JPH0425955B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a novel benz(thio)amide having an antagonistic effect on leukotrienes. [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
(ThromboxaneA 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 the various PGs that have been well known so far, 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. The arachidonic acid casgate is produced by the action of cyclooxygenase on arachidonic acid, resulting in PGG ₂ and further
Through 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
Lipoxygenase acts on arachidonic acid to produce hydroperoxyicosatetraenoic acid.
acid, hereinafter 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. showed that SRS-A (Slow Reacting) can be used to sensitize antigens during perfusion of the lungs of sensitized guinea pigs.
This study showed that SRS-A (Substance of Anaphylaxis) was released, and showed for the first time the relationship between SRS-A and allergic reactions [Quant.J.Exp.Physiol., 30 , 121
(1940)]. In addition, Brocklehurst 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 was produced.
SRS-A is released and strongly contracts the bronchial muscles, and this contraction is not relieved by antihistamines.
It has been suggested that SRS-A is an important bronchoconstrictor during asthma attacks [see Progr. Allergy, 6 , 539 (1962)]. Subsequently, SRS-A obtained from a piece of human lung tissue contracts the bronchial muscle rings of normal people [Int.Arch.Allergy.
Appl. Immunol., 38 , 217, (1970)]; when rat SRS-A is intravenously injected into guinea pigs, an increase in pulmonary airway resistance is observed [J. Clin. Invest., 53 , 1679
(1974)], SRS-A in guinea pigs, rats,
Increases vascular permeability when injected intradermally in monkeys [Advances in Immunology, 10 , 105
(1969), J. Allergy Clin. Immunol., 621 , 371
(1978), Prostaglandins, 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 diseases 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;
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 produced, which is then released by the action of diglyceride lipase and then monoglyceride lipase [Chemistry and Biology, 21 , 154 (1983)]. The liberated arachidonic acid is further metabolized into physiologically active substances such as prostaglandin (PG) and thromboxane A ₂ (TXA ₂ ) by two pathways: (1) the cyclooxygenase metabolic pathway; (2) Through the lipoxygenase metabolic pathway,
SRS-A (Slow Reacting Substances of
Anaphylaxis), hydroxyeicosatetraenoic acid (HETE) and leukotriene B ₄
It is known to be metabolized into physiologically active substances such as (LeukotrieneB ₄ ) [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 Makoto 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 ^1a to R ^5a and R ^7a are hydrogen atoms, hydroxyl groups, alkyl groups having 1 to 6 carbon atoms, alkoxy groups having 1 to 6 carbon atoms, amino groups, acyl groups, and 2 to 6 carbon atoms.
6 acylamino group, alkenyl group having 2 to 6 carbon atoms, halogen atom or phenyl group (having 1 to 6 carbon atoms)
6) represents an alkoxy group, X ^a represents a hydrocarbyl group having 1 to 10 carbon atoms which may be substituted with a hydroxyl group, A ^a represents an oxygen atom or is absent, and Q ^a represents an alkoxy group having 2 carbon atoms. ~6 optionally branched alkylene, alkenylene, or alkynylene group, and D ^a represents a carboxy group, 5-tetrazolyl, or carbamido-5-tetrazolyl group. ]
A patent application has been filed for a group of compounds represented by (see JP-A-55-127384). In addition, the present inventors have so far found the general formula [In the formula, R ^1b is the general formula or or () represents a linear or branched alkyl, alkenyl or alkynyl group having 1 to 20 carbon atoms (in the formula, R ^5b and R ^6b each independently represent a hydrogen atom or a halogen atom, or any one or two
One or three hydrogen atoms are oxygen atoms, sulfur atoms,
