one (compound of formula (I))

In an acetonitrile solution (6 ml) of the compound (746 mg) obtained in step 18), the compound (459 mg) obtained in step 3) of Example 1 and potassium carbonate (276 mg) were heated at reflux overnight. The reaction mixture was evaporated, water was added to the residue, and the solution was extracted with chloroform. The extract was washed with water and saturated sodium chloride solution and dried over sodium sulfate. The residue thus obtained was purified by silica gel column chromatography (eluent: ethyl acetate: hexane = 1: 1 to ethyl acetate) to obtain the title compound (205 mg, yield 22%) as a brown amorphous substance.

Step 13) Using the compound (205 mg) obtained in step 4), the reaction was carried out in the same manner as in step 13) of Example 1 to give the title compound (200 mg, 90% yield) as a white powder.

· »·· ·«. 90

0 9 9 9 0 0

9 · 9 9'0 .0 • 999 (9 1990 990

0 0 9

Example 24

Synthesis of 3- [1- [3- (N-phenyl-N-pyridin-3-ylamine) propyl] piperidin-4-yl] -3H-quinazolin-4-one dihydrochloride

Step 15) N- (3-tert-Butyldimethylsilyloxypropyl) -N-pyridin-3-ylaniline (compound of formula (XXVIII))

To a solution of N-pyridin-3-ylaniline (2.55 g) in dimethylsulfoxide (30 mL) was added sodium hydride (1.2 g), and the resulting solution was stirred under argon for 3 hours at room temperature. 3-Bromopropoxy-tert-butyldimethylsilane (4 mL) was then added dropwise and the resulting solution was stirred overnight. Chloroform, ice and water were added to the reaction mixture, and the resulting solution was extracted with chloroform. The extract was washed with water and saturated sodium chloride solution and dried over sodium sulfate. The residue thus obtained was purified by silica gel column chromatography (eluent: ethyl acetate: hexane gradient = 1: 10 to 1: 3) to obtain the title compound (4.04 g, 79% yield) as an oil.

Step 16) 3- (N-phenyl-N-pyridin-3-ylamine) propanol (compound of formula (XXIX))

To a solution of the compound (4.04 g) obtained in step 15) in tetrahydrofuran (80 ml) was added, under ice-cooling, tetra-n-butylammonium fluoride in tetrahydrofuran (1 mol / L, 23.6 ml) and the resulting reaction mixture was stirred for 3 hours at room temperature. The reaction mixture was then concentrated under reduced pressure, water was added to the residue, and the solution was extracted. ethyl acetate. The extract was washed with saturated sodium chloride solution. To the organic layer was added 2 N hydrochloric acid (20 mL) and water. The aqueous layer was separated and washed with ethyl acetate. To the aqueous layer was added 1 N sodium hydroxide in water, and the resulting solution was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried over sodium sulfate and evaporated to give a 4 4 44 (4 4 9 9 4 4) solution.

The title compound (2.41 g, yield 90%) was obtained as an oil.

Step 18) N- (3-Chloropropyl) -N-pyridin-3-ylaniline (compound of formula (XIII))

To a solution of the compound (2.34 g) obtained in step 16) in chloroform (30 mL) was added thionyl chloride (1.5 mL) and the resulting solution was heated under reflux for 1 hour under nitrogen. A cold aqueous sodium bicarbonate solution was added to the reaction mixture, and the resulting mixture was extracted with chloroform. The extract was washed with saturated sodium chloride solution and dried over sodium sulfate. The residue thus obtained was evaporated under reduced pressure to give the title compound (2.47 g, yield 98%) as an oil.

Step 4) 3- [1- [3- (N-phenyl-N-pyridin-3-ylamino) propyl] piperidin-4-yl] -3H-quinazolin-4-one (compound of formula (I))

Using the compound (530 mg) obtained in step 18) and the compound (500 mg) obtained in step 3) of Example 1, the reaction was carried out in the same manner as in step 4) of Example 7.

The residue thus obtained was purified by silica gel column chromatography (eluent: chloroform: methanol = 20: 1) to obtain the title compound (420 mg, yield 44%).

Step 13) Using the compound (420 mg) obtained in step 4), the reaction was carried out in the same manner as in step 13) of Example 1 to give the title compound (591 mg, quantitative yield) as a white powder.

Examples 25 to 26

The compounds listed in Table 11 were obtained in the same manner as in Example 1, Example 6 and Example 7.

0 00 00

0 0 0 0 ·

0 0 0 0 0 • 00 ι · ··· ···

0 0

00 00 • 0 00 4 4

4 4 4 • • 9.4 4 • · 4 4

4444 4449 10

Example 27

Synthesis of 3- [1- [2- (N-benzhydryl-N-benzylamino) ethyl] piperidin-4-yl] -3H-quinazolin-4-one

Step 19) N-Benzhydryl-N-benzylacetoxyacetoamide (compound of formula (XXXII))

To a solution of the compound (1.55 g) obtained in Production Example 12 in chloroform (30 mL) was added acetoxyacetyl chloride (0.6 mL) under ice-cooling. Triethylamine (1.6 mL) was then added dropwise to the reaction mixture. The reaction mixture was stirred at room temperature for 0.5 hour, water was added and the solution was evaporated under reduced pressure. The precipitated crystals were filtered off and washed with water. The residue thus obtained was crystallized from ethyl acetate-hexane to give the title compound (1.59 g, yield 85%).

Step 20) 2- (N-Benzhydryl-N-benzylamine) ethanol hydrochloride (compound of formula (XXIX))

To a solution of the compound (1.29 g) obtained in step 19) in a mixture of ether (20 mL) with tetrahydrofuran (80 mL) was added a solution of lithium aluminum hydride (0.4 g) in ether— (2Ό-mL ·) under argon. The reaction mixture was heated to reflux for 0.5 hours. Under ice-cooling, water (0.4 ml), 15% sodium hydroxide in water (0.4 ml) and water (1.2 ml) were added successively to the reaction mixture, and the resulting solution was stirred under laboratory conditions. temperature. Then the solution was filtered through celite, the filtrate was washed with ethyl acetate, evaporated and dried under reduced pressure to give a yellow oil (1.21 g). To the ethyl acetate solution of this oily product (1.21 g) was added water, concentrated sulfuric acid and hexane. The precipitated crystals were filtered and washed with ethyl acetate to give the title compound (893 mg, yield 73%) as crystals.

44 «V 44 44 44

4444 · <4 4444

4 4 4 4 444 444 444 444 4 4 4 4

4444 4444 44 44

Step 18) N-Benzhydryl-N-benzyl-N- (2-chloroethyl) amine (compound of formula (XIII))

To a solution of compound (842 mg) of dichloromethane (10 mL) was added triethylamine (1.6 mL) under methanesulfonyl chloride (0.4 mL) and obtained in step 20) under ice-cooling, and the resulting reaction mixture was stirred for 8.5 hours at room temperature. The reaction mixture was washed with saturated sodium chloride solution and dried over sodium sulfate. The residue thus obtained was purified by silica gel column chromatography (mobile phase - ethyl acetate: hexane = 1: 10) to obtain the title compound (442 mg, yield 55%) as an oil.

Step 4) In a dimethylformamide solution (5 ml) of the compound (442 mg) obtained in step 18), the compound (286 mg) obtained in step 3) of Example 1, potassium carbonate (200 mg) and sodium iodide (one grain) was heated for 19 hours at 85 ° C. Water was added to the reaction mixture, the precipitated solid was filtered off and washed with water. The residue thus obtained was purified by column chromatography on silica gel (mobile phase - gradient ethyl acetate: hexane = 1: 2 to

1 ~: 1). The resulting product was recrystallized from ethanol / water to give the title compound (245 mg, 37% yield) as colorless crystals.

Example 28

Synthesis of 3- [1- [2- (N, N-dicyclohexylamine) ethyl] piperidin-4-yl] -3H-quinazolin-4-one dihydrochloride

Step 19) N, N-Dicyclohexylbenzyloxyacetamide (compound of formula (XXXII))

To a solution of N, N-dicyclohexylamine (2.14 g) in chloroform (10 mL) was added benzyloxyacetyl chloride (3.72 mL) and the resulting reaction mixture was heated to reflux for 4.5 hours under a stream of argon. The reaction mixture was then allowed to cool to room temperature, water was added thereto, and the solution was allowed to cool to room temperature. · Extracted with ethyl acetate. The extract was washed with water and saturated sodium chloride solution and dried over sodium sulfate. The residue thus obtained was purified by silica gel column chromatography (mobile phase - ethyl acetate: hexane = 1: 5) to obtain the title compound (2.09 g, yield 54%) as a colorless transparent oil.

'HER

O—! NT KT_ / 4 ί ~ r Ir Ir Ί ο ^ ^ ^ m m m m r

J. IXXL1-L. XX j In CXXUXXV-L of general formula (XXIX))

To a solution of the compound (2.0 g) obtained in step 19) in ether (30 mL) was added a solution of lithium aluminum hydride (132 mg) under a stream of argon under ice-cooling. The reaction mixture was then allowed to warm to room temperature and then heated to reflux for 24 hours. The reaction mixture was allowed to cool to room temperature and then water was added and the solution was acidified with 2N hydrochloric acid. The solution was then neutralized with a 2N aqueous sodium hydroxide solution and extracted. The extract was washed with water and saturated sodium chloride solution and dried over sodium sulfate. The residue thus obtained was evaporated and dried to give a colorless transparent oil (1.76 g, yield 92%). An argon purged vial was charged with Raney nickel (50% slurry, 1 mL) and suspended in methanol (10 mL). To this solution was added a solution of the oil (1.7 g) from the previous step in methanol (20 mL) and catalytic reduction was carried out for 15 hours at three times atmospheric pressure. The reaction mixture was filtered through diatomaceous earth, the filtrate was evaporated and dried to give the title compound (956 mg, 79% yield) as a pale yellow oil.

Step 18) N, N-Dicyclohexyl-N- (2-chloroethyl) amine (compound of formula (XIII))

To a solution of the compound (950 mg) obtained in step 20) in dichloromethane (20 mL) was added under a stream of ice *

Methanesulfonyl chloride (329 μΐ) and triethylamine (706 μΐ) were added and the resulting reaction mixture was stirred at room temperature. Water was then added to the solution, and the reaction mixture was washed with saturated sodium bicarbonate solution, water and saturated sodium chloride solution, and dried over sodium sulfate. The residue thus obtained was purified by silica gel column chromatography (mobile phase - ethyl acetate: hexane = 1: 10 to 1: 1) to obtain the title compound (390 mg, yield 38%) as a light yellow oil.

Step 4) 3- [1- [2- (N, N-Dicyclohexylamino) ethyl] piperidin-4-yl-3H-quinazolin-4-one (compound of formula (I))

In an acetonitrile solution (4 mL) of the compound (390 mg) obtained in step 18), the compound (376 mg) obtained in step 3) of Example 1, potassium carbonate (442 mg) and sodium iodide (240 mg) was heated for 14 hours. reflux. The reaction mixture was then allowed to cool to room temperature and extracted with water and ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution and dried over sodium sulfate. The residue thus obtained was purified by silica gel column chromatography (eluent: chloroform: methanol = 10: 1) to obtain the title compound (437 mg, yield 63%) as a white solid.

Step 13) To a chloroform solution (0.2 mL) of the compound (350 mg) obtained in step 4) was added 4 N hydrogen chloride in ether (1 M, 2.4 mL) under ice-cooling, and the resulting solution was stirred at room temperature for 0.5 hours. The formed crystals were filtered, washed with ether and dried to give the title compound (290 mg, 71% yield) as a white solid.

o e o «c

Example 29

Synthesis of 3- [1- (2-carbazol-9-ylethyl) piperidin-4-yl] -3H-quinazolin-4-one

Step 21) N- (2-Propenyl) carbazole (compound of formula (XXXIV))

Sodium hydride (1.05 g) was dissolved under a stream of argon (40 mL) in dimethylformamide (40 mL) and stirred for 10 minutes. The solution was stirred for an additional 0.5 hour at room temperature, and a solution of 3-bromo-1-propene (2.27 g) in dimethylformamide (8 mL) was added thereto under ice-cooling, and the resulting reaction mixture was stirred for 14 hours at room temperature. Water was then added to the reaction mixture and the solution was extracted with ethyl acetate. The extract was washed with water and saturated sodium chloride solution and dried over sodium sulfate. After filtration, the filtrate was allowed to stand. The deposited solid was filtered and washed with hexane to give the title compound (5.3 g, quantitative yield) as a light yellow-white solid.

Step 22) 9H-Carbazole-9-acetaldehyde (compound of formula (XXXV))

To a solution of the compound (4.95 g) obtained in step 21) in a mixture of tetrahydrofuran (80 mL) with water (40 mL) was added sodium periodate (6.08 g) and a 4% aqueous solution of osmium tetroxide under ice-cooling under argon. (1.56 mL), and the resulting solution was stirred for 14 hours at room temperature. The solution was extracted with ethyl acetate, the extract was washed with water and saturated sodium chloride solution and dried over sodium sulfate. The residue thus obtained was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 3) to give the title compound (407 mg, yield 8%) as an orange solid.

Step 23) N- (2-hydroxyethyl) carbazole (compound of formula (XXIX))

To a solution of the compound (400 mg) obtained in step 22) in methanol (25 mL) was added sodium borohydride (72 mg) under ice-cooling, and the resulting solution was stirred for 2 hours at room temperature. Then the reaction mixture was

X «* V4. Water was added and the resulting solution was extracted with ethyl acetate. The extract was washed with water and saturated sodium chloride solution and dried over sodium sulfate. The residue thus obtained was purified by silica gel column chromatography (mobile phase - ethyl acetate: hexane = 1: 3) to obtain the title compound (368 mg, yield 91%) as a light yellow solid.

Step 17) 2- (9H-Carbazol-9-yl) ethyl methanesulfonate (compound of formula (XIII)) To a solution of the compound (360 mg) obtained in step 23) in dichloromethane was added triethylamine (284 mL) and methanesulfonyl chloride (284 mL) under ice-cooling. 158 ml) and the resulting solution was stirred for 1.5 hours. Water was then added to the reaction mixture, and the solution was washed successively with aqueous sodium bicarbonate solution, water and saturated sodium chloride solution, and dried over sodium sulfate. The residue thus obtained was purified by silica gel column chromatography (mobile phase - ethyl acetate: hexane = 1: 2) to obtain the title compound (448 mg, yield 91%) as a white solid.

Step 4) In a acetonitrile solution (7 ml) of the compound (400 mg) obtained in step 17) under argon flow, the compound (316 mg) obtained in step 3) of Example 1 and potassium carbonate (381 mg) were heated to reflux. for 38 hours. The solution was allowed to cool to room temperature, water was added to the reaction mixture, and the solution was extracted with ethyl acetate. The extract was washed with water and saturated sodium chloride solution and dried over sodium sulfate. The residue thus obtained was purified by silica gel column chromatography (mobile phase - ethyl acetate) to obtain the title compound (200 mg, yield 34%) as a white solid.

Example 30 / Ί τ l ~ x τ 7Z4 in * · / - 'Ί λ v 4 i »vt.Jl.y_y ± UU3Γ 1 Γ -'Ί / χτ V - 1 X“ t Z. ”V1N-I iz- N, N-Olyl-aryl-1 H -mernylamino) ethyl] piperidin-4-yl] -3 H -quinazolin-4-one

Step 24) N-Benzhydrylacetoxyacetamide (compound of formula (XXXIII))

To a solution of benzhydrylamine (17.04 g) and triethylamine (14.26 ml) was added acetoxyacetyl chloride (10 ml) under ice-cooling, and the resulting solution was stirred for 0.5 hour at room temperature. Water was then added to the reaction mixture and the solution was extracted with chloroform. The extract was washed sequentially with 1 N hydrochloric acid, water, saturated aqueous sodium bicarbonate, water and saturated brine, and dried over sodium sulfate. The residue thus obtained was evaporated and dried under reduced pressure to give the title compound (26.53 g, quantitative yield) as a white solid.

