JPH0430955B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to novel condensed benz(thio)amides. More specifically, the present invention relates to novel condensed benz(thio)amides having an antagonistic effect on leukotrienes, methods for producing the same, and pharmaceuticals containing them as active ingredients. [Conventional technology] Prostaglandin (hereinafter referred to as PG)
It is abbreviated as ) Several important discoveries have been made one after another in the last few years in the field of research. Therefore, there have been major changes in the flow of PG research and development in recent years. Among the newly discovered or newly determined PG families, PG has particularly strong and unique biological activity.
Endoperoxides (PG endoperoxides, i.e. PGG ₂ and PGH ₂ ), thromboxane A ₂
(Thrombo-xaneA ₂ , hereinafter abbreviated as TXA ₂ ),
Prostacyclin (i.e.
PGI ₂ ) and leukotrienes C, D and E (hereinafter abbreviated as LTC, LTD and LTE, respectively). In addition to these compounds,
All of the PG families, including various PGs that have been well known, are biosynthesized in vivo using a common parent substance, so the entire metabolic pathway starting from arachidonic acid is the arachidonic acid cascade. )It is called. For detailed explanations of each pathway and pharmacological properties of each product, see Medical History, 114 , 378 (1980),
Ibid., 114, 462 (1980), Ibid., 114, 866 (1980), Ibid.
114, 929 (1980), Modern Medicine, 12, 909 (1980), same.
12, 1029 (1980), 12, 1065 (1980) and
12, 1105 (1980), etc. In the arachidonic acid cascade, cyclooxygenase acts on arachidonic acid to generate PGG ₂ and further
After PGH ₂ , various PGs such as prostaglandin F ₂ 〓 (hereinafter abbreviated as PGF ₂ 〓), prostaglandin E ₂ (hereinafter abbreviated as PGE ₂ ), PGI ₂ , TXA ₂
etc., and lipoxygenase acts on arachidonic acid to produce hydroperoxyeicosatetraenoic acid (hereinafter referred to as hydroperoxyeicosatetraenoic acid).
Abbreviated as HPETE. ) to hydroxyeicosatetraenoic acid (hereinafter abbreviated as HETE) or leukotrienes. Since the former route is already well known, we will not discuss it in detail here. For details, please refer to Nobu Katori et al., eds., Prostaglandins (1978), published by Kodansha. Regarding the latter route, it is known that various compounds are produced by the route shown in the reaction scheme. Arachidonic acid is metabolized by a well-known pathway, that is, via PG endoperoxide, and also by lipoxygenase in a completely different pathway. That is, lipoxygenase such as 5-lipoxygenase, 12-lipoxygenase or 15-lipoxygenase acts on arachidonic acid to produce 5-HPETE and 12-HPETE, respectively.
−HPETE or 15−HPETE is generated. These HPETEs are processed by peroxidase,
Hydrogen peroxide group is converted to hydroxyl group to form 5-HETE,
Converted to 12-HETE or 15-HETE.
Further, among these HPETEs, 5-HPETE is converted to LTA ₄ by being dehydrated. Furthermore, LTA ₄ is enzymatically converted to leukotriene B ₄ (hereinafter abbreviated as LTB ₄ ) or LTC ₄ . LTC ₄ is then converted to LTD ₄ by γ-glutamyl transpeptidase. It has recently become clear that LTD ₄ is further metabolized to LTE ₄ [Biochem.Biophys.Res.Commun., 91,
1266 (1979) and Prostaglandins, 19(5) , 645
(1980)]. On the other hand, when talking about SRS, SRS is Slow
This name is an abbreviation for Reacting Substance.
This substance was used by Feldberg et al. for the substance released when cobra venom was perfused into the lungs or when cobra venom was incubated with egg yolk. This substance slowly constricted the isolated guinea pig ileum, and the effect lasted for a long time. It has been reported [J.Physiol., 94, 187
(1938)]. Furthermore, Kellaway et al. sensitized SRS-A (Slow
Reacting Substance of Anaphylaxis) was shown to be released, and the relationship between SRS-A and allergic reactions was shown for the first time [Quant.J.Exp.Physiol.,
30, 121 (1940)]. Brocklehurst also reported that when an antigen was applied to a surgically removed lung section from a patient with bronchial asthma for whom a specific antigen was known, histamine and SRS-A were released, causing strong contraction of the bronchial muscles.
This contraction was not alleviated by antihistamines, suggesting that SRS-A is an important bronchoconstrictor during asthma attacks [see Progr. Allergy, 6, 539 (1962)].
Subsequently, SRS-A obtained from human lung tissue fragments contracted the bronchial muscle rings in normal humans [Int.Arch.
Allergy. Appl. Immunol., 38, 217, (1970)], and when rat SRS-A is intravenously injected into guinea pigs, an increase in pulmonary airway resistance is observed [J. Clin.
Invest., 53, 1679 (1974)], and intradermal injection of SRS-A into guinea pigs, rats, and monkeys increases vascular permeability [Advances in
Immunology, 10, 105 (1969), J. Allergy Clin.
Immunol., 621, 371 (1978), Prostag-landins,
19 (5), 779 (1980), etc.]. As mentioned above, SRS is divided into two types: SRS-A, which is released due to immune reactions, and SRS, which is released without immune reactions such as calcium ionophore treatment. Although they are distinct, there are many similarities between the two, and it is thought that there is a strong possibility that they are the same substance. Furthermore, it has become clear that LTC ₄ and LTD ₄ are the same substances as SRS or SRS-A, and therefore the pharmacological properties of these leukotrienes are
It can be considered in place of the pharmacological properties of SRS or SRS-A [Proc.Natl.Acad.Sci.USA,
76, 4275 (1979), Biochem.Biophys.Res.
Commun., 91, 1266 (1979), Proc. Natl. Acad.
Sci.USA, 77, 2014 (1980), Nature, 285, 104
(1980)]. Based on the results of many studies such as these, various leukotrienes (LTC ₄ , LTD ₄ and LTE ₄ , as well as leukotrienes whose structures may be determined in the future) that are biosynthesized from arachidonic acid via LTA ₄ , It is considered to be an important factor involved in the development of allergic tracheal and bronchial or pulmonary diseases, allergic shock, and various types of allergic inflammation. Therefore, by suppressing these leukotrienes, allergic tracheal, bronchial, and pulmonary diseases such as asthma, allergic lung diseases, allergic shots, and allergic symptoms can be prevented in mammals including humans, especially in humans. It is effective in preventing and/or treating various diseases. Furthermore, arachidonic acid is liberated from phospholipids by the action of phospholipase, but a closer look shows that there are two routes: (1) phosphatidyl choline (phosphatidyl choline);
choline) and the pathway by which phospholipase _A2 acts on
(2) Phosphatidyl inositol (phosphatidyl inositol)
phospholipase C acts on 1,2
It is generally thought that the pathway is that diglyceride (1,2-diglyceride) is generated, which is then released by the action of diglyceride lipase (diglycerideli-pase) and then mono-glyceride lipase (mono-glyceride lipase) [Chemistry and Biology] , 21 , 154 (1983)]. The liberated arachidonic acid is further metabolized into physiologically active substances such as prostaglandis (PG) and thromboxane A ₂ (TXA ₂ ) by two pathways: (1) the cyclooxygenase metabolic pathway; (2) SRS-A (Slow Reacting Substances of SRS-A)
Anaphylaxis), hydroxyeicosatetraenoic acid (HETE) and leukotriene _B4 (Leukotriene
It is known that it is metabolized into physiologically active substances such as B ₄ ) [see Chemistry and Biology 21, 154 (1983)]. These metabolites include, for example, TXA ₂ , which is a substance that has strong platelet aggregation and vasoconstriction effects, SRS-A, which is a chemical mediator for asthma, and LTB ₄ , which is a chemical that causes inflammation such as gout. being a mediator;
In addition, PG is known to be a chemical mediator that has vasodilatory, analgesic, fever, and leukocyte migration effects in inflammation [Metabolism 20,
317 (1983), The Lancet 1122 (1982), Prostaglandins (1978) edited by Shin Katori et al., Kodansha]. In this way, arachidonic acid is converted and metabolized into chemical mediators that play physiologically important roles in living organisms, but it is known that a number of diseases are caused by an imbalance of these mediators. In addition, as antagonists of these SRS, FISONS has developed the general formula [In the formula, R ¹ to R ⁵ and R ⁷ are hydrogen atoms, hydroxyl groups,
Alkyl group having 1 to 6 carbon atoms, alkoxy group having 1 to 6 carbon atoms, amino group, acyl group, acylamino group having 2 to 6 carbon atoms, alkenyl group having 2 to 6 carbon atoms,
Halogen atom or phenyl (having 1 to 6 carbon atoms)
represents an alkoxy group; X represents a hydrocarbyl group having 1 to 10 carbon atoms which may be substituted with a hydroxyl group; A represents an oxygen atom or is absent; alkylene, which may be
represents an alkenyllene or alkynylene group,
D represents a carboxy group, 5-tetrazolyl, or carbamide-5-tetrazolyl group. ] A patent application has been filed for a group of compounds represented by [see Japanese Patent Application Laid-Open No. 127384/1984]. [Disclosure of the Invention] The present inventors have synthesized a new group of compounds represented by the following general formula (1) whose structural feature is that the condensed benzene ring is substituted with (thio)amide. , as described below, found that these are very useful as leukotriene (SRS) antagonists, and completed the present invention. In addition, the compounds of the present invention inhibit phospholipase and suppress the release of arachidonic acid from phospholipids, thereby preventing diseases caused by arachidonic acid metabolites such as TXA ₂ , PG, and leukotrienes in mammals including humans, especially humans. Effective for prevention and/or treatment. Examples of target diseases include the aforementioned various allergic diseases caused by leukotrienes and thrombosis, such as thrombosis caused by damage to the endothelium and intima of the brain and coronary arteries, and inflammation, such as arthritis and rheumatism. [See Circulation Science 3, 484 (1983) and Pharmacy 34, 167 (1983)]. Furthermore, in addition to the above-mentioned uses of the compound of the present invention as a leukotriene antagonist and phospholipase inhibitor, the following 5α-reductase inhibitory action has also been found. 5α-reductase exists in the endoplasmic reticulum and nucleic acids, and has the effect of converting testosterone ingested into target tissues into the active form of 5α-dihydrotestosterone. This active form of 5α-dihydrotestosterone is It is said that binding to the molecule causes cell proliferation, and when this effect is enhanced, it causes the onset of benign prostatic hyperplasia, alopecia, or acne. The compound of the present invention does not have hormone-specific effects, and moreover, it inhibits 5α-reductase and inhibits 5α-reductase.
- Since it suppresses the increase in dihydrotestosterone and suppresses cell proliferation, it can effectively prevent and/or treat benign prostatic hyperplasia, alopecia, and acne in mammals including humans, especially humans. Furthermore, the following aldose reductase inhibitory activity has also been found in the compounds of the present invention. Aldose reductase is a enzyme that converts aldose (glucose, galactose, etc.) in humans and other animals.
It is an enzyme that reduces polyols to corresponding polyols (sorbitol, galactitol, etc.), and the sorbitol and galactitol produced by the action of this enzyme accumulate in the crystalline lens, peripheral nerves, kidneys, etc. of diabetic patients (including patients with galactosemia). and as a result,
Complications include retinopathy, diabetic cataracts,
It is known to cause neuropathy and kidney damage [Jap.J.Opthalmol., 20, 399 (1976), Int. Congr.
