JPH043377B2 - - Google Patents

Description

[Detailed description of the invention] The present invention relates to novel aniline derivatives. The present invention provides antagonism to leukotrienes,
Phospholipase inhibitory effect and 5α-reductor
Concerning new aniline derivatives with enzyme-inhibiting action
do. Prostaglandin (PG)
It is abbreviated as ) In the field of research, in recent years
Several important discoveries were made one after the other.
Ta. Therefore, the flow of PG research and development has been greatly affected in recent years.
You can see the changes. newly discovered or new
Particularly powerful among the structurally determined PG families
PG as a substance with unique biological activity.
Endoperoxides (PG endoperoxides)
Nawachi PGG₂and PGH₂), thromboxane A₂
(Thromboxane A₂, hereafter TXA₂It is abbreviated as ),
Prostacyclin (i.e.
P.G.I.₂) and leukotrienes C, D and E (hereinafter
Below, each is abbreviated as LTC, LTD and LTE.
Ru. ) etc. In addition to these compounds,
Including various PGs that were already well known.
All members of the PG family share arachidonic acid.
Because it is biosynthesized in the body as a parent body of
The entire metabolic pathway that starts with chydonic acid is arachidonic acid.
It is called cascade (Arachidonate cascade).
ing. Detailed explanation of each pathway and pharmacological characteristics of each product
Regarding the nature, the history of medicine,114, 378 (1980),
same,114, 462 (1980), same.114866 (1980), ibid.
114, 929 (1980), Modern Medicine,12, 909 (1980), same.
12, 1029 (1980), same.12, 1065 (1980) and the same,
12, 1105 (1980), etc. The arachidonic acid cascade is synchronized with arachidonic acid.
Clooxygenase acts to produce PGG₂,moreover
PGH₂Various PGs, such as prostagrange
F₂〓(Hereafter referred to as PGF₂Abbreviated as 〓. ), prostagran
Jin E₂(hereinafter referred to as PGE₂It is abbreviated as ), P.G.I.₂,TXA₂
Lipoxygenase to arachidonic acid with a pathway leading to etc.
acts on hydroperoxyeicosatetrae
neutsukashid
(hydroperoxyeicosatetraenoicacid, hereafter
Abbreviated as HPETE. ) via hydroxyray
Kosatetra Enoitsuku Assist
(hydroxyeicosatetraenoicacid, hereinafter abbreviated as HETE)
Write down. ) or the route leading to leukotrienes.
It is broadly divided into The former route is already well known.
Therefore, we will not discuss it in detail here. In detail
Edited by Nobuo Katori et al., Prostaglandin
(1978), published by Kodansha. For the latter route, follow the route shown in the diagram.
It is known that various compounds are produced by
Ru. Arachidonic acid is a well-known pathway, i.e.
It is metabolized via the PG endoperoxide pathway.
In addition, a completely different process is caused by lipoxygenase.
enters the tract and is metabolized. In other words, arachidonic acid
Lipoxygenase, e.g. 5-lipoxygenase
12-lipoxygenase or 15-lipoxygenase
Genase acts to produce 5-HPETE and 5-HPETE, respectively.
12-HPETE or 15-HPETE is produced. 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.
Furthermore, among these HPETEs, 5-HPETE is
LTA by being watered_Fouris converted to Further LTA_Fouris oxygenated with leukotriene B_Four(Hereafter
Bottom, LTB_FourIt is abbreviated as ), and also glutathione
-LTC by S-transferase_FourConversion to
be done. And LTC_Fouris γ-glutamyl transpep
LTD by titase_Fouris converted to LTD_FourHasasa
more LTE_FourIt has recently become clear that it is metabolized to
[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.
Pulmonary perfusion of cobra venom or cobra venom by Feldberg et al.
What is liberated when incubating with egg yolk
This substance was used to treat isolated guinea pigs.
Slowly contracts the ileum and its effect lasts for a long time
It has been reported that [J.Physiol.,94,187
(1938)]. Additionally, Kellaway et al. perfused sensitized guinea pig lungs.
Sometimes, when sensitized with antigen, SRS-A (Slow
Reacting Substance of Anaplylaxis) is released.
The relationship between SRS-A and allergic reactions was shown to be
[Quant.J.Exp.Physiol.,
30, 121 (1940)]. Brocklehurst is also unique.
Surgery for bronchial asthma patients with known antigens
When antigens are applied to lung sections taken out by
and SRS-A are released, strongly contracting the bronchial muscles,
This contraction is not relieved by antihistamines
Therefore, SRS-A plays an important role in the bronchus during asthma attacks.
Indicates that it is a bronchoconstrictor.
[Progr.Allergy,6, 539 (1962)].
Subsequently, SRS-A obtained from a piece of human lung tissue was found to be positive.
Contract the bronchial muscle rings of a normal person [Int.Arch.
Allergy Appl. Immunol.38, 217 (1970)],
When rat SRS-A is intravenously injected into guinea pigs, lung
An increase in road resistance was observed [J.Clin.Invest.,53，
1679 (1974)], SRS-A
When injected intradermally into monkeys, it increases vascular permeability.
[Advances in Immunology,Ten,105
(1969), J. Allergy Clin. Immunol.621,371
(1978), Prostaglandins,19(5), 779 (1980), etc.
There are many reports such as As mentioned above, SRS is released due to the involvement of immune reactions.
SRS-A, calcium ionophore
(calcium ionophore) treatment, etc.
There are two types of substances, SRS and SRS.
However, there are many similarities between the two and they are
It is thought that there is a strong possibility that it is the same substance. Also, further LTC_Fourand LTD._Fouris SRS or
It is clear that the substance is the same as SRS-A.
Therefore, the pharmacological properties of these leukotrienes are
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 such studies, currently
is LTA from arachidonic acid_FourEach biosynthesized
Seed leukotrienes (LTC)_Four，LTD_Fouror LTE_Fourand
Further new structures may be determined in the future.
Ikotriene) is an allergic tracheal and respiratory
Diseases of the ducts or lungs, allergic shots
or serious diseases that are involved in the development of various types of allergic inflammation.
It is considered an important factor. Therefore, suppressing these leukotrienes
This causes damage to mammals including humans, especially humans.
allergic tracheal and bronchial diseases, e.g.
asthma, allergic shots, allergic
Effective in preventing and/or treating various diseases.
Ru. In addition, arachidonic acid is a phospholipase
Due to the action of (phospholipase), phospholipids
However, if you look closely, as shown in the diagram,
Two pathways, namely (1) phosphatidyl choline;
(phosphatidyl chlorine) to phospholipase A₂but
Pathway of action and (2) phosphatidyl inositol
(phosphatidyl inositol) contains phospholipase C.
1,2-diglyceride (1,2-
diglyceride) is generated, which is further added to diglyceride.
ceride lipase (diglyceridelipase), then
monoglyceride lipase
(monoglyceridelipase) acts and is released.
[chemistry and biology,twenty one，
154 (1983)]. The liberated arachidonic acid can be further processed by two routes.
