JPH01100172A - Pyridine derivative - Google Patents

Abstract

NEW MATERIAL:A compound formula I [A is S or O; R1 is (substituted)amino, hydrazino or 6- or 7-membered heterocyclic group containing one or more N atoms; R2 and R3 are halogen, (substituted)alkyl or aryl; m is 0-2; n is 0-4] and salts thereof. EXAMPLE:N-(2-Aminoethyl)-benzo[b]thieno[2,3-c]pyridine-3-carboamide hydrochloride. USE:A medicine and psychotropic agent having antianxiety and learning improving action. PREPARATION:For example, a compound expressed by formula II is reacted with a compound expressed by formula VIII (R4 is H or R2) to form a compound expressed by formula III, which is then reacted with a compound expressed by formula IX to afford a compound expressed by formula IV. The resultant compound expressed by formula IV is subsequently reacted with Fe and HCl to form a compound expressed by formula V, which is then reacted with a compound expressed by formula X (R4' is same as R4) to provide a compound expressed by formula VI. The obtained compound expressed by formula VI is subsequently reacted with a compound expressed by the formula HX1 (X1 is leaving group, etc.) and then dehydrosulfurized with NaHCO3 and S to provide the aimed compound expressed by formula I.

Description

[Detailed description of the invention] (Industrial application field) The invention affects the central nervous system of coralline mammals and has anxiolytic effects,
The present invention relates to a pyridine compound represented by the following general formula (I) and a salt thereof that is useful as a psychotropic drug having a learning-improving effect.

(In the formula, A is a sulfur atom or a tR atom, and R8 is an unsubstituted or substituted amino group or a hydrazino group.

R3 and R are halogen atoms, unsubstituted atom is a substituted δ alkyl group, aryl group 1m is 0 to
n is an integer of 0 to 4, and when 0m and n are 2 or more, Rt and R3 may be the same or different, respectively. ) (Prior Art) It is known that the β-carboline-3-carvone #iLs conductor represented by the general formula below is useful as a drug for psychosis having anti-aggressive effects (% 45285>.

In addition, 1,2,5,4-tetrahydrobenzo [b] represented by the following general formula
(2,3-c) Pyridine derivatives are central nervous system depressants.

It is known to be useful as a tranquilizer (Japanese Patent Publication No. 5G-2519).

Furthermore, it is also known that pyridine derivatives represented by the following general formula (where R is alkoxy, OH, or halogen) have psychoactive effects (% Kaisho 61-256779).

Regarding 1,2,3,4-tetrahydrobenzo(b)cheno[2,3-c]pyridine, methods for synthesizing its derivatives and their biochemical effects, Gerhard Wolf, Felix Timorkowski, Archipelago・Der Farmage (Gerhard Wolf and Feli)
x Zymalkowski, Arch, Phar
m, ) 279.

s09 (t976), and Klineschmidt Bradley Bui, Reis Duane γ-L.

Hechhorn, Touklas, G., Robinson, Janet E., Journal of Pharmacology and Experimental Theory (Bran
dley V C1inC11nesch, Duan
eR.

Re1ss, Douglas J, Pettibon.
E and Janet L, Robinson, J.
, Pharmacol, Exp, Ther.), 696
-708.

235 (3) (1985), etc.

However, the pyridine derivative represented by the general formula (I) is not known, nor is its medicinal efficacy known.

(Zhao Points to be Solved by the Invention) The present inventors have conducted intensive research on the method for producing the pyridine derivative of general formula (I) and its usefulness, and have found that it is useful as a medicine having anxiolytic and word-correcting effects. The purpose of the present invention is to provide a novel pyridine derivative 'Ik.

(1') Means for solving the problem) The present invention provides a pyridine derivative represented by the general formula (1) and a salt thereof.

In the above general formula (I), A is a sulfur atom and t7t is an oxygen atom. R1 is an amino group or a hydrazino group.

A six-membered group having at least one nitrogen atom is a seven-membered heterocyclic group. Hydrogen bonded to the carbon or nitrogen atom of these groups may be substituted with another group.

Examples of substituents include 1, an alkyl group having 1 to 6 carbon atoms, and a phenyl group, which may be unsubstituted or in which hydrogen bonded to a carbon atom may be substituted with a amino group, a carboxy group, an ester group, etc. , a 5- to 7-membered heterocyclic group containing a nitrogen atom, and the like. Specific examples of R1 include piperidino group, 2,6-dimethylbiperidino group 1
Morpholino group, piperazinyl group, 5-methylpiperazinyl group, 4-methylpiperazinyl group, hexahydro-I
H-1,4-diazevinyl group, hexahydro-1H-4
-metherdiazebiel group, 2-aminoethylamino group,
3-aminopropylamino group, amine group, hydrazino group, 2-dimethylaminoethylamino group, methylamine group, ethylamine group, rhopropylamino group, n-hexylamino group, butyric acid group, butyric acid ethyl ester group, etc. .

Bird and R1 are a halogen atom, an alkyl group, or an aryl group. The number of carbon atoms in the IL group is about 1 to 20, and the hydrogen bonded to the carbon atom may be substituted with another group. Examples of - and R include a chlorine atom, a methyl group, and a 7-enyl group.

m1j is an integer of 0 to 2, and n is an integer of 0 to 4.

When m and n are 2 or more, R1 and Rs may be the same or different.

An example of the pyridine derivative of the present invention is shown below.

