JPH04282370A - Dihydroxyquinoline derivative - Google Patents

Abstract

PURPOSE:To obtain the new title compound having action capable of suppressing peroxilipid production and useful for prevention and treatment of arteriosclerosis, liver disease, cerebrovascular accident, etc. CONSTITUTION:A compound expressed by formula I (ring A is a benzene ring having 1-4 substituent groups and at least one in these substituent groups in an unsaturated aliphatic group; R<1> and R<2> are aliphatic; R<3> and R<4> are H, aliphatic or aromatic ring), e.g. 6-styryl-2,2,4-trimethyl-1,2-dihydroquinoline hydrochloride. The compound expressed by formula I is obtained by subjecting a compound expressed by formula II to dehydrogenation reaction with a compound expressed by formula II in the presence of an acid (e.g. hydrochloride) in a solvent such as xylene at 100-175 deg.C. The objective derivative has improvement of metabolism of polyvalent unsaturated fatty acid, action capable of suppressing production of 5-lipoxygenase based metabolite, action capable of inhibiting thromboxane A2 synthetic enzyme, action capable of promoting storage of prostaglandin I2 synthetic enzyme, LTD4 receptor antagonism as well as anti- allergic action, etc.

Description

[Detailed description of the invention]

0001

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel cyclic amine derivative or a salt thereof and a pharmaceutical composition containing the same as an active ingredient. More specifically, novel cyclic amine derivatives or salts thereof, which have an inhibitory effect on lipid peroxide production and are useful for the prevention and treatment of various diseases such as arteriosclerosis, liver disease, and cerebrovascular disorders, and lipid peroxide containing the same as an active ingredient. Regarding generation inhibitors.

0002

[Prior art and problems to be solved by the invention] It has become clear that the production of lipid peroxide in the body and the accompanying radical reactions have various adverse effects on the living body through membrane damage, enzyme damage, etc. Over time, antioxidants and lipid peroxide production inhibitors have come to be applied to medicines. Currently, lipid peroxide production inhibitors used in these fields are mainly derivatives of natural antioxidants such as vitamin C and vitamin E, and phenol derivatives, but their basic skeletons are limited and they are not practical. is not necessarily satisfactory. In order to widely utilize lipid peroxide production inhibitors in the medical field, there is a need to develop lipid peroxide production inhibitors having a new structure. The main object of the present invention is to provide a novel compound having such an effect of inhibiting lipid peroxide production and a lipid peroxide production inhibitor containing the same as an active ingredient.

0003

[Means for Solving the Problems] In order to solve the above-mentioned problems, the present inventors synthesized a number of new compounds and investigated the antioxidant activity and lipid peroxide production inhibiting effect of each compound. As a result, the formula [I]

[In the formula, ring A represents a benzene ring having 1 to 4 substituents, at least one of the substituents is an unsaturated aliphatic group substituted with an aromatic ring, and R1 and R2 are the same or different and are an aliphatic group which may have a substituent; R3 and R4 are the same or different and are a hydrogen atom or an aliphatic group which may each have a substituent; Indicates an aromatic ring group. ] We succeeded in creating a novel cyclic amine derivative or its salt represented by completed.

[0004] Antioxidant compounds having a structure similar to the compound represented by formula [I] include formula [II]

The compound represented by [C.C. Tung, Tetrahcdron, 19
, 1685 (1963)] and formula [III]

Examples include the compound represented by the formula (Japanese Patent Publication No. 11103/1983). However, Compound [II] was developed as an additive to feed, and Compound [III] was developed as a stabilizer for plastics such as rubber, and their use in pharmaceuticals has not been reported.

