Claims
- 1. A compound of the formula ##STR29## wherein R.sup.1 and R.sup.2 are the same or different and are methyl or methoxy, or R.sup.1 and R.sup.2 bind together to form --CH.dbd.CH--CH.dbd.--,
- R.sup.3 is methyl,
- R.sup.4 is pyridyl or pyridyl substituted by 1 to 3 substituents selected from the group consisting of alkyl of 1 to 3 carbon atoms, phenyl, p-tolyl, m-tolyl, pyridyl and 3-pyridylmethyl,
- R.sup.5 is hydrogen, methyl, hydroxymethyl, methoxymethyl, acetoxymethyl, nitroxymethyl or carbamoyoloxymethyl,
- n is an integer of from 0 through 12,
- m is an integer of from 0 through 3
- k is an integer of from 0 through 7, and
- Z is --CH.dbd.CH--, ##STR30## wherein R' is hydrogen or methyl, or the corresponding hydroquinone derivative thereof.
- 2. A compound as claimed in claim 1, wherein m is 0 or 1.
- 3. A compound as claimed in claim 1, wherein m is 1 and k is an integer from 0 through 3.
- 4. A compound as claimed in claim 1 wherein R.sup.4 is pyridyl.
- 5. A compound according to claim 1 wherein R.sup.4 is 3-pyridyl.
- 6. A compound as claimed in claim 1, wherein each of R.sup.1 and R.sup.2 is methyl or R.sup.1 and R.sup.2 bind together to form --CH.dbd.CH--CH.dbd.CH--.
- 7. A compound as claimed in claim 1, wherein the compound is 3,5,6-trimethyl-2-(3-pyridyl)methyl-1,4-benzoquinone hydrochloride.
- 8. A compound as claimed in claim 1, wherein the compound is 3,5,6-trimethyl-2-[1-(3-pyridyl)ethyl]-1,4-benzoquinone.
- 9. A pharmaceutical composition for the treatment of a disease due to dysfunction of heart, brain, lung or kidney which comprises a pharmaceutically effective amount of a compound according to claim 1 or the corresponding hydroquinone derivative thereof and a pharmaceutically acceptable carrier therefor.
- 10. A method for the treatment of a disease due to dysfunction of heart, brain, lung or kidney which comprises administering to a mammal a pharmaceutically effective amount of a compound of claim 1 or the corresponding hydroquinone derivative thereof.
Priority Claims (2)
| Number |
Date |
Country |
Kind |
| 61-19547 |
Jan 1986 |
JPX |
|
| 61-94168 |
Apr 1986 |
JPX |
|
PRIOR ART
This application is a division of application Ser. No. 07/343,142, filed Apr. 25, 1989, now U.S. Pat. No. 4,985,447 which is a division of application Ser. No. 07/004,138, filed Jan. 16, 1987, now U.S. Pat. No. 4,851,413.
This invention relates to novel quinone derivatives each of which exerts two or more effects among thromboxane A.sub.2 synthetase inhibition, thromboxane A.sub.2 receptor antagonism, 5-lipoxygenase inhibition and scavenging action of active oxygen species, and is useful, based on the composite effects, for treatment and prevention of diseases due to dysfunction of heart, brain, lung and kidney. This invention also relates to the method of production of the said quinone derivatives, and pharmaceutical compositions containing such derivatives. This invention is useful in the field of medicine.
A number of reports have been published on specific inhibitors, antagonists, or scavengers for one of thromboxane A.sub.2 (hereinafter abbreviated as TXA.sub.2) synthetase, TXA.sub.2 receptor, 5-lipoxygenase and active oxygen species. However, no attempt has been made to design a compound having a composite pharmacological action consisting of two or more effects among TXA.sub.2 synthetase inhibition, TXA.sub.2 receptor antagonism, 5-lipoxygenase inhibition and scavenging action of active oxygen species.
This invention offers novel quinone compounds exerting two or more effects among TXA.sub.2 synthetase inhibition, TXA.sub.2 receptor antagonism, 5-lipoxygenase inhibition, and scavenging action of active oxygen species.