(1) 1-(benzo, [b]cheno[2,3-c]pyridine-6-carbonyl)-piperidine i211- (benzo(b)cheno[:2,3-c]pyridine-5-carbonyl)- 2,6-dimethylpiperidine+314- (benzo(b)cheno(2,5-c]pyridine-3-carbonyl)-7ulfoline i411- (benzo[b]thieno[2,3-c]pyridine- 3-carbonyl)-piperazine (5) 1-(benzo[b]cheno[2,3-c]pyridine-3-carbonyl)-3-methylpiperazine (6
11-(benzo[b]cheno(:2.3-clpyridine-3-carbonyl)-4-methylbiperazine (7)hexahydro-1-(benzo[b]cheno[2゜3-C]pyridine-5- carbonyl) IH-1゜4-diazepine (8) hexahydro-1-(benzo[b]naeno[2゜3-C]pyridine-5-carbonyl)IH-4-methyldiazepine (9IN-(2-7 (minoethyl)-benzo[b]cheno[2,3-c]pyridine-3-carboxamide αtjN-
(3-7minoprovir)-benzo[:b]? Nino (2,
3-c) Pyridine-3-carboxamide αIJN-(2-
7minoethyl)-4-methylbenzo[b]cheno(2,
3-C]Pyridine-3-carboxamide 021N-(2-7minoethyl)-6-chlorobenzo[
b) Cheno(2,3-c]pyridine-3-carboxamide 4131N-(2-7minoethyl)-benzo(b]furano(2,3-c)pyridine-3-carboxamide α4)N
-(2-aminoethyl)-(1-phenylbenzo[b]
Cheno[2,3-c]pyridine-3-carboxamide us benzo[b]chi! /[2,3-clbiIJcy
-5-carboxamide 0.61benzo[blcheno(2,3-c)pyridine-
3-Carbohydrazide compound ηN-(2-dimethylaminoethyl)-benzo[b]
Cheno(2,3-C]pyridine-5-carboxamide (18)N-methyl-benzo[b]cheno(2,3-c
) Pyridine-3-carboxamide (21) N-propyl-benzo[b]cheno[b]cheno[2,3-c]pyridine-3-carboxamide (2,3-
cl pyridine-3-carboxamide-υN-hexyl-benzo(blcheno(2,3-c)
4-(benzo(b)cheno[2,5-c]pyridine- of pyridine-3-carboxamide)
3-Carboamino)butyric acid ethyl ester (234-(benzo[b]cheno(2,3-c]pyridine-3-carboamino)butyric acid The compound represented by the general formula (I) of the present invention can be synthesized by the following synthesis method. 1) Method 1 R4 σD (Ill) & (IV) (Vli) where A, R1, R1, R1, m, n have the same meanings as above, and R and Hiki' are hydrogen Or R7.

X is a halogen atom, methanesulfone group, 4,6-dimethylpyrimidinylmerkabuto group, etc.

Represents something that combines with a hydrogen atom to form an acid, or something that is excellent as a leaving group.

A method for obtaining compound (lit) t from compound 0 is described by H. R. Sinider, Donald Niss Matterson, Journal of American Chemistry-Sot.
Iati (H, R, 5nyder and Donal
dS., Matteson, J., Am., Chem., Soc.
), 79.

2217 (1957) as reference.

The solvent used in the method for synthesizing compound (111) from compound (1) is a mixed solvent of a polar solvent such as acetic acid or dimethylformamide, and a nonpolar solvent such as benzene or toluene, preferably compound 91JQJ). It is preferable to dissolve 7 and dropwise add a benzene solution of rudenisoglobilamine in alcohol to the solution. The alkyldene isoglobylamine is generally used in an amount of 1 to 5 equivalents, preferably 1.1
~1.5 equivalents.

Furthermore, alkyldentertiarybutylamine or the like may be used instead of alkyldeneisopropylamine. Hydrochloric acid, sulfuric acid, etc. may be added as a reaction catalyst. The reaction temperature is -20 to 50C, preferably 0 to 10C. Generally, it is completed in 10 to 70 hours.

Compound (Ill) to compound (IV) and (V)?
-How to get it: Dayney Little, Dayi Little
Uniis Plate, Journal of ◆American Chemistry Society (D, A, Littlelean
d D, 1. Wesblat, J., Am., Chem, S.
oc, ), 69.

2118 (1947) as a reference.

The solvent used in the method for synthesizing compound (IV) from compound (lit) is xylene, toluene, etc., preferably xylene. This reaction has a degree of 50
It is carried out at ~150C, preferably 90-100C. Generally, it is completed in 1 to 12 hours. The alkyl nitroacetate is used in an amount of 1 to 3 equivalents.

The solvent used in the method for synthesizing Compound 18 (V)' from compound (IV) is preferably a mixed solvent of water and a polar solvent such as methyl alcohol or ethyl alcohol.

The reaction temperature is 10-120C, preferably 6
It is 0-80C. Generally, the process is completed in 10 to 120 minutes. Iron powder is used in an amount of 1 to 10 equivalents, and hydrogen chloride is used in an amount of 1 to 20 equivalents. Further, metal such as zinc may be used instead of iron powder, or reduction with hydrogen may be performed in the presence of a catalyst such as Raney nickel or palladium-activated carbon.

Method for synthesizing compounds (Vl) and (■) from compound (V) ri1 Gerhard Wall7. Felicus Timorkovsky, Artev Bear Pharmacy (Ger
hard Wolf and Fe1ix Zymal
kowski.

Arch, Pharm, ), 279, 309 (1
976) f: Reference friend.

The solvent used in the method for synthesizing compound (Vl)'e from compound (V) is an organic solvent such as ethanol or benzene. The reaction temperature is 50 to 150C and is generally completed in 1 to 12 hours.

Solvent, methanol, ethanol used in the method of synthesizing compound (v11) from compound (Vl).

Water may be used, preferably water. This reaction temperature Hso
It is carried out at ~120C and is generally completed in 10 minutes to 2 hours. In addition, as a reaction catalyst, 10 to 100 equivalents of am,
4. An acid such as p-toluenesulfonic acid is used.

The method for obtaining compound (I) from compound (■) is described in Mino El Cain et al., Journal of Medicinal Chemistry (Michael Cain et al.,
J, Med.

Chem, ), 1081.25 (1982) f.