Thus, the present invention provides a novel cyclic amine derivative represented by formula [I], a salt thereof, and a pharmaceutical composition containing the same as an active ingredient, which is useful as a lipid peroxide production inhibitor. Among the compounds represented by formula [I],
Preferred compounds include formula [I']

embedded image [wherein R1, R2, R3 and R4 have the same meanings as above,
R5 represents an unsaturated aliphatic group substituted with an aromatic ring group, and R
6, R7 and R8 are the same or different, a hydrogen atom,
A hydroxyl group that may be protected, an aliphatic group or an alkoxy group that may each have a substituent, or a cyclic group in which two of R6, R7, and R8 may have a substituent may be formed. ] Compounds represented by:

In formula [I], the aliphatic group represented by R1 and R2 may be a saturated group or an unsaturated group, such as an alkyl group, an alkenyl group, an alkynyl group, etc. It will be done. The alkyl group may be linear, branched or cyclic. Among these alkyl groups,
Lower alkyl groups having about 1 to 6 carbon atoms are preferred, for example,
Methyl, ethyl, propyl, i-propyl, butyl, i
-butyl, t-butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl and the like. In addition, the alkenyl group represented by R1 and R2 is generally preferably one having 2 to 6 carbon atoms, for example,
Allyl, propenyl, i-propenyl, 2-butenyl,
Examples include 2,4-butadienyl and 2-pentenyl. Furthermore, the alkynyl group represented by R1 and R2 is generally preferably a group having 2 to 6 carbon atoms, such as ethynyl, 2-propynyl, and the like. The substituents that these aliphatic groups may have are not particularly limited, and may be any group commonly used in medicine. Specifically, for example, hydroxyl, C
1-3 alkoxy (e.g. methoxy, ethoxy, n-
propoxy or i-propoxy), mercapto, C
1-3 alkylthio (such as methylthio or ethylthio), arylthio (such as phenylthio),
amino, mono- or di-substituted amino substituted with C1-3 alkyl (such as methylamino, ethylamino or dimethylamino), halogen (such as chloro, bromo, iodo or fluoro), esterified carboxy (
For example, C1-6 alkoxycarbonyl such as methoxycarbonyl or ethoxycarbonyl), C2-5 acyl (
For example, alkylcarbonyl such as acetyl, propionyl), C2-5 acyloxy (e.g. alkylcarbonyl such as acetoxy, propionyloxy), C2-5 acylamide (e.g. alkylcarbonylamino such as acetamide), C2-5 alkoxycarbonylamino (e.g. methoxy carbonylamino or ethoxycarbonylamino), cyclic amino groups (e.g., 5- to 6-membered cyclic amino groups such as pyrrolidino and morpholino), carboxyl groups,
Examples include a carbamoyl group and an optionally substituted aromatic ring group. Examples of aromatic ring groups include phenyl groups,
Examples of substituents on the phenyl group include an amino group, a mono- or dialkylamino group substituted with a lower alkyl group having 1 to 3 carbon atoms, halogen (e.g., chloro, bromo, iodo or fluoro), nitro, sulfo, Cyano,
Hydroxy, carboxy, lower alkyl having 1 to 5 carbon atoms, lower alkoxy having 1 to 3 carbon atoms, acyl group having 2 to 5 carbon atoms (for example, C1-6 alkylcarbonyl), lower alkyl mercapto group having 1 to 3 carbon atoms Examples include. The number of substituents is not particularly limited.

[0007] The aliphatic groups represented by R3 and R4 and the substituents when these aliphatic groups have substituents are R1
and the same as in the case of R2. The aromatic ring group represented by R3 and R4 includes a phenyl group. Substituents on the phenyl group include, for example, an amino group, a mono- or dialkylamino group substituted with a lower alkyl group having 1 to 3 carbon atoms, a halogen group (e.g., chloro, bromo,
iodo or fluoro), nitro, sulfo, hydroxy, carboxy, lower alkyl having 1 to 5 carbon atoms, 1 carbon number
-3 lower alkoxy, a C2-5 acyl group, a C1-3 lower alkylmercapto group, and the like. The number of substituents is not particularly limited.