Namely (1) cyclooxygenase
(cyclooxygenase) metabolic pathway
Landin (PG) and thromboxane A₂(TXA₂) na
(2) which bioactive substances are metabolized to
Due to the lipoxygenase metabolic pathway,
SRS-A (Slow Reacting Substances of
Anaphylaxis), hydroxyeicosatetraene
Acid (HETE) and leukotriene B_Four
(Leukotriene B_Four) is metabolized into physiologically active substances such as
[Chemistry and Biology]twenty one,154
(1983)]. These metabolites are e.g. TXA₂is a strong blood small
It is a substance that has plate aggregation and vasoconstriction effects.
and SRS-A is a chemical mediator of asthma.
(chemical mediator), LTB_Fouris gout
It is a chemical mediator of inflammation such as
In addition, PG has a vasodilatory effect in inflammation,
Chemical with pain effect, fever effect, and leukocyte migration effect
It is known to be a lumediator.
Xie 20, 317 (1983), The Lancet 1122 (1982), Deer
Prostaglandin (1978) edited by Torinobu et al. Kodansha.
Light]. In this way, arachidonic acid is physiologically
As a chemical mediator that plays an important role in
Although these mediators are metabolized,
A number of diseases are caused by the collapse of the
It will be done. The present inventors have developed compounds that antagonize leukotrienes.
or phospholipase (phospholipase A₂Oyo
and/or compounds that inhibit phospholipase C)
As a result of extensive research to discover the
The purpose of the aniline derivative represented by the general formula (1) is
The present invention has been completed based on the discovery that the present invention can be achieved. The compound of the present invention strongly inhibits phospholipase.
To suppress the release of arachidonic acid from phospholipids
Araki in mammals including humans, especially humans
Don acid metabolites, e.g. TXA₂, PG, leucotri
For the prevention and/or treatment of diseases caused by
It is valid. Examples of target diseases include the above-mentioned leuco
Various allergic diseases caused by triene
and thrombosis, such as damage to the endothelium or lining of the brain or coronary arteries.
Thrombosis, inflammation caused by, e.g. arthritis, rheumatism
[Circulation science]3, 484 (1983)
and pharmacy34, 167 (1983)]. Furthermore, the compounds of the present invention include the above-mentioned leukotriesters.
Applications as phospholipase antagonists and phospholipase inhibitors
In addition, the following 5α-reductase inhibitory effects
has also been found. 5α-reductase is located in the endoplasmic reticulum and in nucleic acids.
It activates the ingested testosterone in the target tissue.
Converts to sexual form of 5α-dihydrotestosterone
This active form of 5α-dihydrote
Stesterone binds to receptors in cells
This effect is enhanced by causing more cell proliferation.
and the onset of prostatic hyperplasia, alopecia, or acne.
It is said to bring For example, when talking about benign prostatic hyperplasia,
Estrogen, a female hormone, is used as drug therapy.
gestagen, which has anti-androgenic effects and anti-androgen effects.
agents have been used. However, both are original
Sufficient treatment is required as the Lumon effect remains as a side effect.
It was difficult to say that this was being done. The compounds of the present invention naturally have hormone-specific effects.
Strongly inhibits 5α-reductase
and suppresses the increase in 5α-dihydrotestosterone.
In order to suppress cell proliferation, mammals including humans
Benign prostatic hypertrophy, alopecia and
Can effectively prevent and/or treat acne
be. The present invention is based on the general formula [In the formula, R¹is (i) straight chain or minute chain with 1 to 15 carbon atoms
Branched alkyl or alkoxy group, 2 carbon atoms
~15 straight or branched alkenyl groups or
(ii) unsubstituted phenyloxy group;
represents a benzyl group or a hydrogen atom
or (iii) a cycloalkyl group having 4 to 7 carbon atoms.
Representation, R²and R²′ are each independently hydrogen
linear or branched atom or carbon number 1-20
Represents a rukyl group, R³(i) Carboxy group, car
boxymethyl group, or carboxymethoxy group,
or a linear or branched chain alkoxycarbonate having 2 to 6 carbon atoms.
oxycarbonyl group, or a straight chain with 3 to 7 carbon atoms
or branched chain alkoxycarbonylmethyl group or
is an alkoxycarbonylmethoxy group or a hydroxyl group
or (ii) a mercapto group, a sulfo group,
diethoxyphosphonoyl group, or trifluoro
Represents a methyl group, R^Fourand R^Fiveindependence of each
hydrogen atom, halogen atom, carbon number 1-4
Straight or branched alkyl group or alkoxy
group, carboxy group, straight chain or segment having 2 to 6 carbon atoms
Branched chain alkoxycarbonyl group, hydroxyl group, acetyl group
represents a group or a nitro group, and n is 0, 1 or
2, and the symbol 〓 represents a double bond (E, Z or
EZ mixture) or a single bond. However, R³
falls under (i) above, R^Fourand R^Fiveis at the same time
is not a hydrogen atom. ] Aniline derivatives and their non-toxic salts shown in
related. In the general formula (), R¹represents a carbon number of 1 to 15
straight-chain or branched alkyl group, or alkoxy
As the alkyl group in the group, methyl group, ethyl group
group, propyl group, butyl group, pentyl group, hexyl group
group, heptyl group, octyl group, nonyl group, decyl group
Ru group, undecyl group, dodecyl group, tridecyl group
group, tetradecyl group, pentadecyl group and
The isomers of R¹as a preferred group of
is isobutyl group, n-pentyl group (amyl group),
n-heptyl group, n-decyl group and n-octyl group
ruoxy group. In the general formula (), R¹represents a carbon number of 2 to 15
Straight-chain or branched alkenyl groups, or alkenyl groups
As the alkenyl group in the nyloxy group, ethenyl
Ru group, propynyl group, butenyl group, pentenyl group
group, hexenyl group, heptenyl group, octenyl group
group, nonenyl group, decenyl group, undecenyl group,
dodecenyl group, tridecenyl group, tetradecenyl group
groups, pentadecenyl groups, and their isomers
Can be mentioned. However, ethenyloxy group is excluded. Among the compounds represented by the general formula (), R¹but
When representing an alkenyloxy group, an oxygen atom
double between carbon atoms other than those adjacent to
shall have a bond. In the general formula (), R¹has 4 to 7 carbon atoms
Examples of cycloalkyl groups include cyclobutyl group,
Clopentyl group, cyclohexyl group and cyclo
A heptyl group is mentioned, and a preferable group is a heptyl group.
Examples include lohexyl group. In the general formula (), R¹When represents a hydrogen atom
is also preferable. In the general formula (), R²and R²′ represents the number of carbon atoms
1 to 20 straight or branched alkyl groups, or
As the alkyl group in the alkoxy group, methyl
group, ethyl group, propyl group, butyl group, pentyl group
group, hexyl group, heptyl group, octyl group, noni
group, decyl group, undecyl group, dodecyl group,
Lydecyl group, tetradecyl group, pentadecyl group,
hexadecyl group, heptadecyl group, octadecyl group
group, nonadecyl group, eicosyl group, and these
The isomers of R²and R²’ preferred group
as methyl group, ethyl group and pentadecyle group.