The solvent used in the method of synthesizing compound (1) from compound (■) is an organic solvent such as benzene, toluene, xylene, dioxane, and tetrahydrofuran. Elemental io-9 is generally used in an amount of 1 to 30 equivalents, preferably 15 to 25 equivalents.

The reaction temperature is 50 to 150C, preferably 1
00-120C. Generally, it will be completed in 1 to 7 days.

Other IL methods include dichlorodicyanopenzoquinone, chloroanisole, lead tetraacetate, palladium-black, and palladium-activated carbon.

Using the substance of formula (Ill) above as a starting material, the following method 2
But it can be done.

2) Method 2 (■) (%II)' (IX) (X) (XI) (XI
) <xm> (XIV
) (XV) In the formula, 1 person e R1e R1e R1e R4e Melon' has the same meaning as above. R11 and Rlm are each a hydrogen atom, unsubstituted and substituted alkyl groups, and amine7
group, a 5- to 7-membered heterocyclic group containing an S1 element,
Alternatively, R11 and R4g together form a 6- to 7-membered heterocyclic group together with the adjacent nitrogen atom. H/ is a methyl group.

9. An alkyl group having 1 to 6 carbon atoms such as an ethyl group; Boc is a tert-butoxylponyl group, Xl-Xs and X are halogen atoms.

It represents a group that forms an acid by bonding with a hydrogen atom, such as a methanesulfone group or a 4,6-dimethylbilimidinylmercabuto group, or one that is excellent as a leaving group.

Compound (Ill) to compound (■) and ([X)'
How to get T-T
Chemistry Society (D, A, Littlea)
nd D., L. Wesblat, J. Am., Chem.
, 9oc, 69, 2118 (1947).

Solvent #i, xylene, toluene, etc. used in the method of synthesizing compound (■) from compound (In),
Preferred is xylene. This reaction temperature is 50-15
It is carried out at 0C, preferably 90-100C. Generally, it is completed in 1 to 12 hours. The alkyl nitroacetate is used in an amount of 1 to 3 equivalents.

The solvent used in the method for synthesizing compound (IX) from compound (Vl) is preferably a mixed solvent of water and a polar solvent such as methyl alcohol or ethyl alcohol.

The reaction temperature is 10 to 120C, preferably <6
It is 0-80C. Generally, the process is completed in 10 to 120 minutes. Iron powder tit to 10 equivalents are used, and hydrogen chloride is used in an amount of 1 to 20 equivalents. Further, metal such as zinc may be used instead of iron powder, or reduction with hydrogen may be performed in the presence of a catalyst such as Raney nickel or palladium-activated carbon.

What is the method for synthesizing compound (X) (XI) from compound (IX)?

Gerhard Wolff, Felix φ Timorkovsky, Archib Peer Pharmacy (Gerhard
Wolf and Fe1ix Zymalkows
ki, Arch.

Pharm, ), 27? , 309 (197S) f for reference.

The solvent used in the method of synthesizing compound (X) from compound (LX) is an organic solvent such as ethanol or benzene. This reaction temperature is 50-150C,
Generally, it is completed in 1 to 12 hours.

The solvent used in the method of synthesizing compound OQ) from compound (X) is methanol and ethanol.

Water may be used, preferably water. This reaction temperature is 50
It is carried out at ~120C and is generally completed in 10 minutes to 2 hours. As a reaction catalyst, an acid such as hydrochloric acid, sulfuric acid, p-toluenesulfone@, etc. of 10 to 100 a-i is used.

The method for obtaining compound (■) from compound (XI) is described by T. Nakagawa, K. Kuroiwa, and K. Narita.

The Chemical Society of Japan (T, Nakagawa).

K,Kuroiwa, K,Narita, Y,Is.
owa, Bull, Chern.

Soc, Japan, ), 1269.46 (197
Please refer to 5). The solvent used in the method for synthesizing compound (■) from compound (XI) is an organic solvent such as chloroform, methylene chloride, tetrahydrofuran, or dimethylformamide.

The reaction temperature is 0 to 100C, generally 1 to 4
It will be finished in 8 hours. In order to neutralize HX, 'i of compound (XI), a tertiary amine such as triethylamine or N-methylmorpholine is used. Also.

As a method for completely introducing tertiary-butoxycarbonyl groups (Boc groups), a Boc-forming agent such as Boc-azide may be used. Alternatively, other amino group-protecting groups such as benzyloxycarbonyl may be used in place of the Boc group.

A method for obtaining compound (XII[) from compound (Xll) is described in E. Brand, BF Ellanker, H. Sachs, J. Boratnick, Journal of American Chemistry Nos.
and,B,F,ErIanger,H,5ack
s, J.

Po1athick, J. Am. Chem. Soc.
), 73, 5510 (1951)'i.

Solvent #'i used in the method of synthesizing compound (Xll) from compound (Xll) is alcohol such as methanol or ethanol, or water. This reaction temperature is Ω~8
It is carried out at 0C and is generally completed in 1 to 48 hours. Sodium hydroxide is used in an amount of 1 to 5 equivalents. Alternatively, potassium hydroxide or the like may be used in place of sodium hydroxide.

Citric acid and acetic acid are used as acids to neutralize alkali.

The method for obtaining compound αIV) t- from compound (XII['') is.

G.D. Anderson, J.E. Zimmerman, F. Callahan* '/Yaf/', Op American Chemistry Society
Anderson, J.E., Zimmer-mann;
F. Ca1lahan.

J, Am, Chem, Soc, ), 85.3039 (
1963)'. The solvent used in the method for synthesizing compound α■) from compound (XII[) is chloroform.

Methylene chloride, dioxane, tetrahydrofuran.

An organic solvent such as dimethylformamide. The reaction temperature is -20 to 100C, and generally 10 minutes to 48℃.
Finish in time. As a method for amide bond formation reaction, N
- It was carried out by the active ester method using hydroxysufushiimide. Usually 1 to 5 equivalents of N-hydroxysufushiimide are used.

