JPS63225358A - Cyclopenta(b)quinoline derivative - Google Patents

Abstract

NEW MATERIAL:The cyclopenta[b]quinoline derivative of formula I (R<1>-R<3> are H at the same time and at least one of R<4>-R<6> is F, CF3, alkylthio, OH, phenyl, etc., and the others are H, halogen, CF3, alkyl, etc., or at least one of R<1>-R<3> is alkyl, hydroxymethyl, phenyl, etc., the other R<1>-R<3> are H, alkyl, cycloalkyl, etc., and R<4>-R<6> are H, halogen, CF3, alkyl, etc.; R<7> is H, alkyl, aralkyl, etc.) or its pharmacologically permissible acid addition salt. EXAMPLE:9-Amino-3-methyl-2,3-dihydro-1H-cyclopenta[b]quinoline. USE:A remedy for senile dementia. It has excellent action to inhibit acetylcholine esterase. PREPARATION:The compound of formula I can be produced e.g. by reacting a compound of formula II (R<8>-R<10> are H, halogen, CF3, etc.) with a compound of formula III.

Description

DETAILED DESCRIPTION OF THE INVENTION (Field of Industrial Application) The present invention relates to novel cyclopenta[b]quinoline derivatives and pharmaceutically acceptable acid addition salts thereof.

More specifically, the present invention relates to cyclopenta[b]quinoline derivatives and pharmaceutically acceptable acid addition salts thereof, which have excellent acetylcholinesterase inhibitory activity and are extremely useful as therapeutic agents for senile dementia.

[Prior art]

In the Aging Plain, a decrease in acetylcholine in the brain is associated with senile dementia.
e Aging Braln), Berlin (Berl)
In), 1982, 140th True Review. Additionally, using an acetylcholinesterase inhibitor,
Attempts are being made to treat senile dementia by increasing acetylcholine in the brain, for example using physostigmine, a typical acetylcholinesterase inhibitor.
, Dan, 397 (197B).

Furthermore, it is reported in JP-A-61-148154 that aminoacridine' derivatives have an acetylcholinesterase inhibitory effect and are effective in treating Alzheimer's disease.

In addition, U.S. Patent No. 3,232,945 states that aminoacridine derivatives have central stimulating effects, anesthetic effects,
It has been reported to have sedative effects. In addition, 9-amino-1,2,3,4-tetrahydroacridine is an inhibitor.
This compound was used as a treatment for drug overdose, but
Neurobiology has recently been considered for use in combination with lecithin and intravenous injection for the treatment of Alzheimer's disease.
Aging) 4.139 (1983).

(Problems to be Solved by the Invention) Acetylcholinesterase inhibitors are thought to be able to increase acetylcholine in the brain, so they are thought to be useful therapeutic agents for senile dementia. No acetylcholinesterase inhibitor has been found, and it is hoped that one will appear.

The purpose of the present invention is precisely in this regard, and is to provide a novel compound that is extremely effective as a therapeutic agent for senile dementia and has fewer side effects.

[Means for solving problems]

The present inventors have conducted various studies with the aim of developing a therapeutic agent for senile dementia, and found that the following general formula (1)
), which has an excellent acetylcholinesterase inhibitory effect, exhibits this effect orally, and has few side effects; therefore, it is an extremely useful compound as a therapeutic agent for senile dementia. They found that this is the case, and after further research, they completed the present invention.

That is, the gist of the present invention is the general formula [wherein R', R, R3, R4, R5 and R& represent any of the following combinations of Φ to ■.

■R1, R8 and Rs simultaneously represent a hydrogen atom, and at least one (preferably one) of R4, R% and R- is a fluorine atom, trifluoromethyl group, lower alkylthio group, hydroxyl group, lower alkanoyl Represents an amino group, a nitro group, a phenyl group, or a phenyl group substituted with a halogen atom, a lower alkyl group, or a lower alkoxy group, with the remainder being a hydrogen atom, a halogen atom, a trifluoromethyl group, a lower alkyl group, a lower alkoxy group, Represents a lower alkylthio group, lower cycloalkyl group, nitro group, amino group, or lower alkylamino group.

■At least one (preferably one) of R■, R寞, and R3 is a lower alkyl group, a lower cycloalkyl group, a hydroxylmethyl group, a lower alkoxydimethyl group, a lower alkoxy group, a halogen atom, a phenyl group, or represents a phenyl group substituted with a halogen atom, a lower alkyl group, or a lower alkoxy group, and the remainder represents a hydrogen atom, a lower alkyl group, a lower cycloalkyl group, a lower alkoxymethyl group, or a lower alkoxy group, and R4, R4, and R6
are hydrogen atom, halogen atom, trifluoromethyl group, lower alkyl group, lower alkylthio group, lower cycloalkyl group, lower alkoxy group, nitro group, amino group,
It represents a lower alkylamino group, a lower alkanoylamino group, a hydroxyl group, a phenyl group, or a phenyl group substituted with a halogen atom, a lower alkyl group, or a lower alkoxy group.

R7 represents a hydrogen atom, a lower alkyl group, an aralkyl group, a dialkyl group, or a group represented by R"-Co- (wherein R is a lower alkyl group, a lower cycloalkyl group, an aralkyl group, a phenyl group, or a halogen atom) , represents a phenyl group substituted with a lower alkyl group or a lower alkoxy group, and the 2nd and 3rd positions represent a single bond or a double bond] [b) quinoline derivative [hereinafter referred to as the compound ( +)) and pharmaceutically acceptable acid addition salts thereof.

In this specification, each group represented by each symbol means the following.