Examples include ru groups. Also R²and R²′ is a hydrogen atom
It is also preferable if In the general formula (), R³,R^Fourand R^Fivenumber of carbons in
2 to 6 straight or branched chain alkoxycarbonyl
Straight chain or branched chain alkali having 1 to 4 carbon atoms in the group
Kill groups include methyl, ethyl, and propyl groups.
group, butyl group and their isomeric groups.
R, R³and R^FivePreferred groups include each
methoxycarbonyl group and ethoxycarbonyl group of
Examples include ru groups. In the general formula (), R³Straight chain with 3 to 7 carbon atoms
or a branched alkoxycarbonylmethyl group or
and the number of carbon atoms in the alkoxycarbonylmethoxy group
As 1 to 4 straight chain or branched alkyl groups
are methyl group, ethyl group, propyl group, butyl group
and these isomeric groups, R³preference
As a new group, methoxycarbonylmethoxy
and ethoxycarbonylmethoxy group.
It will be done. In the general formula (), R^Fourand R^Fivenumber of carbons represented by
1 to 4 straight or branched alkyl groups, or
As the alkyl group in the alkoxy group, methyl
group, ethyl group, propyl group, butyl group and
The isomers of R^Fourand R^Fivepreferred
Examples of groups include methyl, ethyl, methoxy, and
and ethoxy groups. In the general formula (), R^Fourand R^Fiverepresents the halogen
Examples of fluorine atoms include fluorine atoms, chlorine atoms, and bromine atoms.
and iodine atoms, R^Fourand R^Fiveof
Preferred atoms include fluorine atoms and chlorine atoms.
Children are mentioned. The compound of the present invention represented by the general formula () has different
The existence of sexual bodies is considered, especially if the symbol 〓 represents a double bond.
When expressed, by E or Z of this double bond,
Also, the symbol 〓 represents a single bond, and R²and/also
is R²′ represents an alkyl group, these alkyl groups
The carbon to which the kill group is attached becomes an asymmetric carbon atom.
Isomers exist. Furthermore, in each substituent in general formula (), a
alkylene, alkenyl and/or
Branched chain of alkenylene moiety and alkenyl
and/or by the double bond of the alkenylene moiety
Isomers may arise in the same manner as above. The present invention is
All these isomers and mixtures thereof are also included.
It includes. Patent publications containing compounds with structures similar to the compounds of the present invention
Several patent applications have been filed, but are these patent applications?
However, the present invention cannot be easily achieved. To give a specific example, JP-A-50-135047
This is the compound described as Example 2 in
formula There is a compound shown by However, the above statement
Some of them contain Leukotrie, which is one of the objects of the present invention.
There is nothing in the description that suggests that it is antagonized by difference
Furthermore, the compound represented by the above formula (A) is described herein.
Listed LTD_Fourantagonism and phospholipid
-ze A₂When subjected to a system for measuring inhibitory effects, each
Ono ID₅₀The values were 30 μM and 100 μM. However, the compound of the present invention has the formula and As represented by LTD_Fourantagonism and phos
As mentioned below, the holipase inhibitory effect is very strong,
The present inventors introduced a specific substituent to the benzene ring on the right.
or replace the carboxy group with a specific substituent.
Therefore, the above activity cannot be easily inferred.
It was also revealed that it would become stronger. In addition, the present inventors have previously disclosed Japanese Patent Application Laid-Open No. 57-106651.
In the specification, compounds similar to the compounds of the present invention are disclosed.
The aim is to inhibit leukotriene biosynthesis.
However, the mechanism of action is 5-lipoxygener.
By selectively inhibiting the
There is. On the other hand, the present invention is antagonizing leukotriene itself.
The gist of the invention is the action of
They have different effects. In addition, these two applications further state that the present invention
similar phospholipase inhibitors, 5α-reductase
No use as an inhibitor has been described, and antithrombotic
drugs, prophylaxis against benign prostatic hyperplasia, alopecia, and acne.
The therapeutic use was discovered for the first time in the present invention.
The present invention is based on these prior art.
This is an invention that cannot be easily inferred from the above. According to the present invention, the aniline represented by the general formula ()
Phosphorus derivatives have (i) general formula [In the formula, all symbols have the same meaning as above.
vinegar. ] The acid chloride represented by the general formula [In the formula, all symbols have the same meaning as above.
vinegar. ] By reacting with the amine shown in
or (ii) general formula [In the formula, R^Four′ is the above R^Fourexpresses the same meaning as
R^Five′ is the above R^FiveIt expresses the same meaning as , but at the same time hydrogen field
It may be a child, and other symbols have the same meanings as above.
represents taste. ] The phenol compound shown by the formula or (C₂H_FiveO)₂POX² () [In the formula, R⁶is a straight chain or branched chain with 1 to 4 carbon atoms
represents the alkyl group of the chain,¹and X²haonoo
represents a halogen atom. ] By reacting with a halide represented by
can be manufactured. The reaction of (i) between acid chloride and amine is well known.
For example, inert organic solvents (e.g. chlorinated solvents)
tyrene, chloroform, tetrahydrofuran)
Medium, tertiary amines (e.g. triethylamine, pi
lysine) at temperatures between -20°C and 40°C.
It will be done. Preferably triethyl chloride in methylene chloride
Carry out at 0°C to room temperature in the presence of amine or pyridine.
be exposed. (ii) Reaction of phenol compound and halide
is also a well-known reaction, for example, when an inert organic solvent is
Medium (methylene chloride, chloroform, methyl ethyl
Ketone, tetrahydrofuran, ethyl ether
etc.), bases (triethylamine, sodium hydride,
um, potassium carbonate, etc.), in some cases.
In the presence of sodium iodide, under anhydrous conditions, from 0°C
It is carried out at reflux temperature. The compound represented by the general formula () is a known compound
For example, R³is a 2-carboxy group and R^Fouris 5
-chloro group, R^FiveThe compound where is a hydrogen atom is 4
-chloroanthranilic acid and R³is 2-
In the sulfo group, R^Fourand R^Fiveare both hydrogen atoms
The compound is orthanilic acid, and both are commercially available.
ing. A compound represented by the general formula () is a compound represented by the general formula [In the formula, all symbols have the same meaning as above.
vinegar. ] Convert the carboxylic acid shown to acid chloride
Manufactured by The reaction that converts carboxylic acid to acid chloride is
It is well known that inert organic solvents (e.g. chloride solvents)
in tyrene, tetrahydrofuran) or without solvent
Thionyl chloride, oxalyl chloride,
-40℃~30℃ using chloride such as ethyl roroformate
It is carried out at a temperature of °C. Preferably, it is oxidized without solvent.
Use salyl chloride or
Performed using ethyl roroformate at 0°C to room temperature.
Ru. The carboxylic acid represented by the general formula () is itself
is known or manufactured by a known method.
An example of the manufacturing method is shown in the diagram below.
Listed below. In addition, each symbol in the diagram has the following meaning.