This invention relates to
1. Quinone derivatives represented by the general formula ##STR3## (wherein, R.sup.1 and R.sup.2, which are the same or different, refer to hydrogen atom, methyl or methoxy group, or R.sup.1 and R.sup.2 bind together to form --CH.dbd.CH--CH.dbd.CH--; R.sup.3 is a hydrogen atom or methyl group; R.sup.4 is a nitrogen-containing heterocyclic group which may be substituted; R.sup.5 is a hydrogen atom, methyl group, hydroxymethyl group which may be substituted, or carboxyl group which may be esterified or amidated; Z is ##STR4## (wherein, R' is a hydrogen atom or methyl group); n is an integer from 0 through 12, m is an integer from 0 through 3, and k is an integer from 0 through 7, providing that when m is 2 or 3, Z and k are able to vary appropriately in the repeating unit shown in []), and the hydroquinone derivatives thereof,
2) a method of production of quinone derivatives represented by the general formula (I) characterized by the reaction of a compound represented by the general formula ##STR5## (wherein, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, Z, k, m and n are the same as described above; R.sup.6 is a hydrogen atom, methyl, methoxymethyl, benzyl, or 2-tetrahydropyranyl group; R.sup.7 is a hydrogen atom, hydroxyl, methoxy, methoxymethyloxy, benzyloxy, or 2-tetrahydropyranyloxy group) with an oxidant,
3) a method of production of hydroquinone derivatives represented by the general formula ##STR6## (wherein, the symbols are the same as described above) characterized by the protective-group eliminating reaction of a compound having the general formula ##STR7## (wherein, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, Z, k, m, and n are the same as described above; R.sup.8 is methyl, methoxymethyl, benzyl, or 2-tetrahydropyranyl), and,
4) pharmaceutical compositions containing, as the active ingredient, a quinone derivative represented by the general formula (I) or a hydroquinone derivative thereof.
The nitrogen-containing heterocyclic groups represented by R.sup.4 in the general formula (I) described above include 5- or 6-membered cyclic groups containing at least one nitrogen atom as the ring member atom, in the concrete, pyridyl groups (2-pyridyl, 3-pyridyl, 4-pyridyl), thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl), imidazolyl (1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), and quinolyl, among which 3-pyridyl, 5-thiazolyl and 1-imidazolyl are preferable, and 3-pyridyl is the most desirable. These nitrogen-containing heterocyclic groups may contain 1 to 3 substituents at a given position on the ring, and such substituents include alkyl groups having 1 to 3 carbon atoms such as methyl and ethyl, phenyl group, p-tolyl group, m-tolyl group, pyridyl group (2-pyridyl, 3pyridyl), and 3-pyridylmethyl group.
The hydroxymethyl group represented by R.sup.5 may be substituted, including, in addition to the unsubstituted hydroxymethyl group, methoxymethyl, acetoxymethyl, nitroxymethyl, and carbamoyloxymethyl; the esterified carboxyl group includes alkoxycarbonyl groups having 2 to 5 carbons such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, and butoxycarbonyl. The amidated carboxyl group represented by R.sup.5 may be a substituted aminocarbonyl in which the amino group is substituted, or a cyclic aminocarbonyl. The substituents for the amino group in the substituted aminocarbonyl include alkyl having 1 to 4 carbon atoms such as methyl, ethyl, propyl and butyl, aryl having 6 to 10 carbon atoms such as phenyl and naphthyl (which may be substituted by hydroxyl, amino, nitro, halogen, methyl or methoxy at a given position of the ring), and the hydroxyl group; the amidated carboxyl groups are exemplified by aminocarbonyl, mono- or di-alkylaminocarbonyl having 2 to 4 carbon atoms (methylaminocarbonyl, ethylaminocarbonyl, iscpropylaminocarbonyl, dimethylaminocarbonyl), phenylaminocarbonyl, substituted phenylaminocarbonyl (p-hydroxyphenylaminocarbonyl, p-methoxyphenylaminocarbonyl, m-chlorophenylaminocarbonyl), diphenylaminocarbonyl, hydroxyaminocarbonyl, N-hydroxy-N-methylaminocarbonyl, and N-hydroxy-N-phenylaminocarbonyl. The cyclic aminocabonyl includes morpholinocarbonyl and piperidinocarbonyl.
The quinone compounds represented by the general formula (I) and the hydroquinone derivatives thereof (IIb) may be the salts of inorganic acids such as hydrochloric acid, nitric acid, and phosphoric acid, or of organic acids such as methanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, and succinic acid.
The compounds represented by the general formula (I) of this invention are able to be produced by the reaction of a compound represented by the general formula (II) with an oxidant.
The kind of the oxidant used and the conditions of the oxidation of a compound represented by the general formula (II) vary according to the species of R.sup.6 and R.sup.7.
The compounds in which R.sup.6 and R.sup.7 are hydrogen atoms in the general formula (II), i.e. phenol compounds, are able to be easily converted into quinone compounds (I) by using a Fremy's salt as the oxidant. The amount of the Fremy's salt used is 2 to 4 moles per 1 mole of the compound (II), the solvent being preferably methanol, acetonitrile, ethanol, dioxane, 1,2-dimethoxyethane, or a aqueous solvent thereof. The reaction temperature is 10.degree.-80.degree. C. and the reaction time is usually about 2-10 hours.
