WO1997003986A1 - Fused triazole compounds - Google Patents

Fused triazole compounds Download PDF

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WO1997003986A1
WO1997003986A1 PCT/JP1996/002004 JP9602004W WO9703986A1 WO 1997003986 A1 WO1997003986 A1 WO 1997003986A1 JP 9602004 W JP9602004 W JP 9602004W WO 9703986 A1 WO9703986 A1 WO 9703986A1
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obtained
dihydro
example
echiru
le
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PCT/JP1996/002004
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French (fr)
Japanese (ja)
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Hiroshi Tanaka
Takanobu Kuroita
Seigo Ishibuchi
Hiroyuki Ushio
Takashi Futamura
Yoshitaka Ohashi
Kazuhiro Yano
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Yoshitomi Pharmaceutical Industries, Ltd.
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D498/00Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04Ortho-condensed systems

Abstract

Fused triazole compounds represented by general formula (1), optical isomers thereof, pharmaceutically acceptable salts thereof, medicinal compositions comprising the same, and radioactive fused triazole optical isomers thereof and salts thereof, wherein each symbol is as defined in the specification. The fused triazole compounds, optical isomers thereof or pharmaceutically acceptable salts thereof are D4 receptor antagonists having a selective and potent blocking effect on the D4 receptor. Thus, they are a useful antipsychotic agent which is efficacious against not only positive symptoms typified by hallucination, delusion, etc., characteristic to the acute state of schizophrenia but also negative symptoms such as apathy, autism, etc. Also, they are expected as an antipsychotic agent with relieved side effects, for example, extrapyramidal symptoms and endocrine abnormalities accompanying the administration of conventional antipsychotic agents having D2 receptor antagonism. Thus the compounds are usable as a remedy for diseases such as schizophrenia. Further, the radioactive fused triazole compounds are useful as a radioligand having an affinity for the human or animal D4 receptor.

Description

Specification

Condensation triazole compound

Technical field

The present invention is dopamine D 4 (hereinafter, also dopamine receptor subtypes described that. After D 4 pursuant to this approximately normal.) Novel fused tri Azoru compounds with affinity for the receptor and to a radioactive substance. D 4 receptor blockers central dosage used in the medical field in particular as antipsychotic agents.

BACKGROUND

D 4 about the central dosage having affinity for receptors, for example, patent applications as follows have been published. International Patent Application Publication WO 9 4 1 0 1 6 2 No., WO 9 4 2 1 6 3 0 No., WO 9 4Z2 1 6.2 The No. 6, tricyclic heteroaromatic compounds with affinity for D 4 receptor s is disclosed in International Patent application Publication WO 9 4/2 1 6 2 7 No., WO 9 4/2 1 6 2 8 No., the W09 4 2 4 1 0 5 No., the affinity D 4 receptor such indole derivatives having is disclosed in International Patent application Publication WO 9 4/2 0 4 5 9 No., the "WO 94Z20 4 9 7 No., etc. Piropirijin derivatives having affinity for D 4 receptor is disclosed, International Patent Publication WO 9 4/2 1 6 1 5 No., the WO 9 4 2 2 8 3 No. 9, etc. benzimidate da Boolean derivatives having affinity for D 4 receptor have been disclosed. Further, International Patent Publication WO 9 4/1 0 1 4 5 No., the WO 9 4/2 0 4 7 1 No. and pyrazole derivatives Contact and quinolone derivatives having affinity for D 4 receptors, respectively is disclosed.

Antipsychotics to schizophrenia adaptive diseases, the most have a common pharmacological action of receptor blockade of dopamine which is one of the brain neurotransmitter, particularly potent D 2 receptors blocking action shows. These drugs (typical antipsychotic agents), characteristic hallucinations acute phase of schizophrenia, delusional shown but the efficacy against positive symptoms centering on, apathy and inaction, autism, etc. the negative symptoms has been pointed out that show little effect. Further, 維体 outside tract symptoms expressed when acute administration and long-term use (tardive Jisukinejia, acute dystonia, etc. Akashijia) and endocrine abnormalities /

Side effects such as (hyperprolactinemia, etc.) has become a serious problem.

Dopamine receptor, the nature of conventional pharmacological approaches ligand binding by, be classified into two receptor subtypes from association form of the adenylate cyclase one peptidase has been recognized et al [Neichiya (Na ture) first 227, pp. 93 pp. (1 979)]. Ie, D to produce cyclin click AMP by activating adenylyl two Le cyclase via stimulatory G proteins, and receptor types, via the inhibitory G protein to suppress adenylate cyclase Ichize, rhinoceros inhibit the production of click AMP is a D 2 receptor type. However, with the recent molecular revolutionary development, dopamine receptors are five different genes are cloned, D belonging to the family,, D 5 receptor and body, D 2 belonging to the D 2 family, D 3, D 4 is it is clearly an ivy classified as receptor [Trends. in. Pharmacol logical Saienshizu (Tr end sin Pha rma col Sc i.) a first Volume 5, 264 pp. (1 994)].

The Haroperi Dole a typical antipsychotic exhibits a high affinity to D 2 receptors than D 4 receptor, the effective clozapine also less negative symptoms extrapyramidal side effects D 2 receptors than D 4 receptor 1 0-fold has been reported to exhibit high affinity [Neichiya foremost (Na ture) # 350 Volume 6 1 0 page (1 99 1), Trends Inn 'file one Makorojikaru Sciences (T rendsin Pha rma col Sc i.) a first Volume 5, 264 pp. (1 994)]. Moreover, effective therapeutic plasma concentration of clozapine D 4 have been reported to correlate with the affinity constant of the receptor [Torre lens Inn 'Pharmacol logical Saienshizu (Tr en dsin

Pha rma col Sc i. :) The first five volumes, 264 pages (1 994)]. Further, results of the binding studies with spirit postmortem brains of schizophrenic patients, D 4 receptor is also reported that even had a six-fold increase compared to normal subjects [Neichiya (Na ture) Vol. 365, 44 1 page (1 993)]. Therefore, it is highly possible that D 4 receptors are involved in the action site of the pathogenesis of schizophrenia or jig Ryoyaku. Moreover, the difference is recognized between subtypes in the brain distribution of dopamine receptors, D 2 receptors for most multi Ino in striatum, D 4 receptors in the cerebral cortex frontal lobe which governs the emotional function most often there it is obviously summer. From these, it can be expected as a selective D 4 receptor en evening antagonistic strike維体out path side effects less positive and negative symptoms in effective antipsychotics. Although the appearance of radioactive substances to target D 4 receptors also to elucidate the relationship between the pathogenesis of diseases such as D 4 receptor and schizophrenia are desired, such materials ever It is not known.

Disclosure of the Invention

The present invention, D 4 selective and show a strong blocking action on receptors, are more effective against negative symptoms and positive symptoms as compared to conventional compound, and D 4 provide less side effects compounds and to provide radioactive substance having a selective affinity to receptor (La Jiorigando).

The present inventors have result of intensive studies, novel condensed triazole compound represented by the following general formula (1), acceptable salts optical isomers or its pharmaceutically is, D 4 receptor than D 2 receptors found to have selective and strong blocking action on the body, to be et al, not only the compound (1) is the acute phase JP 徵的 hallucinations, delusions, etc. only the central and the positive disease wipe, apathy and inaction one way to be effective against negative symptoms, such as autism, conventional antipsychotics side effects such as extrapyramidal symptoms and endocrine abnormalities seen when administered with D 2 receptor antagonism柽減and heading the resulting Rukoto be a useful anti-psychotic drugs that are, and have completed the present invention.

That is, the present invention fused Toriazo Ichiru compounds shown below, pharmaceutical compositions and uses thereof that contains it.

① the general formula (1)

(1)

In indicates Chiofuwen or benzene represented,

R 1 and R 2 may be the same or different, are each hydrogen, halogen, Shiano, nitro, Amino, Ashiruamino force Rubamoiru, alkyl force Rubamoiru, alkoxycarbonyl, Ashiru, Arukiruamino, aminoalkyl, Arukirua aminoalkyl, hydroxy, Ashiruokishi , hydroxyalkyl, Ashiruokishi alkyl, alkoxyalkyl, indicates an alkyl, alkenyl, alkynyl, an alkoxy, alkylthio, an alkylsulfinyl or alkylsulfonyl,

W is methylene, sulfur atom, SO, S 0 2, an oxygen atom or N-R 3 (wherein, R 3 is hydrogen, alkyl, Fuenashiru or an optionally substituted § reel alkyl or heteroalkyl § reel alkyl, are shown.) shows,

X represents a methylene, ethylene or vinylene,

Y is absent or indicates a straight or branched TECHNICAL chain § Le Killen chain having 8 carbon atoms of 1,

Z one NH 2, - NH R 4 (wherein, R 4 is alkyl, cycloalkyl, which may have a substituent § reel alkyl, hetero § reel alkyl to heteroalkyl § reel alkyl or fused, or a substituent may have Ariru, Heteroariru if Ku denotes a heteroaryl fused.), one N (R 4) (R 5 ) ( wherein, R 5 may have Al kill, cycloalkyl, substituents § reel alkyl, Heteroari Ruarukiru or terrorist § reel alkyl to condensation or an optionally substituted Ariru, showed Teroariru to Heteroariru or fused, synonym and R 4 above.), or formula (a), (b cyclic amines) or (c)

(A) (b) (c)

(Wherein the cyclic amine in the formula (a) has a further oxygen atom in the ring

Even if well, pyrrolidine, shows a piperidine or morpholine, cyclic amines one NN in formula (b) shows a piperazine or Homopi Bae Rajin formula

(C) cyclic Amin in the further have an oxygen atom in the ring

Ku, pyrrolidine, piperidine, 3, 6-dihydro-2 H- pyridine or Moruho shows phosphorus bond represented by a solid line and a dotted line represents a single bond or a double bond, or A is not present or carbon, It indicates a straight or branched TECHNICAL chain alkylene chain having 8 from Equation 1, absent of B, or a sulfur atom, an oxygen atom, a carbonyl or human Dorokishimechiru, R e is hydrogen, hydroxy, alkyl or alkoxy shown, R 7 is hydrogen, an optionally substituted Ariru, Teroariru to Heteroariru or condensation, cycloalkyl, or optionally Ariruaru kill may have a substituent, the heteroaryl § reel alkyl or fused hetero § reel alkyl show. ) Shows the. ]

Condensation triazol Ichiru compounds, salts acceptable optical isomers thereof, or its pharmaceutically represented by.

② In Z in the general formula (1), cyclic amine (a) is a compound represented by the following formula (2) (3), (4) (5) (6) or (7) a cyclic amine represented by ① according Chijimigoto Riazor compounds, salts acceptable optical isomers thereof, or its pharmaceutically.

(Wherein each symbol is as defined in the formula)

In ③ general formula (1) Zeta, cyclic amines (b) a fused triazole compound of ①, wherein the annular Amin represented by the following formula (8) or (9), its optical isomers or its pharmaceutically acceptable salts can be.

(8) (9)

(Wherein each symbol is as defined in the formula)

④ In Z in the general formula (1), cyclic amines (c) is a compound represented by the following formula (1 0), (1 1) or (1 2) is a cyclic Amin represented by ① condensation Toriaburu compounds described, their optical isomers or a pharmaceutically acceptable salt thereof c

Ά 'Λ' ', • Rt> 7

(10) (11) (12)

(Wherein each symbol is as defined in the formula)

⑤ In the general formula (1),

R 1 represents hydrogen, halogen, nitro, Amino, Ashiru, Arukiruamino, alkyl or alkoxy;

R 2 represents hydrogen, halogen or alkoxy

W is methylene, sulfur atom or oxygen atom

X represents a methylene, ethylene or vinylene

Y is present and Do, or shows a linear Arukiren 鏆 having three carbon chain 1;

Z is formula (a), (b) or an cyclic amine represented by (c); condensation triazol Ichiru compounds ① condensate Toriaburu compounds described, its optical isomers or a pharmaceutically acceptable salt thereof.

⑥ In the general formula (1),

R 1 and R 2 each represent hydrogen;

W is methylene, sulfur atom or oxygen atom;

X represents a methylene, ethylene or vinylene;

Y is absent or shows a linear Arukiren chain having three carbon chain 1;

Z is the formula (2 ') or formula (8') PT / JP96 / 02004

, Amount,, B

A, R 7,

(2¾

(Wherein, A 'is absent, or a straight-chain alkylene chain having from 1 to 4 carbon atoms, B' is absent or indicates a carbonyl, R 6 'represents hydrogen, R 7' It is a group represented by) represents an Ariru or heteroaryl may have a substituent.;

Condensation triazol Ichiru compound of ①, wherein the condensation triazole compounds, salts acceptable optical isomers thereof, or its pharmaceutically.

⑦ 3- (1 i (2- (4 one black port phenyl) Echiru) piperidine one 4 one I le) one 6, 7-dihydro-5H-1, 2, 4-Toriazoro [3, 4-a] [2] benzo Azepin,

3 - (1 i (2 - (4 one black port phenyl) Echiru) piperidine one 4-I le) one 5, 6-dihydro-1, 2, 4 one Toriazoro [4, 3- d] [1, 4] Benzoo Kisazepin,

3 - (2- (4 one (4 one black port phenyl) piperidines Rajin one 1 one I le) Echiru) one 5, 6-dihydro-1, 2, 4-Toriazoro [4, 3- d] [1, 4 ] Benzoo Kisazepin,

3- (2- (4 i (3 black port phenyl) piperidines Rajin one 1 one I le) Echiru) one 5, 6-dihydro-1, 2, 4-Toriazoro [4, 3-d] [1, 4 ] Benzoo Kisazepin,

3- (3- (4 one (4 one black port phenyl) piperidines Rajin one 1 one I) propyl) one 5, 6-dihydro-1, 2, 4-Toriazoro [4, 3 - d) [1, 4 ] benzo Okisazepin,

3 - (1- (2- (4 one black port phenyl) Echiru) piperidine one 4 one I le) one 1, 2, 4-Toriazoro [4, 3 - d) [1, 4] benzo O hexa Ze pin,

3- (1 - (2- (4 one black port phenyl) Echiru) piperidine one 4 one I le) one 5, 6-dihydro-1, 2, 4-Toriazoro [4, 3-d] [1, 4] Benzochi Azepin,

3- (1 i (2- (4 one black port phenyl) Echiru) piperidine one 4 one I le) one 5, 6-dihydro-1, 2, 4-Toriazoro [4, 3-a] isoquino phosphorus,

3 - (1 i (2 - (4 one black port phenyl) Echiru) piperidine one 4 one I le) one 5, 6-dihydro-1, 2, 4-Toriazoro [4, 3- d] [1, 4] Benzochi Azepin 7, 7-Jiokishido,

5, 6 - dihydro 3- (2- (4 one phenylene Rubiperijin one 1 one I le) Echiru) one 1, 2, 4-Toriazoro [4, 3-d] [1, 4] benzo O hexa Ze pin,

3 - (2- (4 one (6 Furuorobenzo [d] Isokisazo one rule 3 I le) peak Perijin one 1 one I le) Echiru) one 5, 6-dihydro-1, 2, 4-Toriazo port! : 4, 3 - d) [1, 4] benzo O hexa Ze pin,

5, 6-dihydro-one 3- (2- (3, 6-dihydro-4 one (2-naphthyl) Single

2 H- pyridine one 1 one I le) Echiru) one 1, 2, 4-Toriazoro [4, 3- d] [1, 4] benzo O hexa peptidase pins, and

3- (2- (4 one (4 one black port phenyl) piperidines Rajin one 1 - I le) Echiru) one 1, 2, 4 one Toriazoro [4, 3 - d) [1, 4] Benzookisaze condensed triazole compound or a pharmacologically acceptable salt thereof according ① selected from the pin.

⑧ 6, 7- dihydro-one 3- (1 i (2- (4 one black port phenyl) Echiru) Piperi Jin one 4 one I le) Single 5 H- thieno [3, 2-c] one 1, 2, 4 - Toriazoro [4,

3- a] Azepin,

9 - chloro 6, 7-dihydro-one 3- (1 - (2- (4 one black port phenyl) E chill) piperidine one 4 one I le) Single 5H- thieno [3, 2-c] one 1, 2, 4-preparative Riazoro [4, 3- a] Azepin,

6, 7 dihydric draw 3- (1 i (2- (2-naphthyl) Echiru) piperidine one 4 one I le) Single 5 H- thieno [3, 2-c] one 1, 2, 4 one Toriazoro [4 , 3 - a] Azepin,

3- (1 i (2- (2 one-naphthyl) Echiru) piperidine one 4 one I le) one 5, 6 Jihi Dorochieno [3, 2 - f) one 1, 2, 4-Toriazoro [4, 3 - d) [1, 4] thiazepine,

3- (1- (2- (4 one black port phenyl) Echiru) piperidine one 4 one I le) one 5, 6-dihydrothieno [3, 2 - f] one 1, 2, 4 one Toriazoro U, 3 - d ] [1, 4] thiazepine,

6, 7-dihydro-3- (1 i (4 one (4 one-fluorophenyl) one 4 one Okiso butyl) piperidine one 4 one I le) Single 5 H- thieno [3, 2-c] -1, 2 , 4-triazolo [4, 3- a] Azepin,

3- (1 - (- (4 one-fluorophenyl) one 4 one year old Kisobuchiru) piperidine one 4 one I le) one 5, 6 - dihydrothieno [3, 2-f] one l, 2, 4-Toriazo port [4, 3- d] [1, 4] thiazepine,

5, 6-dihydro-3- (1 i (2- (4 one black port phenyl) Echiru) Piperi Jin one 4 one I le) thieno [2, 3-f] one l, 2, 4-Toriazoro [4, 3 - d] [1, 4] Okisazepin,

5, 6-dihydro-3- (1 i (2- (2-naphthyl) Echiru) piperidine one 4 one I le) thieno [2, 3 - f) one 1, 2, 4 one Toriazoro [4, 3 - d) [1, 4] Okisazepin,

5, 6-dihydro-3- (1 i (4 one (4 one-fluorophenyl) one 4 one Okiso heptyl) piperidine one 4 one I le) thieno [2, 3-f] one l, 2, 4-Toriazo mouth [4, 3 - d) [1, 4] Okisazepin

6, 7-dihydro-3- (2- (4 one (4 one black port phenyl) piperidines Rajin one 1 one I le) Echiru) Single 5H- thieno [3, 2-c] one 1, 2, 4-Toriazoro [4, 3- a] Azepin,

6, 7-dihydro-one 3- (3- (4 i (4 - black port phenyl) piperidines Rajin one 1 one I) propyl) - 5 H- thieno [3, 2-c] - l, 2, 4 - Toriazoro (: 4, 3- a] Azepin, and

3- (2- (4 one (4 one black port phenyl) piperidines Rajin one 1 one I le) Echiru) one 5, 6-dihydrothieno [3, 2-f] one 1, 2, 4-Toriazoro [4, 3 -d) [1, 4] fused triazole compound or a pharmacologically acceptable salt thereof according ① selected from thiazepine.

⑨① fused triazole compound according its enantiomer or a pharmaceutical composition comprising a pharmaceutically acceptable cormorants Ru salt and a pharmaceutically acceptable carrier.

⑩① fused triazole compound according its enantiomer or a pharmaceutically acceptable cormorants Ru medicaments comprising salts.

⑪ medicament ⑩ wherein the antipsychotic.

The present invention relates to radioactive condensate triazole compounds and their use of the general formula (gamma).

⑫ general formula (1 ')

Wherein, R 1 'and R 2' may be the same or different, are each hydrogen, halogen, Shiano, nitro, Amino, Ashiruamino force Rubamoiru, alkyl force Rubamoiru, alkoxycarbonyl, Ashiru, Arukiruamino, aminoalkyl, shows alkylaminoalkyl, hydroxy, Ashiruokishi, hydroxyalkyl, § sill O, alkoxyalkyl, alkyl, alkenyl, alkynyl or alkoxy,

W is methylene, (wherein, R 3 is hydrogen, alkyl, Hue Nasir or. Showing also good § reel alkyl or Heteroariru alkyl substituted) oxygen atom or N-R 3 indicates,

T indicates the tritium,

Y is absent or C 1 force atoms, indicates a straight or branched TECHNICAL chain § Le Killen chain having eight al,

Z is - NH 2, -NHR 4 (wherein, R 4 is alkyl, cycloalkyl, Yes Good § reel alkyl optionally substituted, hetero § reel alkyl to heteroalkyl § reel alkyl or fused, or a substituent and may be Ariru, Heteroariru if Ku denotes a heteroaryl fused.), one N (R 4) (R 5 ) ( wherein, R 5 is optionally have Al kill, cycloalkyl, substituents § reel alkyl, Heteroari Ruarukiru or terrorist § reel alkyl to condensation or an optionally substituted Ariru, showed Teroariru to Heteroariru or condensation, is the same definition.), or formula (a), (b) or the formula of (c) an annular Amin

(A) (b) (O

(Wherein the cyclic amine in the formula (a) has a further oxygen atom in the ring

Even if well, pyrrolidine, shows a piperidine or morpholine, cyclic amines one NN in formula (b) shows a piperazine or Homopi Bae Rajin, a cyclic amine of the formula (c) is further oxygen atom in the ring It may have, pin Mouth lysine, piperidine, 3, 6-dihydro-2 .eta. shows pyridine or morpholine, bond represented by a solid line and a dotted line represents a single bond or a double bond, Alpha squid exist, or carbon 1 from shows a straight or branched TECHNICAL chain alkylene chain having eight, B is absent, or a sulfur atom, an oxygen atom, a carbonyl or Hidorokin methyl, R 6 represents hydrogen, hydroxy, alkyl or alkoxy, R 7 is hydrogen, an optionally substituted Ariru, Teroa reel to Heteroariru or fused, cycloalkyl or optionally § reel alkyl which may have a substituent, to te lower reel alkyl or fused hetero § reel alkyl to show. ) Shows the. Radioactive condensation Toriazoru compounds, optical isomers thereof or a salt thereof represented by]. ⑬ 3- (2-(4 one (4 one black port phenyl) piperidines Rajin one 1 one I le) Echiru) one 5, 6-di-tritium one 1, 2, 4-Toriazoro [4, 3- d] [ 1, 4] radioactive condensate Toriaburu compound or salt thereof according ⑫ is Ben Zookisazepin. Radioactive condensed triazole compound of ⑭⑫ described or D 4 receptor ligand consisting of a salt thereof

Radioactive condensed triazole compound of ⑩⑫ described or method of labeling the D 4 receptor in the human or animal you characterized by using a salt thereof.

Describing each symbol used herein below.

The general formula (1) and 'relates, R 1, R 2, R 1 (1)' and put that halogen and R 2 'means chlorine, bromine, fluorine, iodine. § The Ashiruamino Sechiruamino, Benzoiruamino, hexyl carbonyl § amino cyclohexane, indicates like Shikurobu α pills carbonyl § Mino, Al force Noiru of 2 carbon atoms 5 as Ashiru site Benzoiru, Aroiru such naphthoyl, 3 carbon to alkoxy Rukaruponiru preferably 6 cycloalkyl. Methylcarbamoyl The alkyl force Rubamoiru, E Ji carbamoyl, propyl force Rubamoiru, butylcarbamoyl, dimethyl carbamoyl, such as GETS Ji carbamoyl carbon atoms in the alkyl moiety rather preferably has 1 to 4, in which the alkyl group is a nitrogen atom 1 or 2 is substituted. Alkoxycarbonyl and the main butoxycarbonyl, ethoxy Kin, propoxycarbonyl, isoproterenol Po, butoxycarbonyl, shows and the like tertiary butoxycarbonyl, carbon atoms in the alkoxy moiety is preferably 1-4. Formyl The Ashiru, Asechiru, propionyl, butyryl, isobutyryl, Pentanoiru, to Kisanoiru, shows etc. Okuta Noiru, having a carbon number of 1 to 8 Arukanoiru, Benzoiru, naphthoyl of which Aroiru and Nikochinoiru, Tenoiru, fart heteroaryl forces such as furoyl Ruponiru is preferable. Arukiruamino and Mechiruamino is Jimechiruamino, E Ji Ruamino, Jechiruamino, Puropiruamino indicates like Jipuropiruamino, the number of carbon atoms of § alkyl moiety 1-4 atoms are preferred, the alkyl group is 1-2 pieces substituted Amino groups. Aminomethyl and aminoalkyl, 2-aminoethyl, 3 - amino knobs port pills, 4 indicates like primary amino butyl, the number of carbon atoms in the alkyl moiety is preferably 1-4. Methylaminomethyl and alkylaminoalkyl, dimethylamino methylation, 2- (Mechiruamino) Echiru, 2- (Jimechiruamino) Echiru shows the like, the number of carbon atoms in the alkyl moiety is preferably 1-4. Ashiruokishi and Asechiruokishi is propionyl Ruo alkoxy, Buchiriruokishi indicates like Benzoiruokishi, Ashiru unit position is 2 to 5 carbon atoms Arukanoiru, are preferred. Hydro and hydroxyalkyl Kishimechiru, 1 one or 2 - hydroxy E chill, 1 one, 2- or 3 - hydroxy Shipuropiru shows the like, the number of carbon atoms in the alkyl moiety is preferably 1-4. Ashiruo Kishiarukiru and Asetokishimechiru is 2- Asetokishechiru, 3 Asetokishibu port pills, propionyloxy Ruo carboxymethyl shows the like, Ashiru site of C2-5 § Rukanoiru, is preferred. Alkoxyalkyl The main Tokishimechiru, Etokishime chill, Provo carboxymethyl, isoproterenol Bo, butoxymethyl, 2-main Toki Shechiru, 2 - Etokishechiru, 3 main Tokishipuropiru shows the like, an alkoxy number 1-4 carbons substituted to have a carbon number 1-4 alkyl is preferred. Methyl and alkyl Le, Echiru, propyl, isopropyl, heptyl, Isopuchiru, tertiary butyl, hexyl pentyl, heptyl, Okuchiru, decyl, the Kisadeshiru, O octadecyl shows the like, having from 1 to 4 carbon atoms Ryo alkyl It is preferred. The alkenyl vinyl, 1 one propenyl, shows and isopropenyl, has preferably the number 2 or 3 carbon atoms. Alkynyl and indicates such Echuru, 2-3 carbon atoms are preferred. An alkoxy The main butoxy, ethoxy, Purobokishi, Isopurobokishi, butoxy, Isobuto Kin, tertiary butoxy, Penchiruokishi, to Kishiruokishi, Hepuchiruokishi, shows and O Kuchiruokishi, is 1-4 alkoxy carbon atoms preferred.

The alkylthio R 1, in R 2, methylthio, Echiruchio, propylthio, isopropylthio, shows etc. Puchiruchio, the alkyl moiety having 1 to 4 carbon atoms are favorable preferable. Alkylsulfinyl and methylsulfinyl is E chill sulfinyl, propyl sulfinyl, isopropyl-sulfinyl, shows and butyl sulfinyl, alkyl moiety preferably has 1 to 4 carbon atoms. Methylol The alkylsulfonyl Rusuruhoniru, Echirusuruhoniru, propylsulfonyl, isopropylsulfonyl two Le, shows etc. Puchirusuruhoniru, alkyl moiety preferably has 1 to 4 carbon atoms.

The alkyl in R 3 may be similar to those listed alkyl in R 1, R 2, R 1 ' and R 2'. Benzyl and § reel alkyl, 1 one Hue Niruechiru, 2- Fueniruechiru, 3-phenylpropyl, 4-phenylbutyl, naphthylmethyl, 2-naphthylmethyl, 3-naphthyl-propyl, 4 one Nafuchirubu chill, shows etc. Jifuenirumechiru, Ariru phenyl is as sites, naphthyl, carbon atoms in the alkyl moiety is preferably 1-4. Pyridylmethyl and heteroalkyl § reel alkyl, Pirijiruechiru, furylmethyl, Furiruechiru, Choi two Rumechi Le indicates like Cheniruechiru, Heteroariru pyridyl, furyl, thienyl in which the number of carbon atoms in the alkyl moiety is preferably 1-4. Examples of the substituent of § reel alkyl and the tape lower reel alkyl, fluorine, chlorine, bromine, halo gen such as iodine, triflate Ruo b haloalkyl such as methyl, methyl, Echiru, propyl, I an isopropyl, butyl, Isopuchiru, third alkyl such as grade butyl, main butoxy, E butoxy, Purobokishi, Isopurobokishi, butoxy, isobutoxy, tertiary butoxy shea, Penchiruokishi to, Kishiruokishi, Hepuchiruokishi, alkoxy such as Okuchiruokishi shown.

Number 1 force atoms in Y, and the straight or branched TECHNICAL 鏆状 Arukiren chain having eight al, methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, Okutamechiren, methylmethylene, Jimechirumechire emissions, 1 one methylethylene, 2-methylethylene, 1, 1-dimethylethylene, 2, 2-dimethylethylene, Echirumechiren, Jefferies chill methylene, 1 Echiruechire down, 2 Echiruechiren, -1-methyltrimethylene, 2-methyl tri methylene, and 3-methyltrimethylene and the like, methylene or ethylene is preferable.

Alkyl and is for R 4 and R 5, shown methyl, Echiru, propyl, isopropyl, butyl, Isopuchiru, tertiary heptyl, pentyl, hexyl, heptyl, O corruptible, decyl, the Kisadeshiru, etc. Okutadeshiru, preferred carbon the number is 1 to 4. Cyclopropyl cycloalkyl, cyclopentyl, shows and cyclohexyl, preferably the number of carbon atoms is three to six. § reel alkyl The base Njiru, 1 Fuweniruechiru, 2- Fuweniruechiru, 3-phenylene Ruburopiru, 4 Fuwenirubuchiru, 1 one naphthylmethyl, 2-naphthylmethyl, 3-Nafuchirupu port pills, 4 one naphthylbutyl, shows and the like Jifuenirumechiru, phenyl is a Ariru site, naphthyl, carbon atoms in the alkyl moiety is preferably 1-4. Pyridylmethyl and Te lower reel alkyl to, 2-Pirijiruechiru, furylmethyl, 2-Furiruechiru, Chenirumechiru, 2 Cheniruechiru shows the like, Heteroa reel pyridyl, furyl, thienyl in which the number of carbon atoms in the alkyl moiety is 1-4 pieces but good Masui. Phenyl and Ariru, naphthyl, 2-indanyl shows the like, phenylene Le is preferred. Pyridyl and Heteroariru represents furyl, thienyl, a etc. pyridinium Mijiru, pyridyl, pyridinium Mijiniru are preferred. The Teroariru to condensation, 1, 4 one base Nzojiokisan one 2-I le, 6- Asechiru 3 Echiru 4, 5, 6, 7 over tetrahydropyran Choi Bruno [2, 3 - c] pyridine one 2-I le, 1 , 2-base Nzoiso Kisazo one rule 3 I le, 1, 2-base Nzoisochiazo one rule 3 I le, indole one 3-I le, benzo [b] furan one 3-I le, benzo [b] Chiofen one 3-le shows the like, 1, 2-base Nzoisokisazo one rule 3 I le are preferred. The Te lower reel alkyl to condensation, indole over 3 Irumechiru, 2- (indol-3 one I le) Echiru, 3- (indol over 3 I) propyl, benzo [b] furan over 3 Irumechiru, 2- (benzo [b] furan one 3-I le) Echiru, benzo [b] Chiofen one 3- Irumechiru, shows and 2- (benzo [b] Chiofen one 3-I le) E Chi le, benzo [b] furan one 3 - Irumechiru, benzo [b] Chiofen one 3- Irumechiru are preferred. These substituents include fluorine, chlorine, bromine, halogen iodine, haloalkyl such as triflate Ruo B, methyl, Echiru, propyl, isopropyl, heptyl, Isopuchiru, alkyl such as tertiary butyl, main butoxy, ethoxy, Purobokishi, Isopurobokishi, Butokin, isobutoxy, tertiary butoxy, Penchiruokishi to, Kishiruokishi, Hepuchiruokishi, alkoxy such as Okuchiru Okishi, hydroxy, nitro, Amino, Mechiruamino, such as dimethylcarbamoyl Ruamino the like.

The cyclic Amin of formula (a) in Z include the following.

, R '

(5) (6) The ring Fushimi Amin of (7) (b) include the following, ■ N, Day,

A, R '

Li

(8) (9)

It includes the following as an annular Amin of formula (c) <

R 6 ¾A - R,

(10) (1) (12)

The straight or branched TECHNICAL chain Arukiren chain having 8 carbon atoms of 1 in A, methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, Okutamechiren, methylmethylene, Jimechirumechire down, 1 one methylethylene, 2-methylethylene, 1, -1-dimethylethylene, 2,

2-dimethylethylene, Echirumechiren, Jefferies chill methylene, 1 Echiruechire down, 2 Echiruechiren, -1-methyltrimethylene, 2-methyltrimethylene,

And 3-methyltrimethylene and the like, methylene or ethylene is preferable.

Methyl alkyl in R 6, Echiru, propyl, isopropyl, butyl, Isopuchiru, such as tertiary butyl and the like, preferably an alkyl of 1 to 4 carbon atoms. Main and alkoxy butoxy, ethoxy, Purobokishi, Isopurobokishi, butoxy, isobutoxy, tertiary butoxy and the like, alkoxy having 1 to 4 carbon atoms virtuous preferable.

Which may have a substituent in R 7 Ariru, heteroaryl Heteroariru or fused, cycloalkyl, hetero § reel alkyl to te lower reel alkyl or fused to a good § reel alkyl, which may have a substituent, R 4 and the like, and those similar to the case of R 5. These may have a substituent, examples of the substituent include fluorine, chlorine, bromine, halogen iodine, triflate Ruo b haloalkyl such as methyl, methyl, Echiru, propyl, isopropyl, butyl, iso-heptyl, 3 alkyl such as grade butyl, main butoxy, ethoxy, Purobokishi, iso Purobokishi, Butokin, isobutoxy, tertiary butoxy, Penchiruokin, the key Shiruokishi, Hepuchiruokishi, alkoxy such as Okuchiruokishi, Hidorokin, nitro, Amino, Mechiruamino, Jimechiruamino, alkylsulfonyl (methyl sulfonyl, Echirusuruhoniru, propylsulfonyl, butyl-sulfonyl),

-S0 2 N (R.) ( R b) ¾ ( wherein, the R ,, R b identical or different, hydrogen, or methyl, Echiru, propyl, heptyl, isopropyl, an alkyl such as isobutyl) ', etc. and the like.

In the general formula (1), a benzene ring and is a ring E

In Chiofuwen ring is preferably represented, particularly the former are preferred as Chiofuwen ring.

- general formula (1), 'in, R 1 and R 1 (1)' is a hydrogen, halogen, nitro, Amino, Ashiru (Asechiru, propionyl, etc.), alkylamino (main Chiruamino, etc. Echiruamino), alkyl (methyl , Echiru, propyl, iso-propyl, butyl, etc.) or alkoxy (main butoxy, ethoxy, Purobokishi, Isopurobokishi, butoxy) are preferred, R 2 is hydrogen, halogen or alkoxy (main butoxy, ethoxy, Purobokishi, Isopurobokishi, butoxy ) is preferable. Particularly preferably, R 1 and R 2, R 1 'and R 2' is Ru both hydrogen der. W is methylene, preferably a sulfur atom or an oxygen atom, especially oxygen atom preferably les. One Y- The Z, Y is absent or C1-4 straight-chain alkylene down chain carbon, Z is a cyclic amine Ngayoshimi represented by formula (a), (b) or (c) better not. Also, of formula annular Amin of formula (a) (2 '), of which type of annular Amin of formula (b) (8'), of which type of annular Amin of formula (c) (1 0 ')

R, β,> β,

(2) (10)

(Wherein the bond represented by a solid line and a dotted line represents a single bond or a double bond, A 'is absent, or a straight-chain alkylene chain having 1-4 carbon chains, B' does not exist or shows a carbonyl, R e 'represents a hydrogen, R 7' is Moyoi Ariru substituted, the groups are Ru represented by.) showing the Teroariru to Heteroariru or condensation particularly preferred. Here, the Ariru in R 7 'phenyl, naphthyl or a halogen, methyl, triflusulfuron Ruo Russia methyl, methoxy, nitro, § Mino, include Fuweniru having a substituent 1-2 such Mechiruamino, hetero Ariru and the like thienyl as. Halo Gen as Teroariru to condensation, methyl, triflusulfuron Ruo Russia methyl and three chromatic-substituents such as main butoxy 1, 2 base Nzoisokisazo one rule 3 I le, benzo [b] furan one 3-I le, 1, 4 one base Nzojiokisan one 2-I le, 6- Asechiru 2 Echiru - 4, 5, 6, 7-tetrahydronaphthalene Choi Bruno [2, 3-c] pyridine one 3-I le can be mentioned.

Note the general formula (1) include a compound of 3 the following embodiments in accordance with the definition of X.

(Wherein each symbol is as defined in the formula)

Preferred compounds of general formula (1), 3 - (1 i (2- (4-black port phenyl) Echiru) piperidine one 4 one I le) one 6, 7-dihydro-5 H- 1, 2, 4-Toriazoro [3, 4-a] [2] benzo Azepin,

3 - (1 i (2 - (4 one black port phenyl) Echiru) piperidine one 4 one I le) one 5, 6-dihydro-1, 2, 4-Toriazoro [4, 3 - d) [1, 4] Benzoo Kisazepin,

3- (2- (4 one (4 one black port phenyl) piperidines Rajin one 1 one I le) Echiru) one 5, 6-dihydro-1, 2, 4-Toriazoro [4, 3 - d] [1, 4 ] Benzoo Kisazepin,

3 - (2- (4 i (3 black port phenyl) piperidines Rajin one 1 one I le) Echiru) - 5, 6-dihydro-1, 2, 4-Toriazoro [4, 3 - d) [1, 4 ] Benzoo Kisazepin,

3- (3- (4 one (4 one black port phenyl) piperidines Rajin one 1 one I) propyl) - 5, 6-dihydro-1, 2, 4 - Toriazoro [4, 3 - d) [1, 4 ] benzo Okisazepin,

3 - (1 i (2 - (4 one black port phenyl) Echiru) piperidine one 4 one I le) one 1, 2, 4-Toriazoro [4, 3 - d) [1, 4] Benzookisaze pin,

3- (1 i (2- (4 one black port phenyl) Echiru) piperidine one 4 one I le) one 5, 6-dihydro-1, 2, 4 one Toriazoro [4, 3-d] [1, 4] Benzochi Azepin,

3 - (1 i (2- (4 - black port phenyl) Echiru) piperidine one 4-I le) one 5, 6-dihydro-1, 2, 4 one Toriazoro [4, 3- a] isoquino phosphorus,

3- (1 i (2- (4 one black port phenyl) Echiru) piperidine one 4 one I le) one 5, 6-dihydro-1, 2, 4-Toriazoro [4, 3 - d) [1, 4] Benzochi Azepin 7, 7-Jiokishido,

5, 6-dihydro-3- (2- (4 one phenylene Rubiperijin one 1-I le) Echiru) one 1, 2, 4 one Toriazoro [4, 3-d] [1, 4] benzo O hexa Ze pin, 3 - (2- (4- (6-Furuorobenzo [d] Isokisazo one rule 3 I le) peak Perijin one 1 - I le) Echiru) one 5, 6-dihydro-1, 2, 4-Toriaburo [4, 3 - d] [1, 4] benzo O hexa Ze bottle,

5, 6-dihydro-3- (2- (3, 6-dihydro-4 one (2-naphthyl) Single 2H- pyridin one 1 one I le) Echiru) one 1, 2, 4-Toriazoro [4, 3-d] [1, 4] benzo O hexa peptidase pins, and

3 - (2- (4 one (4 one black port phenyl) piperidines Rajin one 1 - I le) Echiru) one 1, 2, 4-Toriazoro [4, 3- d] [1, 4] Benzookisaze pin

Compound or a pharmaceutically acceptable salt thereof selected from the like.

Pharmaceutically acceptable salts of the compounds of the general formula (1), an inorganic acid (hydrochloric acid, Nioikamizu periodate, sulfuric acid, phosphoric acid, nitric acid, etc.) or organic acids (acetic, propionic, succinic, glycolic acid , lactic acid, malic acid, tartaric acid, Kuen acid, maleic acid, fumaric acid, methane sulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid, cans Firth sulfonic acid include acid addition salts with such Asukorubin acid).

Since the compounds and their pharmaceutically acceptable salts of the general formula (1) is also be present in the form of hydrates or solvates thereof, hydrates thereof, solvates are also wrapped including the present invention that. The compounds of general formula (1) at least two kinds of optical isomers are present in the case of having an asymmetric atom. These optical isomers and racemates thereof are encompassed in the present invention.

The compounds and the invention compounds included in general formula (1) of the general formula (1) The following method (1) can be synthesized by - (1 8).