Step 25) 2-Benzhydrylaminethanol (Compound of Formula (XXXI))

To a solution of lithium aluminum hydride (2.0 g) in anhydrous tetrahydrofuran (100 mL) was added under ice-cooling under nitrogen flow the compound (5.0 g) obtained in step 24) and the resulting solution was heated at reflux for 2 hours. hours. Water (2 mL), 15% aqueous sodium hydroxide (2 mL), and water (6 mL) were added to the reaction mixture under ice-cooling, and the resulting solution was stirred at room temperature. Potassium carbonate was then added to the solution and after stirring all was filtered through diatomaceous earth. The filtrate was washed with ethyl acetate, evaporated and dried under reduced pressure to give the title compound (4.08 g, quantitative yield) as a yellow oil.

Step 26) 2- (N-formyl-N-benzhydrylamine) ethanol (compound of formula (XXXVI))

A solution of the compound (1.0 g) obtained in step 25) in ethyl formate (1 mL) was stirred overnight with heating. The reaction solution was evaporated and azeotroped with toluene. The residue was dried under reduced pressure to give the title compound (1.13 g, quantitative yield) as a yellow oil.

Step 27) 2- (N-Benzhydryl-N-methylamine) ethanol (compound of formula (XXXI))

To a solution of the compound (528 mg) obtained in step 26) in anhydrous tetrahydrofuran (10 mL) was added lithium aluminum hydride (235 mg) three times under a stream of argon, and the resulting solution was heated to reflux for 2 hours. Water (0.75 mL), 15% aqueous sodium hydroxide (0.75 mL), and water (2.25 mL) were added to the reaction mixture under ice-cooling, and the resulting solution was stirred at room temperature. for 0.5 hour. Potassium carbonate (3 g) was added to the solution, and after stirring, it was filtered through celite and washed with chloroform. The residue thus obtained was purified by silica gel column chromatography (mobile phase - ethyl acetate: hexane = 1: 2) to obtain the title compound (405 mg, yield 81%) as a colorless oil.

Step 18). N-benzhydryl-N-methyl-2-bromoethylamine (compound of formula (XIII))

Using the compound (780 mg) obtained in step 27), the reaction was carried out in the same manner as in step 18) of Example 23. The residue thus obtained was purified by chromatography on silica gel (mobile column ethyl acetate: hexane = 1:50) to give the desired compound (694 mg, 71% yield) as a colorless oil.

Step 4) 3- [1- [2- (N-Benzhydryl-N-methylamino) ethyl] piperidin-4-yl] -3 H -quinazolin-4-one (compound of formula (I))

Using the compound (694 mg) obtained in step 18) and the compound (523 mg) obtained in step 3) of Example 1, the reaction was carried out in the same manner as in step 4) of Example 23. The residue thus obtained was purified by silica gel column chromatography (mobile) phase - chloroform: methanol = 50: 1) and then crystallized from hexane-ethyl acetate to give the title compound (605 mg, 59% yield) as a white solid.

Step 13) Using the compound (605 mg) obtained in step 4), the reaction was carried out in the same manner as in step 13) of Example 1. The desired compound (702 mg, quantitative yield) was obtained as a white powder.

Example 31

Synthesis of 3- [1- [2- (Ν, Ν-benzylamine) ethyl] piperidin-4-yl] -3Hquinazolin-4-one

Step 28) N, N-dibenzyl-2-tert-butyldimethylsilyloxyethylamine; (compound of formula (XXIX))

A solution of the compound (5.3 g) obtained in Production Example 13, benzyl bromide (2.36 ml) and potassium carbonate (4.1 g) in dimethylformamide (40 ml) was stirred under a stream of argon for 15 hours at 140 ° C. . The reaction mixture was allowed to cool, water (400 mL) was added thereto, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and saturated sodium chloride solution and dried over sodium sulfate. The residue thus obtained was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 10) to give the title compound (5.1 g, yield 72%) as a colorless transparent oil.

• 9 9 999 9 9 9 9 9 9 9

9999 9999 99 9 9 9 9 9 7

Step 16) 2- (N, N-dibenzylamine) ethanol (compound of formula (XXXI))

To a solution of the compound (5 g) obtained in step 28) in tetrahydrofuran (50 mL) at 0 ° C was added a solution of tetrabutylammonium fluoride in tetrahydrofuran (1 M, 21.4 mL) and the resulting reaction mixture was stirred for 1 hour at room temperature. temperature. Saturated aqueous ammonium chloride solution (50 mL) was added to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and saturated sodium chloride solution. The residue thus obtained was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 3) to give the title compound (3.96 g, quantitative yield) as a colorless oil.

Step 18) N, N-Dibenzyl-2-bromoethylamine (compound of formula (XIII))

To a solution of the compound (3.96 g) obtained in step 16) in dichloromethane (70 mL) was added triphenylphosphine (3.75 g) and carbon tetrabromide (5.22 g), and the resulting solution was stirred under argon for 14 hours. at room temperature. The reaction mixture was evaporated and the residue thus obtained was purified by silica gel column chromatography (ethyl acetate: hexane = 1:30) to give the title compound (1.95 g, yield 45%) as a pale yellow oil.

Step 4) Using the compound (332 mg) obtained in step 18), the reaction was carried out in the same manner as in step 4) of Example 23 to give the title compound (410 mg, 83% yield) as a white solid.

Example 32

Synthesis of 3- [1- [2- (N-benzoyl-N-phenylamino) ethyl] piperidin-4-yl] -3H-quinazolin-4-one hydrochloride

Step 28) N-Benzoyl-N-phenyl-2-tert-butyldimethylsilyloxyethylamine (compound of formula (XXXIX))

To a solution of N-phenyl-2-tert-butyldimethylsilyloxyethylamine (1.5 gr and triethylamine (832 μΐ)) was added benzoyl chloride (693 μΐ) under an argon stream under ice-cooling, and the resulting solution was stirred for 1 hour at room temperature. Water was added to the reaction mixture, the solution was extracted with chloroform, the extract was washed with water and saturated sodium chloride solution and dried over sodium sulfate, and the residue was evaporated and dried to give the title compound (2.20 g, quantitative yield) as of yellow oil.

Step 16) 2- (N-Benzoyl-N-phenylamine) ethanol (compound of formula (XLII))

To a solution of the compound (2.2 g) obtained in step 28) in tetrahydrofuran (20 mL) was added a solution of tetrabutylammonium fluoride in tetrahydrofuran (1 M, 20 mL) under ice-cooling, and the resulting reaction mixture was stirred for 1.5 hours at room temperature. temperature. The reaction mixture was evaporated under reduced pressure, water was added thereto, and the resulting solution was extracted with chloroform. The extract was washed with water and saturated sodium chloride solution and dried over sodium sulfate. The residue thus obtained was purified by silica gel column chromatography (mobile phase - gradient ethyl acetate: hexane = 1: 1 to 2: 1) to obtain the title compound (1.35 g, yield 94%) as a light yellow oil.

··

»· ·· ··· · ··· ·· ··

Step 18) N-Benzoyl-N-phenyl-2-chloroethylamine (compound of formula (XIII))

Using the compound obtained in step 16), the reaction was carried out in the same manner as in step 17) of Example 6. The residue thus obtained was purified by column chromatography on silica gel (mobile phase - ethyl acetate: hexane gradient and thus cl. 1 / * \ ττ-5 v. A

Xj CXV_X \ - / in σ. (490 mg, 54% yield) as a pale yellow oil e.

Step 4) 3- [1- [2- (N-Benzoyl-N-phenylamino) ethyl] piperidin-4-yl] -3H-quinazolin-4-one (compound of formula (I))

Using the compound (490 mg) obtained in step 18) and the compound (433 mg) obtained in step 3) of Example 1, the reaction was carried out in the same manner as in step 4) of Example 6. The residue thus obtained was purified by silica gel column chromatography (mobile) phase - chloroform: methanol = 10: 1) to give the title compound (260 mg, 30% yield) as a white solid.

Step 13) Using the compound (255 mg) obtained in step 4), the reaction was carried out in the same manner as in step 13) of Example 1. The resulting product was crystallized from ethanol to give the title compound (63 mg, yield 23%). molar) as a white solid.

Example 33

Synthesis of 3- [1- [2- [N- (4-chlorophenyl) -N-pyridin-2-ylamine] ethyl] piperidin-4-yl] -3H-quinazolin-4-one dihydrochloride

Step 5) 1-Benzyl-4-tert-butoxycarbonylaminopyperidine (compound of formula (XV))

To a solution of 1-benzyl-4-aminopiperidine (50 g) in dichloromethane (450 mL) was added a solution of pivalic anhydride (63 g) in dichloromethane under ice-cooling, and the brownish solution was stirred overnight at room temperature. The reaction mixture was then evaporated and crystallized from ether to give the title compound (69 g, yield 91%) as white crystals.

Step 6) 4-tert-Butoxycarbonylaminopiperidine (compound of formula (XVI))

To a solution of the compound (10 g) obtained in step 5) in ethanol (80 mL) was added acetic acid (4 mL). Then it was until

Ή rvh r \ ΙΟ JTOZtokU. pCd by argonova citi J. or ci luti pd. On carbon (1 g), expressed as a percentage by mass. Hydrogen was introduced to the solution at 2.8 times normal pressure in total and the solution was stirred for 4 hours at room temperature. The reaction mixture was filtered through diatomaceous earth and the filtrate was evaporated. The residue was then azeotroped with toluene. The residue thus obtained was dissolved in chloroform and washed with a mixture of 3 N potassium hydroxide and saturated sodium chloride solution. The aqueous layer was further extracted with chloroform. The resulting organic layer was dried over sodium sulfate and evaporated to give the title compound (6.9 g, quantitative yield) as a white solid.

Step 7) 1- (2-Bromoethyl) -4-tert-butoxycarbonylamino-piperidine (compound of formula (XVIII))

To a suspension of the compound (23.4 g) obtained in step 6) in tetrahydrofuran (400 mL) was added 1,2-dibromoethane (219 g) and potassium carbonate (16.1 g), and the resulting solution was stirred for 6 days at room temperature. room temperature. Then the reaction mixture was filtered and the filtrate was evaporated. The residue thus obtained was purified by silica gel column chromatography (mobile phase gradient ethyl acetate: hexane - 1: 3 to ethyl acetate) to obtain the title compound (12.1 g, yield 34%) as pale beige crystals.

Step 8) 4-tert-Butoxycarbonylamino-1- [2- [N- (4-chlorophenyl) -1H-pyridin-2-ylamine] ethyl] piperazine (compound of formula (XX))

To a solution of 4-chloro-N-pyridin-2-aniline (800 mg) obtained in Production Example 14 in anhydrous dimethylsulfoxide (10 mL) was added. * A a a 4 4 4 4 4 4 4

Sodium hydride (156 mg) was added under argon flow, and the resulting solution was stirred for 0.5 h at room temperature. The compound (600 mg) obtained in step 7) was then added to the reaction mixture, and the resulting solution was stirred at room temperature under argon for 2 hours. Water was then added to the reaction mixture and the solution was extracted with ethyl acetate. The extract was washed with water and saturated sodium chloride solution and dried over sodium sulfate. The residue thus obtained was purified by silica gel column chromatography (mobile phase gradient ethyl acetate: hexane = 2: 1 to ethyl acetate) to obtain the title compound (680 mg, yield 81%) as a pale yellow amorphous substance.

Step 9) 4-Amino-1- [2- [N- (4-chlorophenyl) -N-pyridin-2-ylamine] ethyl] piperidine (compound of formula (XXI))

To a solution of the compound (680 mg) obtained in step 8) in dichloromethane (6 mL) was added acetic acid (6 mL) under ice-cooling, and the resulting solution was stirred at room temperature for 20 minutes. The reaction solution was evaporated and azeotroped with toluene. A 10% aqueous potassium carbonate solution was added to the residue, and the solution was extracted with a 10: 1 mixture of chloroform and tetrahydrofuran. The extract was washed with saturated sodium chloride solution and dried over sodium sulfate. The residue thus obtained was evaporated under reduced pressure to give the title compound (516 mg, yield 99%) as a yellow oil.

Step 10). 2-Amino-N- [1- [2- [N- (4-chlorophenyl) -N-pyridin-2-amine] ethyl] piperidin-4-yl] benzamide (compound of formula (XXIII))

To a solution of anthranilic acid (213 mg), compound (513 mg) obtained in step 9) and 1-hydroxybenzotriazole (209 mg) in dimethylformamide (5 mL) was added 1-ethyl-3- (3-dimethylaminopropyl) hydrochloride under ice-cooling. carbodiimide (297 mg) and the resulting solution was stirred for 5 hours at room temperature

4 4 4 99 44 44 · »

4 4 4 4 4 4 4 C 4 4 4 • * 4444 4444

4 4 4 4 4 * 4 4 ··· 444

4 4 4 4 4 5

444 4 44 4 '4 0 4'4 4 4 4 »room temperature. A 10% aqueous potassium carbonate solution was added to the residue, and the solution was extracted with chloroform. The extract was washed with saturated sodium chloride solution and dried over sodium sulfate. The residue thus obtained was purified by silica gel column chromatography (mobile phase - ethyl acetate) to obtain the title compound (670 mg, yield 96%) as a pale yellow amorphous substance.

Step 11) 3- [1- [2- [N- (4-Chloro-phenyl) -N-pyridin-2-ylamine] -ethyl] -piperidin-4-yl] -3H-quinazolin-4-one

A solution of the compound obtained in step 10) (670 mg) in formic acid (10 ml) was heated at reflux overnight. The reaction solution was evaporated and azeotroped with toluene. A 10% aqueous potassium carbonate solution was added to the residue, and the solution was extracted with chloroform. The extract was washed with saturated sodium chloride solution and dried over sodium sulfate. The residue thus obtained was crystallized from ethyl acetate to give the title compound (498 mg, yield 73%) as a white solid.

Step 13) To a dichloromethane solution (5 mL) of the compound (494 mg) obtained in step 11) was added 4 N hydrogen chloride in ethyl acetate (1 mL) and the resulting solution was stirred at room temperature for 0.5 hours. The formed crystals were filtered, washed with ethyl acetate and dried under reduced pressure at 50 ° C to give the title compound (572 mg, quantitative yield) as a white powder.

00

4 ·

00 0 0 '0 0' • 0 · 0 · »· ···

0 e> e 99

Example 34

Synthesis of 3- [1- [2- (10,11-dihydro-5H-dibenzo [b, f] azepin-5-yl) ethyl] piperidin-4-yl] -3H-quinazolin-4-one

Step 8) 4-tert-Butoxycarbonylamino-1- [2- (10,11-dihydro-5H-dibenzo [b, f] azepin-5-yl) ethyl] piperidine (compound of formula (XX))

To a solution of 10,11-dihydro-5H-dibenzo [b, f] azepine salt in anhydrous dimethylsulfoxide (8 mL) was added sodium hydride (104 mg) under argon flow and the resulting solution was stirred for 0.5 h at room temperature. temperature. The compound (400 mg) obtained in step 7) of Example 33 was then added to the reaction mixture and the resulting solution was stirred at room temperature for 1.5 hours. Water was then added to the reaction mixture and the solution was extracted with ethyl acetate. The extract was washed with water and saturated sodium chloride solution and dried over sodium sulfate. The residue thus obtained was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1) to give the title compound (75 mg, yield 11%) as a light pink amorphous substance.