Ser Excerpta Med., 403, 594 (1977) and
Metabolism, 28, 456 (1979)]. Since the compounds of the present invention inhibit aldose reductase, they are effective in preventing and/or treating the aforementioned diabetic complications in mammals including humans, especially humans. That is, the present invention is based on the general formula [In the formula, R ¹ is the general formula A group represented by [Formula] or [Formula], or () represents a straight or branched alkyl, alkenyl or alkynyl group having 1 to 20 carbon atoms. (R ⁵ and R ⁶ in the formula are each independently a hydrogen atom, a halogen atom, or any one,
Two or three carbon atoms are oxygen atom, sulfur atom, halogen atom, nitrogen atom, benzene ring, thiophene ring, hydrocarbon ring having 4 to 7 carbon atoms, carbonyl group, carbonyloxy group, hydroxyl group, carboxy group, azido group , represents a straight-chain or branched alkyl, alkenyl or alkynyl group having 1 to 20 carbon atoms which may be substituted with a nitro group. ) R ² represents a hydrogen atom or a straight or branched alkyl group having 1 to 6 carbon atoms. R ³ is a hydrogen atom, a halogen atom, a hydroxyl group, a nitro group, or is represented by the general formula -COOR ⁷ (wherein R ⁷ represents a hydrogen atom or a straight or branched alkyl group having 1 to 6 carbon atoms). represents a straight-chain or branched alkyl, alkoxy or alkylthio group having 1 to 6 carbon atoms. R ⁴ is a group represented by the general formula -COOR ⁸ or -CH ₂ COOR ⁸ (wherein R ⁸ represents a hydrogen atom or a straight or branched alkyl group having 1 to 6 carbon atoms), 2- Represents a tetrazolyl group or 2-tetrazolylmethyl group. Symbol A is a methylene, ethylene, trimethylene, tetramethylene, vinylene, propenylene, butenylene, butadienylene, or ethynylene group which may be substituted with a single bond or a linear or branched alkyl group having 1 to 6 carbon atoms or a phenyl group. represents. The symbol [formula] represents a ring represented by the formula [formula] [formula] or [formula]. The symbol T represents an oxygen atom or a sulfur atom. ] The present invention relates to a novel condensed benz(thio)amide represented by the above, a non-toxic salt thereof, a method for producing the same, and a drug containing the same as an active ingredient. The compounds of the present invention may contain a benzene ring and/or a chromone core, but one of the essential requirements is that they have a (thio)amide in the middle portion, and are a chemically completely novel group of compounds. The compounds of the present invention can be roughly classified into the following three compound groups depending on the type of ring represented by symbol B. That is, the present invention is based on the general formula and [In the formula, all symbols have the same meanings as above. ] Includes compounds shown in the following. In the general formula (), examples of the groups represented by R ⁵ and R ⁶ include those shown below.・Hydrogen atom, halogen atom ・Alkyl group having 1 to 20 carbon atoms, ・Alkenyl or alkynyl group having 1 to 20 carbon atoms, ・Alkoxy or alkylthio group having 1 to 19 carbon atoms, ・Alkenyloxy having 3 to 19 carbon atoms, Alkenylthio, alkynyloxy, alkynylthio group, - Alkyl group substituted with a halogen atom or hydroxyl group having 1 to 19 carbon atoms - Alkenyl or alkynyl group substituted with a halogen atom or hydroxyl group having 2 to 19 carbon atoms - 1 carbon number Alkoxy, alkylthio groups substituted with ~18 halogen atoms or hydroxyl groups, alkenyloxy, alkenylthio, alkynyloxy, alkynylthio groups substituted with halogen atoms or hydroxyl groups having 3 to 18 carbon atoms, and alkylthio groups having 2 to 19 carbon atoms. Oxyalkyl, alkenyloxyalkyl, alkyloxyalkenyl group・Cycloalkyl (hydrocarbon ring) having 4 to 7 carbon atoms, cycloalkyloxy, cycloalkylthio group・Phenyl, phenoxy, phenylthio group・Hydrocarbon ring having 4 to 7 carbon atoms , an alkyl group having 1 to 19 carbon atoms having a benzene ring, or a thiophene ring in the middle or at the end ・An alkyl group having 1 to 18 carbon atoms having a hydrocarbon ring having 4 to 7 carbon atoms, a benzene ring, or a thiophene ring in the middle or at the end Alkoxy, alkylthio, alkenyloxy, alkenylthio, alkynyloxy, alkynylthio group, phenylthioalkoxy or phenyloxyalkyloxy (alkyl moiety has 1 or more carbon atoms)
17) Group: carboxyalkyloxy having 2 to 19 carbon atoms,
Alkoxycarbonylalkyloxy group, alkylcarbonyloxyalkyloxy group having 3 to 19 carbon atoms, alkenylcarbonyloxy group having 3 to 20 carbon atoms, alkylcarbonyl group having 2 to 20 carbon atoms, azidoalkyl, nitro having 1 to 19 carbon atoms Alkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl group, azidoalkyloxy with 1 to 18 carbon atoms, nitroalkyloxy, aminoalkyloxy, alkylaminoalkyloxy, dialkylaminoalkyloxy group, alkenyl with 3 to 19 carbon atoms Carbonylamino group/Alkylamino group having 1 to 19 carbon atoms Among these, preferable groups as R ⁵ and R ⁶ include the groups shown below.・ Hydrogen atom ・ Halogen atom ・ Straight chain or branched chain alkyl group having 1 to 20 carbon atoms ・ Straight chain or branched chain alkoxy group having 1 to 19 carbon atoms ・ Straight chain or branched chain having 3 to 19 carbon atoms Chain alkenyloxy group, straight chain or branched chain alkynyloxy group having 3 to 19 carbon atoms, straight chain or branched chain alkylthio group having 1 to 19 carbon atoms, or chain having 1 to 1 carbon atoms substituted with a halogen atom 18
straight-chain or branched-chain alkyl group, straight-chain or branched-chain alkyloxyalkyl group with 2 to 19 carbon atoms, straight-chain or branched alkyl group with 1 to 8 carbon atoms, even if substituted with Good cycloalkyl, cycloalkylalkyl (alkyl moiety has 1 to 8 carbon atoms), cycloalkylalkyloxy (alkyl moiety has 1 to 8 carbon atoms) groups, straight chain or branched carbon atoms having 4 to 7 carbon atoms. Phenyl, phenylalkyl (the alkyl part has 1 to 8 carbon atoms), phenylalkyloxy (the alkyl part has 1 to 8 carbon atoms), phenylalkenyloxy (the alkenyl part has 1 to 8 carbon atoms), which may be substituted with a branched alkyl group. is a group with 2 to 8 carbon atoms, a straight-chain or branched alkoxy, alkenyloxy, or alkoxyalkoxy group with 1 to 18 carbon atoms substituted with a carbonyl group, carbonyloxy group, or hydroxyl group ・substituted with a phenoxy or phenylthio group Straight-chain or branched alkoxy group with 1 to 17 carbon atoms substituted with a thiophene ring
18 straight or branched chain alkoxy groups, 1 to 1 carbon atoms substituted with an amino (including dialkylamino) group which may be substituted with an azide group, a nitro group, or an alkyl group with 1 to 6 carbon atoms 18 straight-chain or branched alkyl, alkenyl, alkoxy or alkenyloxy groups; straight-chain or branched alkyl, alkenyl, having 1 to 18 carbon atoms, substituted with two groups: a carbonyl group and an amino group; Alkoxy or alkenyloxy group The alkyl group having 1 to 20 carbon atoms in the present invention is
Methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group, decyl group, undecyl group, dodecyl group, tridecyl group, tetradecyl group, pentadecyl group, hexadecyl group, heptadecyl group , octadecyl group, nonadecyl group, eicosyl group, and isomers thereof, and alkenyl and alkynyl groups having 1 to 20 carbon atoms refer to groups corresponding to the above groups. Examples of the alkyl group having 1 to 6 carbon atoms in the present invention include methyl, ethyl, propyl, butyl, pentyl, hexyl and isomers thereof. Examples of the halogen atom in the present invention include chlorine, bromine, iodine, and fluorine atoms. Furthermore, in the present invention, "a carbon atom is replaced by another atom, ring, or group" may be any carbon atom as long as it is chemically and physically permissible.
For example, when an isobutyl group has a benzene ring in the middle or end, it means isopropylphenyl, dimethylphenylmethyl, and 2-phenylpropyl groups. However, when replacing, hydrogen atoms shall be added or subtracted as appropriate. For example, replacing the 2-position of a pentyl group with a nitrogen atom means an N-propylaminomethyl group. [Method for producing the compound of the present invention (1)] The present invention does not only relate to the compound itself, its non-toxic salt, and its use and usage, but also includes a method for producing the compound. According to the present invention, the compound of the present invention represented by the general formula () has the general formula R ¹ -A-COOH () [wherein all symbols have the same meanings as above]. ] The compound represented by or the corresponding dithionic acid and the general formula [In the formula, all symbols have the same meanings as above. ] It can be obtained by reacting the compound shown in the following to form an amide bond, and subjecting it to a Ken reaction or an esterification reaction if necessary. Reactions for forming an amide bond from an acid and an amine are known, and include (A) a method using a mixed acid anhydride, (B) a method using an acid halide, and (C) a method using DCC. To explain these methods specifically, (A) a method using mixed acid anhydride, for example, the acid represented by the general formula () is dissolved in an inert organic solvent (chloroform, methylene chloride, diethyl ether, THF, etc.) or Without a solvent, in the presence of a tertiary amine (pyridine, triethylamine, picoline, etc.), acid halides (pivaloyl chloride, thionyl chloride, tosyl chloride, mesyl chloride, oxalyl chloride, etc.) or acid derivatives (ethyl chloroformate, chloroformate, etc.) isobutyl acid, etc.) at 0°C to 40°C, and the resulting mixed acid anhydride and the general formula ()
It is carried out by reacting the amine represented by in an inert organic solvent (same as above) at 0°C to 40°C. (B) A method using an acid halide is, for example, an acid represented by the general formula () in an inert organic solvent (same as above) or without a solvent with an acid halide (same as above) at -20℃ to reflux temperature. The resulting acid halide is reacted in the presence of a tertiary amine (same as above),
or in the absence of the amine represented by the general formula () in an inert organic solvent (same as above) at 0°C to 40°C.
It is carried out by reacting at ℃. The method using (C)DCC is, for example, the general formula ()
The acid represented by and the amine represented by the general formula ) at 0°C to 40°C. These reactions (A), (B) and (C) are preferably all carried out under anhydrous conditions under an inert gas (argon, nitrogen, etc.) atmosphere. [Method for producing the compound of the present invention (2)] Among the compounds of the present invention, the general formula [In the formula, R ²⁰ represents a methylene group or a single bond, and the other symbols have the same meanings as above. ] The compound represented by the general formula [In the formula, all symbols have the same meanings as above. ] It can be obtained by reacting the compound represented by the following with azide. The reaction of reacting a cyano group with azide to derive a 2-tetrazolyl group is known, for example, in an inert organic solvent (dimethylformamide, dimethylformamide, etc.) under anhydrous conditions.
By heating using an azide (sodium azide, lithium azide, potassium azide, etc.) in the presence of a weak acid (pyridium chloride, ammonium chloride, dimethylaniline hydrochloride, etc.) in N-methylpyrrolidone, etc. It is done. [Method for producing the compound of the present invention (3)] Among the compounds of the present invention, the general formula [In the formula, R ⁵⁵ represents a hydrogen atom or a straight or branched alkyl group having 1 to 6 carbon atoms, and the other symbols have the same meanings as above. ] The compound represented by the general formula [In the formula, all symbols have the same meanings as above. ] The compound represented by and the general formula or [In each formula, X ¹⁰ and X ²⁰ represent a halogen atom, R ⁵⁰ represents a straight or branched alkyl group having 1 to 6 carbon atoms, and other symbols have the same meanings as above. ] It can be obtained by reacting the compound represented by the following and subjecting it to an esterification reaction or a saponification reaction if necessary. The reaction of ring-closing catechol to form a benzodioxane ring is known, for example, under anhydrous conditions.
Condensing agent (potassium carbonate,
It is carried out by heating in the presence of sodium carbonate, etc.). [Method for producing the compound of the present invention (4)] Furthermore, among the compounds of the present invention represented by the general formula (), specific compounds can be derived from the corresponding compounds of the present invention. For example, the following reaction formula and reaction process formula [A]
can be mentioned. [In this case, a butadienylene group or a butenylene group may be used in place of the vinylene group, and the same effect may be obtained even if these are substituted with an alkyl or phenyl group. ] [Each represents the entire substituent R ¹ ,
The symbols therein indicate that each is included in R ¹ and has been converted by reaction. Similarly in the following process formula, R ³⁰ represents an alkyl, alkenyl or alkynyl group having 1 to 18 carbon atoms. [Table] Each symbol in the reaction scheme [A] on the previous page has the following meaning, and the other symbols have the same meanings as above. R ⁴⁰ , R ⁴¹ - alkyl, alkenyl or alkynyl group having 1 to 18 carbon atoms. R ⁴⁵ - hydrogen atom or alkyl, alkenyl or alkynyl group having 1 to 18 carbon atoms. T ¹⁰ - oxygen or sulfur atom or imide group. M ¹⁰ - lithium, potassium or sodium atom. X ¹ - halogen atom. [Method for producing intermediates] The intermediates represented by the general formulas (), (), and () described above can be obtained by the operations shown in the following reaction schemes. Each symbol in the reaction scheme has the following meaning, and the other symbols have the same meanings as above. ^R21 - Straight chain or branched alkyl group having 1 to 6 carbon atoms. R ⁵¹ , R ⁵² , R ⁵⁶ - Straight chain or branched alkyl group having 1 to 6 carbon atoms. R ⁵⁴ - hydrogen atom or a straight or branched alkyl group having 1 to 6 carbon atoms. R ⁷⁰ , R ⁷¹ − trifluoroacetyl group. X ³⁰ , X ⁴⁰ , X ⁵⁰ - halogen atoms. [Table] [Table] [Table] [Table] Furthermore, the intermediate of the 1,4-dithianaphthalene skeleton can also be replaced with the compound of formula () by using the general formula [In the formula, all symbols have the same meanings as above. ] General formula obtained by hydrolyzing the compound represented by [In the formula, all symbols have the same meanings as above. ] It can be obtained by using the compound shown below. In the method for producing the compound of the present invention, the esterification and saponification reactions are carried out as follows. Reactions for converting acids into esters (esterification) are well known, and include (1) a method using a diazoalkane, (2) a method using an alkyl halide, (3) a method using a DMF-dialkyl acetal, and (4) a method using a corresponding alkanol. Examples include a method of reacting with. To explain these reactions specifically, (1) the method using a diazoalkane is a method using an inert organic solvent (diethyl ether, ethyl acetate, methylene chloride,
acetone, methanol, ethanol, etc.) using the corresponding diazoalkanes. (2) A method using an alkyl hydride is, for example, a base (potassium carbonate, sodium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, calcium oxide, etc.) in an organic solvent (acetone, DMF, N,N-dimethylformamide, DMSO, etc.). ) in the presence of
This is carried out using the corresponding alkyl halide. (3) The method using DMF-dialkyl acetal is carried out, for example, using the corresponding DMF-dialkyl acetal in an inert organic solvent (benzene, toluene, etc.). (4) The method of reacting with the corresponding alkanol is
For example, acids (hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, hydrogen chloride gas, etc.) in the corresponding alkanol.
Alternatively, it is carried out using a condensing agent (DCC, pivaloyl halide, arylsulfonyl halide, alkylsulfonyl halide, etc.). These reactions are usually carried out at a temperature of -10°C to 100°C, and may be carried out with the addition of an inert organic solvent (THF, methylene chloride, etc.) that does not participate in the reaction. The reaction (saponification) for converting an ester into an acid is well known. For example, (1) an alkali (potassium hydroxide, sodium hydroxide, water (2) using an aqueous solution of lithium oxide, potassium carbonate, sodium carbonate, etc.), or (2) using the above-mentioned alkalis in alkanol (methanol, ethanol, etc.) under anhydrous conditions. These reactions are usually carried out at temperatures of -10°C to 100°C. The reaction product can be purified by conventional purification means, such as distillation under normal pressure or reduced pressure, high performance liquid chromatography using silica gel or magnesium silicate, thin layer chromatography, or column chromatography or washing and recrystallization. It can be purified by methods such as Purification may be performed for each reaction or after completion of several reactions. [Starting Materials] All starting materials and reagents in the present invention are known per se or can be synthesized by known methods. For example, the carboxylic acid represented by the general formula () is
-142936, 60-142941 or 60-146855
It can be synthesized by the method described in the specification. Compounds represented by the general formula () in which R ³ is a hydrogen atom are described in J.Med.Chem., 8, 446 (1965).
It is described in. Compounds represented by the general formula () in which R ³ is a hydrogen atom, J.Am.Chem.Soc., 75,
3277 (1953). The compound represented by the general formula () is described in J.Med.