Methods (1)

Nippon Kagaku Journal 8 Volume 3 No. 3 34 3 - 3 4 7 p. (1 9 6 2 years), Kemikarua Busutoraku' 6 9 Volume 1 8 5 6 5 x (1 9 6 8 years), U.S. Patent No. 4, 7 3 5, 9 4 0 No., International Patent application Publication WO 9 3/1 3 1 0 I like the method described in 5 JP connexion obtained formula (1 3)

(Wherein each symbol is as defined above.)

In a suitable solvent a compound represented by (benzene, toluene, xylene, or these optional mixed solvent), a chlorinating agent (phosphorus pentachloride, phosphorus trichloride, Okishi phosphorus chloride, etc.) and refluxed at room temperature or at the solvent by reacting at a temperature 1 to 24 hours, the general formula (1 4)

(Wherein each symbol is as defined above.)

Compounds represented by is obtained. The compounds suitable solvent (methanol, ethanol, blanking evening Nord, ethylene glycol, N- methyl-2-pyrrolidone, 1, 3-dimethyl-2-imidazolidinone or the like of any of these mixed solvent) in the general formula (1 5)

H 2 NHNOC-YZ (1 5 )

(Wherein each symbol is as defined above.)

Presence of a compound represented by by the this reacted for 1 to 24 hours at 20 0 hands from room, the compounds of general formula (1) is obtained.

The method (2)

In the general formula (1 3) a suitable solvent a compound of (benzene, toluene, xylene or the like of any of these mixed solvent), thione agent, for example phosphorus pentasulfide, L awe sson reagent [2, 4- bis (4 over main Tokishifue sulfonyl) one 1, 3-dithia one 2, 4 Jihosufuetan and such as single 2, 4 one disulfide], generally by reacting 1 to 24 hours at reflux temperature of room temperature or solvent type (1 6)

(Wherein each symbol is as defined above.)

Compounds represented by is obtained. During the compound appropriate solvent (methanol, ethanol, blanking evening Nord, ethylene glycol, N- methyl-2-pyrrolidone, 1, 3-dimethyl-2-Imidazorijinon or the like of any of these mixed solvents), - general formula ( the presence of a compound represented by the 1 5), by reaction between 1 to 24 hours at 20 0 e C from room temperature, the compound of the general formula (1) is obtained.

The method (3)

- the compound of general formula (1 6), in a suitable solvent that does not inhibit the reaction (tetrahydrofuran, Jefferies chill ether, Jiokisan, water or and mixtures of these solvents), benzyl chloride, p- two Torobenjiru, methyl iodide and the like, potassium hydroxide in the presence of a base such as force Riumu tertiary butoxide, by I~ 24 hours at the reflux temperature of room temperature or solvents, the general formula (1 7)

(Wherein, R 8 is methyl, benzyl, shows and the like ρ- two Torobe Njiru, and other symbols the same meanings as defined above.) The compound represented by can be obtained. The compounds suitable solvent (methanol, ethanol, blanking evening Nord, ethylene glycol, N- methyl one 2-pyrrolidone, 1, 3-dimethyl-2-imidazolidinone or the like of any of these mixed solvent) in the general by 24 hours reaction at the reflux temperature of the compound at room temperature or solvent represented by the formula (1 5), the compound of the general formula (1) is obtained.

The method (4)

The general formula (1 8)

(Wherein each symbol is as defined above.)

Compound or an acid addition salt thereof represented by, for example hydrochloride, hydrobromide, sulfate salts, and the like oxalic acid salt, a suitable solvent (methylene chloride which does not inhibit the reaction, black hole Holm, dichloroethane, tetrahydrofuran, Jefferies chill ether, N, N-di-methyl formamidine de or the like of any of these mixed solvent) in the general formula (1 9)

G -R (1 9)

(Wherein, G 1 represents a chlorine, bromine, iodine, methanesulfonyl O carboxymethyl, p- toluenesulfonic Ruhoniruokishi, and triflate Ruo b methanesulfonyl O carboxymethyl, R 4 are as defined above.) And a compound represented by, Toryechiruamin, pyridine, in the presence of a base, such as dimethyl chill § amino pyridine, by reacting under ice-cooling or at room temperature for 1 to 24 hours, the general formula (20) 0 "

(Wherein each symbol is as defined above.)

Compounds represented by is obtained.

The method (5)

- general formula (20) compound or an acid addition salt, such as hydrochloride, hydrobromide, sulfate, etc. oxalic acid salt does not inhibit the reaction a suitable solvent (methylene chloride, black hole Holm, dichloroethane, during Jefferies like chill ether or these optional mixed solvent), the general formula (21)

G 2 one R (21)

(Wherein, G 2 represents chlorine, bromine, iodine, methanesulfonyl O carboxymethyl, p- toluenesulfonic Ruhoniruokishi, and triflate Ruo b methanesulfonyl O carboxymethyl, R 5 is as defined above.) And a compound represented by, Toryechiruamin, pyridine, in the presence of a base, such as dimethyl chill § amino pyridine, by reacting under ice-cooling or at room temperature 1-24 h, the general formula (22) (Wherein each symbol is as defined above.)

Compounds represented by is obtained.

Method 6

- general formula (23)

(Wherein each symbol is as defined above.)

Compounds or formula represented by (24)

(Wherein each symbol is as defined above.)

Compound or an acid addition salt thereof represented by, for example hydrochloride, hydrobromide, sulfate salts, and the like oxalic acid salt, a suitable solvent (methylene chloride which does not inhibit the reaction, black hole Holm, Jikuroroetan, tetrahydrofuran, Jefferies chill ether, N, N-di-methyl formamidine de or the like of any of these mixed solvent) in the general formula (25)

G 3 -ABR '(25)

(Wherein, G 3 is chlorine, bromine, iodine, methanesulfonyl O carboxymethyl, p- toluenesulfonic Ruhoniruokishi, triflumizole Ruo b methanesulfonyl O carboxymethyl shows the like, and other symbols are as defined above.)

A compound represented by, potassium carbonate, sodium hydroxide, Toryechiruamin, the presence of a base such as pyridine or dimethyl § amino pyridine, by reaction with ice-cooling or under room temperature for 1 to 24 hours, the general formula (26)

(26)

(Wherein each symbol is as defined above.)

Compounds represented by, or the general formula (27)

(Wherein each symbol is as defined above.)

Compounds represented by is obtained.

Method (7)

- general formula (23) or a compound or an acid addition salt of the general formula (24), such as the hydrochloride, hydrobromide, a suitable solvent (Te tetrahydrofuran which does not inhibit the sulfates, oxalic acid salt reaction, dichloromethane, dimethylformamidine de or the like of any of these mixed solvent) in the general formula (28)

HOOC (CH 2) m R ( 28)

(Wherein, R 11 is substituted indicates heteroaryl which may Ariru or to, m represents. A number of 1 to 7) the presence of a tertiary Amin such compound Toriechiruamin represented by lower, 1, 3 - dicyclo hexyl Cal positive imide, 1 Echiru 3 - (3-dimethylaminopropyl blanking opening pill) carbodiimide under ice-cooling and condensing agent such Shianohosuhon acid diester Le or at room temperature 1-2 4 hours by reacting the general formula (2 9)

(Wherein each symbol is as defined above.)

Compounds represented by, or the general formula (3 0)

(Wherein each symbol is as defined above.)

Compounds represented by is obtained. Incidentally, the reactive induction of a compound of the general formula (28) (acid Kurori de, § sill imidazole, etc.) is used, reaction is carried out in a suitable solvent (tetrahydrofuran which does not inhibit the reaction, dichloromethane, black hole Holm, Ben Zen or in these or any of the mixed solvent), the presence of such tertiary Amin or pyridine such as Toryechiruamin, by reacting under ice-cooling or at room temperature 1-2 4 hours, the reaction proceeds.

The thus obtained formula (2 9) or formula (3 0) a suitable solvent which does not inhibit the reaction of a compound of (tetrahydrofuran, Jefferies chill ether, Toruenma others such as any mixture of these solvents) in , lithium aluminum hydride, by performing 1 to 24 hours the reduction reaction at room temperature from a 78 using any reducing agent borane of the general formula (3 1)

R e

(Wherein each symbol is as defined above.)

Compounds represented by, or the general formula (32)

(Wherein each symbol is as defined above.)

Compounds represented by is obtained.

Method 8

The general formula (3 3)

(Wherein each symbol is as defined above.)

Usual manner a compound represented by the appropriate acid, e.g., hydrochloric, hydrobromic, when deprotected by the action of such birds Furuoro acid, formula (34)

(Wherein each symbol is as defined above.)

Compounds represented by is obtained. This suitable solvent that does not inhibit the reaction (chloride main styrene, black hole Holm, etc. Jikuroroetan) in the presence of a base such as Toryechiruamin, p- toluenesulfonyl chloride Li de or methanesulfonyl loose black Li de, etc. leaving group by the action of after introducing the reaction inhibition was not solvent (methylene chloride, black hole Holm, Jikuroroetan, tetrahydrofuran, Jefferies chill ether or these optional mixed solvent) in potassium carbonate, pyridine, a suitable dehydrogenating agent such Toryechiruamin under the presence of the general formula (35), (36) or (37)

(35) (36) (37)

(Wherein each symbol is as defined above.)

Compound or an acid addition salt thereof represented by, for example hydrochloride, hydrobromide, more reacted for 1 to 24 hours at reflux sulfate, from room temperature to as oxalic acid salt of the solvent, the general formula (22) the compound or formula (27) (3 8) (38)

(Wherein each symbol is as defined above.)

A compound represented by the obtained respectively.

Method (9)

Formula W to be due connexion produced in any of the above methods is a sulfur atom (3 9)

(Wherein each symbol is as defined above.)

Compound or its acid adduct represented by, for example hydrochloride, hydrobromide, sulfate, in such a methylene chloride oxalate salt, under ice-cooling, by for it creates the m- black port perbenzoate , or in a formic acid or acetic acid, by Rukoto allowed to act like hydrogen peroxide, the general formula (4 0- a) or the general formula (4 0- b)

(40-a) (40-b) (wherein each symbol is as defined above.)

Compounds represented by is obtained.

The starting compounds used in the above methods can be synthesized by the following method.

Methods (1 0)

Formula (1 4), (1 6) or a compound of formula (1 7), an appropriate solvent (methanol does not inhibit the reaction, ethanol, butanol, ethylene glycol, N- methylcarbamoyl Lou 2- pyrrolidone, 1, 3 dimethyl 2-in-imidazolidinone or the like of any of these mixed solvent), the general formula (4 1)

H 2 NHNOC-Y-NHR 9 (4 1)

(Wherein, R 9 is. Other symbols indicating the unaffected protecting groups on the reaction, such as a tertiary butoxycarbonyl group some base Nji Ruo alkoxycarbonyl group as defined above.) In the presence of the compound represented by the lower, by the this reacting 1 to 24 hours at room temperature 20 (TC, formula (42)

(Wherein each symbol is as defined above.)

Compounds represented by is obtained.

Formula (1 8 Compound of> in accordance with a conventional method a compound of the general formula (42), a suitable acid such as hydrochloric acid, hydrobromic acid, obtained by row Ukoto deprotected by the action of such Torifuruoro acetate . method (1 1)

Formula (1 4), (1 6) or a compound of formula (1 7), an appropriate solvent (methanol does not inhibit the reaction, ethanol, blanking evening Nord, ethylene glycol, N- methylcarbamoyl Lou 2- pyrrolidone, 1, during 3- dimethyl 2-imidazolidinone or the like of any of these mixed solvent), the general formula (4 3) or (44)

(Wherein, R 9 is. Other symbols indicating a protecting group that does not disturb the reaction, such as tertiary butoxycarbonyl group or a benzyl O alkoxycarbonyl group as defined above.) In the presence of a compound represented by , by the this reacting 1 to 24 hours at 20 0 ° C from room temperature, the general formula (4 5)

(Wherein each symbol is as defined above.)

Compounds represented by, or the general formula (4 6) "46)

(Wherein each symbol is as defined above.)

Compounds represented by is obtained.

- general formula (23) or a compound of general formula (24), the general formula (4 5) or - general formula according to a conventional method a compound of formula (4 6), a suitable acid such as hydrochloric acid, hydrobromic acid, preparative such Rifuruoro acetate allowed to act obtained by performing deprotection. Methods (1 2)

- general formula (1 4), (1 6) or a compound of formula (1 7), suitable equivalent solvent (methanol does not inhibit the reaction, ethanol, blanking evening Nord, ethylene glycol, N- main Chiru 2-pyrrolidone, 1, 3-dimethyl-2-imidazolidinone or the like of any of these mixed solvent) in the general formula (4 7)

H 2 NHNOC-Y-OR 10 (4 7)

(Wherein, R 10 is main Tokishimechiru group, tetrahydrofuryl Vila group, a protecting group which does not affect the reaction such as Toryechirushiriru group. Other symbols are as defined above.) In the presence of a compound represented, room temperature more from 20 (that is reacted for 1 to 24 hours at TC, compounds of general formula (33) is obtained.

Next will be described preparation of radioactive condensation trisazo Ichiru compound.

The method (1: 3)

- general formula (4 8)

Wherein, R '', R 2 'independently represent hydrogen, halogen, Shiano, nitro, § Mino, Ajiruamino force Rubamoiru, alkyl force Rubamoiru, alkoxycarbonyl, cycloalkenyl, Ashiru, Arukiruamino, aminoalkyl, alkylaminoalkyl , human Dorokishi, Ashiruokishi, hydroxyalkyl, § sill O carboxyalkyl, alkoxyalkyl Kishiarukiru, alkyl, alkenyl, shows alkynyl or alkoxy, W is methylene, oxygen atom or N-R 3 (wherein, R 3 is hydrogen, alkyl, Fuenashi shown Le, or better § reel alkyl or heteroalkyl § reel al kills may have a substituent.) indicates, the other symbols are as defined above. ]

Suitable solvents which do not a compound represented inhibit the reaction by (methanol, ethanol, isopropyl alcohol, acetic acid Echiru, water, acetic acid, aqueous sodium hydroxide or the like of any of these mixed solvent,) in a suitable reduction catalyst presence of (platinum, palladium, nickel, rhodium, ruthenium, and these catalysts etc., such that adsorbed on a carrier), while through the tritium 厶 gas, 1-2 4 hours at the reflux temperature of room temperature or solvent, stirring or shaking by catalytic reduction in the general formula (4 9)

(Wherein each symbol is as defined above.)

Compound is obtained.

The method (1 4) In formula (1 8 ')

(Wherein each symbol is as defined above.)

The same conditions as the method (1 3) a compound represented by, by reducing the general formula (50)

(Wherein each symbol is as defined above.)

Compound is obtained. In a compound of general formula (50), a suitable solvent that does not inhibit the reaction (methylene chloride, black hole Holm, Jikuroroetan, tetrahydrofuran, Jechi ether, N, N-dimethyl formamidine de or the like of any of these mixed solvent), the general formula (1: 9)

G 1 one R (1 9)

(Wherein, G 1 represents a chlorine, bromine, iodine, methanesulfonyl O carboxymethyl, p- toluenesulfonic Ruhoniruokishi, and triflate Ruo b methanesulfonyl O carboxymethyl, R 4 is as defined above.)

A compound represented by, Toryechiruamin, pyridine, in the presence of a base, such as dimethyl § amino pyridinium down, the general formula by reacting under ice-cooling or at room temperature to 24 hours (5 1)

(Wherein each symbol is as defined above.)

Compounds represented by is obtained.

Methods (1 5)

Formula (5 1) or an acid addition salt, for example hydrochloride, hydrobromide, sulfate, etc. oxalic acid salt, a suitable solvent (methylene chloride which does not inhibit the reaction, black hole Holm, Jikuroroetan, Jefferies chill ether or these including any mixture solvent), the general formula (2 1)

G -R (2 1)

(Wherein, G 2 represents chlorine, bromine, iodine, methanesulfonyl O carboxymethyl, .rho. toluenesulfonic Ruhoniruokishi, and triflate Ruo b methanesulfonyl O carboxymethyl, R 5 is as defined above.)

A compound represented by, Toryechiruamin, pyridine, in the presence of a base, such as dimethyl § amino pyridinium down, by reacting under ice-cooling or at room temperature 1-24 h, the general formula (52)

(Wherein each symbol is as defined above.)

Compounds represented by is obtained.

Methods (1 6)

The general formula (23 ')

(Wherein each symbol is as defined above.)

Compounds or formula represented by (24 ')

(Wherein each symbol is as defined above.)

The same conditions as the method (1 3) a compound represented by, by reducing the general formula (3) 20

(Wherein each symbol is as defined above.)

Compound, or the general formula (54)

(Wherein each symbol is as defined above.)

Compounds represented by is obtained.

Formula (53) or the general compound represented by the formula (54) or an acid addition salt, such as hydrochloride, hydrobromide, a suitable solvent which does not sulfates, and oxalic acid salts, to inhibit the reaction ( methylene chloride, black hole Holm, Jikuroroetan, tetrahydro furan, Jefferies chill ether, New, Nyu- dimethylformamidine de or the like of any of these mixed solvent) in the general formula (25)

G 3 -ABR '(25)

(Wherein, G 3 represents chlorine, bromine, iodine, methanesulfonyl O carboxymethyl, .rho. toluenesulfonic Ruhoniruokishi, and triflate Ruo b methanesulfonyl O carboxymethyl, and other symbols are as defined above.)

A compound represented by, potassium carbonate, sodium hydroxide, Toryechiruamin, the presence of a base such as pyridine or dimethyl § amino pyridine, by reaction with ice-cooling or under room temperature for 1 to 24 hours, the general formula (55)

(Wherein each symbol is as defined above.)

Compound, or the general formula represented by (5 6)

(Wherein each symbol is as defined above.)

Compounds represented by is obtained.

Methods (1 7)

Formula (3) or a compound or an acid addition salt of the general formula (54), such as the hydrochloride, hydrobromide, a suitable solvent (Te tetrahydrofuran which does not inhibit the sulfates, oxalic acid salt reaction, dichloromethane, dimethylformamidine de or the like of any of these mixed solvent) in the general formula (28)

HOOC (CH 2) m R ( 28)

(Wherein, R 11 represents an optionally Ariru or heteroaryl may have a substituent, m represents a number of 1-7.)

The presence of a tertiary Amin such compound Toryechiruamin represented by, 1, 3 CT / JP96 / 02004 Jishikuro hexyl Cal positive imide, 1 Echiru 3- (3-dimethylamino blanking opening pill) Karupojiimi de, Shianohosuhon under condensing agent and ice, such as diesters or by converting the compound 1-2 4 hours at room temperature and has the general formula (5-7)

(Wherein each symbol is as defined above.)

Compound, or a compound represented by general formula (5 8)

(Wherein each symbol is as defined above.)

Compounds represented by is obtained.

In general formula (28) a reactive derivative (acid Kurori de, Ashiruimidazo Lumpur, etc.) of the compounds when using, reaction is carried out in a suitable solvent (tetrahydro furan does not inhibit the reaction, dichloromethane, black hole Holm, benzene or in these or any of the mixed solvent), the presence of such tertiary Amin is pyridine such Toryechiruamin, by reacting under ice-cooling or at room temperature for 1-2 4 hours, to proceed.

The thus obtained formula (5 7) or the general formula (5 8) suitable solvent compound that does not inhibit the reaction of (tetrahydrofuran, Jefferies chill ether, Toruenma others such as any mixture of these solvents) in , lithium aluminum hydride, borane such which reducing agent general formula by performing 1-2 4 hours reduction at room temperature from a 7 8 ° C using (5 9)

(Wherein each symbol is as defined above.)

Compound, or a compound represented by general formula (6 0)

(Wherein each symbol is as defined above.)

Compounds represented by is obtained.

Methods (1 8)

The general formula (3 4 ')

(34,)

(Wherein each symbol is as defined above.) The same conditions as the method (1 3) a compound represented by, by reducing the general formula (6 1)

(Wherein each symbol is as defined above.)

Compounds represented by is obtained. The compounds of general formula (61), reaction inhibition and such have a suitable solvent (methylene chloride, black hole Holm, etc. Jikuroroetan) in the presence of a base such as triethyl Chiruamin, p- toluenesulfonyl chloride Li de or methane Suruhonirukurori after introducing a leaving group to act like de, a solvent which does not interfere with the reaction in (methylene chloride, black hole Holm, Jikuroroetan, tetrahydrofuran, Jechi like ether or any mixture solvent), potassium carbonate, pyridine, Toryechiruamin etc. the presence of a suitable dehydrogenating agent, the general formula (35), (3 6) or (3 7)

(Wherein each symbol is as defined above.)

Compound or an acid addition salt thereof represented by, for example hydrochloride, hydrobromide, by the this reacted for 1 to 24 hours at the reflux temperature of the solvent at room temperature sulfates, such as oxalic acid salt with a general formula (52 ), (compound or formula 5 6) (62)

(Wherein each symbol is as defined above.)

A compound represented by the obtained respectively.

Pharmaceutically acceptable salts of the compounds of the general formula (1) include acid addition salts with inorganic or organic acids, by conventional methods inorganic acid compounds of general formula (I) (hydrochloride, Nioikamizu containing acid, sulfuric acid, phosphoric acid, nitric acid, etc.), organic acids (acetic, propionic, succinic, grayed recall acid, lactic acid, malic acid, tartaric acid, Kuen acid, maleic acid, fumaric acid, meta Nsuruhon acid, benzenesulfonic acid, p - toluenesulfonic acid, Kanfasuru acid may be a salt by treatment with such Asukorubin acid). Thus the present invention compound obtained may be isolated and purified by normal methods such as recrystallization, Karamuguromato method. When the resulting product is a racemate, for example by fractional crystallization of salts with optically active acid, or by passing through a column Hama charging an optically active carrier, it is resolved into a desired optically active substance can. Individual Jiasutereoma one can be separation by fractional crystallization means such as chromatography. These can also be obtained by using such optically active starting compound. Further, stereoisomers may Rukoto away single recrystallization method, or column chromatography.

The compounds of the present invention, acceptable salts optical isomers or its pharmaceutically are the D 4 receptor Ann evening agonist having selective and strong blocking action against the D 4 receptor, not positive symptoms only negative useful antipsychotic showing an effect against symptoms. The expected as antipsychotic conventional維体out path side effects such symptoms and endocrine abnormalities seen when administered antipsychotic drugs with D 2 receptor antagonism has been reduced. Moreover, since compounds of general formula (1) having a high affinity and selectivity to the D 4 receptor, radioactive substance of these compounds (radioligand) is industry as selective radioligand for D 4 receptors it is a top useful compounds. In other words, the general formula (gamma) of La Jiorigando human or animal (mouse, rat, guinea pig, I j, monkey, etc.) biometric each site (cerebral cortex, hippocampus, etc. linear body) a membrane fraction prepared from it can be used for D 4 receptor binding test using, also D 4 receptor binding using a membrane fraction prepared from D 4 receptor-expressing cells or biological each site that was human and other animals than claw-learning the test method can be used for subscription-learning of compounds with affinity for D 4 receptors. Furthermore, it is possible to know the change in D 4 receptor number in the brain of D 4 receptor distribution, number of receptors or partial裂病patient in a human or animal by autoradiography Gras Fi one labeled the D 4 receptor.

Condensate Toriazoru compounds of the present invention, when using the optical isomers or pharmaceutically acceptable cormorants Ru salt thereof as a medicine, the compound of the present invention the pharmaceutically acceptable carrier (excipient, binder, disintegrating agents, flavoring agents, flavoring agents, emulsifiers, diluents, solubilizers and the like) obtained by mixing with a pharmaceutical composition or preparation (tablets, pills, capsules, granules, powders, syrups, Emarujiyon, elixirs, suspensions , solutions, injections can be administered orally or parenterally in the form of drops or suppositories and the like). The pharmaceutical compositions may be formulated according to conventional methods. And has it herein, a parenteral, subcutaneous injection, intravenous injection, intramuscular injection, is intended to include like intraperitoneal injection or points drop method. Injectable preparations, for example sterile injectable aqueous suspensions walking oily suspensions, be prepared by methods known in the art using suitable dispersing or wetting agents and suspending agents it can. Its sterile injectable preparation may also be a solution or suspension capable of injection of sterility of diluent or solvent can be administered parenterally in non-toxic, such as an aqueous solution, for example. As for allowable base Hikuru or solvent which can be employed are water, Ringer's solution and isotonic saline and the like. Furthermore, it can be used normally even sterile, fixed oils as a solvent or suspending solvent. For this purpose, any nonvolatile oil can be used either fat proof acid, natural or synthetic or semi-synthetic fatty oil or fatty acid and natural or synthetic or semi-synthetic mono- or di- or triglyceride such, also included. Suppositories for rectal administration, the drug with a suitable non-irritating excipients, for example, in the Kokoaba coater or polyethylene glycols and time was room temperature is solid, liquid at temperatures in intestinal, rectally melted, the drug can be prepared by mixing the like that emits. Solid dosage forms for oral administration include powders, granules, tablets, pills, include those described above, such a force Buseru agent. In such dosage forms, the active ingredient compound is at least one additive, for example sucrose, lactose, cellulose sugar, Ma two tall, maltitol, dextran, starches, agar, alginates, chitin, chitosans, pectin such, tragacanth acids, gum arabic, gelatin, collagen, casein, albumin, synthetic or semi-synthetic polymers Ruima others can be mixed with glycerin earth. Such dosage forms thereof may also, as in ordinary, can contain further additives, for example inert diluents, lubricants such as magnesium stearate, paraben, preservatives such as sorbic acids, Asukorubi down acid, one Tokofuyuroru, antioxidants such as cysteine, disintegrants, binders, thickening agents, buffering agents, sweetening imparting agents, flavoring agents, perfumes agents. Tablets and pills as possible out also prepared by further Enterikkuko one coating. Solutions for oral administration can Emarujiyon agents include pharmaceutically acceptable, syrups, elixirs, suspensions, etc. solutions and the like, usually used et inert diluent at their art, including for example water it may be Idei.

Dosage, the age, body weight, general health, sex, diet, administration time, administration method, excretion rate, drug combination, depending on the extent of the condition is carried out treatment at that time of the patient, those or other It is determined in consideration of the factors. The compound of the present invention, the light Science isomers or a pharmaceutically acceptable salt thereof can be safely used at low toxicity, the daily dose is the patient's condition and body weight, type of compound, the route of administration It varies depending on, for example, parenterally subcutaneously, intravenously, or rectally intramuscular, about 0.

0 1 to 5 0 mg AZB, preferably 0. 0 1~2 O mg Z's Z Date administered, the or orally about 0. 0 1~1 5 OmgZ person Bruno day, preferably 0. l to 1 0 0mg

Z's "days it is desirable administration.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is a diagram showing a part of a nucleotide sequence of DNA of D4.2 and D4.5.

Figure 2 is a diagram showing a part of a nucleotide sequence of DNA of D4.2 and D4.5, shows the part following in FIG.

Figure 3 is a diagram showing a part of a nucleotide sequence of DNA of D4.2 and D4.5, shows the part following in FIG.

Figure 4 is a diagram showing a part of a nucleotide sequence of DNA of D4.2 and D4.5, shows the part following in FIG.

Figure 5 is a diagram showing a part of the nucleotide sequence of DN A of D4.2 and D4.5, shows the part following FIG. 4.

Figure 6 is a diagram showing a part of a nucleotide sequence of DNA of D4.2 and D4.5, shows the part following FIG. 5.

Figure 7 is a diagram showing a part of a nucleotide sequence of DNA of D4.2 and D4.5, shows the part following in FIG.

Hereinafter, examples of the present invention Starting Material Synthesis Example, although a detailed explanation of the formulations Formulation Examples and Experimental Examples, the present invention should not be construed as being limited thereto.

Starting Material Synthesis Example 1

Bentsue (WL B encze)'s method [Journal O Bed & Medishina le Chemistry (J. Me d. Ch em. :) first volume 4, 4 0 p. (1 9 7 1)] was follow synthesis .

α- tetralone in 30 Om l acetate solvent solution containing 2 O g and sodium azide 1 O g, 5 0 ° (: was added dropwise over concentrated sulfuric acid 3 0 m 1 2~ 3 hours at at ~ 5 5. after completion of the reaction, was treated with sodium carbonate solution, the reaction solution was extracted with acetic acid Echiru, and the organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. the solvent reduced pressure was evaporated , 2 by separating purified by obtained residue was purified by silica gel column chromatography (acetic Echiru only), 3, 4, to give 5 Tet draw 1 H- 2-Benzoazepin one 1 one on 1. 1 2 g .

• H-NMR (2 70 MHz, CDC ") (5 = 2. 1 2 (2H, dt, J = 6. 6, 7. 3Hz), 2. 78 (2H, dd, J = 6. 6, 7 . 3Hz), 3

¾.

. 1 8 - 3. 28 (2H, m), 7. 1 3 (1 H, dd, J = 1. 3, 7. 3H z), 7. 27 - 7. 4 0 (2 H, m), 7. 8 9 - 7. 93 (1 H, m) 9. 3 6 (1 H, m)

Further, the present compounds by the action of the Tetoraron with hydroxylamine shed, also obtained by performing obtained that Okishimu body to base Beckman rearrangement reaction.

Starting Material Synthesis Example 2

Chromanone to 1 35 g and 1 000 m 1 acetic acid solution was added sodium azide 77 g, was added dropwise over concentrated sulfuric acid 220 ml. 2 to 3 hours at 5 0 to 55. After completion of reaction, was treated with sodium carbonate solution, the reaction solution was extracted with acetic acid Echiru, and the organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, by resulting solid recrystallized from toluene, 2, 3 Jihidoro 4 H- 1, to obtain an base Nzookisazepin one 5- on-1 23 g.

Ή-NR (270 MHz, CDC ls) (5 = 3. 49 (2H, dd, J = 5. 3, 9. 5 Hz), 4. 3 9 (2 H, dd, J = 5. 6, 9 . 5 H z), 7. 00 (1 H, dd, J = 1. 3, 7. 9Hz), 7, 1 3 (1 H, ddd, J = 1. 3, 7. 9, 8. 6 H z), 7. 4 2 (1 H, ddd, J = 2. 0, 7. 9, 8. 6Hz), 7. 9 5 (1 H, dd, J = 2. 0, 7. 9 Hz), 8. 0 9 (1 H, br)

Starting Material Synthesis Example 3

Starting Material Synthesis Example 2 obtained in 2, 3-dihydro-4 H- 1, 4 one Benzookisazepi Hmm 5 on 5 g of N, N-dimethylformamide § Mi de solution 5 0 m 1 N-Kurorosa Kushin'imi de 4.5 after addition of g, it was 3-4 hours heated and stirred at 80. After completion of the reaction, the reaction mixture was washed with water, the organic layer 5 was extracted with acetic acid Echiru, washed with brine and dried over anhydrous magnesium sulfate. . . The solvent was evaporated under reduced pressure, the resulting solid by the recrystallized from toluene, 7-chloro-2, 3-dihydro

? H

To give 5-one 5. 0 g - one 1, 4 one base Nzookisazepin.

At the melting point 1 0 5-1 0 6

Starting Material Synthesis Example 4

Starting Material Synthesis Example 2 obtained in 2, 3-dihydro-4H-1, 4 one Benzookisazepi Hmm 5 on 5 g of N, N- to N- dimethylformamide § Mi de solution 5 0 m 1 Puromosa Kushin'imi de 6. O g and the mixture was 3-4 hours heated and stirred at at 80 °. After completion of the reaction, the reaction mixture was washed with water, the organic layer was extracted with acetic acid Echiru, washed with saturated brine, and then dried over magnesium sulfate. The solvent was evaporated under reduced pressure, by resulting solid recrystallized from toluene, 7 one-bromo - 2, 3-dihydro-4 H- 1, 4 one base emission zone Okisazepin one 5- turned 5. 2 g It was obtained. 02

Te mp 1 0 1-1 0 3

Starting Material Synthesis Example 5

After adding 1 Om l and under ice-cooling to a mixed solution of sulfuric acid 1 Om 1 acetate, Starting Material Synthesis Example 2 obtained in 2, 3-dihydro-4 H- 1, 4 one base Nzookisazepin one 5- on 3 g, It was added dropwise fuming nitric acid 0. 8 3m l, after stirring for 30 minutes, and further 1 hour 撹 拌 at room temperature. After completion of the reaction, treating the reaction mixture with aqueous sodium bicarbonate solution, the organic layer was extracted with acetic acid Echiru, washed with saturated brine and Drying over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, the resulting solid more that recrystallized from toluene, to give the 3-dihydro 7- two Torrox 4 H- 1, 4 one base Nzookisazepin one 5 one on 4. 8 g It was.

Mp 2 1 0-2 1 2

Starting Material Synthesis Example 6

Hoffman (H. Ho f ma nn) et al method [Liebig ■ Ana one Ren 'da one' Kemi one (L iebig s. Ann. Ch em.) 9 1 6 page (1 9 9 0)] was synthesized according to It was.

2- (2, 2-diethoxy-ethoxy) Benzuami de 3. 0 g and ρ- Torue Nsuruhon acid 0. 1 0 0 m 1 of a toluene solution containing 2 g was heated and stirred one hour 2 at the reflux temperature of the solvent. After completion of the reaction, and treating the reaction mixture with saturated sodium bicarbonate, an organic layer was extracted with acetic acid Echiru, washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, by separating purified by obtained residue was purified by silica gel column chromatography (black port Holm only), 1, 4 one Benzooki Sazepin one 5 (4H) one on 1. 2 g Obtained. Mp 1 24-1 26

Starting Material Synthesis Example 7

Chiokuromanon to 1 60 m 1 of acetic acid solution containing 20 g and sodium azide 8. 6 g, was added dropwise over concentrated sulfuric acid 35m 1 2 to 3 hours at at ~ 55 at 50. After completion of reaction, was treated with sodium carbonate solution, the reaction solution was extracted with acetic acid Echiru, and the organic layer was washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, the resulting residue was purified by silica gel column chromatography by separation and purification by (chloroform: methanol = 20 1), 2, 3 Jihido low 4H-1, 4 one base Nzochiazepin to give an 5 on 5. 4 g.

At the melting point 1 87-1 88

Starting Material Synthesis Example 8

Idon (B. I DDON)'s method - was synthesized according to the Journal-O Bed Chemical Fusae position one Perkin trans Akushonzu I (JCS Pe rkinl) 1 80 pp. (1 978)].

(2 Fueniruechiru) Amin in 1 50 ml black hole Holm solution containing 24 g and Toryechiruamin 20 g, was added dropwise chloroform Le 厶溶 solution 1 100 ml of chloroformate Echiru with stirring under ice-cooling. After completion of dropwise addition, the mixture was further stirred for 2 hours at room temperature. Obtained after completion of the reaction, the solvent was distilled off under reduced pressure, GETS chill ether to the resulting residue to filter off insoluble added, the Echiru N-(2-Fueniruechiru) force Rubameto 27. 5 g by distilling the filtrate It was. Boiling 1 1 4 ° C (0. 6mmHg) was then added Echiru N-(2-Fueniruechiru) force Rubameto 27, 5 g in 1 2 0 polyphosphate ° C, after additional 1 hour heating and stirring, the reaction the solution was treated with water. The organic layer was extracted with black port Holm, washed with saturated sodium bicarbonate and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, 3 by distilling the resulting residue to give 4-dihydroisoquinoline one 1 one on 1 1. 2 g.

Boiling 1 5 0 ° C (0. 4mmHg)

Starting Material Synthesis Example 9

2 obtained in Starting Material Synthesis Example 2, 3-dihydro-4 H- teeth 4 one Benzookisazepi Hmm 5-one 1 0 g under ice-cooling Jikuroroetan solution 1 0 0 m l of acetic anhydride 1 7. 3 g and aluminum chloride 1 after addition of 33 g, 1 hour, and further heated for 1 hour stirring at the solvent reflux temperature in the room. After completion of the reaction, the reaction mixture was poured into ice-cold water, was acidified with concentrated hydrochloric acid, an organic layer was extracted with black port Holm, and dried washed with water sulfate anhydride Magne Shiumu. Recrystallization of the next was obtained by evaporating the solvent under reduced pressure the solid with isopropyl alcohol 1 Asechiru - 2, 3-dihydro-4 H- 1, 4 one base Nzookisazepin one 5-on 9. 8 g Obtained.

It added Toryechirushiran 2 1. 3m l to Torifuruoro acetate 1 0 0 m l solution of the compound 5. 5 g, was stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was treated with carbonate force potassium solution, and the organic layer was extracted with acetic acid Echiru, washed with water, and dried over anhydrous sulfate Ma Guneshiumu. Then, the solvent was evaporated under reduced pressure, the resulting residue was purified by silica gel column chromatography (hexane n-: acetate Echiru = 20: 1) 2 by separating purified by 3-dihydro 7- Echiru 4H - 1 '4 - Benzooki Sazepin give an 5 on 4. 5 g.

'H - negation R (270 MHz, CDC ") 5 = 1 22 (t, 3H), 2. 65 (q, 2H), 3. 4 1 - 3. 50 (m, 2H) 4. 3 3 (s , 2H), 6. 9 3 (d, 1 H), 7. 25 (dd, 1 H), 7 7 6 (d, 1 H) 7. 98 -. 8. 1 3 (br, 1 H)

Starting Material Synthesis Example 1 0

Black hole propionic acid 1 9 0 g, hydroquinone monomethyl ether 2 1 0 g in an aqueous solution 6 00 m 1 of sodium bicarbonate 1 4 5 g, water solution 6 0 0 ml of hydroxide force potassium 1 20 g was added, 8 5 and stirred for 3 days at ~ 95 ° C. After completion of the reaction was adjusted to pH 5 with 1 0% hydrochloric acid, an organic layer was extracted with Echirueteru, then the aqueous layer was extracted with Echiru ether. It was then washing the ether layer with 1 0% aqueous sodium bicarbonate. Washing solution to give white crystals by returning to pH 5 with again 1 0% hydrochloric acid. This was extracted with black port Holm, and dried over anhydrous magnesium sulfate. It was distilled off under reduced pressure Solvent recrystallization resulting solid with benzene 3- (4 Meto Kishifueniru) propionic acid 5 6. 7 g. Mp 1 0 6~1 07 ° C

Next, with respect to acetic anhydride 20 0 ml, the above 3- (4-menu Tokishifueniru) propionic acid 5 6. 7 g, the phosphoric acid lml added was 7 hours under reflux in 1 3 8-1 4 0 . After completion of the reaction, the reaction solution was treated with aqueous potassium carbonate solution, and extracted with black port Holm, washed with water, and dried over anhydrous magnesium sulfate. The distillation was Tokura the residue of the solvent under reduced pressure to give 6-methoxy chroma Non 4 1 g by distillation under reduced pressure. Boiling point 6 5~75Z0. 1 4mmHg

Over the above 6-methoxy chroma Non 3 0 g, while sodium azide 1 4. 2 g maintaining 5 0-5 5 hands dissolved in glacial acetic acid 20 0 ml of concentrated sulfuric acid 4 0 m 1 1 to 2 hours It was dropped Te. After completion of the reaction, the reaction solution was treated with aqueous potassium carbonate solution, an organic layer was extracted with black port Holm, washed with water, and dried over anhydrous magnesium sulfate. Obtained by evaporating the solid solvent under reduced pressure to give a 2, 3 dihydric chondroitinase 7- main Tokishi 4 H- 1, 4 one base Nzookisazepin one 5- on-1 9 g By recrystallization from toluene

0 u 0

Te melting point 8 5-8 6

Starting Material Synthesis Example 1 1

6, 7-dimethyl Toki cycloalkyl Manon, by performing the same reaction and treatment as Starting Material Synthesis Example 2 using sodium azide and concentrated sulfuric acid, 2, 3-dihydro-7, 8 Jime Tokishi 4 H- 1, 4 one base Nzookisazepin one 5-one is obtained.

Starting Material Synthesis Example 1 2

7-methyl chroma non, by performing the same reaction and treatment as Starting Material Synthesis Example 2 using sodium § di reduction and concentrated sulfuric acid, 2, 3-dihydro-7-methyl - 4 H- 1, 4 one base Nzookisazepin one 5-one is obtained.

Starting Material Synthesis Example 1 3

7 main butoxy Chio chroma non, by performing the same reaction and process as a raw material if Narurei 2 using sodium azide and concentrated sulfuric acid, 2, 3-dihydro-7-menu preparative carboxymethyl one 4 H- 1, 4 one base Nzochiazepin one 5-one is obtained.

Starting Material Synthesis Example 1 4

Starting Material Synthesis Example 1 obtained in 2, 3, 4, 5-tetrahydro reaction similar to that of raw material in Synthesis Example 3 using 1 H- 2-base Nzoa Zepin one 1 one one and N- chloro-zag Shin I Mi de and processing by performing, 7-click J b "row 2, 3, 4, 5-tetrahydro

Roh HN,

1 H- 2-Benzoazepin one 1 one-one is obtained.

0

Starting Material Synthesis Example 1 5

Obtained in Starting Material Synthesis Example 7 2, 3-dihydro-4 H- 1, 4 one base Nzochiazepin - 5 one-one and N- chloro-zag Shin I Mi de similar reaction and treatment as Starting Material Synthesis Example 3 using by performing, 7-chloro-2, 3-dihydro - 4 H- 1, 4 one Ben Zochiazepin one 5-one is obtained.

