JPH0247989B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a novel arylcarbamoyl compound having an antagonistic effect on leukotrienes or an inhibitory effect on 5α-reductase. [Conventional technology] Prostaglandin (hereinafter referred to as PG)
Several important discoveries have been made in recent 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 characterized PG families, PG endoperoxides (i.e.
PGG ₂ and PGH ₂ ), thromboxane A ₂
(Thromboxane A 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
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
etc., and lipoxygenase acts on arachidonic acid to produce hydroperoxyeicosatetraenoic acid (hereinafter referred to as hydroperoxyeicosatetraenoic acid).
The route leads to hydroxyeicosatetraenoic acid (hereinafter abbreviated as HETE) or leukotriene via hydroxyeicosatetraenoic acid (hereinafter abbreviated as HETE). 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 15HETE. 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 referred to as
(abbreviated as LTB ₄ ) or converted to 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
See Prostaglandins, 19 (5), 645 (1980)]. On the other hand, when talking about SRS, SRS is Slow
It is an abbreviation for Reacting Substance, and this name was used by Eldberg et al. for the substance released when cobra venom was perfused into the lungs or when cobra venom was incubated with egg yolk. It has been reported that the effect lasts for a long time [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.
See 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)]; intradermal injection of SRS-A in guinea pigs, rats, and monkeys increases vascular permeability [Advances in Immounology, 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 can be considered in place of the pharmacological properties of SRS or SRS-A [ Proc.Natl.Acad.Sci.USA,
76, 4275 (1979), Biochem.Biophys.Pes.
Commum., 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 , LTE ₄ , and leukotrienes whose structures may be determined in the future) that are biosynthesized from arachidonic acid via LTA ₄ are now: 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 diseases, allergic shots, and various allergic diseases in mammals including humans, especially humans, can be prevented. Effective for prevention and/or treatment. 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) Phosphatidylinositol
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) is 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 has a vasodilatory effect in inflammation, an analgesic effect,
It is known to be a chemical mediator with thermogenic and leukocyte migration effects [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 the body, 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 group (having 1 to 6 carbon atoms) ~6)
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 alkenylene or alkynylene group, D
represents a carboxy group, 5-tetrazolyl, or carbamido-5-tetrazolyl group] A patent application has been filed for a group of compounds represented by the formula [JP-A-55-1999].
Specification No. 127384]. The present inventors have also filed a patent application for an arylcarbamoyl compound. To summarize, 1) The symbol -B- shown in the general formula () of the present application
A group of compounds in which R ⁴ is a group represented by the formula -OCH ₂ COOR [JP-A No. 60-97946, No. 60-116657,
60-142941 and 60-146855]. 2) Compound group represented by the following general formula (A) [JP-A-Sho
61-50977]. That is, the general formula [In the formula, R ^1a is the general formula or or (iv) a linear or branched alkyl, alkenyl or alkynyl group having 1 to 20 carbon atoms. (R ^5a and ^6a in the formula are each independently a hydrogen atom, a halogen atom, or any one
1, 2 or 3 carbon atoms: oxygen atom, sulfur atom, halogen atom, nitrogen atom, benzene ring, thiophene ring, carbon ring having 4 to 7 carbon atoms, carbonyl group, carbonyloxy group, hydroxyl group, carboxy group, azide represents a straight or branched alkyl, alkenyl or alkynyl group having 1 to 20 carbon atoms which may be substituted with a nitro group. ) R ^2a represents a hydrogen atom or a straight or branched alkyl group having 1 to 6 carbon atoms. R ^3a is a hydrogen atom, a halogen atom, a hydroxyl group, a nitro group, represented by the general formula -COOR ^7a (wherein R ^7a represents a hydrogen atom or a straight or branched alkyl group having 1 to 6 carbon atoms) group, carbon number 1~