Step 9) T-Amino-1- [2- (6,11-dihydro-5H-dibenzo [b, f] azepin-5-yl) ethyl] piperidine (compound of formula (XXI))

To a solution of the compound (75 mg) obtained in step 8) in dichloromethane (0.5 mL) was added trifluoroacetic acid (420 μΐ) and the resulting solution was stirred at room temperature for 2 hours. The reaction solution was evaporated and azeotroped with toluene (0.5 mL). A 10% aqueous potassium carbonate solution was added to the residue, and the solution was extracted with a 9: 1 mixture of chloroform and tetrahydrofuran (2 mL). The extract was dried over sodium sulfate. The residue thus obtained was evaporated under reduced pressure and dried to give the title compound (60 mg, quantitative yield) as a light brown oil.

100 ALIGN!

Step 10) 2-Amino-N- [1- [2- (10,11-dihydro-5H-dibenzo [b, f] azepin-5-yl] ethyl] piperidin-4-yl] benzamide (compound of formula ( XXIII))

To a solution of anthranilic acid (25 mg), compound (58 mg) obtained in step 9) and 1-hydroxybenzotriazole (24 mg) in dimethylformamide (1 mL) was added hydrochloride

the resulting solution was stirred for 14 hours at room temperature. A 10% aqueous potassium carbonate solution was added to the residue, and the solution was extracted with chloroform-tetrahydrofuran (9: 1) (5 mL). The extract was evaporated under reduced pressure and azeotroped with xylene. The residue thus obtained was purified by silica gel column chromatography (mobile phase: chloroform: methanol = 20: 1) to obtain the title compound (77 mg, yield 97%) as a pale red amorphous substance.

Step 11) A solution of the compound (77 mg) obtained in step 10) in formic acid (2 mL) was heated to reflux for 14 hours. The reaction solution was allowed to cool, evaporated under reduced pressure and azeotroped with toluene. A 10% aqueous sodium bicarbonate solution was added to the residue, and the solution was extracted with chloroform. The extract was washed with water and saturated sodium chloride solution and dried over sodium sulfate. The residue thus obtained was purified by silica gel column chromatography (mobile phase: chloroform: methanol = 20: 1) to obtain the title compound (57 mg, yield 74%) as a white amorphous substance.

'9 9

0 * ♦ 0 0 '»9 _Z · 9

- · 0 0 0 0 '0 0 9 0 c $ β © e · · ·

9 · 9 9 9

99 9 00 0 0 00 -0 0 9 0 99

101

Example 35

Synthesis of 3- [1- [2- (10,11-dihydro-5H-dibenzo [b, f] azepin-5-yl) ethyl] piperidin-4-yl] -3-H-quinazolin-4-one hydrochloride

Step 13) To a dichloromethane solution (0.2 mL) of the compound (57 mg) obtained in step 11) was added 4 N hydrogen chloride in ethyl acetate (0.33 mL), and the resulting solution was stirred at room temperature for 0.5 hours. The formed crystals were filtered, washed with ethyl acetate and dried to give the title compound (59 mg, yield 94%) as a white solid.

Example 36

Synthesis of 3- [1- [2- (5,11-dihydro-5H-dibenzo [b, e] [1,4] oxazepin-5-yl) ethyl] piperidin-4-yl] -3H-quinazolin-4- Step 8) 4-tert-Butoxycarbonylamino-1- [2- (5,11-dihydrodibenzo [b, e] [1,4] oxazepin-5-yl) ethyl] piperidine (compound of formula (XX))

To a solution of 5,11-dihydrodibenzo [b, e] [1,4] oxazepine (642 mg) obtained in Production Example 15 in anhydrous dimethylsulfoxide (10 mL) was added sodium hydride (130 mg) under argon flow and the resulting solution was stirred for 0.5 hour at room temperature. The compound (500 mg) obtained in step 7) of Example 33 was then added to the reaction mixture and the resulting solution was stirred at room temperature for 1.5 hours. Water was then added to the reaction mixture and the solution was extracted with ethyl acetate. The extract was washed with water and saturated sodium chloride solution and dried over sodium sulfate. The residue thus obtained was purified by silica gel column chromatography (ethyl acetate: hexane = 3: 1) to give the title compound (324 mg, yield 47%) as a brown solid.

102 • 4? 44 44 44

4 9 4

4 9 4 4 ·

4 4 4 4 4 44 9

4 4 4 9 4444 9994 94 44

44 to the residue was added 10% aqueous expressed as a compound (5 mL) was (115 mg) and (mobile phase ethyl acetate) to give (343 mg, quantitative

Step 9) 4-Amino-1- [2- (5,11-dihydrodibenzo [b, e] [1,4] oxazepir-5-yl) ethyl] piperidine (compound of formula (XXI))

To a solution of the compound (321 mg) obtained in step 8) in dichloromethane (3.5 mL) was added trifluoroacetic acid (3.5 mL) and the resulting solution was stirred at room temperature for 0.5 h. The reaction solution was evaporated and azeotroped with toluene. Then the potassium carbonate solution was by weight, and the solution was extracted with chloroform. The extract was washed with saturated sodium chloride solution and dried over sodium sulfate. The residue thus obtained was evaporated under reduced pressure to give the title compound (245 mg, quantitative yield) as a yellow oil.

Step 10) 2-Amino-N- [1- [2- (5,11-dihydrodibenzo [b, e] [1,4] oxazepin-5-yl) ethyl] piperidin-4-yl] benzamide (compound of formula (XXIII))

To a solution of anthranilic acid (106 mg), (249 mg) obtained in step 9) in dimethylformamide, 1-hydroxy-benzotriazole hydrochloride 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (162 mg) was added under ice-cooling, and the resulting solution was stirred room temperature overnight. A 10% aqueous potassium carbonate solution was added to the residue, and the solution was extracted with a 10: 1 mixture of chloroform and tetrahydrofuran. The extract was washed with water and saturated sodium chloride solution and dried over sodium sulfate. The residue thus obtained was purified by silica gel column chromatography using a gradient of ethyl acetate: hexane = 2: 1 to obtain the title compound (yield) as a brown solid.

Step 11) A solution of the compound (338 mg) obtained in step 10) in formic acid (10 mL) was heated to reflux overnight. The reaction solution was then evaporated and azeotroped with toluene. Then, 6 β 6 β β 9 9-9 was added to the residue

9 (· ^! 9 9 · 99 '· ··· 9 * 9 9 9 · · 9 9 *

103 ......... ´ · ’· * · · ♦

10% aqueous potassium carbonate solution, and the solution was extracted with chloroform. The extract was washed with water and saturated sodium chloride solution and dried over sodium sulfate. The residue thus obtained was purified by silica gel column chromatography (mobile phase gradient ethyl acetate: hexane = 2: 1 to ethyl acetate) to obtain the title compound (192 mg, yield 55%) as a light yellow solid.

Example 37

Synthesis of 3- [1- [2- [N- (3,5-dimethylphenyl) -N-pyridin-2-ylamine] ethyl] piperidin-4-yl] -3H-quinazolin-4-one dihydrochloride

Step 8) 4-tert-Butoxycarbonylamino-1- [2- [3,5-dimethylphenyl) -N-pyridin-2-ylamine] ethyl] piperidine (compound of formula (XX))

To a solution of 3,5-dimethyl-N-pyridin-2-ylaniline (773 mg) obtained in Production Example 16 in anhydrous dimethylsulfoxide (8 mL) was added sodium hydride (78 mg) under argon at room temperature and the resulting solution was stirred for 0.5 hours. The compound (600 mg) obtained in step 7) of Example 33 was then added to the reaction mixture and the resulting solution was stirred for 2 hours. Water was then added to the reaction mixture and the solution was extracted with ethyl acetate. The extract was washed with water and saturated sodium chloride solution and dried over sodium sulfate. The residue thus obtained was purified by silica gel column chromatography (eluent: ethyl acetate: hexane = 2: 1 to ethyl acetate gradient) to obtain the title compound (490 mg, yield 59%) as a white amorphous substance.

Step 9) 4-Amino-1- [2- [N- (3,5-dimethylphenyl) -N-pyridin-2-ylamine) ethyl] piperidine (compound of formula (XXI))

To a solution of the compound (480 mg) obtained in step 8) in dichloromethane (2.5 mL) was added trifluoroacetic acid (2.5 mL) and the resulting solution was stirred at room temperature for

104 »0 00 00 0 0 0 0 ·· '0 0' 0 0 ·% 0 0> 0>> 0 · · 0 0 '0 0 · .0 10 0' 0 • 0 (0 0 0 00 0 ' 0 1000 00 0 • 0 '0 0 0 0 0

0 ··· 0000 00 00 00 00.

for 1 hour. The reaction solution was then evaporated under reduced pressure and azeotroped with toluene. A 10% aqueous potassium carbonate solution was added to the residue, and the solution was extracted with a 10: 1 mixture of chloroform and tetrahydrofuran. The extract was dried with potassium carbonate and filtered. The filtrate was evaporated under reduced pressure and dried to yield. to give the title compound (320 mg, 87% yield) as a pale yellow oil.

Step 10) 2-Amino-N- [1- [2- [N- (3,5-dimethyl-phenyl) -N-pyridin-2-ylamino] -ethyl] -piperidin-4-yl] -benzamide (compound of formula (XXIII) )

To a solution of anthranilic acid (133 mg), compound (315 mg) obtained in step 9) and 1-hydroxybenzotriazole hydrate (131 mg) in dimethylformamide (2 mL) was added 1-ethyl-3- (3-dimethylaminopropyl hydrochloride) under ice-cooling. The carbodiimide and the resulting solution was stirred at room temperature for 15 hours. A 10% aqueous potassium carbonate solution was added to the residue, and the solution was extracted with chloroform-tetrahydrofuran (9: 1). The extract was evaporated under reduced pressure and azeotroped with xylene. The residue thus obtained was purified by silica gel column chromatography (mobile phase: chloroform: methanol = 10: 1) to obtain the title compound (315 mg, yield 73%) as a white amorphous substance.

Step 11). 3- [1- [2- [N- (3,5-dimethyl-phenyl) -N-pyridin-2-ylamino] -ethyl] -piperidin-4-yl] -3H-quinazolin-4-one (compound of formula (I)) )

A solution of the compound (310 mg) obtained in step 10) in formic acid (3 mL) was heated to reflux for 40 hours. The reaction solution was then allowed to cool to room temperature and azeotroped with toluene. Aqueous sodium bicarbonate solution was added to the residue

105 ··, φ · ·· ·· ··>

· ♦ ♦ e e 9 9 9 9 9 9 4 9 ‘1 9‘ 9 99 .4 9 4 9 9 9

4499 999 9 9 9 9 9 9 9 The solution was extracted with chloroform. The extract was washed with saturated sodium chloride solution and dried over sodium sulfate. The residue thus obtained was purified by silica gel column chromatography (mobile phase - chloroform: methanol - 20: 1) to obtain the title compound (272 mg, yield 86%) as a white amorphous substance.

Step 13) Using the compound (265 mg) obtained in step 111, the reaction was carried out in the same manner as in step 13) of Example 33 to give the title compound (280 mg, yield 92%) as a white solid.

Examples 38 to 71

The compounds listed in Tables 15 to 26 were obtained in the same manner as in Example 33.

Example 72

Synthesis of 3- [1- [2- [N- (2-propylphenyl) -N-pyridin-2-ylamine] ethyl] piperidin-4-yl] -3H-quinazolin-4-one

Step 8) 4-tert-Butoxycarbonylamino-1- [2- [N- (2-propylphenyl) -N-pyridin-2-ylamine] ethyl] piperidine (compound of formula (XX))

Using the compound (509 mg) obtained in step 7) of Example 33 and 2-propyl-N-pyridin-2-ylaniline (691 mg) obtained in Production Example 41, the reaction was carried out in the same manner as in step 8) of Example 33. Thus The obtained residue was purified by silica gel column chromatography (mobile phase - gradient ethyl acetate: hexane = 3: 1 to ethyl acetate) to obtain the title compound (453 mg, yield 62%) as a light yellow oil.

Step 9) 4-Amino-1- [2- [N- (2-propylphenyl) -N-pyridin-2-ylamine] ethyl] piperidine (compound of formula (XXI))

Using the compound (453 mg) obtained in step 8), the reaction was carried out in the same manner as in step 9) of Example 33,

106

4 · 4 4 4 4; '·' · · · · 4 · 4 4 44 4> 4 4 4 ί · 4 4 • 4 4 4 4 4 4

444 4444 to give the crude product (375 mg) as a pale yellow oil.

Step 12) To a solution of the crude product (375 mg) obtained in step 9) in toluene (5 mL) was added 4H-3,1-benzoxazin-4-one (169 mg) obtained in Production Example 43, and the resulting solution was stirred for for 15 minutes at room temperature. It was then added to the reaction mixture. triethyl orthoformate (1 ml) and the resulting mixture was heated under reflux for 2 hours. The reaction mixture was then evaporated under reduced pressure and extracted with chloroform. The extract was washed with aqueous sodium bicarbonate solution and dried over sodium sulfate. The residue thus obtained was purified by silica gel column chromatography (mobile phase - gradient chloroform: methanol = 100: 1 to 100: 3) and the obtained product was crystallized from

mixtures of ethanol with water, thereby was obtained required compound (355 mg, yield 73 O. Ό molar) in the form colorless of crystals. Examples 73 to 74 Compounds listed in Table 27 Mar: were obtained by the same

as in Example 72.

Example 75

Synthesis of 3- [1- [2- (10,11-dihydro-10-hydroxy-5H-dibenzo [b, f] azepin-5-yl) ethyl] piperidin-4-yl] -3H-quinazolin-4-one

Step 4) Using the compound obtained in Production Example 44 and the compound obtained in Step 3) of Example 1, the reaction was carried out in the same manner as in Step 4) of Example 7 to give the title compound (47% yield) as a white solid. substances.

• ·

107 «« ·· ··· <

* e e e e e β · »β · β β · · · · ·

Example 76

Synthesis of 3- [1- [2- (10,11-dihydro-2-hydroxy-5H-dibenzo [b, f] azepin-5-yl) ethyl] piperidin-4-yl] -3H-quinazolin-4-one

In order to protect the hydroxyl compounds synthesized in Production Example 45, a hydroxyl protecting group was first introduced.

To a solution of the crude crystals (4.05 g) obtained in Production Example 45 in dimethylformamide (40 mL) was added sodium hydride (710 mg) under nitrogen atmosphere under ice-cooling. Chloromethyl methyl ether (1.35 mL) was then added to the reaction mixture and the resulting solution was stirred overnight at room temperature. The reaction mixture was evaporated, water was added and the solution was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over sodium sulfate, and filtered. The filtrate was evaporated and the residue thus obtained was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1 as eluent) to give N- (2-chloroethyl) -10,11-dihydro-2-methoxy-5H-dibenzo [ b, f] azepine (4.64 g, 99% yield) as a yellow oil.

Step 4) Using the N- (2-chloroethyl) -10,11-dihydro-2-methoxy-5H-dibenzo [b, f] azepine obtained in the previous step and the compound obtained in step 3) of Example 1, the reaction was carried out in the same manner. according to the method of Step 4) of Example 7 to give 3- [1- [2- (10,11-dihydro-2-hydroxymethoxy-5H-dibenzo [b, f] azepin-5-yl) ethyl] piperidin-4 -yl] -3H-quinazolin-4-one (74% yield) as a white amorphous solid.