The compounds in which R.sup.6 is a hydrogen atom and R.sup.7 is a hydroxyl group in the general formula (II), i.e. hydroquinone compounds, are able to be easily converted into quinone compounds (I) by using a mild oxidant such as air, oxygen, a Fremy's salt, ferric chloride, ferric sulfate, hydrogen peroxide and a peracid. Such reactions are usually conducted in the presence of a solvent, and such solvents include methanol, acetonitrile, dioxane, 1,2-dimethoxyethane and aqueous solvents consisting of the said organic solvents and water. When air or oxygen is used as the oxidant, the reaction is carried out at a neutral or weakly alkaline pH (pH 7.0-pH 9.0). A buffer solution (e.g. phosphate buffer) is used to maintain the pH. The reaction temperature is -10.degree. C. to 30.degree. C., and the reaction time is usually within 2 hours. When the oxidant used is ferric chloride, ferric sulfate or a Fremy's salt, the amount of the oxidant used is preferably about 1 to 2 moles per 1 mole of the compound (II). The reaction temperature is -10.degree. C. to 30.degree. C., and the reaction time is usually within 1 hour.
The compound (II) in which R.sup.6 is methyl, methoxymethyl, benzyl, or 2-tetrahydropyranyl group, and R.sup.7 is methoxy, methoxymethyloxy, benzyloxy, or 2-tetrahydropyranyloxy group, i.e. hydroquinone diether compounds, are able to be easily converted into quinone compounds (I) by using silver oxide (AgO) or cerium(IV) ammonium nitrate (hereinafter abbreviated as CAN) as the oxidant. When silver oxide (AgO) is used the reaction is conducted in water or a aqueous organic solvent (e.g. dioxane, acetonitrile) in the presence of nitric acid at -10.degree. C. to 30.degree. C. When CAN is used as the oxidant, the reaction is conducted in a aqueous organic solvent (e.g. acetonitrile, methanol), especially aqueous acetonitrile, in the presence of CAN alone or CAN together with pyridine-2,6-dicarboxylic acid N-oxide, pyridine-2,4,6-tricarboxylic acid or pyridine-2,6-dicarboxylic acid or the like. The suitable mixing ratio of CAN and the pyridine carboxylic acid described above is usually about 1:1 (molar equivalent). The reaction temperature is about -5.degree. C. about 30.degree. C.
The compounds in which R.sup.5 is carbamoyloxymethyl, hydroxyaminocarbonyl, N-substituted hydroxyaminocarbonyl, hydroxymethyl, carboxyl, alkoxycarbonyl, aminocarbonyl, or substituted aminocarbonyl group are derived from the compounds in which R.sup.5 is hydroxymethyl, carboxyl, alkoxycarbonyl, or acyloxymethyl group by the per se known reactions described below. ##STR8## (wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, n, m, k, and Z are the same as described above); R.sup.9 and R.sup.10 are C.sub.1-3 alkyl groups (e.g. methyl, ethyl, propyl); and R.sup.11 and R.sup.12 are hydrogen atoms, C.sub.1-7 lower alkyl groups (e.g. methyl, ethyl, propyl, i-propyl, butyl, pentyl, hexyl) or aryl groups (e.g. phenyl, naphthyl).
The hydroquinone compounds represented by the general formula (IIb) are able to be produced by protective group removing reaction (acid hydrolysis) of a compound represented by the general formula (IIa). When R.sup.8 is a methyl group in the general formula (IIa), the acid catalyst is preferably hydrogen bromide and the solvent is preferably acetic acid or water. The reaction temperature is 60.degree. C.-120.degree. C., preferably about 80.degree. C. When R.sup.8 is a methoxymethyl group or 2-tetrahydropyranyloxy group in the general formula (IIa), the acid catalyst used is an organic or inorganic acid such as sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, and camphorsulfonic acid, and the solvent is methanol, ethanol, or an aqueous organic solvent (e.g. methanol, acetone, tetrahydrofuran, ether, acetonitrile). The reaction temperature is 20.degree.-80.degree. C., preferably 50.degree.-60.degree. C.
When R.sup.8 is a benzyl group, the compounds (IIb) are able to be produced by catalytic reduction by a usual method of a compound (IIa) in the presence of a catalyst such as palladium-carbon.