That is, preferred examples of the halogen atom include fluorine atom, chlorine atom, bromine atom, and corona atom.

lower alkyl group, lower alkoxy group, lower alkylthio group, lower alkoxymethyl group, lower alkylamino group,
Examples of lower alkanoylamino groups include linear or branched alkyl groups of 04 or less, alkoxy groups, alkylthio groups, alkoxymethyl groups, alkylamino groups, and alkanoylamino groups, and more specifically methyl and ethyl groups, respectively. , n-propyl, isopropyl, n-butyl, 5ec-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,
5ec-butoxy, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, 5ec
-butylthio, methoxymethyl, ethoxymethyl, n-
Propoxymethyl, isopropoxymethyl, n-butoxymethyl, 5ec-butoxymethyl, methylamino, ethylamino, n-protoruamino, isopropylamino, n-butylamino, 5ec-butylamino, acetylamino, propionylamino, butyrylamino, Examples include isobutyrylamino. Examples of the lower cycloalkyl group include unsubstituted or lower alkyl-substituted cycloalkyl groups of C2° or less, and specific examples include cyclopropyl, cyclopentyl, cyclohexyl, and cycloheptyl.

Examples of the aralkyl group include aralkyl groups of C11 or less in which the allyl group is a phenyl group or a phenyl group substituted with a halogen atom, a lower alkyl group, or a lower alkoxy group, and more specifically, benzyl, phenethyl,
2-(4-methoxyphenyl)ethyl, 2-(4-fluorophenyl)ethyl, 2-(4-methylphenyl)ethyl, 3-phenylpropyl, 4-(4-fluorophenyl)butyl, 4-phenylbutyl, Examples include 2-naphthylmethyl. Examples of the dialkyl group include dialkyl groups having C2° or less in which the allyl group is a phenyl group or a phenyl group substituted with a halogen atom, a lower alkyl group, or a lower alkoxy group, and more specifically, 4,4-diphenylbutyl, 4,4-bis(4-fluorophenyl)butyl, 4.4-bis(4-methoxyphenyl)-butyl, 4.4-bis(4-methylphenyl)butyl, 3.3-diphenylpropyl, 2.2 -diphenylethyl, etc. can be exemplified.

Compound (1) can be converted into a pharmaceutically acceptable acid addition salt if necessary. Examples of the acids of pharmaceutically acceptable acid addition salts include citric acid, fumaric acid, maleic acid,
Examples include organic acids such as tartaric acid, or mineral acids such as hydrochloric acid, hydrobromic acid, nitric acid, and sulfuric acid. Further, the acid addition salt can be converted into a free compound by conventional means.

The compound (r) of the present invention is, for example, Tetrahedron Letters,
1277 (1963) or ActaChemica 5candin
avica), B, 33.313 (1979) or a method analogous thereto, but it is particularly preferable to use the method described in the above-mentioned Tetrahedron Letter or a method analogous thereto, i.e. , General formula (■): 1O [In the formula, R-1R9 and R1 are each a hydrogen atom,
Halogen atom, trifluoromethyl group, lower alkylthio group, lower alkoxy group, lower alkyl group, lower cycloalkyl group, hydroxyl group, nitro group, lower alkanoylamino group, phenyl group or halogen atom, lower alkyl group or lower alkoxy group A 2-aminobenzonitrile derivative (II) represented by ] representing a substituted phenyl group and a cyclopentanone derivative (III) represented by the general formula: [wherein R1, R*, and R1 are the same as above] The nitro group is reduced to an amino group if necessary, and the amino group is further alkylated or acylated to produce the compound →.

In the case of a compound in which at least one of R4, R% and R& is an amino group, lower alkylamino group or hydroxyl group, the amino group, lower alkylamino group or hydroxyl group is protected and then alkylated or acylated, Examples of the retaining group, which is preferably removed after the reaction is completed, include benzyloxycarbonyl group,
Examples include acetyl group, benzyi, ru group, etc.
Further, a compound in which at least one of R4, R% and R- is an amino group can be produced by alkylating or acylating the corresponding nitro form, and then reducing the nitro group.

In addition, by alkylating and acylating the compounds obtained in this way, R4, R8 and R&
A compound in which at least one of the following is a lower alkylamino group or a lower alkanoylamino group can be produced.

A compound in which at least one of R4, R1 and R1 in compound (1) is a nitro group is subjected to a reduction reaction to produce a compound in which the nitro group is changed to an amino group. Alkylating the compound thus obtained,
By acylation, R4, Rs and R
A compound in which at least one of 1 is a lower alkylamino group or a lower alkanoylamino group can be produced.

The reaction between the 2-aminobenzonitrile derivative (11) and the cyclopentanone derivative (nl) is preferably carried out in the presence of a Lewis acid or a dehydration condensing agent.

At this time, as the Lewis acid, anhydrous zinc chloride, anhydrous zinc bromide, anhydrous zinc wax, anhydrous aluminum chloride, tin tetrachloride, titanium tetrachloride, boron trifluoride/ether complex, etc. can be used, preferably anhydrous. Aluminum chloride, anhydrous zinc chloride, and boron trifluoride/ether complex can be used. The dehydration condensation side is preferably polyphosphoric acid (
PPA), etc.

Further, the reaction between the 2-aminobenzonitrile derivative (n) and the cyclopentanone derivative (III) is carried out in the presence or absence of a solvent inert to the reaction. Examples of such solvents include dimethylformamide, dimethylsulfoxide, xylene, toluene, etc.The reaction temperature is 50 to 200°C, preferably 120 to 170°C.
It is.

The reduction of the nitro group, if necessary, can be carried out by conventional means, and can be carried out particularly preferably by using iron-hydrochloric acid or the like.

Alkylation of amino groups can also be carried out by conventional means. For example, it can be carried out according to the method described in "New Experimental Chemistry Course Vol. 14 Synthesis and Reactions of Organic Compounds ■" page 1332 (Japanese Chemistry Complete Edition), or a method similar thereto.
In addition, as described in JP-A No. 61-148154, a strongly alkaline aqueous layer such as a 50% aqueous sodium hydroxide solution, an appropriate organic solvent such as dichloromethane or toluene, and a solvent such as tetrabutylammonium hydrogen sulfate are used. It can be carried out in a two-phase system containing a phase transfer catalyst.

Acylation of amino groups can also be carried out by conventional methods, such as a method of reacting with an alkanoyl halide in the presence of a tertiary amine such as triethylamine ("New Experimental Chemistry Course 14S Synthesis and Reaction of Organic Compounds", No. 1134Et ((
(Refer to the Chemical Society of Japan).