At least one of the substituents on the benzene ring represented by ring A is an unsaturated aliphatic group substituted with an aromatic ring group, and the unsaturated aliphatic group includes an alkenyl group and an alkynyl group. can be mentioned. As the alkenyl group, those having 2 to 4 carbon atoms are generally preferred, for example,
Examples include vinyl, 1-propenyl, 1,3-butadienyl, and the like. Examples of the alkynyl group include ethynyl group and the like. Examples of aromatic ring groups substituted with these unsaturated aliphatic groups include aromatic heterocyclic groups in addition to phenyl groups. The aromatic heterocyclic group is, for example, a 5 to 6 group containing 1 to 4, preferably 1 to 2, heteroatoms such as nitrogen, oxygen, and sulfur.
A membered aromatic ring is preferred. Specific examples of aromatic heterocyclic groups include:
Pyridyl, furyl, thienyl, pyrazinyl, pyrrolyl,
Examples include imidazolyl and isoxazolyl. Furthermore, a group in which the same or different aromatic ring (the above-mentioned aromatic heterocycle or aromatic carbocycle) is condensed to such an aromatic ring group is also preferable. Examples of these fused rings include, for example, indolyl,
Examples include benzimidazolyl, quinolyl, imidazopyridyl and thiazolopyridyl. When the aromatic ring group has a substituent, the substituent is the same as that of the aromatic ring group represented by R3 and R4. The number of substituents is preferably 1-4.

The other substituents on ring A are not particularly limited, and may be any group that is normally used in medicine. For example, R6 and R7 in formula [I']
Alternatively, a group other than a hydrogen atom represented by R8 may be mentioned. In formula [I'], the unsaturated aliphatic group substituted with an aromatic ring group represented by R5 is as defined above, and R
Examples of the protecting group for the optionally protected hydroxyl group represented by R7 or R8 include an acyl group, and examples of the acyl group include a linear or branched acyl group having 2 to 5 carbon atoms (preferably is alkylcarbonyl). Further, the aliphatic group represented by R6, R7 or R8 and its substituent include the same groups as defined for R1 and R2 above, and the alkoxy group has 1 to 1 carbon atoms.
6, a straight-chain or branched alkyl group, or an alkoxy group consisting of a cyclic alkyl group. Examples of the substituent that the alkoxy group has include an amino group, a mono- or dialkylamino group substituted with a lower alkyl group having 1 to 3 carbon atoms, halogen, hydroxy, lower alkoxy (preferably having 1 to 4 carbon atoms), Examples include lower alkylmercapto groups (preferably having 1 to 4 carbon atoms). Further, two of R6, R7 and R8 may form a cyclic group which may have a substituent, and in this case, a 5- or 6-membered saturated or unsaturated ring is preferred. The ring may be a carbon homocycle or a heterocycle containing nitrogen, oxygen or sulfur. Specific examples of such cyclic groups include benzene rings and pyridine rings. Examples of the substituent include an alkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, and a hydroxyl group.

The compound represented by formula [I] may have stereoisomers depending on the type of substituent, and the present invention includes not only these isomers alone but also mixtures thereof. The salt of the compound represented by formula [I] is preferably a pharmaceutically acceptable salt, and examples of pharmaceutically acceptable salts include hydrohalic acid (e.g., hydrochloric acid, hydrobromic acid), ), inorganic acids such as phosphoric acid and sulfuric acid, and organic carboxylic acids (e.g.
Examples include organic acids such as oxalic acid, phthalic acid, fumaric acid, maleic acid), and sulfonic acids (eg, methanesulfonic acid, benzenesulfonic acid). In addition, when compound [I] has an acidic group such as a carboxyl group as a substituent, inorganic base salts with alkali metals (e.g., sodium, potassium) or alkaline earth metals (e.g., magnesium) and organic bases (e.g. , dicyclohexylamine, triethylamine, 2,6-lutidine, and other amines). Hereinafter, the compound represented by formula [I] and its salt will be collectively referred to as compound [I].