To an ethyl acetate solution (20 mL) of the compound so obtained (2.00 g) was added 4 N hydrogen chloride in ethyl acetate (20 mL) and the resulting solution was stirred at room temperature for 3 hours. The reaction mixture was evaporated and the residue was dissolved by adding saturated aqueous sodium bicarbonate solution and chloroform / methanol (10: 1) and heating. Then the organic layer was separated, the aqueous layer was extracted with chloroform and the extract

108

··· was added to the first separated organic layer. The combined organic layers were washed with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. After evaporation of the filtrate, the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 20: 1) to give the title compound (1.83 g, quantitative yield) as a white amorphous compound.

Examples 1 to 76 are shown in Tables 3 to 28.

999 • ·

Table 3 ··

9 9 • · ·········

9 9

9 9

9

9

99

9 9 9

9 9 9

999 999

9

99

1 Příklac Compound J Yield from (properties, last step) 'H NMR ($) ppm MS DMSO-d 300 MHz FAB * 1.90-2 ^ 20 (2 H, m) 425 iíX 2 ^ 45-2 / 72 (2¾m) 3.16-3.42 (4¾ ra) 3.65-3.80 (2H, m) IN 4.15-4 ^ 1 (2¾ m) O 4.76-4 ^ 95 (1¾ m) 7.01 (2¾ t, J = 7.3 Hz) if i J 7.02-7.15 (4¾ m) 1 xy 2HCI 7.26-7 ^ 5 (4¾m) 7.53-7.62 (1¾ m) 7.69-7.76 7.82-7.91 (1¾ ra) 8.18 (1¾ d. J = 8.0Hz) (white crystals, 94%) DMSO-d 300 MHz FAB * 2.00-2.30 (2¾ m) 449 O- 2.55-2.67 (2¾ m) 3.06-3.48 (4¾ m) AND 3.52-3.82 (2¾ m) 4.20-4.35 (2¾ m) 4.70-5.30 (111, m) M O 6.83 (4¾ s) 7.05-7.42 (8¾ m) 752-7.63 (1H, m) 2 on 7.39 (1¾ d, J = 6 _f 8Hz) 7.80-7.90 (1¾ m) N 8.18 (1¾ dd, J = 8.0Hz, 1.2Hz) 8.33 (1¾ s) (light yellow powder, 100 mole%) DMSO-d 300 MHz FAB * 2.03-2.20 (2¾ m) 439 0 2.42-2.57 (2¾ m) 3.15-3.44 (4¾ m) 3 64-3.80 (2¾ m) 1 3.83-3.99 (2¾ m) XI at 4.63 (2¾ s) 4 77-4.92 (1¾ m) 6.66 (1¾t, J = 7.2Hz) 3 kA 6.80 (2¾ d, J = 8.1Hz) 7.10-7 ^ 9 (7¾ m) 758 (1¾ t. J = 8.1Hz) hq 7.70 (1¾ d, 7.80-7.92 (1¾ m) 8.18 (1¾ dd, J = 8.1, 12Hz) (colorless needle crystals, 8.29 (1¾ s) 89 mole%) 10.67 (1¾ brs)

Table 4

“Ί Příkla 1 Compound (properties, ^α yield from the last step) Ή NMR (δ) ppm MS CDCl3 300 MHz FAB * 1.62-2.00 (5¾ m) 465 of Λ 2.04-2.20 (2 H, m) 2.46 (2¾ t, J = 7.5Hz) 2.92-3.06 (2¾ m) 3.17 (4¾s) 1 ΠI 3., 79 (2¾t, J = 6.8Hz) 4.76-4.90 (1¾ m) 4 Γϊ ί J fy 6.88-6.95 (2¾ m) 7.02-7.18 (6¾ m) 7.44-7 ^ 4 (1¾ m) 7.65-7.80 (2¾ m) 8.11 (1¾ s) 8.30 (1H, dd, J = 8 ^ Hz, 1 _f 5Hz) (white solid, 74%) DMSO-ds 300 MHz FAB * 2.00-2.17 (2¾ ra) 466 2.48-2.64 (2¾ ra) z ° 3.15-3.33 (4¾ m) 3.64-3.80 (2¾ m) J, NH 7 4.20-4.40 (2¾ m) 4.76-4.97 (1¾ m) 7.06-7.12 (4¾ ra) ) 7.28-7.45 (2¾ m) 5 7.50-7.76 (4¾ m) 7.80-7.89 (1¾ ra) kz 8.13-8.16 (1¾ m) N 8.31 (1¾ s) 10.33 (1¾ s) 11.19 (1¾ brs) 1 (white solid, 91% mole) DMSO-d 300 MHz FAB * 1.56-2.16 (6¾ m) 2.52-2.69 (2¾ m) 453 9 3.03-3.23 (3¾ m) 3.35-3.43 (1¾ m) 3.55-3.65 (2¾ m) 3.68-3.80 (2¾ m) 6.90-7.05 (6¾ m) ááj> 1 J 7.25-7.33 (4¾ m) 6 Ha 7.57-7.64 (1H, m) υ 7.71-7 ^ 80 (1¾ m) 7.84-7.92 (1¾ m) 8.19 (1¾ dd, J = 8.1Hz, 1.5Hz) 8.37 (1¾ s) 10.68 (1¾ brs) (white belt, 100 mole%)

© © β · e e

Table 5> ee eeee

AAA

-! : Příklc Compound (properties, yield from last step) 'H NMR (<J) ppm MS CDCl3 300 MHz FAB * 1.80-2.02 (4¾ m) 439 n 2.13 (3¾ J) 2 ^ 0-2.37 (2¾ m) 2.73 (2¾ L J = 7.2Hz) 'Me 3 ^ 04-3.12 (2¾m) 3.80 (2¾ t, J = 7.2Hz) 4.76-4.95 (1¾ m) χ 1 J L JI 6.51 (4¾ d, J = 8.1Hz) 7 CQ 6.70 (1¾t,] = 7.5Hz) 7.09-7J7 (6H, m) 7.46-7.56 (1¾ m) 7.65-7.80 (2¾ m) 8.13 (1¾ s) 8.31 (1¾ dd, J = 8.1Hz, 1.5Hz) (white solid, 65 mole%) DMSO-? 300 MHz FAB ’ 2.06 (3¾s) 439 f * l 2.12 (2¾ brs) 2.35-2.65 (2¾ m) 3.15-3.75 (5¾ m) Me 3.70-3.80 (2¾ m) χ ΓΎ ^ ΊΟ 4.00-4.15 (2¾ m) 4.75-4.90 (1¾ m) 6.56 (2¾ d, J = 8.4Hz) 8 fYY ^ ^κ · 6.70 (1H, t, J = 7.3 Hz) 7.10-7.42 (6¾ m) 7.57 (1¾t, J = 7.5Hz) 7.70 (1¾ d, J = 8.4Hz) N 7.85 (1H, t, J = 7.7Hz) 8.17 (1¾ d, J = 7.0Hz) (white solid, 96%) 8.29 (1¾ s) 10.95 (1¾ brs) CDCl3 300 MHz FAB * 1.80-2.10 (8¾ m) 2.25-2.43 (2¾ m) 427 2.64-2.80 (6¾ m) ΓΛ 3.00-3.16 (2¾ tn) 4.18 (2¾t, J = 7.2Hz) 4.80-4.94 (1¾ m) 7.00-7.10 (2¾ m) 7.20-7.32 (1¾ m) 9 oc 7.40-7.55 (2¾ m) 7.63-7.80 (2¾ m) 8.15 (1¾ s) 8.31 (1¾ dd, J = 8.1Hz, 1 ^ Hz) (white solid, 13 mole%) ______—----

Example β ·· · 999 9

99

Table 6

Compound (properties, yield from last step) _

(white solid, 100 mol%)

HCl

(light purple fabric, 100% mole)

(pale yellow, 88%) @ 1 H NMR (.delta.) ppm

DMSO46 300 MHz 1.92-2.15 (4½ m) 2.48-2.52 (2½ m) 3.06-3.27 (4½ m)

3.52- 3.67 (2½ m) 3.78 (2H, i, J = 7.2Hz)

4.82- 4.97 (1½ m) 95 .95-7.07 (6½ m) 7.24-7.38 (4½ m)

7.52- 7.64 (1½ m) 7.68-7.78 (1½ m)

7.82- 7.92 (1½ m) 8.12-8.22 (1½ m) 8.32 (1½ s)

10.68 (1½ brs)

DMSO-de 300 MHz 1.90-2.22 (2½ m) 2.46-2.70 (2½ m)

3.20- 3.45 (4½ m) 3.60-3.90 (2½ to) 4.08-4.25 (2½ m) 4.74-5.00 (1½ m) 6.87-6.96 ( 2½ m) 6.96-7.05 (3½ m>)

7.21- 7.32 (2½ m) 7.58 (1½ t, J = 7.2Hz) 7.71 (1½ d. J = 8.1Hz) 7.81-7.91 (1½m) 8.14- 8.22 (1½ m) 8.30 (1½ brs)

1103 (1½ brs)

300 MHz

I, 94-2.25 (2½ m) 2.45-2.80 (2½ m) 3.15-3.60 (4½ m) 3.62-3.85 (2½ m) 4.25-4, 50 (2½ m)

4.76- 5.00 (1½ m) 7.38-7.52 (3½ m) 7.55-7.65 (3½ m) 7.72 (1½ d, J = 8.1Hz)

7.77- 7.94 (3½ m) 8.18 (1½ d, J = 7.8Hz) 8.25 (1½ d, J = 5 1Hz) 8.32 (1½s)

8.40-8.46 (1H, ra)

II, 60 (1½ brs)

MS

FAB *

439

FAB ’

431

FAB *

426

X3

Table 7

- : Příkla Compound (properties, d yield from last step) ¹ H NMR (? 5) ppm MS CDCl3 300 MHz FAB ⁺ 0.88 (311, t, J = 7.1Hz) 1.50-1.68 (2¾ m) 467 ί Ί ϋ .xX 1.86-2.05 (4¾ m) · ^Μ Ζ 'Me 2.46 (2¾ t, J = 7.9Hz) O 2.75 (2¾t, J = 7.7Hz) 3.03-3.14 (2¾ m) 13 JU N 3.76 (2¾t, J = 7.7Hz) 4.80-4.95 (1¾ m) 6.51 (2H, d, J = 7.7Hz) 6.69 (1¾t, J = 7.3Hz) 7.12-7.38 (6¾ m) 7.47-7.53 (1¾ m) 7.68-7.79 (2¾ m) 8.14 (1¾ s) (white solid, 8.31 (1¾ d, J = 81Hz) 42 mole%) DMSOA 300 MHz FAB * ( 1.90-2.26 (2¾ m) 2.45-2.65 (2¾ m) 3.18-3.45 (4¾ ra) 3.55-3.85 (2¾ m) 4.10-4.25 (2¾ m) 4.75-4.95 (1 H, m) 6.91 (1¾ dd, 1 = 5.1Hz, 1.5Hz) 431 O X''N '^ ^S ' sX 6.96 (1¾ d, J = 7 ^ Hz) 14 Xj 7.05 (2¾ L, J = 8.1Hz) 7.08-7.16 (1¾ ra) 7.23-7.34 (2¾ m) 7 _r 52-7.63 (2H, m) 7.71 (1¾ d. J = 7.8Hz) 7.82-7.90 (1¾ m) 8.15-8.22 (1¾ ra) (white solid, 80 mole%) 8,30 (1¾ sec) 10,99 (1¾ brs) DMSOA 300 MHz FAB * 2.06-2.20 (2¾ ra) 2.50-2.65 (2¾ m) 427 C 3.10-3.48 (4¾ m) r 3.65-3.85 (2¾ m) 4 ^ 0-4.40 (2¾ m) , hL yX 4.75-4.93 (1¾ m) Ό ¹ 7.22-7.38 (3¾ m) 7.48 (2¾t, J = 7.8Hz) 15 Dec || | NW 7.59 (111, t J = 6.9Hz) 7.72 (1¾ d, J = 8.1Hz) X ^ N ^ Ha 7.81-7.92 (1¾ m) 8.19 (1¾ d, J = 6.3Hz) 8.34 (1¾ s) 8.47 (2¾ s) (yellow solid, 100 mol%) 8.72 (1¾ s) 11j14 (1H, brs)

4¼

Table no

Compound (properties, Example yield from last step) _

(white solid, 67%)

(white solid, 40 mol%)

(white solid, 38%)

Ή NMR (<0 ppm

DMSO / d 300 MHz

I, 90-2.22 (2¾ m) 2.50-2 ^ 8 (2¾ m) 320-3.42 (4¾ m) 3.65-3.80 (2¾ m) 3.74 (3¾ s) 4 , 17-4,30 (2¾ m) 4,78-4,96 (1¾ m) 6,52-6,64 (3¾ ta) 7 /) 4 (1¾ t, J = 7 ^ Hz) 7,12 ( 2¾ d, J = 7.5Hz) 7.14-7.24 (1¾ m)

7.34 (2H, t, J = 7.8 Hz) 7 _f 59 (1H, t. J = 8.1 Hz) 7.73 (1¾ d. J = 8.1 Hz) 7.82-7.94 (1¾ m) ) 8.19 (1¾ d, J = 6.0Hz) 8.37 (1¾ s)

II, 30 (1¾ brs)

CDCl3 300 MHz

1.05-1.25 (6¾ m) 1.90-2.10 (4¾ m) 2.22-2.40 (2¾ m)

2.68- 2.84 (2¾ m) 3.00-3.18 (3¾ m)

3.68- 3.85 (2¾ m) 4.79-5.00 (1¾ m) 6.43-6.56 (2¾ m) 6.62-6.74 (1¾ m) 7.06-7.57 (7¾ m) ) 7.65-7.82 (2¾ m) 8.09-8.19 (1¾ m) 8.24-8.37 (1¾ m)

CDCl 3 300 MHz 0.84 (3¾ t. J = 7.1Hz)

1.21- 1.36 (2¾ m) 1.48-1.60 (2¾ ra) 1.86-2.04 (4¾ ra)

2.22- 2.38 (2¾ m)

2.47 (2¾ t. J = 7.9Hz) 2.75 (2¾ t. J = 7.7Hz) 3.04-3.16 (2¾ m)

3.76 (2¾ t> J = 7 ^ Hz) 4.80-494 (1¾ m)

6.51 (2¾ d, 1 = 7.7Hz) 6.69 (1¾ t, J = 7.1Hz)

20-7.38 (6¾ m) 7.47-7.53 (1¾ m) 7.68-7.80 (2¾ m)

8.14 (1¾ s)

8.31 (1¾ dd, J = 8.1Hz, 1.5Hz)

MS

FAB *

455

FAB *

467

FAB *

481

Table 9

- Příkla Compound (properties, yield from last step) 1 H NMR (?) Ppm MS CDCl3 300 MHz FAB * n 1.15 (3¾t, J = 7.5Hz) 1.85-2.00 (4¾ m) 220-2.38 (2¾ m) 2_51 (2H, SD, J = 7Hz) 2.74 (2¾t, J = 7.5Hz) 453 3.03-3.14 (2¾ m) 3.78 (2¾ t. J = 7.5Hz) - 4.80-4.95 (1¾ m) 1 1 J LJ 19 Dec rťj 6.50 (2¾ d, 1 = 8.1Hz) 6.69 (1¾t, i = 7.4Hz) 7.12-7.38 (6¾ m) 7.47-7.53 (1¾ m) 7.68-7.79 (2¾ m) 8.14 (1¾ s) 8.31 (1¾ dd. J = 8 ^ Hz, 1.4Hz) (white solid, < 4 6 mole%) CDCl3 400 MHz FAB 1.09 (3¾ t. 7 = 5.2Hz) 391 fT 2.05-2.19 (2¾ m) 2,30 (3¾s) Ύ 2.50-2.73 (2¾ m) 3.15-3.55 (6¾ ro) 3.59-3.77 (2¾ m) I Γ j 3,797-3.98 (2¾ m) 4.81-5.00 (1¾ m) 6.56-7 ^ 6 (4¾ m) 20 May řYj me 7.60 (1¾t, J = 5.6Hz) 7.75 (1¾ d, J = 6.1Hz) 7.82-7.95 (1¾ m) 820 (1¾ L, J = 5.9Hz) 8.47 (1¾ brs) (white solid, 96%) 11, .39 (1H, brs) DMSO-dj 400 MHz FAB * 2.00-2.23 (2¾ ra) 363 2.50-2.74 (2¾ m) 0 2,96 (3¾ «) 3.09-3.44 (4¾ m>) 3.57-3.79 (2¾ m) AND 3.80-3.96 (2¾ m) 4.84-5.01 (1¾ m) 6 75 (1¾ t. J = 5.4Hz) 6.94 (2¾ d, 1 = 6.0Hz) 21 2HQ 724 (2¾ t. J = 5.8Hz) 7.62 (1¾t, J = 5.6Hz) 7.78 (1¾ d, J = 6.1Hz) 7 ^ 90 (1¾t, J = 5.4Hz) 8.20 (1¾ d, J = 5.9Hz) (white solid, 8.52 (1¾ brs) 100 mole%) 11.44 (1¾ brs)

AA <ó

Table 10 Compound (properties, ^Pr1 ' ^and yield from the last step).