6 straight chain or branched alkyl, alkoxy or alkylthio group. R ^4a is the general formula −COOR ^8a or −CH ₂ COOR ^8a
(In the formula, R ^8a 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' is methylene, ethylene, which may be substituted with a single bond or a linear or branched alkyl group having 1 to 10 carbon atoms or a phenyl group;
Represents a trimethylene, tetramethylene, vinylene, propenylene, butenylene, butadienylene or ethynylene 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 aryl(thio)carbamoyl compound and its non-toxic salt. In the applications listed in 2), a large number of compounds have been synthesized and pharmacological activity tests have been conducted, but any of these substituents (especially the R ^1a group on the left) may be sufficient for medical treatment. It is stated that it has an activity that can be used as a. It is also stated that when the ring moiety indicated by B' on the right is [Formula] [Formula] and [Formula], the compound having either ring has sufficient pharmacological activity [ Application specification, pages 122-129]. [Disclosure of the Invention] The present inventors attempted to convert the ring moiety of the aryl(thio)carbamoyl compound represented by formula (A), synthesized these compounds, and measured their pharmacological activity. The present invention was completed based on the discovery that the group of compounds represented by the following general formula () are extremely useful as leukotriene (SRS) antagonists or 5α-reductase inhibitors, as described below. That is, the present invention is based on the general formula [In the formula, symbol A represents a single bond or a methylene, ethylene, trimethylene, tetramethylene, vinylene, propenylene, butenylene, butadienylene or ethynylene group which may be substituted with a C1-C4 alkyl group or phenyl group. . The symbol B represents a divalent group represented by the formula [Formula] or [Formula]. The symbol T represents an oxygen atom. 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
Alkyl or alkenyl having 1 to 20 carbon atoms, in which 1, 3, 4, or 5 carbon atoms may be substituted with an oxygen atom, a sulfur atom, a halogen atom, a benzene ring, or a carbon ring having 4 to 7 carbon atoms. Or represents an alkynyl group. ) R ² represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms. R ³ represents a hydrogen atom or a halogen atom. R ⁴ ' has the general formula -(CH ₂ ) _s -COOR ⁸ or [Formula] (wherein, R ⁸ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms. S represents an integer of 1 to 4; , q represents 0 or an integer of 1 to 4.) However, compounds represented by the following general formula (In the formula, A' represents a single bond or a vinylene or ethylene group which is unsubstituted or substituted with a straight or branched chain alkyl having 1 to 4 carbon atoms, and R ⁴ ' represents the general formula -(CH ₂ ) _s COOR ⁸ (in the formula, R ⁸ and s have the same meanings as above), and R ¹ ' is the general formula (In the formula, R ⁵ ' and R ⁶ ' each independently represent a hydrogen atom, a halogen atom, a trifluoromethyl group, a straight or branched chain alkyl having 1 to 4 carbon atoms, alkenyl, alkynyl, alkoxy, alkenyloxy , or acyloxy group or carbon number 3-6
represents a cycloalkyl group. ) represents a group represented by R ³ ' represents a hydrogen atom or a halogen atom. ) are excluded. ] The present invention relates to a novel arylcarbamoyl compound and a non-toxic salt thereof. 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. and/or therapeutically effective. 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)]. In addition, 5α-reductase exists in the endoplasmic reticulum and nucleic acids, and has the effect of converting testosterone ingested into target tissues into active 5α-dihydrotestosterone. Binding to the receptor causes cell proliferation, and when this effect is enhanced, it is said to lead to the onset of prostatic hypertrophy, alopecia, or acne. Of course, the compound of the present invention does not have any hormone-specific effects, and moreover, it inhibits 5α-reductase, suppresses the increase in 5α-dihydrotestosterone, and suppresses cell proliferation. It can effectively prevent and/or treat erectile hypertrophy, alopecia and acne. 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 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.