0

In C

Starting Material Synthesis Example 1 6

Starting Material Synthesis Example 8 obtained in 3, 4-dihydroisoquinoline - 1 Ri by one one and N- black Rozakushinimi de carrying out the same reaction and treatment as Starting Material Synthesis Example 3 using 7-chloro-3, 4 - dihydroisoquinoline quinoline one 1 one-one is obtained, Starting Material Synthesis Example 1 7

2 obtained in Starting Material Synthesis Example 1, 3, 4, 5-tetrahydro-1 H- 2-Benzoa Zepin one 1 one one and N- Promo succinimide imide reaction and treatment analogous to Starting Material Synthesis Example 4 using by performing, 7 promoter 2, 3, 4, 5-tetrahydro-1 H- 2 one Benzoazepin one 1 one-one is obtained.

Starting Material Synthesis Example 1 8

Performing the same reaction and treatment as Starting Material Synthesis Example 4 using 5 one on and N- Puro乇 Sakushinimi de - Starting Material Synthesis Example 7 2 obtained in 3-dihydro 4 H- 1, 4 one base Nzochiazepin by, 7-bromo-2, 3 - dihydro - is 4 H- 1, 4 one Ben Zochiazepin one 5-on is obtained.

Starting Material Synthesis Example 1 9

2- (2, 2-GETS Toki Chez chill ethylsulfanyl) using Benzuami de, by performing the same reaction and treatment as Starting Material Synthesis Example 6, 1, 4 one base Nzochiazepin - 5 (4 H) - On the obtained It is.

Starting Material Synthesis Example 20

Coral (C. Co rral)'s method according to [Journal O Bed Heterocyclic click * Chemistry (J. He tero cyc li c. Chem.) 99th Volume, 9 9 pp (1 977)], 1 one base Njiru 2, 3-dihydro-4H-1, 4 one base Nzojiazepin one 5-one is obtained.

Aluminum chloride benzene 1 0 m l in 0.075 molar amount, 0.1 molar amount of the N- base Nji Ruan anthranilate methyl and 0.075 molar amounts of aziridine was added for 45 minutes heated and stirred at 90 ° C followed by addition of the reaction mixture into ice-cold water, 1 one base Njiru 2, 3-dihydro-4 H- 1, 4 one base Nzojiazepin one 5-on of crystals are obtained.

Starting Material Synthesis Example 21

Aluminum chloride, by carrying out the same reaction and treatment as Starting Material Synthesis Example 20 using N- methyl-anthranilic acid methyl and aziridine, 2, 3-dihydro-one 1-methyl 4 H- 1, 4 one base Nzojiazepin one 5- one is obtained.

Starting Material Synthesis Example 22 Starting Material Synthesis Example 1 2 obtained by, 3, 4, 5-tetrahydro-1 H- 2-base Nzoa Zepin - 1 one on 0. 97 g and L a we ss 0 n reagent 1. 33 g 3 0 m l toluene solution was added to 3-4 hours under reflux. After completion of the reaction, the treated organic layer and the reaction liquid was bicarbonate Natoriumu aqueous solution was extracted with acetic acid Echiru, after rinsing with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, by resulting solid recrystallized from toluene, 2, 3, 4, 5-tetrahydro-1 H - to give 2 Benzoazepin one 1-thione 1. 1 g.

! H-NMR (270 MHz, CDC ") 5 = 3. 1 6 (2 H, t, J = 5. 9Hz), 3. 38 (2H, dd, J = 5. 9, 6. 6 Hz), 7. 39 (2 H, m), 7. 5 1 -7. 54 (1 H, m), 7. 67-7. 71 (1 H, m) 8. 1 4 (1 H, br)

Starting Material Synthesis Example 23

Starting Material Synthesis Example 2 obtained in 2, 3-dihydro-4H-1, 4-Benzookisazepi Hmm 5-one 44 g and Lawe sson reagent 55 g was 3-4 hours heated under reflux for 300 ml Bokuru E emissions solution was added . After completion of the reaction, the treated organic layer and the reaction liquid was aqueous sodium bicarbonate solution and extracted with acetic acid Echiru, washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, by resulting solid recrystallized from toluene, 2, 3-dihydro-4H-1, 4 one base Nzookisa Zepin - give 5-thione 48 g.

] H-NMR (270 MHz, CDC 1 3) 5 = 3. 50 (2H, dd, J = 5. 9, 1 1. 2Hz), 4. 42 (2 H, dd, J = 5. 9, 1 1. 2Hz), 7. 04 (1 H, dd, J = 1. 3, 7. 9Hz), 7. 1 9 (1 H, ddd, J = 1. 3, 7. 2, 8. 4Hz), 7. 4 2 (1 H, ddd, J = 2. 0, 7. 9, 8. 4 Hz), 8. 0 1 (1 H, dd, J = 2. 0, 7. 2Hz), 9. 8 3 (1 H, br)

Starting Material Synthesis Example 24

Starting Material Synthesis Example 3 resulting 7-chloro 2, 3-dihydro-4H-1, 4 one Ben Zookisazepin one 5-on-5 g and L awe sson reagent 5.5 plus 3 g

0 m l toluene solution was 3-4 hours under reflux. After completion of the reaction, the reaction solution was treated with aqueous sodium bicarbonate solution, the organic layer was extracted with acetic acid Echiru, washed with saturated brine, and then dried over anhydrous magnesium sulfate. By obtained by evaporating the solid solvent under reduced pressure and recrystallized from toluene to give 7-chloro 2, 3-dihydro-4H-

1, 4 to obtain one base Nzookisazepin one 5-thione 4. 2 g.

At the melting point 1 27-1 28

Starting Material Synthesis Example 25

Starting Material Synthesis Example 4 resulting 7 promoter 2, 3-dihydro-4 H- 1, 4 one Ben Zookisazepin one 5- turned 5. 2 g and L a we ss 0 n reagent 4. 5 0 m plus 5 g the l toluene solution was heated to reflux for 3-4 hours. After completion of the reaction, the reaction solution was treated with aqueous sodium bicarbonate solution, the organic layer was extracted with acetic acid Echiru, washed with saturated brine, and then dried over anhydrous magnesium sulfate. Recrystallization of the solid body that is obtained by evaporating the solvent under reduced pressure from toluene, 7 promoter 2 to give 3-dihydro 4 H one 1, 4 one base Nzookisazepin one 5-thione 4. 8 g. Mp 1 3 9~ 1 4 1 e C

Starting Material Synthesis Example 2 6

2 obtained in Starting Material Synthesis Example 5, 3-dihydro-7- two Torrox 4 H- 1, 4 one Ben Zookisazepin one 5-on 2. O g and L awe sson reagent 1. 3 Om l toluene plus 0 g the solution was 3-4 hours under reflux. After completion of the reaction, the reaction solution was treated with aqueous sodium bicarbonate solution, the organic layer was extracted with acetic acid Echiru, washed with saturated brine, and then dried over anhydrous magnesium sulfate. Recrystallization 'the 减圧 solvent under solid was removed by distillation, and the body from toluene, 2, 3-dihydro - 7-nitro-one 4 H one 1, 4 one base Nzookisazepin one 5-thione 1. 8 g Obtained.

Mp 2 3 1~2 32 e C

Starting Material Synthesis Example 27

1 obtained in Starting Material Synthesis Example 6, 4 one base Nzookisazepin one 5 (4H) - on-5 g and L awe sson reagent 6. 5 g of 6 0 m l toluene solution was added and heated to reflux for between at 3-4. After completion of the reaction, the reaction solution was treated with aqueous sodium bicarbonate solution, the organic layer was extracted with acetic acid Echiru, washed with saturated brine, and then dried over anhydrous magnesium sulfate. More Recrystallization obtained by evaporating the solid solvent under reduced pressure from Toruen, 1, 4 one base Nzookisazepin one 5 (4H) - to obtain a thione 3. 4 g. Mp 1 1 0~ 1 1 2 ° C

Starting Material Synthesis Example 28

Starting Material Synthesis Example 7 2 obtained in 3-dihydro 4 H- 1, 4 one base Nzochiazepin one 5-on 5. 4 g and L awe ss 0 n reagent 6.1 was added 7 g 2 Om l preparative Ruen the solution was 3-4 hours under reflux. After completion of the reaction, the reaction solution was treated with sodium hydrogen carbonate solution, and the organic layer was extracted with acetic acid Echiru, washed with saturated brine, and then dried over anhydrous sulfate Maguneshiumu. Recrystallization of the obtained by evaporating the solid solvent under reduced pressure from Toruen, 2 to give 3-dihydro 4H-1, 4 one base Nzochiazepi Hmm 5- thione 3. 8 g.

Mp 1 4 2-1 4 5

Starting Material Synthesis Example 2 9

Obtained in Starting Material Synthesis Example 8 3, and heated to reflux between hours 4 dihydroisoquinoline one 1 one on 1 1. 20 0 ml toluene solution were added 2 g and L awe ss on reagent 1 7 g 3 to 4. After completion of the reaction, the reaction solution was treated with aqueous sodium bicarbonate solution, the organic layer was extracted with acetic acid Echiru, washed with saturated brine, and then dried over anhydrous magnesium sulfate. More recrystallization the obtained by evaporating the solid solvent under reduced pressure from Toruen, 3 to give 4-dihydroisoquinoline one 1-thione 1 0. 2 g. Melting point 9 5-9 8. C

Starting Material Synthesis Example 3 0

Starting Material Synthesis Example 2 obtained in 9, 3-dihydro - 7- Echiru 4 H- 1, 4 one Ben Zochiazepin one 5-one 4. 5 g, L a we ss 0 n reagent 4. toluene solvent solution of 8 g the 5 Om 1 was heated and stirred for 6 hours at the solvent reflux temperature. After completion of the reaction, the reaction solution was treated with carbonate force potassium solution, and the organic layer was extracted with acetic acid Echiru, washed with saturated brine, and then dried over anhydrous magnesium sulfate. Then, the residue that is obtained by evaporating the solvent under reduced pressure by silica gel column chromatography (black port Holm: methanol = 20: 1) 2 by separating purified by 3-dihydro 7- Echiru 4 H- 1 to obtain a 4 one base Nzochiazepin one 5-thione 4. 5 g.

Mp 8 1~ 8 2 ° C

Starting Material Synthesis Example 3 1

2 obtained in Starting Material Synthesis Example 1 0, 3-dihydro-7- methoxy-4 H- 1, 4 one benzothiazepine one 5-on 3. 9 g,; L Torue down solution of awe ss 0 n reagent 4. lg the 5 Om 1 was heated and stirred for 6 hours at the solvent reflux temperature. After completion of the reaction, the reaction solution was treated with charcoal potassium solution, and the organic layer was extracted with acetic acid Echiru, washed with saturated brine, and then dried over anhydrous magnesium sulfate. Then, after crystallization added Toruen to the resulting residue and the solvent was evaporated under reduced pressure, 2 By recrystallization Toruen, 3-dihydro-7-menu Tokishi 4H-1, 4 one base Nzochiazepin one It was obtained 5-thione, 4. 5 g.

Mp 1 1 1~ 1 1 2 'C

Starting Material Synthesis Example 3 2

2 obtained in Starting Material Synthesis Example 1 1, 3-dihydro-7, 8-dimethyl Tokishi 4 H- 1, 4 one base Nzochiazepin one 5-one, similar reaction operation as in Starting Material Synthesis Example 2 2 with L awe sson reagent 2 by performing, 3-dihydro-7, 8-dimethyl Tokishi 4 H- 1, 4 one base Nzochiazepin one 5-thione is obtained.

Starting Material Synthesis Example 3 3

Performing the same reaction and treatment as Starting Material Synthesis Example 2 2 with 2 obtained in Starting Material Synthesis Example 1 2, 3-dihydro-7- methyl-4 H- 1, 4-base Nzookisazepin one 5-one and L awe sson reagent by, 2, 3-dihydro-7- methyl-4 H- 1, 4 one base Nzookisazepin one 5- Chio, emission is obtained.

Starting Material Synthesis Example 3 4

2 obtained in Starting Material Synthesis Example 1 3, 3-dihydro-7- main Tokishi 4 H- 1, 4 Starting Material Synthesis Example 2 2 a similar reaction using an benzothiazepine one 5-one and L aw'e sson reagent and processing by performing, 2, 3-dihydro-7-menu butoxy - is 4 H- 1, 4 one base Nzochiazepin one 5-thione obtained.

Starting Material Synthesis Example 35

Starting Material Synthesis Example 1 4 resulting 7-chloro-2, 3, 4, the same reaction and treatment as Starting Material Synthesis Example 22 using 5-tetrahydro-1 H one 2- Benzoazepin one 1 one-one and L awe sson reagent by performing, 7-chloro-2, 3, 4, 5 - tetrahydro 1 H- 2-Benzoazepin one 1-thione is obtained.

Starting Material Synthesis Example 3 6

Starting Material Synthesis Example 1 5 resulting 7-chloro 2, 3-dihydro-4 .eta. 1, 4 similar reaction and treatment as Starting Material Synthesis Example 22 using an base Nzochiazepin one 5-one and L awe ss 0 n reagent by performing, 7-chloro-2, 3-dihydro-4 H- 1, 4 one base Nzochiazepin one 5-thione is obtained.

S

CI NH

- Raw Materials Synthesis Example 37

Starting Material Synthesis Example 1 6 obtained 7- chloro 3, 4-dihydroisoquinoline quinoline one 1 - by performing the same reaction and treatment as Starting Material Synthesis Example 22 using the on-and L a we sson reagent, 7- chloro 3, 4-dihydroisoquinoline one 1 Chio emission is obtained.

Starting Material Synthesis Example 38

7 one obtained in Starting Material Synthesis Example 1 7 promoter 2, 3, 4, 5-tetrahydro performs the same reaction and treatment as Starting Material Synthesis Example 22 using 1 H one 2- Benzoazepin one 1 one-one and L awe sson reagent it makes 7- promoter 2, 3, 4, 5 over tetrahydropyran over 1 H- 2-Benzoazepin one 1-thione is obtained.

Starting Material Synthesis Example 3 9

Starting Material Synthesis Example 1 8 obtained 7- promoter 2, 3-dihydro-4 H- 1, 4 carrying out the same reaction and treatment as Starting Material Synthesis Example 22 using an base Nzochiazepin one 5-one and L awe sson reagent the 7-promoter 2, 3-dihydro-4 H- 1, 4-base Nzochiazepin one 5-thione is obtained.

Starting Material Synthesis Example 4 0

By and using 1, 4 one base Nzochiazepin one 5-one and L awe ss o n reagent obtained in Starting Material Synthesis Example 1 9 performs the same reaction and treatment as Starting Material Synthesis Example 22, 1, 4 one base Nzochiazepin one 5-thione is obtained,

Starting Material Synthesis Example 4 1

Starting Material Synthesis Example 2 0 1 one base Njiru 2 obtained in 3-dihydro 4 H- 1, 4 one Benzojiazepin one 5-one and L a we sson reagents same reaction and treatment as Starting Material Synthesis Example 2 8 using a by performing, 1 one base Njiru 2, 3-dihydro - is 4 H- 1, 4 one base Nzojiazepin one 5-thione obtained

Starting Material Synthesis Example 4 2

2 obtained in Starting Material Synthesis Example 2 1, 3-dihydro-1-methyl-4 H- 1, 4 carrying out the same reaction and treatment as Starting Material Synthesis Example 2 2 with an base Nzojiazepin one 5-one and L awe sson reagent by, 2, 3-dihydro-1-methyl 4 H- 1, 4 one base Nzojiazepin one 5-thione is obtained.

Starting Material Synthesis Example 4 3

Starting Material Synthesis Example 2 obtained in 2 2, 3, 4, 5-tetrahydro-1 H- 2-base emission zone Azepin one 1-thione 1. dissolving 1 g in a mixed solvent consisting of water 2 Om l of tetrahydrofuran 2 0 m 1 after, addition of potassium hydroxide 0. 7 g and methyl iodide 1 g, the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was treated with water, the organic layer was extracted with acetic acid Echiru, washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the residue to n- as crystals by adding hexane 4, 5 Jihidoro 1 Mechiruchio one 3 H- 2-Benzoazepin 0. 6 g. s.Me

Melting point 64-6 5. C

Starting Material Synthesis Example 44

2 obtained in Starting Material Synthesis Example 23, 3-dihydro-4 H- 1, 4 one base Nzookisaze pin one 5-thione 4 8. 0 g were dissolved in a mixed solvent of water 20 Om 1 tetrahydrofuran 20 Om 1 or al after the potassium hydroxide 30 g and methyl iodide 1 6 2 g was added, the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was treated with water, the organic layer was extracted with acetic acid Echiru, washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, by separating purified by obtained residue was purified by silica gel column chromatography (black port Holm only), 2, 3-dihydro-5- main Chiruchio one 1, 4 one base Nzookisazepin 4 1. to give the O g.

'Η - NMR (270 MHz, CDC 1 3) 6 = 2. 5 8 (3 H, s), 3 74 (2H, t, J = 5. 3Hz), 4. 54 (2 H, t, J = 5. 3Hz): 7. 0 3 (1 H, dd, J = 1. 3, 7. 9Hz), 7. 1 1 (1 H, ddd: J = 2. 0, 7. 3, 7. 9Hz) , 7. 37 (1 H, ddd, J = 1. 3,. 3, 7. 9Hz), 7. 57 (1 H, dd, 2. 0, 7. 9Hz) Starting material synthesis example 4 5

Starting Material Synthesis Example 24 resulting 7-chloro 2, 3-dihydro - 4H-1, 4 dissolved one base Nzookisazepin one 5-thione 4. O g in a mixed solvent consisting of water 4 Om l of tetrahydrofuran 4 0 m 1 after, potassium hydroxide 2. lg and iodine turtle chill 2. 3 g was added, the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was treated with water, the organic layer was extracted with acetic acid Echiru, washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, by separating purified by obtained residue was purified by silica gel column chromatography (black port Holm only), 7-chloro-2, 3 Jihidoro 5- methylthio one 1, 4 one base Nzookisazepin 4 4. was obtained 2 g.

Starting Material Synthesis Example 4 6

Starting Material Synthesis Example 25 resulting 7-bromo-2, 3-dihydro-4H-1, after a 4-base Nzookisazepin one 5-thione 4. 8 g were dissolved in a mixed solvent consisting of water 50 m 1 of tetrahydrofuran 50 m 1 , potassium hydroxide 2. lg and iodine turtle chill 3 g was added, the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was treated with water, the organic layer was extracted with acetic acid Echiru, washed with brine and Drying over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue is separated purified by silica gel column chromatography one (black port Holm only), 7-promoter 2, 3-di Hidoro 5- methylthio one 1, 4 one base Nzookisazepin 5. were obtained 2 g.

Starting Material Synthesis Example 47 Starting Material Synthesis Example 2 6 2 obtained in 3-dihydro 7- two Torrox 4 H- 1, 4-base Nzookisazepin one 5-thione 1. 8 g of water 2 Om 1 tetrahydrofuran 2 0 m 1 It was dissolved in a mixed solvent consisting of added potassium hydroxide 0. 9 g and an iodine turtle chill 0. 5 5 m l, and stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was processed with water, the organic layer was extracted with acetic acid Echiru, washed with saturated brine, and then dried over anhydrous sulfate magnesium © beam. The solvent was evaporated under reduced pressure, by separating purified by resulting residue was purified by silica gel column chromatography (black port Holm only), 2, 3 dihydric draw 7- two Torrox 5- methylthio one 1, 4 one to obtain a base Nzookisazepin 1. 3 g.

Starting Material Synthesis Example 4 8

After Starting Material Synthesis Example 1 obtained in 2 7, 4 one base Nzookisazepin one 5 (4H) thione 3. 2 g was dissolved in a mixed solvent consisting of water 3 0 m 1 tetrahydrofuran 3 0 m 1, potassium hydroxide 2. O g and methyl iodide 2 6 m l, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was treated with water, the organic layer out extracted with acetic acid Echiru, washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, by separating the obtained residue was purified by silica gel column chromatography (only black port Holm) to give 5-methylthio one 1, 4 one Benzookisazepi down 2. 8 g.

Me

S '

Starting Material Synthesis Example 4 9 Starting Material Synthesis Example 28 2 obtained in 3-dihydro - 4 H- 1, 4 mixed-solvent consisting of an base Nzochiazepi Hmm 5- thione 3. 8 g of water 30 m l of tetrahydrofuran 3 0 m l was dissolved in potassium hydroxide 2. adding 1 g and methyl iodide 3. 4 g, the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was treated with water, the organic layer was extracted with acetic acid Echiru, washed with saturated brine, and then dried over anhydrous magnesium sulfate. Distilling off the reduced pressure solvent, by the obtained residue was separated and purified by silica gel column chromatography (black port Holm only), 2, 3-dihydro - 5-Mechiruchi O-1, 4 one base Nzochiazepin 2. to obtain a 1 g.

'Eta - 丽 R (270 MHz, CDC 13) 5 = 2. 4 9 (3 H, s), 3. 54 (2H, dd, J = 5. 3, 6. 9Hz), 3. 6 9 (2 . H, dd, J = 4 0, 6. 9Hz), 7. 33 - 7. 3 9 (3 H, m), 7. 52 (1 H, dd, 7. 3, 9. 2Hz)

Starting Material Synthesis Example 5 0

Starting Material Synthesis Example 2 9 obtained in 3, 4 after the dihydroisoquinoline one 1-thione 1 0. 2 g was dissolved in a mixed solvent consisting of water 30 m l of tetrahydrofuran 3 0 m 1, potassium hydroxide 7 g and iodine methyl 1 4 g, and the mixture was under 1 hour 撹捽 room temperature. After completion of the reaction, the reaction mixture was treated with water, the organic layer was extracted with acetic acid Echiru, washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, by Seisuru separating fine in the resulting ZanKiyoshi silica gel column chromatography (black port Holm only), 3 to give 4-dihydro 1-methylthio one isoquinoline 9. 0 g .

! H-NMR (270 MHz, CDC ") (5 = 2. 44 (3 H, s), 2. 73 (2H, t, J = 7. 3Hz), 3. 75 (2 H, t, J = . 7. 3Hz), 7. 1 7 (1 H, d, J = 7 3Hz), 7. 27 -. 7. 35 (2 H, m), 7 64 (1 H, dd, 1. 3, 8 . 4Hz)

Starting Material Synthesis Example 5 1

After Starting Material Synthesis Example 30 2 obtained by the 3-dihydro 7- Echiru 4 H- 1, 4 one base Nzochiazepin one 5-thione 3. 5 g was dissolved in a mixed solvent consisting of water 30ml and tetrahydrofuran 30 m 1, potassium hydroxide 1. 9 g and iodide methylation 2. 3 g was added, the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was treated with water, the organic layer was extracted with acetic acid Echiru, washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue is separated purified by silica gel column chromatography (black port Holm only), 2, 3-dihydro-5-methylthio one 1, 4 one base Nzookisazepin 3.5 It was obtained g.

Starting Material Synthesis Example 52

Starting Material Synthesis Example 3 1 2 obtained in 3-dihydro 7- methoxy 4 H- 1, 4 an benzo O hexa peptidase pin one 5-thione 3. 7 g in a mixed solvent consisting of water 30ml of tetrahydrofuran 3 0 m 1 after dissolution, potassium hydroxide 1. 9 g and methyl iodide 2. 3 g, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was treated with water, the organic layer was extracted with acetic acid Echiru, washed with saturated brine, and then dried over anhydrous sulfate Maguneshiu beam. The solvent was evaporated under reduced pressure, by separating purified by obtained residue was purified by silica gel column chromatography (black port Holm only), 2, 3 Jihido low 7- main Tokishi 5- methylthio one 1, 4 one Nzookisazepin 1. were obtained 7 2 g. .Me

S.

Mp 4 6~ 4 8 "C

Starting Material Synthesis Example 5 3

2 obtained in Starting Material Synthesis Example 3 2, 3-dihydro-7, 8-dimethyl Tokishi 4 H- 1, 4 one base Nzookisazepin one 5-thione and methyl iodide, a raw material in Synthesis Example 2 2 have use a hydroxide force potassium by performing the same reaction and treatment, 2, 3 Jihido low 7, 8 dimethyl Tokishi 5- methylthio one 1, 4 one base Nzookisazepin is obtained, et al. Starting Material Synthesis Example 5 4

2 obtained in Starting Material Synthesis Example 3 3, 3-dihydro-7-methyl - 4 H- 1, 4 one base Nzookisazepin one 5-thione and methyl iodide, a raw material in Synthesis Example 2 2 with hydroxide force Liu 厶by performing the same reaction and treatment, 2, 3-dihydro-7 - methyl one 5- methylthio one 1, 4 one base Nzookisazepin is obtained.

Starting Material Synthesis Example 5 5

2 obtained in Starting Material Synthesis Example 3 4, 3-dihydro-7- main Tokishi 4 H- 1, 4 one benzothiazepine one 5-thione and methyl iodide, a raw material in Synthesis Example 2 2 with water 酵化 potassium by performing the same reaction and treatment, 2, 3-dihydro-7 Ichime Tokishi 5- methylthio one 1, 4 one base Nzochiazepin is obtained.

Starting Material Synthesis Example 5 6

Starting Material Synthesis Example 3 5 obtained 7-chloro-2, 3, 4, 5-tetrahydro-1 H one 2- Benzoazepin one 1-thione, and methyl iodide, analogous to Starting Material Synthesis Example 2 2 have use of potassium hydroxide reaction and processing by performing, 8-chloro-4, 5-dihydro-1 Mechiruchio one 3 H- 2-Benzoazepin is obtained.

Starting Material Synthesis Example 5 7

Starting Material Synthesis Example 3 6 obtained 7-chloro-2, 3-dihydro-4 H- 1, 4 one base Nzochiazepin one 5-thione and methyl iodide, analogous to Starting Material Synthesis Example 2 2 with hydroxide force potassium reaction and that the 7-chloro-2 to perform processing, 3- dihydric draw 5- methylthio one 1, 4 one base Nzochiazepin is obtained.

Starting Material Synthesis Example 5 8

Starting Material Synthesis Example 3 7 obtained 7- chloro 3, 4-dihydroisoquinoline quinoline one 1-thione and methyl iodide, by performing reaction and treatment analogous to Starting Material Synthesis Example 2 2 with hydroxide force Riumu , 7-chloro 3, 4-dihydro-1 - Mechiruchi Oisokino phosphorus is obtained. Starting Material Synthesis Example 5 9

Obtained in Starting Material Synthesis Example 3 8. 8 promoter 2, 3, 4, 5-tetrahydro-1 H one 2- Benzoazepin one 1-thione and methyl iodide, analogous to Starting Material Synthesis Example 2 2 with hydroxide force Riumu by performing the reaction and treatment, 7- promoter 3, 4 Jihidoro 1 Mechiruchio one 3 H- 2-Benzoazepin is obtained.

Starting Material Synthesis Example 6 0

Starting Material Synthesis Example 3 9 obtained 7- promoter 2, 3-dihydro-4 H- 1, 4 one base Nzochiazepin one 5-thione and methyl iodide, analogous to Starting Material Synthesis Example 2 2 with hydroxide force Riumu reaction and processing by performing, 7 promoter 2, 3-di hydro - 5- methylthio one 1, 4 one base Nzochiazepin is obtained.

Starting Material Synthesis Example 6 1

Obtained in Starting Material Synthesis Example 4 0 4 H- 1, 4 one base Nzochiazepin - 5-thione Oyo PT /

Fine methyl iodide by performing the same reaction and treatment as Starting Material Synthesis Example 22 using the hydroxide force Riumu, 5-methylthio one 1, 4 one base Nzochiazepin is obtained.

Starting Material Synthesis Example 62

Starting Material Synthesis Example 4 1 1 one base Njiru 2 obtained in, 3-dihydro-4H-1, 4-Benzojiazepin one 5-thione and methyl iodide, analogous to raw materials Synthesis Example 4 3 using a hydroxide force Riumu reaction and processing by performing, 1 one base Njiru 2, 3 - dihydro 5-methylthio one 1, 4 one base Nzojiazepin is obtained.

Starting Material Synthesis Example 6 3

2 obtained in Starting Material Synthesis Example 4 2, 3-dihydro-1-methyl-4 H- 1, 4 one base Nzojiazepin one 5-thione and methyl iodide, analogous to Starting Material Synthesis Example 4 3 using a hydroxide force Riumu reaction and by performing the processing, 2, 3-dihydro-1 one-methyl 5-methylthio one 1, 4 one base Nzojiazepin is obtained.

Starting Material Synthesis Example 64

® bite Pian Journal O Bed Medicinal, Chemistry one (Eu r. J. Me d. Ch e m.) 1 1 Volume, follow the method described in 22 page 1 (1 9 76), 6, 7 - dihydro 5 H- base emission zone [b] Chiofen one 4 5 by an on-utilizing Okishimu reduction and Beckmann rearrangement reaction as a starting material, 6, 7, 8 - tetrahydro 4 H- thieno [3, 2 - c] Azepin obtain an 4 one on.

Hereinafter, by using the same raw material in Synthesis Example 6 4 method, lactams described in the following Starting Material Synthesis Example 6 5-7 8 as departure raw material corresponding ketone is obtained. Starting Material Synthesis Example 6 5

5, 6, 7, 8-tetrahydro-4 H- thieno [3, 4-c] Azepin one 4 one on

Starting Material Synthesis Example 6 6

4, 5, 6, 7-tetrahydro-8 H- thieno [2, 3- c] Azepin one 8-one

Starting Material Synthesis Example 6 7

3, 4-dihydro-thieno [3, 2 - f - 1, 4 one thiazepine one 5 (2H) one-on Starting Material Synthesis Example 6 8

3, 4-dihydrothieno [3, 4 - f) one 1, 4 one thiazepine one 5 (2H) On

Starting Material Synthesis Example 6 9

3, 4 Jihidorocheno [2, 3- f] one 1, 4 one thiazepine one 5 (2H) On

Starting Material Synthesis Example 70

3, 4-dihydrothieno [3, 2-: f] one 1, 4 Okisazepin 5 (2H) one-on

Starting Material Synthesis Example 7 1

3, 4-dihydro-Choi Bruno [3, 4 - f) - 1, 4 one year old Kisazepin one 5 (2H) one-on Starting Material Synthesis Example Ί 2

3, 4-dihydro-thieno [2, 3- f] - 1, 4 one year old Kisazepin one 5 (2 H) one-on

Starting Material Synthesis Example 73

7-methyl-3, 4-dihydrothieno [2, 3- f] one 1, 4 one year old Kisazepin - 5 (2H) one-on Starting Material Synthesis Example 74

6, 7-Jihidorocheno [3, 2-c] pyridine one 4 (5 H) one on

Starting Material Synthesis Example 75

2, 3-dihydro-4H- thieno [3, 2-e] one 1, 3-thiazine one 4-O emissions Starting Material Synthesis Example 7 6

2, 3 dihydric draw 4 H- thieno [3, 2-e] one 1, 3-Okisajin one 4-one

Starting Material Synthesis Example 7 7

1-methyl-1, 2, 3, 4 draw 5 H- thieno [2, 3- e] one 1, 4 one Jiazepin one 5- ON

Starting Material Synthesis Example 7 8

1 one base Njiru 1, 2, 3, 4 Tetorahido port one 5H- thieno [2, 3- e] - 1, 4 - Jiazepin one 5- ON

The resulting lactam body the raw material synthesis example as a starting material, organic chemistry on well-known chemical reaction, for example, halogenation reaction, Mannich reaction, the raw material synthesized by chemical modification of Chiofen ring such as by Friedel-Crafts reaction lactam derivative according to example 7 9-9 1 are obtained.

Starting Material Synthesis Example 7 9

2 promoter 5, 6, 7, 8-tetrahydro-4 H- thieno [3, 2-c] § Zepin one 4- On

Starting Material Synthesis Example 8 0

2-dimethyl § amino methyl one 5, 6, 7, 8 Tetorahido port one 4 H- thieno [3, 2-c] Azepin one 4 one on

Starting Material Synthesis Example 8 1

2-methylaminomethyl one 5, 6, 7, 8-tetrahydro-4 H- thieno [3 2-c] Azepin one 4 one on

Starting Material Synthesis Example 8 2

2 Shikurobu port pills aminomethyl -5, 6, 7, 8-tetrahydro-4 H- Ji eno [3, 2-c] Azepin one 4 one on

Starting Material Synthesis Example 8 3

2 Asechiru 5, 6, 7, 8-tetrahydro-4 H- thieno [3, 2-c] Azepin one 4 one on

Starting Material Synthesis Example 8 4

2 Echiru 5, 6, 8-tetrahydro-4 H- thieno [3, 2-c] § Zepin one 4 one on

Starting Material Synthesis Example 8 5

2-hydroxymethyl -5, 6, 7, 8-tetrahydro-4 H- thieno [3 2-c] Azepin one 4 one on

Starting Material Synthesis Example 8 6

2- (1-hydroxy E chill) one 5, 6, 7, 8-tetrahydro-one 4 H- Choi Bruno [3, 2-c] Azepin one 4- On

Starting Material Synthesis Example 8 7

3 Echiru 5, 6, 8-tetrahydro-4 H- thieno [3, 2-c] § Zepin one 4 one on

Starting Material Synthesis Example 8 8

2-methylthio one 5, 6, 7, 8-tetrahydro-4 H- thieno [3 2-c] Azepin one 4 one on

Starting Material Synthesis Example 8 9

8 Asechiru 7- methyl-3, 4-dihydro-thieno [2, 3 - f) - 1, 4 one year old Kisazepin one 5 (2H) one-on

Starting Material Synthesis Example 9 0

8 Echiru 7- methyl-3, 4-dihydro-thieno [2, 3- f] one 1, 4 Okisazepin - 5 (2H) one-on

Starting Material Synthesis Example 9 1

8- bromo-7-methyl-3, 4-dihydro-thieno [2, 3- f] one 1, 4 Okisazepin one 5 (2H) - On

Starting Material Synthesis Example 9 2

5 obtained in Starting Material Synthesis Example 6 4, 6, 7, 8-tetrahydro-4 H- thieno [3, 2-c] Azepin - 4 with stirring to single on 5 0 g of toluene 5 0 0 m l solution, L awe sson reagent 6 0 g was added, 1 1 0 ° C~ 1 2 0 e C at 1 cause reaction for 24 hours. After cooling, the reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution, and extracted with acetic acid Echiru, washed with water, dried over magnesium sulfate. After concentration under reduced pressure, by subjecting the resulting residue to silica gel column chromatography, pale 5 yellow crystals, 6, 7, 8-te Torahidoro 4 H- thieno [3, 2-c] Azepin one 4-thione 4 7 g Obtained.

Mp 9 4-9 6 hand below, by using the same method as Starting Material Synthesis Example 9 2, thione compound described in the following Starting Material Synthesis Example 9 3-1 1 9 the corresponding lactams as starting material is obtained . Starting Material Synthesis Example 9 3

5, 6, 7, 8-tetrahydro-4 H- thieno [3, 4 one c] Azepin one 4 - thione

Starting Material Synthesis Example 9 4

4, 5, 6, 7-tetrahydro-8 H- thieno [2, 3- c] Azepin one 8-thione

Starting Material Synthesis Example 9 5

3, 4-dihydrothieno [3, 2 - f] - 1, 4 one thiazepine one 5 (2H) thione

Starting Material Synthesis Example 9 6

3, 4-dihydrothieno [3, 4-f] one 1, 4 one thiazepine one 5 (2 H) thione Starting Material Synthesis Example 9 7

3, 4 Jihidorocheno [2, 3- f] one 1, 4 one thiazepine one 5 (2H) thione

Starting Material Synthesis Example 9 8

3, 4-dihydro-thieno [3, 2-f] one 1, 4 one year old Kisazepin one 5 (2H) thione

Starting Material Synthesis Example 9 9

3, 4-dihydrothieno [3, 4-f] one 1, 4 one year old Kisazepin one 5 (2H) thione

Starting Material Synthesis Example 1 0 0

3, 4-dihydro-thieno [2, 3 - f) one 1, 4 one year old Kisazepin one 5 (2H) thione

Starting Material Synthesis Example 1 0 1

7-methyl-3, 4-dihydrothieno [2, 3- f] one l, 4 one year old Kisazepin - 5 (2H) thione

Starting Material Synthesis Example 1 02

6, 7-dihydrothieno [3, 2-c] pyridine one 4 (5 H) - thione

Starting Material Synthesis Example 1 0 3

2, 3-dihydro-4 H- Choi 'Bruno [3, 2-e] one l, 3-thiazine one 4-thione

Starting Material Synthesis Example 1 0 4

2, 3-dihydro-4H- thieno [3, 2-e] one 1, 3-Okisajin one 4-thione Starting Material Synthesis Example 1 0 5

2-bromo-5, 6, 8-tetrahydro-4 H- thieno [3, 2-c] § Zepin one 4-thione

Starting Material Synthesis Example 1 0 6

2-dimethyl § amino methyl one 5, 6, 7, 8-tetrahydro-4 H- thieno [3, 2-c] Azepin one 4-thione

Starting Material Synthesis Example 1 0 7

2-methylaminomethyl -5, 6,, 8-tetrahydro-4 H- thieno [3 2-c] Azepin one 4-thione

Starting Material Synthesis Example 1 0 8

2-cyclopropylamino-methyl -5, 6, 7, 8 Tetorapidoro 4H- Chi perilla [3, 2-c] Azepin one 4-thione

Starting Material Synthesis Example 1 0 9

2 Asechiru 5, 6, 8-tetrahydro-4 H- thieno [3, 2-c] Azepin one 4-thione

Starting Material Synthesis Example 1 1 0

2 Echiru 5, 6, 8-tetrahydro-4 H- thieno [3, 2-c] § Zepin one 4-thione

Starting Material Synthesis Example 1 1 1

2-hydroxymethyl -5, 6 8- tetrahydro one 4 H- thieno [3 2-c] Azepin one 4-thione

Starting Material Synthesis Example 1 1 2

2- (1-hydroxy E chill) one 5, 6, 7, 8-tetrahydro-4 H- Choi Bruno [3, 2 - c) Azepin one 4-thione

8 g PT /

Starting Material Synthesis Example 1 1 3

3 Echiru 5, 6 8- tetrahydro 4 H- thieno [3, 2-c] § Zepin one 4-thione

Starting Material Synthesis Example 1 1 4

2-methylthio one 5, 6, 7, 8-tetrahydro-4 H- thieno [3, 2-c] Azepin one 4-thione

Starting Material Synthesis Example 1 1 5

8 Asechiru 7- methyl-3, 4-Jihidorocheno [2, 3- f] one 1, 4 Okisazepin one 5 (2 H) thione

Starting Material Synthesis Example

1 1 6

8 Echiru 7- methyl-3, 4-dihydrothieno [2, 3 - f) one 1, 4 one Okisazepin one 5 (2H) thione

Starting Material Synthesis Example 1 1 7

8-bromo-one 7- methyl-3, 4-dihydrothieno [2, 3- f] one 1, 4 one Okisazepin - 5 (2H) - thione

Starting Material Synthesis Example 1 1 8

1 one methyl one 1, 2, 3, 4-tetrahydronaphthalene over 5 H- thieno [2, 3- e] one 1, 4 one Jiazepin one 5- thione

Starting Material Synthesis Example 1 1 9

1 one base Njiru 1, 2, 3, 4-tetrahydro-one 5H- thieno [2, 3- e] - 1, 4-Jiazepin one 5- thione

Starting Material Synthesis Example 1 2 0

Starting Material Synthesis Example 9 2 5 obtained in, 6, 7, 8-tetrahydro-4 H- thieno (3, 2-c) Azepin one 4-thione 4 6 g of tetrahydrofuran 4 0 0 ml of water 4 0 0 m l mixed solution under ice-cooling with stirring to potassium hydroxide 2 8 g, methyl iodide 1 7m l was added and stirred for 2 hours at room temperature. After completion of the reaction, and extracted with acetate Echiru, washed with water, dried over magnesium sulfate. After concentration under reduced pressure, by performing the obtained crystals recrystallized from a mixed solvent of hexane and acetic E Ji Le, pale 4 one methyl Chio 7 as yellow crystals, 8-dihydro-one 6 H- thieno [3, 2- was obtained c] Azepin 4 2 g.

Mp 6 4~ 6 5 e C

Hereinafter, by using the same raw material in Synthesis Example 1 2 0 methods, methylthio body according to corresponding thione compound in the following Starting Material Synthesis Example 1 2 1-1 4 7 as starting material is obtained, et al.

