JPH09208584A - Amide derivative, pharmaceutical preparation containing the same, and intermediate for synthesizing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new amide derivative having excellent antihistaminic activity and an inhibitory activity against eosinophilic leukocyte infiltration, capable of highly inhibiting both immediate and delayed allergic reactions, thus esp. useful for treating atopic dermatitides. SOLUTION: This new amide derivative is expressed by formula I (X is H or a halogen; (m) is 1-9; (n) is 2-12), e.g. 1-(3- [4-(diphenylmethoxy)-1- piperidineacetyl]amino}propyl)-1H-imidazo[4,5-c]quinoline-4-amine. The compound of formula I is obtained by heating a compound of formula II (X' is a halogen) and a compound of formula III in an organic solvent, optionally in the presence of a base. It is preferable that this new compound is used as a formulation for percutaneous administration such as ointment, lotion or cream.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel amide derivative having an eosinophil infiltration suppressing action and an antihistamine action and useful as a therapeutic agent for atopic dermatitis and the like, and a pharmaceutical preparation containing the same. It relates to a synthetic intermediate.

[0002]

2. Description of the Related Art For the treatment of atopic dermatitis, conventionally, external use of steroids and oral administration of antihistamines or antiallergic agents have been basically performed. In addition, hyposensitization therapy, allergens (tick, food) Ablation therapy, PUVA
(Psoralen-long wavelength ultraviolet irradiation) therapy, bacterial vaccine therapy, etc. have been tried. However, none of them is a decisive factor, especially for external use of steroids, although sharpness is good, skin atrophy, capillary expansion, flushing,
Side effects such as purpura and susceptibility to infection have become a problem. Recently, the direction of atopic dermatitis treatment is shifting from steroids to cytokine therapy (Hidemi Nakagawa, Clinical Immunity,
27 [supple 16] 597-602, 1995, Shoko Kobayashi et al., Clinical Immunity, 27 [supple 16] 603-609,
1995). In patients with atopic dermatitis, Th1
An imbalance in the balance between helper cells and Th2 helper cells, that is, Th2 cell-dominated state, and as a result of increased productivity of cytokines such as interleukin-4 and interleukin-5 from Th2 cells, inflammatory cells such as eosinophils The theory that inflammation is induced by enhancing differentiation / proliferation / invasion of Escherichia coli is predominant. Therefore, interferons and immunosuppressive agents that suppress Th2 cell dominance have been tried, but satisfactory results in terms of effects and side effects have not yet been obtained.

[0003] Generally, when an antigen is administered to sensitized human skin, the maximum is 24 to 4 immediately after administration and 4 to 8 hours after administration.
A skin reaction occurs which lasts for 8 hours. The former is an immediate reaction,
The latter is called a delayed allergic reaction. In particular, it has been pointed out that the delayed reaction is closely related to the pathology of allergic diseases including asthma. Although the mechanism of the delayed-onset reaction has long been unknown, today there is a time-delayed phase in the type I allergic reaction involving IgE-mast cells, namely l
ate phase reaction of the type I allergy, T
It has come to be thought that h2 helper cells and eosinophils are deeply involved (Motohiro Kurosawa, Clinical Immunity, 27 (5),
564-574, 1995). Thus, atopic dermatitis is a disease that involves both immediate-type and delayed-type allergic reactions, and it is considered that the onset mechanism of the delayed-type reaction is not unique. The effect is insufficient when a release inhibitor or antagonist or an inflammatory cell infiltration inhibitor is used alone. therefore,
It is known that in treating atopic dermatitis, histamine (histamine is involved in not only immediate type but also partial delayed type) and delayed type reaction, which are especially important among chemical mediators released from mast cells. It is necessary to suppress both eosinophil infiltration, but no such compound has been presented.

Also, some compounds similar to the compound of the present invention have been known. For example, 1-substituted-1H-imidazo [4,5-c] quinolin-4-amines include 1-isobutyl-1H-imidazo [4,5-c] quinolin-4-amine (which is an antiviral agent. Imiquimod)
Are known (European Patent No. 145
340, U.S. Pat. No. 4,689,338, U.S. Pat. No. 4
698348, U.S. Pat. No. 4,929,624, European Patent 385630, U.S. Pat. No. 5,346,905). However, they do not disclose antihistamine action and eosinophil infiltration inhibiting action. Also, 4-
(Diphenylmethoxy) -1-piperidine alkanoic acids are disclosed in JP-A-3-264562, but no eosinophil infiltration suppressing action is described.

[0005]

Therefore, the present invention has a sufficient antihistamine action and an eosinophil infiltration inhibitory action, and in atopic dermatitis, an immediate allergic reaction mainly due to histamine involvement and the involvement of eosinophil and histamine involvement. It is intended to provide a novel compound that suppresses both delayed-type allergic reactions and a pharmaceutical preparation containing the same.

[0006]

The present invention for solving the above-mentioned problems is as follows. (1) An amide derivative represented by the following formula I and a pharmaceutically acceptable acid addition salt thereof.

[0007]

Embedded image

In the formula I, X represents a hydrogen atom or a halogen atom, m is an integer of 1 to 9, and n is an integer of 2 to 12.

(2) A pharmaceutical preparation containing the amide derivative described in (1) above.

(3) A synthetic intermediate for synthesizing the amide derivative of the formula I represented by the following formula II.

[0011]

Embedded image

In formula II, X'represents a halogen atom and m
Represents an integer of 1 to 9 and n represents an integer of 2 to 12.

(4) A synthetic intermediate for synthesizing an amide derivative of formula I represented by the following formula II '.

[0014]

Embedded image

In the formula II ', n represents an integer of 2 to 12.

(5) A synthetic intermediate for synthesizing the amide derivative of the formula I represented by the following formula III.

[0017]

Embedded image

In the formula III, n represents an integer of 2 to 12.

(6) A synthetic intermediate for synthesizing the amide derivative of the formula I represented by the following formula IV.

[0020]

Embedded image

In the formula IV, n represents an integer of 2 to 12.

(7) A synthetic intermediate for synthesizing an amide derivative of formula I represented by the following formula V:

[0023]

Embedded image

In the formula V, when R is hydrogen, R'is 1 carbon atom.
A branched alkanoyl group having 1 to 8 carbon atoms
A haloalkanoyl group which may have a branched chain at ˜8, a phenylalkanoyl group which has 1 to 12 carbon atoms and may have a halogen, nitro or methoxy substituent on the benzene ring,
Phenoxyalkanoyl group having 1 to 12 carbon atoms and optionally having a halogen, nitro or methoxy substituent on the benzene ring, alkoxycarbonyl group having 1 to 8 carbon atoms and optionally having a branched chain, having 1 to 8 carbon atoms A haloalkoxycarbonyl group which may have a branched chain or a phenylalkoxycarbonyl group which has 1 to 12 carbon atoms and may have a halogen, nitro or methoxy substituent on the benzene ring is shown. Also, R and R'are united to form an aromatic cyclic imide which may have halogen, nitro or methoxy substituents. n represents an integer of 2 to 12.

(8) A synthetic intermediate for synthesizing the amide derivative of the formula I represented by the following formula VI.

[0026]

Embedded image

In the formula VI, when R is hydrogen, R'is an alkanoyl group having 1 to 8 carbon atoms which may have a branched chain, and a haloalkanoyl group having 1 to 8 carbon atoms which may have a branched chain. Group, a phenylalkanoyl group having 1 to 12 carbon atoms and optionally having a halogen, nitro or methoxy substituent on the benzene ring, and a C 1 to 12 group having optionally halogen, nitro or methoxy substituent on the benzene ring. Phenoxyalkanoyl group, alkoxycarbonyl group having 1 to 8 carbon atoms and optionally branched chain, haloalkoxycarbonyl group having 1 to 8 carbon atoms and optionally having branched chain, or 1 to 1 carbon atoms
2 represents a phenylalkoxycarbonyl group which may have a halogen, nitro or methoxy substituent on the benzene ring. Also, R and R'are united to form an aromatic cyclic imide which may have halogen, nitro or methoxy substituents. n represents an integer of 2 to 12.

(9) A synthetic intermediate for synthesizing the amide derivative of the formula I represented by the following formula VII.

[0029]

Embedded image

In the formula VII, when R is hydrogen, R'is an alkanoyl group having 1 to 8 carbon atoms which may have a branched chain, or a haloalkanoyl group having 1 to 8 carbon atoms which may have a branched chain. Group, a phenylalkanoyl group having 1 to 12 carbon atoms and optionally having a halogen, nitro or methoxy substituent on the benzene ring, and a C 1 to 12 group having optionally halogen, nitro or methoxy substituent on the benzene ring. Phenoxyalkanoyl group, alkoxycarbonyl group having 1 to 8 carbon atoms and optionally branched chain, haloalkoxycarbonyl group having 1 to 8 carbon atoms and optionally having branched chain, or 1 to 1 carbon atoms
2 represents a phenylalkoxycarbonyl group which may have a halogen, nitro or methoxy substituent on the benzene ring. Also, R and R'are united to form an aromatic cyclic imide which may have halogen, nitro or methoxy substituents. n represents an integer of 2 to 12.

(10) A synthetic intermediate for synthesizing the amide derivative of the formula I represented by the following formula VIII.

[0032]

Embedded image

In the formula VIII, when R is hydrogen, R'is an alkanoyl group having 1 to 8 carbon atoms which may have a branched chain, and a haloalkanoyl group having 1 to 8 carbon atoms which may have a branched chain. Base,
Phenylalkanoyl group having 1 to 12 carbon atoms and optionally having a halogen, nitro or methoxy substituent on the benzene ring, and phenoxyalkanoyl having 1 to 12 carbon atoms and optionally having a halogen, nitro or methoxy substituent on the benzene ring. Group, an alkoxycarbonyl group having 1 to 8 carbon atoms and optionally having a branched chain, a haloalkoxycarbonyl group having 1 to 8 carbon atoms and optionally having a branched chain, or 1 to 1 carbon atoms
2 represents a phenylalkoxycarbonyl group which may have a halogen, nitro or methoxy substituent on the benzene ring. Also, R and R'are united to form an aromatic cyclic imide which may have halogen, nitro or methoxy substituents. n represents an integer of 2 to 12.