1 to 20 carbon atoms optionally substituted with a halogen atom, nitrogen atom, benzene ring, thiophene ring, carbon ring with 4 to 7 carbon atoms, carbonyl group, carbonyloxy group, hydroxyl group, carboxy group, azide group, or nitro group represents a straight-chain or branched alkyl, alkenyl or alkynyl group). R ^2b represents a hydrogen atom or a straight or branched alkyl group having 1 to 6 carbon atoms. R ^3b is a hydrogen atom, a halogen atom, a hydroxyl group, a nitro group, or represented by the general formula -COOR ^7b (wherein R ^7b represents a hydrogen atom or a straight or branched chain 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 ^4b is the general formula −COOR ^8b or −CH ₂ COOR ^8b
(In the formula, R ^8b represents a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms.), a 2-tetrazolyl group, or a 2-tetrazolylmethyl group. Symbol A ^b is a single bond, or methylene, ethylene, trimethylene, tetramethylene, vinylene, propenylene, butenylene, butadienylene or Represents an ethynylene group. The symbol [formula] represents a ring represented by the formula [formula] [formula] or [formula]. The symbol T ^b represents an oxygen atom or a sulfur atom. It was discovered that the condensed benz(thio)amide and its non-toxic salt shown _in
50977). [Disclosure of the Invention] This time, the present inventors have discovered that the condensed benz(thio)amide derivative represented by the general formula (B) proposed earlier
When R ^{5b and} /or R ^6b , which are substituents of R 1b, represent an alkyl, alkenyl, or alkynyl group substituted with a naphthalene ring, or when 4 or more carbon atoms are substituted with a substituent, Even when representing an alkyl, alkenyl, or alkynyl group, it is the same as the compound represented by general formula (B).
It was discovered that it has an antagonistic effect on LTD ₄ , and the present invention was completed. 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. Binding the body causes cell proliferation, and when this effect is enhanced, it is said to lead to the onset of prostatic hyperplasia, alopecia, and 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 prostatic hypertrophy, alopecia, and acne in mammals including humans, especially humans. Furthermore, the following aldose-reduced oxygen inhibitory action 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 are used in diabetic patients (including patients with galactosemia).
It is known that it accumulates in the crystalline lens, peripheral nerves, kidneys, etc. of the body, resulting in complications such as retinopathy, diabetic cataracts, neuropathy, and kidney damage [Jap.J.Opthalmol., 20 , 399 (1976), Int.
See 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 represents a group represented by (In the formula, R ⁵ and R ⁶ are each independently a hydrogen atom, a halogen atom, or any one, 2
Substitutable groups with 1, 3, 4, or 5 carbon atoms (i.e., oxygen atoms, sulfur atoms, halogen atoms, nitrogen atoms, benzene rings, naphthalene rings, thiophene rings, hydrocarbon rings having 4 to 7 carbon atoms, a straight or branched alkyl, alkenyl or alkynyl group having 1 to 20 carbon atoms which may be substituted with a group arbitrarily selected from a carbonyl group, a carbonyloxy group, a hydroxyl group, a carboxy group, an azide group or a nitro group) represents. However, at least one of R ⁵ or R ⁶ shall satisfy the following conditions. () Represents a straight-chain or branched alkyl, alkenyl or alkynyl group having 1 to 20 carbon atoms, in which at least one carbon atom is necessarily replaced with a substitutable naphthalene ring, or () any 4 Represents a straight-chain or branched alkyl, alkenyl or alkynyl group having 1 to 20 carbon atoms, in which 1 or 5 carbon atoms are replaced by substitutable groups. ) represents a group represented by 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 straight 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 formula, a non-toxic salt