Starting Material Synthesis Example 1 2 1

4 Mechiruchio one 7, 8-dihydro-6H- thieno [3, 4-c] Azepin

Starting Material Synthesis Example 1 2 2

8 methylthio one 5, 6-dihydro-4 H- thieno [2, 3- c] Azepin

Starting Material Synthesis Example 1 2 3

5-methylthio one 2, 3-dihydrothieno [3, 2-f] 1, 4-Chiazepi down

Starting Material Synthesis Example 1 2 4

5 Mechiruchio one 3, 4-dihydrothieno [3, 4 - f) - 1, 4 one Chiazepi down

Starting Material Synthesis Example 1 2 5

5-methylthio one 3, 4-dihydrothieno [2, 3- f] one 1, 4 one Chiazepi down

Starting Material Synthesis Example 1 2 6

5-methylthio one 2, 3-dihydrothieno [3, 2 - f one 1, 4 Okisaze pin

Starting Material Synthesis Example 1 2 7

5-methylthio one 3, 4-dihydrothieno [3, 4 - f) one 1, 4- Okisaze pin Starting Material Synthesis Example 1 2 8

5 Mechiruchio one 3, 4-dihydro-thieno [2, 3-: f] one 1, 4 one year old Kisaze pin

Starting Material Synthesis Example 1 2 9

7-methyl-5-methylthio one 3, 4-dihydro-thieno [2, 3- ί] one 1 4 Okisazepin

Starting Material Synthesis Example 1 3 0

4 Mechiruchio one 6, over-dihydro thieno [3, 2-c] pyridine

Starting Material Synthesis Example 1 3 1

4 Mechiruchio one 2H- thieno [3, 2-e] one 1, 3-thiazine

Starting Material Synthesis Example 1 3 2

4-methylthio one 2 H- thieno [3, 2-e] one 1, 3-Okisajin

Starting Material Synthesis Example 1 3 3

2-bromo-4 Mechiruchio one, 8-dihydro-6 H- thieno [3, 2-c] Azepin

Starting Material Synthesis Example 1 3 4

2-dimethyl § amino methyl one 4 Mechiruchio one 7, 8-dihydro-one 6 H- Choi Bruno [3, 2-c] Azepin

Starting Material Synthesis Example 1 3 5

2-methyl § amino methyl -4 Mechiruchio one 7, 8-dihydro-6 H- thieno [3, 2-c] Azepin Starting Material Synthesis Example 1 3 6

2-cyclopropyl § amino methyl -4 Mechiruchio one 7, 8-dihydro-6 H Chieno [3, 2-c] Azepin

Starting Material Synthesis Example 1 3 7

2- Asechiru 4 Mechiruchio one 7, 8-dihydro-6 H- thieno [3, 2-c] Azepin

Starting Material Synthesis Example 1 3 8

2- Echiru 4 Mechiruchio one 7, 8-dihydro-6H- thieno [3, 2-c] Azepin Starting Material Synthesis Example 1 3 9

2-hydroxymethyl -4 Mechiruchio one 7, 8-dihydro-6 H- thieno [3, 2-c] Azepin Starting Material Synthesis Example 1 4 0

2 - (1-hydroxy E chill) one 4-methylthio-one 7, 8-dihydro-6 H- thieno [3, 2-c] Azepin

Starting Material Synthesis Example 1 4 1

3 Echiru 4 methylthio one 7, 8-dihydro-6 H- thieno [3, 2-c] Azepin

Starting Material Synthesis Example 1 4 2

3, 4 one dimethylthio one, 8-dihydro-6 H- thieno [3, 2-c] § peptidase pin

Starting Material Synthesis Example 1 4 3

8 Asechiru 7- methyl-5-methylthio one 3, 4-dihydrothieno [2, 3 - f) one 1, 4 one year old Kisazepin

Starting Material Synthesis Example 1 4 4

8 Echiru 7- methyl-5-methylthio one 3, 4-dihydro-thieno [2, 3 one f] one 1, 4 one year old Kisazepin

Starting Material Synthesis Example 1 4 5

8- bromo-7-methyl-5-methylthio one 3, 4-dihydrothieno [2, 3 one f] one 1, 4 Okisazepin

Starting Material Synthesis Example 1 4 6

1 - methyl-5-methylthio one 2, 3-dihydro-1 H- thieno [2, 3-e] one 1, 4 one Jiazepin

Starting Material Synthesis Example 1 4 7

1 one base Njiru 5- methylthio one 2, 3-dihydro-1 .eta. thieno [2, 3-e] one 1, 4 one Jiazepin

Starting Material Synthesis Example 1 4 8

Starting Material Synthesis Example 6 4 obtained in 5, 6, 7, 8-tetrahydro-4 .eta. thieno with stirring to [3, 2-c] Azepin one 4 one on 4 g dimethylformamidine de 5 Om l solution, 1 an chlorosuccinimide imide 3. 5 g was added, to 1 to 2 4 hours reaction at 8 0 ° C. After completion of the reaction, the reaction mixture was poured into ice water, and extracted with acetic acid Echiru, washed with water, dried over magnesium sulfate. And concentrated under reduced pressure, the resulting residue was dissolved in toluene 5 0 m l, stirring the L awe ss 0 n reagent 6 0 g added with 1-2 4 hours 1 1 0 e C~ 1 2 0 ° C reacting. After cooling, the reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution, and extracted with acetic acid Echiru, washed with water, dried over magnesium sulfate. After concentration under reduced pressure, by subjecting the obtained Zan查 to silica gel column chromatography, pale 2- chloro 5 yellow crystals, 6, 7, 8-tetrahydro-4 H- thieno [3, 2-c] Azepin one 4- thione 2. was obtained 2 g.

Starting Material Synthesis Example 1 4 9

Starting Material Synthesis Example 1 4 2 chloro 5 obtained in 8, 6, 7, 8-tetrahydro-4 H- thieno [3, 2-c] Azepin using one 4-thione Starting Material Synthesis Example 1 1 6 the same like by performing the reaction and treatment 2- chloro 4 Mechiruchio one 7, 8-dihydrazide draw 6 H- thieno give the [3, 2-c] Azepin. Starting Material Synthesis Example 1 5 0

7- Echiru 3, 4 Jihidorocheno [3, 2 one "M - 1, 4 one thiazepine

5 (2H) - on Starting Material Synthesis Example 1 5 1

7- Echiru 3, 4 Jihidorocheno [3, 2-: Π - 1. 4 one thiazepine 5 (2H) - thione

Starting Material Synthesis Example 1 5 2

7 - Echiru one 5-methylthio one 2, 3 Jihidorocheno [3, 2- f) U 4] thiazepine Example 1

Starting Material Synthesis Example 4 2 obtained in 4, 3-dihydro-5-methylthio - teeth 4 one base Roh Zookisazepin 1 0 and 1 _ a (tertiary butoxycarbonyl) piperidine one 4 one Rubo hydrazide 1 6. 4 g the blanking evening Nord solution 2 0 0 ml was added were 3-4 hours heated and stirred at reflux temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, to which water and acetic acid Echiru added, the organic layer was separated and extracted, washed with saturated brine, and then dried over anhydrous sulfate mug Neshiumu. The solvent was distilled off under reduced pressure, the obtained residue was purified by silica gel column chromatography (black port Holm: methanol = 3 0: 1) by line Ukoto separation and purification by, 3- (1 - (tert-butoxycarbonyl ) piperidine one 4 - I le) -. 5, 6-dihydro-1, 2, 4-Toriazoro [4, 3- d] to give the teeth 4] benzo Okisazepin 8. 1 g. Mp 1 8 1~1 8 3 ° C.

The above compound 8. 1 g was added under ice-cooling Torifuruoro acetate 8 0 m l. After completion of the reaction, the reaction mixture was treated with at aqueous potassium carbonate solution, the organic layer was extracted with acetic acid Echiru, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give a solid by adding a residue of saturated hydrogen chloride one isopropyl alcohol 1 0 m 1 obtained. By performing recrystallized from methanol, 5, 6-dihydro-one 3- (piperidin-one 4 one I le) one 1, 2, 4-Toriazoro [4, 3 - d] [1, 4] Benzookisazepi down dihydrochloride monohydrate 5. give 2 g.

Mp 2 9 3~ 2 9 5 ° C

Example 2

2 obtained in Starting Material Synthesis Example 3 1, 3-dihydro-7-methoxy-5-methylthio one 1, 4 one base Nzookisazepin and 1 i (tertiary butoxide pheasant carbonyl) Piperi Gin - 4 by using an carbohydrazide Example by a child that is responsible for 1 a similar reaction and treatment, 5, 6-dihydro-1 0-methoxy-3- (piperidin-one 4 one I le) one 1, 2, 4 one Toriazoro [4, 3 -d] [1, 4] benzo O hexa peptidase pin resulting et al is,

Example 3

Starting Material Synthesis Example 4 8 5 methylthio one 1 obtained in four one base Nzookisazepin and 1 one same reaction and as described in Example 1, using (tertiary butoxycarbonyl) piperidine one 4 one carbohydrazide by performing the process, 3- (piperidin-one 4 one I le) Single Toriazoro [4, 3 - d] [1, 4] benzo O hexa peptidase pin is obtained.

Example 4

Obtained in Starting Material Synthesis Example 4 9 2, and 3-dihydro-5-methylthio one 1, 4 one Ben Zochiazepin and 1 an embodiment 1 by using (tertiary butoxide Kin carbonyl) piperidine one 4 one carbohydrazide by performing the same reaction and treatment, 3- (piperidine one 4 one I le) one 1, 2, 4-Toriazoro [4, 3 - d] [1, 4] base Nzochiazepin is obtained.

Example 5

0 2 Starting Material Synthesis Example 5 5 2 obtained in 3-dihydro - 4 one carbohydrazide - 1 0- main Tokishi 5 Mechiruchi O-1, 4 one base Nzochiazepin and 1 i (tertiary butoxycarbonyl) Piperi Gin by a child that is similar reaction and treatment as in example 1 using, 5, 6-dihydro-1 0-main butoxy one 3- (piperidin-one 4 one I le) one 1, 2, 4 one Toriazoro [4, 3 -d] [1, 4] that benzothiazepine are obtained 0

Example 6

Performing the same reaction and treatment as in Example 1 using 4-carbohydrazide - raw synthesis obtained in Example 6 1 5-methylthio - 1, 4 one base Nzochiazepin and 1 - (tert-butoxycarbonyl) piperidine it makes 3- (piperidin one 4-I le) one 1, 2, 4 one Toriazoro [4, 3 - d] [1, 4] benzothiazepine is obtained.

Example 7

Starting Material Synthesis Example 5 0 obtained in 1- methylthio one 3, 4-dihydroisoquinoline per cent pre 1 i (tertiary butoxycarbonyl) similar reaction and treatment as in Example 1 to have use of the piperidine one 4- carbohydrazide by performing, 5, 6-dihydro-3 - (piperidin-one 4 one I le) one 1, 2, 4-Toriazoro [4, 3- a] isoquino phosphorus is obtained. Example 8

Starting Material Synthesis Example 6 2 1 one base Njiru 2 obtained in 3-dihydro - 5-methylthio one 1, 4 one base Nzojiazepin and 1 i (tertiary butoxycarbonyl) Piberiji Hmm 4 Example 1 using an carbohydrazide by performing the same reaction and treatment as, 7- benzyl-3- (piperidin-one 4 one I le) one 1, 2, 4-Toriazo port [4, 3 - d] [1, 4] Benzojiazepin is obtained.

Example 9

Material obtained in Synthesis Example 4 3 4, 5-dihydro-1 - methylthio one 3 .eta. 2-base Nzoazepin and 1 an embodiment 1 by using (tert-butoxycarbonyl) piperidine one 4 one carbohydrazide and by performing the same reaction and treatment, 3- (piperidine one 4 one I le) one 6, 7-dihydro-5 .eta. 1, 2, 4-Toriazoro [3, 4 one a] [2] Benzoazepin can get.

Example 1 0

Starting Material Synthesis Example 5 7 obtained 7-chloro-2, 3-dihydro-5-methylthio one 1, 4 one base Nzochiazepin and 1 i (tertiary butoxycarbonyl) piperidine - 4 Example 1 using an carbohydrazide more carrying out the same reaction and treatment as, 1 0-chloro 5, 6 - dihydro 3- (piperidin-one 4 one I le) one 1, 2, 4-Toriazoro [4, 3 -d] [1, 4 ] benzothiazepine is obtained.

Example 1 1

Starting Material Synthesis Example 4 4 ​​obtained in 3, 5-dihydro-1 Mechiruchio one 3 H- 2-base Nzoazepin 0. 6 g and 1 i (2- (4 one black port phenyl) Echiru) Piperi Jin one 4 one carbohydrazide 1. 0 g 1, 3- dimethyl-2-imidazolidino down 1 0 0 m was added to 1 and stirred at 2 8 0 hands 3-4 hours. The reaction mixture was treated with water, the organic layer was extracted with acetic acid Echiru, washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the obtained residue was purified by silica gel chromatography I i (black port Holm: methanol = 3 0: 1) to recover purified by 3 - (1 - (2- (4 one Black mouth phenyl) Echiru) piperidine one 4 one I le) one 6, 7-dihydro-5 H- 1, 2, 4 one Toriazoro [3, 4- a] [2] Benzoaze pin, 1/2-hydrate 0.32 It was obtained g.

Decomposition in 2 0 4

2 obtained in Example 1 2 Starting Material Synthesis Example 4 4 ​​3- dihydro 5- methylthio one 1, 4 one Ben Zookisazepin 2. 4 g and 1 i (2- (4 one black port phenyl) Echiru) Pipet lysine 1 an 4 one carbohydrazide 3. 8 g, 3- dimethyl 2- Imidazoriji addition to non 1 0 Om 1, was stirred for 2-3 hours at 2 8 0. The reaction mixture was treated with water, the organic layer was extracted with acetic acid Echiru, washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the resulting residue was purified by silica gel chromatography one (black port Holm: methanol = 3 0: 1) to recover purified by 3- (1 - (2- (4-Black port phenyl ) Echiru) pin base lysine one 4 one I le) one 5, 6 Jihidoro 1, 2, 4 one Toriazoro [4, 3 - d] [1, 4] was obtained Benzookisaze Pinshi 8 g.

Mp 1 9 8 e C

Example 1 3

Starting Material Synthesis Example 4 7 2 obtained in, 3- dihydro 5- methylthio one 7- two Torrox 1, 4 one base Nzookisazepin 1. 3 g and 1 i (2- (4 one black port phenyl) Echiru) piperidine one 4 an carbohydrazide 3 1. 6 g n-blanking evening addition to Nord 6 0m 1, 1 2 0~1 3 (was stirred for 2 days at TC. the solvent was evaporated under reduced pressure, water to the obtained residue and acetic acid . Echiru was added and the organic layer was separated and extracted, washed with saturated brine, and then dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure, the obtained residue was purified by silica gel chromatography (black port Holm: methanol = 3 0: 1 by separating purified by), 3- (1 i (2- (4 one black port phenyl) Echiru) piperidine one 4 one I le) one 5, 6-dihydro-1 0-two Torrox 1, 2, 4 one Toriazoro [4, 3 - d] [1, 4] benzo O Kisa Ze pin 1 · lg. Mp 1 6 9~ 1 7 0 e C

EXAMPLE 1 4

2 obtained in Starting Material Synthesis Example 4 4 ​​3- dihydro 5- methylthio one 1, 4 one Ben Zookisazepin 1. 2 g and 1 i (2- (4 one triflate Ruo Russia methyl phenylalanine) Echiru) piperidine one 4 one carbohydrazide 2. 5 g 1, 3- dimethyl-2-Imidazorijinon added to 1 5 Om 1, and stirred 2-3 h at 2 8 0. The reaction mixture was treated with water, the organic layer was extracted with acetic acid Echiru, washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the resulting residue Shirikageruku port Matogurafi one (black port Holm: methanol = 3 0: 1) and the child separated and purified by, 5, 6- dihydro-3- (1 i ( 2- (4 one triflate Ruo Russia methyl Hue sulfonyl) Echiru) piperidine one 4 one I le) one 1, 2, 4-Toriazoro [4, 3 - d]

[1, 4] benzo O hexa peptidase pin 1. O g.

Mp 2 1 5~ 2 1 7 'C

Example 1 5

Starting Material Synthesis Example 4 5 resulting 7-chloro 2, 3-dihydro-5-methylthio one 1, 4 one base Nzookisazepin 2. 0 g and 1 i (2- (4 one black port phenyl) Echiru) piperidine one 4 one carbohydrazide 2. adding 4 g in n- blanking evening Nord 5 Om 1, was stirred for 2 days at 1 2 0-1 3 0. The solvent was distilled off under reduced pressure, water and acetic acid Echiru to the resulting residue were added and the organic layer was separated and extracted, washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the obtained residue was purified by silica gel chromatography (black port Holm: methanol = 2 0: 1) to recover purified by 1 0-chloro 3- (1 - (2- ( 4 one black port phenyl) E Chi le) piperidine one 4 one I le) one 5, 6 - dihydro 1, 2, 4-Toriazoro [4, 3 - d] [1, 4] benzo O Kisa Ze pin 0 . were obtained 7 g.

Te mp 1 8 2-1 8 4

Example 1 6

Starting Material Synthesis Example 4 6 resulting 7 promoter 2, 3-dihydro-5-methylthio one 1, 4 one base Nzookisazepin 2. 0 g and 1 i (2- (4 one black port phenyl) Echiru) piperidine one 4 one force Rubo hydrazide 2. 0 g n-blanking evening addition to Nord 5 0 m l, and refluxed for 2 days at reflux temperature. The solvent was distilled off under reduced pressure, water and acetic acid Echiru added and the organic layer was separated and extracted, washed with saturated brine, and then dried over magnesium sulfate. The obtained by evaporating the residue of the solvent under reduced pressure by silica gel column chromatography (black port Holm: methanol = 2 0: 1) to recover purified by 1 0-bromo 3- (1 i (2- (4 one black port phenyl) Echiru) piperidine one 4-I le) one 5, 6-dihydro-1, 2, 4-Toriazoro [4, 3 - d] [1, 4] to give the base Nzookisazepin 0. 8 g .

Mp 1 9 0-1 9 2

Example 1 7

Starting Material Synthesis Example 4 4 ​​2 obtained in, 3-dihydro-5-methylthio one 1, 4 one Ben Zookisazepin 0. 5 8 g and 2-(N- base Njiru N- Mechiruamino) E Chi le carbohydrazide 0. 6 2 g the n- Bed evening addition to Nord 1 0 m 1, and stirred for 24 hours at 1 2 0-1 3 0. The solvent was distilled off under reduced pressure, the resulting residue, water and acetic acid E chill addition, the organic layer was separated and extracted, washed with saturated brine, and then dried over anhydrous sulfate Maguneshiu beam. The solvent was distilled off under reduced pressure, the obtained residue was purified by silica gel chromatography one (black port Holm: methanol = 2 0: 1) in a subsequent separation and purification, the I isopropyl alcohol solution containing oxalic acid 7 3 mg eluate to give a solid by adding. Recrystallization This is a methanol, 3- (2-(N- base Njiru N- main Chiruamino) Echiru) one 5, 6-dihydro-1, 2, 4 one Toriazoro [4, 3- d] [1 , 4] benzo O Kisa Ze pin 3/2 oxalic acid salt 0. 1 7 g.

Mp 1 8 3 e C

Example 1 8

Starting Material Synthesis Example 4 2 obtained in 4, 3-dihydro-5-methylthio one 1, 4 one Ben Zookisazepin 0. 5 8 g and 2- (4 one (4 black port phenyl) piperidines Rajin one 1 one I le ) e in e chill carbohydrazide 0.5 to 8 5 g n-blanking evening Nord 1 0 m 1 pressure to distill off 1 2 0-1 3 (was stirred for 24 hours at TC. the solvent under reduced pressure, the resulting residue water and acetic acid Echiru was added to the organic layer separated and extracted, washed with saturated brine, and then dried over anhydrous magnesium sulfate. by evaporating the solvent under reduced pressure solid, recrystallized from isopropyl alcohol by, 3- (2 - (4 one (4-click Rorofueniru) piperidines Rajin one 1 one I le) Echiru) one 5, 6-dihydro-one 1, 2, 4-Toriazoro [4, 3 - d] [1, 4] benzo O hexa peptidase pins 0.3 82 ( Mp 2 3 0 ° C

Example 1 9

2 obtained in Starting Material Synthesis Example 4 4 ​​3- dihydro 5- methylthio one 1, 4 one Ben Zookisazepin 0. 5 8 g and 2-(N- (2-Fueniruechiru) Single N- methylcarbamoyl Ruamino) E chill carbohydrazide It was added 0. the 6 7 g in n- butanol 1 Om 1, was stirred for 24 hours at 1 2 0-1 3 0. The solvent was distilled off under reduced pressure, the resulting residue, water and acetic acid Echiru addition, the organic layer was separated and extracted, washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, after separated and purified by resulting residue Shirikageruku port Mato chromatography (black port Holm only), oxalic acid eluate 0.

To give a solid by adding isopropyl alcohol solution containing 1 0 g. Recrystallization from ethanol, 5, 6- dihydro 3- (2- (N-

(2 Fueniruechiru) Single N- Mechiruamino) Echiru) one 1, 2, 4-Toriazo α [4, 3 - d] [1, 4] benzo O Kisa Ze Pin 1 oxalic acid salt 0. 1 3 g

Mp 1 8 3 e C

Example 2 0

Starting Material Synthesis Example 4 4 ​​obtained in 2, 3-dihydro-5-methylthio one 1, 4-Ben Zookisazepin 0. 5 8 g and 3 (N- base Njiru N- Mechiruamino) propyl carbohydrazide 0. 6 7 g of n - in addition to ethylene glycol 1 0 m 1, and stirred for 24 hours at 1 8 0 ° C. The reaction mixture was treated with water, the organic layer was extracted with black port Holm, washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, after separation the resulting residue was purified by silica gel chromatography (black port Holm only), a solid by adding isopropyl alcohol solvent solution containing oxalic acid 0. 2 1 g in eluent Obtained. Recrystallization from ethanol, 3 - (3- (N- base Njiru N- Mechiruamino) propyl) one 5, 6-dihydro-one 1, 2, 4-Toriabu port [4, 3 - d] [1 , 4] benzo O Kisa Ze pin 2 Shi Yu salts 0. 1 0 g.

Mp 1 9 4 e C

Example 2 1

Starting Material Synthesis Example 4 2 obtained in 4, 3-dihydro-5-methylthio one 1, 4 one Ben Zookisazepin 2. 3 g and 2- (4 - (3-black port phenyl) piperidines Rajin one 1 one I le) E chill carbohydrazide 4.4 ^ 1, 3-dimethyl-2-imidazolidine Rijinon addition to 6 0 m 1, and stirred at 2 8 0 hands 2-3 hours. The reaction mixture was treated with water, the organic layer was extracted with acetic acid Echiru, washed with saturated brine, and then dried over anhydrous sulfate magnesium © beam. The solvent was distilled off under reduced pressure, the obtained residue was purified by silica gel chromatographic Fi one (black port Holm: methanol = 2 0: 1) to recover purified by 3- (2- (4 i (3-Black mouth phenyl) piperidines Rajin one 1 - I le) Echiru) one 5, 6-dihydro-1, 2, 4 one Toriazoro [4, 3 - d] to give the [1, 4] Benzookisa Zepin 0. 1 3 g.

1 1 Mp 1 6 7~ 1 6 8 e C

Example 2 2

Starting Material Synthesis Example 4 2 obtained in 4, 3-dihydro - 5-methylthio one 1, 4 one base Nzookisazepin 0. 5 8 g and 3- (4 one (4 one black port phenyl) piperazine Hmm 1 one I le) added propyl carbohydrazide 0. 8 9 g in n- butanol 1 0 m 1, and stirred for 24 hours at 1 2 0~1 3 0 e C. The reaction mixture was treated with water, the organic layer was extracted with black port Holm, washed with brine and Drying over anhydrous magnesium sulfate. Solid was obtained when the solvent was distilled off under reduced pressure, by recrystallized from isopropyl alcohol, 3- (3- (4 one (4 one black port phenyl) piperazine Hmm 1 one I) propyl) Single 5, 6-dihydro-1, 2, 4 one Toriazoro [4, 3 - d] to give the [1, 4] benzo O hexa peptidase pin 0. 3 5 g.

Mp 1 8 3 ° C

Example 2 3

Starting Material Synthesis Example 4 2 obtained in 4, 3-dihydro-5-methylthio one 1, 4 one Ben Zookisazepin 0. 5 8 g and 4 one (4 one black port phenyl) piperidines Rajin one 1 one I methyl carbohydrazide adding 0.1 to 8 1 g in n- butanol 1 5 m 1, and stirred for 24 hours at 1 2 0~1 3 0 ° C. The solvent was distilled off under reduced pressure, the resulting residue water and acetic acid Echiru addition, the organic layer was separated and extracted, washed with saturated brine, and then dried over anhydrous sulfate Ma Guneshiumu. The obtained by evaporating the residue of the solvent under reduced pressure silica gel column 厶Ku port Mato chromatography (black port Holm: methanol = 2 0: 1) and the child separated and purified by, 3- (4 one (4 one black port phenyl) piperidines Rajin one 1 one I le) methyl-5, 6-dihydro-1, 2, 4 to obtain an Toriazoro [4, 3 -d] [1, 4] Benzoo Kisazepin 0. 2 4 g.

With a melting point of 2 0 0

Example 24

Material obtained in Synthesis Example 4 8 5 methylthio one 1, 4 one base Nzookisazepin 2. 8 g and 1 i (2- (4 one black port phenyl) Echiru) piperidine one 4 one carbohydrazide 3. 0 g of n - in addition to butanol 5 0 m l, and stirred for 2 days at reflux temperature. The solvent was evaporated under reduced pressure, water was added and acetic acid Echiru, separated and extracted the organic layer. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (black port Holm

: Methanol = 3 0: by separating 1) to give 3- (1 i (2- (4 one black port phenyl) Echiru) piperidine one 4 one I le) one 1, 2, 4-Toriazoro

[4, 3 - d] to give the [1, 4] benzo O hexa peptidase pin 0. 4 2 g.

Mp 2 0 7~2 0 9 ° C

Example 2 5

Starting Material Synthesis Example 4 2 obtained in 9, 3-dihydro-5-methylthio one 1, 4-ben Zochiazepin 1. 9 g and 1 i (2- (4 one black port phenyl) Echiru) Piperi Jin one 4 one carbohydrazide 3. 0 £ 1, 3-dimethyl-2-imidazolidino emissions 8 0 m addition to 1, and stirred for 2-3 hours at 2 8 0 ° C. The reaction mixture was treated with water, the organic layer was extracted with acetic acid Echiru, washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the obtained residue was purified by silica gel chromatography (black port Holm: methanol = 2 0: 1) to recover purified by 3- (1 i (2 - (4 one black port phenyl ) Echiru) piperidine one 4 one I le) one 5, 6-dihydro-1, 2, 4-Toriazoro [4, 3 - d] to give the [1, 4] benzothiazepine 0. 3 6 g.

Te melting point 2 0 4-2 0 6

Example 2 6

Starting Material Synthesis Example 4 5 resulting 7-chloro 2, 3-dihydro-5-methylthio one 1, 4 one base Nzookisazepin 2. 0 g and 1 i (2- (4 one Torifuruoromechi Rufueniru) Echiru) piperidine one 4 one carbohydrazide 2. adding 4 g in n- butanol 5 0 m l, and stirred for 2 days at 1 2 0~ 1 3 0 e C . The solvent was distilled off under reduced pressure, the resulting residue to water and acetic acid Echiru added, the organic layer was separated and extracted, washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the obtained residue was purified by silica gel chromatography (black port Holm: methanol = 2 0: 1) to recover purified by 1 0- chloro 5, 6- dihydro-3- (1 one (2- (4 one triflate Ruo Russia methyl phenylalanine) Echiru) piperidine one 4 one I le) one 1, 2, 4-Toriazoro [4, 3 - d] [1, 4] benzo O Kisa Ze pin 0 . was obtained 5 4 g.

Mp 2 1 5~ 2 1 7 e C

Example 2 7

Starting Material Synthesis Example 5 0 obtained in 3, 4-dihydro - 1-methylstyrene thio iso quinoline 1. 3 g and 1 i (2- (4 one black port phenyl) Echiru) piperidine one 4 one carbohydrazide 2. 2 g 1, 3-dimethyl-2-imidazolidinone 8 addition to Om 1, was stirred for 2-3 h at 2 8 0 ° C. The reaction mixture was treated with water, the organic layer was hand extracted into acetate Echiru, washed with saturated brine, and then dried over anhydrous magnesium sulfate. After evaporation under reduced pressure Solvent, by resulting solid was recrystallized from toluene, 3- (1 i (2- (4 one-chlorophenyl) Echiru) piperidine one 4 one I le) one 5, 6 - Jihido low 1, 2, 4-Toriazoro was obtained [4, 3- a] isoquinoline 3 dihydrate 0. 6 g.

Mp 1 9 4~ 1 9 5 e C

Example 2 8

2 obtained in Starting Material Synthesis Example 4 4, 3-dihydro-5-methylthio one 1, 4-ben Zookisazepin 0. 64 g and 1 i (2- (4 one Buromofueniru) Echiru) peak Perijin - 4-carbohydrazide 0.9 the 8 g n-blanking evening addition to Nord 20 m 1, and 2 days heated and stirred at reflux temperature. The obtained by evaporating the residue of the solvent under reduced pressure Karamukuro Matogurafi one (black port Holm: methanol = 20: 1) Ri by the purification by 3- (1- (2- (4-Buromofuweniru) Echiru) piperidine one 4 one I le) one 5, 6-dihydro-1, 2, 4 to obtain an Toriazoro [4, 3 -d] [1, 4] Benzoo Kisazepin 0. 4 5 g.

Mp 1 94-1 9 6.

Example 29

2 obtained in Starting Material Synthesis Example 44, 3-dihydro-5-methylthio one 1, 4 an Ben Zookisazepin 3 0 g and ethoxycarbonyl two methyl Cal Po hydrazide 22. 7 g was added to the toluene solution 30 0 m 1, reflux heating the mixture was stirred in 2 days. After completion of the reaction, reduced E solvent under silica and obtained by evaporating the residue was purified by force gel column chromatography (black port Holm: methanol = 1 0: 1) to recover purified by (5, 6 Jihidoro 1, 2, 4 to obtain an Toriazoro [4, 3 -d] [1, 4] Benzookisaze pin one 3-I le) acetate Echiruesuteru 1 8 g.

'Η- NMR: 1. 25 - 1. 72 (m, 2H), 1. 8 8 - 2. 0 0 (m, 2 H), 2. 64 - 2. 8 1 (m, 2 Η), 3 . 28 (dt, 1 Η), 4. 0 5 (s, 2Η), 4. 38 - 5. 54 (m, 5Η), 4. 6 6 - 4. 73 (m, 1 Η), 7. 0 3 - 7. 37 (m, 8 Η), 8. 6 6 (dd, 1 Η)

Adding the compound 1 0 g to 1.5 N aqueous sodium hydroxide 5 0 m l, and the mixture was heated and stirred for 1-2 hours at 8 5 hands. After completion of the reaction, hydrochloric acid was added to the reaction solution was adjusted to PH 2, by filtering the aqueous layer (5, 6-dihydro-1, 2, 4 one Toriazoro [4, 3 - d] [1, 4] Benzoo Kisazepin one 3-I le) to give the acetate 7. 3 g. Mp 2 1 5-2 1 7. C.

Then, the obtained (5, 6-dihydro-1, 2, 4-Toriazoro [4, 3 - d]

[1, 4 "benzo O Kisa Ze pin one 3-I le) acetic 1. 0 g, 4 one phenylene Rubiperi Jin 0. 5 9 g and Toryechiruamin 1. dimethylformamide Ryomi de 1 Om 1 to 1 5 m 1 in addition, it added under ice cooling Shianohosuhon acid Jechiru 0. 1 5 m l, and stirred further at room temperature for 1 hour. After completion of the reaction, 5 Recrystallization obtained by evaporating the solid solvent under reduced pressure at Asetoni tolyl, 6- dihydro 3- (2-Okiso one 2- (4 one phenylene Rubiperijin one 1 one I le ) Echiru) one 1, 2, 4-Toriazoro [4, 3 - d] to give the [1, 4] benzo O hexa peptidase pin 0. 5 g.

Mp 2 1 5~ 2 1 6 ° C

Example 3 0

5 obtained in Example 1, 6- dihydro-3- (piperidin-one 4 one I le) one 1, 2, 4-Toriazoro [4, 3 -d] [1, 4] benzo O hexa peptidase pins and 2- (3 black port propyl) Single 2- (4-fluorophenyl) one [1, 3] pressure to give a Jiokisora ​​down 0. 7 1 g and potassium carbonate 2. 0 g of dimethyl formamidine de 3 Om 1, 7 0 was 2-3 hours heating and stirring at in. After completion of the reaction, the reaction mixture was treated with water, the organic layer was extracted with acetic acid Echiru, the solvent was distilled off under reduced pressure, added 2 N hydrogen chloride one ethanol solution 2 Om l to the resulting residue 3 hours heating the mixture was stirred. After completion of the reaction, treating the reaction solution with aqueous potassium carbonate solution, the organic layer was extracted with black port Holm, washed with saturated saline, and dried over anhydrous magnesium sulfate. Then, the solvent was evaporated under reduced pressure, the obtained residue was purified by silica gel column chromatography one (black port Holm: main evening Nord-1 0: 1) at the separating purified 3- (1 i (4 one ( 4 one Furuo port phenyl) Single 4 one year old Kisobuchiru) piperidine one 4 one I le) one 5, 6-dihydro-one 1, 2, 4 one Toriazoro [4, 3 - d] [1, 4] Benzookisa It was obtained Zepin 0. 3 5 g.

Mp 1 6 1-1 6 2

Example 3 1

5 obtained in Example 1, 6- dihydro-3- (piperidin-one 4 one I le) one 1, 2, 4 one Toriazoro [4, 3 -d] [1, 4] benzo O Kisa Ze Pin 0.7 5 g, with respect Toryechiruamin 0. 9 2 g and (naphthalene one 1 one I le) No free acetic acid 0.4 1 dimethylformamidine de solution 3 0 m l, under ice cooling Shianohosuhon acid Jechiru 0. 4m l was added, It was further stirred for 1 hour at room temperature. After completion of the reaction, was distilled off under reduced pressure Solvent, added the resulting residue in tetrahydrofuran 3 0 m 1, after adding under ice cooling lithium aluminum hydride 0. 2 5 g, 3 0 minutes at 5 0 ° C It stirred. After completion of the reaction, the reaction mixture was treated with a saturated aqueous solution of sodium sulfate, the precipitated solid was filtered, washed with hot I isopropyl alcohol, and concentrated under reduced pressure The combined filtrate and washings. The obtained residue was purified by silica gel column chromatography (black port Holm: methanol = 1 0: 1) 5 by separating purified by 6- dihydro 3- (1 i (2 i (1 one-naphthyl) Echiru) pin Bae lysine one 4 one I le) one 1, 2, 4 one Toriazoro

[4, 3 - d] [1, 4] benzo O Kisa Ze pin 0. 2 6 g.

Mp 1 5 9~ 1 6 1 ° C

Example 3 2

5 obtained in Example 1, 6- dihydro-3- (piperidin-one 4 one I le) one 1, 2, 4-Toriazoro [4, 3 - d] [1, 4] benzo O Kisa Ze Pin 0.7 5 g, Toryechiruami down 0. 9 2 g and (naphthalene one 2-I le) acetate 0.4 1 containing added di-methyl formamidine de 3 0 m 1, under ice cooling Shianohosuhon acid Jechiru 0. 4m l in addition, further stirred at room temperature for 1 hour. After reaction ^ completion, was distilled off under reduced pressure Solvent, tetrahydrofuran 3 Om 1 was added to the resulting residue, after addition of under ice cooling lithium aluminum hydride 0. 2 5 g, 3 0 minutes at 5 0 It stirred. After completion of the reaction, the reaction mixture was treated with a saturated aqueous solution of sodium sulfate, the solids were filtered the precipitated, Netsuitsuzu. After washing with pills alcohol, filtrate and washes and then combined and concentrated under reduced pressure was c resulting residue by silica force gel column chromatography (black port Holm: methanol = 1 0: 1) at the separating purified 5 , 6- dihydro 3- (1 i (2 i (2-naphthyl) Echiru) piperidine one 4 one I le) one 1, 2, 4-Toriabu port [4, 3 - d] [1, 4] benzo It was obtained Okisazepin 0. 0 5 g.

Mp 2 2 6-2 2 8

Example 3 3

Starting Material Synthesis Example 5 1 2 obtained in 3-dihydro 7- Echiru - 5-methylthio one 1, 2, 4 one Toriazoro [4, 3 - d] [1, 4] benzo O hexa peptidase pin 0. 8 g and 2- (4 i (4 - black port phenyl) piperazine one 1 one I le) Echirukarubohi hydrazide 1. adding 1 g in n- butanol 3 Om l, and 2 days heated and stirred at reflux temperature. After completion of the reaction, was crystallized by adding 1 N hydrogen chloride one isopropyl alcohol solvent solution to the resulting residue, isopropyl alcohol one toluene (5: 1) and recrystallized with a solution of 3- (2- (4 - ( 4 one black port phenyl) piperidines Rajin one 1 one I le) Echiru) one 5, 6-dihydro-1 0 Echiru 1 2, 4-Toriazoro [4, 3 - d] [1, 4] benzo O hexa peptidase pin - 2 to give the hydrochloride salt monohydrate 0. 7 3 g.

Mp 1 8 9 1 9 0 ° C

Example 3 4

Starting Material Synthesis Example 5 1 2 obtained in 3-dihydro 7- Echiru 5- methylthio one 1, 2, 4 one Toriazoro [4, 3 - d] [1 4] benzo O hexa peptidase pin 0. 8 g and 1 one (2- (4 one Buromofueniru) Echiru) a piperidine one 4 one Karubohido Hydrazide 1. 1 g n-blanking evening addition to Nord 3 0 m l, 2 days stirred under heating after completion to the reaction at the reflux temperature, under reduced pressure the solvent was removed by distillation, and the solid with ethanol one toluene (3: 1) 3 by recrystallization solution (1 i (4 one Buromofueniru) Echiru) piperidine one 4 one I le) one 5, 6- dihydro 1 0 Echiru 1, 2, 4-tri Azoro [4 3 - d] to give the [1, 4] benzo O Kisa Ze pin 1 / pentahydrate 0. 5 1 g. Mp 1 7 0 1 7 1 e C

Example 3 5

Starting Material Synthesis Example 5 1 2 3 dihydro Echiru 5- methylthio one 1 obtained in 2, 4 one Toriazoro [4, 3 - d] [1, 4] benzo O hexa peptidase pin 0. 8 g and 3- ( 4 one addition to (one black port phenyl) piperidines Rajin one 1 one I) propyl Cal Pohidorajido 1. 1. g of n- butanol was 2 days heated and stirred at reflux temperature. After completion of the reaction, the solvent under reduced pressure was removed by distillation, and the residue was separated and purified by silica gel column chromatography, 1 N hydrochloric acid thereto - after ethanol solution was added crystallization, by recrystallization from ethanol, 3 - (3- (4- (4-black port Hue yl) piperidines Rajin one 1 one I) propyl) one 5, 6-dihydro-1 0-Echiru one 1, 2, 4 one Toriazoro [4, 3 -d ] [1, 4] benzo O Kisa Ze pin dihydrochloride monohydrate 0. 7 3 g.

Mp 2 6 3~ 2 6 5 'C

Example 3 6

; 5- Puropioraku ton 2 0 g, was added hydrazine monohydrate 1 0 0 m l of ethanol 2 0 0 ml, the mixture was heated and stirred 6 h. After completion of the reaction, the solvent was distilled off under reduced pressure, by crystallizing toluene was added to the obtained residue to give 2-hydroxy-E chill Cal Bohidorajido 2 7 g. The Compound 1 0. 4 g of the raw material in Synthesis Example 4 2 obtained in 4, 3-dihydro-5-methylthio one 1, 4 one base Nzookisazepin 1 9. 3 g was added to isopropyl alcohol 3 0 0 ml, at reflux 2 4 hours under heating and stirring. After completion of the reaction, solvent was evaporated under reduced pressure and the resulting residue by silica gel column chromatography (black port Holm: methanol = 1 5: 1) 2-purified by a (5, 6-dihydro-1, 2 4- Toriazoro [4, 3 - d] [1, 4] Benzoo Kisazepin one 3-I le) to give the ethanol 1 1. 3 g. Mp 1 3 7-1 3 8 ° C Further the compound 7. 8 g and Toriechiruamin 9. 4m l in dichloromethane 2 0 0 m l, contrast was added under ice-cooling Meshiruku port ride 5. 2m l . After completion of the dropwise addition, the mixture was further stirred at room temperature for 4 hours. After completion of the reaction, the reaction solution was treated with sodium hydrogen carbonate solution, and the organic layer was extracted with black port Holm, washed with saturated brine, and then dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, resulting et the residue was purified by silica gel column chromatography one (black port Holm: methanol - 30: 1) Methanesulfonic acid '2- (5 purified by a 6-dihydro one 1, 2 to give 4 Toriazoro [4, 3 -d] [1, 4] benzo O hexa peptidase pin one 3-I le) Echiruesuteru 6. 5 g. Mp 1 4 1-1 42. C.