Chem., 20, 371 (1977). Among the compounds represented by the general formula (),
When R ³ is a hydrogen atom, J.Org.Chem., 42,
1925 (1977). [Salt in the compound of the present invention] The compound of the present invention represented by the general formula () can form a salt at the tetrazolyl or carboxylic acid moiety. Since the solubility of the compound of the present invention in water increases by converting it into a salt, it is useful when administered as a pharmaceutical. The compound of the present invention can be easily converted into a salt by a known method described below. Preferably, the salts according to the invention are non-toxic. Non-toxic salts as used herein are relatively harmless to animal tissues, and when used in amounts necessary for treatment, the effective pharmacological properties of the compound represented by the general formula () are expressed by the cation. refers to salts consisting of cations that are not impaired by the side effects caused by. Moreover, it is preferable that the salt is water-soluble. Suitable salts include, for example, alkali metal salts such as sodium or potassium, alkaline earth metal salts such as calcium or magnesium, ammonium salts and pharmaceutically acceptable (non-toxic) amine salts. Suitable amines that form such salts with carboxylic acids are well known and include, for example, amines that could theoretically be obtained by replacing one or more hydrogen atoms of ammonia with other groups. The groups may be the same or different when one or more hydrogen atoms are substituted, and are selected from, for example, alkyl groups having 1 to 6 carbon atoms and hydroxyalkyl groups having 1 to 3 carbon atoms. Suitable non-toxic amine salts include tetraalkylammonium salts such as tetramethylammonium, and methylamine salts, dimethylamine salts, cyclopentylamine salts, benzylamine salts, phenethylamine salts, piperidine salts, monoethanolamine salts, diethanolamine salts. Examples include organic amine salts such as , lysine salt, and arginine salt. The salts of the compounds of the present invention can be prepared by preparing the compounds of the present invention represented by the general formula () by a known method, for example, by adding a suitable base, such as an alkali metal or alkaline earth metal hydroxide or carbonate, or an organic amine, in a suitable solvent. It is obtained by reacting with The salt is isolated by lyophilizing the solution, concentrating it under reduced pressure, or filtering it if sufficiently insoluble in the reaction solution, or if necessary by removing a portion of the solvent and then filtering it. [Pharmacological activities of the compounds of the present invention] As described above, the compounds of the present invention have leukotriene antagonism, phospholipase inhibitory activity, 5α-reductase inhibitory activity, and aldose reductase inhibitory activity. It showed a similar effect. The compounds of the present invention exhibited antagonistic effects against LTD ₄ in an in vitro system (described below) as shown in the table below. [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] As is clear from the table and the table, among the compounds of the present invention, general formulas having a 1,4-benzodioxane skeleton It can be seen that the compounds represented by (A′) and (A″) have sufficient activity to be used as a medicine, regardless of which group R in each formula is. It can be seen that sufficient activity is maintained even when the skeleton is converted from 1,4-benzodioxane to 4-oxo-4H-1-benzopyran and 2,3-dihydro-1,4-dithianaphthalene. Therefore, even if the basic skeleton is replaced with 4-oxo-4H-1-benzopyran or 2,3-dihydro-1,4-dithianaphthalene from 1,4-benzodioxane, there are still compounds that have useful activity as pharmaceuticals. These results can be applied to the table as well. The antagonistic effect of the compound of the present invention on LTD ₄ was determined by the following experimental method. The ileum (2.5 cm) was placed in oxygen (95 cm) in Tyrde solution at 37°C.
%) - suspended in a Magnus tube venting a mixed gas of carbon dioxide (5%), and after stabilizing for about 30 minutes,
LTD ₄ was added at a concentration of 5X10 ^-9 g/ml, and the compound of the present invention was added at different concentrations in response to the contraction, the contraction height was measured, and the IC ₅₀ value was calculated from this. [Medicinal applications] In mammals including humans, especially humans, by suppressing leukotrienes, allergic tracheal, bronchial, and pulmonary diseases such as asthma, allergic lung diseases, allergic shots,
It is effective in the prevention and/or treatment of various allergic diseases, and by inhibiting phospholipase (phospholipase A ₂ and/or phospholipase C), it can prevent diseases caused by arachidonic acid metabolites including the above-mentioned leukotrienes, such as thrombosis. It is effective in the prevention and/or treatment of diseases such as thrombosis caused by damage to the endothelium and intima of the brain and coronary arteries, and various inflammations such as arthritis and rheumatism. moreover
Inhibiting 5α-reductase is effective in preventing and/or treating benign prostatic hyperplasia, alopecia, and acne. Furthermore, by inhibiting aldose converting enzyme, it is effective in preventing and/or treating diabetic complications such as retinopathy, diabetic cataract, neuropathy, and renal disorder. Furthermore, it has been confirmed that the compound of the present invention is sufficiently safe for use as a medical product. In order to use the compound of the present invention represented by the general formula () or a non-toxic salt thereof for the above-mentioned purposes, each compound is usually administered systemically or locally, orally or parenterally. Dosage depends on age, weight,
Although it varies depending on the symptoms, therapeutic effects, administration method, processing time, etc., it is usually given once per adult.
in the range of 0.1 mg to 100 mg, preferably 2 mg to 20 mg,
It is administered orally once to several times a day, or parenterally administered once to several times a day, each in the range of 10 μg to 10 mg, preferably 0.1 mg to 1 mg, at a time per adult. Of course, as mentioned above, the dosage varies depending on various conditions, so there are cases where it is sufficient to use an amount smaller than the above-mentioned dosage range, and there are also cases where it is necessary to administer the dosage beyond the range. Solid compositions for oral administration according to the present invention include tablets, powders, granules, and the like. In such solid compositions, one or more active substances are present in at least one inert diluent, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, aluminum metasilicate. mixed with magnesium acid. The compositions may contain additives other than inert diluents in conventional manner, such as lubricants such as magnesium stearate and disintegrants such as fibrin calcium gluconate. Tablets or pills may be coated with a film of gastric or enteric substances such as white sugar, gelatin, hydroxypropyl cellulose, hydroxypropyl methyl cellulose phthalate, or may be coated with two or more layers, if necessary. Also included are capsules of absorbable materials such as gelatin. Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc., and commonly used inert diluents, such as purified water. , including ethanol. In addition to an inert diluent, the composition may contain adjuvants such as lubricants, suspending agents, sweeteners, flavoring agents, aromatics,
It may also contain a preservative. Other compositions for oral administration include sprays containing one or more active substances and formulated in a manner known per se. Injections for parenteral administration according to the present invention include sterile aqueous or non-aqueous solutions, suspensions,
Includes emulsifying agents. Examples of aqueous solutions and suspensions include distilled water for injection and physiological saline. Examples of non-aqueous solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and polysorbate 80 (registered trademark).
etc. Such compositions may further contain preservatives,
It may also contain auxiliary agents such as wetting agents, emulsifying agents, dispersing agents, which are rendered sterilized, for example by passing through a bacteria-retaining filter, incorporating a disinfectant, or by irradiation. They can also be prepared as sterile solid compositions and dissolved in sterile water or sterile injectable solvents before use. Other compositions for parenteral administration include:
Included are topical solutions, liniments, suppositories and pettu saris, which contain one or more active substances and are formulated in a manner known per se. [Nomenclature and Excluded Compounds] In this specification including the claims, the compounds of the present invention are 1,4-benzodioxane, 4H-1
- It is named with benzopyran or 1,4-dithianaphthalene as the mother nucleus. In addition, in the present specification including the claims, all isomers caused by stereoconfiguration (asymmetric carbon, double bond, etc.) that are not particularly limited are included. However, in the present invention, compounds that cannot exist chemically or physically (for example, those having multiple carbon-carbon bonds adjacent to oxygen, nitrogen, or sulfur atoms) are excluded. [Reference Examples and Examples] An example of the production of the compound of the present invention will be described in detail with reference to Reference Examples and Examples, but the invention is not limited thereto, of course. In addition, "TLC" in the reference examples and examples,
"LR", "NMR" and "Mass" stand for "thin layer chromatography", "infrared absorption spectrum", "nuclear magnetic resonance spectrum" and "mass spectrometry", respectively. The proportions of solvents listed in the chromatographic separation section represent volume ratios, and the solvent in the box indicates the developing solvent or elution solvent used. Unless otherwise specified, infrared absorption spectra were measured using the KBr tablet method, and nuclear magnetic resonance spectra were measured in a mixed solution of deuterated chloroform and deuterated methanol. Reference Example 1 Synthesis of 3-(m-methoxy-p-pentyloxycinnamoyl)aminopyrocatechol Oxalyl chloride (4.5 ml) was added to m-methoxy-p-pentyloxybenzoic acid (528 mg), stirred at room temperature under an argon atmosphere for 30 minutes, and concentrated under reduced pressure. The residue was dissolved in methylene chloride (10
ml), and this was added dropwise to a mixed solution of 3-aminopyrocatechol (275 mg) in methylene chloride (10 ml) and pyridine (3 ml) under ice cooling under an argon atmosphere, and the mixture was stirred at the same temperature for 1 hour. After further stirring at room temperature for 2 hours, the mixture was poured into IN hydrochloric acid and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried, and concentrated under reduced pressure. The obtained solid was washed with hexane and dried to obtain the title compound (700 mg) having the following physical properties. TLC: R0.20 (ethyl acetate:hexane=1:
2); NMR (CDCl ₃ ): δ10.00 (1H, s), 7.75 (1H,
d), 7.60 (1H, s), 6.30−7.25 (7H, m),
6.10 (1H, s), 4.10 (2H, t), 1.90 (3H,
s); Mass: m/e371 (M ⁺ ), 247, 177, 145, 125,
117, 89. Reference Example 2 Synthesis of 8-(m-methoxy-p-pentyloxycinnamoyl)amino-1,4-dioxane-2-carbonitrile Anhydrous potassium carbonate (770 mg) and 2-chloroacrylonitrile (0.30 ml) were added to a solution of 3-(m-methoxy-p-pentyloxycinnamoyl) aminopyrocatechol (690 mg; synthesized in Reference Example 1) in acetone (10 ml). under an argon atmosphere.
The mixture was heated under reflux for 3 hours. The reaction solution cooled to room temperature was poured into ice water (50 ml), extracted with ethyl acetate, and the extract was dried and concentrated under reduced pressure. The residue was purified using silica gel column chromography (methylene chloride: ethyl acetate = 10:1) to obtain the title compound (565 mg) having the following physical properties. TLC: R0.15 (ethyl acetate:hexane=1:
2); NMR (CDCl ₃ ): δ8.25 (1H, dd), 7.70 (1H,
d), 7.55 (1H, s), 7.00−7.25 (2H, m),
6.90 (1H, d), 6.85 (1H, d) 6.70 (1H, dd),
6.45 (1H, d), 5.20 (1H, dd), 4.30−4.55
(2H, m), 4.05 (2H, t) 3.93 (3H, s); Mass: m/e422 (M ⁺ ), 247, 177, 145, 117. Reference Example 3 (Example A) 8-(p-pentylcinnamoyl)amino-1,
Synthesis of 4-benzodioxane-2-acetic acid methyl ester Potassium carbonate (509 mg) was added to a solution of 3-(p-pentylcinnamoyl)aminopyrocatechol (300 mg; synthesized in the same manner as in Reference Example 1) and 4-bromo-2-butenoic acid methyl ester (826 mg) in acetone (10 ml). ) and heated under reflux for 10 minutes. The reaction mixture was poured into water, extracted with ethyl acetate, the extract was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 5:
1) to obtain the title compound (341 mg). Reference example 4 8-(p-pentylcinnamoyl)amino-1,
Synthesis of 4-benzodioxane-2-acetamide 8-(p-pentylcinnamoyl)amino-1,
4-Benzodioxane-2-acetic acid methyl ester (341 mg; synthesized in Reference Example 3) was dissolved in ammonia-saturated ethanol (20 ml) and left at 100°C for 3 days. The reaction mixture was concentrated, and the resulting residue was purified by column chromatography (hexane: ethyl acetate = 2:1) to obtain the title compound (191 mg).
I got it. Reference example 5 8-(p-pentylcinnamoyl)amino-1,
Synthesis of 4-benzodioxane-2-acetonitrile 8-(p-pentylcinnamoyl)amino-1,
4-Benzodioxane-2-acetamide (191
mg: Synthesized in Reference Example 4. ) to THF (10 ml) under ice, trifluoroacetic anhydride (0.1 ml) and then pyridine (0.02 ml) were added to the solution, stirred for 10 minutes, and then poured into water. The mixture was extracted with ethyl acetate, and the extract was dried and concentrated under reduced pressure to obtain the title compound. Example 1 8-[p-(3Z-hexenyloxy)benzoyl]amino-2-(5-tetrazolyl)-1,4-
Synthesis of benzodioxane p-(3Z-hexenyloxy)benzoic acid (110
mg) and oxalyl chloride (1 ml) at room temperature.
After stirring for an hour, excess oxalyl chloride was removed under reduced pressure. The residue was dried with a vacuum pump and then dissolved in methylene chloride (2 ml). 8-Amino-2- cooled on ice under an argon atmosphere.
The above solution was added dropwise to a mixed solution of (5-tetrazolyl)-1,4-benzodioxane hydrochloride (128 mg) in methylene chloride (2 ml) and pyridine (0.7 ml). After dropping, stir the reaction solution at room temperature for 5 hours,
Diluted with ethyl acetate. Dilute the diluted solution with 1N hydrochloric acid (1ml)
and extracted with ethyl acetate. The extract was dried and concentrated under reduced pressure. The residue was recrystallized from benzene to obtain the title compound (112 mg) having the following physical properties.