thereof, a method for producing the same, and a drug containing the same as an active ingredient. The compound (1) of the present invention may contain a benzene ring and/or a chromone skeleton, but one of the essential requirements is that it has a (thio)amide in the middle part, and from this point, the SRS represented by the general formula (A) They have a different chemical structure from antagonists and can be said to be a completely new group of compounds. Furthermore, in comparison with the compound represented by the general formula (B) already proposed by the present inventors, the substituent R ⁵ and R ⁶ portions are different. That is, in general formula (B), R ^5b
and when R ^6b represents an alkyl group substituted with a naphthalene ring, etc., or an alkyl group etc. in which 4 or more carbon atoms are substituted with a substitutable group, it cannot be included, but in the compound (1) of the present invention, They differ in that this is an essential requirement, and therefore, from this point as well, the compounds of the present invention can be said to be a completely new 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. ]. In general formula (1), the groups represented by R ⁵ and R ⁶ are:
Examples include those shown below. Γ hydrogen atom, halogen atom, Γ alkyl group having 1 to 20 carbon atoms, Γ alkenyl having 2 to 20 carbon atoms, alkynyl group, Γ alkoxy having 1 to 19 carbon atoms, alkylthio group, Γ alkenyloxy having 3 to 19 carbon atoms , alkenylthio, alkynyloxy, alkynylthio group, Γ Alkyl group substituted with a halogen atom or hydroxyl group having 1 to 19 carbon atoms, Γ Alkenyl or alkynyl group substituted with a halogen atom or hydroxyl group having 2 to 19 carbon atoms, Γ Alkoxy, alkylthio group substituted with a halogen atom or hydroxyl group having 1 to 18 carbon atoms, Γ Alkenyloxy or alkenylthio substituted with a halogen atom or hydroxyl group having 3 to 18 carbon atoms,
Alkynyloxy, alkynylthio group, Γ alkyloxyalkyl having 2 to 19 carbon atoms, alkenyloxyalkyl, alkyloxyalkenyl group, Γ cycloalkyl having 4 to 7 carbon atoms (hydrocarbon ring),
cycloalkyloxy, cycloalkylthio group, Γ phenyl, phenoxy, phenylthio group, Γ alkyl having 1 to 19 carbon atoms having a hydrocarbon ring having 4 to 7 carbon atoms, a benzene ring, a naphthalene ring, or a thiophene ring in the middle or at the end, Alkenyl, alkynyl group, alkoxy, alkylthio, alkenyloxy, alkenylthio having 1 to 18 carbon atoms having a hydrocarbon ring having 4 to 7 carbon atoms, a benzene ring, a naphthalene ring, or a thiophene ring in the middle or at the end;
Alkynyloxy, alkynylthio group, Γphenylthioalkoxy or phenyloxyalkyloxy (alkyl moiety has 1 to 1 carbon atoms)
17) group, Γ carboxyalkyloxy group having 2 to 19 carbon atoms, alkoxycarbonylalkyloxy group, Γ alkylcarbonyloxyalkyloxy group having 3 to 19 carbon atoms, Γ alkenylcarbonyloxy group having 3 to 20 carbon atoms, Γ carbon number 2-20 alkylcarbonyl group, ΓAzidoalkyl, nitroalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl group having 1-19 carbon atoms, Γazidoalkyloxy, nitroalkyloxy, aminoalkyl having 1-18 carbon atoms oxy, alkylaminoalkyloxy, dialkylaminoalkyloxy group, Γ alkenylcarbonylamino group having 1 to 19 carbon atoms, Γ alkylamino group having 1 to 19 carbon atoms. Among these, preferable groups as R ⁵ and R ⁶ include the groups shown below. Γ hydrogen atom, Γ halogen atom, Γ straight chain or branched alkyl group having 1 to 20 carbon atoms, Γ straight chain or branched alkyl group having 1 to 19 carbon atoms, Γ straight chain or branched chain alkyl group having 1 to 19 carbon atoms, Γ straight chain or branched alkyl group having 1 to 19 carbon atoms Chain or branched alkenyloxy group, Γ Straight or branched alkynyloxy group having 3 to 19 carbon atoms, Γ Straight or branched alkylthio group having 3 to 19 carbon atoms, Γ Substituted with halogen atom Straight chain or branched alkyloxy group having 1 to 18 carbon atoms, Γ Straight chain or branched alkyloxyalkyl group having 2 to 19 carbon atoms, Γ Straight chain or branched chain having 1 to 8 carbon atoms Cycloalkyl, cycloalkylalkyl (alkyl moiety has 1 to 8 carbon atoms), cycloalkylalkyloxy (alkyl moiety has 1 to 8 carbon atoms) groups having 4 to 7 carbon atoms which may be substituted with a branched alkyl group , Γ Straight chain or branched alkyl group having 1 to 8 carbon atoms, phenyl or naphthyl, phenylalkyl or naphthylalkyl which may be substituted with a halogen atom, hydroxyl group, nitro group or carboxy group (the alkyl part is a carbon Numbers 1 to 8),