(white solid, 91%)

(white powder,% mole)

(white powder,

100 mole% H NMR (a) ppm

DMSO-dg 300 MHz

1.10 (3¾ t, J = 6, 9Hz) 2.00-2.24 (2¾ m) 2.49-2.78 (2¾ m) 3 / 2-3 ^ 40 (4¾ m) 3.45 ( 2¾ q, J = 6, 9Hz) 3.54-3 _r 98 (4H, m) 4.85-5.02 (1¾ m) 6.62-7.10 (3¾ m) 7.12-7.38 (2¾ m) 7.60 (1¾ t, J = 8.1Hz) 7.75 (1¾ d, J = 8.1Hz) 7.89 (1¾ t, J = 7.2Hz) 8.20 (1¾ d, J = 6 / Hz) 8.46 (1¾ brs) 11 ^ 28 (1¾ brs)

DMSO-dg 300 MHz

MS

FAB *

377

FAB ’

2.06-2.20 (2¾ m) 459

2.50-2.70 (2¾ m)

3.20- 3/0

3.65-3.78 (2¾ m)

4.20- 4.34 (2¾ m)

4.77-4.90 (1¾ m)

6.84-7.00 (3¾ m)

7.20- 7/2 (4¾ m)

7.43 (2¾t, J = 7.7Hz)

7.60 (1¾ t, J = 7.5Hz)

7.75 (1¾d, J = 8.1Hz)

7.88 (1¾t, J = 7.7Hz)

8.19 (1¾ d, J = 7j2Hz)

8,40 (1¾ sec)

11.34 (1¾ brs)

DMSO-H 300 MHz FAB *

2.10 (4¾ brd. J = 10 / Hz) 2 / 0-2.70 (211 m) 3.10-3.25 (4¾ m) 3.61 (2¾ brd, J = 12.3Hz) 3.93 (2¾ t-J-7.5Hz) 4.88-5.04 (1¾ m) 7.39-7 / 9 (10¾ m> 8.17-8.80 (4¾ m) 11 /) 2 (1¾ brs)

440 β β

Table 11

Ή?

-r

Example

Compound (properties, yield from last step) 'H NMR ($) ppm DMSO-d6 MHz

MS

FAB *

1.56-2.18 (6¾ m) 2.55-2.70 (2¾ m) 3.00-3.70 (6¾ m)

Λ · aa / att _ * w /

4.85-5.05 (1¾ m)

6.69 (1¾ d, J = 9.3Hz), 7.01 (1¾ t, J = 6.6Hz) 7.42-7.78 (7¾ m). 7.82-7.96 (2¾ m)

8.08 (1¾ dd, J = 5 ^ Hz) 8.18 (1¾ dd, J = 8.0Hz, 1.2Hz)

454 (white powder,% mole)

DMSO-d 300 MHz.

2.02-2.20 (2¾ m) 2.40-2.60 (2¾ m) 3.10-3.75 (8¾ m) 4.80-5.00 (1¾ m) 5.69 (1¾ brs) 7.30 -7.55 (6¾ m) 7.59 (1¾ t, J = 7.5Hz) 7.65-7.80 (5¾ m) 7.87 (1¾ t. J = 7.5Hz) 8.18 (1¾ t) d, J = 6.3Hz), 8.29 (s 1¾) iq.5-LL 00 _f (2H. brs)

FAB *

439 (white powder,

100 mole%)

CDC1 ₃

300 MHz

FAB *

1.75-1.95 (4¾ m) 2.02-2.11 (2¾ m) 2.45-2.50 (2¾ m) 2.65-2.71 (2¾ m) 2.81 (2¾ d, J = l 1.7Hz) 3.67 (2¾ s) 4.73-4.84 (1¾ m) 4.92 (1¾ s)

7.20-7.51 (16¾ m) 7.67-7.77 (2¾ m) 8.10 (1¾ s)

8.30 (1¾d, J = 8Hz)

529 (colorless crystals, 37 mol%) ·········

Table 12

She said d Compound (properties, yield from last step) 1 H NMR (d 6) ppm MS DMSO 300 MHz FAB * 1,10-1 ^ 0 (0, ro) 437 n 1 ^ 0-1,74 (5¾ ro) 1.76-1.80 (4¾ m) About ΠΛ-Ο »Λ »·· / 2.48-2.65 (2¾ m) 3.18-3 ^ 52 (4¾ ro) O η Ί0 3.55-3.85 (6¾ m) 4.70-4.95 (1¾ m) 28 7.55-7.64 (1¾ m) AND/ 2HCl 7.69-7.75 (1¾ m) 7.83-7.90 (1¾ m) 8.19 (1¾ dd. J = 8.1Hz, 0.9Hz) 8.29 (1¾ s) 10.46 (1¾ brs) (white solid, 11,50 (1¾ brs) 71%) CI & gt _; 13,300 MHz FAB * 1.84-2.08 (4¾ m) 423 /AND 2.26-2.48 (2¾ m) 2.86 (2¾t, J = 7.4Hz) 3.05-3.22 (2¾ m) 4.48 (2¾ t. J = 7 _? 4Hz) 4.78-4.96 (1¾ m) 7.20-7.30 (2¾ m) O 29 JL 7.40-7.55 (5¾ m) C XJ 7,66-7,80 (2¾ ro) 8.05-8.12 (3H.m) 8.26-8.33 (1¾ m)  (white solid, 34%) DMSO-d 400 MHz FAB * 2.02-2.20 (2¾ m) 453 Me 2.43-2.50 (2¾ m) 2.55-2.85 (3¾ m) 3.21 (2¾ brs) 3.52 (4¾ brs) O f Y 3.81 (2¾ brs) 4.76-4.92 (1¾ m) XJ O 5.74 (1¾ brs) 30 · 7.30-7.50 (6¾ m) 2Hd 7.58 (1¾ t, J = 5.6Hz) 7.72 (1¾ d, J = 6.1Hz) 7.75-8.00 (5¾ m) 8.17 (1¾ d, J = 5.5Hz) 8.30 (1¾ brs) (White powder, 11.00 (l ^ rs) 12.46 (1H, brs) 100% molar)

Table 13

-pExample

Compound (properties, yield from last step)

(white solid, 83%)

(white solid, 23 mole%)

(white powder, '100 mole%)

'H NMR ($) ppm CDCl3 300 MHz

1.80-2.05 (4¾ m) 2.09-2.28 (2H, m) 2 ^ 0-2.71 (4¾ ra) 2.90-3.14 (2¾ m) 3.62 (4¾ m) s) 4.75-4.93 (1¾ m) 7.12-7.43 (10¾ m) 7.43-7.56 (1¾ ra) 7.62-7.82 (2¾ m) 8.13 ( 1¾ s) 8.24-8.33 (1¾ s)

DMSCWe 300 MHz

2.00-2.08 (2¾ m) 2.48-2.70 (2¾ m) 3.18-3.42 (4¾ m) 3.70-3.85 (2¾ ra) 4.14-4, 35 (2¾ m)

4.85- 5.00 (1¾ m)

7.10- 7.45 (10¾ m) 7.59 (1¾ t, J = 6.9Hz) 7.72 (1¾ d, J = 8.1Hz)

7.85- 7.95 (1¾ m)

8.10- 8.24 (1¾ m) 8.34 (1¾ s) 10.68 (1¾ brs)

DMSO-4,300 MHz

2.04-2.20 (2¾ m) 2.50-2.70 (2¾ m) 3.22-3.56 (4¾ m) 3.63-3.80 (2¾ m) 4.38-4 ^ 0 (2¾ m) 4.82-5.00 (1¾ m) 6.80 (1¾ d, J = 8.7Hz) 6.97 (1¾ t, J = 6.3Hz) 7.46-7.94 ( 8¾ m) 8.16-8.22 (2¾ ra) 8.47 (1¾ brs)

MS

FAB *

453

FAB *

453

FAB *

460 • 0 ·

• ·

000

0/20

Table 14

00 »0 0 0 • 0 000 000« »0 00 0

TU Compound (properties, yield from last step)

(white amorphous substance, 74%)

(white solid, 94%)

(pale yellow solid, 55%)

@ 1 H NMR (.delta.) Ppm MS CDCl3 300 MHz FAB * 1 82-2,04 (4¾ m) 2,15-2 ^ 30 (2¾ m) 2,60 (2¾ t, J = 7,1Hz) 2 ^/ (92-? _F 06 (7H. M) 3I18 (4H) 3.94 (2¾ t J = 7.2Hz) 4.74-4.90 (1¾ m) € 188-6.98 (2¾ ra) 7.08-7.20 (6¾ m) 7.46-7 ^ 6 (1¾ m) 7 68-7.82 (2¾ m) 451 8.29 (1¾ s) ^ 30 (1¾dd. J = 8.1Hz, 0.9Hz) DMSO-α 300 MHz FAB * 2.05-2.15 (2¾ m) 2.45-2.70 (2¾ m) 3.10-3.40 (4¾ m) 451 3.60-3.82 (2¾ m) 4.10-4 47 (6¾ m) 4.80-4.95 (1¾ m) 6.90-7.10 (2¾ m) 7.10- 7.40 (6¾ m) 7.59 (1¾ t. J = 7.8Hz) 7 72 (1¾d, J = 7_5Hz) 7.85 (1¾t, J = 1.2Hz) 8.18 (1¾ d, J = 8.1Hz) 8.33 (1¾ s> Π, 11 (1Η, brs) CDQj 300 MHz 1.80-1.98 (4¾ ro) 2.18-2.30 (2¾ m) 2.67 (2¾ t, J = 6.8Hz) 2.98-3.06 (2¾ m) 3.95 (2¾ m) t, J = 6.8Hz) 4.78-4.90 (1¾ m) 5.34 (2¾ s) 6.76-6.88 (3¾ m) 7.0Q-7 _r 20 (3H, m) 7, 24-7.36 (2¾ m) 746-7.54 (1¾ m) 7.66-7.80 (2¾ ro) 8.12 (1¾ s) 8.30 (1¾ dd, J = | 0Hz. 1 4Hz ) FAB *

Table 15 9 9 9 · 9 99 9999

AU

Příkla Compound (properties, ^d yield from last step) 1 H NMR (δ) ppm MS DMSO-d 300 MHz FAB * l J 2.04-2.22 (2¾ ra) 2.34 (6¾ j) 2 ^ 0-2.72 (2¾ m) 3.17-3.58 454 T 3 ^ 61-3 ^ 82 4.32-4.50 (2¾ m) 4.76-5.00 (1¾ m) 11 1 J w. J 6.70-6.88 (1¾ m) 37 2HQ 6.98 (1¾ t, 7 = 6.2Hz) 7.11 (3¾ s) 7.58 (1¾ t. J = 10.5Hz) 7.73-7.95 (2¾ m) 7.74 (1¾ d. J = 7.8Hz) 8.08-8.27 (2¾ m) (white solid, 92 mole%) 8.44 (1H, hrs) 300 MHz FAB * 2.12 (2¾ d, J = 12.0Hz) 2.50-2.62 (2¾ m) 3.20-3.40 (2¾ m) 444 • JL η i 3,44 (2¾ bra) 3.73 (2¾ d, J = 11.7Hz). Ozjz 4.35-4.41 (2¾ m) 38 Μ: - 4.80-4.96 (1¾ m) 6.61 (1¾ bra) 6.86-6.96 (1¾ m) OO ^2,0 7.41 (2¾t, J = 8.7Hz) 7.50-7.74 (5¾ ra) 7.87 (1¾ t. J = 6.6Hz) 8.19 (2¾ d, J = 6.6Hz) 8.40 (1¾ brs) (white powder, 100 mole%) DMSO 300 300 MHz FAB * 2.05-2.20 (2¾ m) 2.44-2.67 (2¾ m) 426 h 1 3.25-3.54 (4¾ m) IN 3.66-3.78 (2¾ ra) 4.32-4.53 (2¾ m) 4.80-4.96 (1¾ m) 6.68 (1¾ d, J = 8.7Hz) 39 him 6.95 (1¾t, J = 6.3Hz) 7.41-7.64 (6¾ m) 7.69-7.81 (2¾ m) 7.83-7.92 (1¾ ra) 8.19 (1¾ d, J = 6.9Hz) 8.19 (1¾ d. J = 7Hz) 8.43 (1¾ s) (white powder, 100 mole%)

Table 16 9 e e e β e e e e e e e e e e,,,,,,, 9 9 ·· φφ

Γ

Example

Compound (properties, yield from last step)

(white powder,

100% mole% @ 1 H NMR (.delta.) Ppm DMSOde 300 MHz

2.07-2.22 (2¾ m)

2.48- 2.69 (2¾ ra) 324-3.50 (4¾ m)

Ulf

4.48- 4.68 (2¾ m) 4.80-4.98 (1¾ m)

7.14 (2¾ dd. J = 7.2Hz, 5.1Hz) 7.33 (2¾ d. J <= 8.7Hz) 7.60 (1¾ t, J = 7.2Hz)

7.74 (1¾ d. J = 8.1Hz) 7.76-7.92 (3¾ m)

8.20 (1 «, d J = $ .1Hz) 8.38-8.52 (3¾ m)

10.83 (1H, brs)

BMSG-dg

300 MHz

MS

FAB *

427

FAB

(white powder, even molar)

(white solid, 72 t molar)

2.05-2.18 (2H, m) 2.48-2.67 (2¾ m)

3.22- 3 ^ 8 (4¾ m) 3.63-3.87 (2¾ ra) 4.04-4.30 (2¾ m) 4.89 (2¾ s) 4.86-4.98 (1¾ m) 6 , 82-6.95 (1¾ m) 6.97-7.17 (1¾ ra)

7.22- 7.42 (5¾ m) 7.58 (1¾ t, J = 7 ^ Hz) 7.72 (1¾ d. J = 75Hz) 7.73-7.91 (2¾ m) 8.10-8, 23 (2¾ m) 8.36 (1¾ s)

DMSO-4,300 MHz

95-2.26 (4¾ m) 2.50-2.72 (2¾ ra)

3.08-3.32 (4H. M) 3.45-3.73 (2¾ m) 4.05-4.15 (2¾ ra) 4.85-5.08 (1¾ m) 6.60-6.72 (1¾ m) 6.95-7.08 (1H m) 7.48-7.68 (6¾ m)

7.72 (1¾ d. J = 7.9Hz) 7.80-7.94 (2¾ m) 8.08-8.16 (1¾ m)