I got it. TLC: R0.57 (Chloroform: Methanol =
3:1); NMR: δ7.90 (2H, d), 7.88 (1H, m), 7.46
(1H, dd), 6.96 (2H, d), 6.92 (1H, t),
6.78 (1H, dd), 5.77 (1H, dd), 5.70 (2H,
m), 4.61 (2H, m), 4.04 (2H, t) 2.57 (2H,
dt), 2.12 (2H, m), 1.01 (3H, t); IR: ν 3600−2300, 1650, 1610, 1540,
1505, 1460, 1250, 1175, 1090, 840, 770cm ^-
1 ; Mass: m/e 421 (M ⁺ ), 203; Shape: White powder. Example 1(1)-1(118) By the same operation as in Example 1, the corresponding carboxylic acid and 8-amino-2-(5-tetrazolyl)-
The compounds shown in the following table [ ] were synthesized using 1,4-benzodioxane hydrochloride. [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] ] [Table] [Table] [Table] [Table] [Table] [Table] [Table] Example 1 (201)-1 (253) By the same operation as in Example 1, the corresponding carboxylic acid and the corresponding substitution 8-amino- with group R ³
2-(5-tetrazolyl)-4-oxo-4H-1
- Compounds shown in the following table [] were synthesized using benzopyran hydrochloride. [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] Example 1 (301)-1 (302) By the same operation as in Example 1, p-pentylcinnamic acid and 8-amino-2-(5-tetrazolyl)-
2,3-dihydro-1,4-dithianaphthalene hydrochloride or 5-amino-2-(5-tetrazolyl)
Two compounds shown in the following table [] were synthesized using -2,3-dihydro-1,4-dithianaphthalene hydrochloride. [Table] Example 1 (401) By the same operation as in Example 1, p-heptyloxybenzodithionic acid and 8-amino-2-(5-
The following compound was synthesized using (tetrazolyl)-1,4-benzodioxane hydrochloride. However, thionyl chloride was used instead of oxalyl chloride. TLC: R0.14 (Chloroform: Methanol =
17:3); NMR: δ7.87 (2H, d), 7.77 (1H, m), 6.90
(4H, m), 5.74 (1H, m), 4.58 (2H, m),
3.98 (2H, t), 1.78 (2H, m), 1.30 (8H, m),
0.88 (3H, t); IR; ν 3600−2400, 1600, 1495, 1450,
1255, 1170, 1090, 1005, 960, 830cm ^-1 ; Mass: m/e453 (M ⁺ ), 420, 354, 326, 235,
219, 137, 121; Shape: Orange powder. Example 2 8-(3-methoxy-4-pentyloxycinnamoyl)amino-2-(5-tetrazolyl)-
Synthesis of 1,4-benzodioxane 8-(3-methoxy-4-pentyloxycinnamoyl)amino-1,4-benzodioxane-
To a solution of 2-carbonitrile (560 mg; synthesized in Reference Example 2) in anhydrous dimethylformamide (3 ml) were added sodium azide (490 mg) and pyridinium chloride (870 mg), and the mixture was heated at 100°C under an argon atmosphere.
Stirred for 1.5 hours. The reaction solution cooled to room temperature was poured into 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to obtain a compound (390 mg) having the following physical properties. TLC: R0.10 (Chloroform: Methanol =
5:1); NMR: δ7.69 (1H, d), 7.68 (1H, s), 7.05
−7.25 (2H, m), 6.80 −7.00 (2H, m), 6.74
(1H, m), 6.65 (1H, d), 5.73 (1H, m),
4.69 (1H, dd), 4.51 (1H, dd), 4.05 (2H,
t), 3.92 (3H, s), 1.87 (2H, m), 1.30−
1.55 (4H, m) 0.94 (3H, t); IR; ν 2940, 2850, 1655, 1600, 1540,
1505, 1450, 1260 cm ^-1 ; Mass: m/e465 (M ⁺ ), 247, 177, 145. Example 2(1)-2(46) The compounds shown in the following table [ ] were synthesized using the corresponding carboxylic acid and 3-aminopyrocatechol in the same manner as in Reference Examples 1 and 2 and Example 2. did. [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] Example 2 (101)-2 (107) Same as Reference Examples 1, 2 and Example 2 By operation, the corresponding carboxylic acid and the corresponding substituent R ² ,
Using 3-aminopyrocatechol with R ³
The compounds shown in the following table [] were synthesized. [Table] [Table] Example 2 (201) - 2 (204) 3-Aminopyrocatechol having the corresponding carboxylic acid and the corresponding substituent R ³ was prepared by the same procedure as in Reference Examples 1 and 2 and Example 2. The following compound was synthesized using 2 (201) TLC: R0.21 (Chloroform: Methanol =
3:1); NMR: δ8.03 (1H, d), 7.70 (1H, d), 7.48
(2H, d), 7.20 (2H, d), 6.71 (1H, d),
6.65 (1H, d), 5.57 (1H, s), 4.70−4.40
(2H, m), 2.62 (2H, t); IR; ν 3700−3000, 1680, 1625, 1610,
1535, 1470, 1440cm ^-1 ; Mass: m/e 201, 179, 162; Shape: White powder. 2 (202) (However, it is a single substance.) TLC: R0.22 (methylene chloride: methanol =
5:1); NMR: δ8.21 (1H, d), 7.74 (1H, d), 7.57
(1H, d), 7.49 (2H, d), 7.20 (2H, d),
6.62 (1H, d), 5.74 (1H, dd), 4.89 (1H,
dd), 4.54 (1H, dd); IR; ν 3370, 3200−2300, 1695, 1630,
1610, 1520, 1430, 1270, 1140 cm ^-1 ; Mass: m/e477 (M ⁺ ), 291, 201; Shape: white crystal. 2 (203) - 2 (204) and・ Less polar compound: TLC: R0.18 (methylene chloride: methanol =
5:1); NMR (CDCl ₃ ): δ9.88 (1H, s), 7.81 (1H, d), 7.45
(3H, s), 7.18 (2H, s), 6.69 (1H, s),
6.64 (1H, d), 6.04 (1H, s), 5.60 (1H, s),
4.50 (1H, s) 3.84 (3H, s), 0.88 (3H, t); IR; ν 3600−2300, 1695, 1630, 1610,
1515, 1470, 1280 cm ^-1 ; Mass: m/e477 (M ⁺ ), 446, 291, 201; Shape: White crystal.・ More polar compounds: TLC: R0.12 (methylene chloride: methanol =
5:1); NMR (CDCl ₃ ): δ9.44 (1H, s), 7.46 (1H, s), 7.25
(1H, s), 7.13 (2H, s), 6.88 (2H, s),
6.60−6.30 (2H, s), 5.20 (1H, s), 4.20−
3.60 (2H, s) 3.72 (3H, s), 0.83 (3H, t); IR; ν 3600−3000, 1695, 1630−1610,
1520, 1480, 1280 cm ^-1 ; Mass: m/e477 (M ⁺ ), 446, 291, 201; Shape: White crystal. Example 2 (301) In the same manner as in Example 2, using 8-(p-pentylcinnamoyl)amino-1,4-benzodioxysan-2-acetonitrile (synthesized in Reference Example 5), the following The compound was synthesized. TLC: R0.36 (methylene chloride: methanol =
5:1); NMR: δ 7.88 (1H, d), 7.70 (1H, d),
7.47 (2H, d), 7.20 (2H, d), 6.84 (1H, t),
6.63 (1H, dd), 6.57 (1H, d), 3.36 (2H,
d); IR; ν 3300, 3200−2300, 1660, 1605,
1530, 1460 cm ^-1 ; Mass: m/e433 (M ⁺ ), 233, 201; Shape: Brown powder. Example 3 8-(p-pentylcinnamoyl)amino-4
-Synthesis of oxo-4H-1-benzopyran-2-carboxylic acid ethyl ester Oxalyl chloride (3.4 ml) was added to p-pentyl cinnamic acid (327 mg), stirred at room temperature for 30 minutes, and then excess oxalyl chloride was removed under reduced pressure. The residue was dissolved in methylene chloride (5 ml).
Methylene chloride (5 ml) and triethylamine (0.6 ml) were added to this under an argon atmosphere at 0°C.
8-amino-4-oxo- dissolved in a mixed solvent of
4H-1-benzopyran-2-carboxylic acid ethyl ester (420 mg) was slowly added. After stirring the reaction solution at room temperature for 1 hour, it was poured into 0.1N hydrochloric acid and extracted with ethyl acetate. The extract was washed successively with water, saturated aqueous sodium bicarbonate solution, and saturated brine, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:3) to obtain the title compound (140 mg) having the following physical properties. TLC: R0.60 (ethyl acetate:hexane=1:
1); NMR (CDCl ₃ ): δ 8.76 (1H, dd), 8.23 (1H,
s), 7.72 (1H, dd), 7.65 (1H, d), 7.38
(2H, d), 7.27 (1H, t), 7.07 (2H, d),
7.00 (1H, s), 6.52 (1H, d); IR; ν 3270, 2930, 1730, 1660, 1630,
1530, 1430, 1290, 1260, 1180, 770cm ^-1 ; Mass: m/e433 (M ⁺ ), 404, 388, 376, 360,
318, 233, 201, 131; Shape: White powder. Example 4 8-(p-pentylcinnamoyl)amino-4
-Synthesis of oxo-4H-1-benzopyran-2-carboxylic acid 8-(p-pentylcinnamoyl)amino-4
-oxo-4H-1-benzopyran-2-carboxylic acid ethyl ester (132 mg: synthesized in Example 3)
was dissolved in ethanol (10 ml), an aqueous solution (1 ml) of sodium hydrogen carbonate (126 mg) was added, and the mixture was heated under reflux for 15 minutes. After cooling the reaction solution to room temperature, water (20
ml) and 1N hydrochloric acid (2 ml), and then extracted with ethyl acetate. The extract was washed with water and saturated brine, dried, and concentrated under reduced pressure. The residue was washed with a mixed solvent of ethyl acetate-hexane (1:1) and dried to obtain the title compound (62 mg) having the following physical properties.
I got it. TLC: R0.25 (ethyl acetate: methanol = 5:
1); NMR: δ 8.66 (1H, dd), 7.86 (1H, dd),
7.73 (1H, d), 7.53 (2H, d), 7.43 (1H, t),
7.22 (2H, d), 7.15 (1H, s), 7.08 (1H,
d); IR; ν 3400, 2930, 1635, 1520, 1430,
1360cm ^-1 ; Mass: m/e405 (M ⁺ ), 361, 201, 181, 169,
131, 69; Form: Yellow powder. Example 4(1)-4(3) By the same operation as in Examples 3 and 4, 8- having the corresponding carboxylic acid and the corresponding substituent R ³
Amino-4-oxo-4H-1-benzopyran-
The compounds shown in the following table [] were synthesized using 2-carboxylic acid ethyl ester. [Table] [Table] Example 4 (101) - 4 (104) By the same operation as in Examples 3 and 4, the corresponding carboxylic acid and 8-amino-1,4-benzodioxysan-2-carboxylic acid were prepared. Using ethyl ester, the compounds shown in the following table [] were synthesized. [Table] Example 5 8-[3-(p-pentylphenyl)propionyl]amino-2-(5-tetrazolyl)-1,4-
Synthesis of benzodioxane 8-(p-pentylcinnamoyl)amino-2
-(5-tetrazolyl)-1,4-benzodioxane (216 mg; synthesized in Example 2 (1)) and palladium-carbon (50 mg; containing 5%) were mixed in methanol-ethanol-ethyl acetate (1:1:1). The mixture was suspended in a mixed solvent (6 ml) and stirred at room temperature under a hydrogen atmosphere for 90 minutes. After stirring, it was filtered through Celite, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol =
19:1) to obtain the title compound (202 mg) having the following physical properties. TLC: R0.54 (methylene chloride: methanol =
4:1); NMR (CDCl ₃ ): δ 7.28 (1H, s), 7.11 (4H,
2d), 6.76 (2H, m), 6.60 (1H, dd), 5.68
(1H, t), 4.93 (1H, dd), 3.04 (2H, t),
2.77 (2H, m) 2.56 (2H, t), 1.58 (2H, m),
1.30 (4H, m), 0.88 (3H, t); IR; ν 3600−2300, 1650, 1615, 1530,
1460, 1260, 1100, 780 cm ^-1 ; Mass: m/e 421 (M ⁺ ), 219; Shape: White crystal. Example 6 8-[p-(6-hydroxyhexyloxy)benzoyl]amino-2-(5-tetrazolyl)-
Synthesis of 1,4-benzodioxane A solution of 8-[p-(6-acetyloxyhexyloxy)benzoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane (100 mg; synthesized in Example 1 (96)) in methanol (0.5 ml) A 1N aqueous sodium hydroxide solution (0.5 ml) was added to the mixture at room temperature. The reaction solution was stirred for 10 minutes, concentrated under reduced pressure, made acidic with dilute hydrochloric acid, and then extracted with ethyl acetate.
The extract was dried and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (methylene chloride:methanol = 100:1) to obtain the title compound (95 mg) having the following physical properties. TLC: R0.23 (methylene chloride: methanol =
5:1); NMR: δ 7.89 (2H, d), 7.46 (1H, dd),
6.95 (2H, d), 6.92 (1H, t), 6.76 (1H,
dd), 4.02 (2H, t), 3.60 (2H, t); IR; ν 3400, 3200−2300, 1630, 1600,
1520, 1500, 1440, 1250 cm ^-1 ; Mass: m/e439 (M ⁺ ), 221, 149, 121; Shape: White amorphous. Example 7 8-[p-(5-(N,N-dimethylamino)pentyloxy]cinnamoyl]amino-1,4-
Synthesis of benzodioxane sodium salt A 40% aqueous dimethylamine solution (1 ml) was added to a solution of 8-[p-(5-bromopentyloxy)cinnamoyl]amino-1,4-benzodioxane (176 mg; synthesized in Example 1 (113)) in dimethylformamide (1 ml). ) was added dropwise, stirred at room temperature for 1 hour, and then stirred at room temperature for 1 hour using a vacuum pump.
Volatiles were distilled off at 90°C for 3 hours. The residue was dissolved in methanol (1 ml), 2N aqueous sodium hydroxide solution (360μ) was added, concentrated, a small amount of methanol was added, hexane (4 ml) was added, and the mixture was filtered. The filtrate was heated at room temperature overnight and then at 80°C overnight using a vacuum pump to remove volatiles to obtain the title compound (179 mg) having the following physical properties. TLC: R0.33 (ethyl acetate: acetic acid: water = 3:
3:1); NMR: δ 7.87 (2H, d), 7.62 (1H, dd),
6.98 (2H, d), 6.86 (1H, t), 6.71 (1H,
dd), 4.06 (2H, t), 2.85 (2H, t), 2.64
(6H, s); IR; ν 3430, 2930, 1655, 1605, 1505,
1445, 1255 cm ^-1 ; Mass: m/e 452 (M ⁺ ), 233; Shape: White powder. Example 8 8-(p-octyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane-7-carboxylic acid 8-(p-octyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane-7-carboxylic acid methyl ester (332
mg: Synthesized in Example 2 (107). ) was dissolved in methanol (1.5 ml), 1N aqueous sodium hydroxide solution (1.36 ml) was added to this solution, and the mixture was stirred at room temperature for 50 minutes and then at 40°C for 2 hours. After cooling, 1N hydrochloric acid (2 ml) was added and extracted with ethyl acetate.