In addition, in the synthesis of the compound (RI), methylene moieties are grown on both sides of the carbonyl group, and asymmetric cyclopentanone derivative (I[) and 2-aminobenzonitrile derivative (n
) may yield two isomers, which can be separated using commonly used separation means, such as silica gel column chromatography.

Furthermore, the compound (1) of the present invention can also be converted into its optically active form according to conventional methods.

Of course, the compound (+) of the present invention includes such isomers and optical antipodes.

Compound (1) or its acid addition salt thus produced can be collected in any purity by appropriately using known means such as concentration, extraction, chromatography, reprecipitation, recrystallization, etc.

The compound (1) of the present invention and its acid addition salts have excellent acetylcholinesterase inhibitory effects on mammals such as humans, cows, horses, dogs, rats, and mice, and are also toxic and non-toxic. It has few side effects and is therefore extremely useful as a therapeutic agent for senile dementia, for example.

Compound (1) of the present invention and its acid addition salts can be administered orally or parenterally.

That is, it can be administered orally in commonly used dosage forms, such as tablets, capsules, syrups, suspensions, etc., or in the form of solutions, emulsions, suspensions, etc. can be administered parenterally in the form of an injection. It can also be administered rectally in the form of suppositories.

The appropriate dosage forms also include acceptable conventional carriers,
It can be manufactured by blending the active compound with excipients, binders, stabilizers, and the like.

Furthermore, when used in the form of an injection, acceptable laxation buffers, solubilizing agents, isotonic agents, etc. may be added.

Dosage and frequency of administration vary depending on symptoms, age, body weight, administration form, etc., but usually 1 to 50 doses per day for adults.
0■ can be administered once or in divided doses.

Examples of the compound (+) and its pharmaceutically acceptable acid addition salts include those listed in Tables 1 and 2 below (the compounds shown in Table 1 have a single bond between the 2nd and 3rd positions). Compounds, Table 2 are double bond compounds).

(Leaving space below) Table 1 (1) () Inner number 6 meters wide Table 1 (2) () Inner number! :IM1fA Filter Table 1 (3) () indicates the substituent (Yuichi Table 2) () indicates the position of the substituent [Example] Example 1 9-Amino-3-methyl-2,3-dihydro-IH -Synthesis of cyclopenta[b]quinoline 2-aminobenzonitrile (4,00 g, 33.9 mmol), 2-methylcyclopentanone (10,00 g, 101.9 mmol)
1) and anhydrous zinc chloride (4,60g, 33,9 mea
1) was heated at 140° C. for 30 minutes with stirring under a nitrogen stream. Dimethylformamide was added to dissolve the mass. After cooling with water, alkalizing with 10% aqueous sodium hydroxide solution, extracting with ethyl acetate, and washing with saturated saline,
It was dried with anhydrous magnesium sulfate. The oil obtained by distilling off ethyl acetate was subjected to silica gel column chromatography and eluted with ethyl acetate to obtain 9-amino-3-methyl-2,3-dihydro-IH-cyclopenta[b]quinoline. . mp161-163°C.

NMR (CDsOD-COCl) δ: 1.37 (
3H, d, J-6, 3Hz), 1.50-1.87
(LH, m).

2.13-2.90 (3H, *), 3.00-3
．． 40 (18, m).

4.95(2H,br, -Nl(z), 7.2
0-8.03 (4N, m).

Example 2 Synthesis of 9-amino-2-methyl-2,3-dihydro-IH-cyclopenta[b]quinoline 2-aminobenzonitrile (4,80 g, 40.8111101), 3-methylcyclopentanone (5, OOg.

50,9 auwol) and anhydrous zinc chloride (5,60 g
, 40.8 anol) was reacted in the same manner as in Example 1, and similarly purified by silica gel column chromatography,
9-Amino-2-methyl-2,3-dihydro-IH-cyclopenta[b]quinoline was obtained.

mp175-177°C.

N M R (CDCIz) δ: 1.23 (31, d, J-5, 6Hz).

2.47 (1B, dd, J-6,9Hz, J-3
,0Hz).

2.62-2.80 (2B, m).

3.03 (LH, dd, J-7, 3Hz, J-14
, 8H2).

3.23 (IH, dd, J-16, 2Hz, J-7
,5Hz>.

4.51 (2H, brs, -NHx), 7.36-7.
42 (18, m).

7.54'-7,61 (IH, m), ? ,6
9-7.73 (LH, w).

7.92-7.95 (IH, m).

Example 3 Synthesis of 9-amino-2-methyl-IH-cyclopenta[b]quinoline 2-aminobenzonitrile (2.50 g, 20.8II
IIo1), 3-methyl-2-cyclopenten-1-one (2,50 g, 26.0 m5 ol) and anhydrous zinc chloride (2,80 g -20,8+u+ol) were reacted in the same manner as in Example 1, and the same was applied to a silica gel column. Purified by chromatography to give 9-amino-2-methyl-IH
- Cyclopenta[b]quinoline was obtained.

trip　265-274℃.

NMR(CDCIs-CD30D) δ:2.2
5(3I(,s), 2.86(2H,s)
).

4.37 (2H, br, -NHz), 6.45
(IH, s).

7.42-7.56 (2H, s), 7.9
2-7.97 (IH, m) + 8.08-9.37 (II
, m).

Example 4 (R)-9-amino-1-methyl-2,3-dihydro~
IH-cyclopenta[b]quinoline and (R)-9-
Synthesis of amino-2-methyl-2,3-dihydro-IH-cyclopenta[b]quinoline 2-aminobenzonitrile (2.40 g, 20.4 anol), (R)-(+
)-3-methylcyclopentanone (2,50g, 2
5.5 smol) and anhydrous zinc chloride (2.80 g, 2
0.4 mgo+) was reacted in the same manner as in Example 1, purified by silica gel column chromatography in the same manner, and (
R)-9-amino-1-methyl-2,3-dihydro-I
A mixture of H-cyclopenta[b]quinoline and (R)-9-amino-2-methyl-2,3-dihydro-IH-cyclopenta[b]quinoline was obtained. According to NMR spectrum data, the composition ratio of 1-methyl form and 2-methyl form was 1:4. mpf 47-172℃.