8.18 (1¾ dd. J = 8.0Hz, 1 1Hz) 8.30 (1¾ brs)

440

FAB *

440

Table 17 • φ φ φ · · · · · · · φ φ φ · • • • φ φ φ φ · · · 'φ φ φ φ φ φ φ φ φ φ φ φ φ

Example

Compound (properties, yield from last step) @ 1 H NMR (d6) for DMSO-d6 MHz

MS

FAB *

(white powder,

100 mole%)

2.09-2.14 (2¾ ra) 2.39 (3H, s) 252-2.64 (2¾ ra) 3.28-3.50 (4¾ m) 3) 69-3.73 (2¾ m) 4.42-4.47 (2¾ ra) 4.85-4.94 (1¾ m) 6.75-6.81 (1¾ m) 6.98 (1¾ t, J = 6.3Hz) 7.37- 7.43 (4¾ m) 758 (1¾ t, J = 6.9Hz) 7.75 (1¾ d. J = 8.1Hz) 7.80-7.91 (2¾ m)

8.12-8.21 (2¾ m) 8.46 (1¾ brs)

11.18 (1¾ brs)

DMSO-d 300 MHz

440

FAB *

(white powder,

100 mole%)

2.02-2.18 (2¾ m) 2.50-2.70 (2¾ m) 3.25-3.52 (4¾ m) 3.65-3 / 75 (2¾ ra)

3.84 (3¾ s)

4.32-4 ^ 0 (2¾ m)

80-4.98 (1¾ m) 6.76-6.88 (1¾ m)

6.98 (1¾ t, J = 6.6Hz) 7.12-7.20 (2¾ m)

7 ^ 45 (2¾d, J = 8.7Hz)

7.56-7 68 (1¾ m)

7.74 (1¾ d, J = 7.2Hz) 7.78-7.96 (2¾ m)

8.09-8 13 (1¾ m)

8.19 (1¾ dd, J = 8.0Hz, 1.4Hz) 8.75 (1¾ brs)

456

DMSOA 300 MHz

FAB *

2.08-2.18 (2¾ m) 2.50-2.67 (2¾ m) 3.23-3.50 (4¾ m)

3.70- 3.80 (2¾ m) 4.38-4.48 (2¾ m) 4.83-4.98 (1¾ m) 6.87 (1¾ d, J = 8.7Hz) 6.98 (1¾ t) J = 6 3Hz) 7.47-7.53 (1¾ m) 7.60 (1¾ t. J = 7.5Hz)

7.71- 7.92 (5¾ m) 8.18- ^ 25 (2¾ m) 8.46 (1¾ bre) 1γΟ7 (1Η, brs)

494 (white powder,

100 1 molar)

9 · 44 44 • · · 4 4 · · 44 «4 4 4 * • 4 '4 4 • 4 4 · 4 4 4 · 4 4

44 ·· · 4 4 4

4 4 4 4 4

444 4,444 444

4 4

44 44

Table 18

- "- Příkla Compound (properties, yield from last step) 'H NMR ($) ppm MS DMSO-d 300 MHz FAB * 2.05-2 / 20 (2H, m) 440 Γ5 20-40 (3H, s) 2.50-2 _f 72 (2H, m) 3J-35714H. (m) T O 3 ^ 64-3 ^ 85 (2Η, m) 4.36 to 4.55 (2H, m) _f 4 80-5,00 (lH, jn) Nile II J 6.32 (1HA J «= 8.4Hz) 46 II and 2Ha T Me 6.74 (1H, d, J 7,2Hz) 7.35-7.70 (7 H, m) 7.75 (1H, d, J = 7.8Hz) N 7.80-7.95 (1H, m) 8.19 (1H, dd, J = 8.1Hz, 1.5Hz) 8.46 (111, bis) (white solid, 100 mole%) DMSO-d 300 MHz FAB * zCF ₃ 2.06-2.14 (2Η, tn) 494 Ex 2 _R5O-2.7O (2H, m) 3 I2-3.60 (3H, m), 3.62-3.82 (2H, m) Y 4.49 (2H, t, J = 6.9Hz) 4.80-5.0O (1H, m) 6 _f 81 (1H, d, J = 8.4Hz) 7.0O (1H, t, J = 6.6Hz) ů ΡΡΎ ✓χΑΥΥ Ν ' 47 7.61 (1 H, t, J = 7.2 Hz) 7.68-7.95 (8 H, m) 8.16-8.30 (2 H, ra) 8.53 (1 H, brs) Η ιΓ i ^2Ηα (white solid, 32 s molar) DMSO-d 300 MHz FAB * 2.02-2.18 (2 H, m) 444 2.50-2.70 <2H, m) Q · 3 _r 22-3.52 (4H, m) 3.65-3.8 (X 2 H, m) 4.40-4.50 (2H, m) 4.8O-4.98 (1H, ra) 6, 81 (1H, d, J = 8.7Hz) zvlJxJ 1 il i ^2Ha WY 6.97 (1H, t, J = 6.2 Hz) 48 7.21-7.46 (3 H, tn) 7.56-7.64 (2 H, m) 7.70-7.80 (2H, tn) N 7.83-7.92 (1H, m) 8.16-8.26 (2 H, m) 8.47 (1 H, brs) (white powder, 100 mole%)

φ φ φ φ e e e e e e e e e e e e e e e 5 5 5 5 5 5 5 5 5 5 5 5

Table 19

-r

Example

Compound yield (properties, final step) 1 H NMR (δ) ppm DMSO-d 6 MHz

MS

FAB ⁴

9¾

i (white powder,

100 mole%)

(white powder,

100 mole%)

Bílý (white powder,

100 * molar;

2.02-2.20 (2¾ m) 2.50-2.70 (2¾ m) 3.20-3.50 (4¾ m) 3.67-3-82 (2¾ ml 4 ^ 40-4.58 (2¾ m) 4.80-4.98 (1¾ m) 6.89 (1¾ d, J «8.4Hz) 7.00 (1¾ t. J = 6.3Hz) 736-7.94 (8¾ m) 8.19 (1¾ m, J = 6.6Hz) 8.26-8.36 (1¾ m> 8.47 (1¾ brs))

DMSO-ds 300 MHz

494

FAB ⁴

2.07-2.18 (2¾ m) 460

2.50-2.68 (2¾ m)

3.25-3.50 (4¾ m)

3.68-3.80 (2¾ m)

4 ^ 38-4.48

4.82-4 ^ 98 (1¾ m)

78 (1H, d, J = 9.3Hz)

6.97 (1¾t, J = 6.3Hz)

7.44-7.50 (2¾ rn)

735-7.65 (3¾ m)

7.70-7.80 (2¾ m)

7.88 (1¾t, J = 7.5Hz)

8.17-8.25 (2¾ m)

8.47 (1¾ bis)

11.06 (1¾ brs)

DMSO-ds 300 MHz 2.06-2.20 (2¾ m) 2.50-2.68 (2¾ m) 3.22-3.58 (4¾ m) 3.70-3.80 (2¾ m) 4.30-4 , 46 (2¾ m) 4.80-5.00 (1¾ m) 6.46-6.58 (1¾ m) 6.87-6.96 (1¾ m> 7.36-7.80 (7¾ m)) 7.84-7.93 (1¾ m) 8.17-8.27 (2¾ m) 8.45 (1¾ brs)

11 /) 9 (1¾ brs)

FAB ⁴

444 • 0 0 0 ee

Example / 26

Table 20

Compound (properties, yield from last step).

¹ H NMR (δ) ppm

MS

DMSO-de 300 MHz 2.09-233 (2¾ m) 2.52-2.71 (2¾ m) 3.18-3.59 (4¾ m) 3.66-3.85 (2¾ m) 4.20-4 ^ 45 (2¾ m) m) 4.77-5.00 (1¾ m) 6310¾ bis)

6.89 (1¾ t, J = 6.0Hz) 7.45-7.82 (7¾ m) 7.84-7.95 (1¾ m) 8.14-8.30 (2¾ ra) 8.46 (1¾ bre)

FAB ⁴

460 (white solid, 99%)

(white solid, 96%)

DMSO-de 300 MHz 2.05-2.15 (2¾ tn) 2150-2.70 (2¾ tn) 3.20-3.55 (4¾ m) 3.60-3.92 (2¾ tn) 4.40 -4.52 (2¾ m) 4.80-4.95 (1¾ tn) 6'.93 (1H, d J = 8.4Hz) 7.00 (1¾ t. J = 6.6Hz) 7.10-7 , 35 (3¾ tn) 7.60 (1¾ t, J = δ, 9Hz) 7.64-7.80 (2¾ tn) 7.86-7.94 (1¾ m) 8.19 (1¾ d, J = 7 ^ Hz) 8.23-8.33 (1¾ m) 8.40 (1¾ brs) 1103 (1¾ brs)! FAB *

Í462

Ha

DMSO-de 300 MHz 2.06-2.20 (2¾ tn) 2.50-2.70 (2¾ m)

3.20- 3.40 (4¾ tn) 3.65-3.78 (2¾ m)

4.20- 4.34 (2¾ tn) 4.78-4.95 (1¾ ra) 6.64-6.80 (3¾ ra) 7.16-7.26 (4¾ m)

7.41 (2¾t, J = 7.7Hz) 7/58 (1¾t, J = 7 ^ Hz) 7.72 (1¾d, J = 8.1Hz) 7.87 (1¾t, J = 6, 8Hz)

8.17 (1¾ dd, J = 7.8Hz, 0.9Hz) 8.39 (1¾ s)

11.28 (1¾ brs)

FAB ⁴

443

• white powder, even molar)

Hive

Table 21

Sloučen7 Compound (properties, Extract from last step) _ (ΓΎ

Y

2HCJ (white solid, 90%)

2Ha .OMe

(white solid, 90 mol%)

2HO

(white solid, 39 ¥ molar) 1 H NMR (s) ppra

DMSO-d6 300 MHz 2.02-2.20 (2H, m) 2.37 (3¾ s, 2.50-2.68 (2¾ m) 3.24-3.52 (4 «, m) 3, 64-3.82 (2¾ m) 4.32-4.44 (2¾ m) 4.75-4.94 (111, m) 6.62-6.71 (1¾ m) 6.92 (1¾ t. J = 6.6Hz) 7.20-7.3 1 (3¾ m) 7.46 (1¾ t. J = 7 ^ Hz) 7 ^ 9 (1H, t. J = 6.9Hz) 7.68-7 , 80 (2¾ m) 7.82-7.92 (1¾ ra) 8.12-8.22 (2¾ m) 8.40 (1¾ brs)

DMSO-d 300 MHz 2.05-2.20 (2¾ m) 2.50-2.71 (2¾ ra) 3.24-3.54 (4¾ m) 3.63-3.80 (2¾ m) 3.81 (3¾ s) 4.32-4.52 (2¾ m) 4.78-4.94 (1¾ m) 6.69-6.82 (1¾ m) 6.95 (1¾ t, J = 6 , 3Hz) 6.98-7.13 (3¾ m) 7.48 (1H, t, J = 8.1Hz) 7.59 (1¾ t. J = 7.8Hz) 7.68-7.81 (2¾ m) ). 7.88 (1¾ t, J = 6.6Hz) 8.11-8.24 (2¾ m) 8.41 (1¾ brs)

DMSO-dg 300 MHz 2.05-2.20 (2¾ m) 2.50-2.72 (2¾ m) 2.55 (3¾ s)

3.20- 3.57 (4¾ m) 3.62-3.86 (2¾ m) 4.35-4.52 (2¾ m) 4.80-4.98 (1¾ m) 6.72-6.90 ( 1¾ m) 6.98 (1¾ u J = 5.9Hz)

7.20- 7.38 (2¾ m) 7.40-7.51 (2¾ m) 7.59 (1H, q, 1 = 8.0Hz) 7.72 (1H, d, J = 3.7Hz) 7 , 68-7.81 (1¾ d) 8.02 (1¾ d, J = 7.0Hz) 8.23 (1¾ d, J = 5.5Hz) 8.38 (1¾ bis)

FAB *

440

FAB *

456

FAB ⁴

458 β β β β β e

Table 22

Příkle 'd Compound (properties, yield from last step) 1 H NMR (s) ppm MS DMSO-d 300 MHz FAB * 2.07-2.17 (2½ m) 461 2 ^ 52-2.65 (2½ m) 3.27-3.36 (4½ m) in 3.69 (2½. Brs) 430-4.32 (2½ m) 4.77-4.90 (1½ m) 6.82-7.04 (6½ m) 58 I i j u 734 (2½ q. 1 = 7.8Hz) 1 j * 7.58 (1½ t. 1 = 7.5Hz) 7.69-7.76 (1½ m) 7.82-7.91 (1½ m) 8.16-8.72 (1½ m) 836 (1H, «) (white powder, 95 mole%) 11.26 (1½ brs) DMSG-dc 300 MHz FAB ⁺ 2.00-2.46 (2½ m) 440 AND 2.49 (3½s) 2.50-2.66 (2½ m) 'Me 3.20-3.38 (2½ m) 3.42-3.56 (2½ m) «ΠΆ 3.64-3.80 (2½ m) 4.80-4.96 (1½ m) 6.90-7.00 (1½ m) 59 * ’* II I 2HCl 'rf? 732-7.92 (8½ m) 8.08-8.22 (2½ m) AND- N 8.44 <1H. brs) (white powder, 100 mole%) DMSO-4,300 MHz FAB ⁺ 2.06-2.18 (2½ m) 456 AND 2.50-2.68 (2½ m) 3.22-3.52 (4½ m) ιψι 'About me 3.66-3.78 (2½ m) 3.84 (3½s) 4.26-4.42 (2½ m) 4.82-4.96 (1½ s) and γ'-Ύ ^ Ύ phi 1 1 ll 6.90-7.00 (1½ m) 60 jf 1 “O 7.15 (1½ t. J = 7.5Hz) 730 (1½ d, J = 8.1Hz) 7 44-7.64 (3½ m) 7.72-7.92 (3½ m) 8.12-8.22 (2½ m) 8.42 (1½ brs) (white powder, 92 š molar) 11.12 (1½ brs)

eeee eeee ee 6 β fis

Example

413

Table 23

Compound (properties, yield from last step)

(light violet solid, 100 mol%)

(white amorphous, 40 mol%) H NMR (δ) ppm

DMSO-dj 300 MHz

2.02-2.10 (2¾ di) 2.20-2.36 (2¾ m) 3.18-3.64 (4¾ m)

Πηΐ ίχου mi · «« /

4.47 (2¾ t, J = 7.0Hz) 4.70-5.00 (1¾ ni). 7.04 (2¾t, J = 7.1Hz) II 7.20-7.40 (6¾m) ^X 7 ^ 58 (1¾t, J = 7.5Hz)

7.72 (1¾ d, J = 8.4Hz) 7.86 (1¾ t, J = 7.3Hz) 8.18 (1¾ d, 1 = 7.7Hz) 8.33 (1¾ s) 1 ^ 27 (1¾ brs)

CDCl3 300 MHz

1.65- 1.94 (4¾ m) 2.02-2.20 (2¾ m)

2.49 (2¾ t. J = 6.7Hz)

2.80- 2.98 (2¾ m) 3.05-3.18 (2¾ m) 3.22-3.35 (2¾ m)

3.41 (2¾ t, J = 6.7Hz) 4.24 (2¾ s)

4.70-4 88 (1¾ m)

6.80- 6.92 (1¾ m) 7.00-7.22 (6¾ m) 7.45-7.56 (1¾ m)

7.65- 7.80 (2¾ m)

8,10 (1¾ sec)

8.29 (1¾ dd, J = 8.0Hz, 1.0Hz)