The extract was dried and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform:
The title compound (263 mg) was purified with methanol (9:1) to obtain the title compound (263 mg) having the following physical properties. TLC: R0.15 (Chloroform: Methanol =
4:1); NMR: δ 8.00 (2H, d), 7.68 (1H, d),
6.98 (2H, d), 6.82 (1H, d), 6.04 (1H, m),
4.56 (2H, m), 4.03 (2H, t), 1.82 (2H, m),
1.31 (10H, m), 0.88 (3H, t); IR; ν 3600−2300, 1680, 1640, 1600,
1490, 1460, 1250, 1170, 1080, 900, 840,
760cm ^-1 ; Mass: m/e495 (M ⁺ ), 477, 383, 233; Shape: Light brown powder. Example 9 8-(p-pentylcinnamoyl)amino-2
-Synthesis of (5-tetrazolyl)-6-methyl-1,4-benzodioxane sodium salt 8-(p-pentylcinnamoyl)-2-(5-
Tetrazolyl)-6-methyl-1,4-benzodioxane (50 mg; synthesized in Example 2 (103)) was dissolved in methanol (0.5 ml), added with an equivalent amount of 1N aqueous sodium hydroxide solution, stirred, and then dried under reduced pressure. It solidified to give the title compound (51 mg). Example 9(1) By the same operation as in Example 9, Examples 1 and 1(1)-
1 (118), 1 (201) - 1 (253), 1 (301) - 1 (30
2),
1 (401), 2, 2 (1)-2 (46), 2 (101), 2 (102
),
2 (104) - 2 (107), 2 (201) - 2 (204), 2 (30
1),
The corresponding sodium salts of compounds 4, 4(1)-4(3), 4(101)-4(104), 5, 6, and 8 were also synthesized. Example 10 8-[p-(3Z-hexenyloxy)benzoyl]amino-2-(5-tetrazolyl)-1,4-
Benzodioxane 0.5g, cellulose calcium glyconate (disintegrant) 200mg, magnesium stearate (lubricant) 100mg and microcrystalline cellulose 9.2g
were mixed and tableted in a conventional manner to obtain 100 tablets each containing 5 mg of active ingredient.

Claims (1)

[Claims] 1. General formula [In the formula, R ¹ is a general formula [Formula] or or () represents a linear or branched alkyl, alkenyl or alkynyl group having 1 to 20 carbon atoms (in the formula, R ⁵ and R ⁶ are each independently a hydrogen atom or a halogen atom, or any one, two or three carbon atoms are an oxygen atom, a sulfur atom, a halogen atom, a nitrogen atom, a benzene ring, a thiophene ring, a hydrocarbon ring having 4 to 7 carbon atoms, a carbonyl group,
It represents a straight or branched alkyl, alkenyl or alkynyl group having 1 to 20 carbon atoms which may be substituted with a carbonyloxy group, hydroxyl group, carboxy group, azide group or nitro group. ). R ² represents a hydrogen atom or a straight or branched alkyl group having 1 to 6 carbon atoms. R ³ is a hydrogen atom, a halogen atom, a hydroxyl group, a nitro group, or is represented by the general formula -COOR ⁷ (wherein R ⁷ represents a hydrogen atom or a straight or branched alkyl group having 1 to 6 carbon atoms). represents a straight-chain or branched alkyl, alkoxy or alkylthio group having 1 to 6 carbon atoms. R ⁴ is a group represented by the general formula -COOR ⁸ or -CH ₂ COOR ⁸ (wherein R ⁸ represents a hydrogen atom or a straight or branched alkyl group having 1 to 6 carbon atoms), 2- Represents a tetrazolyl group or 2-tetrazolylmethyl group. Symbol A is methylene, ethylene, trimethylene, tetramethylene, vinylene, propenylene, butynylene, butadienylene, or ethynylene, which may be substituted with a single bond, or a linear or branched alkyl group or phenyl group having 1 to 6 carbon atoms. represents a group. The symbol [formula] represents a ring represented by the formula [formula], [formula] or [formula]. The symbol T represents an oxygen atom or a sulfur atom. ] A novel condensed benz(thio)amide or a non-toxic salt thereof. 2 General formula [In the formula, all symbols have the same meanings as described in claim 1. ] The compound according to claim 1, which is represented by: 3. The compound according to claim 1 or 2, wherein symbol A is a single bond and symbol T is an oxygen atom. 4 R ¹ is the general formula [Formula] [wherein R ⁵ and R ⁶ represent the same meanings as described in claim 1]. ] The compound according to any one of claims 1 to 3, which is a group represented by the following. 5 R ⁵ is a hydrogen atom, and R ⁶ is a hydrogen atom or a straight or branched alkyl group having 1 to 20 carbon atoms, according to any one of claims 1 to 4. compound. 6 8-(p-pentylbenzoyl)amino-2
The compound according to claim 1, which is -(5-tetrazolyl)-1,4-benzodioxane. 7 8-(p-pentylbenzoyl)amino-2
The compound according to claim 1, which is -(5-tetrazolyl)-6-chloro-1,4-benzodioxane. 8 8-(m-octylbenzoyl)amino-2
The compound according to claim 1, which is -(5-tetrazolyl)-1,4-benzodioxane. 9 8-(o-pentylbenzoyl)amino-2
The compound according to claim 1, which is -(5-tetrazolyl)-1,4-benzodioxane. 10 8-(p-pentylbenzoyl)amino-
The compound according to claim 1, which is 2-(5-tetrazolyl)-1,4-benzodioxane. 11 8-(p-hexylbenzoyl)amino-
The compound according to claim 1, which is 2-(5-tetrazolyl)-1,4-benzodioxane. 12 8-(p-heptylbenzoyl)amino-
The compound according to claim 1, which is 2-(5-tetrazolyl)-1,4-benzodioxane. 13 8-(p-octylbenzoyl)amino-
The compound according to claim 1, which is 2-(5-tetrazolyl)-1,4-benzodioxane. 14 8-(p-nonylbenzoyl)amino-2
The compound according to claim 1, which is -(5-tetrazolyl)-1,4-benzodioxane. 15 8-(p-decylbenzoyl)amino-2
The compound according to claim 1, which is -(5-tetrazolyl)-1,4-benzodioxane. 16. The compound according to claim 1, which is 8-(p-undecylbenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane. 17 8-(p-dodecylbenzoyl)amino-
The compound according to claim 1, which is 2-(5-tetrazolyl)-1,4-benzodioxane. 18 R ⁵ is a hydrogen atom, R ⁶ has 1 to 19 carbon atoms
The compound according to any one of claims 1 to 4, which is a linear or branched alkoxy group. 19 The compound according to claim 1, which is 8-(p-pentyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane. 20 The compound according to claim 1, which is 8-(m-pentyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane. 21 The compound according to claim 1, which is 8-(o-pentyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane. 22 The compound according to claim 1, which is 8-(p-butyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane. 23 The compound according to claim 1, which is 8-(p-nonyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane. 24 The compound according to claim 1, which is 8-(p- propoxybenzoyl )amino-2-(5-tetrazolyl)-1,4-benzodioxane. 25 The compound according to claim 1, which is 8-(p-hexyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane. 26 The compound according to claim 1, which is 8-(p-heptyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane. 27 The compound according to claim 1, which is 8-(p-octyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane. 28 The compound according to claim 1, which is 8-(p-decyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane. 29 8-(p-isopentyloxybenzoyl)
The compound according to claim 1, which is amino-2-(5-tetrazolyl)-1,4-benzodioxane. 30 8-(p-isohexyloxybenzoyl)
The compound according to claim 1, which is amino-2-(5-tetrazolyl)-1,4-benzodioxane. 31 8-[p-(1-methylbutoxy)benzoyl]amino-2-(5-tetrazolyl)-1,4-
The compound according to claim 1, which is a benzodioxane. 32 The compound according to claim 1, which is 8-[N-methyl-N-(p-octynyloxybenzoyl)amino]-2-(5-tetrazolyl)-1,4-benzodioxane. 33 The compound according to claim 1, which is 8-(p-octyloxybenzoyl)amino-1,4-benzodioxane-2-carboxylic acid or its ethyl ester. 34 8-(p-isobutyloxybenzoyl)
The compound according to claim 1, which is amino-2-(5-tetrazolyl)-1,4-benzodioxane. 35 8-(p-isooctyloxybenzoyl)
The compound according to claim 1, which is amino-2-(5-tetrazolyl)-1,4-benzodioxane. 36 The compound according to claim 1, which is 8-[p-(3,7-dimethyloctyloxy)benzoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane. 37 The compound according to claim 1, which is 8-(p-octyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane-7-carboxylic acid methyl ester. 38 The compound according to claim 1, which is 8-(p-octyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane-7-carboxylic acid. 39 R ⁵ is a hydrogen atom, R ⁶ has 3 to 19 carbon atoms
The compound according to any one of claims 1 to 4, which is a linear or branched alkenyloxy group. 40 8-[p-(2E-octenyloxy)benzoyl]amino-2-(5-tetrazolyl)-1,
Claim 1 which is 4-benzodioxane
Compounds described in Section. 41 8-[p-(3-butenyloxy)benzoyl]amino-2-(5-tetrazolyl)-1,4-
The compound according to claim 1, which is a benzodioxane. 42 8-[p-(3Z-hexenyloxy)benzoyl]amino-2-(5-tetrazolyl)-1,
Claim 1 which is 4-benzodioxane
Compounds described in Section. 43 8-[p-(2Z-octenyloxy)benzoyl]amino-2-(5-tetrazolyl)-1,
Claim 1 which is 4-benzodioxane
Compounds described in Section. 44 8-[p-(2E-nonineroxy)benzoyl]amino-2-(5-tetrazolyl)-1,4
- The compound according to claim 1, which is benzodioxane. 45 8-[N-methyl-N-[p-(2E-octenyloxy)benzoyl]amino]-2-(5-tetrazolyl)-1,4-benzodioxane according to claim 1 Compound. 46 8-[p-(2E-hexenyloxy)benzoyl]amino-2-(5-tetrazolyl)-1,
Claim 1 which is 4-benzodioxane
Compounds described in Section. 47 8-[p-(3E-heptenyloxy)benzoyl]amino-2-(5-tetrazolyl)-1,
Claim 1 which is 4-benzodioxane
Compounds described in Section. 48 8-[p-(2E-octenyloxy)benzoyl]amino-1,4-benzodioxane-2
- The compound according to claim 1, which is a carboxylic acid or its ethyl ester. 49 8-[p-(2E-heptenyloxy)benzoyl]amino-2-(5-tetrazolyl)-1,
Claim 1 which is 4-benzodioxane
Compounds described in Section. 50 8-[p-(4-pentenyloxy)benzoyl]amino-2-(5-tetrazolyl)-1,4
- The compound according to claim 1, which is benzodioxane. 51 8-[p-(2E-decenyloxy)benzoyl]amino-2-(5-tetrazolyl)-1,4
- The compound according to claim 1, which is benzodioxane. 52 The compound according to claim 1, which is 8-(p-geranyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane. 53 The compound according to claim 1, which is 8-[p-(2E,7-octadienyloxy)benzoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane. 54 8-[p-(2E-pentenyloxy)benzoyl]amino-2-(5-tetrazolyl)-1,
Claim 1 which is 4-benzodioxane
Compounds described in Section. 55 8-[p-(2E-butenyloxy)benzoyl]amino-2-(5-tetrazolyl)-1,4
- The compound according to claim 1, which is benzodioxane. 56 8-[p-(3E-octenyloxy)benzoyl]amino-2-(5-tetrazolyl)-1,
Claim 1 which is 4-benzodioxane
Compounds described in Section. 57 8-[p-(7-octenyloxy)benzoyl]amino-2-(5-tetrazolyl)-1,4
- The compound according to claim 1, which is benzodioxane. 58 The compound according to claim 1, which is 8-[p-(2E,4E-octadienyloxy)benzoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane. 59 8-[p-(2E-octenyloxy)benzoyl]amino-2-(5-tetrazolyl)-1,
Claim 1 which is 4-benzodioxane
Compounds described in Section. 60 R ⁵ is a hydrogen atom, R ⁶ has 3 to 19 carbon atoms
The compound according to any one of claims 1 to 4, which is a linear or branched alkyloxy group. 61 8-[p-(2-octynyloxy)benzoyl]amino-2-(5-tetrazolyl)-1,4
- The compound according to claim 1, which is benzodioxane. 62 8-[p-(2-octynyloxy)benzoyl]amino-1,4-benzodioxane-2-
The compound according to claim 1, which is a carboxylic acid or its ethyl ester. 63 8-[p-(2-isooctynyloxy)benzoyl]amino-2-(5-tetrazolyl)-
The compound according to claim 1, which is 1,4-benzodioxane. 64 R ⁵ is a hydrogen atom, R ⁶ has 1 to 19 carbon atoms
The compound according to any one of claims 1 to 4, which is a linear or branched alkylthio group. 65 The compound according to claim 1, which is 8-(p-pentylthiobenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane. 66 The compound according to claim 1, which is 8-(m-pentylthiobenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane. 67 The compound according to claim 1, which is 8-[o-pentylthiobenzoyl)-amino-2-(5-tetrazolyl)-1,4-benzodioxane. 68 The compound according to claim 1, which is 8-(p-heptylthiobenzoyl)-amino-2-(5-tetrazolyl)-1,4-benzodioxane. 69 Any one of claims 1 to 4, wherein R ⁵ is a hydrogen atom and R ⁶ is a straight or branched alkoxy group having 1 to 18 carbon atoms substituted with a halogen atom. Compounds listed in section. 70 8-[p-(6-chlorohexyloxy)benzoyl]amino-2-(5-tetrazolyl)-
The compound according to claim 1, which is 1,4-benzodioxane. 71 8-[p-(5-chloropentyloxy)benzoyl]amino-2-(5-tetrazolyl)-
The compound according to claim 1, which is 1,4-benzodioxane. 72 8-[p-(4-chlorobutyloxy)benzoyl]amino-2-(5-tetrazolyl)-1,
Claim 1 which is 4-benzodioxane
Compounds described in Section. 73 8-[p-(7-chloroheptyloxy)benzoyl]amino-2-(5-tetrazolyl)-
The compound according to claim 1, which is 1,4-benzodioxane. 74 8-[p-(8-chlorooctyloxy)benzoyl]amino-2-(5-tetrazolyl)-
The compound according to claim 1, which is 1,4-benzodioxane. 75 8-[p-(9-chlorononyloxy)benzoyl]amino-2-(5-tetrazolyl)-1,
Claim 1 which is 4-benzodioxane
Compounds described in Section. 76 8-[p-(5-bromopentyloxy)benzoyl]amino-2-(5-tetrazolyl)-
The compound according to claim 1, which is 1,4-benzodioxane. 77 R ⁵ is a hydrogen atom, R ⁶ has 2 to 19 carbon atoms
The compound according to any one of claims 1 to 4, which is a linear or branched alkyloxyalkyl group. 78 8-[p-(hexyloxymethyl)benzoyl]amino-2-(5-tetrazolyl)-1,4
- The compound according to claim 1, which is benzodioxane. 79 R ⁵ is a hydrogen atom, R ⁶ has 1 to 8 carbon atoms
cycloalkyl or cycloalkylalkyl having 4 to 7 carbon atoms, which may be substituted with a straight-chain or branched alkyl group (the alkyl portion has 1 to 1 carbon atoms)
8) or a cycloalkylalkyloxy (alkyl moiety has 1 to 8 carbon atoms) group. 80 8-(p-cyclohexylmethoxybenzoyl)amino-2-(5-tetrazolyl)-1,4
- The compound according to claim 1, which is benzodioxane. 81 8-[p-(4-cyclohexylbutoxy)
benzoyl]amino-2-(5-tetrazolyl)-
The compound according to claim 1, which is 1,4-benzodioxane. 82 8-[p-(2-cyclohexylethoxy)