Sodium hydroxide is used in an amount of 1 to 3 equivalents. Also.

As other methods, #L chloride method, dicyclohexylcarbodiimide method, mixed acid anhydride method, etc. may be used.

The method for obtaining compound (XV) t- from compound α■) is G-/”7”! J. Anderson, K. McGregor, Journal of the American Chemistry Society (G., W. Anderson,
A, C.

McGregor, J, Am, Chem, 8oc,)
, 79, 6180 (1957) All references. The solvent used in the method for synthesizing compound (Xv) from compound (X) is ethyl acetate and dioxane.

This reaction is carried out at a temperature of 11-20 to 100C and is generally completed in 10 minutes to 5 hours. The hydrochloric acid used is 1-2
It is 0 equivalent.

In addition, trifluoroacetic acid and hydrogen bromide are substituted for hydrochloric acid.

Fluorinated water, methanesulfonic acid, etc. may also be used.

A method for obtaining compound (I) from compound (XV) is described in Michael Cain et al., Journal of Medicina.
J*Med-Chem, 1081.25 (1982
) T - Used as a reference.

18 The solvent used in the method for synthesizing compound (I) from compound (XV) is an organic solvent such as benzene, toluene, xylene, dioxane, and tetrahydrofuran. Elemental sulfur is generally used in an amount of Fi 1 to 50 equivalents, preferably 15 to 25 equivalents.

The reaction temperature is 50 to 150C, preferably 1
00-120C. Generally, it will be completed in 1 to 7 days.

Mayu, another method is dichlorodicyanobenzoquinone,
Chloranisole, lead tetraacetate, palladium-black, palladium-activated carbon may also be used.

As a method for obtaining compound (I), 18 of the above formula (IX)
Synthesis may be performed from the compound by the route shown in Method 5 below.

3) Method 3 (IX) (XVD circle (X■) (X■) (XX) As another amidation method, an ester may be directly converted into an amide according to method 4 below.

4) Method 4 (I) In this case, a catalyst such as phenyllithium may be used.

Furthermore, the compound represented by the general formula (I>) can be in the form of an acid or base addition salt that is acceptable for mulberry embedding.

'As an acid addition salt that is acceptable for medical implantation.

Examples include inorganic acids such as hydrochloric acid, sulfuric acid, and phosphorus;
1)-) Acid addition salts with organic acids such as luenesulfonic acid and maleic acid can be mentioned. 7t.

Examples of base addition salts include sodium hydroxide.

Base addition salts with inorganic bases such as calcium hydroxide, or organic bases such as ammonia and triethylamine can be mentioned.

When the compound of the present invention is administered to humans for central nervous system diseases, it is administered orally or by intravenous injection. The dosage is 6yc, 6to to 500Ili per day for adults, divided into 1 to 3 doses.

Is the administration period daily for several days to 6 months?

The daily dosage and administration period may vary depending on the patient's condition.

In addition, 1. Compound #-i of the present invention may be used in combination with other drugs depending on the patient's condition.2. Used together.

(Example) Hereinafter, the present invention will be explained in more detail with reference to Examples.
The present invention is not limited to this.

Example 1 1-(Benzothieno(2,3-c)pyridine-3-carbonyl)-piperidine was obtained by the following method.

A small piece of sodium metal is added to 700111 t of dry dioxane, and 50 t of acetaminomalonic acid diethyl ester is added at room temperature, and the mixture is refluxed day and night. 52.5 f of 3-chloromethylbenzo(5)thiophene was added to the reaction solution, and the mixture was further refluxed for 1.5 days. After turning, 20 ml of methanol was added and stirred for 30 minutes at room temperature. After filtering off the insoluble matter and concentrating the P solution under reduced pressure, it was purified by silica gel column chromatography (chloroform) to obtain ethyl α-acetamino-α-carbetroxy β-(3-benzo(
5) Thiophene)-propionate 30. ．． 5 t (
Yield 47t) t-obtained 7t.

IR(ν, crrl-”)3275,1740,1
640°ax 151 O NMR (δ, CDC/4) 1.30 (t,
J=6Hz, 6H).

1.95 (s, 3H), 3.67 (s, 2H), 4.1
7 (q, J=6Hz, 4H), 6.50-8.00 (m
, 5H) Ethyl α-acetamino-α-carbetroxy β-(5-benzothiophene)--yropione)
Add 30.5 t of mep)-250 dK, dissolve the solution in 13.45 fft of sodium hydroxide and 50011 It of water, and add to the methanol solution, and reflux for 2 hours. After the reaction, methanol was distilled off under reduced pressure, and the aqueous solution was diluted with concentrated hydrochloric acid.
After reducing the temperature to H1.0, the mixture was extracted twice with 300% chloroform. After drying the chloroform layer with magnesium sulfate, the bath medium was distilled off under reduced pressure to obtain 16.757 α-7cetamin-α-carboxy-β-(3-benzyl-thiophene)-propionic acid (yield 65%). ) IR(νmax, cr!1-凰) 1730,
1 635.154ONMR (δ, CDCl5)1.
87 (s, AH), 3.45 (m.

2H), 7.17-8.00 (m, 5H), 943 (s
, 2B) α-acetamino-α-carboxy-β-(3
-benzo(5)thiophene)-furopionic acid so t
Add 200 dK of water and reflux for 3 hours. The reaction temperature was returned to room temperature, 15.6 t of sodium hydroxide was added little by little, and the mixture was refluxed for 2.5 days. After the reaction is complete, return to room temperature.