Compound [I] of the present invention can be produced, for example, by the method shown in Reaction Formula-1. Reaction formula-1

embedded image [In the formula, A ring, R1, R2, R3 and R4 have the same meanings as above, and formula [V] is β-hydroxyketone or α,
Indicates a β-unsaturated ketone. ] That is, compound [I] is obtained by reacting compound [IV] and compound [V] in the presence of an acid. The acid used is not particularly limited, but hydrogen chloride, hydrogen bromide, hydrogen iodide, etc. are generally used, and iodine or bromine may be used instead of hydrogen halide. When using these acids, small amounts of aluminum chloride, iron chloride, zinc chloride, etc. may be added. The solvent is
Any material may be used as long as it does not inhibit the reaction, but benzene, toluene, xylene, butanol, etc. are common. In some cases, no solvent may be used. This reaction is a dehydration reaction, and during the reaction, it is preferable to remove water from the reaction system using an azeotrope or a molecular sieve. The reaction temperature is usually 100-175°C, preferably 130-150°C. The time required for the reaction is 2 to 24 hours. R1,
The groups represented by R2, R3 and R4 and the substituents on ring A are replaced at any stage by R1, R2, R3 and R, respectively.
It may be converted into other groups represented by 4 and other substituents on the A ring. Compound (I) thus obtained can be isolated by conventional separation and purification means (eg, extraction, chromatography, recrystallization, etc.). In addition, the compound (I
) exists as diastereomers, each can be isolated by the separation and purification means described above, if desired. Furthermore, when Compound (I) is an optically active form, it can be separated into d-form and l-form by ordinary optical resolution means. Compounds [IV] and [V] and their salts used as raw materials can be easily produced by known methods or methods analogous thereto.

Compound [I] of the present invention improves the metabolism of polyunsaturated fatty acids (linoleic acid, γ-linolenic acid, α-linolenic acid, arachidonic acid, dihomo-γ-linolenic acid, eicosapentaenoic acid), particularly , the effect of suppressing the lipid peroxide production reaction (antioxidant effect), 5-lipoxygenase metabolites [e.g., leukotrienes, 5-hydroperoxyeicosatetraenoic acid (HPETE), 5-hydroxyeicosatetraenoic acid ( HETE), lipoxins, leukotoxins, etc.], thromboxane A
It has circulatory system-improving effects and antiallergic effects, such as inhibition of prostaglandin I2 synthase, retention promotion of prostaglandin I2 synthase, LTD4 receptor antagonism, and scavenging of reactive oxygen species. Among the above-mentioned effects, the compound [I] of the present invention has an effect of inhibiting lipid peroxide production reaction (antioxidant effect).
There is a tendency for this to be noticeable. In addition, the toxicity of compound [I],
Side effects are low. Therefore, the compound [I] of the present invention is suitable for mammals (mouse, rat, rabbit, dog, monkey, human, etc.)
Thrombosis due to platelet aggregation in the heart, lungs, brain, and kidneys, ischemic diseases (e.g., myocardial infarction, stroke), neurodegenerative diseases (e.g., Parkinson's disease, Alzheimer's disease, Lou Gehrig's disease, muscular dystrophy), functional disorders associated with central injuries such as head trauma and spinal cord trauma, memory disorders and emotional disorders (
Disorders associated with nerve cell necrosis caused by oxygen deficiency, brain damage, stroke, cerebral infarction, cerebral thrombosis, etc.), convulsions and epilepsy that occur after a stroke, cerebral infarction, brain surgery, or head trauma, nephritis, pulmonary failure, and bronchus Asthma, inflammation, arteriosclerosis, atherosclerosis, hepatitis, acute hepatitis, cirrhosis,
Hypersensitivity pneumonitis, immunodeficiency, enzymes caused by reactive oxygen species (superoxide, hydroxyl radicals, etc.), biological tissues,
Circulatory system diseases caused by disorders such as cells (
It has therapeutic and preventive effects on various diseases such as myocardial infarction, stroke, cerebral edema, nephritis), tissue fibrosis phenomenon, and carcinogenesis. Allergy medicine, heart and brain circulatory system improver, nephritis treatment,
It is useful as a preventive/therapeutic drug, such as a therapeutic agent for hepatitis, a tissue fibrosis inhibitor, an active oxygen species scavenger, and an agent for improving the regulation of arachidonic acid cascade substances.