R and R'in the formulas V, VI and VII are amino-protecting groups, preferably acetyl, propionyl, pivaloyl, benzoyl, methoxycarbonyl, ethoxycarbonyl, iso-butoxycarbonyl, tert-
Examples thereof include butoxycarbonyl, benzyloxycarbonyl, phthalimide and the like.

The pharmaceutically acceptable acid addition salts of compounds of formula I include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid,
Examples thereof include salts of acetic acid, lactic acid, maleic acid, fumaric acid, citric acid, malic acid, tartaric acid, oxalic acid, methanesulfonic acid and p-toluenesulfonic acid. These are prepared by a conventional method.

[0036]

BEST MODE FOR CARRYING OUT THE INVENTION The novel amide derivative represented by the formula I of the present invention can be produced, for example, as follows.

[0037]

Embedded image

In step (1), the starting material of formula IX
2,4-dichloro-3-nitroquinoline is a known substance and can be synthesized by the method of Gabriel (Chem. Ber., 1918, 51, 1500) and the like. Further, a monoamino protected form of the alkylenediamine of the formula X is also known by a known method (Synth.Co.
mmun., 1990,20,2559, J.Med.Chem., 1988,31,898, J.Or
g.Chem., 1981,46,2455, J.Amer.Chem.Soc., 1941,63,852
Etc.). The reaction between the compound of formula IX and the compound of formula X can be carried out by heating in a suitable solvent (preferably a basic solvent such as triethylamine or pyridine) to give the compound of formula VIII.

In the step (2), the reduction of the nitro group can be carried out in a suitable solvent (preferably alcohol) with iron powder-hydrochloric acid or tin chloride [II] at a temperature from 0 ° C to the reflux temperature. The compound of formula VII can also be obtained by catalytic reduction with hydrogen in the presence of a palladium or platinum catalyst.

In step (3), the compound of formula VI can be obtained by heating the compound of formula VII with a trialkylorthoformate or in formic acid in the presence of a metal formate salt.

In the step (4), for the deprotection reaction of the amino protecting group of the compound of formula VI, suitable reaction conditions can be selected depending on the kind of the protecting group. For example, if the protecting group is
The compound of formula IV can be obtained by selecting trifluoroacetic acid in a suitable solvent for tert-butoxycarbonyl (Boc) and hydrogen bromide-acetic acid for benzyloxycarbonyl (Z).

In step (5), the compound of formula V can be obtained by heating with benzylamine in a suitable solvent or with excess benzylamine without solvent.

In step (6), the compound of formula III can be obtained by heating and reacting with ammonia in an alcohol solvent or concentrated aqueous ammonia in an autoclave (pressure-resistant steel cylinder).

In step (7) the compound of formula III can be obtained by heating in a carboxylic acid (preferably formic acid) with palladium hydroxide on a carbon support.

In step (8), the compound of formula III is combined with the haloalkanoic acid in a suitable solvent (eg, N, N-).
In dimethylformamide), the compound of formula II can be obtained by condensation with a suitable condensing agent / condensation method (for example, carbodiimide, mixed acid anhydride method, acid chloride method, etc.). Further, instead of the haloalkanoic acid, an alkanoic acid substituted with a suitable leaving group (eg, methanesulfonyloxy, p-toluenesulfonyloxy, etc.) may be used.

In the step (9), the compound of the formula XI is a known substance, and together with the compound of the formula II or II ′, a suitable solvent (benzene, toluene, xylene, N, N-dimethylformamide, methanol, ethanol, n-). The compound of formula I can be obtained by heating in propanol, isopropanol, etc.). At this time, a suitable base (eg, sodium hydrogen carbonate, potassium carbonate,
Triethylamine etc.) may be used.

The amide derivative of the formula I and the pharmaceutically acceptable acid addition salt thereof of the present invention can be orally and parenterally administered to mammals as a therapeutic agent for atopic dermatitis. The dosage form of the pharmaceutical composition used for oral administration includes tablets, capsules, powders, fine granules, granules, suspensions, emulsions, solutions and syrups. The dosage forms used for parenteral administration include injections, suppositories, inhalants, eye drops, nasal drops,
Examples include ointments, creams, lotions, patches and the like. In any dosage form, a suitable drug
Pharmaceutically acceptable additives can be used. As additives, excipients, binders, lubricants, disintegrants, diluents, flavors, colorants, solubilizers, suspending agents, emulsifiers, preservatives, buffers, isotonic agents, ointment bases Examples include agents, oils, solubilizers, absorption promoters, adhesives, sprays and the like.

The compounds of formula I and their acid addition salts are preferably in the form of preparations for transdermal administration such as ointments, lotions, creams and the like.

Since the compound of the formula I and its acid addition salt show an eosinophil infiltration inhibitory action and an antihistamine action, other diseases in which those actions are effective, for example, allergic rhinitis, urticaria, asthma, etc. It is suggested to be useful for.

[0050]

Next, the present invention will be described in more detail by way of examples. In addition, the spectroscopic data of the compounds synthesized in the examples are as follows: IR spectrum: JASCO IR-810, ¹
H-NMR spectrum is Varian Unity 400 NMR Appara
Measured by tus.

Example 1 4- [3- (benzyloxycarbonylamino) propyne
Synthesis of Lumino] -2-chloro-3 -nitroquinoline 0.19 g ( 0.1%) of 2,4-dichloro-3-nitroquinoline.
768 mmol) and N- (benzyloxycarbonyl)-
0.13 g (0.768 mmol) of 1,3-propanediamine
Was heated to 70 ° C. in 5 ml of triethylamine and stirred for 1 hour. After triethylamine was distilled off under reduced pressure, the residue was dissolved in methylene chloride, washed with water and dried (MgSO ₄ ), and then the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and n-hexane-ethyl acetate (2: 1 v /
v) The eluted fractions gave 0.27 g (0.651 mmol) of 4- [3- (benzyloxycarbonylamino) propylamino] -2-chloro-3-nitroquinoline as a yellow powder. The spectroscopic data of this product are as follows.

¹ H-NMR (CDCl ₃ ) δ (ppm): 1.
79 (2H, m), 3.35 (4H, m), 5.02 (1
H, br), 5.18 (2H, s), 7.15 (1H, b)
r), 7.37 (5H, m), 7.57 (1H, t, J = 8.
0Hz), 7.73 (1H, t, J = 7.8Hz), 7.90
(1H, d, J = 8.4Hz), 8.21 (1H, d, J = 8.
0Hz)

(Example 2) 3-amino-4- [3- (benzyloxycarbonyl )
Synthesis of ( mino) propylamino] -2-chloroquinoline 4- [3- (benzyloxycarbonylamino) propylamino] -2-chloro-3-nitroquinoline 0.27
g (0.651 mmol) was dissolved in methanol (10 ml), concentrated hydrochloric acid (1 ml) and iron powder (0.22 g, 0.390 mmol) were added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution, extracted with ethyl acetate, washed with brine, dried (Na ₂ SO ₄ ), and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with chloroform-methanol (300: 1 v / v) fraction to give 3
-Amino-4- [3- (benzyloxycarbonylamino) propylamino] -2-chloroquinoline 0.12 g
(0.312 mmol) was obtained as a pale yellow powder. The spectroscopic data of this product are as follows.

¹ H-NMR (CDCl ₃ ) δ (ppm): 1.
76 (2H, m), 3.30 (2H, m), 3.42 (2
H, q, J = 6.3 Hz), 4.21 (2H, bs), 4.44
(1H, br), 4.92 (1H, br), 5.16 (2
H, s), 7.30-7.39 (5H, m), 7.46 (2
H, m), 7.89 (2H, m)

Example 3 1- [3- (benzyloxycarbonylamino) propyi
]]-4-Chloro-1H-imidazo [4,5-c] quino
Synthesis of phosphorus 3-amino-4- [3- (benzyloxycarbonylamino) propylamino] -2-chloroquinoline 0.12
g (0.312 mmol) triethyl orthoformate
Add 52 ml (3.12 mmol) and heat to 100 ° C. for 3.
Stir for 5 hours. The reaction solution is concentrated under reduced pressure to give 1- [3-
(Benzyloxycarbonylamino) propyl] -4-
Chloro-1H-imidazo [4,5-c] quinoline 0.12
g (0.304 mmol) was obtained as a pale yellow solid. The spectroscopic data of this product are as follows.

¹ H-NMR (CDCl ₃ ) δ (ppm): 2.
24 (2H, m), 3.36 (2H, q, J = 6.4Hz),
4.67 (2H, t, J = 7.0Hz), 4.95 (1H, b
r), 5.14 (2H, s), 7.31-7.39 (5H,
m), 7.62 (1H, t, J = 7.8Hz), 7.71 (1
H, t, J = 7.8 Hz), 8.09 (1H, s), 8.13
(1H, d, J = 8.4Hz), 8.21 (1H, d, J = 8.
4Hz)

(Example 4) 1- (3-aminopropyl) -4-chloro-1H-imi
Synthesis of Dazo [4,5-c] quinoline Acetate 1- [3- (Benzyloxycarbonylamino) propyl] -4-chloro-1H-imidazo [4,5-c] quinoline 0.12 g (0.304 mmol) ) To hydrogen bromide-acetic acid [3
3%] 3 ml was added, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure, 1N-aqueous sodium hydroxide solution and brine were added to the residue, and the mixture was extracted 5 times with chloroform. After drying (Na ₂ SO ₄ ), the solvent was evaporated under reduced pressure, the residue was subjected to silica gel column chromatography, and chloroform-methanol-32% acetic acid (12: 6: 1 v / v) eluate fraction 1- ( 3-Aminopropyl) -4-chloro-1H
-Imidazo [4,5-c] quinoline acetate 60 mg (0.
187 mmol) was obtained as a pale yellow solid. The spectroscopic data of this product are as follows.