Additional methanesulfonic acid 2- (5, 6-dihydro - 1, 2, 4 _ Toriazoro

[4, 3 -d] [1, 4] benzo O hexa peptidase pin one 3-I le) Echiruesuteru 0. 7 g, 2- (piperazin-one 1 one I le) pyrimidine dihydrochloride 1. 0 g, carbonate added Chikarari © beam 2 g and iodide force tumefaciens 1 g in dimethylformamide § Mi de 20 m 1, was 2-3 hours heating and stirring at 7 0. After completion of the reaction, the solvent and aqueous potassium carbonate was added to the resulting residue was evaporated under reduced pressure, an organic layer was extracted with black port Holm, washed with water, and dried over anhydrous magnesium sulfate. Then, the solvent was evaporated under reduced pressure, the resulting residue by silica gel column black Malo chromatography (black port Holm: methanol = 20: 1) 5 by hand separation and purification, the 6-dihydro 3- (2- (4- (2-pyrimidine sulfonyl) piperidines Rajin one 1 one I le) Echiru) one 1, 2, 4-Toriazoro [4, 3 -d]

[1, 4] benzo O hexa peptidase pin 0. 1 4 g.

Mp 23 8~ 23 9 ° C

Example 3 7

Example 3 6 Methanesulfonic acid 2- obtained in (5, 6-dihydro-1, 2 4 one Toriazoro [4, 3 - d] [1, 4] benzo O hexa peptidase pin one 3-I le) E Chi glycol ester 0. 7 g, 4 i (3-triflate Ruo Russia methyl phenylpropyl) piperazine. 1 oxalic hydrobromide 1. 0 g, carbonate 2 g of potassium and potassium iodide 1 g in dimethyl Chiruhorumuami de 2 Om l in addition, and for 2-3 hours heated and stirred at 7 0 ° C. After completion of the reaction, the solvent and aqueous potassium carbonate was added to the resulting residue was evaporated under reduced pressure, an organic layer was extracted with black port Hol 厶, washed with water, and dried over anhydrous magnesium sulfate. Then, distilling off the reduced pressure solvent, the resulting residue was purified by silica gel column black Malo chromatography (black port Holm: methanol = 2 0: 1) to recover purified by 5, 6 Jihido low 3- (2 - (4 i (3-triflate Ruo Russia methyl phenylalanine) piperidines Rajin one 1-I le) Echiru) -1, 2, 4- Toriazoro [4, 3 - d] [1, 4] Benzookisa Zepin 0.1 4 were obtained g.

Mp 1 6 7~ 1 6 8 ° C

Example 3 8

Example 3 6 obtained in methanesulfonic acid 2- (5, 6-dihydro-1, 2, 4 one Toriazoro [4, 3 - d] [1, 4] benzo O hexa peptidase pin one 3-I le) Additionally E Ji glycol ester 0. 7 g, 4 one base Nzuhidorirupi Bae Rajin 0. 5 g, potassium carbonate 1 g dimethyl formamidine de 2 0 m l, and 2-3 畤間 heated and stirred at 7 0 ° C. After completion of the reaction, the solvent and aqueous potassium carbonate was added to the resulting residue was evaporated under reduced pressure, an organic layer was extracted with chloroform, washed with water, and dried over anhydrous magnesium sulfate. Then, the solvent was evaporated under reduced pressure, after crystallization adding isopropyl ether, 3- By recrystallization from isopropyl alcohol (2- (4 one base Nzuhidoriru piperidines Rajin one 1 one I le) Echiru) one 5, 6-dihydro-1, 2, 4-Toriazoro

2 3 [4, 3 - d ] [1, 4] benzo O hexa peptidase pin 0. 1 3 g {

Te melting point 1 8 8-1 8 9

Example 3 9

Example 3 Methanesulfonic acid 2- (5 obtained in 6, 6-dihydro-1, 2, 4 one Toriabu port [4, 3 -d] [1, 4] benzo O hexa peptidase pin one 3- I le ) E Ji glycol ester 0. 7 g, 6- Furuoro 3- (piperidin-one 4 one I le) benzo [d] Isokisazo Ichiru 'monohydrochloride 0. 5 g and dimethylformamidine de potassium carbonate 1 g 2 0 m l in addition to, 7 0 "after C in 2-3 hours heated stirred. completion of the reaction, the carbonate force potassium aqueous solvent the resulting residue was was evaporated under reduced pressure was added, an organic layer was extracted with black port Holm, after washing with water, and dried over anhydrous magnesium sulfate. the solvent was evaporated under reduced pressure, after crystallization added I isopropyl ether to the resulting residue, 3- by recrystallization from isopropyl alcohol (2 - (4 one (6 Furuoro base emission zone [d] Isokisazo one rule 3 I le) piperidine one 1 one I le) E Ji Le) one 5, 6 Jihido port one 1, 2 to give 4 Toriazoro [4, 3 -d] [1, 4] benzo O hexa peptidase pin 0. 1 2 g.

Te mp 2 1 2-2 1 4

Example 4 0

Example 3 6 obtained in methanesulfonic acid 2- (5, 6-dihydro-1, 2, 4 one Toriazoro [4, 3 - d] [1, 4] benzo O hexa peptidase pin one 3-I le) Echiru ester 0. 7 g, 4 one (4 Metokishifue) piperazin 'succinate 0. 6 g and carbonate force Riumu 1 g was added to dimethylformamide § Mi de 2 0 m 1,. 2 to at 7 0 ° C 3 It was time heating and stirring. After completion of the reaction, the solvent potassium carbonate aqueous solution was added to the 'was removed by distillation, and under 减圧 residue, an organic layer was extracted with black port Holm, washed with water, and dried over anhydrous sulfate Ma Guneshiumu. The solvent was evaporated under reduced pressure, after crystallization adding isopropyl E one ether to the obtained residue, 5 By recrystallization I isopropyl alcohol one methanol solution, 6 - dihydro 3- (2 - ( 4- (4-menu Tokishifue two Le) piperidines Rajin one 1 one I le) Echiru) one 1, 2, 4-Toriazoro [4, 3 - d]

[1, 4] benzo O hexa peptidase pin 0. 3 g.

Mp 2 1 8-2 1 9

Example 4 1

Example 3 6 obtained in methanesulfonic acid 2- (5, 6-dihydro-1, 2, 4 one Toriazoro [4, 3 - d] [1, 4] benzo O hexa peptidase pin - 3-I le) Additionally E Ji glycol ester 0. 7 g, 4 one phenylene Rubiperajin 0. 3 g, potassium carbonate 1 g of di-methyl formamidine de 20 m l, and 2-3 hours heating and stirring at 7 0 hands. After completion of the reaction, the solvent and aqueous potassium carbonate was added to the resulting residue was evaporated under reduced pressure, an organic layer was extracted with chloroform, washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, after crystallization of isopropyl ether was added to the resulting residue, 5 By recrystallization I isopropyl alcohol, 6-dihydro-3 - (2-

(4 one phenylene Rubiperajin one 1 one I le) Echiru) one 1, 2, 4 one Toriazoro [4,

3 - d] [1, 4] benzo O Kisa Ze pin 0. 2 g.

Mp 1 9 7~ 1 9 9 ° C

Example 4 2

Example 3 6 obtained in methanesulfonic acid 2- (5, 6-dihydro-1, 2, 4 one Toriabu port [4, 3 - d] [1, 4] benzo O hexa peptidase pin over 3 I le) Additionally E Ji glycol ester 0. 7 g, 4 one (2 main Tokishifue yl) piperidines Rajin 0. 4 g, potassium carbonate 1 g in dimethylformamide § Mi de 2 0 m 1, 2 to 3 at 7 0 ° C It was time heating and stirring. After completion of the reaction, the solvent and aqueous potassium carbonate was added to the resulting residue was evaporated under reduced pressure, an organic layer was extracted with black port Holm, washed with water, and dried over anhydrous magnesium sulfate. Then, the solvent was evaporated under reduced pressure, the resulting residue was purified by silica gel column chromatography (Black hole Holm: methanol = 2 0: 1) more 5 to be separated and purified by, 6 - dihydro 3- (2 - (4 - (2 - main Tokishifue sulfonyl) piperidines Rajin one 1 one I le) Echiru) one 1, 2, 4-Toriabu port [4, 3 - d] [1, 4] Ben Zookisazepin 0. 2 g It was obtained.

Mp 1 2 0~ 1 2 C

Example 4 3

Example 3 6 obtained in methanesulfonic acid 2- (5, 6-dihydro-1, 2, 4 one Toriazoro [4, 3 - d] [1, 4] benzo O hexa peptidase pin one 3-I le) Additionally E Ji glycol ester 0. 7 g, 4 one benzylpiperazine 0. 5 g, potassium carbonate 1 g of di-methyl formamidine de 2 0m l, 7 0. 2-3 hours heated and stirred at C. After completion of the reaction, the solvent and aqueous potassium carbonate was added to the resulting residue was evaporated under reduced pressure, an organic layer was extracted with chloroform, washed with water, and dried over anhydrous magnesium sulfate. Then, the solvent was evaporated under reduced pressure, after crystallization added I isopropyl ether to the obtained residue, 5 By recrystallization from isopropyl alcohol one methanol solution, 6 Jihidoro one 3- (2- (4 one benzylpiperazine one 1 one I le) Echiru) to give an 1, 2, 4 one Toriazoro [4, 3 -d] [1, 4] benzo O hexa peptidase pin 0. 4 g.

Mp 1 4 9-1 5 0

Example 4 4

Example 3 6 Methanesulfonic acid 2- (5 obtained in 6-dihydro - 1, 2, 4 one Toriazoro [4, 3 - d] [1, 4] benzo O hexa peptidase pin one 3- I le ) E Ji glycol ester 0. 7 g, 1 one phenylene Lou 1, 3, 8-Toriazasupiro [4, 5] dec Hanil 4 - one 0. 5 g, carbonate force potassium 1 g of dimethylformamide § Mi de 2 0 m in addition to 1 and 2 to 3 hours heated and stirred at 7 0 ° C. After completion of the reaction, the solvent and aqueous potassium carbonate solution was added to Tokura the residue was distilled off under reduced pressure, an organic layer was extracted with black port Holm, washed with water, and dried over anhydrous magnesium sulfate. Then, the solvent was evaporated under reduced pressure, after crystallization of isopropyl ether was added to the resulting residue, 5 By recrystallization from isopropyl alcohol one methanol solution, 6- dihydro 3- (2- (4 one Okiso one 1 one-phenylene Lou 1, 3, 8-Toriazasupiro [4, 5] decane one 8-I le) Echiru) one 1, 2, 4 one Toriazoro [4, 3 - d] [1, 4] Benzookisa It was obtained Zepin-1 dihydrate 0. 4 8 g.

Mp 1 4 9~ 1 5 0 e C

Example 4 5

Example 3 6 obtained in methanesulfonic acid 2- (5, 6-dihydro-1, 2, 4 one Toriazoro [4, 3 - d] [1, 4] benzo O hexa peptidase pin one 3-I le) E Ji glycol ester 0. 6 g, 4 one (4 one-fluorophenyl) piperidines Rajin 0. 4 g, Jimechiruhoru 厶 § Mi de solution 2 0 m 1 7 0 containing potassium carbonate 1. 0 g. It was heated and stirred for 2-3 hours at C. After completion of the reaction, the solvent and aqueous potassium carbonate was added to the resulting residue was evaporated under reduced pressure, an organic layer was extracted with black port Holm, washed with water, and dried over anhydrous sulfate Maguneshiu beam. Then, the solvent was evaporated under reduced pressure, after crystallization of isopropyl ether was added to the obtained residue, 3- By recrystallization from isopropyl alcohol one toluene (2- (4 one (4 one fluorophenyl) piperidines Rajin one 1 over I le) Echiru) one 5, 6-dihydro-1, 2, 4-Toriazoro [4, 3 - d] [1, 4] benzo O hexa peptidase pin 0. 4 g It was.

Mp 1 4 9~ 1 5 0 e C

Example 4 6

Example 3 6 obtained in methanesulfonic acid 2- (5, 6-dihydro-1, 2, 4 one Toriazoro [4, 3 - d] [1, 4] benzo O hexa peptidase pin - 3-I le) E Ji glycol ester 0. 7 g, 1 i (piperidin one 4-I le) one Mr. 3- dihydro base emission zone Imidazo one Roux 2-one 0. 4 g, carbonate force potassium 1 g of dimethylformamide § Mi de 2 0 m in addition to l, and 2-3 hours heated and stirred at 7 0 e C. After completion of the reaction, the solvent of carbonate force Riumu aqueous solution was added to the residue obtained was removed by distillation under reduced pressure, an organic layer was extracted with black port Holm, washed with water, and dried over anhydrous magnesium sulfate. Then, the solvent was evaporated under reduced pressure, after crystallization with 1 N hydrogen chloride one isopropyl alcohol 0, 7 m 1 was added to the obtained residue, 3- By recrystallization from methanol (2. (4 one (2-O key saw 1, 3-dihydro-base emission zone imidazol-1 one I le) piperidine one 1 one I le) Echiru) one 5, 6-dihydro-1, 2, 4-Toriazoro [4 , 3 - d] to give the [1, 4] benzo O Kisa Ze pin dihydrochloride 0. 1 7 g.

Mp 2 6 0~2 6 2 e C

Example 4 7

Example 3 6 obtained in methanesulfonic acid 2- (5, 6-dihydro-1, 2, 4 _ Toriazoro [4, 3 - d] [1, 4] benzo O hexa peptidase pin - 3-I le) Additionally E Ji glycol ester 0. 7 g, 4 one phenylene Rubiperijin 0. 3 g, potassium carbonate 1 g of di-methyl formamidine de 2 0 m l, and 2-3 hours heated and stirred at 7 0 ° C. After completion of the reaction, the solvent and aqueous potassium carbonate was added to the resulting residue was evaporated under reduced pressure, an organic layer was extracted with chloroform, washed with water, and dried over anhydrous magnesium sulfate. Then, the solvent was evaporated under reduced pressure, was crystallized by addition of I isopropyl ether to the obtained residue, 5 By recrystallization from isopropyl alcohol, 6- dihydro 3- (2 i (4 one Hue two Rubiperijin one 1 one I le) Echiru) one 1, 2, 4-Toriazoro [4, 3 - d] [1, 4] benzo O hexa peptidase pin 0. 3 g. Mp 1 9 3~ 1 9 5 e C

Example 4 8

Example 3 6 obtained in methanesulfonic acid 2- (5, 6-dihydro-1, 2, 4 one Toriazoro [4, 3 - d] [1, 4] benzo O hexa peptidase pin one 3-I le) E Ji glycol ester 0. 7 g, 4 one (2, 3-dichloro port phenyl) piperidines Rajin 0. 4 5 g, added carbonate force potassium 1 g in dimethylformamide § Mi de 2 0 m 1, at 7 0 ° C 2 to 3 hours heating the mixture was stirred. After completion of the reaction, the solvent and potassium carbonate aqueous solution was added to the ZanKiyoshi that is obtained was distilled off under reduced pressure, an organic layer was extracted with black port Holm, washed with water, and dried over anhydrous magnesium sulfate. Then, the solvent was evaporated under reduced pressure, and crystallized by adding isopropyl ether to the resulting residue, 3- (2- (4 one by recrystallization from toluene (2, 3-dichloro port phenyl ) piperidines Rajin one 1 one I le) Echiru) one 5, 6 Jihido port one 1, 2, 4-Toriazoro [4, 3 - d] [1, 4] benzo O hexa peptidase pin 0. 0 7 g Obtained. NN CI

Mp 2 3 4~ 2 3 5 e C

Example 4 9

Starting Material Synthesis Example 5 1 2 obtained in 3-dihydro 7- Echiru 5- methylthio one 1, 2, 4-Toriazoro [4, 3 -d] [1, 4] benzo O hexa peptidase pin 0. 8 g 1 - (2- (4-black port phenyl) Echiru) a piperidine one 4 one carbohydrazide 1. 1 g n-blanking evening addition to Nord 5 Om l, and 2 days heated and stirred at reflux temperature. After completion of reaction, the solvent was evaporated under reduced pressure, the obtained residue was purified by silica gel column chromatography (black port Holm: methanol = 2 0: 1) to recover purified by three to (1 i (2- (4 black port phenyl) Echiru) piperidine one 4 one I le) one 5, 6-dihydro-one 1 0 Echiru 1, 2, 4-Toriazoro [4, 3 - d] [1, 4] Benzoo It was obtained Kisazepin 0. 3 4 g.

Mp 1 7 7-1 7 8

Example 5 0

Starting Material Synthesis Example 5 2 2 obtained in 3-dihydro 7- main Tokishi 5- methylthio one 1, 2, 4 one Toriazoro [4, 3 - d] [1, 4] benzo O hexa peptidase pin 0. 8 g , 1 i (2- (4-black port phenyl) Echiru) piperidine one 4 one Karubohidora disilazide 1.1 2 1, was added to 3-dimethyl-2-imidazolidinone 3 0m 1, 2 2 0~2 3 0 ° It was heated with stirring for 6 hours at C. After completion of the reaction, the reaction mixture was treated with water, an organic layer was extracted with acetic Echiru, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the obtained residue was purified by silica gel column chromatography (black port Holm: methanol = 2 0: 1) at the separating purified 3- (1 i (2- (4-Black port phenyl ) Echiru) piperidine one 4-I le) one 5, 6-dihydro-1 0-main Tokishi 1, 2, 4-Toriazoro [4, 3 - d] [1, 4] to give the Benzooki Sazepin 0. 2 g It was. Mp 1 6 8 ° C

Example 5 1

Starting Material Synthesis Example 5 6 obtained 8-chloro-4, 5-dihydro-1 Mechiruchio one 3 H- 2 Benzoazepin and 1 i (2 Fueniruechiru) as in Example 1 1 using piperidine one 4 one carbohydrazide by performing Do reaction and treatment, 1 0-chloro-3- (1 i (2 Fueniruechiru) piperidine one 4 one I le) one 6, 7-dihydro-5 H- 1, 2, 4-Toriazoro [3 , 4 - a] [2] Benzoaze pin is obtained.

Example 5 2

Starting Material Synthesis Example 5 9 obtained 8-promoter 4, 5-dihydro-1 Mechiruchio one 3 .eta. 2 Benzoazepin and 1 i (2 Fueniruechiru) as in Example 1 1 using piperidine one 4 one carbohydrazide by performing Do reaction and treatment, 1 0 Buromo 6, 7-dihydro-3 - (1 i (2 Fueniruechiru) piperidyl Hmm 4 Iru) Single 5 .eta. 1, 2, 4 one Toriazoro [3, 4 one a] [2] Benzoa Zepin is obtained.

Example 5 3

Starting Material Synthesis Example 4 2 obtained in 4, 3-dihydro - 5-methylthio one 1, 4 one Ben Zookisazepin and 1 one with (2- (4 twelve Torofueniru) Echiru) piperidine one 4 one carbohydrazide more carrying out the same reaction and treatment as in example 1 1, 5, 6- dihydro-3- (1 i (2- (4-nitrophenyl) Echiru) peak Perijin one 4 one I le) one 1, 2, 4 one Toriazoro [4, 3 -d] [1, 4] Ben Zookisazepin be obtained.

Example 5 4

2 obtained in Starting Material Synthesis Example 4 4 ​​3- dihydro 5- methylthio one 1, 4 one Ben Zookisazepin and 1 one (2- (4 one-fluorophenyl) Echiru) using piperidine one 4 one carbohydrazide embodiment by performing example 1 1 a similar reaction and treatment, 3- (1 - (2- (4-fluorophenyl) Echiru) piperidine one 4 one I le) -5, 6-dihydro-1, 2, 4-Toriazoro [4, 3 - d] [1, 4] benzo O hexa peptidase pin is obtained.

Example 5 5

Starting Material Synthesis Example 4 was obtained in 4 2, similar to the 3-dihydro 5-methylthio one 1, 4 one Ben Zookisazepin and Example 1 1 using (4 one base Njiruhomopi Bae Rajin one 1 one I le) Mechirukarubo hydrazide by performing the reaction and treatment, 3- (4-Benjiruhomopi Bae Rajin one 1 one I le) methyl-5, 6-dihydrazide draw 1, 2, 4-Toriazoro [4, 3 - d] [1, 4] Benzoo c obtained the Kisazepin

Example 5 6

2 obtained in Starting Material Synthesis Example 5 3, 3-dihydro-7, 8-dimethyl Tokishi 5- methylcarbamoyl thio one 1, 4 one base Nzookisazepin and 1 one (2- (4 Kurorofuweniru) Echiru) piperidine one 4 one carbohydrazide Starting material synthesis example 1 1 and by performing the reaction and treatment similar, 3- (1 i (2- (4 one black port phenyl) E Chi le) piperidine one 4-I le) Single 5 using , 6-dihydro-9, 1 0-dimethyl Tokishi 1, 2, 4 one Toriazoro [4, 3 - d] [1, 4] benzo O hexa peptidase pin is obtained.

Example 5 7

Starting Material Synthesis Example 4 2 obtained in 4, 3-dihydro-5-methylthio one 1, 4 _ Ben Zookisazepin and 1 one (2- (4-methyl § Minofu enyl) Echiru) Piperi gin with one 4 one carbohydrazide by performing the same reaction and treatment as in example 1 1, 5, 6- dihydro-3- (1 - (2- (4-methyl § Minofu enyl) Echiru) piperidine one 4-I le) one 1, 2, 4-Toriazoro [4, 3 - d] [1, 4] benzo O hexa peptidase pin is obtained.

Example 5 8

2 obtained in Starting Material Synthesis Example 5 4, 3-dihydrazide draw 5- methyl-5-methylthio one 1, 4 one base Nzookisazepin and 1 one (2- (4 one black port phenyl) Echiru) piperidine one 4 Ichiriki Lupo hydrazide by performing the same reaction and treatment as Starting material synthesis example 1 1 using 3- (1 i (2- (4 Kurorofuweniru) Echiru) piperazinyl lysine one 4 one I le) one 5, 6-dihydro-1 0- methyl-1, 2, 4 one Toriabu port [4, 3 - d] [1, 4] benzo O hexa peptidase pin is obtained.

Example 5 9

2 obtained in Starting Material Synthesis Example 5 5, using 3-dihydro 7- main Tokishi 5- methylthio one 1, 4 one base Nzochiazepin and 1 one (2- (4 one black port phenyl) Echiru) piperidine one 4 one carbohydrazide by performing the same reaction and treatment as Starting material synthesis example 1 5 Te, 3- (1 i (2- (4 Kurorofuweniru) Echiru) piperazinyl lysine one 4 one I le) one 5, 6-dihydro-1 0-menu Tokishi 1, 2, 4 Toria Zorro [4, 3- d] [1, 4] benzothiazepine is obtained.

Example 6 0

Starting Material Synthesis Example 6 0 obtained 7- promoter 2, 3-dihydro-5-methylthio one 1, 4 one base Nzochiazepin and 1 one with (2- (4 one Buromofueniru) Echiru) peak Perijin one 4 Ichiriki Lupo hydrazide by performing the same reaction and treatment as Starting material synthesis example 1 1, 1 0-bromo-3- (1 - (2- (4 one Puromofue sulfonyl)

3 5 Echiru) piperidine one 4 one I le) one 5, 6-dihydro-1, 2, 4 one Toriazoro

[4, 3 - d] [1, 4] benzothiazepine is obtained.

Example 6 1

Starting Material Synthesis Example 6 5-methylthio one 1 obtained in 1, 4 one base Nzochiazepin and 1 one (2- (4-black port phenyl) Echiru) using piperidine one 4 Ichiriki Lupo hydrazide Starting Material Synthesis Example 1 1 by performing the same reaction and treatment as, 3- (1 i (2- (4 one black port phenyl) Echiru) piperidine one 4 one I le) one 1, 2, 4-Toriazoro [4, 3 - d] [1, 4] benzothiazepine is obtained.

Example 6 2

Starting Material Synthesis Example 6 2 1 one base Njiru 2 obtained in, 3- dihydro 5- methylthio one 1, 4 one base Nzojiazepin and 1 i (2 Fueniruechiru) Starting Material Synthesis Example 1 using piperidine one 4 one carbohydrazide by performing the same reaction and treatment as 1, 7-base Njiru 5, 6- dihydro-3- (1 i (2 Fueniruechiru) piperidine one 4 one I le) one 1, 2, 4 one Toriazoro [4 , 3 -d] [1, 4] base Nzojiazepin is obtained.

Example 6 3

2 obtained in Starting Material Synthesis Example 6 3, 3-dihydro-1-methyl-5-methylthio eleven 1, 4 one base Nzojiazepin and 1 i (2 Fueniruechiru) Starting Material Synthesis Example 1 1 using piperidine one 4 one carbohydrazide by performing the same reaction and treatment as, 5, 6- dihydro-7- methyl-3- (1 i (2 Fueniruechiru) peak Perijin one 4 one I le) one 1, 2, 4-Toriazoro [4, 3 - d] [1, 4] Ben Zojiazepin is obtained.

Example 6 4

Starting Material Synthesis Example 5 8 obtained 7- chloro 3, using 4-dihydro 1 Mechiruchioi Sokino phosphorus and 2- (4 i (3 black port phenyl) piperidines Rajin one 1 one I le) E chill carbohydrazide embodiment example 1 1 and more in performing the same reaction and treatment, 9 one-chloro 3- (2- (4 i (3 black port phenyl) piperidines Rajin one 1 one I le) Echiru) one 5, 6-dihydro 1, 2, 4-Toriazoro [4, 3- a] I Sokino phosphorus is obtained.

Example 6 5

5 obtained in Example 1, 6- dihydro-3- (piperidin-one 4 one I le) one 1, 2, 4-Toriazoro [4, 3 - d] [1, 4] benzo O hexa peptidase pin 1, by 4 one base Nzojiokisan one 2-I le) alkylation process commonly used with methyl ρ- toluenesulfonate, 3- (1 i (1, 4 one base Nzojiokisan one 2-I le) Mechirubiperijin one 4 one I le) one 5, 6-dihydro-1, 2, 4-Toriazo port [4, 3 - d] [1, 4] benzo O hexa peptidase pin is obtained.

Example 6 6

5 obtained in Example 1, 6- dihydro-3- (piperidin-one 4 one I le) one 1, 2, 4 one Toriazoro [4, 3 -d] [1, 4] benzo O hexa peptidase pin and 6- § Sechiru 3- (2-Kuroroechiru) Single 2- Echiru 4, 5, 6, by 7 Tetorahido Rochieno [2, 3-c] Usually the alkylation method used with pyridine, 3- (1 i (2- ( 6- Asechiru 2 Echiru 4, 5, 6, 7-tetrahydro-thieno [2, 3-c] pyridine one 3-I le) Echiru) piperidine one 4 one I le) one 5, 6-dihydro-1, 2 , 4 one Toriazoro [4, 3 - d] [1, 4] Benzoo Kisazepin is obtained.

Example 6 7

Example 2 5 obtained in 3- (1 i (2 - (4 one black port phenyl) Echiru) piperazinyl lysine one 4 one I le) one 5, 6-dihydro-1, 2, 4-Toriazoro [4, 3 -d]

[1, 4] benzothiazepine was dissolved in acetic acid solution under ice-cooling, by the action of aqueous hydrogen peroxide, 3- (1 - (2 - (4 one black port phenyl) Echiru) Piberiji Hmm 4 one I le) one 5, 6-dihydro-1, 2, 4 one Toriazoro [4, 3 - d] [1, 4] benzothiazepine 7-year old Kishido is obtained.

o Example 6 8

Obtained in Example 2 5 3- (1 i (2 - (4 Kurorofuweniru) Echiru) piperazinyl lysine one 4 one I le) one 5, 6-dihydro-1, 2, 4-Toriazoro [4, 3 - d ]

[1, 4] benzothiazepine was dissolved in formic acid solution, by the action of aqueous hydrogen peroxide at room temperature, 3- (1 i (2- (4 one black port phenyl) Echiru) piperazinyl lysine one 4 one I le) one 5, 6-dihydro-1, 2, 4 one Toriazoro [4, 3 - d]

[1, 4] benzothiazepine 7, 7 Jiokishido is obtained.

Example 6 9

7- butyrolactone 1 2 0 g, hydrazine 'monohydrate 2 5 0 ml was added to ethanol 1 1, after stirring for 3 0 minutes at room temperature for 2 hours heating and stirring at the solvent reflux temperature. After completion of reaction, to obtain a 4-hydroxy Petit Luke Lupo hydrazide 1 3 6 g by cooling. This compound 2. 3 g and the raw material Synthetic Example 4 4 ​​2 obtained in 3-dihydro 5 Mechiruchio one 1, 4 plus one base Nzookisazepin 3. 8 g in n- butanol · 2 Om 1, 24 h at reflux temperature heating the mixture was stirred. The solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography (black port Holm: methanol = 2 0: 1) By Seisuru fine at, 3- (5, 6-dihydro-one 1, 2, 4 - Toriazoro [4, 3 - d] to give the [1, 4] benzo O hexa peptidase pin one 3-I le) propanol 2. 8 g. In addition the compounds 0. 7 g, the Toryechiruamin 0. 8 4m 1 to dimethylformamidine de 1 0 m l, which was added dropwise under ice-cooling Meshiruku port ride 0. 4m l, and stirred further at room temperature for 4 hours. After completion of the reaction, 4- (4 Kurorofuweniru) one 1, 2, 3, 6-tetrahydrate port pyridine 0. 4 5 g, potassium carbonate 1. O g were added and stirred on heating for 1 hour at 7 0 ° C. The reaction mixture was treated with water, the organic layer was extracted with black port Holm, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the resulting residue by silica gel column chromatography (black port Holm: methanol = 2 0: 1) to obtain 3- (3- (4 - (4 one black port phenyl) Single 3, 6-dihydro-2 H- pyridine one 1 one I) propyl) one 5, 6-dihydro-1, 2, 4-Toriazoro [4, 3 - d] [1, 4] benzo O hexa peptidase pin 0.5 was obtained 1 4 g.

Mp 1 7 8 - 1 8 0 e C

Example 7 0

2 obtained in Starting Material Synthesis Example 4 4 ​​3- dihydro 5- methylthio one 1, 4 one Ben Zookisazepin 1. 9 g, 2- (4- (4 one black port phenyl) one 4-hydroxy-piperidine one 1 one I le ) E chill carbohydrazide 2. 0 g of n- blanking evening addition to Nord 3 5 ml, was heated and stirred for 2 days the solvent reflux temperature. After completion of the reaction, was removed by distillation of the solvent under reduced pressure, after crystallization adding ethanol to the residue, recrystallized from ethanol, 3- (2- (4 one (4 one black port phenyl) Single 4- hydroxypiperidine one 1 one I le) Echiru) one 5, 6-dihydro-1, 2, 4 one Toriazoro [4, 3- d] [1, 4] benzo O hexa peptidase pin 0. 5 g.

Mp 2 3 2 ° C

Example 7 1

Example 1 3 obtained in 3- (1 i (2- (4 Kurorofuweniru) Echiru) piperazinyl lysine one 4 one I le) one 5, 6-dihydro-1 0-two Torrox 1, 2, 4 one Toriazo port [4, 3 - d] [1, 4] benzo O hexa peptidase pin 0. 5 g and the Raney nickel 0. 2 g was added 2 h of hydrogen at room temperature in ethanol as a catalyst. After completion of the reaction, after removal of the catalysts by the solvent was distilled off under reduced pressure, the obtained residue was crystallized added hydrochloric one ethanol solvent solution, recrystallized from ethanol, 1 0-amino-3 i (1 i (2- (4 one black port phenyl) Echiru) piperidine one 4 one I le) one 5, 6-dihydro-1, 2, 4-Toriazoro [4, 3 - d] [1, 4] It was obtained Benzookisa Zepin dihydrochloride 1/4 hydrate 0. 2 5 g.

Mp 2 5 0- 2 5 2 ° C

Example 7 2

Example 3 6 Methanesulfonic acid 2- obtained in (5, 6-dihydro-1, 2, 4 one Toriazoro [4, 3 - d] [1, 4] benzo O hexa peptidase pin one 3-I le) E Chi glycol ester 0. 6 g, 4 one (1 one-naphthyl) piperidines Rajin 0. 4 g, 1 hour heating was stirred at 7 0 manually added potassium carbonate 1. 0 g in dimethylformamide § Mi de 2 0 m 1. After completion of the reaction, the reaction mixture was treated with water, the organic layer was dried extracted sulfate anhydride Ma Guneshiumu with acetic acid Echiru. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (Black hole Holm: methanol = 2 0: 1) More be separated and purified by, 5, 6- dihydro 3- (2- (4 one ( 1 one-naphthyl) piperidines Rajin one 1 one I le) Echiru) one 1, 2, 4-Toriazoro [4, 3 - d] [1, 4] was obtained Benzooki Sazepin 1 tetrahydrate 0. 2 g.

Mp 1 9 4 one 1 9 7 'C

Example 7 3

Example 3 6 obtained in methanesulfonic acid 2- (5, 6 dihydric draw 1, 2, 4 one Toriazoro [4, 3 -d] [1, 4] benzo O hexa peptidase pin one 3-I le) E Ji glycol ester 0. 6 g, 4 one (4 one black port phenyl) one 1, 2, 3, 6-Tetoraha Lee de port pyridine 0. 4 g, potassium carbonate 1. 0 g of dimethyl formamidine de 2 0 m and 7 hours of heating stirring at added 7 0 hands 1. The reaction mixture was treated with water, and dried extracted over anhydrous magnesium sulfate and the organic layer was black port Holm. Distilled off Tokura the residue of the solvent under reduced pressure was purified by silica gel column chromatography (black port Holm: methanol = 2 0: 1) to recover purified by 3- (2- (4 i (4 - Black port Fuweni Le) Single 3, 6-dihydro-2 H- pyridine one 1 one I le) Echiru) one 5, 6 dihydric draw 1, 2, 4-Toriazoro [4, 3 - d] [1, 4] Benzookisa It was obtained Zepin 0. 2 g.

Mp 1 7 9 - 1 8 0 ° C

Example 7 4

Starting Material Synthesis Example 5 2 2 obtained in 3-dihydro 7-menu butoxy - 5-methylthio one 1, 2, 4 one Toriazoro [4, 3 - d] [1, 4] benzo O Kisa Ze Pin 1.0 g, 2-(4 one (4 one black port phenyl) piperidines Rajin one 1 one I le) Echirukarubohi hydrazide 1. 3 g n-blanking evening addition to Nord 1 0 Om 1, 2 days pressurized heat at reflux temperature of the solvent and the mixture was stirred. After completion of the reaction, the solvent was distilled off under reduced pressure, was collected by filtration to obtain while handling ethanol to the resulting residue solid. This was added to an ethanol solution of maleic acid and the resulting solid was recrystallized from methanol aqueous solution 3- (2- (4 i (4-click Rorofueniru) piperidines Rajin one 1 one I le) Echiru) Single 5, 6-dihydro-1 0-main Tokishi 1, 2, 4-Toriazoro [4, 3 - d] to give the [1, 4] benzo O hexa peptidase pins maleate 0. 5 g.

Mp 1 9 8 (decomposition)

Example 7 5

Example 6 9 obtained 3- (5, 6-dihydro-1, 2, 4-Toriazoro [4, 3 - d] [1, 4] benzo O hexa peptidase pin one 3-I le) propanol 0.7 g, in dimethylformamide § Mi de 1 0 m 1 solution of preparative Riechiruamin 0. 8 4m l, added Korihiyakame silk port chloride 0. 4m l, was stirred at room temperature for 4 hours. Then 4 one (2, 3-dichloro port phenyl) piperidines Rajin 0. 8 5 g, potassium carbonate 1 g was added and stirred on heating for 1 hour at 70. The reaction mixture was treated with water, put extract the organic layer was black port Holm, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the obtained residue was purified by silica gel column chromatography (black port Holm: methanol = 2 0: 1) to obtain 5, 6- dihydro-3- (3- (4 one ( 2, 3-dichlorobenzoyl Rorofueniru) piperidines Rajin one 1 one I) propyl) one 1, 2, 4-Toriazoro [4, 3 - d] [1, 4] benzo O hexa peptidase pin 1 Bruno pentahydrate 0 . to obtain a 1 7 g. CI CI

1 / 5H 2 0 mp 1 2 3- 1 2 6 e C

Example 7 6

2 obtained in Starting Material Synthesis Example 4 4 ​​3- dihydro 5- methylthio one 1, 4 one Ben Zookisazepin 2. 9 g, 2-(4 i (3 black port phenyl) one 4-hydroxy-piperidine one 1 one I le ) E chill carbohydrazide 1. in addition to the 9 g n-butanol 3 5 ml, was heated and stirred for 2 days the solvent reflux temperature. By recrystallization it Seo bromide pills alcohol after distilling off the solvent under reduced pressure, was crystallized added Jie isopropyl ether to the resulting residue, 3- (2- (4 one (3- black port phenyl) Single 4-hydroxycarboxylic piperidine one 1 one I le) Echiru) one 5, 6-dihydro-1, 2, 4-preparative Riazoro [4, 3 - d] [1, 4] benzo O hexa peptidase pin 1. 3 were obtained g.

Mp 1 3 7- 1 3 8 ° C

Example 7 7

Obtained in Example 7 6 3- (2- (4 i (3 Kurorofuweniru) Single 4 Hidoro carboxymethyl piperidine one 1 one I le) Echiru) one 5, 6-dihydro-1, 2, 4-triazolopyrimidine [4 , 3 - d] [1, 4] benzo O hexa peptidase pin 1. O g was added to the concentrated sulfuric acid 1 0 m l, and heated and stirred for 3 hours at 8 0 ° C. The resulting solid was collected by filtration, which was added to the carbonate force Liu anhydrous solution, the organic layer was extracted with black port Holm, and dried over anhydrous magnesium sulfate. The obtained by evaporating the residue of the solvent under reduced pressure by silica gel column chromatography

- (Black hole Holm: methanol = 4 0: 1) to recover purified by 3- (2- (4 - (3-chlorophenyl) one 3, 6-dihydro-2 H- pyridine one 1

- I le) Echiru) one 5, 6-dihydro-1, 2, 4-Toriazoro [4, 3 - d]

[1, 4] benzo O hexa peptidase pin 0. 5 g.

Mp 1 4 9 one 1 5 0 e C

Example 7 8

Example 3 6 Methanesulfonic acid 2- obtained in (5, 6-dihydro-1, 2, 4 one Toriazoro [4, 3 - d] [1, 4] benzo O hexa peptidase pin one 3-I le) E Chi glycol ester 0. 9 g, 4 one (2, 3-dichlorophenyl) one 1, 2, 3, 6-Te Torahai Doropirijin 0. 8 g, a carbonate force potassium 2 g in dimethylformamide § Mi de 2 0 ml added was 7 hours heated with stirring at 6 0 ° C. The reaction mixture was treated with water, the organic layer was extracted with black port Holm, and dried over anhydrous magnesium sulfate. The obtained by evaporating the residue of the solvent under reduced pressure by silica gel column chromatography (black port Holm: methanol one le 4 0: 1) to recover purified by 3- (2- (4 one (2, 3 - Axis Rorofueniru) one 3, 6-dihydro-2 H- pyridine one 1 one I le) Echiru) one 5, 6-dihydro-1, 2, 4-Toriazoro [4, 3 -d] [1, 4] Benzookisa Zepin 0 . were obtained 3 g.

Mp 1 7 8 ° C (decomposition)

Example 7 9

Example 3 6 Methanesulfonic acid 2- obtained in (5, 6-dihydro-1, 2, 4 one Toriazoro [4, 3 - d] [1, 4] benzo O hexa peptidase pin one 3-I le) E Chi glycol ester 0. 9 g, 4 one (4 one Buromofueniru) one 1, 2, 3, 6-Tetoraha Idoropirijin 0. 7 g, added carbonate force Riumu 1 g to Jimechiruhoru 厶 § Mi de 2 0 m 1 6 0 ° C heating the mixture was stirred in 7 hours. The reaction mixture was treated with water, and dried extracted sulfate anhydride Maguneshiumu The organic layer was black port Hol beam. The obtained by evaporating the residue of the solvent under reduced pressure by silica gel column chromatography (black port Holm: methanol = 4 0: 1) to recover purified by 3- (2- (4 one (4 one Puromofuweniru) - 3, 6-dihydro-2 H- pyridine one 1-I le) Echiru) one 5, 6-dihydro-one 1, 2, 4-Toriazoro [4, 3 - d] [1, 4] benzo O Kisa Ze pin 0. 4 were obtained g.