NMR (CDCIs) δ: 1.23 (2,411, J-6,6 Hz, 10 L of 2-methyl form).

1.30 (0,6H, J-6,9Hz, -CH of 1-methyl form).

2.30-2.51 (1,1)1. s),
2.62-2.80 (1,6H, m).

3.00-3.08 (1, LH, M), 3.20-
3.30 (1,2H, m).

4.55 and 4.6N total 28°brs each
, -NHz) + 7.36-7.42 (IH, a+) + 7.55
-7.61 (18, m).

7.69-7.74 (IIl, m), 7.
92-7.95 (IIL blasphemy).

Example 5 Synthesis of 9-amino-7-licol-2-methyl-1]-cyclopenta[b]quinoline 2-amino-5-chlorobenzonitrile (6.30 g,
40.8++wol), 3-methyl-2-cyclopenten-1-one (5,00g, 52.0anol)
and anhydrous zinc chloride (5.60 g, 40.8 wlIo
1) was reacted in the same manner as in Example 1, and similarly purified by silica gel column chromatography to obtain 9-amino-7-
Polycol-2-methyl-I H-cyclopenta[b]quinoline was obtained. mp225-230℃.

NMR(CDCIs) δ: 2.26(3)1. t, J-0,7Hz), 3.
24 (2L d, J=0.7Hz).

4.48 (2H, brs, -NHz), 6.55
-6.66 (11, m).

7.52 (IH, dd, J=8.9Hz, J=2.
3tlz).

7.72 (IL d, J-2, 3112), 7.9
0 (18, d, J=8.9Hz).

Example 6 9-amino-7-chloro-2-methyl-2,3-dihydro-IH-cyclopenta[b]quinoline and 9-amino-7-chloro-1-methyl-2°3-dihydro-IH
-Synthesis of cyclopenta[b]quinoline 2-amino-5-chlorobenzonitrile (6.30g,
3-methylcyclopentanone (5.0 Hg, 50.9 m 5 ol) and anhydrous zinc chloride (5.60 g, 40.8 m + 5 ol) were reacted in the same manner as in Example 1, and similarly subjected to silica gel column chromatography. 9-amino-7-chloro-2-methyl-
2,3-dihydro-IH-cyclopenta[b]quinoline and 9-amino-7-chloro-1-methyl-2,3-
A mixture of dihydro-IH-cyclopenta[b]quinolines was obtained. According to NMR spectrum data, the composition ratio of 2-methyl form and 1-methyl form was 2.6:1. mp2
14-221'e.

NMR (CDCIs) δ: 1.23 (2,2H, d, J-6,6Hz, -C”L of 2-methyl form) 11.29 (0,8H, d, J
-7,0Hz, 1-methyl -CH5).

2.30-2.51 (IH, +*), 2.62
-2.79(1,6H,m)+2.92-3.08(1
8, ■) + 3.20-3.41 (1,4H, ■
).

4.48 and 4.55 (total 28° each br
s, -N, jjl) + 7.48-7.53 (IH, m), 7.68-7
．． 70 (LH, +m).

7.85 (IH, d, J-7, 9Hz).

Example 7 Synthesis of 9-amino-7-chloro-3-methyl-2,3-dihydro-IH-cyclopenta[b]quinoline 2-amino-5-chlorobenzonitrile (3,00 g,
19.7 s-ol), 2-methylcyclopentanone (5,00 g, 50.9-of) and anhydrous zinc chloride (2,70 g -19,7 smol) were reacted in the same manner as in Example 1, and the same reaction was carried out. It was purified by silica gel column chromatography to obtain 9-amino-7-chloro-3-methyl-2,3-dihydro-IH-cyclopenta[b]quinoline. mp210℃.

NMR (CDCIs) δ: 1.41 (3H, d, J-7,0Hz),
1.72-1.85 (IH, m) + 2.40-2.52
(IH, m), 2.70-2.93 (
2H,s).

3.24-3.34 (IH, Zeng).

4.49 (21, brs, -NHri.

7.50 (IH, dd, JJ, 9Hz, J-2
,3Hz)+7.69(IH,d,J-2,0Hz)
.

7.91 (LH, d, J=8.9Hz).

Example 8 Synthesis of 9-amino-7-trifluoromethyl-2,3-dihydro-IH-cyclopenta[b]quinoline 2-Amino-5-trifluoromethylbenzonitrile (1
,0Og, 5.3mmol) cyclopentanone (3
,00g, 35.7 mmol) and anhydrous zinc chloride (0
, 73g, 5.3+mmol) was reacted in the same manner as in Example 1, and similarly purified by silica gel column chromatography to obtain 9-amino-7-trifluoromethyl-2,3-
Dihydro-1H-cyclopenta[b]quinoline was obtained.

mp220-223℃.

NMR(CDCIs) δ: 2.20-2.31(3H,-), 2.81-3.
00(2H,s)+3.12-3.17(2B, m
), 4.69(211,brs, -Ndan□
).

7.73-7.77 (ill, m), 8.
00-8.03 (2H, m).

Example 9 9-amino-1-methyl-7-trifluoromethyl-2,
3-dihydro-LH-cyclopenta[b]quinoline and 9-amino-2-methyl-7-trifluoromethyl-2
,3-dihydro-IH-cyclopenta[b]quinoline Synthesis of 2-amino-5-trifluoromethylbenzonitrile (1
,00g, 5.3mmol), 3-methylcyclopentanone (3,00g, 30.6smol) and anhydrous zinc chloride (0.73g, 5.3ms+ol) were reacted in the same manner as in Example 1, and the mixture was treated with a silica gel column in the same manner. Purified by chromatography as a mixture, 9-amino-1
-Methyl-7-trifluoromethyl-2,3-dihydro-
IH-cyclopenta[b]quinoline and 9-amino-2
-Methyl-7-trifluoromethyl-2,3-dihydro-
IH-cyclopenta[b]quinoline was obtained. According to NMR spectrum data, the composition ratio of 1-methyl form and 2-methyl form was 1:1, mp 181-191°C.