phenylalkyloxy or naphthylalkyloxy (alkyl moiety has 1 to 8 carbon atoms), phenylalkenyloxy or naphthylalkenyloxy (alkenyl moiety has 2 to 8 carbon atoms)
straight-chain or branched alkoxy, alkenyloxy having 1 to 18 carbon atoms substituted with a Γ carbonyl group, carbonyloxy group or hydroxyl group,
Alkoxyalkoxy group, straight chain or branched alkoxy group having 1 to 17 carbon atoms substituted with Γ phenoxy or phenylthio group, straight chain or branched chain having 1 to 18 carbon atoms substituted with Γ thiophene ring A linear or branched chain having 1 to 18 carbon atoms substituted with an alkoxy group, a Γ azide group, a nitro group, or an amino (including dialkylamino) group which may be substituted with an alkyl group having 1 to 6 carbon atoms. Straight-chain or branched alkyl, alkenyl, alkoxy or alkenyloxy groups having from 1 to 18 carbon atoms which are replaced by two groups: a Γ carbonyl group and an amino group in the chain. Furthermore, more preferable R ⁵ and R ⁶ include:
Naphthyl, naphthylalkyl, in which either one represents a hydrogen atom and the other is optionally substituted with a linear or branched alkyl group having 1 to 8 Γ carbon atoms, a halogen atom, a hydroxyl group, a nitro group, or a carboxyl group; naphthylalkyloxy (alkyl moiety has 1 to 8 carbon atoms), naphthylalkenyl or naphthylalkenyloxy (alkenyl moiety has 2 to 8 carbon atoms) group, or Γ linear or branched alkyl group having 1 to 8 carbon atoms; Phenylalkyloxy (alkyl moiety has 1 to 8 carbon atoms) or phenylalkenyloxy (alkenyl moiety has 2 carbon atoms) substituted with two or three groups selected from halogen atoms, hydroxyl groups, nitro groups, or carboxy groups. ~
8) When representing a 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. All groups represented by each symbol are preferred embodiments of the present invention, but more preferably R ¹ is a group represented by the formula [Formula] (R ⁵ and R ⁶ in the formula have the same meanings as above). and R ²
represents a hydrogen atom, R ³ represents a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms, R ⁴ represents a 2-tetrazolyl group or a carboxy group, and A represents a single bond or a vinylene group. , B represents a group represented by the formula [Formula] or [Formula], and T represents an oxygen atom. 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. Among the compounds of the present invention represented by the general formula (1), preferred examples include 8-{p-[2-(2-naphthyl)ethoxy]benzoyl}amino-2-(5-tetrazolyl)-1,
4-Benzodioxane, 8-{p-[3-(2-naphthyl)propoxy]benzoyl}amino-2-(5-tetrazolyl)-
1,4-benzodioxane, 8-{p-[4-(2-naphthyl)butoxy]benzoyl}amino-2-(5-tetrazolyl)-1,
4-Benzodioxane, 8-{p-[2-(2-naphthyl)ethoxy]benzoyl}amino-2-(5-tetrazolyl)-4
-oxo-4H-1-benzopyran, 8-{p-[3-(2-naphthyl)propoxy]
benzoyl}amino-2-(5-tetrazolyl)-
4-oxo-4H-1-benzopyran, 8-{p-[3-(2-naphthyl)butoxy]benzoyl}amino-2-(5-tetrazolyl)-4
-oxo-4H-1-benzopyran, 8-{p-[2-(3,4-dichlorophenyl)
ethoxy]benzoyl}amino-2-(5-tetrazolyl)-1,4-benzodioxane, 8-{p-[3-(3,4-dichlorophenyl)
propoxy]benzoyl}amino-2-(5-
Tetrazolyl)-1,4-benzodioxane, 8-{p-[4-(3,4-dichlorophenyl)butoxy]benzoyl}amino-2-(5-tetrazolyl)-1,4-benzodioxane, 8- {p-[2-(3,4-dichlorophenyl)
ethoxy]benzoyl}amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran, 8-{p-[3-(3,4-dichlorophenyl)