Mp 1 9 5 1 9 7

Example 8 0

Example 3 6 Methanesulfonic acid 2- obtained in (5, 6-dihydro-1, 2, 4 one Toriazoro [4, 3 - d] [1, 4] benzo O hexa peptidase pin one 3-I le) E Ji glycol ester 0, 7 g, 4 one (4 one-chloro 2-methylphenyl) one 1, 2, 3, 6-tetrahydrate port pyridine 0. 8 g, potassium carbonate 0. 4 g of dimethyl formamidine de 2 Om l 1 hour followed by agitation under heating at added 6 0 hands. The reaction mixture was treated with water, the organic layer was dried extracted sulfate anhydride Maguneshiumu with acetic acid Echiru. After crystallization by addition of Toruen to the resulting residue and the solvent was evaporated under reduced pressure, and recrystallized with isopropyl alcohol, 3- (2- (4 one (4 one-chloro 2- Mechirufue sulfonyl) one 3, 6-dihydro-2 H- pyridine one 1-I le) Echiru) one 5, 6-di Hidoro 1, 2, 4-Toriabu port [4, 3 - d] [1, 4] benzo O hexa peptidase pin 0.5 was obtained 2 g.

Mp 1 6 9 ° C (decomposition)

Example 8 1

Example 3 6 Methanesulfonic acid 2- obtained in (5, 6-dihydro-1, 2, 4 one Toriazoro [4, 3 - d] [1, 4] benzo O hexa peptidase pin one 3-I le) E Chi glycol ester 0. 9 g, 4 one (2-naphthyl) _ 1, 2, 3, 6-tetrahydrate port pyridine 1 2 sulfates 1. 0 g, potassium carbonate 1. 0 g of dimethyl formamidine de 1 0 0 m 3 hours and stirred at at addition to l 6 0. The reaction mixture was treated with water, the organic layer was dried extract over anhydrous magnesium sulfate with acetic acid Echiru. After addition of toluene and crystallized to the resulting residue and the solvent was evaporated under reduced pressure and recrystallized from ethanol, 5, 6- dihydro 3- (2- (3, 6- dihydro 4- ( 2-naphthyl) Single 2 H- pyridine one 1 one I le) Echiru) one 1, 2, 4-Toriazoro [4, 3 - d] [1, 4] benzo O Kisa Ze pin 0. 2 g .

Mp 1 7 8 Te (decomposition)

Example 8 2

Example 3 Methanesulfonic acid 2- (5 obtained in 6, 6-dihydro-1, 2,

4 7 4 one Toriazoro [4, 3 - d] [1, 4] benzo O hexa peptidase pin one 3-I le) E Ji glycol ester 0. 9 g, 4 i (4-menu Tokishifueniru) one 1, 2, 3 , 6 tetrahydrate port pyridine 0. 6 g, was stirred on heating for 1 hour with potassium carbonate 1. 0 g was added to dimethylformamidine de 2 0 ml 6 0 ° C. The reaction mixture was treated with water, the organic layer was dried extract over anhydrous magnesium sulfate with acetic acid Echiru. After crystallization with toluene the residue was distilled off the solvent under reduced pressure Tokura, by recrystallization with isopropyl alcohol, 5, 6- dihydro-3- (2 - (3, 6-dihydro one 4- (4-menu Tokishifue sulfonyl) Single 2 H- pyridine one 1 one I le) Echiru) one 1, 2, 4-Toriazoro [4, 3 - d] [1, 4] benzo O Kisa Ze pin 0 . was obtained 2 g.

Te melting point 1 9 7 1 9 9

Example 8 3

Starting Material Synthesis Example 4 2 obtained in 4, 3-dihydro-5-methylthio one 1, 4 one Ben Zookisazepin 2. 7 g, 2-(4-hydroxy-one 4 one (4-methylphenyl) piperidine one 1 one I le) E chill carbohydrazide 1, 9 g of n- blanking evening Nord 3 was added to 5 ml, was heated and stirred for 2 days the solvent reflux temperature. By distilling off the solvent under reduced pressure, recrystallized from I isopropyl alcohol after crystallization added Jie isopropyl ether to the obtained residue, 5, 6- dihydro 3- (2- (4-hydroxy one 4 one (4 one-methylphenyl) piperidine one 1 one I le) Echiru 1, 2, 4-tri Azoro - give [4, 3 d] [1, 4] benzo O hexa peptidase pin 1. 7 g.

Mp 1 9 7- 2 0 1 ° C

Example 8 4

5 obtained in Example 8 3, 6-dihydro - 3 (2 - (4-hydroxy-4 one (4 one-methylphenyl) piperidine one 1 one I le) Echiru) one 1, 2, 4 Toria Zorro [ 4, 3 - d] [1, 4] benzo O hexa peptidase pin 1. O g was added to the concentrated sulfuric acid and stirred for 3 hours while heating at 8 0 ° C. The resulting solid was collected by filtration, which was added to aqueous potassium carbonate solution, the organic layer was extracted with black port Holm, evaporated and purified by silica gel column chromatography (black port a c decrease E under solvent was dried over anhydrous magnesium sulfate Holm: methanol = 4 0: by separating and purifying at 1), 5, 6- dihydro-3- (2 i (3, 6 dihydric draw 4 one (4 one-methylphenyl) Single 2H- pyridin one 1 - I Le) Echiru) one 1, 2, 4 one Toriazoro [4, 3 - d] to give the [1, 4] Benzookisa Zepin 0. 5 g.

Mp 1 8 2- 1 8 3 'C

Example 8 5

Starting Material Synthesis Example 4 2 obtained in 4, 3-dihydro - 5-methylthio - 1, 4 one Ben Zookisazepin 7. 5 g, 2- (4-hydroxy-4 one (2-thienyl) Piperi gin one 1 one I le) added E chill carbohydrazide 5. 4 g in n- butanol 1 0 0 m l, and heated and stirred for 2 days the solvent reflux temperature. By recrystallization I isopropyl alcohol after distilling off the solvent under reduced pressure, was crystallized added Jie isopropyl ether residue obtained, 5, 6-dihydro-one 3- (2 - (4 -hydroxy-4 one (2-thienyl) piperidine one 1 one I le) Echiru) one 1, 2, 4 one Toriazoro [4, 3 - d] [1, 4] benzo O hexa peptidase pin 5. 7 g It was. Mp 1 9 5~ 1 9 7 'C

Example 8 6

5 obtained in Example 8 5, 6- dihydro-3- (2 - (4-hydroxy-4 one (2-thienyl) piperidine one 1-I le) Echiru) one 1, 2, 4-Toriazoro [4, 3 - d] [1, 4] benzo O hexa peptidase pin 1. O g was added to the concentrated sulfuric acid and stirred for 3 hours while heating at 8 0 ° C. The resulting solid was collected by filtration, which was added to aqueous potassium carbonate solution, the organic layer was extracted with black port Holm, and dried over anhydrous magnesium sulfate. After crystallization was added an ethanol solution of maleic acid to the resulting residue and the solvent was evaporated under reduced pressure and recrystallized from ethanol, 5, 6- dihydro 3- (2- (3, 6 Jihidoro 4 i (2-thienyl) Single 2 H- pyridine one 1 one I le) Echiru) one 1, 2, 4-Toriazoro [4, 3 -d] [1, 4] benzo O hexa peptidase pins maleate 0.1 It was obtained g.

N

Because mmaaieate

Mp 1 7 8~ 1 8 0 ° C

Example 8 7

5 obtained in Example 8 5, 6- dihydro 3- (2- (4-hydroxy-4 one (2-thienyl) piperidine one 1 one I le) Echiru) one 1, 2, 4-Toriazoro [4, 3 - d] [1, 4] benzo O hexa peptidase pin 1. 0 £, trimethylsilylchloride Li de 1. 9m 1, was added sodium iodide 2. 2 g to Asetonitoriru 2 5 m 1, stirred for 1 hour at solvent reflux did. The reaction was hand dryer extracted anhydrous sulfate Maguneshiu 厶 treated organic layer was Gro port Holm at aqueous sodium sulfite and carbonate force Li © anhydrous solution. After crystallization was added an ethanol solution of maleic acid to the resulting residue and the solvent was evaporated under reduced pressure and recrystallized from ethanol, 5, 6-dihydro - 3 - (2- (4 - (2 - thienyl) piperidine one 1 one I le) Echiru) one 1, 2, 4 one Toriazoro [4, 3 - d] [1, 4] benzo O hexa peptidase pins maleate 0. 3 g.

Mp 1 8 3~ 1 8 4 ° C

Example 8 8

Obtained in Example 6 9 3- (5, 6-dihydro-1, 2, 4 one Toriazoro [4, 3 - d] [1, 4] benzo O hexa peptidase pin - 3-I le) propanol 0.7 g, in dimethylformamide § Mi de 1 0 m l solution of preparative Ryechiruamin 8 4 ml, was added Korihiyakame silk port chloride 0. 4m 1, followed by stirring at room temperature for 4 hours. Then, 4 one (2, 3-dimethyl-phenylalanine) piperidines Rajin 0. 8 5 g, potassium carbonate 1 g was added and stirred on heating for 1 hour at 7 0 ° C. The reaction mixture was treated with water, put extract the organic layer was black port Holm, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the obtained residue was purified by silica gel column chromatography (black port Holm: methanol = 2 0: 1) to obtain 3- (3- (4 one (2, 3-dimethyl phenyl) piperazinyl Rajin one 1-I) propyl) one 5, 6-dihydro-1, 2, 4-Toriazoro [4, 3 - d] [1, 4] benzo O hexa peptidase pin 1 Z5 monohydrate 0 . to obtain a 1 7 g. Mp 1 2 1-1 2 2

Example 8 9

Starting Material Synthesis Example 4 8 5 methylthio one 1 obtained in four one base Nzuokisazepin 0. 5 8 g and 2- (4 one (4 one black port phenyl) piperidines Rajin one 1 one I le) Echiru carbohydrazide 0 . added 8 5 g in n- butanol 1 Om 1, was stirred for 24 hours at 1 2 0~1 3 0 ° C. The solvent was distilled off under reduced pressure, the obtained residue was purified by silica gel chroma preparative chromatography (Black hole Holm: methanol = 2 0: 1) after separation and purification by recrystallization from isoprene port pills alcohol, 3- (2 - (4 one (4 one black port Hue yl) piperidines Rajin one 1 one I le) Echiru) one 1, 2, 4-Toriazoro [4, 3 -d]

[1, 4] benzo O hexa peptidase pin 0. 4 5 g.

Mp 2 2 1~ 2 2 2 e C

Example 9 0

3 - (2- (4 one (4 one black port phenyl) piperidines Rajin one 1 one I le) Echiru) - 1, 2, 4-Toriazoro [4, 3 - d] [1, 4] Benzookisaze black port Holm pins 3 Omg: methanol = 4: 1 solution 5 m 1 to 1 0% palladium-carbon 1 2 0 mg was added, 4 0-4 2 in, although a windsock radioactivity tritium hydrogen et 2 hours the catalytic reduction was carried out. After completion of the reaction, the catalyst was concentrated filtered furnace solution. The resulting residue high-performance liquid chromatography (0. 1 M acetic Anmoniumu: Asetonito Lil = 1: 1) to obtain 3- (2- (4 one (4 one black port phenylene Le) Pipet Rajin one 1 one I le) Echiru) one 5, 6-di-tritium one 1, 2, 4-preparative Riazoro [4, 3 - d] [1, 4] benzo O hexa peptidase pin (2 6 Kiyuurino mm 0 1) It was obtained.

Example 9 1

3- (1 - (2- (4-black port phenyl) Echiru) piperidine one 4 one I le) one 1, 2, 4-Toriazoro [4, 3 -d] [1, 4] benzo O Kisa Ze pins 3 Omg the black hole Holm: methanol = 4: 1 solution 5 m 1 1 0% palladium-carbon 1 2 0 mg added to 4 0-4 2 in, although the radioactive tritium hydrogen gas of streamers et 2 hours catalytic reduction It was carried out. After completion of the reaction, the catalyst was concentrated filtered furnace solution. The resulting residue high-performance liquid chromatography (0. 1 M acetic Anmoniumu: Asetonito Lil = 1: 1) to obtain 3- (1 - (2- (4-black port phenylene Le) Echiru) piperidine one 4 one I le) one 5, 6-di-tritium one 1, 2, 4-preparative Riazoro [4, 3-d] [1, 4] benzo o hexa peptidase pin (2 6 Kiyuuri ZMM o 1) It was obtained.

Example 9 2

Starting Material Synthesis Example 1 2 0 obtained 4-methylthio one 7, 8-dihydro-6 H- Choi Roh Do stirred to [3, 2-c] Azepin 3 0 g of n- blanking evening Nord 3 0 Om 1 solution There al, (1 i (tertiary butoxycarbonyl) piperidine one 4-I le) Karubohi Dora disilazide 3 1 g is added and heated to reflux for 1 to 24 hours. After completion of the reaction, concentrated in vacuo to give al was added Torifuruoro acetate 1 5 Om l to the residue, stirred for 1-2 at room temperature for 4 hours. After completion of the reaction, distilled off under reduced pressure Torifuruoro acetate. The resulting residue ethanol construed solvent and an ethanol solution of hydrogen chloride was added, after forming the hydrochloride salt by filtered off, recrystallized from ethanol, 6 of colorless crystals, 7- dihydro 3- (4 Piberiji Le) Single 5 H- thieno [3, 2 - c] - 1, 2, 4- Toriazoro was obtained [4, 3- a] § Zepin dihydrochloride 2 0 g.

2HCI

Mp 2 8 0 ° C or higher

Example 9 3

4 Mechiruchio one 7 of Example 9 2, 8-dihydro-6 H- thieno [3, 2 - c] instead of Azepin 5- methylthio one 2, 3 Jihidorocheno [3, 2 - f] [1,] thiazepine by performing the reaction and treatment in the same manner by using, 5 yellow crystals, 6- dihydro 3- (4-piperidyl) Chieno [3, 2 - f] one 1, 2, 4 one Toriazoro [4, 3 - d] [ 1, 4] to obtain the thiazepine.

Mp 1 7 9~ 1 8 1 ° C

Example 9 4

4 Mechiruchio one 7, 8-dihydro-6 H- thieno with stirring [3, 2-c] Azepin 0 8 g of butanol Ichiru 2 Om 1 solution, 1 - (2-Fueniruechiru) peak Perijin one 4 one carbohydrazide 1 g is added and refluxed for 5 hours. After cooling, the blanking evening Knoll was distilled off under reduced pressure, Ri by that recrystallized with ethanol resulting crystals, 6 colorless powder crystals, 7- dihydro 3- (1 - (2-Fuweniruechiru) Pipet lysine one 4 one I le) Single 5 H- thieno [3, 2 - c] - 1, 2, 4 one bird Ryo Zorro was obtained [4, 3- a] Azepin 0. 7 g.

Mp 1 7 7~ 1 7 8 ° C

Example 9 5

By performing the reaction and treatment in the same manner using 1 one benzylpiperidine one 4 one carbohydrazide instead of 1 i (2 Fueniruechiru) piperidine one 4 one Karubohi hydrazide of Example 9 4, colorless powder crystals 6 , 7- dihydro 3- (1 one benzyl piperidine one 4 one I le) Single 5 H- thieno [3, 2-c] one 1, 2, 4-tri Azoro was obtained [4, 3-a] Azepin .

Te mp 1 7 7-1 7 9

Example 9 6

1 i (2 Fueniruechiru) piperidine Example 9 4 - 4 one Karubohi hydrazide reaction and similarly with 1 i (2- (4 one black port phenyl) Echiru) piperidine one 4 one carbohydrazide instead of by performing the process, 6 colorless powder crystals, 7- dihydro one 3- (1 - (2- (4 one black port phenyl) Echiru) piperidine one 4 one I le) Single 5 H- thieno [3, 2 - c] - 1, 2, 4 one Toriazoro [4, 3 - a] was obtained Azepin. Mp 1 9 2~ 1 9 3 ° C

Example 9 7

Similarly with 1 i (2 Fueniruechiru) in place of piperidine one 4 one-carbohydrazide 2- (4 one (pyrimidine one 2-I le) piperazine one 1 one I le) Aseto hydrazide Example 9 4 after the reaction and treatment in, more possible to form the hydrochloride salt, colorless powder crystals 3- (4 one (pyrimidine one 2-I le) piperidines Rajin one 1 over I Rumechiru) one 6, 7- dihydro 5 H- thieno [3, 2 - c] to give an 1, 2, 4-preparative Riazoro [4, 3- a] Azepin trihydrochloride monohydrate 0. 7 g.

3HCI Η 2 0

Mp 2 2 7~ 2 2 9 ° C

Example 9 8

By performing the reaction and treatment in the same manner using 1 i (2 Feniruechiru) 2- (N- base Njiru N- Mechiruamino) in place of piperidine one 4 Ichiriki Lupo hydrazide § Seto hydrazide Example 9 4 3- colorless powder crystals (N- base Njiru N - methylaminomethyl) one 6, 7-dihydro-5 H- thieno [3, 2-c] one 1, 2, 4-Toriazoro [4, 3-a] It was obtained Azepin 0. 2 g.

Mp 1 4 0~ 1 4 2 e C

Example 9 9

The reaction was carried out and treated similarly, using - (benzylpiperidine one 4 one I le 1) propionohydrazide 1 i (2 Fueniruechiru) in place of piperidine one 4 one carbohydrazide 3 of Example 9 4 after, by forming the hydrochloride salt, colorless powder powder crystals 3- (2- (1 one benzylpiperidine one 4 one I le) Echiru) one 6, 7-dihydro-5 H- thieno [3, 2 - c] - 1, 2, 4 one Toriazoro was obtained [4, 3- a] Azepin dihydrochloride · 1 Z2 monohydrate 0. 1 5 g.

2HCI 1 / 2H 2 0

Mp 24 7~ 2 5 0 ° C

Example 1 0 0

Starting Material Synthesis Example 1 4 2- chloro 4 obtained in 9 Mechiruchio one 7, 8 Jihidoro

- 6H-thieno [3, 2-c] was dissolved Azepin 0. 7 g to blanking evening Nord 2 0 m 1, 1 i (2- (4 one black port phenyl) Echiru) piperidine one 4 one carbohydrazide 1 g added and heated to reflux for 5 hours. After cooling, the blanking evening Knoll was distilled off under reduced pressure, by performing the obtained crystals were recrystallized with isopropyl alcohol, 9 one chloro 6 colorless powder crystals, 7- dihydro 3- (1 i (2- (4 one black port phenyl) E Chi le) piperidine one 4 one I le) Single 5 H- thieno [3, 2 - c] - 1, 2, 4- tri Azoro, 3- a] Azepin 0. 2 3 g It was obtained.

Exemplary Te mp 1 8 5 Example 1 0 1

6, 7-dihydro-3- (4-piperidyl) Single 5 H- thieno [3, 2 - c] one 1, 2, 4-Toriazoro [4, 3-a] Azepin-2-dimethyl Horumuami hydrochloride 0. 5 g de 1 Om under ice cooling to l solution, with stirring, 2-naphthyl acetate 0. 3 8 g, Toryechiruamin 0. 5 1 m 1, Shianohosuhon acid Jechiru 0. 3 1 ml is added and stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was poured into ice water and extracted with acetic acid Echiru, washed with water, dried over magnesium sulfate. After concentration under reduced pressure, by the resulting crystals recrystallized from I isopropyl alcohol, a colorless 6 powder crystal, 7- dihydro 3- (1 - (2- (2-naphthyl) Single 1 one year old Kitsuechiru) Piperi Jin one 4 one I le) Single 5H- thieno [3, 2- c] - 1, 2, 4- Toriazoro was obtained [4, 3- a] Azepin 0. 7 g. Mp 2 0 4. C

6, 7-dihydro-3- (1- (2- (2-naphthyl) Single 1 one year old Kisoechiru) piperidine one 4 one I le) Single 5 H- thieno [3, 2-c] by one tooth 2, 4 - Toriazo port [4, 3- a] under ice-cooling Azepin 0. 5 5 g of tetrahydrofuran 1 0 m 1 solution, with stirring, was added lithium aluminum hydride 0. 1 5 g, stirred 1 hour at room temperature . After completion of the reaction, the reaction mixture was poured into ice water and extracted with acetic acid Echiru, and water washed, dried over magnesium sulfate. After concentration under reduced pressure, by recrystallization from isopropyl alcohol and the resulting crystals, 6 colorless powder crystals, 7-dihydro-3 - (1 i (2- (2-naphthyl) Echiru) piperidine one 4 one I le) Single 5H- Chi eno [3, 2-c] one 1, 2, 4-Toriazoro was obtained [4, 3- a] Azepin 0. lg.

Te melting point 2 2 0

By performing the reaction and treatment in the same manner using 1 one naphthylacetic acid in place of Example 1 0 2 Example 1 0 1 2-naphthyl acetic acid, 6 colorless powder crystals, 7- dihydro 3- (1 - ( 2 - (1 one-naphthyl) Echiru) piperidine one 4 one I le) Single 5 H- thieno [3, 2 - c] - 1, 2, 4-Toriazoro (4 to give 3- a] Azepin n

With a melting point of 1 7 7-1 8 0

Example 1 0 3

By performing the reaction and treatment in the same manner using 4 one Furuorofuweniru acetate in place of Example 1 0 1 2-naphthyl acetic acid, 6 colorless powder crystals, 7- dihydro three to (1 i (2- (4 one fluorophenyl) Echiru) piperidine one 4 one I le) Single 5 H- thieno [3, 2-c] one 1, 2, 4-Toriabu port [4, 3- a] to give a Azepin.

Mp 1 7 4 e C

Example 1 0 4

By performing the reaction and treatment in the same manner using 2-Kurorofuweniru acid in place of Example 1 0 1 2-naphthyl acetic acid, 6 colorless powder crystals, 7- dihydro 3- (1 - (2- (2- black hole phenyl) Echiru) piperidine one 4 one I le) Single 5 H- thieno [3, 2-c] one 1, 2, 4 one Toriazoro [4, 3- a] c to obtain a Azepin

Mp 1 6 4 ° C

Example 1 0 5

Example 1 0 by carrying out the reaction and treatment in the same manner using 4 one-methylphenyl acetic acid in place of 1 of 2-naphthyl acetic acid, 6 colorless powder crystals, 7-dihydro - 3 (1 - (2- (4 one methylphenyl) Echiru) piperidine one 4 one I le) Single 5 H- thieno [3, 2 - c] one 1, 2, 4-Toriazoro [4, 3- a] was obtained Azepin (

Te melting point 1 8 8

Example 1 0 6

By performing the reaction and treatment in the same manner by using instead of 3-Kurorofuweniru acetate of Example 1 0 1 2-naphthyl acetic acid, colorless powder crystals 6, 7-dihydro - 3 (1 - (2 - (3 - black port phenyl) Echiru) piperidine one 4-I le) Single 5 H- thieno [3, 2- c] - 1, 2, 4- Toriazoro was obtained [4, 3- a] Azepin <

Mp 1 3 8~ 1 4 (TC

Example 1 0 7

Example 1 0 1 2-naphthyl instead 3 of acetic acid, by carrying out the reaction and treatment in the same manner using 4 Jikurorofuweniru acetate, 6 colorless powder crystals, 7-dihydro - 3 (1- (2- (3, 4 Jikuro port phenyl) Echiru) piperidine one 4-I le) Single 5 H- thieno [3, 2-c] one 1, 2, resulting 4- Toriazoro [4, 3- a] a § Zepin It was.

Mp 1 3 8-1 4 0

Example 1 0 8

2 instead of Example 1 0 1 2-naphthyl acetic acid, by carrying out the reaction and treatment in the same manner using 4 Jikurorofuweniru acetate, 6 colorless powder crystals, 7- dihydro one 3- (1 i (2- (2, Jikuro port phenyl) Echiru) piperidine one 4-I le) Single 5 H- thieno [3, 2-c] one 1, 2, 4-Toriazoro [4, 3- a] to give a § Zepin .

Te mp 2 9 1-2 9 3

Example 1 0 9

By performing the reaction and treatment in the same manner using 2, 6-1-dichloro-off We sulfonyl acetic acid in place of Example 1 0 1 2-naphthyl acetic acid, 6 colorless powder crystals, 7- dihydro one 3- (1 one (2- (2, 6 Jikuro port phenyl) Echiru) piperidine one 4-I le) Single 5 H- thieno [3, 2- c] - 1, 2, 4 one Toriazoro [4, 3- a] Ύ It was obtained Zepin. Melting point of 2 74-2

Example 1 1 0

By performing the reaction and treatment in the same manner using 4 one triflate Ruo b methylphenylpolysiloxane We sulfonyl acetic acid in place of Example 1 0 1 2-naphthyl acetic acid, 6 colorless powder crystals, 7-di hydro one 3- ( 1 one (2- (4 one triflate Ruo Russia methyl phenylalanine) Echiru) Piperi Jin one 4 one I le) Single 5 H- thieno [3, 2-c] one 1, 2, 4-Toriazoro [4, 3- It was obtained a] Azepin.

Mp 1 9 4

Example 1 1 1

By performing the reaction and treatment in the same manner using 3-triflate Ruo b methylphenylpolysiloxane sulfonyl acetic acid in place of Example 1 0 1 2-naphthyl acetic acid, 6 colorless powder crystals, 7- di Hidoro 3- (1 one (2- (3-triflate Ruo Russia methyl phenylalanine) Echiru) Piperi Jin one 4 one I le) Single 5 H- thieno [3, 2-c] one 1, 2, 4-Toriazoro [4, 3-a ] were obtained Azepin.

Mp 1 1 7 e C

Example 1 1 2 Example 1 0 1 6, 7- dihydro-3- (4-piperidyl) Single 5 H- thieno [3, 2-c] one 1, 2, 4-Toriazoro [4, 3-a] Azepin '2 instead 5 hydrochloride, 6- dihydro 3- (4-piperidyl) Single thieno [3, 2 - f] - 1, 2, 4 one Toriazoro [4, 3 -d] with [1, 4] thiazepine by performing similarly anti 応及 beauty treatment Te, colorless powder crystals 3- (1 i (2- (2-naphthyl) E chill) piperidine one 4 one I le) one 5, 6-dihydrothieno [3, 2 - f] - 1, 2, 4 one Toriazoro [4, 3 - d] to give the [1, 4] thiazepine.

Mp 1 8 6~ 1 8 8 e C

Example 1 1 3

By performing the reaction and treatment in the same manner using 3 full We sulfonyl propionic acid instead of Example 1 0 1 2-naphthyl acetic acid, 6 colorless powder crystals, 7-dihydro-3 - (1 - (3- phenylpropyl) piperidine one 4 one I le) Single 5 H- thieno [3 2 - c] - 1, 2, 4- Toriazoro - was obtained [4, 3 a] Azepin.

Mp 1 3 2-1 3 3

Example 1 1 4

5-methylthio one 2, 3- dihydrothieno [3, 2 - f] [1, 4] Chiazepi down and 1 one (2- (4 one black port phenyl) Echiru) performed using piperidine one 4 one Karubohidora disilazide Example 9 by performing the reaction and treatment in the same manner as 4, colorless powder crystals 3- (1 one (2-C4 one black port phenyl) Echiru) piperidine one 4 one I le) one 5, 6 dihydric Dorochieno [3, 2 - f] - 1, 2, 4- Toriazoro [4, 3- d]

[1, 4] thiazepine. To give the dihydrochloride.

Mp 1 4 1~ 1 4 3 ° C

Example 1 1 5

3- (1 i (2- (4 one black port phenyl) Echiru) piperidine one 4 one I le) one 5, 6-dihydrothieno [3, 2-b] - 1, 2, 4-Toriazoro [4, 3 - d]

[1, 4] thiazepine 0, 5 g ice cooling formic acid solution, with stirring, was added a 3 0% peracetic acid hydrogen solution 0. 3 2m l, reacted for 1 to 24 hours at room temperature. After completion of the reaction, the reaction mixture was poured into saturated aqueous potassium carbonate solution, and extracted with acetic acid Echiru, washed with water, dried over magnesium sulfate. After concentration under reduced pressure, by performing the obtained crystals were recrystallized with isopropyl alcohol one le, colorless powder crystals 3- (1 i (2- (4 one black port phenyl) Echiru) piperidine one 4 Ichii Le) one 5, 6 Jihidorocheno [3, 2 - f] one 1, 2, 4 one Toriazoro [4, 3 - d] [1, 4] to give the thiazepine 7, 7 Jiokishido · 1 Z4 monohydrate.

Mp 1 7 6-1 7 7

Example 1 1 6

6, 7-dihydro-3- (4-piperidyl) Single 5 H- thieno [3, 2-c 1, 2, 4-Toriazoro [4, 3 - a] Azepin the dihydrochloride 1. 24 g dimethylol Ruhorumuami de 1 om l and under ice-cooling to a mixed solution of toluene 1 0 m 1, while stirring, 2 _ (4 main Tokishifue sulfonyl) Echiru ρ- toluenesulfonate 1. 4 7 g, potassium carbonate 2. 2 1 g was added, at 7 0 hand is stirred for 2 hours. After completion of the reaction, the reaction mixture was poured into ice water and extracted with acetic acid Echiru, washed with water, dried over magnesium sulfate. After concentration under reduced pressure, by a child that is responsible for the resulting crystals recrystallized from isopropyl alcohol, 6 colorless powder crystals, 7- dihydro 3- (1 - (2- (4-menu butoxy phenyl) Echiru) piperidine one 4 one I le) Single 5 H- thieno [3, 2-c] to give an 1, 2, 4 one Toriazoro [4, 3- a] Azepin 0. 8 5 g.

Mp 1 9 3

Example 1 1 7

By performing the reaction and treatment in the same manner with Example 1 1 6 2- (4-menu Tokishifue sulfonyl) Echiru p- toluenesulfonic sulfonates Kishiruechiru p- toluenesulfonate to 2-cyclopropyl instead of Ichito, colorless 6 of the powder crystal, 7- dihydro 3- (1 - (2-Kishiruechiru cyclohexylene) piperidine one 4 one I le) Single 5 H- thieno [3, 2-c] one 1, 2, 4- Toriazoro [ 4, was obtained 3- a] Azepin.

Mp 2 1 5 ° C

Example 1 1 8

Example 1 1 6 2- (4-menu Tokishifue sulfonyl) Echiru ρ- toluene sulfonates

- by carrying out the reaction and treatment in the same manner using indanyl Ό one toluenesulfonate instead of bets, 6 colorless powder crystals, 7- dihydro 3- (1 i (2-I Ndaniru) piperidine one 4 Ichii Le) Single 5 H- thieno [3, 2-c] one 1, 2, 4 one Toriazoro was obtained [4, 3- a] Azepin.

Te melting point 2 6 2

Example 1 1 9

Carrying out the reaction and treatment in the same manner using 1, 4 one base Nzojiokisan one 2- Irumechiru ρ- toluenesulfonic Honeto instead of 2- (4-menu Tokishifueniru) Echiru p- toluenesulfonic sulfonates over preparative Example 1 1 6 by, 6 colorless powder crystals, 7 Jihidoro 3- (1 i (1, 4 one base Nzojiokisan one 2- Irumechiru) Piperi Jin one 4 one I le) Single 5H- thieno [3, 2-c] one 1, 2, 4 one Toriazoro was obtained [4, 3- a] Azepin.

Mp 1 4 4-1 4 5

Example 1 2 0

Example 1 1 6 2- (4-menu Tokishifuweniru) Echiru p- toluenesulfonic sulfonates over bets instead 6- Asechiru - 2- (2-Kuroroechiru) Single 3 Echiru 5, 7-2-dihydro-Choi Bruno [2, 3-c after the reaction and treatment in the same manner using a] pyridine, by forming the hydrochloride salt, 6 colorless powder crystals, 7- dihydro 3- (1 i (2- (6- Asechiru 3 Echiru 4, 5 , 6, 7-tetrahydrocannabinol Choi Roh

[2, 3 - c 1 pyridin one 2-I le) Echiru) piperidine one 4 one I le) Single 5 H- thieno [3, 2 - c] - 1, 2, 4 one Toriazoro [4, 3- It was obtained a] Azepin-2 salt salt dihydrate.

2HCJ2H 9 0 mp 2 2 3 e C

Example 1 2 1

By performing the reaction and treatment in the same manner using 2-chloro-E butoxy benzene in place of Example 1 1 6 2- (4-menu Tokishifue sulfonyl) Echiru p- toluenesulfonic sulfonates Ichito, colorless powdery crystals 6, 7-dihydro-3- (1 i (2 Fuwenokishe chill) piperidine one 4 one I le) Single 5 H- thieno [3, 2-c] one 1, 2, 4-preparative Riazoro [4, 3 - was obtained a] Azepin.

Mp 1 3 4-1 3 6

Example 1 2 2

By performing the reaction and treatment in the same manner with Example 1 1 6 2- (4-menu Tokishifue sulfonyl) Echiru p- toluenesulfonic sulfonates instead 4 one-fluorophenyl 2-chloro E chill ketone Ichito , 6 colorless powder crystals, 7- dihydro 3- (1 i (3- (4 one-fluorophenyl) Single 3 Okisopuropiru) piperidine one 4 one I Le) - 5 H- thieno [3, 2-c] one 1, 2, 4 one Toriazoro [4, 3 - a] was obtained Azepi down.

1 6 Mp 1 8 7 ° C

Example 1 2 3

6, 7-dihydro-3- (4-piperidyl) Single 5 H- thieno [3, 2-c] one 1, 2, 4-Toriazoro [4, 3-a〗 Azepin dihydrochloride 0. 3 g of Asetoni tolyl with stirring 5 0 m 1 solution, 2- (3-black port propyl) Single 2- (4 one-fluorophenyl) [1, 3] Jiokisoran, potassium carbonate 1 g, iodide force Liu beam 1 g was added, 7 2 hours and stirred at 0 ° C. After completion of the reaction, the reaction mixture was poured into water and extracted with acetic acid Echiru, washed with water, dried over magnesium sulfate. After concentration under reduced pressure, and the resulting et the residue dissolved in ethanol 3 Om l, concentrated hydrochloric acid was added to 5 ml, is stirred 1 hour at 1 0 0 hands. After completion of the reaction, the alkaline and extracted with black port Holm, washed with water and dried over magnesium sulfate. After concentration under reduced pressure, by performing the obtained crystals recrystallized from ethanol, 6 colorless powder crystals, 7- dihydro 3- (1 i (4 - (4 one-fluorophenyl) Single 4 Okisobuchiru) piperidine one 4 one I le) Single 5 H- thieno [3, 2-c] one 1, 2, 4-Toriazoro [4, 3- a] c to obtain a Azepin

Mp 1 5 5~ 1 5 7 ° C

Example 1 2 4

6 Example 1 2 3, 7- dihydro-3- (4-piperidyl) Single 5 H- thieno [3, 2-c] - 1, 2, 4 one Toriabu port [4, 3-a] Azepin 'dihydrochloride of instead 5, 6- dihydro-3- (4-piperidyl) Chieno [3, 2 - f] one 1, 2, 4 one Toriazoro [4, 3 - d] [1, 4] anti 応及 similarly using thiazepine after the fine processing, by forming the hydrochloride salt, colorless powder crystals 3- (1 - (4- (4 one-fluorophenyl) one 4 one year old Kisobuchiru) piperidine one 4-I le) Single 5 6- dihydrothieno [3, 2 - f] - 1, 2, 4 one Toriazoro [4, 3- d] to give the [1, 4] thiazepine-3Z2 hydrochloride 1 dihydrate.

Mp 1 72 ° C

Example 1 2 5

After the reaction and treatment in the same manner using 4 Fuwenirubuchiru ρ- toluenesulfonate in place of Example 1 1 6 2- (4-menu Tokishifue sulfonyl) Echiru p- toluenesulfonic sulfonates Ichito, forming a hydrochloride salt by, 6 colorless powder crystals, 7- dihydro 3- (1 i (4 one-phenylbutyl) piperidine one 4 one I le) Single 5 H- thieno [3, 2 - c] one 1, 2, 4 one Toriazoro was obtained [4, 3- a] Azepin 'dihydrochloride · 3 dihydrate.

In 2HCI 3 / 2H 2 0 mp 2 2 5

Example 1 2 6

By performing the reaction and treatment in the same manner have use a one (2 Fueniruechiru) pyrrolidine one 3-carbohydrazide instead of 1 i (2 Feniruechiru) piperidine one 4 Ichiriki Rubo hydrazide Example 9 4, 6 as a yellow oil, 7-dihydro - 3 - (1 i (2 Fueniruechiru) pyrrolidine one 3-I le) Single 5 H- thieno 3, 2 - c] one 1, 2, 4-Toriazoro [4, 3 - was obtained a] Azepin.

! H-NMR (CDC 1 3 ) 5: 7. 37 (1 H, d), 7, 4 8 - 7. 1 8 (5H, m), 7. 1 3 (1 H, d), 4. 1 0 (2 H, t),

3. 72 - 3. 4 9 (2 H, m), 3. 22 (2H, t), 3. 05 - 2. 67

(5H, m), 2. 4 3 - 2. 02 (6 H, m)

Example 1 27

Starting Material Synthesis Example 1 2 1 obtained in 4 Mechiruchio one 7, 8-dihydro-6 H- Choi Bruno [3, 4-c] Azepin and 1 one (2- (4 one black port phenyl) Echiru) Pipet Lysine one 4 by performing the reaction and treatment in the same manner as in example 94 by using an carbohydrazide, 6, 7- dihydro-3- (1 i (2- (4 one black port phenyl) E Chi le) piperidine one 4 one I Le) Single 5H- thieno [3, 4- c] - 1, 2, 4- tri Azoro [4, 3- a] Azepin is obtained.

Example 1 2 8

Starting Material Synthesis Example 1 22 obtained in 8-methylthio one 5, 6-dihydro-4 H- Choi Bruno [2, 3- c] Azepin and 1- (2- (4-black port phenyl) Echiru) Pipet Lysine one 4 by performing the reaction and treatment in the same manner as in example 9 4 using one carbohydrazide, 6, 7- dihydro-3- (1 i (2- (.4 one black port phenyl) E Chi le) piperidine one 4 one I le) Single 5 H- thieno [2, 3- c] - 1, 2, 4 Bokuri Azoro [4, 3 - a] Azepin is obtained.

Example 1 2 9

Starting Material Synthesis Example 1 2 4 obtained 5-methylthio one 3, 4- Jihidorocheno [3, 4 - f] one 1, 4 one thiazepine and 1 one (2- (4 one black port phenyl) Echiru) piperidine one 4 by performing the reaction and treatment in the same manner as in example 9 4 using one carbohydrazide, 5, 6- dihydro-3- (1 - (2- (4 one black port phenyl) Echiru) piperidine one 4 - I Le) thieno [4, 3 - f 3 - 1, 2, 4 one Toriazo port [4, 3- d] [l, 4] thiazepine is obtained.

Example 1 3 0

Starting Material Synthesis Example 1 2 5 obtained 5-methylthio one 3, 4- Jihidorocheno [2, 3 - f] one 1, 4 one thiazepine and 1 one (2- (4 one black port phenyl) Echiru) piperidine one 4 by performing the reaction and treatment in the same manner as in example 9 4 using one carbohydrazide, 5, 6-dihydro-one 3- (1 - (2 - (4 one black port phenyl) Echiru) piperidine one 4 one I le) thieno [2, 3 - f] - 1, 2, 4 one Toriazo port [4, 3 - d] [1, 4] thiazepine is obtained.

Example 1 3 1

Starting Material Synthesis Example 1 2 7 obtained 5-methylthio one 3, 4- Jihidorocheno [3, 4 - f] - 1, 4 one year old Kisazepin and 1 one (2- (4 one black port phenyl) Echiru) piperidine one 4 by performing the reaction and treatment in the same manner as in example 9 4 using one carbohydrazide, 5, 6- dihydro-3- (1 i (2- (4 one black port phenyl) Echiru) piperidine one 4 one I le) thieno [4, 3 - f] - 1, 2, 4 one Toriazo port [4, 3 - d] [1, 4] Okisazepin is obtained.

Example 1 3 2

Starting Material Synthesis Example 1 2 8 obtained 5-methylthio one 3, 4- Jihidorocheno (2, 3- f) one 1, 4 Okisazepin and 1 one (2- (4 one black port phenyl) Echiru) piperidine one 4 one by performing the reaction and treatment in the same manner as in example 9 4 with carbohydrazide, 5, 6- dihydro-3- (1 - (2 - (4 one black port phenyl) Echiru) piperidine one 4 one I le ) thieno [2, 3 - f] - 1, 2, 4- Toriazo port [4, 3 - d] [1, 4] Okisazepin is obtained.