NMR (CDCI3) δ: 1.24 (1,5H, d, J-6,6Hz, -CIls of 2-methyl form).

1.31 (1,5H, d, J-6,9) 1z, 1-
-CH1) in the methyl form.

1.84-1.94 (0.5H, m), 2.3
2-2.53 (IL m).

2.65-2.82 (IH, s), 2.9
7-3.11 (IH, m) + 3.18-3.44 (1,
5H, m).

4.65 and 4.71 (2H in total.

brs+, -11LL, respectively).

7.75 (IL d, J-8,9flz), 8.
00-8.03 (2H, m).

Example 10 Synthesis of 9-amino-8-fluoro-2,3-dihydro-IH-cyclopenta[b]quinoline 2-amino-6-fluorobenzonitrile (1,006,7,3@mol),
Cyclopentanone (1.23g.

14,7ssol), and anhydrous zinc chloride (1,00
g.

7.3 mmol) was reacted in the same manner as in Example 1, purified by silica gel column chromatography in the same manner, and 9
-Amino-8-fluoro-2,3-dihydro-IH-cyclopenta[b]quinoline was obtained* m p 177-1
80℃.

NMR(CDCI3)δ22.14-2.26(2)1. m) + 2.7
9-2.84(2)1. m) +3.06-3.12
(2H, s) + 5.12 (2H, brs, -
NJ).

6.92-7.00 (1) 1. m), 7.
40-7.46 (11, m).

7.66-7.70 (IH, m).

Example 11 Synthesis of 9-amino-8-fluoro-3-methyl-2,3-dihydro-IH-cyclopenta[b]quinoline 2-amino-6-fluorobenzonitrile (1,00 g,
7.3 intestinal-ol), 2-methylcyclopentanone (1
40 g, 14.3 ssol) and anhydrous zinc chloride (
1,00 g, 7.3 ++nol) was reacted in the same manner as in Example 1, and similarly purified by silica gel column chromatography to obtain 9-amino-8-fluoro-3-methyl-2.
3-dihydro-IH-cyclopenta[b]quinoline was obtained. mp153-155°C.

N M R (CDCIs) δ: 1.40 (3B, d, J-7,01!z).

1.71-1.84 (IH, m), 2.39
-2.51 (18, m).

2.66-2.88 (2H, +*) + 3.21
−3.31 (IH, m).

5.12(2)1. brs, 4Hri, 6.92-
7.00(1)1. a).

7.38-7.47 (Ill, Seal).

7.73 (18, dd, J-8,6Hz, J-
0,6)1z).

Example 12 9-amino-8-fluoro-2-methyl-2,3-dihydro-IH-cyclopenta[b]quinoline and 9-amino-8-fluoro-1-methyl-2<3-dihydro-IH
-Synthesis of cyclopenta[b]quinoline 2-amino-6-fluorobenzonitrile (1,00g.
7.3smol), 3-methylcyclopenta, non(
1,40g, 14.3ssol) and anhydrous zinc chloride (1
. Cyclopenta[b]quinoline and 9-amino-8-fluoro-1-methyl-2
, 3-dihydro-IH-cyclopenta[b]quinoline was obtained. According to NMR spectrum data, the composition ratio of the nee-methyl form and the 2-methyl form was 1:8.7. mp17
7-180℃.

NMR (CDCIs) δ: 1.23 (2,69!i, d, J-6,614z,
2-methyl form of -CH1).

1.27(0,3LH,d, J-6,9)1z, 1
-methyl -CH5).

2.28-2.46CIH,■)+2.60-2.
77 (1,9H, e+).

2.89-3.03 (lfl, s), 3.15-
3.35 (1, IH, mL5.10 (2L brs,
-Nug).

6.92-7.00 (1B, ■) + 7.39-7.
46(1)1. +w)+7.68(IH, dd, J
-8,6Hz, J-0,7Hz).

Example 13 Synthesis of 9-amino-8-fluoro-2-methyl-IH-cyclopenta[b]quinoline 2-amino-6-fluorobenzonitrile (2,00 g,
14.6ssol), 3-methyl-2-cyclopenten-1-one (3,00g, 31.2 steel-01)
and anhydrous zinc chloride (2.0Bg, 14.6 mmol
) was reacted in the same manner as in Example 1, and similarly purified by silica gel column chromatography to obtain 9-amino-8-fluoro-2-methyl-IH-cyclopenta[b]quinoline. mp200-205℃.

N M R (CDCIs) δ: 2.26 (3H, t+ J-0, 7H2).

3.21-3.22 (2H, m), 5.09 (21
1,brs, -NHri.

6.62-6.65 (IH, m), 6.93-
7.04 (IH, m).

7.41-7.49 (IH, m), 7.71-
7.75 (IH, m).

Example 14 9-Amino-2,8-dimethyl-2,3-dihydro-I
Synthesis of H-cyclopenta[b]quinoline 2-amino-6
-Methylbenzonitrile (1,00g, 7.6+u+
ol), 3-methylcyclopentanone (1,50g,
15.2 mmol) and anhydrous zinc chloride (1.03 g,
7.6 +u+ol) was reacted in the same manner as in Example 1, and similarly purified by silica gel column chromatography,
The obtained crystals were recrystallized from ethyl acetate-ether, and 9
-Amino-2,8-dimethyl-2゜3-dihydro-IH
-Cyclopenta [b] 0mp14T obtained from this Norin
~149℃.

N M R (CDCIs) δ: 1.23 (3H, d, J=6.61(z).

2.36-2.44 (IH, Peng), 2.64-2
．． 77 (211, m).

2.94-3.02 (48,s), 3.19-3
．． 29 (18, 繻).

4.75 (2H, brs, -NHi).

7.07 (IH, d, J-7, 3Hz).

7.37 (IH, dd, J-8, 6Hz, J-
7.3Hz).

7.76 (LH, d, J-8, 6Hz).

Example 15 Synthesis of 9-amino-7-fluoro-2,3-dihydro=IH-cyclopenta[b]quinoline 2-amino-5-fluorobenzonitrile (0.50 g s 3.7 smol
), cyclopentanone (0,70 g.