¹ H-NMR (CD ₃ OD) δ (ppm): 1.
94 (3H, s), 2.39 (2H, m), 3.12 (2
H, t, J = 7.8Hz), 4.82 (2H, t, J = 7.2H)
z), 7.70 (2H, m), 7.97 (1H, d, J = 8.
0Hz), 8.27 (1H, d, J = 8.0Hz), 8.41
(1H, s)

(Example 5) 1- (3-aminopropyl) -1H-imidazo [4,5]
Synthesis of -c] quinolin-4-amine 1- (3-aminopropyl) -4-chloro-1H-imidazo [4,5-c] quinoline acetate 60 mg (0.187)
mmol) in a pressure-resistant steel reaction tube, 10 ml of methanol and 5 ml of liquid ammonia under cooling were added, and the mixture was heated to 150 ° C. and stirred overnight. The reaction solution was concentrated under reduced pressure, the residue was dissolved in a small amount of water, and 0.5 ml of a 1N sodium hydroxide aqueous solution was added. The precipitate was collected by filtration and recrystallized from ethanol to give 1-
(3-Aminopropyl) -1H-imidazo [4,5-
c] Quinoline-4-amine 11 mg (0.0455 mmol)
A pale yellow flocculent crystal (mp: 243-245 ° C (decomposition))
As obtained. The spectroscopic data of this product are as follows.

IR (KBr) cm ^-1 : 3320,317
0.1650 ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 1.93 (2
H, m), 2.57 (2H, t, J = 6.6Hz), 4.64
(2H, t, J = 7.0Hz), 6.55 (2H, s), 7.2
6 (1H, t, J = 7.2Hz), 7.44 (1H, t, J =
7.4 Hz), 7.62 (1H, d, J = 8.0 Hz), 8.12
(1H, d, J = 8.0Hz), 8.19 (1H, s)

Example 6 4- [3- (tert-butoxycarbonylamino) propyne
Synthesis of Lumino ] -2-chloro-3 -nitroquinoline 0.59 g (2.4-dichloro-3-nitroquinoline)
41 mmol) and N- (tert-butoxycarbonyl)-
0.42 g (2.41 mmol) of 1,3-propanediamine was heated to 70 ° C. in 10 ml of triethylamine and stirred for 1.5 hours. Triethylamine was distilled off under reduced pressure, the residue was dissolved in methylene chloride, washed with water, dried (Na ₂ SO ₄ ), and concentrated under reduced pressure. The residue was triturated with methanol and collected by filtration to give 4- [3- (tert-butoxycarbonylamino) propylamino] -2-chloro-3-nitroquinoline (0.61 g, 1.60 mmol) as yellow crystals (mp: 159).
˜161 ° C.). The spectroscopic data of this product are as follows.

IR (KBr) cm ^-1 : 3310,168
0.1580 ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.50 (9 H,
s), 1.77 (2H, m), 3.27 (2H, q, J = 6.
1Hz), 3.36 (2H, q, J = 6.0Hz), 4.82
(1H, br), 7.37 (1H, br), 7.55 (1
H, t, J = 7.8Hz), 7.72 (1H, t, J = 7.7H)
z), 7.89 (1H, d, J = 8.2Hz), 8.27 (1
H, d, J = 8.4Hz)

(Example 7) 3-amino-4- [3- (tert-butoxycarbonyl)
Synthesis of ( mino) propylamino] -2-chloroquinoline 4- [3- (tert-butoxycarbonylamino) propylamino] -2-chloro-3-nitroquinoline 0.27
g (0.70 mmol) was dissolved in 7 ml of ethanol, and 0.55 g (2.45 mmol) of tin chloride [II] dihydrate was added to 1
Heated to reflux for an hour. After cooling, the reaction solution was poured into 2N-ammonia water, extracted twice with chloroform, washed (saline solution),
After drying (Na ₂ SO ₄ ), the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with n-hexane-ethyl acetate (1: 1 v / v) fraction to give 3-
Amino-4- [3- (tert-butoxycarbonylamino) propylamino] -2-chloroquinoline 0.15 g
(0.428 mmol) was obtained as pale yellow crystals. The spectroscopic data of this product are as follows.

¹ H-NMR (CDCl ₃ ) δ (ppm): 1.
49 (9H, s), 1.73 (2H, m), 3.29 (2
H, t, J = 6.2Hz), 3.35 (2H, q, J = 6.0H)
z), 4.28 (2H, bs), 4.60 (1H, br),
4.75 (1H, br), 7.44 (2H, m), 7.87
(1H, d, J = 7.6Hz), 7.94 (1H, d, J = 7.
6Hz)

(Example 8) 1- [3- (tert-butoxycarbonylamino) propyl
Ropil] -4-chloro-1H-imidazo [4,5-c]
Synthesis of quinoline 3-amino-4- [3- (tert-butoxycarbonylamino) propylamino] -2-chloroquinoline 0.15
g (0.428 mmol) to triethyl orthoformate
36 ml (2.14 mmol) was added and the mixture was stirred at 100 ° C. for 2 hours and further at 80 ° C. overnight. The reaction mixture was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography, and chloroform-methanol (150: 1 to 100:
1 v / v) elution fraction gave 0.14 g (0.388 mmo) of 1- [3- (tert-butoxycarbonylamino) propyl] -4-chloro-1H-imidazo [4,5-c] quinoline.
l) was obtained as a white powder (mp: 155-156 ° C). The spectroscopic data of this product are as follows.

IR (KBr) cm ^-1 : 3380,168
0.152 ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.47 (9H,
s), 2.22 (2H, m), 3.30 (2H, q, J = 6.
4Hz), 4.68 (2H, t, J = 7.2Hz), 4.7 (1
H, br), 7.66 (1H, t, J = 7.6 Hz), 7.72
(1H, t, J = 7.6Hz), 8.09 (1H, s), 8.1
6 (1H, d, J = 8.4Hz), 8.21 (1H, d, J =
8.4Hz)

Example 9 1- (3-aminopropyl) -4-chloro-1H-imi
Synthesis of Dazo [4,5-c] quinoline 1- [3- (tert-Butoxycarbonylamino) propyl] -4-chloro-1H-imidazo [4,5-c] quinoline 50 mg (0.139 mmol) in methylene chloride It was dissolved in 3 ml, 0.11 ml (1.39 mmol) of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 1 day. The reaction mixture was concentrated under reduced pressure, 1N-aqueous sodium hydroxide solution (1 ml) and brine were added to the residue,
The mixture was extracted 5 times with chloroform, dried (Na ₂ SO ₄ ), and concentrated under reduced pressure. The residue was triturated with diethyl ether (containing a small amount of methylene chloride), the precipitate was collected by filtration, and 1-
14 mg (0.0536 mmol) of (3-aminopropyl) -4-chloro-1H-imidazo [4,5-c] quinoline were obtained as a white powder. The spectroscopic data of this product are as follows.

IR (KBr) cm ^-1 : 3400,159
0,151 ¹⁰ H-NMR (CDCl ₃ + CD ₃ OD) δ (ppm): 2.
06 (2H, m), 2.72 (2H, t, J = 6.8Hz),
2.98 (2H, br), 4.64 (2H, t, J = 7.0H
z), 7.57 (1H, t, J = 7.6Hz), 7.61 (1
H, t, J = 7.6 Hz), 8.03 (1 Hs), 8.05
(1H, d, J = 8.0Hz), 8.11 (1H, d, J = 8.0.
0Hz)

Example 10 1- (3-Aminopropyl) -1H-imidazo [4,5]
Synthesis of -c] quinolin-4-amine (Part 2) 1- (3-aminopropyl) -4-chloro-1H-imidazo [4,5-c] quinoline 14 mg (0.0536 mmol)
Was placed in a pressure-resistant steel reaction tube, 5 ml of methanol and 3 ml of liquid ammonia under cooling were added, and the mixture was heated to 150 ° C. and stirred overnight. The reaction mixture was concentrated under reduced pressure, to the residue was added 1N-sodium hydroxide aqueous solution (0.3 ml), and the precipitate was collected by filtration.
(3-Aminopropyl) -1H-imidazo [4,5-
8 mg (0.0331 mmol) of c] quinolin-4-amine was obtained. The physical properties of this product were in agreement with those of the compound of Example 5.

Example 11 4-Benzylamino-1- [3- (tert-butoxy)
Carbonylamino) propyl] -1H-imidazo [4,
Synthesis of 5-c] quinoline 1- [3- (tert-butoxycarbonylamino) propyl] -4-chloro-1H-imidazo [4,5-c] quinoline 30 mg (0.0831 mmol) and benzylamine 1 ml.
Was added, and the mixture was heated to 150 ° C. and stirred for 3 hours. Excess benzylamine was distilled off under reduced pressure, 1N-hydrochloric acid and brine were added, and the mixture was extracted twice with methylene chloride. The organic phase was washed with saturated aqueous sodium hydrogen carbonate solution, dried (Na ₂ SO ₄ ), and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and chloroform-methanol (15
0: 1 v / v) The elution fraction allows 4-benzylamino-1
-[3- (tert-Butoxycarbonylamino) propyl] -1H-imidazo [4,5-c] quinoline 35 mg
(0.08111 mmol) as a white powder (mp: 171-17)
2.5 ° C.). The spectroscopic data of this product are as follows.