Example 1 3 3

Starting Material Synthesis Example 1 2 1 4 obtained in Mechiruchio one 7, 8-dihydro-6 H- Choi Bruno [3, 4-c] Azepin and 1 one (2- (2-naphthyl) Echiru) piperidine one 4 one more carrying out the reaction and treatment in the same manner as in example 9 4 using a force Lupo hydrazide, 6, 7- dihydro-3- (1 i (2- (2-naphthyl) Echiru) piperidyl Hmm 4 one I le) Single 5 H- thieno [4, 3- c one 1, 2, 4-Toriazoro [4 3 - a] Azepin is obtained -

Example 1 3 4

Starting Material Synthesis Example 1 2 2 obtained in 8-methylthio one 5, 6-dihydro-4 H- Choi Bruno [2, 3- c] Azepin and 1 one (2- (2-naphthyl) Echiru) piperidine one 4 more carrying out the reaction and treatment in the same manner as in example 9 4 using one carbohydrazide, 6, 7- dihydro-3- (1 i (2- (2-naphthyl) Echiru) piperidyl Hmm 4 one I le) Single 5 H- thieno [2, 3- c] one 1, 2, 4-Toriazoro [4, 3- a] Azepin is obtained.

Example 1 3 5

Starting Material Synthesis Example 1 2 4 obtained 5-methylthio one 3, 4- Jihidorocheno [3, 4 - f] one 1, 4 one thiazepine and 1 one (2- (2-naphthyl) Echiru) Piperi Jin one 4 one by a child that is the reaction and treatment in the same manner as in example 9 4 with carbohydrazide, 5, 6- dihydro-3- (1 i (2- (2-naphthyl) Echiru) piperazinyl lysine one 4 one I le) thieno [4, 3 - f] - 1, 2, 4- Toriazoro [4, 3- d] [1, 4] thiazepine is obtained.

Example 1 3 6

Starting Material Synthesis Example 1 2 5 obtained 5-methylthio one 3, 4- dihydric Dorocheno [2, 3 - f] - 1, 4 one thiazepine and 1 one (2- (2-naphthyl) Echiru) Piperi Gin one 4 by a child that is the reaction and treatment in the same manner as in example 9 4 using one carbohydrazide, 5, 6- dihydro-3- (1 i (2- (2-naphthyl) Echiru) piperazinyl lysine one 4 one I le ) thieno [2, 3 - f] - 1, 2, 4- Toriazoro [4, 3- d] [1, 4] thiazepine is obtained.

Example 1 3 7

Starting Material Synthesis Example 1 2 7 obtained 5-methylthio one 3, 4-dihydro-Choi Bruno [3, 4 - f] - 1, 4 Okisazepin and 1 one (2- (2-naphthyl) Echiru) piperazinyl lysine one 4-carboxyphenyl by performing the reaction and treatment in the same manner as in example 9 4 using hydrazide, 5, 6- dihydro-3- (1 - (2- (2-naphthyl) Echiru) peak Perijin one 4-I le) thieno [4 , 3 - f] - 1, 2, 4 one Toriazoro [4, 3 one d] [1, 4] Okisazepin is obtained.

Example 1 3 8

Starting Material Synthesis Example 1 2 8 obtained 5-methylthio one 3, 4- Jihidorocheno [2, 3 - f] - 1, 4 Okisazepin and 1 one (2- (2-naphthyl) Echiru) piperazinyl lysine one 4 one by performing the reaction and treatment in the same manner as in example 9 4 with carbohydrazide, 5, 6- dihydro-3- (1 i (2- (2-naphthyl) Echiru) peak Perijin one 4 one I le) thieno [ 2, 3- f] - 1, 2, 4 one Toriazoro [4, 3 - d] [1, 4] Okisazepin is obtained.

Example 1 3 9

Starting Material Synthesis Example 1 2 1 4 Mechiruchio one 7 obtained in 8-dihydro 6 H- Choi Bruno [3, 4-c] Azepin and 1 one (4 one (4 one-fluorophenyl) Single 4 Oki Sobuchiru) Pipet by performing the reaction and treatment in the same manner as in example 9 4 with lysine one 4 one carbohydrazide, 6, 7- dihydro-3- (1 i (4 one (4 one Furuo port phenyl) Single 4 Okisobuchiru) Pipet lysine one 4 one I le) Single 5H- thieno [4, 3 - c] one 1, 2, 4-Toriazoro [4, 3- a] Azepin is obtained.

Example 1 4 0

Starting Material Synthesis Example 1 2 0 obtained in 8-methylthio one 5, 6-dihydro-4 H- Choi Bruno [2, 3- c] Azepin and 1 one (4 one (4 one-fluorophenyl) one 4-O key Sobuchiru by performing the reaction and treatment in the same manner as in example 9 4 using) piperidine one 4 Ichiriki Lupo hydrazide, 6, 7- dihydro-3- (1 i (4 one (4 one Furuo port phenyl) Single 4 Okisobuchiru) piperidine one 4 one I le) Single 5 H- thieno [2, 3- c] one 1, 2, 4-Toriazoro [4, 3- a] Azepin is obtained.

Example 1 4 1

Starting Material Synthesis Example 1 2 4 obtained 5-methylthio one 3, 4- Jihidorocheno [3, 4 one f] one 1, 4 one thiazepine and 1- (4 one (4 one-fluorophenyl) one 4 one Okisopuchiru) piperidine by performing the reaction and treatment in the same manner as in example 9 4 using one 4 one carbohydrazide, 5, 6- dihydro-3- (1 i (4 i (4-safe Ruorofeniru) Single 4 one Okisopuchiru) piperidine one 4 one I le) thieno [4, 3 - f] one 1, 2, 4 one Toriazoro [4, 3 - d] [1, 4] thiazepine Ru obtained. Example 1 4 2

Starting Material Synthesis Example 1 2 5 obtained 5-methylthio one 3 4-dihydro-thieno [2, 3 - f] one 1, 4 one thiazepine and 1 - (4 one (4 Furuorofuweniru) one 4 one Okisobuchiru) piperidine one 4 one-carbonitrile by performing the reaction and treatment in the same manner as in example 9 4 using hydrazide, 5, 6- dihydro-3- (1 i (4 i (4-safe Ruorofeniru) Single 4 Okisobuchiru) piperidine one 4 one I le ) thieno [2, 3 - f] - 1, 2, 4 one Toriazoro [4, 3- d] [l, 4] thiazepine Ru obtained. Example 1 4 3

Starting Material Synthesis Example 1 2 7 obtained 5-methylthio one 3, 4- Jihidorocheno [3, 4 - f] one 1, 4 Okisazepin and 1 one (4 one (4 one-fluorophenyl) one 4 one year old Kisobuchiru) pin by performing the reaction and treatment in the same manner as in example 9 4 with Bae Rijin 4 one carbohydrazide, 5, 6- dihydro-3- (1 i (4 one (4 one-fluorophenyl) Single 4 Okisobuchiru) piperidine one 4 one I le) thieno [4, 3 - f] one 1, 2, 4 one Toriazoro [4, 3 - d] [1, 4] to give the Okisazepin relay o

Example 1 4 4

Starting Material Synthesis Example 1 2 8 obtained 5-methylthio one 3, 4-dihydro-Choi Bruno [2, 3 - f] - 1, 4 one year old Kisazepin and 1 one (4 one (4 one-fluorophenyl) one 4 - Okisobuchiru) peak by performing the reaction and treatment in the same manner as in example 9 4 with Bae lysine one 4 one carbohydrazide, 5, 6- dihydro-3- (1 i (4 i (4 - fluorophenyl) Single 4 Okisobuchiru) Pipet lysine one 4 one I le) thieno [2, 3 - f] one 1, 2, 4-Toriazoro [4, 3 -d] [1, 4] Rireru give Okisazepin.

Example 1 4 5

Example 1 1 4 5 obtained in 6- dihydro 3- (1 - (2- (4 one chlorophyll Eniru) Echiru) piperidine one 4 one I le) thieno [3, 2 - f] - 1, 2, 4 one Toriazoro [4, 3 -d] [1, 4] with stirring acetic acid solution of thiazepine, added 3 0% hydrogen peroxide, stirred at room temperature for 6 hours. After completion of the reaction, the reaction mixture was neutralized, extracted with black port Holm, washed with water and dried over magnesium sulfate. After concentration under reduced pressure, by subjecting the resultant residue to silica gel column chromatography, 5, 6-dihydro-one 3- (1 - (2 - (4-black port phenyl) Echiru) piperidine one 4 one I le) thousand eno [3, 2 - f] - 1, 2, 4- Toriazoro [4, 3 - d] to give the [1, 4] Chiaze pin 7 old Kishido.

Example 1 4 6

5 of Example 1 4 5, 6-dihydro-3- (1 i (2- (4 - black port phenyl) Echiru) piperidine one 4 one I le) thieno [3, 2 - f] - 1, 2, 4 one Toriazo port [4, 3 -d] [1, 4] thiazepine 5 obtained in example 1 2 9 instead of 6- dihydro 3- (1 - (2- (4 one black port phenyl) Echiru ) piperidine one 4 one I le) thieno [4, 3- c] one 1, 2, 4 one Toriazoro [4, 3- a] [1, 4] carrying out the reaction and treatment in the same manner using the thiazepine Accordingly, 5, 6 Jihido low 3- (1 i (2 - (4 one black port phenyl) Echiru) piperidine one 4 one I le) thieno, 3 - c] - 1, 2, 4 one Toriazoro [4 , 3 - a] [1, 4] thia Zepin 7 Okishido is obtained.

Example 1 4 7

Example 1 4 5 5, 6 - dihydro 3- (1 i (2- (4 - black port phenyl) Echiru) piperidine one 4-I le) thieno [3, 2-f] one 1, 2, 4 one Toriazo port [4, 3 - d] [1, 4] 5 obtained in example 1 3 0 instead of thiazepine, 6- dihydro 3- (1 i (2- (4 one black port phenyl) Echiru ) piperidine one 4 one I le) thieno [2, 3 - f] - 1, 2, 4- Toriazoro [4, 3 - d] by performing the reaction and treatment in the same manner by using a [1, 4] thiazepine, 5, 6 Jihido low 3- (1 - (2- (4-black port phenyl) Echiru) piperidine one 4-I le) thieno [2, 3 - f] - 1, 2, 4-Toriabu port [4, 3 - d] [1, 4] thia Zepin 7 Okishido is obtained.

Example 1 4 8

Example 1 4 5 5, 6- dihydro-3- (1 i (2- (4 one black port phenyl) Echiru) piperidine one 4 one I le) thieno [3, 2 - f] - 1, 2, 4 one Toriazo port [4, 3 - d] [1, 4] 5 obtained in example 1 1 2 instead thiazepine, 6- dihydro 3- (1 - (2- (2-naphthyl) Echiru) piperidine one 4-I le) thieno [3, 2 - f] - 1, 2, 4 one Toriazoro [4, 3 - d] [1, 4] by performing the reaction and treatment in the same manner using the thiazepine, 5, 6- dihydro 3- (1 i (2- (2 - naphthyl) Echiru) piperidine one 4 one I le) thieno [3, 2 - f] - 1, 2, 4- Toriazoro [4, 3-d] [1 , 4] thiazepine 7-Okishido is obtained.

Example 1 4 9

5 of Example 1 4 5, 6-dihydro-3- (1 - (2- (4 one black port phenyl) Echiru) piperidine one 4 one I le) thieno [3, 2 - f] - 1, 2, 4- Toriazo port [4, 3 - d] [1, 4] 5 obtained in example 1 3 5 instead of the thiazepine, 6- dihydro 3- (1 - (2- (2-naphthyl) Echiru) piperidine one 4-I le) thieno [4, 3 - f] - 1, 2, 4 one Toriazoro [4, 3 - d] [1, 4] by performing the reaction and treatment in the same manner using the thiazepine, 5, 6-dihydro-3 - (1 i (2- (2-naphthyl) Echiru) piperidine one 4 one I le) thieno [4, 3 - f] - 1, 2, 4 one Toriazoro [4, 3- d] [1, 4] thiazepine 7 Okishido is obtained.

Example 1 5 0

5 of Example 1 4 5, 6-dihydro-3- (1 i (2 - (4-chlorophenyl) Echiru) piperidine one 4 one I le) thieno [3, 2 - f] - 1, 2, 4- Toriazo port [4, 3 - d] [1, 4] 5 obtained in example 1 3 6 instead thiazepine, 6- dihydro 3- (1 i (2- (2-naphthyl) Echiru) piperidine one 4-I le) thieno [2, 3 - f] - 1, 2, 4 one Toriazoro [4, 3 - d] [1, 4] by performing the reaction and treatment in the same manner using the thiazepine, 5, 6- dihydro 3- (1 i (2- (2 - naphthyl) Echiru) piperidine one 4 one I le) thieno [2, 3 - f] one 1, 2, 4-Toriazoro [4, 3 - d] [1, 4] thiazepine 7 Okishido is obtained.

Example 1 5 1

Example 1 4 5 5, 6- dihydro-3- (1 i (2- (4-black port Fuyuniru) Echiru) piperidine one 4 one I le) thieno [3, 2 - f] - 1, 2, 4- Toriazo port [4, 3 - d] [1, 4] 5 obtained in example 1 2 4 instead thiazepine, 6- dihydro 3- (1 - (4 one (4 one-fluorophenyl) Single 4 one Okisobuchiru) piperidine one 4 one I le) thieno [3, 2 - f] one 1, 2, 4-Toriazoro [4, 3- d] [1, 4] carrying out the reaction and treatment in the same manner using the thiazepine Accordingly, 5, 6- dihydro-3- (1 i (4 one (4 one-fluorophenyl) Single 4 Okisobu chill) piperidine one 4 one I le) thieno [3, 2 - f] by one tooth 2, 4- Toriabu port

[4, 3 - d] [1, 4] thiazepine 7 Okishido is obtained.

Example 1 5 2

5 of Example 1 4 5, 6-dihydro-3- (1 i (2- (4 one black port phenyl) Echiru) piperidine one 4 one I le) thieno [3, 2- f] - 1, 2, 4 one Toriazo port [4, 3 - d] [1, 4] 5 obtained in example 1 4 1 instead thiazepine, 6- dihydro 3- (1 - (4 one (4 one-fluorophenyl) Single 4 one year old Kisobuchiru) piperidine one 4 one I le) thieno [4, 3 - f] - 1, 2, 4- Toriazoro [4, 3 - d] the reaction and treatment in the same manner by using a [1, 43 thiazepine by performing, 5, 6- dihydro-3- (1 i (4 one (4 one-fluorophenyl) one 4 one year old Kisobu chill) piperidine one 4 one I le) thieno [4, 3-f] one 1, 2, 4-Toriazoro

[4, 3 - d] [1, 4] thiazepine 7 Okishido is obtained.

Example 1 5 3

5 of Example 1 4 5, 6-dihydro-3- (1 i (2- (4 one black port phenyl) Echiru) piperidines Rijin 4 one I le) thieno [3, 2-f] one 1, 2, 4 - Toriazo port [4, 3 - d] [1, 4] 5 obtained in example 1 4 2 instead thiazepine, 6- dihydro 3- (1 - (4 one (4 one-fluorophenyl) Single 4 one old Kisobuchiru) piperidine one 4 one I le) thieno [2, 3 - f] - 1, 2, 4 one Toriazoro [4, 3- d] the reaction and treatment in the same manner by using a [1, 4] thiazepine by performing, 5, 6- dihydro-3- (1 - (4 one (4 one-fluorophenyl) one 4 one year old Kisobu chill) piperidine one 4 one I le) thieno [2, 3 - f] - 1, 2, 4 one Toriazoro

[4, 3 - d] [1, 4] thiazepine 7-year old Kishido is obtained.

Example 1 5 4

Starting Material Synthesis Example 1 2 6 obtained 5-methylthio one 2, 3 Jihidorocheno [3, 2 - f] - 1, 4 Okisazepin and 1 one (2- (4 one black port phenyl) Echiru) piperidine one 4 one by performing the reaction and treatment in the same manner as in example 9 4 with carbohydrazide, 5, 6- dihydro-3- (1 i (2- (4 one black port phenyl) Echiru) piperidine one 4 one I le ) thieno [3, 2-f] one 1, 2, 4-Toriazo π [4, 3 - d] [1, 4] Okisazepin is obtained.

Example 1 5 5

Starting Material Synthesis Example 1 2 6 obtained 5-methylthio - 2, 3 Jihidorocheno [3 2 - f] one 1, 4 Okisazepin and 1 one (2- (2-naphthyl) Echiru) piperazinyl lysine one 4 one-carbonitrile by performing the reaction and treatment in the same manner as in example 9 4 using hydrazide, 3- (1 - (2- (2-naphthyl) Echiru) piperidine one 4 one I Le) - 5, 6-dihydrothieno [3, 2 - f] one 1, 2, 4 one Toriazoro [4, 3 - d] [1, 4] Okisazepin, is obtained.

Example 1 5 6

Starting Material Synthesis Example 1 2 6 obtained 5-methylthio one 2, 3 Jihidorocheno [3, 2 - f] - 1, 4 Okisazepin and 1 one (4 one (4 one-fluorophenyl) one 4 one Okisopuchiru) piperidine one 4 by performing the reaction and treatment in the same manner as in example 9 4 using one carbohydrazide, 5, 6- dihydro-3- (1 i (4 one (4 one-fluorophenyl) Single 4 Okisobuchiru) piperidine one 4 one I le) thieno [3, 2 - f] one 1, 2, 4-Toriazoro [4, 3 - d] [1, 4] Okisazepin is obtained.

Example 1 5 7

Starting Material Synthesis Example 1 2 9 resulting 7-methyl-5-methylthio one 3, 4-dihydro-thieno [2, 3 - f] - 1, 4 one year old Kisazepin and 1 one (2- (4 one black port Hue sulfonyl ) Echiru) by performing the reaction and treatment in the same manner as in example 9 4 using piperidine one 4 one carbohydrazide, 9-methyl-5, 6- dihydro-3- (1 - (2- (4 one black port phenyl) Echiru ) piperidine one 4 one I le) thieno [2, 3] - 1, 2, 4-Toriabu port [4, 3 - d] [1, 4] Okisazepin is Ru obtain < Example 1 5 8

Starting Material Synthesis Example 1 2 9 resulting 7-methyl-5-methylthio one 3, 4-dihydro-thieno [2, 3 - f] one 1, 4 one year old Kisazepin and 1 one (2- (2-naphthyl) Echiru) by performing the reaction 応及 beauty treatment in the same manner as in example 9 4 using piperidine one 4 one carbohydrazide, 9-methyl-5, 6-dihydro - 3 (1 - (2- (2-naphthyl) Echiru) pin Bae lysine one 4 one I le) thieno [2, 3 - f] - 1, 2, 4 one Toriazoro [4, 3 - d] [1, 4] Okisazepin is obtained.

Example 1 5 9

Starting Material Synthesis Example 1 2 9 resulting 7-methyl-5-methylthio one 3, 4-dihydro-thieno [2, 3 - f] one 1, 4 one year old Kisazepin and 1 one (4 one (4 one Furuorofu Eniru) Single the 4 Okisobuchiru) carrying out the reaction and treatment in the same manner as in example 9 4 using piperidine one 4 one carbohydrazide, 9-methyl-5, 6-dihydro - 3 - (1- (4 one (4 one-fluorophenyl ) Single 4 Okisobuchiru) piperidine one 4 one I le) thieno [2, 3 - f] - 1, 2, 4 one Toriazoro [4 '3 - d] [1, 4] Okisazepin is obtained.

Example 1 6 0

Starting Material Synthesis Example 1 3 0 4 Mechiruchio one 6 obtained in 7- Jihidorocheno [3, 2-c] pyridine and 1 one (2- (4 one black port phenyl) Echiru) using piperidine one 4 one carbohydrazide Ri by the carrying out the reaction and treatment in the same manner as in example 9 4, 5, 6 dihydric draw 3- (1 i (2- (4 one black port phenyl) Echiru) piperazinyl lysine one 4 one I le) thieno [3, 2-c] one 1, 2, 4 one Toriazoro [4, 3- a] pyridine is obtained.

Example 1 6 1

Starting Material Synthesis Example 1 3 1 obtained in 4 Mechiruchio one 2 H- thieno [3, 2- e] - 1, 3 one thiazine and 1 one (2- (4 one black port phenyl) Echiru) piperidine one 4 one-carbonitrile Ri by the carrying out the reaction and treatment in the same manner as in example 9 using hydrazide, 5 H- 3- (1 - (2- (4 one black port phenyl) Echiru) piperidine one 4 one I le) thieno [3 , 2- e] - 1, 2, 4- Toriazoro [4, 3 - c] [1, 3] thiazine is obtained.

Example 1 6 2

Starting Material Synthesis Example 1 3 4 obtained in 2 Mechiruchio one 2 H- thieno [3, 2- e] - 1, 3 one Okisajin and 1 one (2- (4 one black port phenyl) Echiru) piperidine one 4 one-carbonitrile more carrying out the reaction and treatment in the same manner as in example 9 4 using hydrazide, 5 H- 3- (1 i (2- (4 one black port phenyl) Echiru) piperidine one 4 one I le) thieno [3 , 2- e 1, 2, 4 one Toriazoro [4, 3- c] [1, 3] Okisajin is obtained.

Example 1 6 3

Starting Material Synthesis Example 1 3 3 obtained in 2 promoter 4 Mechiruchio one 7, 8-dihydro one 6H- thieno [3, 2 - c 3 Azepin and 1 one (2- (4 one black port phenyl) Echiru) piperidine one 4 by performing anti 応及 beauty treatment in the same manner as in example 9 4 using one carbohydrazide, 9 one promoter 6, 7- dihydro-3- (1 - (2- (4 one black port phenyl) Echiru) Pipet lysine one 4 one I le) Single 5 H- thieno [3, 2 one c] one 1, 2, 4-Toriazoro [4, 3 -a] Azepin is obtained.

Example 1 6 4

Starting Material Synthesis Example 1 3 was obtained in four 2-dimethyl § amino methyl -4 Mechiruchio one 7, 8-dihydro-6 H- thieno [3, 2-c] Azepin and 1 one (2- (4 one black port phenyl) by performing the reaction and treatment in the same manner as in example 9 4 using Echiru) piperidine one 4 one carbohydrazide, 9-1 dimethylaminomethyl -6, 7-di Hidoro 3- (1 i (2- (4 one black port phenyl) Echiru) piperidine one 4-I le) Single 5 H- thieno [3, 2-c] one 1, 2, 4-Toriazoro [4, 3- a] § Zepin is obtained. Example 1 6 5

Starting Material Synthesis Example 1 3 2 methyl § obtained in 5 amino methyl -4 Mechiruchio one 7, 8-dihydro-6 H- thieno [3, 2-c] Azepin and 1 one (2- (4 one black port phenyl) by performing the reaction and treatment in the same manner as in example 9 4 using Echiru) piperidine one 4 one carbohydrazide, 9 one methylaminomethyl -6, 7- dihydric draw 3- (1 i (2- (4 one black mouth phenyl) Echiru) piperidine one 4 one I le) Single 5 H- thieno [3, 2 - c] one 1, 2, 4 one Toriazoro [4, 3- a] Azepi emission is obtained.

Example 1 6 6

Starting Material Synthesis Example 1 3 2-cyclopropyl obtained in 6 § amino methyl -4 Mechiruchi O -7, 8-dihydro-6H- thieno [3, 2-c] Azepin and 1 one (2- (4 Kurorofuweniru) Echiru) by performing the reaction and treatment in the same manner as in example 9 4 using piperidine one 4 one carbohydrazide, 9-1 cyclopropylamino methylcarbamoyl Lou 6, 7-dihydro-one 3- (1 i (2- (4 one black port phenyl) Echiru) piperazinyl lysine one 4 one I le) Single 5 H- thieno [3, 2 - c] one 1, 2, 4 one Toriazoro [4, 3- a] Azepin obtain - Ru. Example 1 6 7

Starting Material Synthesis Example 1 3 7 obtained in 2 Asechiru 4 Mechiruchio one 7, 8-Jihido opening one 6 H- thieno [3, 2-c] Azepin and 1- (2- (4 one black port phenyl) Echiru) by performing the reaction 応及 beauty treatment in the same manner as in example 9 4 using piperidine one 4 one carbohydrazide, 9 one Asechiru 6, 7- dihydro-3- (1 chromatography (2- (4 one black port phenyl) Echiru) piperidine one 4 one I le) Single 5 H- thieno [3, 2-c] one 1, 2, 4 one Toriazoro [4, 3- a] Azepin is obtained.

Example 1 6 8

Starting Material Synthesis Example 1 3 2 Echiru 4 obtained in 8 Mechiruchio one 7, 8-dihydro-one 6 H- thieno [3, 2-c] Azepin and 1 one (2- (4 one black port phenyl) Echiru) piperidine by performing the reaction 応及 beauty treatment in the same manner as in example 9 4 using one 4 one carbohydrazide, 9 Echiru 6, 7 - dihydro 3- (1 i (2- (4 one black port phenyl) Echiru) Pipet lysine one 4 one I le) Single 5 H- thieno [3, 2 one c] - 1, 2, 4 one Toriazoro [4, 3 -a] Azepin obtained.

Example 1 6 9

Starting Material Synthesis Example 1 3 9 resulting 2-hydroxymethyl -4 Mechiruchio one 7, 8 Jihidoro 6H- thieno [3, 2-c] Azepin and 1 one (2- (4 one black port phenyl) Echiru) Pipet by performing the reaction and treatment in example 9 4 the same way using a lysine one 4 one carbohydrazide, 9-hydroxy-methyl -6, 7-dihydro - 3 - (1 - (2- (4 one black port phenyl ) Echiru) piperidine one 4 one I le) Single 5 H- thieno [3, 2-c] -1, 2, 4- Toriazoro [4, 3- a] Azepin is obtained.

Example 1 7 0

Obtained in Starting Material Synthesis Example 1 4 0 2- (1-hydroxy E chill) Single 4 Mechiruchio - 7, 8-dihydro-6 H- thieno [3, 2-c] Azepin and 1 one (2- (4 - Kurorofuweniru ) Echiru) by performing the reaction and treatment in the same manner as in example 9 4 using piperidine one 4 one carbohydrazide, 9 i (1-hydroxy E chill) one 6, 7- dihydro-3- (1 i ( 2- (4 one black port phenyl) Echiru) piperidines lysine Hmm 4 one I le) Single 5H- thieno [3, 2 - c] one 1, 2, 4-Toriazoro [4, 3- a] Azepin obtain .

Example 1 7 1

Starting Material Synthesis Example 1 4 1 obtained 3 Echiru 4 Mechiruchio one 7, 8-dihydro-one 6 H- thieno [3, 2-c] Azepin and 1 one (2- (4 one black port phenyl) Echiru) piperidine by performing the reaction 応及 beauty treatment in the same manner as in example 9 4 using one 4 one carbohydrazide, 1 0 Echiru 6, 7-dihydro - 3 (1 i (2- (4 one black port phenyl) Echiru ) piperidine one 4 one I le) Single 5 H- thieno [3, 2 - c 1 one 1, 2, 4 one Toriazoro [4, 3- a] Azepin is obtained. Example 1 7 2

Starting Material Synthesis Example obtained in 1 4 3 8 Asechiru 7- methyl-5-methylthio one 3, 4-dihydro-thieno [2, 3 - f] - 1, 4 Okisazepin and 1 one (2- (4 Kurorofuweniru) Echiru) piperidine one 4 by performing the reaction and treatment in the same manner as in example 9 4 using one carbohydrazide, 8 Asechiru 9-methyl-5, 6- dihydro-3- (1 i (2- (one black port phenyl) Echiru) piperidine one 4 one I le) thieno [2, 3- f] one 1, 2, 4-Toriazoro [4, 3 - d] [1, 4] Okisazepin is obtained.

Example 1 7 3

Starting Material Synthesis Example 1 4 obtained in 4 8 Echiru 7- methyl-5-methylthio one 3, 4-dihydro-thieno [2, 3 - f] one 1, 4 Okisazepin and 1 one (2- (4 - black port phenyl) Echiru ) by performing the reaction and treatment in the same manner as in example 9 4 using piperidine one 4 one carbohydrazide, 8 Echiru 9-methyl-5, 6 Jihidoro 3- (1 i (2- (4 one black port phenyl ) Echiru) piperidine one 4 - I le) thieno [2, 3 - f] - 1, 2, 4- Toriazoro [4, 3 - d] [1, 4] Okisazepin is obtained.

Example 1 7 4

Starting Material Synthesis Example 1 4 5 obtained in 8 promoter 7- methyl-5-methylthio one 3, 4-dihydro-Choi Bruno [2, 3 - f] one 1, 4 one year old Kisazepin and 1 one (2- (4 Kurorofuweniru) Echiru) by performing the reaction and treatment in the same manner as in example 9 4 using piperidine one 4 one carbohydrazide, 8-promoter 9-methyl-5, 6 Jihidoro 3- (1 i (2- (4 one black port phenyl) Echiru) piperidine one 4 one I le) thieno [2, 3 - f] by one tooth 2, 4- Toriazoro. [4, 3 - d] [1, 4] Okisaze pin is obtained.

Example 1 7 5

Starting Material Synthesis Example 1 4 2 obtained in 2, 4-dimethylthio one 7, 8-dihydro-6 H - thieno [3, 2-c] Azepin and 1 one (2- (4 one Kurorofuweniru) Echiru) piperidine one 4 one by performing the reaction and treatment in the same manner as in example 9 4 with carbohydrazide, 9-methylthio one 6, 7- dihydro-3- (1 i (2- (4-black port phenyl) Echiru) piperidine one 4 one I le) Single 5 H- thieno [3, 2 - c] one cog 2, 4- Toriazoro [4, 3- a] Azepin is obtained.

Example 1 7 6

Starting Material Synthesis Example 1 2 0 4 Mechiruchio one 7 obtained in 8-dihydro 6 H- Choi Bruno [3, 2-c] Azepin and 2-(N-methyl-N-(2-Fueniruechiru) Amino) § Seto hydrazide by performing the reaction and treatment in the same manner as in example 9 4 using, 6, 7- dihydro-3- (N- methyl-N-(2-Fueniruechiru) § Minomechiru) Single 5 H- Cheno [3, 2-c ] one 1, 2, 4-Toriazoro [4, three to a] Azepin is obtained.

Example 1 7 7

Starting Material Synthesis Example 1 4 6 obtained in 1-methyl-5-methylthio one 2, 3-dihydro - 1 H- thieno [2, 3-e] - 1, 4 one Jiazepin and 1 one (2- (4-click Rorofueniru ) Echiru), the same reaction and treatment as in example 9 4 using piperidine one 4 one carbohydrazide, 3- ((2- (4-black port phenyl) Echiru) piperidine one 4 one I le ) Single 7-methyl-6, 7-dihydro-5 H- Choi Bruno [3, 2 - f] one 1, 2, 4 one Toriazoro [4, 3 - d] [1, 4] Jiazepi emission is obtained.

Example 1 7 8

Starting Material Synthesis Example 1 4 obtained in 7 1 one base Njiru 5- methylthio one 2, 3 Jihido port one 1 H- thieno [2, 3 - e] one 1, 4 one Jiazepin and 1 one (2- (4 -, the same reaction and treatment as in example 9 2 using black port phenyl) Echiru) piperidine one 4 one carbohydrazide, 7- base Njiru 3- (1 - (2- (4- black port phenyl) Echiru) piperidine one 4 one I le) one 6, 7-dihydro-5 H- thieno [3, 2 - f] one 1, 2, 4-Toriazoro - is [4, 3 d] [1, 4] Jiazepin can get.

Example 1 7 9

Starting Material Synthesis Example 1 2 0 4 obtained in Mechiruchio one 7, 8-dihydro-6 H- Choi Roh. [3, 2 - c] Azepin and 2- (4 one (2- (4 one black port phenyl) E Ji , the same reaction and treatment as in example 9 2 using Le) piperidine one 1 one I le) § Seto hydrazide, 3- (4 - (2- (4 one black port phenyl) Echiru) pin Bae lysine one 1 one Irumechiru) one 6, 7-dihydro-5 H- thieno [3, 2- c] - 1, 2, 4 one Toriazoro [4, 3- a] Azepin is obtained.

Example 1 8 0

Starting Material Synthesis Example 1 2 0 4 Mechiruchio one 7 obtained in 8-dihydro 6 H- Choi Bruno [3, 2-c] Azepin and 4 one (2- (4 one black port phenyl) Echiru) mode Ruhorin 2- , the same reaction and treatment as in example 9 2 with carbohydrazide, 3- (4 one (2- (4 one black port phenyl) Echiru) morpholine one 2-I le) one 6, 7-dihydro 5 H- thieno [3, 2-c] One l, 2, 4 one Toriazoro [4, 3- a] Azepin obtain <

Example 1 8 1

6, 7-dihydro-3- (4 - piperidyl) Single 5 H- thieno [3, 2-c] one 1, 2, 4-Toriazoro [4, 3-a] of Azepin dihydrochloride 0. 6 2 g dimethylol Ruhorumuami de 5 m 1 and under ice-cooling to a mixed solution of toluene 5 m 1, while stirring, 2 i (4 one Buromofueniru) Echiru ρ- toluenesulfonate 0. 7 1 g, potassium carbonate 1. lg addition, 7 0 ° stirred for 2 hours at C. After completion of the reaction, the reaction solution was poured into ice water and extracted with acetic acid Echiru, washed with water, dried over magnesium sulfate. After concentration under reduced pressure, Ri by the fact that the obtained crystals recrystallized from I isopropyl alcohol, 6 colorless powder crystals, 7- dihydro 3- (1 - (2- (4 one Puromofuweniru) Echiru) piperidine one 4 one I le) Single 5 H- thieno [3, 2-c] one 1, 2, 4 - Toriazoro was obtained [4, 3- a] Azepin 0. 4 2 beta.

Mp 1 9 7 ° C

Example 1 8 2

6, 7-dihydro-3- (4-piperidyl) Single 5 H- thieno [3, 2-c] one 1, 2, 4-Toriazoro [4, 3-a] Azepin-2-dimethylcarbamoyl Ruhorumuami hydrochloride 1. 24 g de 1 Om 1 and under ice-cooling to a mixed solution of toluene 1 Om 1, with stirring, 2- (4 twelve Torofueniru) Echiru ρ- toluenesulfonate 0. 9 2 g, charcoal potassium 2. 2 g was added, 2 hours and stirred at 7 0 ° C. After completion of the reaction, the reaction mixture was poured into ice water and extracted with acetic acid Echiru, washed with water, after c concentrated under reduced pressure to dry over magnesium sulfate, by performing the obtained crystals recrystallized from ethanol, colorless powdery crystals 6, 7-dihydro-3- (1 - (2- (4 twelve Torofuweniru) Echiru) peak Perijin one 4 one I le) Single 5 H- thieno [3, 2- c] - 1, 2, 4- Toriazoro

It was obtained [4, 3- a] Azepin 0. 6 2 g.

Mp 2 2 5

Example 1 8 3

4-methylthio one 7, 8-dihydro-6 H- thieno [3, 2-C] with stirring butanol 2 0 m l solution of Azepin 0. 5 9 g, 2- (N- base Njiru N- main Chiruamino) E It added chill carbohydrazide 0. 6 2 g, heated at reflux for 5 hours. The cooling after butanol was distilled off under reduced pressure, the resulting residue was dissolved in ethanol, the isopropyl alcohol solution of hydrogen chloride was added, after forming the hydrochloride salt, was collected by filtration, and recrystallized boiled ethanol, colorless powder 6 crystal, 7- dihydro 3- (2 - (N- benzyl-N- Mechiruamino) Echiru) Single 5 H- thieno [3, 2 - c] - 1, 2, 4 one Toriazoro [4, 3- a] Azepin - 2 to give the hydrochloride salt 0. 4 5 g.

Mp 1 9 7~ 1 9 8 ° C

Example 1 8 4

4 Mechiruchio one 7, 8-dihydro-6 H- thieno with stirring [3, 2-c] Azepin 0 5 9 g of blanking evening Nord 2 0 m 1 solution, 2-(N-methyl-N-(2 one Fueniruechiru) Amino) added E chill carbohydrazide 0. 6 6 g, and heated to reflux for 5 hours. The blanking evening Knoll was distilled off under reduced pressure after cooling, construed dissolved the resulting residue in ethanol, the isopropyl alcohol solution of hydrogen chloride was added, after forming the hydrochloride salt, was collected by filtration and recrystallized from ethanol , 6 colorless powder crystals, 7- dihydric draw 3- (2- (N- methyl-one N-(2-Fueniruechiru) Amino) Echiru) Single 5 H- Ji eno [3, 2 - c] - 1, 2, 4 Toriazoro was obtained [4, 3- a] Azepin dihydrochloride 1 tetrahydrate 0. 4 5 g.

Mp 2 0 9~ 2 1 0 e C

Example 1 8 5

4 Mechiruchio one 7, 8-dihydro-6 H- thieno with stirring [3, 2-c] Azepin 0.5 of 5 9 g blanking evening Nord 2 0 m 1 solution, 3- (N- base Njiru N- main Chiruamino) added propyl carbohydrazide 0. 6 6 g, a c cool after butanol is heated at reflux for 5 hours and evaporated under reduced pressure, the resulting residue was dissolved in ethanol, the isopropyl alcohol solution of hydrogen chloride was added, forming a hydrochloride salt after, filtered, and recrystallized by two ethanol, 6 colorless powder crystals, 7- dihydro 3- (3- (N- benzyl-N- Mechiruamino) propyl) Single 5 H- thieno [3, 2-c ] to give an 1, 2, 4 one Toriazoro [4, 3- a] Azepin dihydrochloride 1/4 hydrate 0. 3 6 g. Mp 1 9 8~ 2 0 C

Example 1 8 6

4 Mechiruchio one 7, 8-dihydro-6 H- thieno with stirring [3, 2-c] Azepin 0.5 of 5 9 g blanking evening Nord 2 Om 1 solution, 4 one (4 Kurorofuweniru) piperidines Rajin one 1 over adding I Rua Seto hydrazide 0. 8 1 g, and heated to reflux for 5 hours. After cooling, the blanking evening Knoll was distilled away under reduced pressure, and recrystallization child the obtained crystals with ethanol, 6 colorless powder crystals, 7- dihydro 3- (4 one (4 one Kurorofuweniru) piperidines Rajin one 1 one Irumechiru) Single 5H- thieno [3, 2 - c] - 1, 2, 4- preparative Riazoro was obtained [4, 3- a] Azepin 0, 5 g.

Mp 2 2 6-2 2 7

Example 1 8 7

4 Mechiruchio one 7, 8-dihydro-6 H- thieno [3, 2-c] with stirring Azepin 5 9 g of butanol 2 Om 1 solution, 2- (4 one (4 one black port Hue yl) piperidines Rajin one 1 one I le) added E chill carbohydrazide 0. 8 5 g, and heated to reflux for between five. After cooling, the blanking evening Knoll was distilled off under reduced pressure, and recrystallized to obtained crystals with ethanol, 6 colorless powder crystals, 7- dihydro 3- (2 - (4 one (4 one black port phenyl ) piperidines Rajin one 1 one I le) Echiru) Single 5 H- thieno [3, 2 - c] - 1, 2, 4 one Toriazoro was obtained [4, 3- a] Azepin 0. 8 7 g.

Mp 2 0 2~2 0 3 e C

Example 1 8 8

4 Mechiruchio one 7, 8-dihydro-6 H- thieno [3, 2-c] with stirring butanol Ichiru 2 0 m 1 solution Azepin 0. 5 9 g, 3- (4 one (4 one black port Hue yl) piperidines Rajin one 1 one I le) propyl carbohydrazide 0. 8 9 g was added and heated to reflux for 5 hours. After allowed to cool, evaporated under reduced pressure butanol, by recrystallizing the obtained crystals with ethanol, the colorless powder crystals 6, 7- dihydro-3- (3- (4 one (4 one black port phenyl) piperidines Rajin one 1 one I) propyl) Single 5 H- thieno

[3, 2-c] to give an 1, 2, 4-Toriazoro [4, 3- a] Azepin 0. 5 7 g. 0 N

Mp 1 6 9~ 1 7 0 'C

Example 1 8 9

6, 7-dihydro-3- (4-piperidyl) Single 5 .eta. thieno [3, 2-c] one 1, 2, 4-Toriazoro of [4, 3-a] Azepin dihydrochloride 0. 6 2 g E evening room temperature to a mixed solution of Roh Lumpur 1 Om 1, while stirring, Toryechiruamin 1. lml, 4 by adding an Promo full We No Le bromide 0. 5 6 g stirred for 2 hours. After completion of the reaction, the reaction mixture was poured into ice water and extracted with black port Holm, washed with water and dried over sulfate Maguneshiu beam. After concentration under reduced pressure, the obtained crystals by performing the re-formed crystals from isopropyl alcohol, 6 colorless powder crystals, 7-dihydro - 3 (1 - (2 - (4 one Buromofueniru) one 2-hydroxy-E chill) piperidine one 4 one I le) two 5 H- thieno [3, 2-c] one 1, 2, 4-Toriazoro was obtained [4, 3- a] Azepin 0. 1 5 g. Mp 2 0 5 e C

Example 1 9 0

5-methylthio one 2, 3- dihydrothieno [3, 2 - f] [1, 4] with stirring Chiazepi down 0. 6 5 g of butanol 2 0 m 1 solution, 1 i (2- (4-pro Mofueniru) Echiru) Piperidin one 4 an carbohydrazide 0. 9 8 g added and heated to reflux for 5 hours. The cooling after blanking evening Nord was distilled off under reduced pressure, and recrystallized to obtained crystals with ethanol, the colorless powder crystals 3- (1 i (2- (4 one Buromofue sulfonyl) Echiru) piperidine one 4 one I le) one 5, 6 Jihidorocheno [3, 2 - f] one 1, 2, 4 one Toriazoro [4, 3 -d] [I , 4] thiazepine 0. 3 3 g was obtained c

Mp 1 7 5-1 7 6

Example 1 9 1

5-methylthio one 2, 3- dihydrothieno [3, 2 - f] [1, 4 with stirring〗 Chiazepi of emissions 0. 6 5 g blanking evening Nord 2 0 m l solution, 2- (4 one (4 one Black mouth phenyl) piperidines Rajin one 1 one I le) E chill carbohydrazide 0. 8 5 g added and heated to reflux for 5 hours. The cooling after butanol was distilled off under reduced pressure, and recrystallized to obtained crystals in ethanol, the colorless powder crystals 3- (2- (4 one (4 one black port Hue yl) piperidines Rajin one 1 one I Le) Echiru) one 5, 6-dihydrothieno [3, 2 - f] one 1, 2, 4-Toriazoro - was obtained [4, 3 d] [1, 4] thiazepine 0. 4 g.