benzoyl]amino-2-(5-tetrazolyl)-
The compound according to claim 1, which is 1,4-benzodioxane. 83 R ⁵ is a hydrogen atom, R ⁶ has 1 to 8 carbon atoms
phenyl, phenylalkyl (alkyl moiety has 1 to 8 carbon atoms), phenylalkyloxy (alkyl moiety has 1 to 8 carbon atoms) group, which may be substituted with a straight chain or branched alkyl group, or enylalkenyloxy (alkenyl part has 2 to 2 carbon atoms)
8) The compound according to any one of claims 1 to 4, which is a group. 84 8-[p-(p-butylphenyl)methoxybenzoyl]amino-2-(5-tetrazolyl)-
The compound according to claim 1, which is 1,4-benzodioxane. 85 8-[p-(5-phenylpentyloxy)
benzoyl]amino-2-(5-tetrazolyl)-
The compound according to claim 1, which is 1,4-benzodioxane. 86 8-[p-(3-phenylpropoxy)benzoyl]amino-2-(5-tetrazolyl)-1,
Claim 1 which is 4-benzodioxane
Compounds described in Section. 87 8-[p-(p-propylphenyl)methoxybenzoyl]amino-2-(5-tetrazolyl)
The compound according to claim 1, which is -1,4-benzodioxane. 88 The compound according to claim 1, which is 8-[p-(3-phenyl-2-propenyloxy)benzoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane. 89 8-[p-(4-phenylbutoxy)benzoyl]amino-2-(5-tetrazolyl)-1,4
- The compound according to claim 1, which is benzodioxane. 90 8-[p-(o-pentylphenyl)methoxybenzoyl]amino-2-(5-tetrazolyl)
The compound according to claim 1, which is -1,4-benzodioxane. 91 8-[p-(m-butylphenyl)methoxybenzoyl]amino-2-(5-tetrazolyl)-
The compound according to claim 1, which is 1,4-benzodioxane. 92 8-(p-phenylmethoxybenzoyl)
The compound according to claim 1, which is amino-2-(5-tetrazolyl)-1,4-benzodioxane. 93 8-[p-(2-phenylethoxy)benzoyl]amino-2-(5-tetrazolyl)-1,4
- The compound according to claim 1, which is benzodioxane. 94 8-[p-(4-phenylbutoxy)benzoyl]amino-2-(5-tetrazolyl)-1,4
- The compound according to claim 1, which is benzodioxane. 95 R ⁵ is a hydrogen atom, R ⁶ is a carbonyl group,
Claims 1 and 2 are linear or branched alkoxy, alkenyloxy or alkoxyalkoxy groups having 1 to 18 carbon atoms substituted with a carbonyloxy group or a hydroxyl group;
A compound according to item 3 or 4. 96 The compound according to claim 1, which is 8-[p-5-methoxycarbonylpentyloxy)benzoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane. 97 The compound according to claim 1, which is 8-[p-(6-acetyloxyhexyloxy)benzoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane. 98 The compound according to claim 1, which is 8-[p-(6-hydroxyhexyloxy)benzoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane. 99 8-[p-(2E-octenoyloxy)benzoyl]amino-2-(5-tetrazolyl)-
The compound according to claim 1, which is 1,4-benzodioxane. 100 The compound according to claim 1, which is 8-[p-octanoylbenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane. 101 R ⁵ is a hydrogen atom, R ⁶ is substituted with phenoxy or phenylthio group, and has 1 carbon number
Claims 1, 2, 3, or 4 which are linear or branched alkoxy groups of ~17
Compounds described in Section. 102 The compound according to claim 1, which is 8-[p-(3-phenylthiopropoxy)benzoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane. 103 8-[p-(3-phenoxypropoxy)
benzoyl]amino-2-(5-tetrazolyl)-
The compound according to claim 1, which is 1,4-benzodioxane. 104 8-[p-(2-phenylthioethoxy)
benzoyl]amino-2-(5-tetrazolyl)-
The compound according to claim 1, which is 1,4-benzodioxane. 105 8-[p-(2-phenoxyethoxy)benzoyl]amino-2-(5-tetrazolyl)-
The compound according to claim 1, which is 1,4-benzodioxane. 106 Claim 1, wherein R ⁵ is a hydrogen atom and R ⁶ is a straight or branched alkoxy group having 1 to 18 carbon atoms substituted with a thiophene ring.
A compound according to item 1, item 2, item 3, or item 4. 107 The compound according to claim 1, which is 8-[p-(2-(3-thienyl)ethoxy]benzoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane. 108 8- The compound according to claim 1, which is [p-[4-(2-thienyl)butoxy]benzoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane. 109 R ⁵ is a hydrogen atom and R ⁶ is an azide group,
Amino group which may be substituted with nitro group or alkyl having 1 to 6 carbon atoms (including dialkylamino)
The compound according to claim 1, 2, 3, or 4, which is an alkoxy group having 1 to 18 carbon atoms substituted with . 110 8-[p-(5-azidopentyloxy)
benzoyl]amino-2-(5-tetrazolyl)-
The compound according to claim 1, which is 1,4-benzodioxane. 111 The compound according to claim 1, which is 8-[p-(5-dimethylaminopentyloxy)benzoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane. 112 8-[p-(4-nitrobutoxy)benzoyl]amino-2-(5-tetrazolyl)-1,4
- The compound according to claim 1, which is benzodioxane. 113 8-[p-(2-azidoethoxy)benzoyl]amino-2-(5-tetrazolyl)-1,4
- The compound according to claim 1, which is benzodioxane. 114 8-[p-(4-azidobutoxy)benzoyl]amino-2-(5-tetrazolyl)-1,4
- The compound according to claim 1, which is benzodioxane. 115 straight-chain or branched alkyl having 1 to 18 carbon atoms, in which R ⁵ is a hydrogen atom and R ⁶ is replaced with two groups, a carbonyl group and an amino group;
A compound according to claim 1, 2, 3 or 4 which is an alkenyl, alkoxy or alkenyloxy group. 116 8-[p-(2-octenoylamino)benzoyl]amino-2-(5-tetrazolyl)-
The compound according to claim 1, which is 1,4-benzodioxane. 117 Any of claims 1 to 4, wherein R ⁵ and R ⁶ are each independently a halogen atom, a linear or branched alkyl group having 1 to 10 carbon atoms, an alkoxy group, or an alkenyloxy group. Compounds described in the above section. 118 8-(p-pentyloxy-m-methoxybenzoyl)amino-2-(5-tetrazolyl)
The compound according to claim 1, which is -1,4-benzodioxane. 119 8-[p-(2E-octenyloxy)-m
-chlorobenzoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane. 120 R ¹ is the general formula or The compound according to any one of claims 1 to 3, which is a group represented by: 121 The compound according to claim 1, which is 8-(naphthalene-2-carbonyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane. 122 The symbol A is a vinylene group optionally substituted with a linear or branched alkyl group having 1 to 6 carbon atoms or a phenyl group, and the symbol T is an oxygen atom, or Compound according to item 2. 123 R ¹ is represented by the general formula [Formula] [wherein R ⁵ and R ⁶ represent the same meanings as in claim 1]. ] Claims 1 and 2 are groups represented by
A compound according to paragraph 122 or paragraph 122. 124 Claims 1, 2, and 12, wherein R ⁵ is a hydrogen atom and R ⁶ is a hydrogen atom or a straight or branched alkyl group having 1 to 20 carbon atoms.
A compound according to any one of paragraphs 2 and 123. 125 The compound according to claim 1, which is 8-(p-pentylcinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane. 126 The compound according to claim 1, which is 8-(p-pentylcinnamoyl)amino-1,4-benzodioxane-2-carboxylic acid or its ethyl ester. 127 The compound according to claim 1, which is 8-(p-pentylcinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane. 128 8-[N-methyl-N-(p-pentylcinnamoyl)amino]-2-(5-tetrazolyl)
The compound according to claim 1, which is -1,4-benzodioxane. 129 5-(p-pentylcinnamoyl)amino-2-(5-tetrazolyl)-7-chloro-1,
Claim 1 which is 4-benzodioxane
Compounds described in Section. 130 8-(p-pentylcinnamoyl)amino-2-(5-tetrazolyl)-6-chloro-1,
Claim 1 which is 4-benzodioxane
Compounds described in Section. 131 The compound according to claim 1, which is 8-(p-ethylcinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane. 132 The compound according to claim 1, which is 8-(p-propylcinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane. 133 The compound according to claim 1, which is 8-(p-butylcinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane. 134 8-(p-pentylcinnamoyl)amino-2-(5-tetrazolyl)-6-methyl-1,
Claim 1 which is 4-benzodioxane
Compounds described in Section. 135 The compound according to claim 1, which is 8-(o-pentylcinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane. 136 The compound according to claim 1, which is 8-(m-octylcinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane. 137 The compound according to claim 1, which is 8-(p-pentylcinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane-5-carboxylic acid or its methyl ester. 138 The compound according to claim 1, which is 5-(p-pentylcinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane-8-carboxylic acid or its methyl ester. 139 The compound according to claim 1, which is 8-(p-hexylcinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane. 140 The compound according to claim 1, which is 8-(p-nonylcinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane. 141 The compound according to claim 1, which is 8-(p-pentylcinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane-6-carboxylic acid or its methyl ester. 142 The compound according to claim 1, which is 5-(p-pentylcinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane-7-carboxylic acid or its methyl ester. 143 The compound according to claim 1, which is 8-(p-octylcinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane. 144 The compound according to claim 1, which is 8-(p-decylcinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane. 145 8-(p-isopropylcinnamoyl)
The compound according to claim 1, which is amino-2-(5-tetrazolyl)-1,4-benzodioxane. 146 The compound according to claim 1, which is 8-(p-isobutylcinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane. 147 8-(p-isopentylcinnamoyl)
The compound according to claim 1, which is amino-2-(5-tetrazolyl)-1,4-benzodioxane. 148 8-(p-pentyl-2-methylcinnamoyl)amino-2-(5-tetrazolyl)-1,
Claim 1 which is 4-benzodioxane
Compounds described in Section. 149 8-(p-pentyl-3-methylcinnamoyl)amino-2-(5-tetrazolyl)-1,
Claim 1 which is 4-benzodioxane
Compounds described in Section. 150 8-(p-pentylcinnamoyl)amino-2-(5-tetrazolyl)methyl-1,4-
The compound according to claim 1, which is a benzodioxane. 151 R ⁵ is a hydrogen atom, and R ⁶ has 1 to 1 carbon atoms.
19. A compound according to any one of claims 1, 2, 122 or 123 which is a linear or branched alkoxy group of 19. 152 8-(p-pentyloxycinnamoyl)
The compound according to claim 1, which is amino-2-(5-tetrazolyl)-1,4-benzodioxane. 153 8-(m-pentyloxycinnamoyl)
The compound according to claim 1, which is amino-2-(5-tetrazolyl)-1,4-benzodioxane. 154 8-(o-pentyloxycinnamoyl)
The compound according to claim 1, which is amino-2-(5-tetrazolyl)-1,4-benzodioxane. 155 The compound according to claim 1, which is 8-(p-propoxycinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane. 156 The compound according to claim 1, which is 8-(p-butoxycinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane. 157 8-(p-octyloxycinnamoyl)
The compound according to claim 1, which is amino-2-(5-tetrazolyl)-1,4-benzodioxane. 158 8-(p-hexyloxycinnamoyl)
The compound according to claim 1, which is amino-2-(5-tetrazolyl)-1,4-benzodioxane. 159 8-(p-heptyloxycinnamoyl)
The compound according to claim 1, which is amino-2-(5-tetrazolyl)-1,4-benzodioxane. 160 8-(p-isopentyloxycinnamoyl)amino-2-(5-tetrazolyl)-1,4
- The compound according to claim 1, which is benzodioxane. 161 8-(p-isohexyloxycinnamoyl)amino-2-(5-tetrazolyl)-1,4
- The compound according to claim 1, which is benzodioxane. 162 8-(p-(1-methylbutoxy)cinnamoyl]amino-2-(5-tetrazolyl)-1,
Claim 1 which is 4-benzodioxane
Compounds described in Section. 163 8-(p-isoheptyloxycinnamoyl)amino-2-(5-tetrazolyl)-1,4
- The compound according to claim 1, which is benzodioxane. 164 8-(p-isooctyloxycinnamoyl)amino-2-(5-tetrazolyl)-1,4
- The compound according to claim 1, which is benzodioxane. 165 The compound according to claim 1, which is 8-(p-isohexyloxy-2-methylcinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane. 166 The compound according to claim 1, which is 8-(p-isohexyloxy-2-phenylcinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane. 167 R ⁵ is a hydrogen atom, R ⁶ has 3 to 3 carbon atoms
19. A compound according to any one of claims 1, 2, 122 or 123 which is a linear or branched alkenyloxy group of 19. 168 8-[p-(2E-octenyloxy)cinnamoyl]amino-2-(5-tetrazolyl)-
The compound according to claim 1, which is 1,4-benzodioxane. 169 8-[p-(2-propenyloxy)cinnamoyl]amino-2-(5-tetrazolyl)-
The compound according to claim 1, which is 1,4-benzodioxane. 170 8-[p-(3-butenyloxy)cinnamoyl]amino-2-(5-tetrazolyl)-1,
Claim 1 which is 4-benzodioxane
Compounds described in Section. 171 8-[p-(3Z-hexenyloxy)cinnamoyl]amino-2-(5-tetrazolyl)-
The compound according to claim 1, which is 1,4-benzodioxane. 172 8-[p-(2Z-pentenyloxy)cinnamoyl]amino-2-(5-tetrazolyl)-
The compound according to claim 1, which is 1,4-benzodioxane. 173 8-[p-(2E-nonenyloxy)cinnamoyl]amino-2-(5-tetrazolyl)-
The compound according to claim 1, which is 1,4-benzodioxane. 174 8-[p-(3E-heptenyloxy)cinnamoyl]amino-2-(5-tetrazolyl)-
The compound according to claim 1, which is 1,4-benzodioxane. 175 8-[p-(2E-heptenyloxy)cinnamoyl]amino-2-(5-tetrazolyl)-
The compound according to claim 1, which is 1,4-benzodioxane. 176 8-[p-(2E-hexenyloxy)cinnamoyl]amino-2-(5-tetrazolyl)-
The compound according to claim 1, which is 1,4-benzodioxane. 177 8-[p-(2E-pentenyloxy)cinnamoyl]amino-2-(5-tetrazolyl)-
The compound according to claim 1, which is 1,4-benzodioxane. 178 8-[p-(4-pentenyloxy)cinnamoyl]amino-2-(5-tetrazolyl)-
The compound according to claim 1, which is 1,4-benzodioxane. 179 8-[p-(2E-butenyloxy)cinnamoyl]amino-2-(5-tetrazolyl)-
The compound according to claim 1, which is 1,4-benzodioxane. 180 8-[p-(2E-decenyloxy)cinnamoyl]amino-2-(5-tetrazolyl)-
The compound according to claim 1, which is 1,4-benzodioxane. 181 R ⁵ is a hydrogen atom, and R ⁶ has 3 to 3 carbon atoms.