Congr. Ser Excerpta Med., 403 , 594 (1977),
and Metabolism, 23 , 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. In the general formula (), examples of the groups represented by R ⁵ and R ⁶ 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 having 1 to 19 carbon atoms, Γ alkenyl substituted with a halogen atom having 2 to 19 carbon atoms, alkynyl group, Γ having 1 to 19 carbon atoms Alkoxy, alkylthio group substituted with 18 halogen atoms, Γ Alkenyloxy, alkenylthio, alkynyloxy, alkynylthio group substituted with halogen atoms having 3 to 18 carbon atoms, Γ Alkyloxyalkyl having 2 to 19 carbon atoms, Alkenyloxyalkyl, alkyloxyalkenyl group, Γ cycloalkyl having 4 to 7 carbon atoms, cycloalkyloxy, cycloalkylthio group, Γ phenyl, phenoxy, phenylthio group, Γ hydrocarbon ring having 4 to 7 carbon atoms, benzene ring in the middle or alkyl having 1 to 19 carbon atoms at the end,
Alkenyl, alkynyl, Γ hydrocarbon ring with 4 to 7 carbon atoms, alkoxy with 1 to 18 carbon atoms having a benzene ring in the middle or end, alkylthio, alkenyloxy, alkenylthio, alkynyloxy, alkynylthio group, Γ phenylthio Alkoxy or phenyloxyalkyloxy (alkyl part has 1 to 1 carbon atoms)
17) Base. Among these, preferable groups as R ⁵ and R ⁶ include the groups shown below. Γ hydrogen atom, Γ halogen atom, Γ alkyl group having 1 to 20 carbon atoms, Γ alkoxy group having 1 to 19 carbon atoms, Γ alkenyloxy group having 3 to 19 carbon atoms, Γ alkynyloxy group having 3 to 19 carbon atoms, Γ an alkylthio group having 1 to 19 carbon atoms, Γ an alkyloxy group having 1 to 18 carbon atoms substituted with a halogen atom, Γ an alkyloxyalkyl group having 2 to 19 carbon atoms, Γ an alkyl group having 1 to 8 carbon atoms; Optionally substituted cycloalkyl having 4 to 7 carbon atoms, cycloalkylalkyl (alkyl part has 1 to 7 carbon atoms)
8), cycloalkylalkyloxy (the alkyl part has 1 to 8 carbon atoms) group, Γ phenyl which may be substituted with an alkyl group having 1 to 8 carbon atoms or a halogen atom, phenyl alkyl (the alkyl part has 1 to 8 carbon atoms) ~8), phenylalkyloxy (alkyl part has 1 carbon number)
~8), phenylalkenyloxy (alkenyl moiety has 2 to 8 carbon atoms) group, straight or branched alkoxy group having 1 to 17 carbon atoms substituted with Γ phenoxy or phenylthio group. The alkyl group having 1 to 20 carbon atoms as used 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 4 carbon atoms in the present invention include methyl, ethyl, propyl, butyl groups and isomers thereof. Examples of the cycloalkyl group having 4 to 7 carbon atoms in the present invention include cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl groups. The halogen atoms referred to in the present invention include chlorine,
Mention may be made of bromine, iodine or fluorine atoms. Furthermore, in the present invention, "a carbon atom is replaced by another atom, ring, or group" may be any carbon as long as it is chemically and physically permissible. For example, the isobutyl group having a benzene ring in the middle or at the end refers to isopropylphenyl, dimethylphenylmethyl, and 2-phenylpropyl groups. However, upon substitution, hydrogen atoms shall be appropriately added or removed. For example, substituting the 2-position of a pentyl group with an oxygen atom means a propyloxymethyl group. [Method for producing the compound of the present invention (1)] The compound of the present invention represented by the general formula () has the general formula R ¹ -A-COOH () [in the formula, all symbols have the same meanings as above]. Carboxylic acid shown and general formula [In the formula, all symbols have the same meanings as above] It can be obtained by reacting the amine represented by 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) 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 With an acid halide (pivaloyl chloride, tosyl chloride, mesyl chloride, etc.) or an acid derivative (ethyl chloroformate, isobutyl chloroformate, etc.) in the presence of a tertiary amine (pyridine, triethylamine, picoline, etc.) without a solvent, 0℃～40℃
The reaction is carried out by reacting the obtained mixed acid anhydride with the amine represented by the general formula () 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, and an acid halide (oxalyl chloride, thionyl chloride, etc.) at -20°C.