propoxy]benzoyl}amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran, 8-{p-[4-(3,4-dichlorophenyl)
butoxy]benzoyl}amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran, and their corresponding cinnamoyl derivatives (symbol A
represents a vinylene group), the corresponding 6-methyl form (when the symbol R ³ represents a methyl group), and the corresponding 2-carboxy form (when the symbol R ⁴ represents a carboxyl group), and non-toxic salts thereof. [Method for producing the compound of the present invention (1)] The compound of the present invention represented by the general formula (1) has the general formula R ¹ -A-COOH () [wherein, all symbols have the same meanings as above. ] 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 saponification reaction or an esterification reaction if necessary. Reactions for forming an amide bond from an acid and an amine are known, and examples thereof 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) 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,
Acid halides (pivaloyl chloride, thionyl chloride, tosyl chloride, mesyl chloride, oxalyl chloride, etc.) or acid derivatives ( ethyl chloroformate, isobutyl chloroformate, etc.) at 0°C to 40°C, and the resulting mixed acid anhydride and the amine represented by the general formula () were reacted at 0°C in an inert organic solvent (same as above).
It is carried out by reacting at ~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, and an acid halide (same as above) at -20°C to reflux temperature. The resulting acid halide is reacted with an amine represented by the general formula () in the presence or absence of a tertiary amine (same as above) and an inert organic solvent (same as above).
The reaction is carried out at a temperature of 0°C to 40°C. (C) In the method using DCC, for example, an amine represented by the general formula ( ) in the presence or absence of DCC (dicyclohexylcarbodiimide) 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. ] can be obtained by reacting the compound represented by the formula 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 with 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 (1), 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 , and the symbol therein represents that it is included in each R ¹ and has been converted by the reaction. The same applies to 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 having 1 to 18 carbon atoms,
Alkenyl or alkynyl group. 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 ⁵³ , R ⁵³ - 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. ^R70 , ^R71 - trifluoroacetyl group. X ¹⁰ , X ²⁰ , X ³⁰ , X ⁴⁰ - halogen atoms. [Table] [Table] [Table] [Table] Furthermore, in addition to the compound of the formula (), intermediates of the 1,4-dithianaphthalene skeleton can also be used with the general formula [In the formula, R ³ represents the same meaning as above. ] General formula obtained by hydrolyzing the compound shown by [In the formula, R ³ represents the same meaning 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. The reaction of converting an acid into an ester (esterification) is known, and includes, for example, (1) a method using a diazoalkane, (2) a method using an alkyl halide, (3) a method using a DMF-dialkyl acetal, (4) Examples include a method of reacting with a corresponding alkanol. 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 halide is, for example, a base (potassium carbonate, sodium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, calcium oxide, etc.) in an organic medium (acetone, DMF, N,N-dimethylformamide, DMSO, etc.). ) with the corresponding alkyl halide. (3) Methods using DMF-dialkyl acetals are carried out, for example, using the corresponding DMF-dialkyl acetals in inert organic solvents (benzene, toluene, etc.). (4) The method of reacting with the corresponding alkanol is