It was washed with OA form'100-. The aqueous layer was brought to JI) H4.0 with concentrated hydrochloric acid, and after being left in a refrigerator for one night, the precipitated sulfur α-amino-(5-benzo(5)thiophene)-propionic acid was collected in an oven and dried under reduced pressure. Yield 16.02 (
Yield 74 h) IR (ν, crIt″″1) 1590, 1420,
1020ax NMR[δe D@O# (CHl)mSt(CH
,)35O1Na]5.00~4.00 (m, 3
H), 7.20-8.00 (m, 5H) 640 ml of dry methanol is OCK cooled and thionyl chloride 20.
8- Gradually add. Stir in OC for 30 min and add α-amino-(3-benzo(5)thiophene)-propion@
16. Of f OCf7J [l, stir for 50 minutes and mix. After stirring at room temperature for 2 days and removing methanol under reduced pressure,
150 g of IJum water (5% hydrogen carbonate) was added, and the mixture was extracted with 500 g of methylene chloride. The methylene chloride layer was dried over Wt magnesium chloride, and then evaporated under reduced pressure to obtain α-amino-(5
15.8 ft of -benzo(5)thiophene)-furopionic acid methyl ester was obtained. (Yield 93%) IRCy, cm″″1. )2975.1-750
．． 1180ax NMR (δ, CDCM) 3.0-5.57 (m,
3H), 4.07(s, 3H), y, 17-8
．． 00 (m, 5H)α-amino-(3-benzothiophene)-clopionic acid methyl ester 15.8 f
F400- is dissolved in ethyl acetate, and a solution of 12.769 p-toluenesulfonic acid monohydrate in ethyl acetate is gradually added while stirring at OC. Collect the precipitated crystals by F.

Clean crystal 't6 with diethyl ether. α-Amino-
(5-benzo(6)thiophene)-clopionic acid methyl ester/p-toluenesulfone a [24,90t. (Yield 91%) IR (cimax@c1r1-')'3050,2940
,1738°15?0,150 α-amino-(3-benzo(5)thiophene)-clopionic acid methyl ester/p-toluenesulfonate4.
Add Oap to a mixed solvent of 25+d of water and 25-d of methanol, and then add 35% of formalin bath solution 1.3-d.
The reaction mixture was refluxed for 4 hours, concentrated to about half, and left overnight at room temperature. The nine precipitated crystals t-F were collected and dried under reduced pressure to give 1
,2,3.4-tetrahydro-benzo(5)cheno[2
,3-c]pyridine-3-carboxylic acid methyl ester.
5.947 p-)luenesulfonate was obtained (yield 93
blood). Furthermore, add 30-1 chloroform and 50 td of water.
Adjust the pH of the aqueous layer to 9-10 with sodium hydrogen carbonate,
Extract the mixture into the chloroform layer. The chloroform layer was dried with Glauber's salt, and after distillation under reduced pressure, 1, 2. S,4-tetrahydrobenzo(6)cheno(2,3-c]pyridine-5-carboxylic acid methyl ester 2,329 was obtained.

In(ν(11Bzet7P1-')5500.173
0,1460°NMR (δ, CDC45) 2.18
(bs, IH), 5.02 (m.

2H),! i, 85 (m, 4H), 4.23 (bs, 2
H), 7.66 (m, 4B) Mass<m7e> 247CM+), 187.16o
, 128°115.94 1.2,3.4-tetrahydrobenzo(5)cheno[2
゜3-c] Pyridine-3-carboxylic acid methyl ester 1
4.64 f xylene 900- and dioxane 100-
Sulfur powder dissolved in a mixed solvent of 411 gold.

Reflux for 5 days. After the reaction was completed, the solvent was distilled off under reduced pressure.

The residue is washed several times with methanol on a glass filter. Methanol was distilled off under reduced pressure, the residue was dissolved in chloroform, and mixed with 5% aqueous citric acid solution and 5% hydrogen carbonate.
Wash with Jum water solution and saturated saline. The chloroform layer was dried with Glauber's salt, and the chloroform was distilled off under reduced pressure. Recrystallization (from chloroform-ether) gave 12.49 (yield: 86%) of benzo(5)cheno[2,3-c]pyridine-3-carboxylic acid methyl ester.

IR (shimaX, t-1n""1) 2950.172G
, 1600° 52O NMR (δ, CDCt,) 4.15 (s, 3
H), 7.50-8.50 (m, 4H), 8.91 (
s, 1H),? , 33(s, 1H)Mass(m/
e) 245 (M”) 212j184 benzo(6)cheno(2,3-c]pyridine-3-carboxylic acid methyl ester 12.169 was dissolved in 200 dK of methanol, 55 d of IN sodium hydroxide-methanol solution was added, and the mixture was dissolved for 50 minutes. After returning to room temperature, leave it in a refrigerator overnight and count the precipitated crystals.Suspend the crystals in water, adjust the pH to 2 to 5 with 1N hydrochloric acid, and then cool at room temperature. Stir all day and night. Count the precipitate and collect benzo(6)cheno[2,5
-C]pyridine-3-carboxylic acid 10.2 t (yield 88 ts)'5r: Obtained.

IR (1m3) (scrrl-”) t 7QO, 11
600, 1570.

55O NMR (δ, d-DMSO) 7.60-7.90 (
m, 2H).

8.10-8.40 (m, IH). 8.60～
8.80 (m, IH).

9.07 (s, IH), 9.51 (s,
IH) Mass (m/e) 229 (M+) 185, 15
8,140benzocheno(2,3-c)pyridine-5
- 458 mg of carboxylic acid and piperidine f70 da were dissolved in dimethylformamide 51 at, and under water cooling, DPPA (
660 η of diphenylphosphoryl azide was added dropwise, followed by the addition of 335 μt of triethylamine.

Stir overnight at room temperature. After the reaction is completed, the reaction solution is diluted with ethyl acetate, washed with an aqueous solution of citric acid, sodium bicarbonate, and saturated saline, and the ethyl acetate layer is dried with sodium sulfate. The ethyl acetate layer was evaporated under reduced pressure, the residue was purified by silica gel thin layer chromatography (solvent: chloroform), and then recrystallized from chloroform-ether.
1-<benzo(5)cheno(2,3-C)pyridine-3-carbonyl)piperidine 230In9 (yield 8
5%).