, and other symbols have the same meanings as above.
vinegar. R^1a- Straight or branched chain alkaline carbon atoms of 1 to 15 carbon atoms
Kill group or straight chain or branched chain having 2 to 15 carbon atoms
chain alkenyl group, unsubstituted phenyl group or
is a benzyl group or a hydrogen atom or a carbon number of 4
~7 cycloalkyl groups. R^1b- Straight or branched chain alkaline carbon atoms of 1 to 15 carbon atoms
Koxy group or straight chain or minute chain with 2 to 15 carbon atoms
Branched alkenyloxy group. R⁷,R⁸- each independently having 1 to 4 carbon atoms
Straight-chain or branched alkyl group. m-1 or 2. 【table】 Each step in the diagram is a known reaction.
Briefly, step (a) is a reaction for introducing a formyl group.
For example, in trifluoroacetic acid, hexame
Performed at 50°C to reflux temperature using tylenetetramine.
be exposed. Step (b) is an oxidation reaction, for example dionzic acid
By the methods of oxidation, Collins oxidation, and Swann oxidation, -
It is carried out at a temperature of 20°C to 40°C. Steps (c) and (d) are Wittig reactions, e.g.
Active organic solvents (ethyl ether, tetrahydrofu
oran, chloroform, benzene, etc.), the equivalent
Wittig reagent (e.g. general formula
[Formula]) In the formula, R⁹is a single bond or or ethenylene group, and other symbols are as above.
expresses the same meaning as ) at −78°C to room temperature.
This is done by reacting. Steps (e), (j) and (l) are saponification reactions, e.g.
Water-miscible organic solvents (tetrahydrofuran
methanol, ethanol, etc.), alkali (hydroxy acid)
potassium chloride, sodium hydroxide, lithium hydroxide
etc.) at a temperature of 0°C to 40°C.
be exposed. Steps (f) and (i) are reduction reactions, such as hydrogen
Under atmosphere, organic solvents (methanol, ethanol,
catalyst (palladium-
presence of carbon, palladium, platinum black, nickel, etc.)
The process is carried out at temperatures ranging from 0°C to 40°C. Step (g) is an esterification reaction, e.g.
alkanol (general formula R⁸Represented by OH. )
Medium, acids (p-toluenesulfonic acid, hydrochloric acid, water chloride
carried out at a temperature of 0℃ to 40℃ in the presence of
It will be done. Of course, in addition to the alkanols mentioned above,
organic solvents (tetrahydrofuran,
(methylene chloride, etc.) may also be used. Steps (h) and (k) convert hydroxyl groups to alkoxy groups or
This is a reaction that converts into an alkenyloxy group, for example
Inert organic solvents (ethyl ether, tetrahydride)
Lofuran, etc.), bases (sodium hydride, carbonic acid,
If necessary, add amides (dimethyl, etc.).
Chylformamide, hexamethylphosphamide
) in the presence of the corresponding alkyl hala in anhydrous conditions.
ide or alkenyl halide (general formula R^TenX³，
R in the formula^Tenis a straight or branched chain atom having 1 to 15 carbon atoms.
Represents alkyl group or alkenyl group, X³Ha ha
Represents a rogen atom. ) at 40°C to reflux temperature
It is done in degrees. Steps (m) and (n) are Perkin reaction or
Döbner reaction, e.g. the presence of piperidine
Below, malonic acid or its derivatives are prepared using pyridine as a solvent.
It is carried out at 100°C to reflux using a Stell. Step (o) is a Friedel-Crafts reaction.
For example, inert organic solvents (carbon disulfide, nitro
Benzene, chloroform, methylene chloride, tetrachloride
carbon, tetrahydrofuran, etc.), a catalyst (aluminium chloride, etc.)
(luminium, aluminum bromide, ferric chloride, etc.)
in the presence of the corresponding acid halide (R²′COX^Four,formula
Medium X^Fourrepresents a halogen atom, R²' is the same as above
express meaning. ) at temperatures between -20°C and 50°C.
It is done. Among the compounds represented by the general formula (), the general formula [In the formula, R^3ais carboxy group, carboxymethylene
R represents a group or a carboxymethoxy group, R^4a
and R^5aare each independently a hydrogen atom, a halo
Gen atom, straight chain or branched chain atom having 1 to 4 carbon atoms
alkyl group or alkoxy group, carboxy group, water
Represents an acid group or a nitro group; other symbols are
It has the same meaning as . ] The compound represented by is the corresponding ester compound.
a general formula [In the formula, R^3b,R^4band R^5bR of each³,R^Four
and R^Fiverepresents a group corresponding to
Both are alkoxycarbonyl group, alkoxy
carbonylmethyl group or alkoxycarbonyl
Represents a methoxy group, other symbols are the same as above
express meaning. ] By subjecting the compound shown to saponification reaction to
can be manufactured. Of course, the compound represented by the general formula (b) is
By subjecting it to a stellation reaction, the general formula (a)
It is also possible to produce a compound represented by Saponification reaction and esterification reaction here
For example, step (e) in the above diagram,
Using the method shown in (j) and (l) and step (g)
I can be there. Furthermore, the compound represented by the general formula ()
In other words, a double bond (alkenyl, alkenylene group)
Compounds that do not have the general formula [In the formula, R^1ais a straight chain or branched chain with 1 to 15 carbon atoms
Alkyl or alkoxy group in the chain, phenyl
group, benzyl group, hydrogen atom or having 4 to 7 carbon atoms
Represents a cycloalkyl group; other symbols are as above.
expresses the same meaning as ] The compound represented by has the general formula [In the formula, R^1bis when the symbol 〓 represents a double bond
is R¹It has the same meaning as , but the symbol 〓 is a single bond.
When representing a linear or branched chain with 2 to 15 carbon atoms,
Branched alkenyl or alkenyloxy groups
represent. ] It is produced by subjecting the compound represented by to a reduction reaction.
can be built. In the reduction reaction mentioned here, for example, the above-mentioned scheme
It is possible to use the method used in steps (f) and (i) in
can. The reaction product can be purified by conventional purification means, e.g. under normal pressure.
or distillation under reduced pressure, silica gel or
High performance liquid chromatography using magnesium icate
chromatography, thin layer chromatography, or color
By methods such as muchromatography or recrystallization
Can be purified. Purification is performed for each reaction.
It can be carried out after several reactions have finished.
It's okay. As mentioned above, the compound of the present invention contains leukotrienes.
antagonism, phospholipase inhibition and 5α-
Although it has a reductase inhibitory effect, for example, in the laboratory
The experiment showed the following effects. The compound of the present invention is LTD_FourAntagonism as shown in the table below
The effect was shown. 【table】 The compound of the present invention is a phospholipase A₂against below
It showed the inhibitory effect as shown in the table. 【table】 The compound of the present invention has an inhibitory effect on 5α-reductase.