IR (KBr) cm ⁻¹ : 3330, 170
0,1590,1540 ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.46 (9H,
s), 2.18 (2H, m), 3.25 (2H, m), 4.
57 (2H, t, J = 7.0Hz), 4.64 (1H, b
r), 4.95 (2H, d, J = 5.2Hz), 6.05
(1H, br), 7.26-7.36 (4H, m), 7.4
7 (2H, d, J = 7.6Hz), 7.51 (1H, t, J =
7.6 Hz), 7.82 (1H, s), 7.92 (2H, t, J
= 8.0Hz)

Example 12 1- (3-Aminopropyl) -1H-imidazo [4,5]
-C] Synthesis of quinolin-4-amine (3) 4-benzylamino-1- [3- (tert-butoxycarbonylamino) propyl] -1H-imidazo [4,
30 mg (0.0695 mmol) of 5-c] quinoline was added to 3 m of formic acid.
Dissolve in l, palladium hydroxide-carbon [20%] 0.1 g
Was added and the mixture was heated under reflux for 1 day. The reaction solution was filtered and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the target acetate salt was extracted from the fraction eluted with chloroform-methanol-32% acetic acid (6: 3: 1 v / v). Get
The crystals were collected by filtration with an alkali to give 7-mg (0.0290 mmol) of 1- (3-aminopropyl) -1H-imidazo [4,5-c] quinolin-4-amine as a slightly brown powder. The physical properties of this product were in agreement with those of the compound of Example 5.

Example 13 4- [4- (tert-butoxycarbonylamino) butyl
Synthesis of Amino] -2-chloro-3 -nitroquinoline 0.72 g (2.4-dichloro-3-nitroquinoline)
97 mmol) and N- (tert-butoxycarbonyl)-
0.56 g (2.97 mmol) of 1,4-diaminobutane was heated to 70 ° C. in 12 ml of triethylamine and stirred for 1.5 hours. After concentration under reduced pressure, the residue was dissolved in methylene chloride, washed with water and dried (MgSO ₄ ), and the solvent was evaporated under reduced pressure. The residue is n-hexane-diethyl ether (1: 1 v /
Triturated with v) and filtered to give 4- [4- (ter
t-butoxycarbonylamino) butylamino] -2-
Chloro-3-nitroquinoline 0.97 g (2.46 mmol)
Was obtained as a yellow powder (mp: 125-126.5 ° C.). The spectroscopic data of this product are as follows.

IR (KBr) cm ^-1 : 3340,328
0,1680,1540,1520 ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.46 (9H,
s), 1.63 (2H, m), 1.78 (2H, m), 3.
19 (2H, q, J = 6.4Hz), 3.47 (2H, q, J =
6.1Hz), 4.68 (1H, br), 6.41 (1H, b)
r), 7.52 (1 H, t, J = 7.7 Hz), 7.74 (1
H, t, J = 7.8Hz), 7.91 (1H, d, J = 8.4H)
z), 8.11 (1H, d, J = 8.4Hz)

Example 14 3-Amino-4- [4- (tert-butoxycarbonyl)
Synthesis of ( mino) butylamino] -2-chloroquinoline 4- [4- (tert-butoxycarbonylamino) butylamino] -2-chloro-3-nitroquinoline 0.5 g
(1.27 mmol) was dissolved in 13 ml of ethanol, 1.0 g (4.43 mmol) of tin chloride [II] .dihydrate was added, and the mixture was heated under reflux for 1 hour. Pour the reaction solution into 2N-ammonia water,
Extracted twice with chloroform, washed (saline solution) and dried (N
a ₂ SO ₄ ) and then the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and the target substance was collected by an elution fraction of n-hexane-ethyl acetate (2: 1 v / v),
After distilling off the solvent, triturate with diethyl ether to give 3
-Amino-4- [4- (tert-butoxycarbonylamino) butylamino] -2-chloroquinoline 0.12 g
(0.329 mmol) was obtained as orange crystals. The spectroscopic data of this product are as follows.

IR (KBr) cm ^-1 : 3270,168
0,1540,760 ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.44 (9H,
s), 1.64 (4H, m), 3.17 (2H, q, J = 6.
0Hz), 3.27 (2H, t, J = 6.6Hz), 3.89
(1H, br), 4.15 (2H, bs), 4.59 (1
H, br), 7.47 (2H, m), 7.77 (1H, d, J
= 7.6Hz), 7.89 (1H, d, J = 7.2Hz)

Example 15 1- [4- (tert-butoxycarbonylamino) butyl
]]-4-Chloro-1H-imidazo [4,5-c] quino
Synthesis of phosphorus 3-amino-4- [4- (tert-butoxycarbonylamino) butylamino] -2-chloroquinoline 0.14 g
Triethyl orthoformate 0.3 to (0.384 mmol)
2 ml (1.92 mmol) was added, heated to 100 ° C. and stirred overnight. The reaction mixture was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography, and 1- [4- (tert-butoxycarbonylamino) butyl was eluted with chloroform-methanol (150: 1 to 100: 1 v / v) elution fraction. ] -4-Chloro-1H-imidazo [4,5-c] quinoline 0.12 g (0.321 mmol) was added as a pale orange powder (m
p: 148-150 ° C). The spectroscopic data of this product are as follows.

IR (KBr) cm ^-1 : 1695,1510 ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.42 (9H,
s), 1.62 (2H, m), 2.06 (2H, m), 3.
21 (2H, q, J = 6.4Hz), 4.58 (1H, b
r), 4.65 (2H, t, J = 7.4Hz), 7.66 (1
H, t, J = 7.2Hz), 7.72 (1H, t, J = 7.6H
z), 8.02 (1H, s), 8.13 (1H, d, J = 8.
4Hz), 8.21 (1H, d, J = 8.2Hz)

(Example 16) 1- (4-aminobutyl) -4-chloro-1H-imidazole
Synthesis of Zo [4,5-c ] quinoline 0.10 g (0.267 mmol) of 1- [4- (tert-butoxycarbonylamino) butyl] -4-chloro-1H-imidazo [4,5-c] quinoline It was dissolved in 6 ml of methylene chloride, 0.21 ml (2.67 mmol) of trifluoroacetic acid was added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, 1N-sodium hydroxide aqueous solution (2 ml) and brine were added to the residue, and the mixture was extracted 5 times with chloroform, dried (Na ₂ SO ₄ ), and concentrated under reduced pressure. The residue was triturated with diethyl ether (containing a small amount of methylene chloride), the precipitate was collected by filtration, and 1
45 mg (0.164 mmol) of-(4-aminobutyl) -4-chloro-1H-imidazo [4,5-c] quinoline was obtained as a pale orange powder. The spectroscopic data of this product are as follows.

IR (KBr) cm ^-1 : 3400, 295
0,1670,1520,1360 ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.51 (2H,
m), 1.96 (2H, m), 2.66 (2H, t, J = 7.
2Hz), 3.03 (2H, bs), 4.53 (2H, t, J
= 7.4 Hz), 7.56 (1H, t, J = 7.4 Hz), 7.6
0 (1H, t, J = 7.5Hz), 7.97 (1H, s), 8.
02 (1H, d, J = 6.4Hz), 8.04 (1H, d, J =
6.4Hz)

Example 17 1- (4-aminobutyl) -1H-imidazo [4,5-
Synthesis of c] quinolin-4-amine 1- (4-aminobutyl) -4-chloro-1H-imidazo [4,5-c] quinoline 40 mg (0.146 mmol) was placed in a pressure-resistant steel reaction tube and methanol 8 ml was added. And 4 ml of liquid ammonia under cooling were added, and the mixture was heated to 150 ° C. and stirred overnight. The reaction solution was concentrated under reduced pressure, the residue was dissolved in a small amount of water,
0.5 ml of 1N aqueous sodium hydroxide solution was added. The precipitate was collected by filtration and recrystallized from ethanol to give 1- (4-aminobutyl) -1H-imidazo [4,5-c] quinoline-
14 mg (0.0548 mmol) of 4-amine was obtained as pale yellowish green crystals (mp: 227-230.5 ° C (decomposition)).
The spectroscopic data of this product are as follows.

IR (KBr) cm ^-1 : 3340,318
0,1650,1530,1400 ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 1.30 (2
H, br), 1.39 (2H, m), 1.89 (2H,
m), 2.55 (2H, t, J = 6.8Hz), 4.59 (2
H, t, J = 7.0 Hz), 6.56 (2H, bs), 7.26
(1H, t, J = 7.4Hz), 7.44 (1H, t, J = 7.
7Hz), 7.62 (1H, d, J = 8.0Hz), 8.05
(1H, d, J = 8.0Hz), 8.19 (1H, s)

Example 18 4-Benzylamino-1- [4- (tert-butoxycal
Bonylamino) butyl] -1H-imidazo [4,5-
Synthesis of c] quinoline 1- [4- (tert-butoxycarbonylamino) butyl] -4-chloro-1H-imidazo [4,5-c] quinoline 70 mg (0.187 mmol) was added with benzylamine (2 ml) and the temperature was 150 ° C. It was heated to and stirred for 3 hours. Excess benzylamine was distilled off under reduced pressure, 1N-hydrochloric acid and brine were added, and the mixture was extracted twice with methylene chloride. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, dried (Na ₂ SO ₄ ), and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and chloroform-methanol (15
0: 1 v / v) The elution fraction allows 4-benzylamino-1
-[4- (tert-butoxycarbonylamino) butyl]
-1H-imidazo [4,5-c] quinoline 79 mg (0.1
77 mmol) as a white powder (mp: 151-153.5 ° C.)
As obtained. The spectroscopic data of this product are as follows.