The resulting acid halide was reacted at ~reflux temperature with the 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) at 0°C. It is carried out by reacting at ~40°C. 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 [Wherein, R ²⁰ represents a group represented by the general formula -(CH ₂ ) _q - (in the formula, all symbols have the same meanings as above), and 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)] The compound of the present invention represented by the general formula () has the general formula [In the formula, the symbol U represents an oxygen atom or a sulfur atom, and the other symbols have the same meanings as above. ]
^A compound ^represented by ^the general _formula : ] It can be obtained by reacting the compound represented by the following and, if necessary, subjecting it to saponification or esterification reaction. This O-alkylation or S-alkylation reaction is known, for example, in an aprotic polar solvent (diethyl ether, tetrahydrofuran, acetone, etc.) under anhydrous conditions with a base (sodium hydride,
In the presence of potassium carbonate, sodium carbonate, etc.), 0
The reaction is carried out at a temperature of 100°C to 100°C. [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', and the symbol therein represents that it is included in each R' and is converted by the reaction. ] Each symbol in the reaction scheme (A) on the previous page represents the following meaning, and the other symbols represent the same meaning as above. R ⁴⁵ - hydrogen atom or alkyl, alkenyl or alkynyl group having 1 to 18 carbon atoms, T ¹⁰ - oxygen or sulfur atom, X ¹¹ - halogen atom. 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 solvent (acetone, DMF, N,N-dimethylformamide, DMSO, etc.). is carried out using the corresponding alkyl halide in the presence of . (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 in addition to 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, It is carried out under anhydrous conditions using an aqueous solution of lithium hydroxide, potassium carbonate, sodium carbonate, etc., or (2) using the above-mentioned alkalis in an alkanol (methanol, ethanol, etc.). 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. [Method for producing intermediates] The compounds represented by the general formulas (), (), and () described above can be synthesized according to the following reaction scheme (B). In addition, each symbol in the reaction process formula represents the following meaning. R ¹⁰ - a group represented by the general formula (CH ₂ ) _r - (in the formula, r represents 0 or an integer of 1 to 4), R ²² , R ⁸⁰ - an alkyl group having 1 to 4 carbon atoms, R ²⁵ - General formula - (CH ₂ ) _s - (in the formula, s represents the same meaning as above), R ⁵⁰ - trifluoroacetyl group, X ²⁰ , X ³⁰ , X ⁴⁰ , X ⁵⁰ - Halogen atom, M ¹⁰ - lithium, potassium or sodium atom. In addition, the compound represented by the general formula (d) is a compound represented by the general formula (a) to the compound represented by the general formula (b).
It can be obtained by the same procedure as the method for synthesizing the compound shown in . [Table] [Table] [Starting Materials] All of the starting materials and reagents used 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. The compound represented by the general formula () can be synthesized from the compound represented by the general formula (). The compounds represented by the general formulas (), () and () are themselves known or can be synthesized by known methods. [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 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, but for example, an alkyl group having 1 to 6 carbon atoms, a carbon number 1
-3 hydroxyalkyl groups. Suitable non-toxic amine salts include tetraalkylammonium salts such as tetramethylammonium;
and organic amine salts such as methylamine salt, dimethylamine salt, cyclopentylamine salt, benzylamine salt, phenethylamine salt, piperidine salt, monoethanolamine salt, diethanolamine salt, 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 activity of the compound of the present invention] As described above, the compound of the present invention represented by the general formula () has leukotriene antagonistic activity, phospholipase inhibitory activity, 5α-reductase inhibitory activity, and aldose reductase inhibitory activity, and has been demonstrated, for example, in the laboratory. In the experiment, the following results were obtained. (1) LTD ₄ antagonistic effect in an in vitro system The compound of the present invention exhibited an antagonistic effect against LTD ₄ in an in vitro system (described later) as shown in the following table. [Table] LTD of the compounds of the present invention in in vitro system ₄
The IC ₅₀ value of the antagonistic effect on was determined using the following experimental system. The ileum (2.5 cm) removed from a male guinea pig weighing 300 to 400 g was suspended in Tyrode's solution at 37°C in a Magnus tube aerated with a mixed gas of oxygen (95%) and carbon dioxide (5%) and kept stable for about 30 minutes. After that, LTD ₄ was added at a concentration of 5 x 10 ^-9 g/ml, and the contraction length was measured when different compounds of the present invention were added to the contraction at this time, and the IC ₅₀ value was calculated from these. Calculated. (2) Inhibitory effect on 5α-reductase in an in vitro system The compounds of the present invention inhibit 5α-reductase in an in vitro system.