It showed the inhibitory effect as shown in the table. 【table】 Shows the value at
LTD of the compound of the present invention_FourThe antagonistic effect on
It was measured using the experimental method. Extracted from a male guinea pig weighing 300-400g
Ileum (3 cm), 37°C, Tyrode's solution, oxygen (95%)
- Magnus aeration of mixed gas of carbon dioxide (5%)
After hanging in the tube and stabilizing for about 30 minutes, LTD_Fourof
Ten^-9g/ml concentration, and for the contraction at this time,
Add the compound of the present invention at different concentrations and measure the shrinkage height
From now on, IC₅₀The value was calculated. Phospholipase A of the compound of the present invention₂hindrance to
The harmful effects can be detected by using a modification of the Shakir method as a substrate.
L-β-[1-¹⁴C]-Arachidonyl-α′-Stear
loyl-phosphatidylcholine for enzymes.
Phospholipase A obtained from Motuto lungs₂Using
Measured [Anal Biochem.114, 67 (1981).
Light. ]. The inhibition of 5α-reductase by the compounds of the present invention
Harmful effects were determined by rats based on the method of J. Shimazaki et al.
5α-rida obtained from the nuclear fraction of the prostate of a human.
This was done using Cactase. 5α-reductase
The activity measurement is 0.09M Hepes (PH7.4), 0.22M Hepes (PH7.4),
sugar, 5×10^-3M NADPH, 5 μM [4-¹⁴C〕Tess
Tosterone, 5α-reductase and the invention
The reaction was carried out at 37°C for 60 min using a mixture of compounds.
Ivy. Stop the reaction with chloroform-methanol
(1/2), centrifuge, and sift the supernatant.
Spot chloroform on a thin layer plate of lycagel.
using methanol-acetic acid (99.2:0.6:0.2)
The release of dihydrotestosterone produced by
The enzyme activity was measured using a TLC scanner and
The activity inhibition rate was calculated [Endocrinol, Japan.
See 18, 179 (1971). ]. Preferably, the salts according to the invention are non-toxic. Non-toxic salts as used herein are relatively harmless to animal tissues, and when used in amounts necessary for treatment, the effective pharmacological properties of the compound represented by the general formula () are expressed by the cation. refers to salts consisting of cations that are not impaired by the side effects caused by. Moreover, it is preferable that the salt is water-soluble. Suitable salts include, for example, alkali metal salts such as sodium or potassium, alkaline earth metal salts such as calcium or magnesium, ammonium salts and pharmaceutically acceptable (non-toxic) amine salts. Suitable amines that form such salts with carboxylic acids are well known and include, for example, amines that could theoretically be obtained by replacing one or more hydrogen atoms of ammonia with other groups. The groups may be the same or different when one or more hydrogen atoms are substituted, and are selected from, for example, alkyl groups having 1 to 6 carbon atoms and hydroxyalkyl groups having 1 to 3 carbon atoms. Suitable non-toxic amine salts include tetraalkylammonium salts such as tetramethylammonium, and methylamine salts, dimethylamine salts, cyclopentylamine salts, benzylamine salts, phenethylamine salts, piperidine salts, monoethanolamine salts, diethanolamine salts. Examples include organic amine salts such as , lysine salt, and arginine salt. The salt of the aniline derivative represented by the general formula () can be prepared by adding the acid represented by the general formula () to a suitable base such as an alkali metal or alkaline earth metal hydroxide or carbonic acid in a suitable solvent. Obtained by reaction with salts or organic amines. In mammals including humans, especially humans, by suppressing leukotrienes, it is possible to prevent allergic tracheal and bronchial diseases such as asthma, allergic lung diseases, allergic shots, and various allergic diseases. / or be effective in the treatment and, by inhibiting phospholipases (phospholipase A ₂ and/or phospholipase C), of diseases caused by arachidonic acid metabolites, including the above-mentioned leukotrienes, such as thrombosis, such as the endothelium of the brain and coronary arteries. It is effective in the prevention and/or treatment of thrombosis caused by damage to the intima and various types of inflammation such as arthritis and rheumatism. moreover
Inhibiting 5α-reductase is effective in preventing and/or treating benign prostatic hyperplasia, alopecia, and acne. For use of the aniline derivatives represented by the general formula () or salts thereof for the above purposes (as leukotriene antagonists, phospholipase inhibitors or 5α-reductase inhibitors), each of the following:
It is usually administered systemically or locally, orally or parenterally. The dosage varies depending on age, body weight, symptoms, therapeutic effect, administration method, processing time, etc., but it is usually 1 mg to 1 mg of each at a time per adult.
g, preferably in the range of 20 mg to 200 mg, administered orally once to several times a day, or once per day per adult, each dose in the range of 100 μg to 100 mg, preferably 1 mg to 10 mg, at a time. It is administered parenterally in one to several doses. 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, polysorbate 80, gum arabic, and sodium alginate. 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:
Includes topical solutions, liniments such as ointments, suppositories for intrarectal administration and pettu saris for intracavitary administration, containing one or more active substances and formulated in a manner known per se. It will be done. Among the compounds of the present invention represented by the general formula (), preferred compounds include N-(p-amylcinnamoyl)-3-chloroanthranilic acid, N-(p-amylcinnamoyl)-4-chloroanthranilic acid, N -(p-amylcinnamoyl)-5-chloroanthranilic acid, N-(p-amylcinnamoyl)-4-fluoroanthranilic acid, N-(p-amylcinnamoyl)-3-hydroxyanthranilic acid, N-( p-amylcinnamoyl)-4-hydroxyanthranilic acid, N-(p-amylcinnamoyl)-6-hydroxyanthranilic acid, N-(p-amylcinnamoyl)-4-nitroanthranilic acid, N-(p- amylcinnamoyl)-5-methylanthranilic acid, N-(p-amylcinnamoyl)-4-methoxyanthranilic acid, 6-acetyl-N-(p-amylcinnamoyl)
Anthranilic acid, 2-[N-(p-amylcinnamoyl)amino]
Terephthalic acid, 2-[N-(p-amylcinnamoyl)amino]
-3-chlorophenylacetic acid, 2-[N-(p-amylcinnamoyl)amino]
-4-chlorophenylacetic acid, 2-[N-(p-amylcinnamoyl)amino]
-5-chlorophenylacetic acid, 2-[N-(p-amylcinnamoyl)amino]
-4-fluorophenyl acetic acid, 2-[N-(p-amylcinnamoyl)amino]
-3-hydroxyphenylacetic acid, 2-[N-(p-amylcinnamoyl)amino]
-4-hydroxyphenylacetic acid, 2-[N-(p-amylcinnamoyl)amino]
-6-hydroxyphenylacetic acid, 2-[N-(p-amylcinnamoyl)amino]
-4-nitrophenyl acetic acid, 2-[N-(p-amylcinnamoyl)amino]
-5-methylphenylacetic acid, 2-[N-(p-amylcinnamoyl)amino]
-4-methoxyphenylacetic acid, 6-acetyl-2-[N-(p-amylcinnamoyl)amino]phenylacetic acid, 2-[N-(p-amylcinnamoyl)amino]
-4-carboxyphenylacetic acid, 2-[N-(p-amylcinnamoyl)amino]
-3-chlorophenoxyacetic acid, 2-[N-(p-amylcinnamoyl)amino]
-4-chlorophenoxyacetic acid, 2-[N-(p-amylcinnamoyl)amino]
-5-chlorophenoxyacetic acid, 2-[N-(p-amylcinnamoyl)amino]
-4-fluorophenoxyacetic acid, 2-[N-(p-amylcinnamoyl)amino]
-3-hydroxyphenoxyacetic acid, 2-[N-(p-amylcinnamoyl)amino]
-4-hydroxyphenoxyacetic acid, 2-[N-(p-amylcinnamoyl)amino]
-6-hydroxyphenoxyacetic acid, 2-[N-(p-amylcinnamoyl)amino]
-4-nitrophenoxyacetic acid, 2-[N-(p-amylcinnamoyl)amino]
-5-methylphenoxyacetic acid, 2-[N-(p-amylcinnamoyl)amino]
-4-Methoxyphenoxyacetic acid, 6-acetyl-2-[N-(p-amylcinnamoyl)amino]phenoxyacetic acid, 2-[N-(p-amylcinnamoyl)amino]
-4-carboxyphenoxyacetic acid, 3-[N-(p-amylcinnamoyl)amino]
-4-chlorobenzoic acid, 3-[N-(p-amylcinnamoyl)amino]
-5-chlorobenzoic acid, 3-[N-(p-amylcinnamoyl)amino]
-6-chlorobenzoic acid, 3-[N-(p-amylcinnamoyl)amino]
-5-fluorobenzoic acid, 3-[N-(p-amylcinnamoyl)amino]
Salicylic acid, 3-[N-(p-amylcinnamoyl)amino]
-4-fluorobenzoic acid, 3-[N-(p-amylcinnamoyl)amino]
-6-fluorobenzoic acid, 3-[N-(p-amylcinnamoyl)amino]
-5-nitrobenzoic acid, 3-[N-(p-amylcinnamoyl)amino]
-6-methylbenzoic acid, 3-[N-(p-amylcinnamoyl)amino]
-5-methoxybenzoic acid, N-(p-isobutylcinnamoyl)-3-chloroanthranilic acid, N-(p-isobutylcinnamoyl)-4-chloroanthranilic acid, N-(p-isobutylcinnamoyl)-5 -chloroanthranilic acid, N-(p-isobutylcinnamoyl)-4-fluoroanthranilic acid, N-(p-isobutylcinnamoyl)-3-hydroxyanthranilic acid, N-(p-isobutylcinnamoyl)-4-hydroxy Anthranilic acid, N-(p-isobutylcinnamoyl)-6-hydroxyanthranilic acid, N-(p-isobutylcinnamoyl)-4-nitroanthranilic acid, N-(p-isobutylcinnamoyl)-5-methylanthranilic acid , N-(p-isobutylcinnamoyl)-4-methoxyanthranilic acid, 6-acetyl-N-(p-isobutylcinnamoyl)anthranilic acid, 2-[N-(p-isobutylcinnamoyl)amino]terephthalic acid, N-(p-isopentylcinnamoyl)-3-chloroanthranilic acid, N-(p-isopentylcinnamoyl)-4-chloroanthranilic acid, N-(p-isopentylcinnamoyl)-5-chloroanthranilic acid , N-(p-isopentylcinnamoyl)-4-fluoroanthranilic acid, N-(p-isopentylcinnamoyl)-3-hydroxyanthranilic acid, N-(p-isopentylcinnamoyl)-4-hydroxy Anthranilic acid, N-(p-isopentylcinnamoyl)-6-hydroxyanthranilic acid, N-(p-isopentylcinnamoyl)-4-nitroanthranilic acid, N-(p-isopentylcinnamoyl)-5- Methylanthranilic acid, N-(p-isopentylcinnamoyl)-4-methoxyanthranilic acid, 6-acetyl-N-(p-isopentylcinnamoyl)anthranilic acid, 2-[N-(p-isopentylcinnamoyl) ) Amino]terephthalic acid, N-(p-heptylcinnamoyl)-3-chloroanthranilic acid, N-(p-heptylcinnamoyl)-4-chloroanthranilic acid, N-(p-heptylcinnamoyl)-5- Chloranthranilic acid, N-(p-heptylcinnamoyl)-4-fluoroanthranilic acid, N-(p-heptylcinnamoyl)-3-hydroxyanthranilic acid, N-(p-heptylcinnamoyl)-4-hydroxyanthranilic acid acid, N-(p-heptylcinnamoyl)-6-hydroxyanthranilic acid, N-(p-heptylcinnamoyl)-4-nitroanthranilic acid, N-(p-heptylcinnamoyl)-5-methylanthranilic acid, N-(p-heptylcinnamoyl)-4-methoxyanthranilic acid, 6-acetyl-N-(p-heptylcinnamoyl)anthranilic acid, 2-[N-(p-heptylcinnamoyl)amino]terephthalic acid, N -(p-decylcinnamoyl)-3-chloroanthranilic acid, N-(p-decylcinnamoyl)-4-chloroanthranilic acid, N-(p-decylcinnamoyl)-5-chloroanthranilic acid, N-( p-decylcinnamoyl)-4-fluoroanthranilic acid, N-(p-decylcinnamoyl)-3-hydroxyanthranilic acid, N-(p-decylcinnamoyl)-4-hydroxyanthranilic acid, N-(p- Decylcinnamoyl)-6-hydroxyanthranilic acid, N-(p-decylcinnamoyl)-4-nitroanthranilic acid, N-(p-decylcinnamoyl)-5-methylanthranilic acid, N-(p-decylcinnamoyl)-5-methylanthranilic acid, moyl)-4-methoxyanthranilic acid, 6-acetyl-N-(p-decylcinnamoyl)
Anthranilic acid, 2-[N-(p-decylcinnamoyl)amino]
Terephthalic acid, N-(p-octyloxycinnamoyl)-3-
Chloranthranilic acid, N-(p-octyloxycinnamoyl)-4-
Chloranthranilic acid, N-(p-octyloxycinnamoyl)-5-
Chloranthranilic acid, N-(p-octyloxycinnamoyl)-4-
Fluoroanthranilic acid, N-(p-octyloxycinnamoyl)-3-
Hydroxyanthranilic acid, N-(p-octyloxycinnamoyl)-4-
Hydroxyanthranilic acid, N-(p-octyloxycinnamoyl)-6-
Hydroxyanthranilic acid, N-(p-octyloxycinnamoyl)-4-