Mp 1 7 1~ 1 74 ° C

Example 1 9 2

7- Echiru 5-methylthio one 2, 3- dihydrothieno [3, 2 - f] [1, 4] with stirring butanol 1 0 m 1 solution of thiazepine 0. 4 9 g, 1 i (2 i (4-Chlorophenyl ) Echiru) Piperidin one 4 one force Lupo hydrazide 0. 5 6 g was added and heated to reflux for 5 hours. The cooling after butanol was distilled off under reduced pressure, and recrystallized to obtained crystals with ethanol, the colorless powder crystals 3- (1 i (2- (4 one black port phenyl) Echiru) piperidine one 47 I le) Single 9 Echiru 5, 6-di Hidorocheno - [- d 4, 3] [1, 4 [3, 2 f] one 1, 2, 4-Toriazoro: obtain thiazepine 0. 2 g.

Mp 1 6 5

Example 1 9 3

7- Echiru 5-methylthio one 2, 3- dihydrothieno [3, 2- f] [1, 4] with stirring butanol 1 0 m 1 solution of Chiazapin 0. 4 9 g, 1 i (2 - (4 one Buromofueniru ) Echiru) Piperidin one 4 an carbohydrazide 0. 6 5 g added and heated to reflux for 5 hours. The cooling after blanking evening Nord was distilled off under reduced pressure, and recrystallized to obtained crystals with ethanol, the colorless powder crystals 3- (1 i (2- (4 one Buromofueniru) Echiru) piperidine one 4 one I Le) Single 9 Echiru 5, 6-di-arsenide Dorochieno [3, 2 - f] one 1, 2, 4 one Toriazoro [4, 3 - d] to give the [1, 4] thiazepine 0. 2 5 g .

Melting point 1 6 0 "C

Example 1 9 4

7- Echiru 5-methylthio one 2, 3- dihydrothieno [3, 2 - f] [1, 4] with stirring thiazepine 0. 4 9 g of blanking evening Nord 1 Om 1 solution, 2- (4 one (4 one black port phenyl) piperidines Rajin one 1 one I le) E chill carbohydrazide 0, 5 7 g was added and heated to reflux for 5 hours. The cooling after blanking evening Nord was distilled off under reduced pressure, and recrystallized to obtained crystals with ethanol, the colorless powder crystals 3- (4 one (4 one black port phenyl) piperidines Rajin one 1 one Iruechiru) one 9 Echiru 5, 6 Jihido Rochieno [3, 2-f] one 1, 2, 4 one Toriazoro - give [4, 3 d] [1, 4] Ji Azepin 0. 2 g.

Te melting point 1 7 8

Furthermore, in addition to the above example compounds, also compounds shown below Table 1 [Table 4 8] are included in the present invention. Z 0 z

10 ID

Η) f H0

Ten

^> {Η) 'HO £ 1

'HO 21

HO

β ¾ HD 5 HO

aWO - ^ - ¥ HO) - ^ -

'HO

M i tO0r0 / 96df / XDd

986 £ 0 / Z, 6 OM

/ Bok 6 o one

Table 6

Compound No. R 1 2 WYZ

7 off

CH 2 f \ f

74 (10-) F CH 2 ^ * N - (CH 2) 2 - ^ - CI

76 (10-) F CH 2 CH 2

77 (10-) F CH 2 CH 2 - eight

78 (10-) F CH 2 CH 2 1 eight

80 (10-) F CH 2

81 (10-) F CH 2

82 (10-) F CH 2 ( CH 2) 2

84 (10-) F CH 2 ( CH 2) 3 - -Q

CI CI

s / Bok i-

Divination

o

0_

z one «

0i S, 0. i. j

¾ί- 0 () ώ: τ ί. one

0 () ¾w8 Zll one 5} - Ud fcyJL § /

Table 1 o

Compound No. f ^ R 2 w

127

130, (CH2) 2 "0 ~ C '

132 CH, ~ C N_CH2 "" CI

133 CH,

134 CH

139 (CH 2) 2 - ^^ - Q

140 (CH

CI CI

Table 1 2

Compound number, 1¾ 2 WYZ

158 (10-) Br S N, (CH 2) 2 "" CI

160 (10-) Br S CH 2 -CN-CH 2 -Q-CI

161 (10-) Br S CH 2 • eight CI

162 (10-) Br s CH 2

- ^ -CHa - ^ - CI

163 (10-) Br s CH 2

166 (10-) Br s (CH 2) 2

168 (10-) Br s (CH 2) 3

CI CI s / 869s so

o

. } 2 "} CH

86εο / Bok - § / 96d

(Nio,

> - XXX

oo

o

oooooooo

o

(H0 ""

(¾o Nw- Table 1 7 Compound No. R 1, R 2 W

225 (10-) MeO ~ CN- ( CH 2) 2 -Q

226 (10-) MeO - - ( CH2) 2 - ^ - OMe

227 (10-) MeO

228 (10-) eO

0N, (CH 2) 2 ~ Q ~ CI

229 (! O-) eO

230 (10-) MeO S CH, -C-CHJ-Q-CI

231 (! O-) MeO S CH, ~

232 (! O-) MeO S CH,

, CH ^ CI

234 (TO-) MeO -T - ( CH 2) 2 -Q

o

235 (! O-) MeO

236 (10-) MeO S (CH 2) 2 -N_N-CH 2 -Q-CI

238 (10-) MeO S (CH 2

CI CI

2 one) H CMeo-) ttMeo-

Table 1 9

Compound No. R 1,!? 2 W

253 (10-) eO SO -CN- ( CH 2) 2 -Q

254 (! O-) MeO SO ~ C N_ "CH2) 2") "OMe

255 (10-) MeO SO

257 (10-) eO SO ~ Q * - (CH 2) 3 "2" 0 "F

258 (10-) MeO SO CH, -CN-CH 2 -Q-CI

265 (10-) eO SO (CH 2) 2 -C N - C ¾-Q

CI

266 (! O-) MeO SO ( CH 2) Li "Q

CI CI

6 o / Bok _

o

Table 2 1

1

Compound No. R ", R o2 w

282 (10-) eO SO ~ C N_ (CH2) 2 "O" 0ME

284 (! O-) eO SO N , (CH 2) 2 "" CI

285 (! O-) eO SO

286 (10-) MeO SO CH 2 -CN-CH 2 -Q-CI

287 (! O-) MeO SO -T)

CH, - CH 2 CI

288 (TO-) MeO SO CH,

289 (lO-) MeO SO CH, -NQJ-CH 2 -Q-CI

291 (10-) eO SO -CN- ( CH 2) 2

292 (TO-) MeO SO (CH 2) 2 -N N-CH 2 - ^ - CI

293 (! O-) eO SO ( CH 2) 2 "^ -Q CI

5? Ooooo

(W one -

Ηϋ} Table 24

H

332 (8-) MeO S02 -C- ( C 2) 2 -g

Table 2 5 Compound No. R ,, R 2 W

338 (8-) F -CN- (CH 2) 2 -QO e

340 (8-) F, (CH 2) 2 "^>" CI

341 (8-) F - (N- (CH 2) 3 -g- -F

342 (8-) FC, - ( ^ -CH 2 - ^ - CI

345 (8-) F CH, -NJJ -CH 2 -Q-CI

346 (8-) F

347 (8-) F

348 (8-) F (CH 2 ) 2 -N N-CH 2 -Q-CI

349 (8-) F (CH 2 ) 2 ~ N N-CH 2 -Q

CI ■

350 (8-) F (CH 2 , 3 - "Q

CI CI 2 6

Compound No. w

351 (10-) F

352 (10-) F ~ C N one (CH 2) 2 "" 0ME

354 (10-) F, (CH 2) 2 "Q" CI

356 (10-) F CH, -CN -CH 2 -Q-CI

357 (10-) F CH,

358 (10-) FH 2 ~ Q "CI

360 (10-) FS

362 (10-) FS (CH 2 ) 2 - N two N "CH2 CI

363 (10-) FS (CH 2 ) 2 -N N-CH 2 -Q Table 2 7

Compound No. R 1,!? 2 W

366 (8-) F SO ~ N - (CH2) 2 ~ "0Me

3G7 (8-) F SO ~ Ci- (CH2) 2 -Q

370 (8-) F SO CH, -C-CHJ-Q-CI

371 (8-) F SO CH,

0 Fei

372 (8-) F SO CH

N, CH 2 "Q ~ CI

376 (8-) F SO (CH 2) 2 -N N-CH 2 -Q-CI

378 (8-) F SO (CH 2, 3

CI CI Table 2 8

Compound悉号R 1, R 2 W

379 (10-) F SO

380 (10-) F SO - ( N- (CHj) 2 -Q- 0Mi

381 (10-) F SO ~ ( CH2) 2

384 (10-) F SO CH 2 -CN-CH 2 -Q-CI

385 (10-) F SO CH 2 -

386 (10-) F SO CH 2

387 (10-) F SO CH, -N N-CHz - ^ - CI

388 (10-) F SO -T} j- (CH 2) 2 -

390 (10-) F SO (CH 2) 2 -N w N-CH 2 -Q-CI

391 (10-) F SO (CH 2, 2 -C ^^ - Q

392 (10-) F SO (CH .) 3 one N double CI CI TABLE 2 9

Compound No. R'.R 2 R 3

393 (8-) F

394 (8-) F - <N- (CH 2) 2 -Q-OMe

396 (8-) F

398 (8-) F CH, - n-CH 2 -Qa

399 (8-) F CH, ^ eight

403 (8-) F

404 (8-) F (CH 2 ) 2 -N_N-CH 2 -Q-CI Table 30

Compound No. RR 2

408 00-) F -CN- (CH 2 ) 2 -Q-OMe

410 (10-) F, (CH 2) 2 "^" CI

412 (10-) F CH, -C -CH 2 Q-CI

413 (10-) F CH,

414 (10-) F CH-

417 (10-) F - (j- (CH 2) 2 - ^ - ^

419 (10-) F (CH 2 ) 2

CI

420 (10-) F (CH 2 ) 3

CI CI

twenty three

) Ocl ".

Table 32

Compound No. R ', R 2 R 3

436 (10-) Br Me ~ C N_ (CH 2 "2" "0Me

437 (10-) Br Me N- ( CH 2) 2 "Q

439 (10-) Br Me ~ C N_ (CH2) 3 O "F

440 (10-) Br Me CH 2 - {^ -CHa - ^ - CI

442 (10-) Br Me CH,

, CH 2 "Q" CI

443 (10-) Br Me CH 2 - JJ-CH 2 -Q-CI

444 (10-) Br Me "- (CH 2) 2 -

446 (10-) Br Me (CH 2) 2 -N N-CH 2 -Q-CI

447 (10-) Br Me (CH 2) 2 ~ CN-CH 2 -Q

448 (10-) Br Me (CH 2) 3

CI CI Table 3 3

Compound No. R 1, R 2

449 (10-) CI PhCH2 ~ C N 2 "0

451 (10-) CI PhCH2 ~ ( CH 2) 2 -Q

454 (10-) CI PhCH2 CH, -CN-CH 2 HQ-CI

455 (10-) CI PhCH2 CH, : H 2 -Q-ci

459 (10-) CI PhCH2 -CN- ( CH 2) 2

460 (id-) ci PhCH2 (CH 2) 2

461 (10-) CI PhCH2 (CH 2) 2 - _N-CH 2 -Q

CI

462 (10-) CI PhCH2 (CH 2) 3

CI CI

8H0> W3

You w

Table 3 7 Compound No. R ^ R 2 W

505 0 ~ CN- (cw

CI

506

I

507

-C «- (CH ^ H ^

508

CH 3 0

509

, COCH 3

510

- * - "^

G Br

511 - ^, Ν- (CH ^ j

CI

512 ~ N - (CH 2> 2 ~ _ ^ "CI

513 - ^ N- Wz - ^ - CI

514 - N - (CH2) 2 - ^ - CI

CI

515

CI

, CF 3

516

, CCF 3

517

518 - (i- (CH2) 2 - ^ 6 ε z

ezs

C H303HN "^^ · Ζ ΡΗ3> -Ν ^ - 8ZS

<Μ¾ «0" ^^ ~ S H:)> - Ν) - 9ZS

0 S2S

HO - ^ - ^ HO) -Ν> -

C (C HO) 00 - ^ - Z <Z HO) - Ν> - 0 £ ZS

0 IZS

0 OZS

M

8 ε f00Z0 / 96dr / 13d 986 £ 0 6 OAV

Table 4 1

Compound No. RR 2 W

561 ~ * - (cw

CI

562

~ _} * - (CH2) 2 - ^

CH3O

565

C CF 3

573

CH 3

574 4 2

Compound number, W

578

582 ~ L N- (CH ^ - ^^ - OCHjPh

584 ~ ^ N- (CH2) 2 - ^ - 0 2

585

587 - ^ N- (CH2) 2 - ^ - N (CH3) 2 6/02004 Table 4 3

Compound No. R ', R 2 W

590 CH2 "O

Βι

591 CH2

592 CH2 Br

593 CH2

1

594 CH2 -

595 CH2 • N -Q "1

ci

596 CH2

596 CH2 C,) = v

c CI

598 CH2

CI

600 CH2 -> C N '

601 CH2

- "O

CH 3

602 0 CH2

603 CH2 Table 44

Compound No. R ', R 2 W

CH 3 0

605 CH2

606 0 CH2 "N ^ N O " OCH3

607 O CH2 • OH

608 O CH2 -OPh

610 0 CH2 -N - ^^ - OCHa h

611 CH2 • C N "Q" CN

N0 2

612 CH2

613 CH2

615 CH2

_ N "" NH2

(CH3> 2

616 CH2

-

617 0 CH2 -N - ^ - NHCH 3

618 CH2 - ^ N - ^ - N (CH3) 2

/ S 86 one f / l6d / 9 s one

O

Dimensions

o

Bok dimensions

/ 6_Rei Bok _

CO

Formulation Formulation Example 1

Compound 0.5 parts of Example 1 1, lactose 2 5 parts, 5 parts of crystalline cellulose 3 and co - After mixed well and Nsutachi 3 parts, was combined good rather kneading a binder was manufactured in cornstarch 2 parts. Sieved The kneaded product 1 6 mesh in an oven 5 0. After drying in C, and sieved with 2 4 mesh. Kneading the powder and 8 parts of corn starch obtained here, it was mixed well and crystalline cellulose 1 1 part of talc 9 parts, was then compressed tablet to give tablets of the active ingredient 0. 5 mg containing per tablet .

Formulation Formulation Example 2

Construed soluble in Example 1 Omg per compound and sodium chloride 9. Omg water for injection, filtered to remove pyrogens and the filtrate was transferred to amble under sterile after sterilization, by melting sealing to give the active ingredient 1. Omg injection containing.

Formulation Formulation Example 3

Compound 0.5 parts of Example 1 0 2, lactose 2 5 parts After mixed well and 5 parts of crystalline cellulose 3 and corn starch 3 parts, was combined well kneaded with a binder that is manufactured with corn starch, 2 parts. Sieved The kneaded product 1 6 mesh, dried at in an oven 5 0, sieved at 24 mesh. Kneading the powder and 8 parts of corn starch obtained here, it was mixed well and crystalline cellulose 1 1 part of talc 9 parts, pressed tablet to 1 tablet per active ingredient monument. To obtain a 5 mg tablet containing .

Formulation Formulation Example 4

Compound 1. Omg sodium chloride 9. Omg of Example 1 0 2 dissolved in water for injection, filtered to remove pyrogens and the filtrate was transferred into ampoules under sterile after sterilization, by melting sealing to give the active ingredient 1. 0 mg injection containing.

- excellent pharmacological activity of the compounds of the crotch formula (1) is demonstrated by the series of tests described below.

3 H- spiperone binding; affinity for D 2 receptors: Experiment 1

Crude synaptic membrane preparation and binding experiments crease (I. C reese) et al method [® sip Bien 'journal O Bed & Famako port di one, 4th Volume 6, 3 7 7 p. (1 977)] according to the went. Cryopreserved rat adjust the crude synaptic membrane from striatum papermaking, was reacted for 20 minutes at 37 ° C for a membrane specimen and 3 H- spiperone in the presence of the test compound. After completion of the reaction, immediately Wattoman GFZB with suction filtered through a filter (trade name), was measured radioactivity on the filter one liquid scintillation counter one. Nonspecific binding amount was determined by the 1 0 O zM (Sat) Surupiri de presence. 50% inhibition concentration of the test compound (IC 5.) Calculated from non-linear regression to determine the inhibition constant (K i values).

Experimental Example 2: Preparation of D 4 receptor expressing cells

(1) Amplification鐯型by D 4 receptor cDNA in the PCR (polymerase chain reaction) method using human pituitary cDNA [Clontech (Clontech) Corporation]. Also to amplify in two fragments, primer,

D4S1; 5 '-GCCATGGGGAACCGCAGCACCGCGGACGCGGA-3'

D4A1; 5 '-GCACGGCCACGGCCACGAACCTGTCCACGCT-3'

and,

D4S2; 5 '-GTCATGCTGTGCACCGCCTCCATCTTCAAC-3'

D4A2; 5 * -ATCTCCTTGGTCCCTGAGGCCTGGCCATCA-3 '

It was used.

Amplification by PCR, using PCR reactor CGeneAmp PCR System 9600 (Parkinson down-Elmer one Shea one task (PERKIN ELMER CETUS) company], pretreated with 98 ° C 2 minutes, denaturation (98 ° C , 2 min), annealing and extension reaction (77 ° C, 5 minutes) was carried out 50 sub Ikuru was performed by post-treating further 77 ° C 10 minutes. the enzyme heat resistance of Pfu DNA Borimeraze [Stratagene ( STRATAGENE) Ltd.] were used. PCR after the completion of the reaction, check the primer D4S1, D4A1 about 4 00 bp primer was amplified by D4S2, target DNA bands of about 900 bp amplified by the D4A2 in Agarosugeru electrophoresis, using QIA quick gel extraction Kits [Qiagen (Qiagene) Co.], DNA was extracted from the gel. where the DN a to D 4 S about 40 Ob.P. obtained, DNA of about 90 Ob.P. is referred to as D 4 L. Further, several service be slightly bands D4 L pro one de The presence of subtypes has been suggested.

(2) inserted into a cloning vector

Extracted DNA fragment from the gel (D4S or D4L) is incorporated in Cronin Gubekuta one pUC18 by performing ligase reaction using SureClone Ligation Kit [off Arumashia (Pharmacia) Corporation]. Obtained in the vector one combi E. coli JM10 9 a (Toyobo) was transformed. Extracting plasmid from appearing ampicillin resistant colonies, perform digestion with various restriction enzymes to confirm the insertion of D 4 receptor DNA (D4S or D4L). Next, D4S or D4L containing pUC18 clone (D4S / pU C18 or D4L / PUC18) a restriction enzyme that cuts the restriction enzyme BstXI and the vector portion of the switching f duplicate region of the D4S and D4 Shino D 4 receptor DNA was digested with Xbal, it was Agaro Sugeru electrophoresis. Was confirmed band of interest of DNA C D4S (BstXI-XbaI) or D4L (XbaI-Bs tXI)] extracted was performed. The resulting D4S (BstXI-XbaI) and D4L a (XbaI-BstXI) linked by ligase, and the Escherichia coli JM109 was transformed with this base Kuta scratch. From the appearance and ampicillin resistant colonies were extracted Burasumi de was confirmed the insertion of the D 4 receptor DNA encoding the entire Amino acid performs digestion with various restriction enzymes. Furthermore, the vector one having two D 4 receptor DNA having different molecular weight were confirmed at this point.

(3) determination of the entire nucleotide sequence of the D 4 receptor DNA

The vector and 铸型 those alkali denaturation, the reaction was carried out by Jidokishi method using AutoRead Sequence Kit [fa Pharmacia (Pharmacia) Corporation]. Analysis of electrophoresis and nucleotide sequences was performed using the A. and F.DNA Sequencer II [Pharmacia (Pharmacia) Corporation]. As a result, two types of D 4 receptor DNA of different molecular weights that are confirmed repeatedly in the third intracellular regions are those of a two times (D4.2) and 5 times (D4.5) It was. 0 eighth nucleotide sequence of 04.2 and 04.5 shown in Figures 1-7. Also in the figure, HSD4 D0P the Neichiya (Nature), # 350, pp. The nucleotide sequence of the D 4 receptor DNA described on pages 160-164 (1991), a portion surrounded by a frame is homologous portion of each DNA shows, shows the four Buraima portion using the lower wire unit. The resulting vector, where D4.2 / pU C18 and D4. Called 5 / pUC18.

(4) Preparation of expression vector

D4.2 or D4.5 containing pUC18 clone (D4.2 / pUC18 or D4.5 / pUC18) was digested with restriction enzymes Hindl ll and Kpnl, the purpose of the D NA given the respective digested fragments to Agarosugeru electrophoresis It was to separate the band extraction. Base for expression Kuta one pCEP4 [vitro Gen (Invi trogen) Co.] was also digested with the same enzymes, incorporate D4.2 or D4.5 was separated and extracted into pCEP 4 vector and E. coli JM109 was transformed with this vector. Extracting plasmid from ampicillin resistant colonies is performed the digestion with various restriction enzymes to confirm the insertion and the insertion direction of D4.2 or D4.5. The resulting vector is referred to as D4.2 / P CEP4 and D4.5 / pCEP4 a.

(5) Preparation of D 4 receptor stably expressing cell

The resulting mixed with vector one (D4.2 / pCEP4 or D4.5 / pCEP4) lipoic polyamine reagents der Ru transflector Aix Tam (TRANSFECTAM) [IBF Bio Techniques (IBF Biotechn ics) Co.], derived from human embryonic kidney was added to the culture medium of transformed cells 293 (Dainippon Pharmaceutical) or monkey kidney cells CV-1 (Dainippon Pharmaceutical). Were selected transduced cells by culturing with hygromycin B HYGR0 MYCIN B) [Calbiochem (CALBIOCHEM) Co.] added medium.

(6) RT - confirmation of the transformed cells by PCR

RNA from the resulting transformed cells Microisolation Spin Cartridge System [formic BUKO (GIBCO BRL), Inc., trade name GLASSMAX TM] was extracted each RNA using. The ol igo-dT as a primer, cDNA was prepared using M-MLV reverse transcriptase (reverse transcriptase). Each cDNA obtained was used as a铸型was amplified by PCR method including portions of the third intracellular region of D 4 receptor D NA. As a result of the Agarosugeru electrophoresis, their respective expressed RNA was confirmed to be a D4.2 and D4.5. Transformed cells containing D4.2 / pCEP4 obtained here D4.2 / PCEP4 - 2 9 3 cells and D4.2 / pCEP4 - and CV cells, also transformed cells containing D4.5 / pCEP4 It called D4.5 / pCEP4- 2 9 3 cells and D4.5 / pCEP4 one CV cells. (7) drug binding test

To confirm the D 4 receptor production and properties of the resulting was transformed cells, crude membrane fraction of each transformants conversion cells (P2 fraction) were prepared, and [3 H] spiperone (Daiichi Pure Chemicals) various drugs (hydrochloric Mosaburamin, Haroperi doll, Buromuperi Doll, clozapine, Risuperi Don, chlorpromazine, Rakuropuri de) was added, 27 Te, and allowed to react for 2 hours. After completion of the reaction, through Whatman GF / C glass filter (trade name), the radioactivity remaining on the filter was measured by liquid scintillation counter [Beckman (BE CKMAN) Corporation]. Nonspecific binding amount was determined by Haroperi d'presence of 1 O zM. 50% inhibitory concentration of various drugs to (IC 5 c) was calculated by non-linear regression to determine the D 4 receptor [3 H] spiperone inhibition constants for various drugs on binding (K i values). Table 4 9 shows the results obtained by using the D4.2 / pCEP4-2 9 3 cells as transformed cells.

Table 4 9 Drug K i (nM)

(Mean soil standard deviation) hydrochloride Mosaburamin 3.3 Sat 1 2

Nono CJ Perry Donore 4. 0 ± 0 6 5

Buromuperi Doll 4.1 Sat 0 2 5

Clozapine 2 6 Sat 0 6 8

Risuperi Don 1 1 Sat 1 3

Chloro bromide Mazzin 34 Sat 8 3

From Rakuropuri de 32 0 0 4 4 0 The above results, it obtained D4.2 / pCEP4 - 2 9 3 cells, D4.2 / pCEP4 - CV cells, D4.5 / pCEP4- 2 9 3 cells and D4.5 / pCEP4-CV cells, both expressing uniform D 4 receptor, were able to prepare a good reproducibility large amount D 4 receptor by subculture. Accordingly, the (affinity for D 4 receptor) Measurement pharmacological activity of the compounds of the present invention using the above cell lines.

3 H- spiperone binding; affinity D 4 receptor: Experiment 3

Experimental Example 2 of D4.2 / pCEP4 - a 29 3 D 4 receptor expressing cell membrane specimens were obtained from cells and 3 H- Supiberon Te 27 in the presence of the test compound and incubated for 2 hours. After completion of the reaction, immediately filtered by suction through a Whatman GFZB filter (trade name), and the radioactivity on the filter one was measured by a liquid scintillation counter. Nonspecific binding amount was determined by the 1 0 t M Haroperi d'presence. 50% inhibition concentration of the test compound (IC 5.) Calculated from non-linear regression to determine the inhibition constant (K i values).

Results of Experimental Examples 1 and 3 shown in Table 5 0.

Table 5 0 receptor binding force K i (nM) of the test compound Example No. DD

1 2 270 0 1.1 5> 1 0 0 0 * 8.3 1 8> 1 0 0 0 * 0.52 2 1> 1 0 0 0 * 9.0

24> 1 0 0 0 * 5.6

27> 1 0 0 0 * 2.0

32> 1 0 0 0 * 3.3 7 1> 1 0 0 0 * 2, 6 9 6 1 0 0 0 6.2

1 0 0 1 5 0 0 1 0.0

1 03> 1 0 0 0 * 8.3 1 1 4 1 20 0 1.9

1 9 0> 1 0 0 0 * 2.1

1 9 3> 1 0 0 0 * 2.6

*: The compound of the present invention from the experiments above IC 50 values were confirmed to have a strong affinity for D 4 receptor than D 2 receptors.

Experimental Example 4: [35 S] GTP TS binding assay

Journal O Bed & Neuro chemistry Vol.63, No.1 (J. Neurochem.) : 6 2-65 C, according to the method of Chabert et al. Described in (1994), D 4 receptor Agoni strike-en of the test substance evening was discrimination of agonist.

The D4.2 / pCEP4- 2 9 3 cells, 1 mM EDTA, magnesium 3mM chloride, 1 O Omm sodium chloride, 0. ImM PSF, 2 g / m 1 aprotinin, 1 0 si g / m 25mM HE containing 1 Leupeptine PES-Na OH buffer (pH 8. 0) in, and disrupted using a glass of teflon homogenizer to recover the membrane fraction by centrifugation. This 1 mM EDTA, 3 mM magnesium chloride, l O Omm sodium chloride, 0. 5 mM dithiothreitol, and suspended in 2 5 mM HEPES-NaOH buffer containing 0. 0 1% Lubrol PX (ρΗ8 · 0), final concentration GDP It added to a 1 0 M, and reacted for 10 minutes at 0. Was then reacted for 10 minutes at at 37 was added a test substance. After completion of the reaction, added to give a dopamine is Agonisuto final concentration 1 o- 8 ~ 1 0 one 4 M, further [35 S] GTP r S 3 at (200,000 dpm / assay) were added 37 ° C 0 minutes and allowed to react. Thereafter, the reaction suspension was filtered Wa Tsu Toman GF / B filters, washing the filter 2 5 mM magnesium chloride, 1 0 Omm sodium chloride 2 Omm Tris-HCl buffer containing in (PH 8.0), the vial placed, ACS- Π (Amersham) scintillation Isseki one was added and measured radiation dose. As a result, dopamine increases the binding to membranes of depending on the concentration [35 S] GTP 7 S, Haroperi Dole, clozapine and test compound (compounds of Examples 1 2 and Example 1 8 8) This increased antagonized in a concentration dependent manner the action. Further, the test substance alone did not increase the binding to the membrane of [35 S] GTP 7 S. From the above, the test substance, like Haroperi doll and clozapine, it was suggested that an antagonist to the D 4 receptor.

Experimental Example 5: Affinity for D 4 receptors

1. 5 mM calcium chloride, 5 mM potassium chloride, 1 20 mM NaCl, in 1 s / 1 PMSF 5 OmM Tris-HCl buffer containing (phenylene methyl sulfonyl fluorimeter de) (pH7. 4), D 4 receptor somatic expressing cell membrane preparation as in example 9 0 compound at 27, and incubated in the dark for 2 hours. Note that as the non-specific binding, was used Haroperi Doll final concentration 1 0 M. After Inkyubeto, to terminate the reaction was filtered through a GFZB fill evening one which was previously 0.1% polyethyleneimine process, the scintillator was added and measured / 8 dose.

The results shown in Table 5 1 a. Table 5 1 binding radiation value (DPIN)

Non-specific binding

(N M) the total binding non-specific binding

0 2 1 1 0 0 1 7 0 1 5

0 4 2 0 3 0 3 3 0 1 6

1 4 4 0 0 8 6 0 2 0

(Example 9 0 Compound: 6 4 2 0 0 dpm / pmol)

Scatchard analysis of the results, the affinity of the D 4 receptor of the compound of Example 9 0 (dissociation constants: K d values) were 1 1 n M..

Industrial Applicability

The compounds of the present invention, acceptable salts optical isomers or its pharmaceutically are the D 4 receptor antagonist having a selective and strong blocking action against the D 4 receptor, the acute phase of mental schizophrenia Toku徵hallucinations, not only positive symptoms centering on such delusions, apathy and inaction, useful antipsychotic showing an effect against negative symptoms such as autism. Further, it is expected as antipsychotic conventional antipsychotics time was side effects and extrapyramidal symptoms and endocrine abnormalities seen when administered with D 2 receptor antagonism has been reduced. The present invention compounds can be used as a therapeutic agent for diseases such as schizophrenia. Further, the radioactive substance (radio ligand), for example, binding studies D 4 receptors in a biological each part position, and screening and compounds having an affinity for D 4 receptors in vitro, were labeled D 4 receptor can be used for Otoraji Ogurafi one, D 4 in order to explore the and novel compounds to elucidate the閟communicating with the pathogenesis of diseases such as receptors and schizophrenia, can be obtained useful information on the industry.

Claims

The claims of the amendment
[1 996 December 24, (24.12, 96) The International Bureau accepted: range i of the originally filed claims has been corrected; range of other claims without change. (3 pages)]
[In the formula, ring E of the following formula:
In indicates Chiofen or benzene represented,
R 1 and R 2 may be the same or different, are each hydrogen, halogen, Shiano, nitro, Amino, Ashiruamino force Rubamoiru, alkyl force Rubamoiru, alkoxycarbonyl, Ashiru, Arukiruamino, aminoalkyl, Arukirua aminoalkyl, hydroxy, Ashiruokishi , hydroxyalkyl, Ashiruokishi
270
Corrected ffl paper (Convention Article 19) alkyl, alkoxyalkyl, alkyl, Ryo alkenyl represents alkynyl, Ryo Rukoki shea, alkylthio, an alkylsulfinyl or alkylsulfonyl,
W is methylene, sulfur atom, SO, S0 2, an oxygen atom or N-R 3 (wherein, R 3 is hydrogen, alkyl, full: t Nasir or an optionally substituted § reel alkyl or Heteroa, shows the reel alkyl.) indicates,
X represents a methylene, ethylene or vinylene,
Y is absent or indicates a straight or branched TECHNICAL 鎮伏 al Killen chain having 8 carbon atoms of 1,
Z one NH 2, -NHR 4 (wherein, R 4 is Yes alkyl, cycloalkyl, optionally § reel alkyl optionally substituted, hetero § reel alkyl to heteroalkyl § reel alkyl or fused, or a substituent and may be Ariru, Heteroariru if Ku denotes a heteroaryl fused.), one N (R 4) (R 5 ) ( wherein, R 5 is optionally have Al kill, cycloalkyl, substituents § reel alkyl, Heteroari Ruarukiru or terrorist § reel alkyl to condensation or an optionally substituted Ariru, shows a heteroaryl Heteroariru or fused, synonym and R 4 above.), or formula (a), (b) or ring Fushimi Amin of (c)
Li AR? One Ν
7
(A) Q3> (0
(Wherein the cyclic amine in the formula (a) has a further oxygen atom in the ring Even if well, Pirorijinru shows a piperidine or morpholine, wherein (b)
271
SKTr Min one n H of 徺正 by the sheet (Convention Article 19) shows the piperidines Rajin or Homopi Bae Rajin formula
Cyclic amines -0 in (C) is rather good further have an oxygen atom in the ring, pyrrolidine, piperidine, 3, 6-dihydro-one 2 H- pyridine or Moruho indicates phosphorous, solid and dotted lines in bond represented represents a single bond or a double bond, a is either not exist, or indicates Choku鏆 or branched TECHNICAL chain Arukiren chain having 8 carbon atoms of 1, B is absent, or sulfur atom, an oxygen atom, a carbonyl or human Dorokishimechiru, R e represents hydrogen, hydroxy, alkyl or alkoxy, R 7 is heteroaryl hydrogen, an optionally substituted Ariru, to Heteroariru or condensation, cycloalkyl or may Ariruaru kills have a substituent or a heteroarylalkyl to heteroalkyl § reel alkyl or condensation. ) Shows the. However, ring E represents a benzene, W represents a methylene, and when X represents methylene down one Y- Z is pyrrolidinylmethyl, Amino, aminoalkyl, aralkyl Kiruamino, alkylaminoalkyl, dialkyl § Mino, dialkylamino a alkyl, except when it is piperidinyl or morpholinyl. ]
Condensed triazole compound, its optical isomers or a pharmaceutically acceptable vines represented by <5
2. - In Z of general formula (1), cyclic amine (a) is a compound represented by the following formula (2), (3), (4), (5), an annular Amin represented by (6) or (7) in a fused triazole compound ranging first claim of claim, its optical isomers or a pharmaceutically acceptable cormorants Ru salt o
272
The first term range of manual claims based on the corrected sheet (Art. 19 Convention 1 Article 9 shows one of the compound represented by the general formula (1), ring E is a benzene, W and X are methylene when one Y- Z went pyrrolidinylmethyl, amino, aminoalkyl, Arukiruamino, alkylaminoalkyl, dialkyl § amino, dialkyl § aminoalkyl, piperidinyl or compound removal rather correction morpholinyl.
This correction, USP3, 814, 711 to the disclosed the following formula
Compound represented by the ceased to overlap with the compounds of the present invention
Further, it disclosed in FR1573135, the following formula
(Wherein, R i is Amino, aminoalkyl, Arukiruamino, alkylamino al kills, dialkyl § amino, dialkyl § aminoalkyl shows piperidyl or Moruho Riniru) compounds represented by, no longer overlap with the compounds of the present invention It was. Other publications and literature cited in the international search report, i.e. USP3, 992, 539, Chemi cal Abstracts, Vol. 81, compounds disclosed in Takeda Kennkyuusyo Ho and JP6-501488 includes a compound of any invention non-overlapping.
PCT/JP1996/002004 1995-07-19 1996-07-17 Fused triazole compounds WO1997003986A1 (en)

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JP8/3055 1996-01-11
JP305596 1996-01-11
JP403496A JPH09151186A (en) 1995-09-29 1996-01-12 Condensed triazole compound
JP8/4034 1996-01-12

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* Cited by examiner, † Cited by third party
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WO2005082873A2 (en) * 2004-02-27 2005-09-09 Bioagency Ag 1,4-benzothiazepans and derivatives thereof
WO2005121088A1 (en) * 2004-06-08 2005-12-22 A. Carlsson Research Ab New disubstituted phenylpiperidines as modulators of dopamine and serotonin neurotransmission
WO2006023750A3 (en) * 2004-08-23 2006-07-27 Wallace T Ashton Fused triazole derivatives as dipeptidyl peptidase-iv inhibitors for the treatment or prevention of diabetes
US7417043B2 (en) 1999-12-22 2008-08-26 Neurosearch Sweden Ab Modulators of dopamine neurotransmission
EP2127654A1 (en) * 2004-03-25 2009-12-02 The Trustees of Columbia University in the City of New York Benzothiazepine derivatives as ryanodine receptor (RYR2) inhibitors and their use in the treatment of cardiac diseases
USRE41315E1 (en) 1999-12-22 2010-05-04 Nsab, Filial Af Neurosearch Sweden Ab Modulators of dopamine neurotransmission
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USRE41315E1 (en) 1999-12-22 2010-05-04 Nsab, Filial Af Neurosearch Sweden Ab Modulators of dopamine neurotransmission
USRE46117E1 (en) 1999-12-22 2016-08-23 Teva Pharmaceuticals International Gmbh Modulators of dopamine neurotransmission
US7417043B2 (en) 1999-12-22 2008-08-26 Neurosearch Sweden Ab Modulators of dopamine neurotransmission
US8710045B2 (en) 2004-01-22 2014-04-29 The Trustees Of Columbia University In The City Of New York Agents for preventing and treating disorders involving modulation of the ryanodine receptors
WO2005082873A3 (en) * 2004-02-27 2006-07-13 Bioagency Ag 1,4-benzothiazepans and derivatives thereof
WO2005082873A2 (en) * 2004-02-27 2005-09-09 Bioagency Ag 1,4-benzothiazepans and derivatives thereof
EP2127654A1 (en) * 2004-03-25 2009-12-02 The Trustees of Columbia University in the City of New York Benzothiazepine derivatives as ryanodine receptor (RYR2) inhibitors and their use in the treatment of cardiac diseases
US8314126B2 (en) * 2004-06-08 2012-11-20 Nsab, Filial Af Neurosearch Sweden Ab, Sverige Disubstituted phenylpiperdines/piperazines as modulators of dopamine neurotransmission
WO2005121088A1 (en) * 2004-06-08 2005-12-22 A. Carlsson Research Ab New disubstituted phenylpiperidines as modulators of dopamine and serotonin neurotransmission
US20100256163A1 (en) * 2004-06-08 2010-10-07 Clas Sonesson Disubstituted phenylpiperdines/piperazines as modulators of dopamine neurotransmission
US7625888B2 (en) 2004-08-23 2009-12-01 Merck & Co., Inc. Fused triazole derivatives as dipeptidyl peptidase-IV inhibitors for the treatment or prevention of diabetes
WO2006023750A3 (en) * 2004-08-23 2006-07-27 Wallace T Ashton Fused triazole derivatives as dipeptidyl peptidase-iv inhibitors for the treatment or prevention of diabetes
US7884104B2 (en) 2004-10-01 2011-02-08 Merck Sharp & Dohme Corp. Aminopiperidines as dipeptidyl peptidase-IV inhibitors for the treatment or prevention of diabetes
US8501777B2 (en) 2005-10-13 2013-08-06 Nsab, Filial Af Neurosearch Sweden Ab, Sverige 3,5-disubstituted phenyl-piperidines as modulators of dopamine neurotransmission
US9012476B2 (en) 2011-12-08 2015-04-21 IVAX International GmbH Hydrobromide salt of pridopidine
US9814706B2 (en) 2011-12-08 2017-11-14 Teva Pharmaceuticals International Gmbh Hydrobromide salt of pridopidine

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