8.3 m+wol) and anhydrous zinc chloride (0.50 g
, 3.7+wmol) was reacted in the same manner as in Example 1, and similarly purified by silica gel column chromatography,
9-Amino-7-fluoro-2,3-dihydro-IH-cyclopenta[b]quinoline was obtained. ff1235-23
6℃.

NMR (CIICI δ: 2.05-2.25 (2H, m), 2.91 (2H
, t, J-7, 3Hz).

3.11 (2H, t, J-7, 7Hz).

4.44<2H, brs+ -N! ! t)+7.29-
7.38 (2H, m), 7.89-7.95 (IH
, m) Example 16 9-amino-3,8-dimethyl-2,3-dihydro-I
Synthesis of H-cyclopenta[b]quinoline 2-amino-6
-Methylbenzonitrile (0.50g, 3.8+mo
l), 2-methylcyclopentanone (1,50g,
15.2a+mol) and anhydrous zinc chloride (0.50g
, 3.8 mmol) was reacted in the same manner as in Example 1, and similarly purified by silica gel column chromatography.
9-amino-3,8-dimethyl-2,3-dihydro-I
H-cyclopenta[b]quinoline was obtained. mp97~1
02℃.

N M R (CDCIs) δ: 1.40 (31,t, J-7,0Hz).

1.70-1.84 (IH, m), 2.38-
2.50 (III, Mongolia).

2.64-2.84 (2N, m), 2.94 (3
H,s).

3.23-3.32 (IH, +s), 4.77 (2
H, brs, -NHri.

7.06 (IN, d, J-6,9Hz).

7.37 (IN, dd, J-6,9Hz,
J=8.6Hz).

7.81 (IH, d, JJ, 6Hz).

Example 17 9-amino-3-methyl-7-trifluoromethyl-2,
Synthesis of 3-dihydro-IH-cyclopenta[b]quinoline 2-Amino-5-trifluoromethylbenzonitrile (1
,00g, 5.3ismol), 2-methylcyclopentanone (3,00g, 3G, 6m++ol) and anhydrous zinc chloride (0.73g, 5.3mmol) were reacted in the same manner as in Example 1, and the same reaction was carried out. was purified by silica gel column chromatography to obtain 9-amino-3-methyl-
7-trifluoromethyl-2,3-dihydro-1H-cyclopenta[b]quinoline was obtained.

N M R (CDCIs) δ: 1.43 (3N, d, J-6,9Hz).

1.70-1.86 (IH, m), 2.42-2.
55 (IH, +w).

2.73-2.95 (28, m), 3.27-
3.36 (LH, s).

4.68 (28,brs, -NHZ).

7.72-7.76 (18, Dai), 8.02-8.
08(2H,m)t Example 18 9-Amino-3-ethyl-8-fluoro-2,3-dihydro-IH-cyclopenta[b) Synthesis of quinoline 2-Amino-6-fluorobenzonitrile (1,00 g ,
7.3a++wol), 2-ethylcyclopentanone (1,30g, 11.6mgo+) and anhydrous zinc chloride (1,00g, 7.3nnol) were reacted in the same manner as in Example 1, and subjected to silica gel column chromatography in the same manner. 0mp174-176°C to obtain 9-amino-3-ethyl-8-fluoro-2<3-dihydro-IH-cyclopenta[b]quinoline.

N M R (CDCIs> δ: 1.04 (3H, t+ J-7, 3Hz).

1.50-1.61 (IH, mL 1.81-1.9
4 (IH, m) + 2.07-2.20 (LH, m),
2.34-2.47 (LH, +w).

2.66-2.87 (2L m), 3.08
-3.18 (18, m).

5.10 (28,brs, -NHx).

6.92-7.00 (IH, @), 7.38-
7.46 (IH, -).

7.72 (II, dd, JJ, 6Hz, J-1,
0flz).

Example 19 9-Amino-3-ethyl-2,3-dihydro-Ill-
Synthesis of cyclopenta[b]quinoline 2-aminobenzonitrile (0.87g, 7.3mmol), 2-ethylcyclopentanone (1.30g, 11.6+*mol)
) and anhydrous zinc chloride (1,00 g, 7.3 nn
ol) was reacted in the same manner as in Example 1, purified by silica gel column chromatography in the same manner, and 9-amino-3
-ethyl-2,3-dihydro-IH-cyclopentaCb
) obtained quinoline. mp 131-135°C.

N M R (CDCI) δ: 1.05 (3H, t, J-7, 6Hz).

1.49-1.60 (IH, ■), 1.82-1.
95 (IH, a+).

2.09-2.2t (ltl, m), 2.35-
2.48(1)1. +s).

2.72-2.93 (2H, m), 3.10-3.
20 (IH, m).

4.51 (2H, brs, -N,!!t).

7.36-7.42 (18,s), 7.55-
7.61 (IL m).

7.71 (LH, d, J-8, 3Hz).

7.98 (II, d, J = 8.6 Hz) Example 20 Synthesis of 9-amino-3,7-dimethyl-6-fluorocyclopenta[b]quinoline 2-amino-4-fluoro-5-methylbenzo Nitrile (
0.50g, 3.3mwol), 2-methylcyclopentanone (1.50g, 15.3smol) and anhydrous zinc chloride (0.45g, 3.3+u+ol)
) was reacted in the same manner as in Example 1, purified by silica gel column chromatography in the same manner, and 9-amino-3,7
-dimethyl-6-fluorocyclopenta[b]quinoline was obtained. mp198-202℃.

NMR(CIlCIs) δ:1.40(3H
, d, J-6,9Hz), 1.73-1.85(L
H, m).

2.38-2.50 (4H, m, but 2.43p
There is a doublet peak at pm, J = 1.0Hz).

2.71-2.88 (2H, Akebono), 3.22-3.
30 (LH, edge).

4.48 (2H, brs, -Nu,), 7.49 (
1)1. d, J-8,9)1z).