Nitroanthranilic acid, N-(p-octyloxycinnamoyl)-5-
Methylanthranilic acid, N-(p-octyloxycinnamoyl)-4-
Methoxyanthranilic acid, 6-acetyl-N-(p-octyloxycinnamoyl)anthranilic acid, 2-[N-(p-octyloxycinnamoyl)
Amino]terephthalic acid, N-(p-cyclohexylcinnamoyl)-3-
Chloranthranilic acid, N-(p-cyclohexylcinnamoyl)-4-
Chloranthranilic acid, N-(p-cyclohexylcinnamoyl)-5-
Chloranthranilic acid, N-(p-cyclohexylcinnamoyl)-4-
Fluoroanthranilic acid, N-(p-cyclohexylcinnamoyl)-3-
Hydroxyanthranilic acid, N-(p-cyclohexylcinnamoyl)-4-
Hydroxyanthranilic acid, N-(p-cyclohexylcinnamoyl)-6-
Hydroxyanthranilic acid, N-(p-cyclohexylcinnamoyl)-4-
Nitroanthranilic acid, N-(p-cyclohexylcinnamoyl)-5-
Methylanthranilic acid, N-(p-cyclohexylcinnamoyl)-4-
Methoxyanthranilic acid, 6-acetyl-N-(p-cyclohexylcinnamoyl)anthranilic acid, 2-[N-(p-cyclohexylcinnamoyl)
Amino]terephthalic acid, N-(p-amylcinnamoyl)orthanilic acid, N-(p-isobutylcinnamoyl)orthanilic acid, N-(p-isopentylcinnamoyl)orthanilic acid, N-(p-heptylcinnamoyl) ) ortanilic acid, N-(p-decylcinnamoyl)ortanilic acid, N-(p-octyloxycinnamoyl)ortanilic acid, N-(p-cyclohexylcinnamoyl)ortanilic acid, N-(p-amylcinnamoyl) -4-chloroorthanilic acid, N-(p-isobutylcinnamoyl)-4-chloroorthanilic acid, N-(p-isopentylcinnamoyl)-4-chloroorthanilic acid, N-(p-heptylcinnamoyl) moyl)-4-chloroorthanilic acid, N-(p-decylcinnamoyl)-4-chloroorthanilic acid, N-(p-octyloxycinnamoyl)-4-
Chlororthanilic acid, N-(p-cyclohexylcinnamoyl)-4-
Chlororthanilic acid, N-(p-amylcinnamoyl)-3,5-dichloroanthranilic acid, N-(p-isobutylcinnamoyl)-3,5-
Dichloroanthranilic acid, N-(p-isopentylcinnamoyl)-3,5
-dichloroanthranilic acid, N-(p-heptylcinnamoyl)-3,5-dichloroanthranilic acid, N-(p-decylcinnamoyl)-3,5-dichloroanthranilic acid, N-(p-octyloxycinnamoyl) )-3,
5-dichloroanthranilic acid, N-(p-cyclohexylcinnamoyl)-3,
5-dichloroanthranilic acid, N-(3-pentadecylcinnamoyl)-4-chloroanthranilic acid, 2-[N-(3-pentadecylcinnamoyl)amino]-4-chlorophenylacetic acid, 2-[N-( 3-pentadecylcinnamoyl)-
4-chlorophenoxyacetic acid, N-(p-amyl-3-methylcinnamoyl)-
4-chloroanthranilic acid, 2-[N-(p-amyl-3-methylcinnamoyl)-4-chlorophenylacetic acid and 2-[N-(p-amyl-3-methylcinnamoyl)-4-chlorophenoxy Acetic acid and the corresponding methyl esters, ethyl esters and non-toxic salts of the above acids, and 2-[N-(p-amylcinnamoyl)amino]
-3-chlorophenol, 2-[N-(p-amylcinnamoyl)amino]
-4-chlorophenol, 2-[N-(p-amylcinnamoyl)amino]
-5-chlorophenol, 2-[N-(p-amylcinnamoyl)amino]
-4-fluorophenol, 2-[N-(p-amylcinnamoyl)amino]
-3-hydroxyphenol, 2-[N-(p-amylcinnamoyl)amino]
-4-hydroxyphenol, 2-[N-(p-amylcinnamoyl)amino]
-6-hydroxyphenol, 2-[N-(p-amylcinnamoyl)amino]
-4-nitrophenol, 2-[N-(p-amylcinnamoyl)amino]
-5-methylphenol, 2-[N-(p-amylcinnamoyl)amino]
-4-methoxyphenol, 6-acetyl-2-[N-(p-amylcinnamoyl)amino]phenol, 2-[N-(3-pentadecylcinnamoyl)amino]-4-chlorophenol, 2-[ N-(p-amyl-3-methylcinnamoyl)amino]-4-chlorophenol, 2-[N-(p-amylcinnamoyl)amino]
Thiophenol, 2-[N-(p-isobutylcinnamoyl)amino]thiophenol, 2-[N-(p-isopentylcinnamoyl)amino]thiophenol, 2-[N-(p-heptylcinnamoyl) Amino]thiophenol, 2-[N-(p-decylcinnamoyl)amino]
Thiophenol, 2-[N-(p-octyloxycinnamoyl)
Amino]thiophenol, 2-[N-(p-cyclohexylcinnamoyl)
Amino]thiophenol, 2-[N-(p-amylcinnamoyl)amino]
-4-chlorothiophenol, 2-[N-(p-isobutylcinnamoyl)amino]-4-chlorothiophenol, 2-[N-(p-isopentylcinnamoyl)amino]-4-chlorothiophenol, 2-[N-(p-heptylcinnamoyl)amino]-4-chlorothiophenol, 2-[N-(p-decylcinnamoyl)amino]
-4-chlorothiophenol, 2-[N-(p-octyloxycinnamoyl)
Amino]-4-chlorothiophenol, 2-[N-(p-cyclohexylcinnamoyl)
Amino]-4-chlorothiophenol, 2-[N-(p-amylcinnamoyl)amino]
Benzotrifluoride, 2-[N-(p-isobutylcinnamoyl)amino]benzotrifluoride, 2-[N-(p-isopentylcinnamoyl)amino]benzotrifluoride, 2-[N-(p-heptyl cinnamoyl)amino]benzotrifluoride, 2-[N-(p-decylcinnamoyl)amino]
Benzotrifluoride, 2-[N-(p-octyloxycinnamoyl)
Amino]benzotrifluoride, 2-[N-(p-cyclohexylcinnamoyl)
Amino]benzotrifluoride, 2-[N-(p-amylcinnamoyl)amino]
-4-chlorobenzotrifluoride, 2-[N-(p-isobutylcinnamoyl)amino]-4-chlorobenzotrifluoride, 2-[N-(p-isopentylcinnamoyl)amino]-4-chlorobenzo Trifluoride, 2-[N-(p-heptylcinnamoyl)amino]-4-chlorobenzotrifluoride, 2-[N-(p-decylcinnamoyl)amino]
-4-chlorobenzotrifluoride, 2-[N-(p-octyloxycinnamoyl)
Amino]-4-chlorobenzotrifluoride, 2-[N-(p-cyclohexylcinnamoyl)
Amino]-4-chlorobenzotrifluoride, 2-(p-amylcinnamoyl)aminophenyldiethyl phosphate, 2-(p-isobutylcinnamoyl)aminophenyldiethyl phosphate, 2-(p-isopentylcinnamoyl) 2-(p-heptylcinnamoyl)aminophenyldiethyl phosphate, 2-(p-decylcinnamoyl)aminophenyldiethyl phosphate, 2-(p-octyloxycinnamoyl) ) Aminophenyl diethyl phosphate, 2-(p-cyclohexylcinnamoyl)aminophenyl diethyl phosphate, 2-[N-(p-amylcinnamoyl)amino]
Phenyl-4-chloroaminophenyl diethyl phosphate, 2-[N-(p-isobutylcinnamoyl)amino]phenyl-4-chloroaminophenyl diethyl phosphate, 2-[N-(p-isopentylcinnamoyl) ) Amino]phenyl-4-chloroaminophenyl diethyl phosphate, 2-[N-(p-heptylcinnamoyl)amino]phenyl-4-chloroaminophenyl diethyl phosphate, 2-[N-(p-decyl cinnamoyl) amino]
Phenyl-4-chloroaminophenyl diethyl phosphate, 2-[N-(p-octyloxycinnamoyl)
amino]phenyl-4-chloroaminophenyl diethyl phosphate, and 2-[N-(p-cyclohexylcinnamoyl)
Amino] phenyl-4-chloroaminophenyl diethyl phosphate. Hereinafter, the present invention will be explained in detail with reference to Reference Examples and Examples, but the present invention is not limited to these Examples. In addition, "bp", "TLC", "IR", "NMR" and "MS" in reference examples and examples.