The compounds in which, in the general formula (I), n is 0, Z is --CH.dbd.CH--, k is an integer from 0 through 7, and m is 1, or the compounds in which n is an integer from 4 through 11 and m is 0, that is, the compounds represented by the following formula ##STR9##
[wherein, R.sup.1, R.sup.2, R.sup.3, R.sup.4, and R.sup.5 are the same as described above, A refers to the formula --(CH.sub.2).sub.k'+4 (wherein k' is an integer from 0 through 5) or A-R.sup.5 refers to the formula --CH.dbd.CH--(CH.sub.2).sub.k'+2 --R.sup.5 (wherein k' and R.sup.5 are the same as described above)] are able to be produced by sulfur eliminating reduction of a compound represented by the general formula ##STR10## (wherein, the symbols are the same as described above), followed by oxidation of the products.
The sulfur eliminating reduction of a compound represented by the general formula (Ib) is conducted by using Raney nickel. The reaction is conducted in a solvent such as methanol, ethanol and ethyl acetate, in the presence of about 10 to 20 times by weight of Raney nickel when hydrogen gas is not used, and at a temperature in the range from the room temperature to 100.degree. C. Five to 10 times by weight of Raney nickel is used when hydrogen gas is present and a pressure of 5-200 atm is applied. The compounds produced by the sulfur eliminating reduction are hydroquinone derivatives, and therefore are converted into quinone compounds (Ia) by oxidation with ferric chloride or air as required.
The quinone compounds (I) and the hydroquinone derivatives thereof (IIb) thus produced are able to be isolated by the per se known methods for isolation and purification (e.g. chromatography, crystallization).
The quinone compounds (I) and the hydroquinone derivatives thereof (IIb) of this invention can be converted from one to the other by chemical or biochemical oxidation or reduction of the quinone nucleus or the hydroquinone nucleus of the compounds. In general, hydroquinone derivatives (IIb) are susceptible to oxidation with oxygen, air or the like, and therefore usually treated as the corresponding stable quinone compounds (I). Because hydroquinone compounds (IIb) and quinone compounds (I) are easily converted from one to the other by chemical or biochemical oxidation-reduction, the quinone compounds (I) and the hydroquinone derivatives (IIb) are considered to have equivalent properties when the compounds exert their pharmaceutical actions under physiological conditions.
The quinone compounds (I) are able to be easily converted into the hydroquinone compounds (IIb) by a per se known method using a mild reductant such as sodium hydrosulfite, sodium hydrogen sulfite and sodium borohydride, or by catalytic reduction in the presence of platinum oxide, or palladium-carbon.
Some quinone compounds (I) and (IIb) have structurally an asymmetric center at the alpha (o ) carbon on the side chain of the quinone or hydroquinone nucleus, and such compounds are optically active. This implies that the compounds (I) and (IIb) of this invention include optically active compounds as well as racemic compounds.
Each of the compound (I) and (IIb) of this invention exert improvement effect of metabolism of polycarboxylic unsaturated fatty acids (linoleic acid, .gamma.-linolenic acid, .alpha.-linolenic acid, arachidonic acid, dihomo-.gamma.-linolenic acid, eicosapentaenoic acid), among the effect particularly two or more of inhibition of production of fatty acid peroxide (antioxidation), inhibition of production of metabolites by 5-lipoxygenase system (e.g. leucotrienes, 5-hydroxyeicosatetraenoic acid, 5-peroxyeicosatetraenoic acid, lipoxines), inhibition of thromboxane A.sub.2 synthetase, thoromboxane A.sub.2 receptor antagonist, and scavenging action of active oxygen species, and have very little toxicity and very few side effects. Therefore the compounds (I) and (IIb) are expected to be useful for treatment and prevention of diseases in mammals (mouse, rat, rabbit, dog, monkey, human, etc.), such as thrombosis, ischemic diseases (e.g. myocardial infarction, cerebral stroke) due to contraction or twitch of arterial smooth muscle in heart, lung, brain and kidney, nephritis, pulmonary failure, bronchial asthma, psoriasis, inflammation, immediate allergy, arteriosclerosis, atherosclerosis, fatty liver, hepatitis, cirrhosis of the liver, hypersensitivity pneumonitis, immunodeficiency, diseases of cardiovascular system (myocardial infarction, cerebral stroke, nephritis, etc) due to disorder of tissues, enzymes, and cells caused by active oxygen species (superoxides, hydroxide radicals, lipid peroxides, etc.), and cancer, being useful as medicines such as antithrombotics, anti-vascular constriction agents, anti-asthma agent, antiallergic agents, therapeutics for psoriasis, agents for improvement of heart, brain and cardiovascular system, therapeutics for nephritis, active oxygen-eliminating agents, anticancer agents, agents for improvement of control of arachidonate cascade products, etc.