19. A compound according to any one of claims 1, 2, 122 or 123 which is a linear or branched alkynyloxy group of 19. 182 8-[p-(2-octynyloxy)cinnamoyl]amino-2-(5-tetrazolyl)-
The compound according to claim 1, which is 1,4-benzodioxane. 183 8-[p-(2-pentynyloxy)cinnamoyl]amino-2-(5-tetrazolyl)-
The compound according to claim 1, which is 1,4-benzodioxane. 184 R ⁵ is a hydrogen atom, and R ⁶ has 1 to 1 carbon atoms.
19. A compound according to any one of claims 1, 2, 122 or 123 which is a linear or branched alkylthio group of 19. 185 8-(p-pentylthiocinnamoyl)
The compound according to claim 1, which is amino-2-(5-tetrazolyl)-1,4-benzodioxane. 186 8-(m-pentylthiocinnamoyl)
The compound according to claim 1, which is amino-2-(5-tetrazolyl)-1,4-benzodioxane. 187 8-(o-pentylthiocinnamoyl)
The compound according to claim 1, which is amino-2-(5-tetrazolyl)-1,4-benzodioxane. 188 Claim 1 in which R ⁵ is a hydrogen atom and R ⁶ is a straight or branched alkoxy group having 1 to 18 carbon atoms substituted with a halogen atom
A compound according to any one of Items 1, 2, 122, or 123. 189 8-[p-(6-chlorohexyloxy)
cinnamoyl]amino-2-(5-tetrazolyl)
The compound according to claim 1, which is -1,4-benzodioxane. 190 8-[p-(4-chlorobutoxy)cinnamoyl]amino-2-(5-tetrazolyl)-1,
Claim 1 which is 4-benzodioxane
Compounds described in Section. 191 8-[p-(5-chloropentyloxy)
cinnamoyl]amino-2-(5-tetrazolyl)
The compound according to claim 1, which is -1,4-benzodioxane. 192 8-[p-(7-chloroheptyloxy)
cinnamoyl]amino-2-(5-tetrazolyl)
The compound according to claim 1, which is -1,4-benzodioxane. 193 R ⁵ is a hydrogen atom, and R ⁶ has 2 to 2 carbon atoms.
Claims 1, 2, and 12 are linear or branched alkyloxyalkyl groups of 19.
A compound according to any one of paragraphs 2 and 123. 194 8-(p-isopentyloxymethylcinnamoyl)amino-2-(5-tetrazolyl)-
The compound according to claim 1, which is 1,4-benzodioxane. 195 R ⁵ is a hydrogen atom, and R ⁶ has 1 to 1 carbon atoms.
Cycloalkyl having 4 to 7 carbon atoms, cycloalkylalkyl having 1 to 7 carbon atoms, optionally substituted with 18 linear or branched alkyl groups (the alkyl portion has 1 to 1 carbon atoms)
8) or a cycloalkylalkyloxy (alkyl moiety has 1 to 8 carbon atoms) group, according to claim 1, 2, 122, or 123. 196 8-(p-cyclohexylcinnamoyl)
The compound according to claim 1, which is amino-2-(5-tetrazolyl)-1,4-benzodioxane. 197 8-(p-cyclohexylmethoxycinnamoyl)amino-2-(5-tetrazolyl)-
The compound according to claim 1, which is 1,4-benzodioxane. 198 The compound according to claim 1, which is 8-[p-(4-cyclohexylbutoxy)cinnamoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane. 199 The compound according to claim 1, which is 8-[p-(2-cyclohexylethoxy)cinnamoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane. 200 R ⁵ is a hydrogen atom, R ⁶ has 1 or more carbon atoms
Phenyl, phenylalkyl (alkyl moiety has 1 to 8 carbon atoms) or phenylalkyloxy (alkyl moiety has 1 to 8 carbon atoms) group or phenyl, which may be substituted with 18 straight or branched alkyl groups; Claims 1 and 2 are enylalkenyloxy (alkenyl moiety has 2 to 8 carbon atoms) group.
122 or 123. 201 8-(p-phenylmethylcinnamoyl)
The compound according to claim 1, which is amino-2-(5-tetrazolyl)-1,4-benzodioxane. 202 8-(p-phenylmethoxycinnamoyl)amino-2-(5-tetrazolyl)-1,4-
The compound according to claim 1, which is a benzodioxane. 203 8-[p-(2-phenylethoxy)cinnamoyl]amino-2-(5-tetrazolyl)-
The compound according to claim 1, which is 1,4-benzodioxane. 204 8-[p-(4-phenylbutoxy)cinnamoyl]amino-2-(5-tetrazolyl)-
The compound according to claim 1, which is 1,4-benzodioxane. 205 The compound according to claim 1, which is 8-[p-(5-phenylpentyloxy)cinnamoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane. 206 8-[p-(3-phenylpropoxy)cinnamoyl]amino-2-(5-tetrazolyl)-
The compound according to claim 1, which is 1,4-benzodioxane. 207 A patent claim in which R ⁵ is a hydrogen atom, and R ⁶ is a straight or branched chain alkoxy, alkenyloxy, or alkoxyalkoxy group having 1 to 18 carbon atoms, substituted with a carbonyl group, carbonyloxy group, or hydroxyl group Range 1st term, 2nd term
122 or 123. 208 The compound according to claim 1, which is 8-[p-(6-acetyloxyhexyloxy)cinnamoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane. 209 Claim 1 in which R ⁵ is a hydrogen atom and R ⁶ is a straight or branched alkoxy group having 1 to 18 carbon atoms substituted with a thiophene ring
A compound according to item 1, item 2, item 122 or item 123. 210 The compound according to claim 1, which is 8-[p-[2-(2-thiophenyl)ethoxy]cinnamoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane. 211 Claims 1, 2 and 2, wherein R ⁵ and R ⁶ are each independently a halogen atom, a straight or branched alkyl, alkoxy or alkenyloxy group having 1 to 10 carbon atoms. A compound according to item 122 or item 123. 212 8-(m,p-dimethoxycinnamoyl)
The compound according to claim 1, which is amino-2-(5-tetrazolyl)-1,4-benzodioxane. 213 The compound according to claim 1, which is 8-(m-methoxy-p-pentyloxycinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane. 214 8-(p-pentyloxy-m-chlorocinnamoyl)amino-2-(5-tetrazolyl)
The compound according to claim 1, which is -1,4-benzodioxane. 215 R ⁵ is the general formula or A compound according to claim 1, 2 or 122, which is represented by: 216 8-[3-(5-indanyl)acryloyl]amino-2-(5-tetrazolyl)-1,4-
The compound according to claim 1, which is a benzodioxane. 217 Claims 1, 2, or 122, wherein R ¹ is a straight-chain or branched alkyl, alkenyl, or alkynyl group having 1 to 20 carbon atoms.
Compounds described in Section. 218 N-(2-hexadecenoyl)amino-
The compound according to claim 1, which is 2-(5-tetrazolyl)-1,4-benzodioxane. 219. The compound according to claim 1 or 2, wherein symbol A is a methylene group or ethylene group, and symbol T is an oxygen atom. 220 8-(p-pentylphenylacetyl)
The compound according to claim 1, which is amino-2-(5-tetrazolyl)-1,4-benzodioxane. 221 8-[3-(p-pentylphenyl)propionyl]amino-2-(5-tetrazolyl)-
The compound according to claim 1, which is 1,4-benzodioxane. 222. The compound according to claim 1 or 2, wherein the symbol A is an ethynylene group or a butadienylene group, and the symbol T is an oxygen atom. 223 8-(p-hexylphenylpropioloyl)amino-2-(5-tetrazolyl)-1,4
- The compound according to claim 1, which is benzodioxane. 224 8-[5-(p-propoxyphenyl)penta2E,4E-dienoyl]amino-2-(5-
The compound according to claim 1, which is (tetrazolyl)-1,4-benzodioxane. 225 The compound according to claim 1, which is 8-[5-(p-butylphenyl)penta2E,4E-dienoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane. 226. The compound according to claim 1 or 2, wherein the symbol A is a single bond or a vinylene group, and the symbol T is a sulfur atom. 227 8-(p-heptyloxybenzothioyl)amino-2-(5-tetrazolyl)-1,4-
The compound according to claim 1, which is a benzodioxane. 228 General formula [In the formula, all symbols have the same meanings as described in claim 1. ] The compound according to claim 1, which is represented by: 229. The compound according to claim 1 or 228, wherein symbol A is a single bond and symbol T is an oxygen atom. 230 R ¹ is represented by the general formula [Formula] [wherein R ⁵ and R ⁶ represent the same meanings as described in claim 1]. ] Claims 1 and 2 are groups represented by
A compound of item 28 or item 229. 231 Claims 1, 228, 229, or 230, wherein R ⁵ is a hydrogen atom and R ⁶ is a hydrogen atom or a linear or branched alkyl group having 1 to 20 carbon atoms. Compounds described in Section. 232 8-(p-pentylbenzoyl)amino-2-(5-tetrazolyl)-4-oxo-4H-
The compound according to claim 1, which is 1-benzopyran. 233 The compound according to claim 1, which is 8-(p-pentylbenzoyl)amino-4-oxo-4H-1-benzopyran-2-carboxylic acid or its ethyl ester. 234 8-(p-hexylbenzoyl)amino-2-(5-tetrazolyl)-4-oxo-4H-
The compound according to claim 1, which is 1-benzopyran. 235 8-(p-heptylbenzoyl)amino-2-(5-tetrazolyl)-4-oxo-4H-
The compound according to claim 1, which is 1-benzopyran. 236 8-(p-octylbenzoyl)amino-2-(5-tetrazolyl)-4-oxo-4H-
The compound according to claim 1, which is 1-benzopyran. 237 8-(p-nonylbenzoyl)amino-
2-(5-tetrazolyl)-4-oxo-4H-1
- The compound according to claim 1, which is benzopyran. 238 R ⁵ is a hydrogen atom, and R ⁶ has 1 to 1 carbon atoms.
19. A compound according to claim 1, 228, 229 or 230 which is a straight chain or branched alkoxy group of 19. 239 8-(p-Butoxybenzoyl)amino-2-(5-tetrazolyl)-4-oxo-4H-
The compound according to claim 1, which is 1-benzopyran. 240 8-(p-pentyloxybenzoyl)
Amino-2-(5-tetrazolyl)-4-oxo-
The compound according to claim 1, which is 4H-1-benzopyran. 241 8-(p-hexyloxybenzoyl)
Amino-2-(5-tetrazolyl)-4-oxo-
The compound according to claim 1, which is 4H-1-benzopyran. 242 8-(p-heptyloxybenzoyl)
Amino-2-(5-tetrazolyl)-4-oxo-
The compound according to claim 1, which is 4H-1-benzopyran. 243 8-(p-nonyloxybenzoyl)amino-2-(5-tetrazolyl)-4-oxo-
The compound according to claim 1, which is 4H-1-benzopyran. 244 8-(p-octyloxybenzoyl)
Amino-2-(5-tetrazolyl)-4-oxo-
The compound according to claim 1, which is 4H-1-benzopyran. 245 8-(p-heptyloxybenzoyl)
The compound according to claim 1, which is amino-2-(5-tetrazolyl)-6-fluoro-4-oxo-4H-1-benzopyran. 246 8-(p-octyloxybenzoyl)
Amino-2-(5-tetrazolyl)-6-methyl-
The compound according to claim 1, which is 4-oxo-4H-1-benzopyran. 247 8-(p-heptyloxybenzoyl)
Amino-2-(5-tetrazolyl)-6-methyl-
The compound according to claim 1, which is 4-oxo-4H-1-benzopyran. 248 R ⁵ is a hydrogen atom, and R ⁶ has 3 to 3 carbon atoms.
Claims 1, 228, and 229 are linear or branched alkenyloxy groups of 19.