IR (KBr) cm ^-1 : 3380,331
0,2930,1680,1595,1540,124
5,1160 ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.42 (9H,
s), 1.58 (2H, m), 2.02 (2H, m), 3.
18 (2H, m), 4.55 (2H, t, J = 7.4Hz),
4.55 (1H, br), 4.95 (2H, d, J = 5.6H
z), 6.03 (1H, t, J = 5.6Hz), 7.23-7.
36 (4H, m), 7.47 (2H, d, J = 7.6Hz),
7.51 (1H, t, J = 7.8Hz), 7.75 (1H,
s), 7.90 (2H, d, J = 8.0Hz)

(Example 19) 1- (4-aminobutyl) -1H-imidazo [4,5-
c] Synthesis of quinolin-4-amine 4-benzylamino-1- [4- (tert-butoxycarbonylamino) butyl] -1H-imidazo [4,5-
67 mg (0.150 mmol) of c] quinoline was dissolved in 5 ml of formic acid, 0.15 g of palladium hydroxide-carbon [20%] was added, and the mixture was heated under reflux for 2 days. The reaction solution was filtered, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography. Chloroform-methanol-32% acetic acid (6: 3: 1 v / v) elution fraction gave the target acetate salt. Get
The mixture was treated with alkali and the solid was collected by filtration to give 1- (4-aminobutyl) -1H-imidazo [4,5-c] quinolin-4-amine (14 mg, 0.0548 mmol) as a pale brown powder. The physical properties of this product were in agreement with those of the compound of Example 17.

Example 20 1- [3-[[4- (diphenylmethoxy) -1-pipet
Lysine acetyl] amino] propyl] -1H-imidazo
Synthesis of [4,5-c] quinolin-4-amine a) 0.10 g (1.1 mmol) of chloroacetic acid and 1- (3
-Aminopropyl) -1H-imidazo [4,5-c] quinolin-4-amine 0.24 g (1 mmol) was suspended in 30 ml of N, N-dimethylformamide and 1- (3-dimethylaminopropyl) -3- Ethylcarbodiimide hydrochloride (EDCI) (0.29 g, 1.5 mmol) was added and the mixture was stirred at room temperature for 1 hour.
Stirred overnight. Water was added to the reaction solution, and once with chloroform,
It was extracted three times with chloroform-methanol (10: 1 v / v). The organic layer was washed with brine and dried (Na ₂ SO ₄ ).
Then, the solvent was distilled off under reduced pressure to give 1- [3-[(chloroacetyl) amino] propyl] -1H-imidazo [4,5-
A crude product of c] quinolin-4-amine was obtained. This compound was unstable and was used in the next reaction without purification.

B) The crude product of 1- [3-[(chloroacetyl) amino] propyl] -1H-imidazo [4,5-c] quinolin-4-amine obtained in a) was dissolved in 5 ml of ethanol. Then, 4- (diphenylmethoxy) piperidine hydrochloride (0.14 g, 0.472 mmol) and sodium hydrogencarbonate (48 mg, 0.566 mmol) were added, and the mixture was heated under reflux for 7 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and chloroform-methanol (30: 1 to 20:
1 v / v) elution fraction showed 1- [3-[[4- (diphenylmethoxy) -1-piperidineacetyl] amino] propyl] -1H-imidazo [4,5-c] quinoline-4.
20 mg (0.0364 mmol) of amine was obtained as a pale yellow amorphous. The spectroscopic data of this product are as follows.

IR (KBr) cm ^-1 : 3320,165
0,1525,1070,700 ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.70 (2H,
m), 1.86 (2H, m), 2.19 (2H, m), 2.
27 (2H, t, J = 10.4Hz), 2.74 (2H,
m), 2.98 (2H, s), 3.39 (2H, q, J = 6.
5Hz), 3.45 (1H, m), 4.54 (2H, t, J =
7.0 Hz), 5.49 (1H, s), 5.60 (2H, b)
s), 7.21-7.36 (10H, m), 7.38 (1
H, t, J = 7.2Hz), 7.51 (1H, t, J = 7.7H)
z), 7.82 (1H, d, J = 8.2Hz), 7.89 (1
H, s), 7.90 (1H, d, J = 8.0Hz)

(Example 21) 1- [3- (acrylamino) propyl] -1H-imi
Synthesis of Dazo [4,5-c] quinolin-4-amine 1- (3-aminopropyl) -1H-imidazo [4,5]
-C] quinolin-4-amine (0.24 g, 1 mmol) was added to N,
Suspending in 30 ml of N-dimethylformamide, 75 μl (1.1 mmol) of acrylic acid and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride 0.29
g (1.5 mmol) was added, and the mixture was stirred at room temperature for 3.5 hours. Water was added to the reaction solution, and the mixture was extracted once with chloroform and four times with chloroform-methanol (10: 1 v / v). The organic layer was washed with brine, dried (Na ₂ SO ₄ ), and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the target substance was collected by a fraction eluted with chloroform-methanol (8: 1 v / v). After distilling off the solvent, trituration with a small amount of chloroform and filtration were performed, and 1- [3- ( Acrylamino) propyl] -1H-imidazo [4,5-c] quinolin-4-amine 0.14 g (0.474 mmol) was obtained as a pale yellow powder (mp: 173-175 ° C). The spectroscopic data of this product are as follows.

IR (KBr) cm ⁻¹ : 3330,320
0,1630,1525 ¹ H-NMR (CDCl ₃ ) δ (ppm): 2.25 (2H,
m), 3.47 (2H, q, J = 6.5Hz), 4.61 (2
H, t, J = 7.0 Hz), 5.47 (2H, bs), 5.7
(1H, br), 5.71 (1H, d, J = 10.4Hz),
6.09 (1H, dd, J = 16.8, 10.4Hz), 6.3
2 (1H, d, J = 16.8Hz), 7.33 (1H, t, J =
7.6Hz), 7.53 (1H, t, J = 7.8Hz), 7.83
(1H, d, J = 8.4Hz), 7.92 (1H, s), 7.9
3 (1H, d, J = 8.2Hz)

Example 22 1- [3-[[4- (diphenylmethoxy) -1-pipet
Lysinepropanoyl] amino] propyl] -1H-imi
Synthesis of Dazo [4,5-c] quinolin-4-amine 1- [3- (acrylamino) propyl] -1H-imidazo [4,5-c] quinolin-4-amine 0.12 g
(0.406 mmol) was dissolved in 10 ml of ethanol, and 4-
(Diphenylmethoxy) piperidine hydrochloride 0.13g
(0.427 mmol) and 38 mg of sodium hydrogen carbonate (0.4
447 mmol) was added and the mixture was heated under reflux overnight. The insoluble material was filtered off, the filtrate was concentrated, and the residue was subjected to alumina column chromatography. Chloroform-methanol (4
(0: 1 v / v) The desired product was collected by the elution fraction, the solvent was distilled off, triturated with ether and collected by filtration.
[[4- (Diphenylmethoxy) -1-piperidinepropanoyl] amino] propyl] -1H-imidazo [4,
5-c] quinolin-4-amine 75 mg (0.133 mmo
l) was obtained as a pale yellow powder (mp: 178-182 ° C). The spectroscopic data of this product are as follows.

IR (KBr) cm ⁻¹ : 3330, 320
0, 1640, 1530, 1080, 700 ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.61 (2H,
m), 1.84 (2H, m), 2.13 (2H, m), 2.
20 (2H, m), 2.38 (2H, t, J = 6.0Hz),
2.54 (2H, t, J = 6.0Hz), 2.74 (2H,
m), 5.48 (1H, s), 7.21 to 7.54 (11
H, m), 7.51 (1H, t, J = 7.7 Hz), 7.83
(1H, d, J = 8.4Hz), 7.91 (1H, s), 7.9
4 (1H, d, J = 8.4Hz), 8.68 (1H, br)

(Example 23) 1- [4- (acrylamino) butyl] -1H-imidazole
Synthesis of zo [4,5-c] quinolin-4-amine 1- (4-aminobutyl) -1H-imidazo [4,5-
c] quinolin-4-amine (0.26 g, 1 mmol) was added to N, N
-Suspended in 30 ml of dimethylformamide, acrylic acid 7
5 μl (1.1 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride 0.29 g
(1.5 mmol) was added, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted once with chloroform and then extracted four times with chloroform-methanol (10: 1 v / v). The organic layer was washed with brine, dried (Na ₂ SO ₄ ), and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and chloroform-methanol (10: 1 to 8: 1 v /
v) Depending on the eluted fraction, 1- [4- (acrylamino) butyl] -1H-imidazo [4,5-c] quinoline-4-
90 mg (0.291 mmol) of amine was obtained as a pale yellow powder (mp: 176-178 ° C). The spectroscopic data of this product are as follows.

IR (KBr) cm ^-1 : 3320, 320
0,1640,1530 ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.65 (2H,
m), 2.04 (2H, m), 3.40 (2H, q, J = 6.
7Hz), 4.58 (2H, t, J = 7.2Hz), 5.50
(2H, br), 5.52 (1H, br), 5.65 (1
H, d, J = 10.2 Hz), 6.03 (1H, dd, J = 16.
8,10.4Hz), 6.27 (1H, d, J = 17.0H
z), 7.33 (1H, t, J = 7.6Hz), 7.53 (1
H, t, J = 7.7 Hz), 7.83 (1H, s), 7.83
(1H, d, J = 8.6Hz), 7.93 (1H, d, J = 8.
4Hz)

Example 24 1- [4-[[4- (diphenylmethoxy) -1-pipet
Lysinepropanoyl] amino] butyl] -1H-imida
Synthesis of z [4,5-c] quinolin-4-amine 1- [4- (acrylamino) butyl] -1H-imidazo [4,5-c] quinolin-4-amine 85 mg (0.27)
5 mmol) was dissolved in 7 ml of ethanol, and 88 mg (0.288 mmo) of 4- (diphenylmethoxy) piperidine hydrochloride was dissolved.
l) and 25 mg (0.302 mmol) of sodium hydrogen carbonate were added, and the mixture was heated under reflux overnight. The insoluble material was filtered off, the filtrate was concentrated, and the residue was subjected to alumina column chromatography. The target substance was collected by a fraction eluted with chloroform-methanol (50: 1 v / v), the solvent was distilled off, triturated with ether and collected by filtration to obtain 1- [4-[[4- (diphenylmethoxy) -1-piperidinepropa- Noil] Amino]
Butyl] -1H-imidazo [4,5-c] quinoline-4
-Amine 48 mg (0.0832 mmol) as white powder (m
p: 174-176 ° C). The spectroscopic data of this product are as follows.