In the vitro system (described below), it exhibited the inhibitory effects shown in the table below. [Table] The IC ₅₀ value of the 5α-reductase inhibitory effect of the compounds of the present invention in an in vitro system was determined using the following experimental system. 0.09M Hepes (PH7.4), 0.22M sucrose, 5x
A reaction was carried out at 37° C. for 60 minutes using a mixture of 10 ⁻³ M NADPH, 5 μM [4- ¹⁴ C]testosterone, 5α-reductase and the compound of the present invention,
To stop the reaction, chloroform-methanol (1:
2) was used. The reaction solution was centrifuged, and the supernatant was separated using a silica gel thin layer plate (chloroform: methanol: acetic acid = 99.2:0.6:0.2).
The radioactivity of the generated dihydrotestosterone
The IC ₅₀ value was calculated from the enzyme activity inhibition rate measured using a TLC scanner [Endocrinal,
See Japon., 18 , 179 (1971)]. [Medicinal applications] In mammals including humans, especially humans, by suppressing leukotroliene, allergic tracheal and bronchial 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 prostatic hypertrophy, 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 () 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 for each 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 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, dextrose, hydroxypropyl cellulose, microcrystalline cellulose,
Mixed with starch, polyvinylpyrrolidone, magnesium aluminate metasilicate. The composition is
In accordance with conventional methods, additives other than inert diluents may be included, such as lubricants such as magnesium stearate and disintegrants such as fibrin calcium glycolate. Tablets or pills may be coated with a film of gastric or enteric substances such as sucrose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylulose phthalate, etc., 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 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,
Auxiliary agents such as wetting agents, emulsifying agents and dispersing agents may also be included. These can be sterilized, for example, by filtration through bacteria-retaining filters, by incorporation with disinfectants 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 such as ointments, suppositories and pettu saris, which contain one or more active substances and are formulated in a manner known per se. 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 carbon-carbon multiple bonds adjacent to oxygen or sulfur atoms, etc.) are excluded. [Example] An example of the production of the compound of the present invention will be explained 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 respectively refer to "thin layer chromatography", "infrared absorption spectrum", "nuclear magnetic resonance spectrum" and "mass spectrometry". represents. 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 8-[p-(2E, 7-octadienyloxy)
Synthesis of benzoylamino]-4-hydroxyquinoline-carboxylic acid Oxalyl chloride (4.9 ml) was added to p-(2E,7-octadienyloxy)benzoic acid (540 mg) under an argon atmosphere, and the mixture was stirred at room temperature for 30 minutes. Concentrate under reduced pressure to remove excess oxalyl chloride, and dissolve the residue in methylene chloride (15
ml). Under an argon atmosphere, a methylene chloride-pyridine solution (10 ml: 3.5 ml) of 8-amino-4-hydroxyquinoline-2-carboxylic acid methyl ester hydrochloride (225 mg) was slowly added to this solution at 0°C, and at the same temperature. The mixture was stirred for 1 hour and 30 minutes, and further stirred at room temperature for 1 hour. After the reaction, add 2N hydrochloric acid (50
ml) and then extracted with chloroform (60 ml). The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform) to obtain a yellow powder. This was mixed with methanol-tetrahydrofuran (4 ml: 10
ml) of a mixed solvent, 1N aqueous sodium hydroxide solution (2.0 ml) was added, and the mixture was stirred at 60°C for 3 hours. After the reaction, most of the solvent was removed under reduced pressure,
1N hydrochloric acid (2.5ml) was added. The precipitated solid was collected by filtration, washed sequentially with water and ethanol,
After drying, the title compound (100 mg) having the following physical properties was obtained. TLC: Rf 0.05 (Chloroform: Methanol =
4:1); IR:ν 3280, 2950, 1640, 1605, 1590, 1500,
1260, 1180, 1000, 760 cm ^-1 ; NMR (CDCl ₃ + DMSO−d ₆ ): δ 10.70 (1H,
s), 8.50 (1H, dd), 8.00 (3H, m), 7.50
(2H, m), 7.02 (2H, d), 5.60−6.00
(3H, m), 4.85−5.10 (2H, m), 4.58
(2H, d), 2.10 (4H, m), 1.50 (2H,
m), ppm; Shape: pale yellow powder. Examples 1(a)-1(c) In the same manner as in Reference Example 1, the compounds shown in the following table [] were synthesized using the corresponding carboxylic acids and the corresponding amines. [Table] Reference example 2 8-[p-(4-phenylbutoxy)benzoylamino]-2-(5-tetrazolyl)-2,3-
Dihydrobenzoxazine Under argon atmosphere, 8-[p(4-phenylbutoxy)benzoylamino]-N-trifluoroacetyl-2,3-dihydrobenzoxazine-2
-Nitrile (316mg), sodium azide (196mg)
A mixture of ammonium chloride (161 mg) and dimethylformamide (2.5 ml) was stirred at 100°C for 1 hour. After the reaction, the reaction solution was poured into ice-diluted hydrochloric acid and extracted with ethyl acetate. Wash the extract with water,
It was dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
The residue was dissolved in ammonia-saturated methanol (50 ml), stirred at room temperature for 20 hours, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 3:1) to obtain the title compound (207 mg) having the following physical properties.