IR(max, cm-”>2950.2850,16
50゜1600.14130.144O NMR (δ, CDC1,) 1.50-2.00 (M,
6H), 3.40-4.15 (br, 4H),
7.50-7.80 (m, 2H), 7.90-8.
10 (m, IH), 13.15~8.40 (m
, IH), 8.42 (s.

IH), 9.14 (s, IH) Mass (m/e) 2516 (M+), 212,185
, 113° Dibenzo(5)cheno[2,
3-c]pyridine-3-carboxylic acid as a starting material,
1-(Benzocheno(2,3-c)pyridine-3-carbonyl)-2,6-dimethylhyhelicine, 4-(benzocheno(2,3-c)pyridine-3-carbonylmorpholine) a , (Table 1-10 Table 1-21 Table 1 Table 1-1 Cloth 1-2 Table 1-3 Example 2 Hexahydro-1-(benzo(6)cheno[:2.5-
C] pyridine-3-carbonyl)-1H-1,4-diazepine hydrochloride could be obtained by the following method.

benzo(5)cheno(2,3-c)pyridine-6-carvone gi11458Ing and hexahite 0-IH-1
,4-diazepine 200In9 was dissolved in 5 ml of dimethylformamide, and diphenylphosphoryl azide (
DPPA)660η was added dropwise, followed by hexahydro-2
Add 200 Ing of H-1,4-diazepine and stir at room temperature.
Stir at night. After the reaction is completed, water and sodium hydrogen carbonate are added to adjust the pH to 10, and the mixture is extracted with 507 ethyl acetate.

After washing with saturated saline, drying with Glauber's salt. After ethyl acetate was distilled off under reduced pressure.

Silica gel thin layer chromatography (developing solution, chloroform:methanol:ammonia water, -90:10:2)
Purify it. Further, the product was dissolved in ethyl acetate 20-1. Add 1.5 liters of SN hydrochloric acid-ethyl acetate solution, and collect the precipitated crystals using a furnace.

Yield 520 trip (yield 74 trip) IR (maximum
,01-') 5500,2900,2750.162
0゜1580 142O NMR (δ, d-DMSO) 1.90 F2.2
0 (br, 2H).

3.10A-3,40 (br, 8B), 7.60 hair, 90 (m, 2H), 8.10-8.40 (m, I
H18, 50, 8, 80 (m, IH), 8.85 (S
, IH), 9.50 (S, IH) Mass (m/e)
311 (M+)2', 2. ras, 99 using benzo(6)cheno(2,5-c ]]pyridine-3-carbonyl as a starting material, 1-(benzo(5)cheno(2,3-c)pyridine-3-carbonyl) -piperazine, 1-(benzomount)cheno(2,3-c
) Pyridine-6-carbonyl)-3-methylbiperazine, 1-(benzo(5)cheno(2,5-〇)pyridine-3-carbonyl)-4-methylpiperazine, hexahydro-1-(benzomount)cheno(2e5- C) Pyridine-3-carbonyl)-1H-4-methyldiazepine was obtained. (Table 2-1, Table 2-21 Table 2-5) Table 2-1 Example 3 N-(2-teriminoethyl) -Benzo(6)cheno(2t
'-c) Pyrylan-5-carboxamide hydrochloride was synthesized by the following method.

Benzo(6)cheno(2,5-c゛)pyridine-3-carboxylic acid 4879 synthesized in Example 1 and benzyloxycarbonylethylenediamine hydrochloride (Z-NHC,) 1
4N)(1·HCt) 508 rng was suspended in 10 wt of dimethylformamide (DMF), 307 μ of triethylamine was added, and the mixture was cooled to OC. Subsequently, 660 μt of synenylphosphoryl azide (DPPA) and 356 μt of triethylamine were added, and the reaction solution was stirred at room temperature for 1 hour under water cooling at night. The reaction mixture was diluted with 200 μl of ethyl acetate, and diluted with 5 cs citric acid aqueous solution and 5 cs saturated aqueous sodium bicarbonate solution. After washing with saline.

Dry with sodium sulfate. Ethyl acetate was distilled off under reduced pressure,
The residue was dissolved in 10-acetic acid, 511 It of 25-thiobromide-acetic acid solution was added, and the mixture was stirred at 50C for 2 hours. After diluting the reaction solution with 200 d of water, it was washed twice with ether. After adjusting the pH to 11 with sodium hydroxide, the mixture was extracted three times with chloroform and dried over sodium sulfate. Chloroform was distilled off under reduced pressure, and the residue was diluted with 100% ethyl acetate.
1N hydrochloric acid/ethyl acetate was lowered for 2td@, the precipitated crystals were collected, and 230μ of N-(2-aminoethyl)-benzo(6)cheno(213-C)pyridine-3-carboxamide hydrochloride (harvested) was collected. A rate of 37 cm) was obtained.

IR (ν, plow-1) 5320, 2950, 2900°ax 1650.1520, 1240, 760, 74ONMR
(δ, da-DMSO) 2.90 5.40 (
m.

2H), 5.50 P-3,90 (m, 2H), 7.
50 hair, 90 (m, 4B), 8.10--8.3
0 (m, 1H), 8.50 he 8.7 0 (
m, 2H), 9.30(s, 11(),
q, 5 0 (s, 1 H) Mass (m/e)
271(M), 252,242,229° Also, by performing the same operation as above using penzyloxycarbonyltrimethylethylenediamine instead of benzyloxycarbonylethylenediamine, N-(5 -aminopropyl)-benzo(ro)cheno(2e3-C]]pyridine-3-carboxamide hydrochloric acid was obtained.