For example, it is carried out using an acid (hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, hydrogen chloride gas, etc.) or a condensing agent (DCC, pivaloyl halide, arylsulfonyl halide, alkylsulfonyl halide, etc.) in the corresponding alkanol. 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. A compound represented by the general formula (), where 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 general formula (XI),
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 (1) 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 the amount necessary for treatment, the effective pharmacological properties of the compound represented by general formula (1) are It means a salt consisting of a cation that is not impaired by the side effects caused by the cation. 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, dimethylamine salts, cyclopentylamine salts, benzylamine salts, phenethylamine salts,
Examples include organic amine salts such as piperidine salts, monoethanolamine salts, diethanolamine salts, lysine salts, and arginine salts. The salts of the compounds of the present invention can be prepared using known methods such as preparing the compounds of the present invention represented by the general formula (1) using a suitable base in a suitable solvent, such as an alkali metal or alkaline earth metal hydroxide or carbonate or an organic Obtained by reaction with amine. 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 1 shows that the compound represented by the general formula (1B') in which R represents a naphthylalkyloxy group or a di-substituted phenylalkyloxy group has sufficient LTD ₄ antagonistic activity. Accordingly, compounds in which R ⁵ and/or R ⁶ as a substituent for R ¹ in general formula (1B) are a naphthalene ring-containing group or a di- or tri-substituted phenyl-alkyloxy or -alkenyloxy group It is predicted that the drug also has LTD ₄ antagonistic activity that is sufficiently useful as a medicine. In addition, the inventors have proposed transformations of other parts (for example, transformations of symbols R ² , R ³ , R ⁴ , A, T, and B parts).
It has been confirmed that LTD ₄ antagonism is sufficiently maintained even in compounds obtained by
50977). Therefore, if it is confirmed that the compound group shown in Table 1 has LTD ₄ antagonistic activity, all of the compounds of the present invention will be sufficiently useful as pharmaceuticals based on the above.
It is easily inferred that it has LTD ₄ antagonistic activity. The antagonistic effect of the compounds of the present invention on LTD ₄ was determined by the following experimental method. The ileum (2.5 cm) removed from a male guinea pig weighing 300 to 400 g was placed in Tyrode's solution at 37°C with oxygen (95 cm).
%) and carbon dioxide (5%) mixed gas in a Magnus tube and stabilized for about 30 minutes.
LTD ₄ was added at a concentration of 5 x 10 ^-9 g/ml, and the compound of the present invention was added at different concentrations to respond to the contraction at this time.
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 and bronchial diseases such as asthma, allergic lung diseases, allergic shots, allergic It is effective in the prevention and/or treatment of various diseases caused by arachidonic acid metabolites, including the above-mentioned leukotrienes, such as thrombosis, by inhibiting phospholipase (phospholipase A ₂ and/or phospholipase C). For example, it is effective in preventing and/or treating thrombosis caused by damage to the endothelium or intima of the brain or 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 or treating diabetic complications such as retinopathy, cataract, neuropathy, and renal disorder. In order to use the compound of the present invention represented by the general formula (1) or a non-toxic salt thereof for the above-mentioned purposes, each compound is usually administered systemically or locally, orally or parenterally. The dosage varies depending on age, body weight, Hinayana, therapeutic effect, administration method, processing time, etc., but it is usually administered once per adult.