I got it. TLC: Rf 0.36 (chloroform: methanol =
3:1); IR: ν 3600−2300, 1630, 1600, 1500, 1465,
1250, 1170cm ^-1 ; Mass: m/z 470 (M ⁺ ), 376, 358, 253; Shape: brown powder. Examples 2(a)-2(b) In the same manner as in Reference Example 2, the compounds shown in the following table [] were synthesized using the corresponding nitriles. [Table] Example 3 Synthesis of 4-[2-(p-pentyl-2-methylcinnamoyl)aminophenoxy]butanoic acid and its ethyl ester 2-(p-pentyl-2-methylcinnamoyl)
Aminophenol (267mg), 4-bromobutanoic acid ethyl ester (322mg), potassium carbonate (135mg)
and acetone (2 ml) was heated to reflux overnight. After cooling, the reaction solution was diluted with ethyl acetate.
The precipitate was removed by filtration. Concentrate the filtrate under reduced pressure,
The title compound (ester) having the following physical properties was obtained. TLC: Rf 0.66 (Toluene: Ethyl acetate = 10:
1); Mass: m/z 437 (M ⁺ ). The obtained ester was dissolved in methanol (3.2 ml), and a 2N aqueous sodium hydroxide solution (1.64 ml) was added to this.
ml) and stirred at 40°C for 1.5 hours. After the reaction, the mixture was acidified with diluted hydrochloric acid, extracted with ethyl acetate, and the extract was washed with water, dried, and concentrated under reduced pressure to obtain the title compound (acid; 285 mg) having the following physical properties. TLC: Rf 0.60 (CH ₂ Cl ₂ :CH ₃ OH=5:1); IR: ν 3470, 3200−2300, 1710, 1670, 1620,
1600, 1530, 1450, 750 cm ^-1 ; NMR (CDCl ₃ ): δ 8.44 (1H, dd, ), 8.28 (1H,
s), 7.45 (1H, s), 7.30 (2H, d), 7.18
(2H, d), 7.10−6.90 (2H, m), 6.85
(1H, dd), 4.11 (2H, t) ppm; Mass: m/z 409 (M ⁺ ), 215, 187; Shape: white powder Example 4(a)-(b) Same operation as Example 3 The following compound was obtained using the corresponding phenol. 4(a): TLC: Rf 0.48 (ethyl acetate); IR: ν 3320, 2300−2300, 1700, 1660, 1630,
1610, 1540 cm ^-1 ; NMR (CDCl ₃ ): δ 8.40 (1H, d), 8.22 (1H,
s), 7.60 (1H, d), 7.34 (2H, s), 7.04
(2H, d), 6.85 (1H, dd), 6.76 (1H,
d), 6.99 (1H, dd) ppm; Mass: m/z 395 (M ⁺ ), 201, 195; Shape: white powder. 4(b): TLC: 0.4 (methylene chloride: methanol = 5:
1); IR: ν 1655, 1600, 1520, 1445cm ^-1 ; Mass: m/z 445 (M ⁺ ), 363, 345, 255, 191,
147; Shape: pale yellow powder. Reference Example 3 Synthesis of 3-(m-methoxy-p-pentyloxycinnamoyl)aminopyrocatechol Oxalyl chloride (4.5 ml) was added to m-methoxy p-pentyloxybenzoic acid (258 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
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 1N 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: Rf 0.20 (ethyl acetate:hexane=1:
2); NMR (CDCl ₃ ): δ 10.00 (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) ppm; Mass: m/z 371 (M ⁺ ), 247, 177, 145, 125,
117, 89. Reference example 4 8-(m-methoxy-p-pentyloxycinnamoyl)amino-1,4-dioxane-2-
Synthesis of 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 3) 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 chromatography (methylene chloride: ethyl acetate = 10:1) to obtain the title compound (565 mg) having the following physical properties. TLC: Rf 0.15 (ethyl acetate:hexane) 1:
2); NMR (CDCl ₃ ): δ 8.25 (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) ppm; Mass: m/z 422 (M ⁺ ), 247, 177, 145, 117. Reference example 5 8-(3-methoxy-4-pentyloxycinnamoyl)amino-2-(5-tetrazolyl)-
Synthesis of 1,4-benzoxane 8-(3-methoxy-4-pentyloxycinnamoyl)amino-1,4-benzodioxane-
Sodium azide (490 mg) and pyridinium chloride (870 mg) were added to a solution of 2-carbonitrile (560 mg, synthesized in Reference Example 4) in anhydrous dimethylformamide (3 ml), 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: Rf 0.10 (chloroform: methanol =
5:1); NMR: δ 7.69 (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)
ppm; IR: ν 2940, 2850, 1655, 1600, 1540, 1505,
1450, 1260cm ^-1 ; Mass: m/z 465 (M ⁺ ), 247, 177, 145. Examples 5(a)-5(b) The following compounds were synthesized in the same manner as in Reference Example 5 using the corresponding nitrilo compounds. 5(a) TLC: 0.3 (methylene chloride: methanol = 5:
1); IR: ν 1655, 1615, 1600, 1540, 1490cm ^-1 ; Mass: m/z 391 (M ⁺ ), 349, 309, 217, 201,
191; Shape: Pale yellow powder. 5(b) TLC: 0.22 (chloroform: methanol = 9:
1); IR: ν 3300−2300, 2920, 1655, 1620, 1540,
1470, 1350, 1045, 980cm ^-1 ; Mass: m/z 407 (M ⁺ ), 324, 292, 201; Shape: pale yellow powder. Reference example 6 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) and added with methylene chloride (5 ml) and triethylamine (0.6 ml) at 0°C under an argon atmosphere.
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: Rf 0.60 (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)
ppm; IR: ν 3270, 2930, 1730, 1660, 1630, 1530,
1430, 1290, 1260, 1180, 770cm ^-1 ; Mass: m/z 433 (M ⁺ ), 404, 388, 376, 360,
318, 233, 201, 131; Shape: white powder. Reference example 7 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: manufactured in Reference Example 6)
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 solution of ethyl acetate-hexane (1:1) and dried to obtain the title compound (62 mg) having the following physical properties.
I got it. TLC: Rf 0.25 (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) ppm; IR: ν 3400, 2930, 1635, 1520, 1430, 1360
cm ^-1 ; Mass: m/z 405 (M ⁺ ), 361, 201, 181, 169,
131, 69; Form: Yellow powder. Examples 6(a)-6(r) By the same operation as in Reference Examples 6 and 7, the compounds shown in the following table [] were synthesized using the corresponding carboxylic acids and the corresponding amines. [Table] [Table] [Table] [Table] [Table] Example 7 Synthesis of 4-[2-(p-pentyl-2-methylcinnamoyl)aminophenylthio]butanoic acid sodium salt Dissolve 4-[2-(p-pentyl-2-methylcinnamoyl)aminophenylthio]butanoic acid (35 mg; synthesized in Example 1(a)) in methanol (0.5 ml) and add 1N aqueous sodium hydroxide solution. After adding the equivalent amount and stirring, it was dried under reduced pressure to give the title compound (36
mg) was obtained. Examples 7(a)-7(b) By the same operation as in Example 7, Examples 1(b) and 1
The corresponding sodium salt of compound (c) was synthesized.