Also, by using ethylidene inglobylamine in place of methylidene isopropylamine and performing the same operation as above, N-(z-aminoethyl)-4-methylbenzo(6)cheno(2,!l) -c: ) pyridine-3
-Carboamide hydrochloride was obtained.

Also, in the same manner as above, using 5-chlorobenzo(6)thiophene instead of benzo(6)thiophene,
N-(2-aminoethyl)-6-chlorobenzo(6)cheno(2,5-e)pyridine-3-carboxamide hydrochloride was obtained.

In addition, using benzo(6)furan instead of benzo(6)thiophene and using the same method as above, N-(2-minoethyl)-benzo(5)furano(2,,5-c)pyridine-3 - Obtain carbamide hydrochloride.

In addition, during the cyclization reaction, benzaldehyde was used instead of formalin, the pH was adjusted to 2 with hydrochloric acid, and Eri, N-(2-aminoethyl)-1-phenylbenzo(6 )cheno[,3-C)pyridine-3-
Carbamide hydrochloride was obtained.

Below, the yield and yield of the final step are shown in Table 5-1.

The results of the instrumental analysis are shown in Table 3-2.
) Example 4 Benzo(6)cheno(2,3-e)pyridine-3-carboxamide was obtained by the following method.

Benzo(6)cheno[2,5-〇]pyridine-5-carboxylic acid ethyl ester 487In9 ethanol 50-
Ammonia gas was slowly blown into the solution for 15 minutes while cooling with water. After standing at room temperature for 3 days.

The precipitated crystals were collected as P and benzo(6)cheno(2,3-
C) Pyridine-3-carboxamide 410q (yield 89-
) was obtained.

IR(y, am-') 3400.3280.51
60°ax 16B5, 1600, 1550, 1420, 1360,
72ONMR (δ, d@-DMSO) 7.50 to 7.
90 (m, 28).

8.00 to 8jO (m, IH), 8.50 to 8.8
0 (m, IH).

a, 9s (s, 1H), 9.50 (s, IH) Mass
(m/e) 227 (M), 185, 158,
140 Example 5 Benzo(6)cheno(2,3-1)pyridine-3-carboxylate was obtained by the following method.

Dry benzo(5)cheno[2,3-c]pyridine-3-carboxylic acid ethyl ester 515 #7 with methanol za
ntrtcm was dissolved, and 252 #j of hydrazine dihydrochloride and 700 μtf of triethylamine were added. Stir for 2 days,
After refluxing for a period of time, the temperature was returned to normal and the precipitated crystals kF were collected.
Benzocheno[2,5-c]pyridine-3-calphohydrazide 169In9 (yield 30%) was obtained.

IR('y(1B)(tcrn-')3400.169
0,1570.

1320.74O NMR (a, d, -DMSO) (@tR salt) 5
．． 80-7.20 (br, 3H), 7.50-7
．． 90 (m, 2H), 8.10-8.40 (m,
IH), 8.60-8.80 (m, IH), 9
．． 10 (s, IH).

9.50 (s, IH) mass (m/e) 243,212,184,140 Example 6 N-(2-dimethylaminoethyl)-benzo[
2,3-c]pyridine-3-carboxamide hydrochloride was obtained by the following method.

Benzene (2,3-c)pyridine-3-carboxylic acid 487 Ing and N,N-dimethylethylenediamine 2
12~'! Dissolved in i-dimethylformamide 104,
followed by DPPA660#,) ethylamine 535μt
was added and stirred overnight at room temperature. The reaction solution was diluted with 10 ethyl acetate.
7. Dilute with 0- and wash twice with 1N aqueous sodium hydroxide solution. Dry with sodium sulfate. After distilling off ethyl acetate under reduced pressure, the residue was subjected to silica gel column chromatography (ethyl acetate: ethanol: aqueous ammonia = 10:
3:1) Refined friend. Further, it was diluted with 50 mL of ethyl acetate, 2 m of 1N hydrochloric acid and ethyl acetate was added, and the precipitated crystals were collected.
Benzocheno[2,3-c]pyridine-3-carboxamide salt 570#7 (yield: 85%) was obtained.

IR (νm; 1z * Cm-1) 3500, 2950
,16.60°1400.142G,1320,101
0,760,73ONMR (δ, d, -DMSO)
2.90 (s, 6H), 3.00-5.40
(m, 2H), 3.50-5.80 (m, 2H)
, 7.60-7.90 (m, 2H), 8.20-8.
40 (m, IH), 13.60-8.80 (m, IH)
, 9.10 (s, IH), 9.50 (s, 111) M
ass (m/e) 299 (M+), 229, 212,
184゜Example 7 N-Methyl-benzochlorocheno[2,3-c)pyridine-
3-carboxamide was obtained by the following method.

Benzocheno[2,3-c]pyridine-5-carvone r! i! 459mg and 162~ of methylamine hydrochloride are suspended in 5d of dimethylformamide, and 307μ of triethylamine is added. Under ice cooling, DPPA 660~. Subsequently, 535 μt of triethyl aban was added dropwise, and the mixture was stirred for 3 hours. After diluting the reaction solution with 5 d of ethyl acetate and performing liquid separation according to a conventional method.

The product was purified by silica gel thin layer chromatography (chloroform-methanol = 30:1), and further recrystallized from ethyl acetate-hexane.

434 days of N-methyl-benzo(5)cheno(2,3-c)pyridine-3-carboxamide (yield: 89 days) was obtained.

IR (shimaX 100-') 3400, 3300, 305
0°2950.1660,1520,1320.125
0,770°73O NMR (δ, CDCts) 3.05 (d, J=5Hz
, 3H).

7.50~7.80 (m, 2H), 7.80~
8.00 (m, IH).

8.00-8.20 (m, 2H), 8.80 (s, IH
), 8.90 (s.