IR (KBr) cm ^-1 : 3370,310
0,2950,1640,1530,1090,75
0.705 ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.48-1.6
3 (4H, m), 1.77 (2H, m), 2.01 (4H,
m), 2.30 (2H, t, J = 6.0Hz), 2.44 (2
H, t, J = 6.0 Hz), 2.63 (2H, m), 3.28
(2H, q, J = 6.5Hz), 3.37 (1H, m), 4.5
6 (2H, t, J = 7.2Hz), 5.42 (2H, bs),
5.47 (1H, s), 7.21-7.35 (11H,
m), 7.51 (1H, t, J = 7.7Hz), 7.81 (1
H, s), 7.82 (1H, d, J = 8.0 Hz), 7.92
(1H, d, J = 8.0Hz), 8.58 (1H, br)

(Example 25) 1- [3-[[4-[(4-chlorophenyl) phenyl]
Methoxy] -1-piperidinepropanoyl] amino] p
Ropil] -1H-imidazo [4,5-c] quinoline-4
-Synthesis of amine 1- [3- (acrylamino) propyl] -1H-imidazo [4,5-c] quinolin-4-amine 50 mg (0.1
69 mmol) was dissolved in 5 ml of ethanol, and 4-[(4-chlorophenyl) phenylmethoxy] piperidine hydrochloride (60 mg, 0.178 mmol) and sodium hydrogencarbonate (16 m) were added.
g (0.186 mmol) was added and the mixture was heated under reflux for 1 day. The insoluble material was filtered off, the solvent was evaporated, and the residue was subjected to alumina column chromatography. The target substance was collected by a fraction eluted with chloroform-methanol (40: 1 v / v), the solvent was distilled off, triturated with ether and collected by filtration, and 1- [3-
[[4-[(4-chlorophenyl) phenylmethoxy]]
-1-Piperidinepropanoyl] amino] propyl]-
1H-imidazo [4,5-c] quinolin-4-amine 4
0 mg (0.0669 mmol) of white powder (mp: 170-
172.5 ° C). The spectroscopic data of this product are as follows.

IR (KBr) cm ⁻¹ : 3320, 320
0,2940,1640,1530,1080 ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.59 (2H,
m), 1.81 (2H, m), 2.13 (2H, m), 2.
20 (2H, m), 2.37 (2H, t, J = 6.0Hz),
2.54 (2H, t, J = 5.8Hz), 2.72 (2H,
m), 3.37 (2H, q, J = 6.4Hz), 3.40 (1
H, m), 4.59 (2H, t, J = 7.0Hz), 5.43
(1H, s), 5.45 (2H, bs), 7.23-7.3
4 (10H, m), 7.51 (1H, t, J = 7.6Hz),
7.83 (1H, d, J = 8.4Hz), 7.91 (1H,
s), 7.94 (1H, d, J = 8.4Hz), 8.59 (1
H, br)

Example 26 1- [3- (4-chlorobutanoylamino) propyi
L] -1H-imidazo [4,5-c] quinoline-4-a
Synthesis of Min 1- (3-aminopropyl) -1H-imidazo [4,5]
-C] quinolin-4-amine (0.24 g, 1 mmol) was added to N,
After suspending in 30 ml of N-dimethylformamide, 0.11 ml (1.1 mmol) of 4-chlorobutyric acid and 0.29 g (1.5 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride were added at room temperature. Stirred overnight. Brine was added to the reaction solution, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with brine, dried (Na ₂ SO ₄ ), and the solvent was evaporated under reduced pressure. The residue was triturated with ether and water and collected by filtration to give 1- [3- (4-chlorobutanoylamino) propyl] -1H-imidazo [4,5-c] quinolin-4-amine 30 mg (0.0867 mmol). ) Was obtained as a light brown powder. The spectroscopic data of this product are as follows.

IR (KBr) cm ⁻¹ : 3330,320
0,1650,1530 ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 1.91-2.
04 (4H, m), 2.26 (2H, t, J = 7.4Hz),
3.12 (2H, q, J = 6.2Hz), 3.64 (2H, t,
J = 6.6Hz), 4.59 (2H, t, J = 6.8Hz), 6.
58 (2H, br), 7.26 (1H, t, J = 7.4H
z), 7.45 (1H, t, J = 7.8Hz), 7.62 (1
H, d, J = 8.0Hz), 8.03 (1H, d, J = 7.6H)
z), 8.05 (1H, br), 8.20 (1H, s)

Example 27 1- [3-[[4- (diphenylmethoxy) -1-pipet
Lysinebutanoyl] amino] propyl] -1H-imida
Synthesis of zo [4,5-c] quinolin-4-amine 1- [3- (4-chlorobutanoylamino) propyl] -1H-imidazo [4,5-c] quinolin-4-amine 25 mg (0 0.0722 mmol), 4- (diphenylmethoxy) piperidine hydrochloride 44 mg (0.144 mmol)
And 40 mg (0.289 mmol) of potassium carbonate in 3 ml of N, N-dimethylformamide were heated to 100 ° C. and stirred for 8 hours. Water was added to the reaction solution, extracted twice with chloroform, dried (Na ₂ SO ₄ ), and the solvent was evaporated under reduced pressure.
The residue was subjected to alumina column chromatography, the target product was collected by a fraction eluted with chloroform-methanol (150: 1 to 70: 1 v / v), and the solvent was distilled off, followed by trituration with ether to give 1- [3-[[ 15 mg (0.0260 mmol) of 4- (diphenylmethoxy) -1-piperidinebutanoyl] amino] propyl] -1H-imidazo [4,5-c] quinolin-4-amine as white powder (mp: 1)
58-162.5 ° C). The spectroscopic data of this product are as follows.

IR (KBr) cm ^-1 : 3200,164
0,1530,1070,700 ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.62 (2H,
m), 1.77 (4H, m), 2.10 (2H, m), 2.
19 (2H, m), 2.29 (2H, t, J = 7.0Hz),
2.34 (2H, t, J = 6.4Hz), 2.69 (2H,
m), 3.35 (2H, q, J = 6.5Hz), 3.40 (1
H, m), 4.58 (2H, t, J = 7.0Hz), 5.45
(2H, bs), 5.47 (1H, s), 7.19-7.3
4 (11H, m), 7.51 (1H, t, J = 7.7Hz),
7.82 (1H, t, J = 8.4Hz), 7.92 (1H,
s), 7.93 (1H, d, J = 8.2Hz)

Example 28 1- [3- (5-chlorolupentanoylamino) propyi
L] -1H-imidazo [4,5-c] quinoline-4-a
Synthesis of Min 1- (3-aminopropyl) -1H-imidazo [4,5]
-C] quinolin-4-amine 0.32 g (1.33 mmol)
Was suspended in 40 ml of N, N-dimethylformamide to give 5-
Chlorovaleric acid 0.15 ml (1.46 mmol) and 1- (3-
Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.38 g, 1.99 mmol) was added, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate and twice with chloroform-methanol (10: 1 v / v). The organic layer was washed with brine, dried (Na ₂ SO ₄ ),
The solvent was distilled off under reduced pressure. The residue was triturated with ether and collected by filtration, 0.16 g (0.445 mmol) of 1- [3- (5-chlorolupentanoylamino) propyl] -1H-imidazo [4,5-c] quinolin-4-amine. ) Was obtained as a light brown powder. The spectroscopic data of this product are as follows.

IR (KBr) cm ^-1 : 3470,329
0,1650,1525,1395 ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 1.62 (2
H, m), 1.70 (2H, m), 2.00 (2H, t, J =
7.0Hz), 2.12 (2H, t, J = 7.4Hz), 3.12
(2H, q, J = 6.3Hz), 3.62 (2H, t, J = 6.3.
2Hz), 4.59 (2H, t, J = 6.9Hz), 6.61
(2H, bs), 7.26 (1H, t, J = 7.6Hz), 7.
45 (1H, t, J = 7.8Hz), 7.63 (1H, d, J =
8.4 Hz), 7.98 (1H, br), 8.04 (1H, d,
J = 8.2Hz), 8.21 (1H, s)

Example 29 1- [3-[[4- (diphenylmethoxy) -1-pipet
Lysine pentanoyl] amino] propyl] -1H-imi
Synthesis of Dazo [4,5-c] quinolin-4-amine 1- [3- (5-chlorolupentanoylamino) propyl] -1H-imidazo [4,5-c] quinolin-4-amine 50 mg (0 .139 mmol), 42 mg (0.139 mmol) of 4- (diphenylmethoxy) piperidine hydrochloride and 58 mg (0.417 mmol) of potassium carbonate in 3 ml of N, N-dimethylformamide, heated to 100 ° C. and stirred for 7 hours. . The insoluble material was removed by filtration, and the solvent was evaporated under reduced pressure. The residue was subjected to alumina column chromatography,
Chloroform-methanol (100: 1 to 70: 1 v /
v) The target substance was collected by the elution fractions, the solvent was distilled off, triturated with ether, and collected by filtration to obtain 1- [3-[[4- (diphenylmethoxy) -1-piperidinepentanoyl] amino] propyl] -1H. 20 mg (0.0338 mmol) of imidazo [4,5-c] quinolin-4-amine were obtained as a white powder (mp: 152-154 ° C). The spectroscopic data of this product are as follows.