in the range of 0.1 mg to 100 mg, preferably 2 mg to 20 mg,
It is orally administered once to several times a day, or once a day to several times a day per adult, each at a dose of 10 μg/10 mg, preferably in the range of 0.1 mg to 1 mg. 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 include tablets,
Includes powders, granules, etc. In such solid compositions, one or more active substances are present in at least one inert diluent, such as lactose, mannitol, dextrose, hydroxypropyl cellulose, microcrystalline cellulose, starch,
Polyvinylpyrrolidone is mixed with magnesium aluminate metasilicate. 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 inert diluents, the compositions may also contain adjuvants such as wetting agents and suspending agents, sweetening agents, flavoring agents, aromatic agents, and preservatives. 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 include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. 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). Such compositions may further contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. These are sterilized, for example, by filtration through bacteria-retaining filters, by incorporation of sterilizing agents, 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. [Example] An example of the production of the compound of the present invention will be described in detail with reference to an example, but the invention is of course not limited to this. In addition, "TLC", "IR", "NMR", and "Mass" in the examples refer to "thin layer chromatography,""infrared absorption spectrum,""nuclear magnetic resonance spectrum," and "mass spectrometry," respectively. represent 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. Example 1 8-{p-[2-(2-naphthyl)ethoxy]benzoyl}amino-2-(5-tetrazolyl)-4
-Synthesis of oxo-4H-1-benzopyran After stirring p-[2-(2-naphthyl)ethoxy]benzoic acid (55 mg) and oxalyl chloride (0.5 ml) at room temperature for 1 hour, excess oxalyl chloride was removed under reduced pressure. The residue was dried with a vacuum pump and then dissolved in methylene chloride (1 ml). 8-Amino-2- cooled on ice under an argon atmosphere.
(5-Tetrazolyl)-4-oxo-4H-1-benzopyran hydrochloride (50 mg) in methylene chloride (3
ml) and pyridine (0.3 ml). After the addition, the reaction solution was stirred at room temperature for 1 hour and concentrated under reduced pressure. Add 1N hydrochloric acid (10ml) to the residue
was added, and the resulting solid was collected, washed with water and methanol, and dried to obtain the title compound (41 mg) having the following physical properties. TLC: Rf 0.23 (methylene chloride: methanol =
5:1); NMR: δ 8.76 (1H, dd), 8.01 (2H, d), 7.96
(1H, dd), 7.80 (4H, m), 7.47 (4H, m),
7.23 (1H, s), 7.06 (2H, d), 4.38 (2H, t),
3.11 (2H, t); IR: ν 3400, 3050, 1650, 1580, 1500, 1430,
1370, 1340, 1250, 1160, 1060, 1020, 880,
850, 810, 750cm ^-1 ; Mass: m/e 275; Shape: Yellow powder. Example 1(1)-1(5) By the same operation as in Example 1, 8-amino- having the corresponding carboxylic acid and the corresponding substituent ^R3
2-(5-tetrazolyl)-4-oxo-4H-1
- Compounds shown in the following table [1] were synthesized using benzopyran hydrochloride. [Table] Example 2 8-{p-[2-(2-naphthyl)ethoxy]benzoyl}amino-2-(5-tetrazolyl)-
Synthesis of 1,4-bezodioxane By the same operation as in Example 1, p-[2-(2-
naphthyl)ethoxy]benzoic acid and 8-amino-2
Using -(5-tetrazolyl)-1,4-benzodioxane hydrochloride, the title compound having the following physical properties was obtained. TLC: Rf 0.30 (methylene chloride: methanol =
5:1); NMR: δ 7.86 (2H, d), 7.80 (3H, m), 7.72
(1H, s), 7.58 (1H, dd), 7.44 (3H, m),
6.95 (2H, d), 6.90 (1H, t), 6.73 (1H,
dd), 5.68 (1H, t), 4.55 (2H, d); IR: ν 3700-2300, 1650, 1610, 1520, 1510,
1455, 1260cm ^-1 ; Mass: m/e 493 (M ⁺ ), 450, 437, 399,
275; Shape: White powder. Example 3 8-{p-[2-(2-naphthyl)ethoxy]benzoyl}amino-2-(5-tetrazolyl)-4
-Synthesis of oxo-4H-1-benzopyran sodium salt 8{p-[2-(2-naphthyl)ethoxy]benzoyl}amino-2-(5-tetrazolyl)-4-
Ethanol (5 ml) and 1N sodium hydroxide equivalent were added to oxo-4H-1-benzopyran (100 mg; synthesized in Example 1), stirred to dissolve, and then dried under reduced pressure to obtain the title compound (104 mg). Obtained. Example 3(1) By the same operation as Example 3, Examples 1(1) to 1
The corresponding sodium salts of compounds (3) and 2 were also synthesized. Example 4 8-{p-[2-(2-naphthyl)ethoxy]benzoyl}amino-2-(5-tetrazolyl)-4
-Oxo-4H-1-bezopyran 0.5g, cellulose calcium gluconate (disintegrant) 200mg, magnesium stearate (lubricant) 100mg and microcrystalline cellulose 9.2g are mixed in a conventional manner and tableted.