IH) Mass (m/e) 242 (M+), 215, 185,
140 again. Ethylamine-p-)luenesulfone [17' lobilamine hydrochloride,
By using n-hexylamine hydrochloride or 4-aminobutyric acid ethyl ester hydrochloride41), N-ethyl-benzo(6)cheno[2,3-cJpyridine-5
-Carboamide, N-propyl-benzo-benzo-[2,
3-c]pyridine-3-carboxamide, N-hexyl-
Benzocheno[2,3-c:]]pyridine-3-carboxamide 4-(benzocheno(2,5-c)pyridine-localboamino)-butyric acid ethyl ester t- was obtained.

Table 4-1 shows the reaction conditions.

Table 4-1 shows the reaction conditions, yield, and yield.Table 4-2 shows the data of instrumental analysis.

Example 8 4-(benzo(5)cheno[2,5-c]pyridine-3
-carboamino)-butyric acid was obtained by the following method.

4-(benzo(5)cheno(2,3-c)pyridine-3
-Carboamino)-butyric acid ethyl ester (3.429) was dissolved in 50% of ethanol, 6N aqueous NaOH was added, and the mixture was refluxed for 50 minutes. The ethanol was removed under reduced pressure, water was added to the residue, the pH was adjusted to 3 with citric acid, and the mixture was extracted twice with chloroform. The chloroform layer was dried over sodium sulfate and then concentrated under reduced pressure.
3-c,)pyridine-3-carboamino)-butyric acid 2.5
57 (yield: 81 cm) was obtained.

IR (cmBx, cm-') 3550, 5050.29
00°2850.1700.1!40,1020,79
0. ．． 74ONMR(a,ds-DMSO)'1
．． 70-2.10 (m, 2H).

2.10A-2,50 (m, 2H), 5.5Q ~3.
60 (m, 2H).

7.50-7.90 (m, 2H), 8.00-8
．． 20 (m, IH).

8.30-8.80 (m, 2H), 9.00 (s, IH
), 9.30 (s, IH) Mass (m/e) 314 (M”), 255,241,
212゜185.140 (Effects of the Invention) The compounds according to the present invention exhibit the following specific anxiolytic effects and learning-improving effects.

Using Wistar male rats (6 weeks cold), Forkel
G.R., Bear B., Claw Day Day.
4-,? I: I7 Armacology (Vogel J, R
,, Beer B,, and C1ody D, E,
.

Psychopharmacologia), 1
-7, 21 (1971).
Link conflict test (Water eye ck c
onflic test) using f.

The anxiolytic and learning-improving effects of this compound were investigated.

This test used nine rats for a long time, and an electric shock was applied every time the rats drank water.
This method examines the effects of drugs on anxiety.

(1) Before the anxiolytic effect test, rats were allowed to hydrate for 24 hours and allowed to drink water. , 4
Drugs were administered ~5 hours later, and the study was started after a treatment period. The number of shocks is the number of shocks the rat receives after it starts drinking water.
It is the number of electric shocks per minute, and it is said that if you drink water, you will receive an electric shock! This indicates whether or not to suppress A (anxiety).

In other words, the number of shocks will increase.

This means that the anxiolytic effect is enhanced.

Table 5 shows the values when drug-free rats are set as 100. , (n±5) (21 Learning improvement effect) This test system was conducted at the same time as the measurement of anxiolytic fF- in +1), and measured the latency time until the rat started drinking water after hydration. It is something to do.

It can be concluded that the longer the latency time, the stronger the learning improvement effect. Table 6 shows the values when the average value of rats without drug administration was set as 100. (n=5) The original ornament significantly lengthened the a-hour time r&, indicating that it had a learning-improving effect.

This indicated that this compound could be effective in alleviating butt anxiety and anti-dementia.

(3) Utility of the present invention Regarding the anxiolytic effect of L7, a comparison was made with the prior art. β-carboline-3-ethyl ester (abbreviated as β-CCE), which is a representative compound of JP-A No. 56-43283, and 6-chloro-1, which is a representative compound of JP-A No. 50-2510.
,2,3,4-tetrahydro-benzocheno[2,3-
c] Pyridine (abbreviated as C-1).

Benzocheno[2,3-c]pyridine-5-carboxylic acid ethyl ester (abbreviated as A-1), which is a representative compound of JP-A No. 61-256779, and N, which is a representative compound of the present invention.
-(2-aminoethyl)-benzocheno[2,3-c]
A comparative test was conducted on the anxiolytic effect of lysine-3-carboxamide hydrochloride (abbreviated as A-2). The test method was exactly the same as that for +L) anxiolytic effect. The test results are shown in Table 7.

Table-7 Anxiolytic effect Control
1 0 0.0 ± 1 4.5 (N
=5) β-CCE 10 i, v, 98
．． 9±27.0 (N=5)C-110i,v,
112j±56.6 (N=5)A-110i,v,
1254±28.9 (N=5) A-210i,v,
2.0±27.0 (N=5)"Cont
rol 100.0±14.5 (N
=5) β-CCE 40 p, o, 82.
9±20.0 (N=5) (-140p, o, 1
04.3±28.6 (N=5) A-140p, o,
117.1±25.7 (N=5) A-240p
, o, 514.5shi51. ．． 6 (N = 5)
"**p(0,05 Table 7 From the test results of anxiolytic effect, 1 N-(2-
(aminoethyl)-benzocheno[2,5-C)pyridine-3-carboxamide hydrochloride ri There is a significant difference compared to the conventional technology, and it is thought that it will be sufficiently useful.

Claims (1)

[Claims] The following general formula (I) ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, A is a sulfur atom or an oxygen atom, and R_1 is an unsubstituted or substituted amino group or hydrazino group. , a 6- or 7-membered heterocyclic group having at least one nitrogen atom,
R_2 and R_3 represent a halogen atom, an unsubstituted or substituted alkyl group, or an aryl group, m is an integer of 0 to 2, n is an integer of 0 to 4, and when m and n are 2 or more, R_2 and R_3 may be the same or different. ) Pyridine derivatives and their salts.