IR (KBr) cm ^-1 : 3330, 320
0,2940,1640,1530,1070,700 ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.50 (2H,
m), 1.64 (2H, m), 1.69 (2H, m), 1.84
(2H, m), 2.08 (2H, m), 2.19 (2H, m)
m), 2.20 (2H, t, J = 7.4Hz), 2.30 (2
H, t, J = 7.2 Hz), 2.70 (2H, m), 3.36
(2H, q, J = 6.5Hz), 3.41 (1H, m), 4.5
7 (2H, t, J = 7.0Hz), 5.45 (2H, bs),
5.49 (1H, s), 5.94 (1H, t, J = 5.8H
z), 7.21-7.37 (11H, m), 7.52 (1H,
t, J = 7.7 Hz), 7.83 (1H, d, J = 8.4 Hz),
7.90 (1H, s), 7.92 (1H, d, J = 8.4Hz)

Example 30 1- [3- (6-Bromohexanoylamino) propyi
L] -1H-imidazo [4,5-c] quinoline-4-a
Synthesis of Min 1- (3-aminopropyl) -1H-imidazo [4,5]
-C] quinolin-4-amine (0.24 g, 1 mmol) was added to N,
After suspending in 30 ml of N-dimethylformamide, 0.21 g (1.1 mmol) of 6-bromocaproic acid and 0.29 g (1.5 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride were added. , Stirred at room temperature overnight. Brine was added to the reaction solution, which was extracted twice with ethyl acetate, dried (Na ₂ SO ₄ ), and the solvent was evaporated under reduced pressure. The residue was triturated with ether and then water and collected by filtration, 1- [3
-(6-Bromohexanoylamino) propyl] -1H
-Imidazo [4,5-c] quinolin-4-amine 50 mg
(0.120 mmol) was obtained as an off-white powder. The spectroscopic data of this product are as follows.

IR (KBr) cm ⁻¹ : 3330, 320
0,1540,1540,13995 ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 1.36 (2
H, m), 1.52 (2H, m), 1.70 (2H, m),
2.00 (2H, m), 2.10 (2H, t, J = 7.0H
z), 3.11 (2H, m), 3.60 (2H, t, J = 6.
8Hz), 4.59 (2H, t, J = 7.0Hz), 6.56
(2H, bs), 7.25 (1H, t, J = 7.4Hz), 7.
44 (1H, t, J = 7.4Hz), 7.62 (1H, d, J =
7.8 Hz), 7.95 (1H, br), 8.03 (1H, d,
J = 7.4Hz), 8.20 (1H, s)

(Example 31) 1- [3-[[4- (diphenylmethoxy) -1-pipet
Lysine hexanoyl] amino] propyl] -1H-imi
Synthesis of Dazo [4,5-c] quinolin-4-amine 1- [3- (6-Bromohexanoylamino) propyl] -1H-imidazo [4,5-c] quinolin-4-amine 45 mg (0. 108 mmol), 4- (diphenylmethoxy) piperidine hydrochloride 65 mg (0.215 mmol) and potassium carbonate 59 mg (0.430 mmol) were heated to 100 ° C. in 3 ml of N, N-dimethylformamide and stirred for 8 hours. Water was added to the reaction solution and extracted twice with chloroform,
After drying (Na ₂ SO ₄ ), the solvent was distilled off under reduced pressure. The residue was subjected to alumina column chromatography, the target substance was collected by a fraction eluted with chloroform-methanol (150: 1 to 70: 1 v / v), the solvent was distilled off, triturated with ether and collected by filtration. 28 mg (0.0462 mmol) of-[[4- (diphenylmethoxy) -1-piperidinehexanoyl] amino] propyl] -1H-imidazo [4,5-c] quinolin-4-amine as a pale yellow powder (mp:
151-155 ° C). The spectroscopic data of this product are as follows.

IR (KBr) cm ^-1 : 3330,294
0, 1630, 1540, 1070, 700 ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.31 (2H,
m), 1.48 (2H, m), 1.63 (2H, m), 1.
70 (2H, m), 1.86 (2H, m), 2.07 (2
H, m), 2.17 (2H, t, J = 7.6Hz), 2.20
(2H, m), 2.27 (2H, t, J = 7.6Hz), 2.7
1 (2H, m), 3.37 (2H, q, J = 6.5Hz), 3.
42 (1H, m), 4.57 (2H, t, J = 6.8Hz),
5.45 (2H, bs), 5.50 (1H, s), 5.62
(1H, t, J = 6.0Hz), 7.21-7.37 (11H,
m), 7.53 (1H, t, J = 7.7Hz), 7.83 (1
H, d, J = 8.4 Hz), 7.90 (1H, s), 7.93
(1H, d, J = 8.2Hz)

Example 32 Formulation: An ointment containing the compound of the present invention was prepared by the following method. The compound of the present invention 0.2 g Sorbitan monolaurate (SP-20) 2.0 g Isopropyl myristate (IPM) 0.4 g White petrolatum 7.4 g Total amount 10.0 g

To 2 g of sorbitan monolaurate (SP-20) heated to 80 ° C., 0.2 g of the compound of the present invention was added and dissolved by stirring. Isopropyl myristate (IP
After the addition of 0.4 g of M), 7.4 g of white petrolatum that had been separately dissolved by heating (80 ° C.) was added, and the mixture was cooled to room temperature with stirring.

Comparative Example 1 Preparation of 2% Imiquimod Ointment 5 g of isostearic acid heated to 80 ° C. was added to US Pat.
88 g of imiquimod synthesized by the method described in 88815
Was added and dissolved by stirring. To this was added 19.5 g of white petrolatum that had been heated and dissolved (80 ° C.), and the mixture was cooled to room temperature with stirring.

Comparative Example 2 Betamethasone valerate external preparation 0.12% Linderon V ointment (Shionogi Pharmaceutical Co., Ltd.) was used as it was.

(Example 33) Antihistamine action (1) Test method A male Hartley guinea pig (purchased by Hamley) having a body weight of 300 to 600 g was used. The test method is T.
Ishii et al. (Naunyn-Schmiedeberg's Arch. Pharmaco
L., 332, 219-223, 1986) with some modifications. After killing the guinea pig by exsanguination,
The trachea from the thyroid cartilage to the bronchial bifurcation is removed and transferred to a petri dish filled with nutrient solution. After carefully removing the tissue around the trachea, a transverse section having a width of 2 to 3 mm was cut out along the cricoid cartilage, and a trachea chain specimen was prepared from two pieces of the section. The specimen is a nutrient solution (Krebs bicarbonat) heated to 37 ℃.
Solution e: NaCl 118.1 mM, CaCl ₂ 2.5 mM, K
H ₂ PO ₄ 1.2 mM, KCl 4.6 mM, MgSO ₄ 1.0
mM, NaHCO ₃ 25 mM, glucose 11.1 mM, p
It was suspended in a 10 ml Magnus container filled with H: 7.65), and a mixed gas of 95% O ₂ and 5% CO ₂ was aerated. The initial load of the sample is set to 1g, and the isometric tension change is measured by the ink transducer lectric recorder (RIKADENKI R -50) recorded above.

The sample was incubated for 1 hour and then histamine (10 ⁻⁵ M) was administered to obtain a contractile response. This was repeated several times, and after the reaction of the sample became stable, it was used for the experiment. The test compound was pretreated for 20 minutes, and the inhibition rate was calculated from the histamine contraction height before and after the test compound administration.

Histamine dihydrochloride was added to physiological saline to obtain imiquimod (1-isobutyl-1H-imidazo [4,5-
c] quinolin-4-amine), diphenhydramine hydrochloride and the compound of the present invention are DMSO (dimethyl sulfoxide).
(The final concentration of DMSO in the Magnus container was
1%).

(2) Results The concentrations (IC ₅₀ values) of test compounds that inhibit histamine contraction in guinea pig tracheal muscle by 50% are shown in Table 1 below. The compounds of Examples 22, 24, 27, 29 and 31 strongly suppressed histamine contraction similarly to diphenhydramine.

[0119]

[Table 1]

Example 34 Skin Eosinophil Infiltration Inhibitory Action (1) Test Method As an animal, a 4-week-old Balb / c mouse (male) was purchased from CLEA Japan, Inc., and the experiment was conducted after 1 week of acclimatization period. I went to

Preparation of Mite Antigen Solution To 20 ml of a 0.9% aqueous sodium chloride solution, the mosquito deer (Dermatophagoides pteronyssinus: International B) was added.
iologicals, Inc.; Lot.No.14679) 1g, 30ml
Transfer to a homogenizing pot at 4000-45 under ice cooling.
Homogenized at 00 rpm (the homogenized solution was observed under a microscope and homogenized to such an extent that the original form of mites was not retained). The homogenized solution was transferred to a 50 ml centrifuge tube, centrifuged at 3500 rpm for 5 minutes at room temperature, and the supernatant was transferred to another centrifuge tube (solution A). By repeating this operation twice, Solution B and Solution C were obtained. Purified water (RO
Dialysis membrane thoroughly washed with water (Sanko Junyaku Co., Ltd .: Seamless C)
solutions A, B and C were each enclosed in ellulose Tubinng) and dialyzed against a 0.9% sodium chloride aqueous solution at 4 ° C. overnight. After dialysis, the amount of protein in solutions A, B, and C was measured using a protein assay kit (Protein assay Reagen
t BCA Kit: PIERCE, Inc.)
The protein concentration was adjusted to 0 μg / ml with a 0.9% sodium chloride aqueous solution. Mix these 3 solutions and dispense 10 ml each into a 15 ml polypropylene tube.
A mite antigen solution was used. This solution was frozen and stored at −80 ° C. until use.