A compound according to paragraph 230. 249 The compound according to claim 1, which is 8-[p-(2E,7-octadienyloxy)benzoyl]amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran. 250 8-(p-geranyloxybenzoyl)
Amino-2-(5-tetrazolyl)-4-oxo-
The compound according to claim 1, which is 4H-1-benzopyran. 251 8-[p-(2E-nonenyloxy)benzoyl]amino-2-(5-tetrazolyl)-4-
The compound according to claim 1, which is oxo-4H-1-benzopyran. 252 8-[p-(2E-octenyloxy)benzoyl]amino-2-(5-tetrazolyl)-4
The compound according to claim 1, which is -oxo-4H-1-benzopyran. 253 8-[p-(7-octenyloxy)benzoyl]amino-2-(5-tetrazolyl)-4-
The compound according to claim 1, which is oxo-4H-1-benzopyran. 254 8-[p-(2E-heptenyloxy)benzoyl]amino-2-(5-tetrazolyl)-4
The compound according to claim 1, which is -oxo-4H-1-benzopyran. 255 8-[p-(2E-hexenyloxy)benzoyl]amino-2-(5-tetrazolyl)-4
The compound according to claim 1, which is -oxo-4H-1-benzopyran. 256 8-[p-(2E,7-octadienyloxy)benzoyl]amino-2-(5-tetrazolyl)-6-fluoro-4-oxo-4H-1-
The compound according to claim 1, which is benzopyran. 257 8-[p-(2E-octenyloxy)benzoyl]amino-2-(5-tetrazolyl)-6
-Methyl-4-oxo-4H-1-benzopyran. 258 8-[p-(7-octenyloxy)benzoyl]amino-2-(5-tetrazolyl)-6-
The compound according to claim 1, which is methyl-4-oxo-4H-1-benzopyran. 259 Claim 1 which is 8-[p-(2E,7-octadienyloxy)benzoyl]amino-2-(5-tetrazolyl)-6-methyl-4-oxo-4H-1-benzopyran Compounds described. 260 Claim 1 which is 8-[p-(2E,7-octadienyloxy)benzoyl]amino-2-(5-tetrazolyl)-6-chloro-4-oxo-4H-1-benzopyran Compounds described. 261 R ⁵ is a hydrogen atom, and R ⁶ has 3 to 3 carbon atoms.
Claims 1, 228, and 229 are linear or branched alkynyloxy groups of 19.
A compound according to paragraph 230. 262 8-[p-(2-octynyloxy)benzoyl]amino-2-(5-tetrazolyl)-4-
The compound according to claim 1, which is oxo-4H-1-benzopyran. 263 Claim 1 in which R ⁵ is a hydrogen atom and R ⁶ is a straight or branched alkoxy group having 1 to 18 carbon atoms substituted with a halogen atom
228, 229 or 230. 264 The compound according to claim 1, which is 8-[p-(4-chlorobutoxy)benzoyl]amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran. 265 8-[p-(5-chloropentyloxy)
benzoyl]amino-2-(5-tetrazolyl)-
The compound according to claim 1, which is 4-oxo-4H-1-benzopyran. 266 8-[p-(6-chlorohexyloxy)
benzoyl]amino-2-(5-tetrazolyl)-
The compound according to claim 1, which is 4-oxo-4H-1-benzopyran. 267 8-[p-(6-chlorohexyloxy)
benzoyl]amino-2-(5-tetrazolyl)-
The compound according to claim 1, which is 6-methyl-4-oxo-4H-1-benzopyran. 268 8-[p-(7-chloroheptyloxy)
benzoyl]amino-2-(5-tetrazolyl)-
The compound according to claim 1, which is 4-oxo-4H-1-benzopyran. 269 8-[p-(8-chlorooctyloxy)
benzoyl]amino-2-(5-tetrazolyl)-
The compound according to claim 1, which is 6-methyl-4-oxo-4H-1-benzopyran. 270 8-[p-(7-chloroheptyloxy)
benzoyl]amino-2-(5-tetrazolyl)-
The compound according to claim 1, which is 6-methyl-4-oxo-4H-1-benzopyran. 271 8-[p-(8-chlorooctyloxy)
benzoyl]amino-2-(5-tetrazolyl)-
The compound according to claim 1, which is 4-oxo-4H-1-benzopyran. 272 R ⁵ is a hydrogen atom, and R ⁶ has 1 to 1 carbon atoms.
Phenyl group, phenylalkyl (alkyl part has 1 to 8 carbon atoms) group, phenylalkyloxy (alkyl part has 1 to 8 carbon atoms), which may be substituted with a straight chain or branched chain alkyl group of 8 ) group or phenylalkenyloxy (alkenyl moiety has 2 to 8 carbon atoms) group,
A compound according to paragraph 228, paragraph 229 or paragraph 230. 273 8-[p-(3-phenylpropoxy)benzoyl]amino-2-(5-tetrazolyl)-4
The compound according to claim 1, which is -oxo-4H-1-benzopyran. 274 The compound according to claim 1, which is 8-[p-(3-phenyl-2E-propenyloxy)benzoyl]amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran. 275 8-[p-(4-phenylbutoxy)benzoyl]amino-2-(5-tetrazolyl)-4-
The compound according to claim 1, which is oxo-4H-1-benzopyran. 276 8-[p-(4-phenylbutoxy)benzoyl]amino-2-(5-tetrazolyl)-6-
The compound according to claim 1, which is methyl-4-oxo-4H-1-benzopyran. 277 Claims 1, 228, and 2 in which R ⁵ is a hydrogen atom and R ⁶ is an alkoxy group having 1 to 18 carbon atoms substituted with a thiophene ring
A compound according to item 29 or item 230. 278 The compound according to claim 1, which is 8-[p-[4-(2-thienyl)butoxy]benzoyl]amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran. 279 Claim 1 which is 8-[p-[4-(2-thienyl)butoxy]benzoyl]amino-2-(5-tetrazolyl)-6-methyl-4-oxo-4H-1-benzopyran Compounds described. 280 Claim 1 or 2, wherein the symbol A is a vinylene group optionally substituted with a linear or branched alkyl group having 1 to 6 carbon atoms or a phenyl group, and the symbol T is an oxygen atom. A compound according to item 228. 281 R ¹ is represented by the general formula [Formula] [wherein R ⁵ and R ⁶ represent the same meanings as described in claim 1]. ] Claims 1 and 2 are groups represented by
A compound according to paragraph 28 or paragraph 280. 282 R ⁵ is a hydrogen atom, and R ⁶ is a hydrogen atom or a straight or branched alkyl group having 1 to 20 carbon atoms, Claims 1, 228, 280, or 281 Compounds described in Section. 283 8-(p-pentylcinnamoyl)amino-4-oxo-4H-1-benzopyran-2-
The compound according to claim 1, which is a carboxylic acid or its ethyl ester. 284 8-(p-pentylcinnamoyl)amino-2-(5-tetrazolyl)-4-oxo-4H
The compound according to claim 1, which is -1-benzopyran. 285 8-(p-pentylcinnamoyl)amino-2-(5-tetrazolyl)-6-methyl-4-
The compound according to claim 1, which is oxo-4H-1-benzopyran. 286 8-(p-pentylcinnamoyl)amino-2-(5-tetrazolyl)-6-fluoro-4
The compound according to claim 1, which is -oxo-4H-1-benzopyran. 287 The compound according to claim 1, which is 8-(p-pentylcinnamoyl)amino-6-methyl-4-oxo-4H-1-benzopyran-2-carboxylic acid or its ethyl ester. 288 8-(p-Butylcinnamoyl)amino-2-(5-tetrazolyl)-4-oxo-4H-
The compound according to claim 1, which is 1-benzopyran. 289 8-(p-hexylcinnamoyl)amino-2-(5-tetrazolyl)-4-oxo-4H
The compound according to claim 1, which is -1-benzopyran. 290 8-(p-heptylcinnamoyl)amino-2-(5-tetrazolyl)-4-oxo-4H
The compound according to claim 1, which is -1-benzopyran. 291 The compound according to claim 1, which is 8-cinnamoylamino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran. 292 R ⁵ is a hydrogen atom, and R ⁶ has 1 or more carbon atoms.
19, which is a straight or branched chain alkyl group. 293 8-(p-hexyloxycinnamoyl)
Amino-2-(5-tetrazolyl)-4-oxo-
The compound according to claim 1, which is 4H-1-benzopyran. 294 8-(p-heptyloxycinnamoyl)
Amino-2-(5-tetrazolyl)-4-oxo-
The compound according to claim 1, which is 4H-1-benzopyran. 295 The compound according to claim 1, which is 8-(p-isohexyloxycinnamoyl)amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran. 296 R ⁵ is a hydrogen atom, and R ⁶ has 3 to 3 carbon atoms.
Claims 1, 228, and 280 are linear or branched alkynyloxy groups of 19.
A compound according to paragraph 281. 297 The compound according to claim 1, which is 8-[p-(2-octynyloxy)cinnamoyl]amino-4-oxo-4H-1-benzopyran-2-carboxylic acid or its ethyl ester. 298 Claim 1 in which R ⁵ is a hydrogen atom and R ⁶ is a straight or branched alkoxy group having 1 to 18 carbon atoms substituted with a halogen atom
228, 280 or 281. 299 8-[p-(5-chloropentyloxy)
cinnamoyl]amino-2-(5-tetrazolyl)
The compound according to claim 1, which is -4-oxo-4H-1-penzopyran. 300 8-[p-(6-chlorohexyloxy)
cinnamoyl]amino-2-(5-tetrazolyl)
The compound according to claim 1, which is -4-oxo-4H-1-benzopyran. 301 General formula [In the formula, all symbols have the same meanings as described in claim 1. ] The compound according to claim 1, which is represented by: 302 The compound according to claim 1, which is 8-(p-pentylcinnamoyl)amino-2-(5-tetrazolyl)2,3-dihydro-1,4-dithianaphthalene. 303 The compound according to claim 1, which is 5-(p-pentylcinnamoyl)amino-2-(5-tetrazolyl)2,3-dihydro-1,4-dithianaphthalene. 304. A non-toxic salt of a compound according to any one of claims 1 to 303. 305 Claim 3 which is a sodium salt
Non-toxic salt according to item 04. 306 General formula R ¹ -A-COOH () [wherein R ¹ is the general formula [Formula] or or () represents a linear or branched alkyl, alkenyl or alkynyl group having 1 to 20 carbon atoms. (R ⁵ and R ⁶ in the formula are each independently a hydrogen atom, a halogen atom, or any one,
Two or three carbon atoms are oxygen atom, sulfur atom, halogen atom, nitrogen atom, benzene ring, thiophene ring, hydrocarbon ring having 4 to 7 carbon atoms, carbonyl group, carbonyloxy group, hydroxyl group, carboxy group, azido group , represents a straight-chain or branched alkyl, alkenyl or alkynyl group having 1 to 20 carbon atoms which may be substituted with a nitro group. Symbol A is methylene, ethylene, trimethylene, tetramethylene, vinylene, propenylene, which may be substituted with a single bond, or a linear or branched alkyl group or phenyl group having 1 to 6 carbon atoms;
Represents a butenylene, butadienylene or ethynylene group. ] or the corresponding dithionic acid and the general formula [In the formula, R ² is a hydrogen atom or a carbon number of 1 to 6]
represents a straight-chain or branched alkyl group. R ³ is a hydrogen atom, a halogen atom, a hydroxyl group, a nitro group, or is represented by the general formula -COOR ⁷ (wherein R ⁷ represents a hydrogen atom or a straight or branched alkyl group having 1 to 6 carbon atoms). represents a straight-chain or branched alkyl, alkoxy or alkylthio group having 1 to 6 carbon atoms. R ⁴ is a group represented by the general formula -COOR ⁸ or -CH ₂ COOR ⁸ (wherein R ⁸ represents a hydrogen atom or a straight or branched alkyl group having 1 to 6 carbon atoms), 2- Represents a tetrazolyl group or 2-tetrazolylmethyl group. The symbol [formula] represents a ring represented by the formula [formula] [formula] or [formula]. ] A general formula characterized by reacting the compound represented by to form an amide bond, and subjecting it to saponification and esterification reactions if necessary. [In the formula, the symbol T represents an oxygen or sulfur atom, and the other symbols have the same meanings as above. ] A method for producing a condensed benz(thio)amide. 307 General formula [In the formula, R ²⁰ represents a methylene group or a single bond, and the other symbols have the same meanings as described in Claim 306. ] General formula characterized by reacting a compound represented by with azide [In the formula, R ²⁰ represents the same meaning as above, and other symbols represent the same meanings as described in Claim 306. ] A method for producing a condensed benz(thio)amide according to claim 306. 308 General formula [In the formula, all symbols refer to claim 30.
It has the same meaning as described in Section 6. ] Compounds and general formulas represented by or [In each formula, X ¹⁰ and X ²⁰ represent a halogen atom, R ⁵⁰ represents a straight or branched alkyl group having 1 to 6 carbon atoms, and R ²⁰ represents a methylene group or a single bond. ] A general formula characterized by reacting a compound represented by and subjecting it to esterification or saponification reaction if necessary. [In the formula, R ⁵⁵ represents a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms, R ²⁰ represents the same meaning as above, and other symbols are as described in claim 306. express the same meaning. ] The method for producing a condensed benz(thio)amide according to claim 306. 309 General formula [In the formula, R ¹ is a general formula [Formula] or or () represents a linear or branched alkyl, alkenyl or alkynyl group having 1 to 20 carbon atoms. (R ⁵ and R ⁶ in the formula are each independently a hydrogen atom, a halogen atom, or any one,
Two or three carbon atoms are oxygen atom, sulfur atom, halogen atom, nitrogen atom, benzene ring, thiophene ring, hydrocarbon ring having 4 to 7 carbon atoms , carbonyl group, carbonyloxy group, hydroxyl group, carboxy group, azido group , represents a straight-chain or branched alkyl, alkenyl or alkynyl group having 1 to 20 carbon atoms which may be substituted with a nitro group. ) R ² represents a hydrogen atom or a straight or branched alkyl group having 1 to 6 carbon atoms. R ³ is a hydrogen atom, a halogen atom, a hydroxyl group, a nitro group, or is represented by the general formula -COOR ⁷ (wherein R ⁷ represents a hydrogen atom or a straight or branched alkyl group having 1 to 6 carbon atoms). represents a straight-chain or branched alkyl, alkoxy or alkylthio group having 1 to 6 carbon atoms. R ⁴ is a group represented by the general formula -COOR ⁸ or -CH ₂ COOR ⁸ (wherein R ⁸ represents a hydrogen atom or a straight or branched alkyl group having 1 to 6 carbon atoms), 2- Represents a tetrazolyl group or 2-tetrazolylmethyl group. Symbol A is a methylene, ethylene, trimethylene, tetramethylene, vinylene, propenylene, butenylene, butadienylene or ethynylene group which may be substituted with a single bond or a linear or branched alkyl group having 1 to 6 carbon atoms or a phenyl group. represents. The symbol [formula] represents a ring represented by the formula [formula] [formula] or [formula]. The symbol T represents an oxygen atom or a sulfur atom. ]
A leukotriene (SRS) antagonist containing a novel condensed benz(thio)amide or a non-toxic salt thereof as an active ingredient.