Claims (1)

[Claims] 1. General formula [In the formula, symbol A represents a single bond, or a methylene, ethylene, trimethylene, tetramethylene, vinylene, propenylene, butenylene, butadienylene or ethynylene group which may be substituted with an alkyl group or phenyl group having 1 to 4 carbon atoms. represent The symbol B represents a divalent group represented by the formula [Formula] or [Formula]. The symbol T represents an oxygen atom. 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
Alkyl, alkenyl or alkenyl having 1 to 20 carbon atoms, in which 1, 3, 4 or 5 carbon atoms may be replaced with an oxygen atom, a sulfur atom, a halogen atom, a benzene ring, a carbon ring having 4 to 7 carbon atoms, or Represents an alkynyl group. ). R ² represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms. R ³ represents a hydrogen atom or a halogen atom. R ⁴ is -(CH ₂ ) _s COOR ⁸ or [Formula] (wherein, R ⁸ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms. s represents an integer of 1 to 4,
q each represents 0 or an integer from 1 to 4. )
represents. However, compounds represented by the following general formula (In the formula, A' represents a single bond or a vinylene or ethylene group that is unsubstituted or substituted with an alkyl having 1 to 4 carbon atoms, and R ⁴ ' represents the general formula -(CH ₂ ) _s COOR ⁸ ( In the formula, R ⁸ and s have the same meanings as above.), and R ¹ ' is the general formula (In the formula, R ⁵ ' and R ⁶ ' each independently represent a hydrogen atom, a halogen atom, a trifluoromethyl group, an alkyl having 1 to 4 carbon atoms, alkenyl, alkynyl, alkoxy or alkenyloxy, or a hydrogen atom having 3 to 4 carbon atoms. (6) represents a cycloalkyl group.)
represents a group represented by R ³ ' represents a hydrogen atom or a halogen atom. )
Excludes. ] A novel arylcarbamoyl compound or a non-toxic salt thereof. 2. The compound according to claim 1, wherein A is a single bond or a vinylene group optionally substituted with a methyl group. 3 R ⁵ is a hydrogen atom, R ⁶ is an alkyl having 3 to 12 carbon atoms which may be substituted with a halogen atom,
The compound according to claim 1 or 2, which is an alkoxy, alkenyl or alkenyloxy group. 4 Claims in which R ⁶ is a pentyl, hexyloxy, heptyloxy, octyloxy, nonyloxy, 2-octenyloxy, 2,7-octadienyloxy, 7-octenyloxy or 6-chlorohexyloxy group Compound according to item 3. 5 A claim in which R ⁵ is a hydrogen atom and R ⁶ is an alkyl, alkoxy, alkenyl or alkenyloxy group having 1 to 10 carbon atoms substituted with a phenyl group or a phenylthio group which may be substituted with a halogen atom A compound according to item 1 or 2 of the range. 6. The compound according to claim 5, wherein R ⁶ is 2-phenylethoxy, 4-phenylbutoxy or 4-(p-chlorophenyl)butoxy group. 7. The compound according to claim 1, which is N-[p-(4-phenylbutoxy)benzoyl]-2-(5-tetrazolyl)methoxyanilide or its sodium salt. 8. The compound according to claim 1, which is N-[p-(2E-octenyloxy)benzoyl]-2-(5-tetrazolyl)methoxyanilide or its sodium salt. 9. The compound according to claim 1, which is 4-[2-(p-pentyl-2-methylcinnamoyl)aminophenylthio]butanoic acid or its sodium salt. 10 The compound according to claim 1, which is 4-[2-(p-pentylcinnamoyl)aminophenoxy]butanoic acid or its sodium salt. 11 The compound according to claim 1, which is 4-[2-(p-pentyl-2-methylcinnamoyl)aminophenylthio]butanoic acid or its sodium salt. 12. The compound according to claim 1, which is 4-[2-(p-pentyl-2-methylcinnamoyl)aminophenoxy]butanoic acid or its sodium salt. 13. The compound according to claim 1, which is 4-[2-(p-pentylcinnamoyl)aminophenylthio]butanoic acid or its sodium salt.