7.56 (IH, d, J-11,6Hz) Example 21 9-Amino-3,5,7-drimethylcyclobenta[b
]Synthesis of quinoline 2-amino-3,5-dimethylbenzonitrile (0゜g
Example 1
9-amino-3,5,7-toIJ
) Tylcyclopenta[b]quinoline was obtained.

NMR(CDCIs) δ: 1.41 (3H, d, J-6,9Hz), 1.67
−1.80 (IH, m).

2.38-2.50 (4H, rigid, but 2.46pp
+m has a singlet beak).

2.71-2.90 (5H, m, z, 5ap
Singlet beak on p-).

3.25-3.32 (IH, w), 4.40 (211
,brs, -Nllx).

7.28 (LH,s), 7.32 (18,s) Example 22 9-Amino-8-chloro-2-methyl-2,3-dihydro-IH-cyclopenta(b)quinoline and 9-amino- 8-chloro-1-methyl-2,3-dihydro-IH
-Synthesis of cyclopenta[b]quinoline 2-amino-6-chlorobenzonitrile (0.74 g,
Example 1
and purified in the same manner by silica gel column chromatography to form a mixture of 9-amino-8-chloro-2-methyl-2,3-dihydro-IH-cyclopenta[b]quinoline and 9-amino-8 -Chloro-1
-Methyl-2,3-dihydro-IH-cyclopenta[b
] Quinoline was obtained. According to NMR spectrum data, 1
The composition ratio of the -methyl form and the 2-methyl form was 1:9.

mp153-155℃NMR(CDCIs)
δ: 1.23 (2,7H,d, J-6,6Hz, 2-methyl pair -CH,).

1.25 (0,3H, d, J=7.5Hz, l-methyl pair -CH5) + 2.33-3.33 (5H, m)
, 5.62(21(,brs, -Nllt)
.

7.30-7.42 (2L m).

7.82 (IH, dd, J-1, 6Hz, J-8,
2H2) Example 23 9-amino-6,7-dichloro-2,3-dihydro-L
Synthesis of H-cyclopenta[b]quinoline 2-amino-4
,5-difluoropenzonitrile (0,50g -3,2
s+wol), cyclopentanone (0.55g, 6.5
mmol) and anhydrous zinc chloride (0.66 g, 4.9
m1101) was reacted in the same manner as in Example 1, and similarly purified by silica gel column chromatography to obtain 9-amino-6,7-dichloro-2,3-dihydro=IH-cyclopenta[b]quinoline, 0mp256. °C (decomposition) NMR (CDCIs) δ: 2.03-2.23 (2H, ■), 2.84-3.0
5 (4H, m) + 5.74 (1,8L brs),
7.49-7.65 (IH, s+)+7.94-8.0
2(18,m) Example 24 Synthesis of 9-amino-5-fluoro-2,3-dihydro-IH-cyclopenta[b]quinoline 2-Amino-3-fluorobenzonitrile (0.50g, 3.7+u+ol)
, cyclopentanone (0.62g-7, 3mmol)
and anhydrous zinc chloride (0.75 g, 5.5 ssol) were reacted in the same manner as in Example 1, and similarly purified by silica gel column chromatography. (-cyclopenta[b]quinoline was obtained. mp 259-260°C NMR (CDCIs) δ: 2.15-2.26 (2H, m), 2.87-2.
92 (21, m) + 3.09-3.15 (2H, Mongolia),
5.41 (1,8H, brs).

7.21-7.29 (2H, s), 7.67-7.7
2(18,s) Example 25 Synthesis of 9-amino-6-fluoro-2,3-dihydro-IH-cyclopenta[b]quinoline 2-amino-4-fluorobenzonitrile (0.50 g, 3.7 wIIo
l), cyclopentanone (0.62 g.

7,3 mmol) and anhydrous zinc chloride (0,75 g,
5.5ssol) was reacted in the same manner as in Example 1, purified by silica gel column chromatography in the same manner, and 9-
Amino-6-fluoro-2,3-dihydro-IH-cyclopenta[b]quinoline was obtained. mp230°C (decomposition) NMR (CDCI 3) δ: 2.17-2.28 (21+, -), 2.85
~2.90 (211,s).

3.08-3.14 (2H, m), 4.56 (1,7
H, brs).

7.13-7.20 (IH, g+), 7.53-7
．． 58 (18, Zeng).

7.66-7.72(IH,s) Example 26 9-amino-6,8-dichloro-2,3-dihydro-L
Synthesis of H-cyclopenta[b]quinoline 2-amino-4
,6-difluorobenzonitrile (0.50g, 3.2
ssol), cyclopentanone (0.55g, 5.
5 mmol) and anhydrous zinc chloride (0,66 g.

4, 9 meal) was reacted in the same manner as in Example 1, purified by silica gel column chromatography in the same manner, and 9
-amino-6,8-dichloro-2,3-dihydro-IH
- cyclopenta[b]quinoline obtained 0mp154~1
56°C NMR (CDCh) δ: 2.16-2.27 (2H, m), 2.79-2.
85 (21, request).

3.07-3.12 (2H, s), 5.15 (2H,
brs).

6.77-6.86 (1B, m), 7.33-
7.39 (IH, sr) Example 27 9-Amino-2,8-dimethyl-2,3-dihydro-I
Synthesis of H-cyclopenta[b]quinoline hydrochloride 9-amino-2,8-dimethyl-2,3-dihydro-I
H-cyclopenta[b]quinoline (100 .mu.) was dissolved in ethanol (8-) and then hydrogen chloride-ether solution was added until acidic. The solution was distilled off to obtain 9-amino-2,8-dimethyl-2,3-dihydro-IH-cyclopenta[b]quinoline hydrochloride, 1mp255-26
0℃ (decomposition) procedure amendment (sealed) 1. Indication of the case Patent Application No. 119686 of 1988 2. Name of the invention cyclopenta[b] quinoline derivative 3. Person making the amendment Relationship to the case Name of the patent applicant ( Name) Sumitomo Pharmaceutical Co., Ltd. 4, Agent ■541 Address 4-56 Hirano-cho, Higashi-ku, Osaka (Basue Building) Ta (06) 227-1156 Column 6 of "Detailed Description of the Invention" of the specification, Contents of amendment (1) "Fluorocyclo" in lines 2 to 3 and 10 of the specification No. 45 is replaced with "fluoro-2,3-dihydro-IH" respectively.
-Corrected to ``Cyclo''.