DMSO-dg 300 MHz

MS

FAB *

455

FAB *

465

FAB *

2.08-2.20 (2¾ m) 2.50-2.70 (2¾ m) 3.23-3.52 (4¾ m) 3.62-3.86 (2¾ m) 4.47 (2¾ t) , J = 6.6Hz) 4.81- ^ 96 (1¾ m) 6.82 (1¾ d, J = 8.4Hz) 6.97 (1¾ t. J = 6.9Hz) 7.63 (1¾ t. J = 7.2Hz) 7.67-8.00 (5¾ ra) 8.12-8.24 (2¾ m) 8.26-8.32 (2¾ 111) 8.43 (1¾ brs)

471 (yellow solid, 92 mol%) e e β β β · e · e

Table 24 eeeeesee ··

430

Steep I Compound (properties, d yield from the last step) 1 H NMR (δ) ppm MS DMSO-d 300 MHz FAB * Xu 2.06-2.19 (2¾ m) 2 ^ 33-2.60 (2¾ m) 3.10-3.50 (4¾ m) 3.60-3.85 (2¾ m) 462 A TOZ ^ M »1—2 ....... , ΠΧί λ X Á 7 N_ 5,. · = Ί |: π2; 4.80-4.98 (1¾ m) 6.51 (1¾ d, J = 8.4Hz) 64 6.80- 6.92 (1¾ m) 734 (2¾t, J = 8.4Hz) 7.45-7.70 (3¾ m) 7.75 (1¾ d. J = 9.0Hz) 7.80- 7.92 (1¾ ώ) 1 I 2HO N 8.10-8.20 (2¾ m) 8.43 (1¾ brs) (white solid, 100 mole%) 11.10 (1¾ brs) DMSO-ds 300 MHz FAB * G; 2.04-232 (2¾ m) 2.49-2.68 (2¾ m) 3.22-3.53 (4¾ m) 3.64-3.84 (2¾ m) 4.36 (2¾t, J = 7.5Hz) 462 4.80-4.93 (1¾ m) 6.57 (1¾ d, J = 8.4Hz) 65 6.89 (1¾t, J = 5.1Hz) 7.30-7.68 (5¾ tn) 7.740¾ d, 3 = 7.8Hz) 7.81-7.92 (1¾ m) 1 u 1 ^2Ha 8.14-8.30 (2¾ m) 8.42 (1¾ brs) (white solid, 94%) • CDCl3 300 MHz FAB * Q-z 1.88-2.02 (4¾ tn) 2.22-2.38 (2¾ m) 2.70 (2¾ t, J = 7.2Hz) 3.02-3.14 (2¾ tn) 480 3,57 (3¾s) o X'- ¹ '^ ^xN > A 3.80-4.00 (2¾ m) 4.74-4.91 (1¾ m) 66 XUj o Oj 7.02-7.24 (6¾ tn) 7.32-7.42 (1¾ m) 7.44-7.58 (1¾ m) 7.68-7.80 (3¾ tn) 8.15 (1¾ s) 8.27-8.32 (1¾ m) (white amorphous substance, 80 mole%)

• • ς t t t t t t t t

Table 25

Ex Η Compound extracts (properties, last step) 1 H NMR (δ) ppm MS DMSO-df 300 MHz FAB * 2.05-2.38 (2¾ m) 451  CL · 2.42-2.78 (2¾ m) 3.30-3.98 (6¾ m) 4.50-5.50 (3¾ m) 7.41 (2H, t, J = 5.6 Hz) íi Γ 7.56-8.50 (10¾ m) 12.08 (1¾ tas) 67 F' J M Ha íž yellow solid substance, 100 mole%) DMSO-d * 300 MHz FAB * 2.08-2.26 (2¾ m) 439 2 ^ 50-2.70 (2¾ m) 3.14-3.46 (4¾ m) 3.70-3.89 (2¾ m) in 4.10-4 / 22 (2¾ m) O 4.75-4.92 (1¾ m) 6.55-6.80 (4¾ m) 68 J U 6.80-7.02 (4¾ m) 7,59 (1¾t, J = 8,1Hz) Pcs hq 7.73 (1¾ d, J = 8.1Hz) 7.84-7.92 (1¾ m) 8.20 (1¾ L, J = 8.1Hz) 8/35 (1¾ sec.) 11,40 (1¾ tas) (light yellow-white solid, 83 mole% 1) DMSO-d 300 MHz FAB * 1.50 (3¾s) 454 AND 2.04-2 ^ 2 (2¾ m) 2.29 (3¾s) .. .. 2 ^ 0-2.70 (2¾ m) Me Me 3.20-3.48 (4¾ m) γ ^ Λ 3 ^ 4-3.82 (2¾ m) 4.06-4.19 (2¾ tn) j AL j 4.76-5.00 (1¾ m) 69 6.85-696 (1¾ m) JU N 2Ha 7.00-7.09 (1¾ m) 7.11-7.26 (2¾ m) 7.28-7.39 (1¾ m) 7.50-7.76 (2¾ m) 7.74 (1¾ d. J = 8.1Hz) 7.82-7.95 (1¾ m) (bi j.3 Fixed XáfckS / o »r, r. '-J * mclarc (n) 8.20 (1¾ d. J = ^ 0Hz) 8.25-8.34 (1¾ m) 8.43 (1¾ brs)

• eeee sees ee ee ee ee

Table 26

Ex Compound (properties, yield from last step) 1 H NMR (δ) ppm MS DMSO-d 300 MHz FAB * 1.18 (3¾t, J = 7.2Hz) 454 2.04-2.20 (2¾ m) 2.40-2.68 (4¾ m) 3.22-3.62 (4¾ ra) 70 i - 'ϊ A> .sí) 5.S-3, S2 (2H, ra) 3.85- 4.80 (2¾ m) 4.80-4.94 (1¾ m) 6.86- 7.00 (1¾ m) 1 wa řsA N 732-7.68 (6¾ m) 7.73 (2H, d, J = 7.8 Hz) 7.82-7.91 (1¾ m) 8.11-8.24 (2¾ ra) 8.42 (1¾ brs) (white solid, S5 mole%) DMSO-d 300 MHz FAB * 2.04-2.19 (2¾ m) 458 íY 2.48-2.65 (2¾ m) 2,80 (3¾s) T 3.20-3.54 (4¾ m) 3.65-3.80 (2¾ m) 71 Me O AAhAJ I 1 ^2Ha 4.36-4.50 (2¾ m) 4.75-4.94 (1¾ m) 6.76 (1¾ d, J = 8.7Hz) 6.94 (1¾ t. J = 6.0Hz) 7.12-7.45 (4¾ ra) 7.52-7.62 (2¾ m) 7.66-7.78 (2¾ m) 8.22-8.29 (1¾ m) 8.49 (1 H, brs) (white solid, 100 mole%) CDCl3 300 MHz FAB * 0.89 (3¾t, J = 7.5Hz) 1.52-1.64 (2¾ m) 468 iř ^ l 1.85-2.00 (4¾ m) 2.20-2.35 (2¾ m) 2.47 (2¾t, J = 7.8Hz) 72 ^ λΧΤ '-' Ό 2.75 (2¾t, J = 7.2Hz) 3.14 (2¾ d. J = 11.7Hz) 3.70 (1¾ brs) 4.40 (1¾ brs) UnZ 4.80-4.95 (1¾ m) 5.94 (1¾ d. J = 9.0Hz) 634 (1H, dd, J = 6.3, 5.1 Hz) 7.18-7.39 (5¾ m) 7.45-7.52 (1¾ m) (colorless crystals, 7 68-7.78 (2¾ m) 73 š molar) 8.12 (1¾ s) 8.18 (1¾ d. J = 5.1Hz) 8.31 (1¾ d, J = 7.8Hz)

• • ee eeee

Example •> e ··

Table 27

Compound (properties, yield from last step)

(white solid, 60 mol%)

(takes amorphous substance, 61 i molar)

(white crystals, 47 mol%) 1 H NMR (d 6) ppm

CDCl3 300 MHz

1.55 (3¾s)

-57 (3H, s) θθθ-7 1-ΪΜΗ ml

-i --- 1 ' ^- ' - '

2 / L 2 _f-45 (2H, m)

2.86 (2¾ t, J = 7.7Hz) 3.16-3 / 7 (2¾ m)

4.17 (2¾t, J = 7.0Hz) 4.82-5.00 (111, m)

6.980¾ t, J = 7 _ø 7Hz) 7.03 (1¾ d. J = 8 1Hz) 7.18-7 / 7 (1H, -m)

7.42 (1¾ dd. J = 7.7Hz, 1 / Hz) 7.48-7.56 (1¾ m) ¹ 7.67-7.81 (1¾ m)

8.17 (1¾ s)

30-8.38 (1H, brs)

_CDCl3 300 MHz 1.86 to 2.02 (4¾ m), 2.23-2.38 (m 2¾)

2,30 (3¾s)

2.71 (2¾ t, J = 7 / Hz) 3.04-3.15 (2¾ m)

3.89 (2¾ t, J = 7.8Hz) 4.78-4.94 (1¾ m) 6.75-6.85 (3¾ m)

6.94 (1¾t, J = 7.5Hz) 7.00 (2¾d. J = 7.5Hz) 7.17 (1¾t, J = 7.5Hz) 7.20-7.32 (2¾m) 7 , 40-7 / 8 (1¾ m) 7.65-7.82 (2¾ m)

8.14 (1¾ s)

8.31 (1¾ dd. J = 8.1Hz, 1.5Hz)

CDCl3 300 MHz 1 70-1.88 (2¾ m) 1.96-2.24 (4¾ m) 2.50-2.68 (2¾ m) 2.70-2.96 (2¾ m)

3.34 (1¾ dd, J = 17.3Hz, 3.8Hz) 3.51 (1¾ dd, J = 17AHz, 3.8Hz)

3.76- 3.88 (1¾ m)

92-4.06 (1¾ m)

4.76- 4.96 (2H, m)

6.22 (1¾ bis)

6.85-6.96 (1¾ m) 7.00-7.32 (7¾ m) 7.43-7.54 (1¾ m) 7.65-7.78 (2¾ m) 8.24-8.36 ( 2¾ m)

MS

FAB *

465

FAB *

439

FAB *

467

Table 28

134

1 Compound (properties, ¹ H NMR (δ) ppm MS Příkla H yield from last step) CDCl3 400 MHz FAB * 1.87-2.03 (4¾ m) 2.15-2.29 (2¾ m) 467 Q 2.60 (2H, t, J = 5 Hz) 2.98-3.18 (6¾ m) 3.89 (2¾ t, J = 5.4Hz) ťx OH 4.80-4.92 (1¾ m) 6.52 (1¾dd, J = 6.4Hz, 2.2Hz) 76 6 ^ 64 (1¾ d. Ί = 2.2Ηζ) 6.71 (1¾ brs) 6.84-6.90 (1¾ m) 6.93 (1¾ d, J = 6.5Hz) 7.02-7 .14 (3¾ m) 7.46-7.53 (1¾ tn) 7.67-7.78 (2¾ m) (white amorphous substance, 96%) 8.14 (1¾ s) 8.56 (1¾ dd, J = 6.0Hz, 1.0Hz)

The following are test results for the MTP inhibitory activity of the compounds of the present invention. The following test examples were performed according to Chemistry and Physics of Lipids, 38, 205-222 (1985).

Test Example 1

Effect (in vitro) on the secretion of apolipoprotein Β (Apo B) from human hepatoma cells (HepG2 cells)

HepG2 cells were seeded in 48 or 96 well plates and grown for several days. The culture medium was replaced with DMEM culture medium supplemented with 1.5% bovine serum albumin expressed as a percentage by weight. After 24 hours, the culture medium was replaced with DMEM culture medium supplemented with 1.5% bovine serum albumin expressed as a percentage by weight and 0.8 mM sodium oleate as the test medium. Each of the test compounds was dissolved in dimethylsulfoxide and added to the assay medium to give a final dimethylsulfoxide concentration of 1% by weight. After 5 hours, the culture medium was removed and the Apo B content in ·

4 culture medium was measured by a sandwich ELISA method. The results are shown in Tables 29 and 30.

135

Test Example 2

Influence (in vitro) on triglyceride (TG) transfer between liposomes of small unilamellar vesicles (SUV)

SUV liposomes composed of triolein, [ ¹⁴ C] triolein, phosphatidylcholine (PC) and cardiolipin were prepared as donors, while SUV liposomes composed of triolein, PC and [ ³ H] PC were prepared as acceptors. Donors and acceptors were mixed at a ratio of 1: 5. A dimethylsulfoxide solution of test compounds was added to the assay buffer, adjusted to a final dimethylsulfoxide concentration of 1% by weight, MTP purified from the bovine liver microsomal fraction, and a donor and acceptor mixture. The assay buffer was then incubated for 1 hour at 37 ° C and diethylaminomethylcellulose (DEAE-cellulose) suspension was added. The buffer was shaken for 4 minutes and centrifuged to separate the supernatant. Residual [ ¹⁴ C] triolein in the supernatant was measured by a liquid scintillation counter. This [ ¹⁴ C] triolein count was counted as the TG transfer activity of MTP and the inhibitory activities of the test compounds were calculated. The results are shown in Tables 29 and 30.

Test Example 3

Effect (in. Vitro) on TG increase after oral administration of olive oil

Olive oil was orally administered to 10 to 11 weeks old Syrian hamsters at a dose of 2 ml / kg and blood was collected after 4 hours. Blood was collected from the coronary artery under mild anesthesia with ether using a heparin-impregnated glass capillary at 100 μΙ / head at a time. Test compounds ·· ··

136 'were dissolved or suspended in 0.5% methylcellulose and expressed orally 30 minutes prior to the administration of the olive oil. The collected blood was immediately cooled with ice and the plasma was collected by centrifugation at 12,000 rpm for 5 minutes. Plasma TG was measured using a measurement kit and an automatic blood analyzer. ...

The results are shown in Tables 29 and 30.

Test Example 4

Effect (in vivo) on hepatic TG exit rate (TGOR) on administration of Triton WR-1339

Ten or eleven weeks old Syrian hamsters were used after 24 hours of starvation. (Water was administered as desired.) Under mild ether anesthesia, Triton WR-1339 at 400 mg / kg was administered by penile blood vessel and blood was collected at time 0 (before administration), 1 hour, 2 hours and 3 hours after administration. Blood was collected from the coronary artery under mild anesthesia with ether using a heparin-impregnated glass capillary in an amount of 100 μΙ / piece to 250 μΙ / piece at a time. Test compounds were dissolved or suspended in 0.5% methylcellulose expressed as a percentage by weight and administered orally 30 minutes prior to administration of Triton WR-1339. The collected blood was immediately cooled with ice and the plasma was collected by centrifugation at 12,000 rpm for 5 minutes. Plasma TG was measured using a measurement kit and an automatic blood analyzer. TGOR was calculated from changes in the time course of plasma TG values for each test compound.

The results are shown in Tables 29 and 30.