Compound [I] or a salt thereof can be used as is,
Or safely administered orally or parenterally as a pharmaceutical composition (e.g., tablet, capsule, liquid, injection, suppository) mixed with a known pharmaceutically acceptable carrier, excipient, etc. be able to. The dosage varies depending on the subject, administration route, symptoms, etc., but for example, when orally administered to adult patients with circulatory system diseases, a single dose is usually about 0.1 mg/kg to 20 mg/kg. It is convenient to administer about the same amount as body weight, preferably about 0.2 mg/kg to 10 mg/kg body weight, about 1 to 3 times a day.

The results of testing the inhibitory effect of compound [I] on lipid peroxide production are shown below. Test Example 1 Effect of drug on behavioral changes due to intrathecal administration in ferrous chloride mice 5-week-old male SIc:I of 10 mice per group
CR mice were used. After injecting 5 μl/mouse of physiological saline containing 50 mM ferrous chloride into the subarachnoid space from the 6th lumbar spinal cord to the 1st sacral spinal cord, behavioral observations were made from 15 minutes to 1 hour, and behavioral changes were evaluated. The following criteria were used. Score behavior change 0 points:
Normal 1 point: Biting the lower limbs and lower abdomen frequently. 2 points: a) Biting the lower body violently and sometimes rolling around b) Hypersensitivity to external stimuli is observed and becomes aggressive. c) Tremor occurs. Any of the above three reactions is recognized. 3 points: Clonic convulsion is observed. 4 points: Tonic convulsion is observed. or paralysis of one or both limbs. 5 points: Death. The suppression rate was expressed based on the scores evaluated using the above criteria. The test compound was orally administered 30 minutes before administration of ferrous chloride. Table 1 shows the average score and each inhibition rate when 100 mg/kg of Compound [I] was orally administered.

[Table 1] From the above results, it can be seen that the compounds of the present invention have excellent suppressive effects on central nervous system disorders associated with lipid peroxide production caused by ferrous chloride.

[0015]

[Examples] The present invention will be explained in more detail with reference to Examples below, but the present invention is not limited to these Examples. Elution in column chromatography in the following examples was performed using TLC (Thin Layer Ch).
romatography, thin layer chromatography)
It was carried out under the observation of In TLC observation, TL
Merck Kieselgel 60F254 as C plate
The solvent used as the elution solvent in column chromatography was used as the developing solvent, and a UV detector was used as the detection method. As the silica gel for the column, Kieselgel 60 (70 to 230 mesh), also manufactured by Merck, was used. NMR spectra show proton NMR, Gemini20 using tetramethylsilane as internal reference.
0 (200MHz spectrometer), δ
Values are expressed in ppm. The abbreviations used in the examples have the following meanings. s: singlet, br: broad, d: doublet, t: triplet, q
: quartet, m: multiplet, dd: doublet of doublets, J: coupling constant, Hz: hertz, CDCl3: deuterated chloroform, d6-DMSO: deuterated dimethyl sulfoxide, %: weight%. Means 15-25°C.