Because the compounds of this invention have low toxicity, the compounds as they are or as pharmaceutical compositions produced by mixing with a per se known, pharmaceutically acceptable carrier or excipient or the like [e.g. tablets, capsules (including soft capsules and microcapsules), liquid preparations, injections, suppositories] are able to be given safely orally or parenterally. The dose varies according to the subjects to be treated, the route of administration, symptoms, etc. For example, when given orally to an adult patient with thrombosis, the unit dose is usually about 0.1 mg/kg-20 mg/kg body weight, preferably about 0.2 mg/kg-10 mg/kg body weight which is desirably given about 1-3 times a day.
The compounds (II) are able to be produced by one of the following methods.
The compounds represented by the general formula (IIb) described above are able to be produced by condensation of a hydroquinone compound represented by the general formula ##STR11## (wherein, R.sup.1 is the same as described above) with a compound represented by the general formula ##STR12## (wherein, k, m, n, R.sup.5 and Z are the same as described above, and X is hydroxyl or acetoxy group) in the presence of an acidic catalyst. The said acidic condensation is carried out without solvent or in an organic solvent, in the presence of concentrated sulfuric acid, trifluoromethylsulfonic acid, or fluorosulfonic acid in the atmosphere of nitrogen or argon gas. The reaction solvents include methylene chloride, 1,2-dichloroethane, benzene, and toluene. The reaction temperature is 30.degree.- 100.degree. C., preferably 60.degree.-90.degree. C. The amount of the catalyst is 1.2-5 mole equivalents, preferably 2-3 times moles.
Among the compounds represented by the general formula (II), the compounds in which R.sup.6 is methyl and R.sup.7 is methoxy group are able to be synthesized, for example, by the procedure described below. ##STR13## (wherein, R.sup.1, R.sup.2, R.sup.3 and n are the same as described above; R.sup.13 is a hydrogen atom, methyl group or hydroxyl group which may be substituted; R.sup.14 is a hydrogen atom, methyl group, hyroxyl group which may be substituted, or carboxyl group which may be substituted).
That is, an intermediate (VI) is able to be produced by the reaction of a pyridylketone derivative (V) with a compound represented by the general formula ##STR14## (wherein, R.sup.1, R.sup.2, and R.sup.3 are the same as described above, and Y is Li or MgBr). This condensation can be carried out in anhydrous diethyl ether or anhydrous tetrahydrofuran, in the atmosphere of nitrogen or argon at -80.degree.-20.degree. C. Dehydration proceeds when the said intermediate (VI) is allowed to react in the presence of an acid catalyst (e.g. concentrated sulfuric acid, p-toluenesulfcnic acid) in an organic solvent (e.g. acetic acid, methylene chloride, 1,2-dichloroethane) at 10.degree.-100.degree. C. for 1-3 hours, to give an olefin compound (VII). The said olefin compound (VII) is subjected to catalytic reduction in an organic solvent (e.g. acetic acid, ethanol, ethyl acetate) in the presence of a catalyst (e.g. palladium-carbon, palladium black), to give a compound (VIII). The compound (VIII) is able to be converted into a carboxylic acid derivative (IIc) by a routine method.
Among the compounds represented by the general formula (II), the compounds represented by the following formulas (IId and IIe) are able to be produced also by the following procedure. ##STR15## (wherein, R.sup.1 and R.sup.2 are the same as described above).
That is, reaction of the bromide derivative (X) with 2-, 3-, or 4-pyridyl lithium in an anhydrous solvent (e.g. tetrahydrofuran, diethyl ether) in the atmosphere of an inert gas (e.g. nitrogen gas, argon, helium), to give a compound (IId). The imidazolyl derivative (IIe) is able to be produced by the reaction of the bromide derivative (X) with imidazole in the presence of an acid-binding agent (e.g. triethylamine, sodium hydride) in dimethylformamide or dimethylsulfoxide.
The novel quinone derivatives of this invention are effective in improvement of metabolism of polyunsaturated fatty acids, particularly control of biosynthesis of arachidonate cascade products (inhibition of 5-lipoxygenase, inhibition of TXA.sub.2 synthetase, TXA.sub.2 receptor antagonism) and active oxygen species elimination, and useful as medicines for improvement of dysfunction and circulatory systems in heart, brain, lung and kidney, as antiasthma agents, as antiallergic agents, etc.
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Divisions (2)
|
Number |
Date |
Country |
| Parent |
343142 |
Apr 1989 |
|
| Parent |
4138 |
Jan 1987 |
|
Patent Grant
5106858