100 tablets containing 5 mg of active ingredient in each tablet were obtained.

Claims (1)

[Claims] 1. General formula [In the formula, R ¹ is a general formula (In the formula, R ⁵ and R ⁶ are each independently a hydrogen atom, a halogen atom, or any one, 2
Substitutable groups with 1, 3, 4, or 5 carbon atoms (i.e., oxygen atoms, sulfur atoms, halogen atoms, nitrogen atoms, benzene rings, naphthalene rings, thiophene rings, hydrocarbon rings having 1 to 4 carbon atoms, a straight-chain or branched alkyl, alkenyl, or alkynyl having 1 to 20 carbon atoms, which may be substituted with a group arbitrarily selected from a carbonyl group, a carbonyloxy group, a hydroxyl group, a carboxy group, an azide group, or a nitro group) represents a group. However, R ⁵ or R ⁶
At least one of them shall satisfy the following conditions. () Represents a straight-chain or branched alkyl, alkenyl or alkynyl group having 1 to 20 carbon atoms, in which at least one carbon atom is necessarily replaced with a substitutable naphthalene ring, or () any 4 Represents a straight-chain or branched alkyl, alkenyl or alkynyl group having 1 to 20 carbon atoms, in which 1 or 5 carbon atoms are replaced by substitutable groups. ) represents a group represented by 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, butenylene, 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 condensed benz(thio)amide represented by 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 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: 4. The compound according to any one of claims 1 to 3, wherein the symbol A is a single bond or a vinylene group, and the symbol T is an oxygen atom. 5. The compound according to any one of claims 1 to 4, wherein R ⁴ is a 2-tetrazolyl group or a carboxyl group. 6 Either one of R ⁵ and R ⁶ represents a hydrogen atom, and the other may be substituted with a linear or branched alkyl group having 1 to 8 carbon atoms, a halogen atom, a hydroxyl group, a nitro group, or a carboxy group. Claims 1 to 5 which are naphthyl, naphthylalkyl, naphthylalkyloxy (alkyl portion has 1 to 8 carbon atoms), naphthylalkenyl or naphthylalkenyloxy (alkenyl portion has 2 to 8 carbon atoms) groups. A compound described in any section. 7 The compound is 8-{p-[2-(2-naphthyl)ethoxy]benzoyl}amino-2-(5-tetrazolyl)-
1,4-benzodioxane or its sodium salt, 8-{p-[2-(2-naphthyl)ethoxy]benzoyl}amino-2-(5-tetrazolyl)-4
-oxo-4H-1-benzopyran or its sodium salt, or 6-methyl-8-{p-[2-(2-naphthyl)
7. The compound according to claim 6, which is ethoxy]benzoyl}amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran or its sodium salt. 8 One of R ⁵ and R ⁶ represents a hydrogen atom, and the other is two groups selected from a linear or branched alkyl group having 1 to 8 carbon atoms, a halogen atom, a hydroxyl group, a nitro group, or a carboxy group. or phenylalkyloxy (the alkyl moiety has 1 to 8 carbon atoms) or phenylalkenyloxy (the alkenyl moiety has 2 to 8 carbon atoms) substituted with
8) The compound according to any one of claims 1 to 5, which is a group. 9 The compound is 8-{p-[3-(3,4-dichlorophenyl)
propoxy]benzoyl}amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran or its sodium salt, or 6-methyl-8-{p-[3-(3,4-dichlorophenyl) propoxy]benzoyl}amino-
2-(5-tetrazolyl)-4-oxo-4H-1
- The compound according to claim 8, which is benzopyran or its sodium salt.