Claims (9)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^1, R^2, R^3, R^4, R^5 and R^6 are the following [1] to [ 2]. [1] R^1, R^2 and R^3 simultaneously represent a hydrogen atom, and at least one of R^4, R^5 and R^6 is a fluorine atom, a trifluoromethyl group, a lower alkylthio group, Represents a hydroxyl group, a lower alkanoylamino group, a nitro group, a phenyl group, or a phenyl group substituted with a halogen atom, a lower alkyl group, or a lower alkoxy group, and the remainder is a hydrogen atom, a halogen atom,
Represents a trifluoromethyl group, lower alkyl group, lower alkoxy group, lower alkylthio group, lower cycloalkyl group, nitro group, amino group, and lower alkylamino group. [2] At least one of R^1, R^2, and R^3 is a lower alkyl group, lower cycloalkyl group, hydroxylmethyl group, lower alkoxymethyl group, lower alkoxy group, halogen atom, phenyl group, or halogen atom , represents a phenyl group substituted with a lower alkyl group or a lower alkoxy group, and the remainder represents a hydrogen atom, a lower alkyl group, a lower cycloalkyl group, a lower alkoxymethyl group, or a lower alkoxy group, and R^4, R^5 and R^6
are hydrogen atom, halogen atom, trifluoromethyl group, lower alkyl group, lower alkylthio group, lower cycloalkyl group, lower alkoxy group, nitro group, amino group,
It represents a lower alkylamino group, a lower alkanoylamino group, a hydroxyl group, a phenyl group, or a phenyl group substituted with a halogen atom, a lower alkyl group, or a lower alkoxy group. R^7 represents a hydrogen atom, a lower alkyl group, an aralkyl group, a dialkyl group, or a group represented by R^1^1-CO-. (However, R^1^1 represents a lower alkyl group, a lower cycloalkyl group, an aralkyl group, a phenyl group, or a phenyl group substituted with a halogen atom, a lower alkyl group, or a lower alkoxy group.) The 2nd and 3rd positions The space between them represents a single bond or a double bond. ) represented by cyclopenta [
b] A quinoline derivative or a pharmaceutically acceptable acid addition salt thereof. (2) R^1, R^2 and R^3 are hydrogen atoms at the same time, and one of R^4, R^5 and R^6 is a fluorine atom, a trifluoromethyl group, a lower alkylthio group, A hydroxyl group, a lower alkanoylamino group, a nitro group, a phenyl group or a phenyl group substituted with a halogen atom, a lower alkyl group or a lower alkoxy group,
Claim No. 1 in which the remaining two are each a hydrogen atom, a halogen atom, a trifluoromethyl group, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a lower cycloalkyl group, a nitro group, an amino group, or a lower alkylamino group. 1) Cyclopenta[b]quinoline derivative or a pharmaceutically acceptable acid addition salt thereof. (3) one of R^1, R^2 and R^3 is a lower alkyl group, a lower cycloalkyl group, a hydroxylmethyl group, a lower alkoxymethyl group, a lower alkoxy group, a halogen atom, a phenyl group or a halogen atom, A phenyl group substituted with a lower alkyl group or a lower alkoxy group, and the remaining two are hydrogen atoms, a lower alkyl group, a lower cycloalkyl group, a lower alkoxymethyl group, or a lower alkoxy group, and R^4, R^5 and R^6 are each a hydrogen atom, a halogen atom, a trifluoromethyl group, a lower alkyl group, a lower alkylthio group, a lower cycloalkyl group, a lower alkoxy group, a nitro group, an amino group, a lower alkylamino group, a lower alkanoylamino group, Cyclopenta [b] according to claim (1), which is a hydroxyl group, a phenyl group, or a phenyl group substituted with a halogen atom, a lower alkyl group, or a lower alkoxy group;
A quinoline derivative or a pharmaceutically acceptable acid addition salt thereof. (4) R^4 is a halogen atom, and R^5 and R^
Cyclopenta[b]quinoline derivative or a pharmaceutically acceptable acid addition salt thereof according to claim (1), wherein 6 is a hydrogen atom. (5) The cyclopenta[b]quinoline derivative or a pharmaceutically acceptable acid addition salt thereof according to claim (1), wherein the halogen atom is a fluorine atom. (6) R^4 is a lower alkyl group, R^5 and R
Cyclopenta[b]quinoline derivative or a pharmaceutically acceptable acid addition salt thereof according to claim (1), wherein ^6 is a hydrogen atom. (7) R^4, R^5 and R^6 are hydrogen atoms,
The cyclopenta[b]quinoline derivative or a pharmaceutically acceptable acid addition salt thereof according to claim (1), wherein at least one of R^1, R^2 and R^3 is a lower alkyl group. . (8) The following general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^1, R^2, R^3, R^4, R^5, R
6 and R^7 are as defined in claim 1)]
A cyclopenta[b]quinoline derivative or a pharmaceutically acceptable acid addition salt thereof as described in 2. (9) The compound is (a) 9-amino-8-fluoro-2,3-dihydro-1
H-cyclopenta[b]quinoline (b) 9-amino-3,8-dimethyl-2,3-dihydro-1H-cyclopenta[b]quinoline (c) 9-amino-7-fluoro-2,3-dihydro- 1H-cyclopenta[b]quinoline (d) 9-amino-8-fluoro-2-methyl-1H-cyclopenta[b]quinoline (e) 9-amino-2,8-dimethyl-2,3-dihydro-1H- Cyclopenta[b]quinoline (f) 9-amino-8-fluoro-3-methyl-2,3-dihydro-1H
-cyclopenta[b]quinoline (g) 9-amino-2-methyl-1H-cyclopenta[
b] Quinoline (h) 9-amino-3-methyl-2,3-dihydro-1
The cyclopenta[b]quinoline derivative according to claim (1), which is any H-cyclopenta[b]quinoline, or a pharmaceutically acceptable acid addition salt thereof.