Example 1 6-styryl-2,2,4-trimethyl-1,2-dihydroquinoline hydrochloride 4-aminostilbene (5.0 g), concentrated hydrochloric acid (0.2 m
A mixture of 1) and xylene (5 ml) was heated to 150° C. under an argon atmosphere and the water was azeotroped off with the xylene. Mesityl oxide (3.8 ml) was gradually added dropwise to this. After completion of the dropwise addition, the reaction solution was cooled, diluted with ethyl acetate, and then neutralized with saturated aqueous sodium bicarbonate solution. After further washing with saturated brine, it was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. After the residue was purified by column chromatography, it was converted into a hydrochloride using a hydrochloric acid ethanol solution. The obtained crude crystals were recrystallized from ethanol and had a melting point of 159-
The title compound was obtained as prismatic crystals at 161°C (yield: 1
．． 6g, yield 20.0%). IRν (KBr) cm-1: 2642, 1557, 15
02,1450,1390,6921H-NMR(d6
-DMSO) δ: 1.30 (6H, s), 2.02 (3
H, s), 5.49 (1H, br), 6.83-7.5
8 (10H, m) Elemental analysis C20H21N・HCl
Calculated value: C, 77.03; H, 7.11; N
, 4.49; Cl, 11.37 Analysis value: C, 76.
59; H, 7.05; N, 4.24; Cl, 11.33

Example 2 6-(4-methoxystyryl)-2,2,4-trimethyl-1,2-dihydroquinoline hydrochloride 4-amino-4'-methoxystilbene was prepared in the same manner as in Example 1. The title compound was obtained from and mesityl oxide (yield 14.7%). Melting point: 150-152°C (recrystallized from ethanol-ether) IRν (KBr) cm-1: 2638, 1605, 15
13,1253,1174,1032 1H-NMR (d6-DMSO) δ: 1.26 (6H,
s), 1.99 (3H, s), 3.76 (3H, s),
5.43 (1H, s), 6.66-6.76 (1H, m
), 6.89-6.96 (4H, m), 7.22-7.
27 (2H, m), 7.46 (2H, d, J = 8.4H
z) Elemental analysis Calculated value as C21H23NO/HCl: C, 73.78; H, 7.08; N, 4.10; C
l, 10.37 Analysis value: C, 73.79; H, 6.
89; N, 4.00; Cl, 10.31

Example 3 6-(3,4-dimethoxystyryl)-2,2,4-trimethyl-1,2-dihydroquinoline hydrochloride Example 1
In the same manner as above, the title compound was obtained from 4-amino-3',4'-dimethoxystilbene and mesityl oxide (yield 30.1%). Melting point: 188-190°C (recrystallized from ethanol) IR
ν (KBr) cm-1: 1511, 1462, 1262
, 1228, 1138, 1027 1H-NMR (CDCl3) δ: 1.64 (6H, s)
, 2.16 (3H, s), 3.92 (3H, s), 3.
96 (3H, s), 5.68 (2H, s), 6.85-
7.95 (8H, m) Elemental analysis value C22H25NO
Calculated value as 2.HCl: C, 71.05; H, 7.0
5; N, 3.77 Analysis value: C, 70.86; H, 6.9
3;N, 3.61

[0019]

Effects of the Invention According to the present invention, a novel cyclic amine derivative or a salt thereof is provided which has an inhibitory effect on lipid peroxide production and is useful for the prevention and treatment of various diseases such as arteriosclerosis, liver disease, and cerebrovascular disorders. Ru.

Claims (2)

[Claims] Claim 1: Formula [I] [In the formula, ring A represents a benzene ring having 1 to 4 substituents, and at least one of the substituents is an unsaturated ring substituted with an aromatic ring. R1 and R2 are the same or different aliphatic groups which may have a substituent; R3 and R4 are the same or different and each have a hydrogen atom or a substituent. Indicates an optionally aliphatic group or an aromatic ring group. ] or its salt. [Claim 2] Formula [I] [In the formula, ring A represents a benzene ring having 1 to 4 substituents, and at least one of the substituents is an unsaturated ring substituted with an aromatic ring. R1 and R2 are the same or different aliphatic groups which may have a substituent; R3 and R4 are the same or different and each have a hydrogen atom or a substituent. Indicates an optionally aliphatic group or an aromatic ring group. ] A lipid peroxide production inhibitor characterized by containing a compound represented by the following or a salt thereof as an active ingredient.