9 9 9 9 9 9 9 9

137

Table 29 Test Example

Example in vitro, IC ₅₀ (μΜ) in vivo (mg / kg) Inhibition excretion of Apo B Inhibition of TG transmission Inhibition of TG increase Inhibition hepatic TGOR 1 0.1 0, 6 10 3 0.7 0, 6 4 0.7 O 00 5 0.7 0.1 7 0, 03 0.1 10 8 0, 03 0.1 3 10 0.2 0.2 11 0, 2 0, 6 12 0, 08 0.07 13 0, 03 0, 06 10 14 0.2 0, 2 16 0, 3 0, 5 17 0, 05 0, 06 10 18 0, 09 0, 2 10 19 Dec 0, 04 0.1 10 22nd 0, 3 0, 6 23 0.3 0, 5 10 24 0.1 0.2 25 0, 6 0.2 30 0.4 0.9 34 0, 1 0, 02 3 10 35 0, 2 0, 02 10

0 0 0 e β 0

000

138

0000 0000

Table 30 Test Example

Example in vitro, IC ₅₀ (μΜ) in vivo (mg / kg) Inhibition excretion of Apo B Inhibition of TG transmission Inhibition of TG increase Inhibition hepatic TGOR 36 0, 07 0.02 3 30 39 0.2 0.2 30 40 0.2 0, 8 42 0, 03 0, 04 48 0, 04 0.2 10 30 50 0, 07 0, 3 30 51 0, 03 0.3 52 0, 03 0.1 10 53 0, 3 0, 6 54 0.2 0.3 30 55 0, 3 0.2 30 56 0, 2 0.1 30 · 59, 0, 03 0, 07 60 0, 2 0.2 64 0, 03 0, 2 30 65 0.03 0.1 30 66 0, 3 69 0, 5 0, 5 70 0, 03 0, 06 72 0.02 0, 03 10 73 0.4 0.2 75 0, 3

Industrial applicability

Test examples show that the compounds of formula (I) of the present invention have excellent MTP inhibitory activity. The compounds also reduce HDL. Thus, these compounds not only inhibit the development of LDL, which is the cause of arteriosclerotic diseases, but also reduce TG, cholesterol, and lipoproteins, such as LDL, in the blood and regulate the blood. ΦΦ · ♦ φ φ φ φ φ φ φ φ

ΦΦ ΦΦ • φ · φ • φ • · φ φ

139 cell lipids via regulation of MTP activity. They can also be used as a new type of preventive or therapeutic agent for hyperlipemia or arteriosclerotic disease. In addition, they can be used as preventive or therapeutic agents for pancreatitis, obesity, hypercholesterolemia, and hypertriglyceridemia.

Claims (13)

PATENT CLAIMS 1. A 3-piperidyl-4-oxoquinazoline derivative of the general formula (I): wherein R is a radical of formula (II): Rt —N R ₂ (II) wherein R _x and R ₂ are identical or different and represent hydrogen, lower alkyl having 1 to 4 carbon atoms, an aralkyl group, a benzoyl group, a cycloalkyl having 3 to 7 carbon atoms, aryl or heteroaryl containing 1-3 heteroatoms selected from nitrogen, sulfur and oxygen (wherein the cycloalkyl, aryl or heteroaryl is substituted with 1 to 3 substituents selected from halo, lower alkyl of 1 to 4 carbon atoms, lower haloalkyl of 1 to 4 carbon atoms, nitro, lower alkoxy of 1 to 4 carbon atoms, amino, amino substituted with lower alkyl having 1-4 carbon atoms, hydroxy, phenoxy and sulfo groups), provided that one of _R 'and R ₂ is not hydrogen, »« - φφ' φφ 'φ » • · • e e e e e e>>>>>>>>> · · · · · 141 • φφ φ φ · • φ «C φ «Φ ···· or formula (III): (III) wherein A and B are the same or different and are an aromatic hydrocarbon ring, an aromatic heterocyclic ring containing 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen, a cycloalkane ring of 3 to 7 carbon atoms or a cycloalkene ring of 5 up to 7 carbon atoms (wherein the aromatic hydrocarbon, aromatic heterocyclic, cycloalkane or cycloalkene ring is substituted with 1 to 3 substituents selected from halo, lower alkyl of 1 to 4 carbon atoms, lower haloalkyl of 1 to 4 carbon atoms, hydroxyl, nitro, lower alkoxy having 1 to 4 carbon atoms, amino, amino substituted with lower alkyl having 1 to 4 carbon atoms and sulfo), X is a single bond, straight chain alkylene or branched alkylene having 1 to 4 carbon atoms, lower alkenylene with straight chained or branched C 2 -C 4 alkenylene (wherein the lower alkylene or lower alkenylene includes substituent (s) selected from halogen, hydroxyl, nitro, lower alkoxy of 1 to 4 carbon atoms, amino and sulfo), oxygen, sulfur, imino, is substituted with lower alkyl of 1 to 4 carbon atoms, carbonyl, -Ο-Z-, -Z-Ο-, -SZ-, -ZS-, -NH-Z-, -NR ₅ -Z-, -Z- NH-, or -Z-NR ₅ - (where Z is lower alkylene 11 tttt> tttt tttt tttt tttt tttt. • tt · tt tt _e e tt tt tt tt tt tt tt tt tt tt tt tt tt tt tt tt · - - · · * 142 (having 1 to 4 carbon atoms or carbonyl and R ₅ is lower alkyl having 1 to 4 carbon atoms), Y is a single bond, straight-chain alkylene or branched alkylene having 1 to 4 carbon atoms or carbonyl, n is an integer 1 to 4 and R ₃ to R ₄ are the same or different and represent hydrogen, lower alkyl of 1 to 4 carbon atoms, halogen, lower haloalkyl of 1 to 4 carbon atoms, hydroxyl, amino or nitro, or its a pharmaceutically acceptable salt. A 3-piperidyl-4-oxoquinazoline derivative according to claim 1, wherein R is a group of formula (IV): Ri '—N R a '(IV) wherein R 1 and R' ₂ are the same or different and represent cycloalkyl of 3 to 7 carbon atoms, aryl or heteroaryl containing 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen (wherein cycloalkyl, aryl or heteroaryl is substituted with 1 to 3 substituents selected from halogen, lower alkyl of 1 to 4 carbon atoms, lower haloalkyl of 1 to 4 carbon atoms, nitro, lower alkoxy of 1 to 4 carbon atoms, amino, amino substituted with lower alkyl of 1 up to 4 carbon atoms, hydroxyl and sulfo groups) or a group of formula (V): (IN) 99 99 '9 * 9' 9 9 9 9 9 9 .9 99'9,999 9 9 '9 9 9' 9 143 99 · * ^ ** '- * _Λ ** _Α 9 · · '* 9 · _{9 e} · ₉ - .¼ · 9 ·.. · Where A 'and B' are the same or different and are an aromatic hydrocarbon ring, an aromatic heterocyclic ring containing 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen, a cycloalkane ring of 3 to 7 carbon atoms or a cycloalkene ring of 5 to 7 carbon atoms (wherein the aromatic hydrocarbon, aromatic heterocyclic, cycloalkane or cycloalkene ring is substituted with 1 to 3 substituents selected from halogen, lower alkyl of 1 to 4 carbon atoms, lower haloalkyl of 1 to 4 carbon atoms, hydroxyl, nitro, lower alkoxy of 1 to 4 carbon atoms, amino, amino substituted by lower alkyl of 1 to 4 carbon atoms and sulfo), X 'is a single bond, straight chain or branched alkylene of 1 to 4 carbon atoms; straight chain or branched alkenylene of 2 to 4 carbon atoms (wherein lower alkylene or lower alkenylene include substituent (s) selected from halogen, hydroxyl, nitro, lower alkoxy of 1 to 4 carbon atoms, amino and sulfo), oxygen, sulfur , amino substituted by lower alkyl of 1 to 4 carbon atoms, carbonyl, -O-Z'-, -Ζ'-O-, -S-Z'-, -Ζ'-S-, -NH-Z '-, -NR ₅ '-Z'-, -Z'-NH- or -Z'-NR ₅ ' - (wherein Z 'is a lower alkylene group consisting of 1 to 4 carbon atoms or carbonyl and R ₅ ' is lower alkyl consisting of (1 to 4 carbon atoms), Y 'is a single bond, straight chain or branched alkylene of 1 to 4 carbon atoms or carbonyl, R ₃ to R ₄ are the same or different and represent hydrogen or lower alkyl of 1 to 4 or a pharmaceutically acceptable salt thereof. A 3-piperidyl-4-oxoquinazoline derivative according to wherein R represents a group of the general formula (VI): Claim 2 144 (VI) wherein R 1 and R ₂ are the same or different and represent a cycloalkyl of 3 to 7 carbon atoms, aryl or heteroaryl containing 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen (wherein the cycloalkyl, aryl or heteroaryl is substituted 1 to 3 substituents selected from halogen, lower alkyl of 1 to 4 carbon atoms, lower haloalkyl of 1 to 4 carbon atoms, nitro, lower alkoxy of 1 to 4 carbon atoms and hydroxyl) or a group of formula (VII) : NX '(VII) wherein A and B are the same or different and are an aromatic hydrocarbon ring or an aromatic heterocyclic ring containing 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen (wherein the aromatic hydrocarbon or aromatic heterocyclic ring is substituted with 1 to 3 substituents selected from halogen, lower alkyl of 1 to 4 carbon atoms, lower haloalkyl of 1 to 4 carbon atoms, nitro, lower alkoxy of 1 to 4 carbon atoms and hydroxyl), X is a single bond, straight chain or branched alkylene C 1 -C 4 alkylene, straight-chain lower alkenylene or branched C 2 -C 4 alkenylene (where lower 0 0 0 0 0 0 * 0 0 0 0 0 0 0 0 0 0 0 0 0 00 00 • 0 00 145 o; © t® '* 0 «0« »• 00 0000 1 alkylene or lower alkenylene includes substituent (s) selected from halogen, hydroxyl and lower alkoxy of 1 to 4 carbon atoms), oxygen, sulfur, imino which is substituted with lower alkyl of 1 to 4 carbon atoms, carbonyl, -OZ-, -SZ-, -NH-Z- or -Z- -NR ₅ (wherein Z is a lower alkylene group having 1 to 4 carbon atoms or carbonyl, and R ₅ is lower alkyl having 1 to 4 carbon atoms), and R ₃ and R ₄ are hydrogen or a pharmaceutically acceptable salt thereof. A 3-piperidyl-4-oxoquinazoline derivative according to claim 3, wherein R is a group of formula (VI), wherein R 1 and R ₂ are the same or different and represent a cycloalkyl of 3 to 7 carbon atoms, aryl, heteroaryl containing 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen (wherein the cycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 3 substituents selected from halogen, lower alkyl consisting of 1 to 4 carbon atoms, lower haloalkyl of 1 to 4 carbon atoms , nitro, lower alkoxy of 1 to 4 carbon atoms and hydroxyl), or a pharmaceutically acceptable salt thereof. A 3-piperidyl-4-oxoquinazoline derivative according to claim 4, wherein R 6 and cyclohexyl, pyridazinyl, R ₂ 1 are phenyl, thienyl, said groups being the same or different pyridyl, pirazinyl, furyl or pyrrolyl substituted with 1 to and represent pyrimidinyl, (wherein each of the 3 substituents selected from halo, lower alkyl of 1 to 4 carbon atoms, lower haloalkyl consisting of (1-4 carbon atoms, nitro, lower alkoxy consisting of 1-4 carbon atoms and hydroxyl), or a pharmaceutically acceptable salt thereof. The 3-piperidyl-4-oxoquinazoline derivative according to claim 5, wherein R is diphenylamine, N-phenyl-N-thienyl, N-phenyl-N-pyridylamine, dipyridylamine, N-phenyl-N-pyrimidylamine (wherein each of said groups). is substituted with 1 to 3 selected from halogen, lower alkyl of 1 to 4 carbon atoms, lower haloalkyl of 1 to 4 carbon atoms, nitro, lower 146 · ** «** ** ** ** ** ** ** ** ** ** ** ** substitu substitu substitu substitu substitu substitu substitu substitu substitu substitu substitu substitu substitu substitu alkoxy of 1 to 4 carbon atoms and hydroxyl), or a pharmaceutically acceptable salt thereof. A 3-piperidyl-4-oxoquinazoline derivative according to claim 3, wherein R is a group of formula (V) wherein A and B are the same or different and represent an aromatic hydrocarbon ring or an aromatic heterocyclic ring containing 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen (wherein the aromatic hydrocarbon or aromatic heterocyclic ring is optionally substituted with 1 to 3 substituents selected from halo, lower alkyl of 1 to 4 carbon atoms, lower haloalkyl of 1 to 4 carbon atoms, nitro, lower alkoxy of 1 to 4 X is a single bond, straight chain or branched alkylene of 1 to 4 carbon atoms, lower straight chain alkenylene or branched alkenylene of 2 to 4 carbon atoms (wherein lower alkylene or lower alkenylene include substituent (s) selected from halogen, hydroxy (1-6 and lower alkoxy of 1 to 4 carbon atoms), oxygen, sulfur, imino which is substituted with lower alkyl of 1 to 4 carbon atoms, carbonyl, -O-Z-, -SZ-, -NH-Z- or -NR ₅ -Z- (wherein Z is lower alkylene of 1 to 4 carbon atoms or carbonyl and R ₅ is lower alkyl of 1 to 4 carbon atoms), or a pharmaceutically acceptable salt thereof. The 3-piperidyl-4-oxoquinazoline derivative according to claim 7, wherein A and B are the same or different and represent benzene, pyridine, pyrazine, pyrimidine or pyridazine (wherein each of said rings is substituted with 1 to 3 substituents selected from halogen, lower). alkyl of 1 to 4 carbon atoms, lower haloalkyl of 1 to 4 carbon atoms, nitro, lower alkoxy of 1 to 4 H (carbon and hydroxyl), or a pharmaceutically acceptable salt thereof 147 φ · φ · · · φ φ φ * »* • φ 'salt. The 3-piperidyl-4-oxoquinazoline derivative according to claim 8, wherein R is carbazol-9-yl, phenoxazin-10-yl phenothiazin-10-yl, acridin-10-yl, 9,9-dimethylacridan-10-yl, 10,11-dihydro-5H-dibenzo [b, f] azepin-5-yl, 10,11-dihydro-2-hyd- 10, ii-dihydro-10-hydroxy-o, 5H-dibenzo [b, f] azepin-5-yl, 5,11-dihydrodibenzo [b, e] [1,4] oxazepin-5-yl, 10,11-dihydro-11-oxo-5H-dibenzo [b, e] [1,4] disepepin-5-yl, 11-hydro-10-methyl-11-oxo-5H-dibenzo [b, e] [1,4] disepepin-5-yl, or a pharmaceutically acceptable salt thereof. The 3-piperidyl-4-oxoquinazoline derivative according to claim 3, which is selected from the group consisting of 3- [1- [2- [N- (2-methylphenyl) -N-phenylamino] ethyl] piperidin-4-yl]. -3H-quinazolin-4-one, 3- [1- [2- (10,11-dihydro-5H-dibenzo [b, f] -azepin-5-yl) ethyl] piperidin-4-yl] -3H- quinazolin-4-one, 3- [1- [2- (10,11-Dihydro-10-hydroxy-5H-dibenzo [b, f] azepin-5-yl) ethyl] piperidin-4-yl] -3H-quinazolin-4-one, 3- [1- [2- (10,11-Dihydro-2-hydroxy-5H-dibenzo [b, f] azepin-5-yl) ethyl] piperidin-4-yl] -3H-quinazolin-4-one, 3- [1- [2- (5,11-dihydrodibenzo [b, e] [1,4] oxazepin-5-yl) ethyl] piperidin-4-yl] -3H-quinazolin-4-one, or a pharmaceutically acceptable salt thereof acceptable salt. A pharmaceutical composition comprising the 3-piperidyl-4-oxoquinazoline derivative according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, as an active ingredient. A microsomal triglyceride transfer protein (MTP) inhibitor comprising the 3-piperidyl-4-oxoquinazoline derivative according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, as an active ingredient. 13. A therapeutic or preventive agent for hyperlipaemia or arteriosclerosis, characterized in that: • Φ Φ • •• Φ ΦΦΦ Φ 9 99 ΦΦ ΦΦ 99 9 4 4 • 99 99 99 ·· • Φ Φ Φ 4 4 4 · 9 9 99 4 4 4 4 49 44 148 comprises the 3-piperidyl-4-oxoquinazoline derivative according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, as an active ingredient.