Sensitization and Induction Sensitization solution was prepared by adding 1/40 volume of mite antigen solution to mite antigen solution. Sensitization was carried out by using Myjector (manufactured by Terumo) and subcutaneously administering 200 μl of this solution to the neck of a mouse. This sensitization method was performed three times every seven days including the first sensitization.

21 days after the first sensitization, 50 μl of a mite antigen solution prepared with a 0.9% sodium chloride aqueous solution to a protein concentration of 200 μg / ml was administered intradermally on the dorsal skin using a Myjector (Terumo). Went by.

Collection of Skin and Observation of Pathological Specimen 48 hours after induction, the mouse was sacrificed by cervical dislocation, the skin on the back was peeled off, and the skin was cut into 1 cm squares around the marked portion. The collected skin was placed in a 10% neutral formalin buffer solution (using a Corning 15 ml centrifuge tube) and left at room temperature for 1 day or more to be fixed. The fixed skin was subjected to Luna staining after preparing a paraffin section according to a conventional method (cutting out was performed at two places in the center of the skin sample and 2 mm above the head side in the direction perpendicular to the body axis). The sample was observed with an optical microscope (400 times), and the number of eosinophils per 1 cm of the section was counted. The inhibition rate by the drug (test compound) was calculated from the following formula.

Inhibition rate (%) = {(number of eosinophils in base material administration group-number of eosinophils in test compound administration group) / number of eosinophils in base material administration group) × 100

Preparation of Each Test Drug It was prepared by the method of Example 32.

Drug administration method Transdermal administration (occlusive dressing technique: occlusive dressing technique)
(ODT) The mouse was anesthetized with ether and the center of the back was shaved with an electric clipper so as not to damage the skin. An oil-based marker was used to pre-mark the area of the center of the back that was the point of induction. The drug (test compound) was applied on the marked portion of the back on the 3 cm square in the pre-administration, and after the induction, on the 2 cm square on the induced part. In addition, stretch tape (Johnson & Johnson MEDICAL IN
C: Erascotine). The control group applied only the substrate. The dose was 50 mg / animal, and the administration schedule was continuous injection for 3 days from the day before induction as follows.

The day before induction → the day of induction (immediately after induction) → the day after induction (total 3 times)

(2) Results 2% imiquimod ointment, Example compound 2% ointment, 0.1
Tables 2 and 3 show the inhibitory effect of each test drug of 2% betamethasone valerate ointment on the mite-induced mouse skin eosinophil infiltration reaction. Many of the compounds of Examples suppressed eosinophil infiltration to a level equal to or higher than that of betamethasone valerate ointment.

[0130]

[Table 2]

[0131]

[Table 3]

(Example 35) Biphasic ear edema inhibitory action (1) Test method As an animal, a 4-week-old Balb / c mouse (male) was purchased from CLEA Japan, Inc. I served.

Sensitization and challenge Sensitization and challenge were performed according to the method of Sawada et al. (Allergy, 43 (8), p1099, 1994). That is, 1 μg of ovalbumin (OVA) and 4 of aluminum hydroxide gel (alum)
Sensitization was carried out by intraperitoneally administering 250 μl of physiological saline containing mg. Further, after 2 weeks, additional sensitization was performed by the same method. The challenge was 5 days under ether anesthesia 10 days after the second sensitization.
μg OVA (20 μl) was injected intradermally into the ear. In the induction, a group was administered in which only physiological saline solution was administered instead of OVA in order to eliminate the effect of injection.

Measurement of biphasic ear edema reaction Since an ear edema reaction that peaks after 1 hour and 24 hours occurs when induced by OVA, the thickness of the ear at this time was measured using a dial thickness gauge, and the The effects of the drug and the test compound were examined.

Drug administration method The drug and the test compound were suspended in 1% carboxymethylcellulose (CMC) and orally or intraperitoneally administered 24 hours before and 2 hours before induction. 1 for solvent control group
Only% CMC was administered. Then, the inhibition rate was calculated by the drug (test compound) according to the following formula.

Inhibition rate (%) = {(ear thickness of OVA-induced drug administration group-ear thickness of saline-induced solvent administration group) / OVA
Ear thickness of the solvent-administered group-Ear thickness of the saline-induced solvent-administered group)} × 100

(2) Results As shown in Table 4, the compound of Example 22 orally or intraperitoneally administered at 32 mg / kg suppressed the immediate and delayed ear edema reaction more strongly than the same dose of imiquimod.

[0138]

[Table 4]

[0139]

As described above, the novel amide derivative can be obtained by the present invention. The amide derivative of the present invention strongly suppresses immediate-type and delayed-type allergic reactions due to its antihistamine effect and eosinophil infiltration suppressing effect, and is particularly useful for the treatment of atopic dermatitis.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Takao Iizuka 1500 Inoguchi, Nakai-cho, Ashigaragami-gun, Kanagawa Terumo Corporation

Claims (10)

[Claims] 1. An amide derivative represented by the following formula I: Embedded image In formula I, X represents a hydrogen atom or a halogen atom, and m
Represents an integer of 1 to 9 and n represents an integer of 2 to 12. 2. A pharmaceutical preparation containing the amide derivative according to claim 1. 3. A synthetic intermediate represented by the following formula II. Embedded image In Formula II, X ′ represents a halogen atom, m is an integer of 1 to 9, and n is an integer of 2 to 12. 4. A synthetic intermediate represented by the following formula II ′. Embedded image In formula II ′, n represents an integer of 2 to 12. 5. A synthetic intermediate represented by the following formula III. Embedded image In formula III, n represents an integer of 2 to 12. 6. A synthetic intermediate represented by the following formula IV: Embedded image In formula IV, n represents an integer of 2 to 12. 7. A synthetic intermediate represented by the following formula V: [Chemical 6] In formula V, when R is hydrogen, R ′ is an alkanoyl group having 1 to 8 carbon atoms and optionally a branched chain, a haloalkanoyl group having 1 to 8 carbon atoms and optionally a branched chain, carbon A phenylalkanoyl group which may have a halogen, nitro or methoxy substituent on the benzene ring and has 1 to 1 carbon atoms
2, a phenoxyalkanoyl group which may have a halogen, nitro or methoxy substituent on the benzene ring, an alkoxycarbonyl group which may have a branched chain having 1 to 8 carbon atoms, and a branched chain which has 1 to 8 carbon atoms. Or a phenylalkoxycarbonyl group having 1 to 12 carbon atoms and optionally having a halogen, nitro or methoxy substituent on the benzene ring. Also,
R and R'combine to form an aromatic cyclic imide which may have halogen, nitro or methoxy substituents. n represents an integer of 2 to 12. 8. A synthetic intermediate represented by the following formula VI: Embedded image In the formula VI, when R is hydrogen, R ′ is an alkanoyl group having 1 to 8 carbon atoms and optionally having a branched chain, a haloalkanoyl group having 1 to 8 carbon atoms and optionally having a branched chain, carbon Number 1-12
And a phenylalkanoyl group optionally having a halogen, nitro or methoxy substituent on the benzene ring, having 1 to 1 carbon atoms
12, a phenoxyalkanoyl group which may have a halogen, nitro or methoxy substituent on the benzene ring, an alkoxycarbonyl group which has 1 to 8 carbon atoms and may have a branched chain, and a branched chain which has 1 to 8 carbon atoms. Or a phenylalkoxycarbonyl group having 1 to 12 carbon atoms and optionally having a halogen, nitro or methoxy substituent on the benzene ring. Also,
R and R'combine to form an aromatic cyclic imide which may have halogen, nitro or methoxy substituents. n represents an integer of 2 to 12. 9. A synthetic intermediate represented by the following formula VII. Embedded image In formula VII, when R is hydrogen, R ′ is an alkanoyl group having 1 to 8 carbon atoms and optionally a branched chain, a haloalkanoyl group having 1 to 8 carbon atoms and optionally a branched chain, carbon Number 1-12
And a phenylalkanoyl group optionally having a halogen, nitro or methoxy substituent on the benzene ring, having 1 to 1 carbon atoms
12, a phenoxyalkanoyl group which may have a halogen, nitro or methoxy substituent on the benzene ring, an alkoxycarbonyl group which has 1 to 8 carbon atoms and may have a branched chain, and a branched chain which has 1 to 8 carbon atoms. Or a phenylalkoxycarbonyl group having 1 to 12 carbon atoms and optionally having a halogen, nitro or methoxy substituent on the benzene ring. Also,
R and R'combine to form an aromatic cyclic imide which may have halogen, nitro or methoxy substituents. n represents an integer of 2 to 12. 10. A synthetic intermediate represented by the following formula VIII: Embedded image In formula VIII, when R is hydrogen, R ′ represents an alkanoyl group having 1 to 8 carbon atoms and optionally a branched chain, a haloalkanoyl group having 1 to 8 carbon atoms and optionally a branched chain, carbon Number 1 to 1
2, a phenylalkanoyl group which may have a halogen, nitro or methoxy substituent on the benzene ring, and has 1 carbon atom
A phenoxyalkanoyl group which may have a halogen, nitro or methoxy substituent on the benzene ring, an alkoxycarbonyl group which may have a branched chain with 1 to 8 carbon atoms, and a branched chain with 1 to 8 carbon atoms. A haloalkoxycarbonyl group which may have or a phenylalkoxycarbonyl group which has 1 to 12 carbon atoms and may have a halogen, nitro or methoxy substituent on the benzene ring is shown. Also,
R and R'combine to form an aromatic cyclic imide which may have halogen, nitro or methoxy substituents. n represents an integer of 2 to 12.