The symbols represent "boiling point,""thin layer chromatography,""infrared absorption spectrum,""nuclear magnetic resonance spectrum," and "mass spectrometry," respectively, and indicate the solvents listed in the section for separation by chromatography. The ratio indicates the volume ratio, the solvent inside the "TLC" box indicates the developing solvent, "IR" is measured by the KBr tablet method unless otherwise specified, and "NMR" indicates when there is no special statement. is measured using deuterated chloroform (CDCl ₃ ) solution. Reference example 1 2-hydroxy-3-nitroacetophenone Dissolve 13.6 g of o-hydroxyacetophenone in 300 ml of methylene chloride and 30 ml of glacial acetic acid, and bring the internal temperature to
While maintaining the temperature at 35°C, 4.1 ml of concentrated nitric acid was added dropwise over 15 minutes, followed by heating under reflux for 1 hour. After the reaction, the mixture was allowed to cool to room temperature and poured into ice water to separate the layers. The organic layer 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 (methylene chloride:n-hexane=2:1) to obtain 6.29 g of the title compound having the following physical properties. TLC: Rf = 0.13 (chloroform: n-hexane =
2:1). MS: m/Z = 181 (M ⁺ ), 166, 164, 120. NMR: δ=13.16 (s, 1H), 8.18 (dd, 1H),
8.10 (dd, 1H), 7.06 (t, 1H), 2.73 (s,
3H). Reference example 2 3-amino-2-hydroxyacetophenone
monohydrochloride 6.29 g of the compound produced in Reference Example 1 was dissolved in a mixture of ethanol (300 ml) and chloroform (14 ml), 600 mg of 5% palladium-carbon was added, and the mixture was vigorously stirred at room temperature for 1 hour and 30 minutes under a hydrogen gas atmosphere. After the reaction, it was filtered and the filtrate was concentrated under reduced pressure. Dissolve the residue in 20 ml of methanol, slowly add 5 ml of concentrated hydrochloric acid, collect the resulting crystals by filtration, wash with ethyl ether, dry in a desiccator,
6.06 g of the title compound having the following physical properties was obtained. MS: m/Z = 151 (M ⁺ ), 136, 133, 108, 104. NMR (CD ₃ OD + DMSO - d ₆ ): δ = 8.05 (dd,
1H), 7.52 (dd, 1H), 7.12 (t, 1H), 2.71
(s, 3H). Reference example 3 p-amylbenzaldehyde 21 g of hexamethylenetetramine was dissolved in 200 ml of trifluoroacetic acid, 150 ml of amylbenzene was added, and the mixture was stirred at 90° C. overnight. The reaction solution was concentrated under reduced pressure, 50 ml of ice water was added and stirred for 30 minutes, and an aqueous sodium hydrogen carbonate solution and ethyl acetate were added to separate the layers. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by distillation under reduced pressure to obtain 13 g of the title compound having the following physical properties. bp: 147℃/12mmHg. MS: m/Z = 176 (M ⁺ ), 147, 133, 120, 119. NMR: δ=9.93 (s, 1H), 7.76 (d, 2H), 7.29
(d, 2H), 7.63 (t, 2H), 1.40−1.70 (m,
2H), 0.85 (m, 3H). Reference example 3(a) p-isobutylbenzaldehyde The same procedure as in Reference Example 3 was carried out using 121 g of isobutylbenzene to obtain 103 g of the title compound having the following physical properties. Note that vacuum distillation was used for purification. bp: 125℃/20mmHg. MS: m/Z = 162 (M ⁺ ), 120, 115, 91. NMR: δ=9.99 (s, 1H), 7.80 (d, 2H), 7.30
(d, 2H), 2.54 (d, 2H), 1.90 (m, 1H),
0.89 (d, 6H). Reference example 3(b) p-isopentylbenzaldehyde Using 132 g of isopentylbenzene, 79 g of the title compound having the following physical properties were obtained by the same operation as in Reference Example 3. Note that vacuum distillation was used for purification. MS: m/Z=176 (M ⁺ ), 133, 131, 120, 92,
91. NMR: δ=9.98 (s, 1H), 7.8 (d, 2H), 7.34
(d, 2H), 2.70 (m, 2H), 1.54 (m, 2H),
0.96 (d, 6H). Reference example 3(c) p-cyclohexylbenzaldehyde The same procedure as in Reference Example 3 was carried out using 120 g of cyclohexylbenzene to obtain 61 g of the title compound having the following physical properties. Note that vacuum distillation was used for purification. NMR: δ = 9.93 (s, 1H), 7.8 (d, 2H),
7.33 (d, 2H), 2.40~2.60 (m, 1H), 1.60~
1.90 (m, 5H), 1.10-1.50 (m, 5H). Reference example 3(d) p-heptylbenzaldehyde Using 130 g of heptylbenzene, 65 g of the title compound having the following physical properties was obtained by the same operation as in Reference Example 3. Note that vacuum distillation was used for purification. bp: 115℃/5mmHg. MS: m/Z=204 (M ⁺ ), 175, 161, 120, 92,
91. NMR: δ=9.96 (s, 1H), 7.78 (d, 2H),
7.31 (d, 2H), 2.65 (t, 2H), 1.40-1.70
(m, 2H), 1.27 (m, 8H), 0.84 (m, 3H). Reference example 3(e) p-decylbenzaldehyde Using 134 g of decylbenzene, the title compound having the following physical properties was obtained by the same operation as in Reference Example 3.
Obtained 65g. TLC: Rf=0.53 (cyclohexane:ethyl acetate=1:9). NMR: δ=9.76 (s, 1H), 7.40 (dd, 4H),
2.70 (t, 2H), 0.88 (m, 3H). Reference example 4 p-amylcinnamic acid Dissolve 5.88 g of the compound produced in Reference Example 3 in 150 ml of chloroform, add 16.7 g of methoxycarbonyl methylidene triphenyl phosphorane, and add 16.7 g of the compound produced in Reference Example 3.
Refluxed for 30 minutes. After cooling to room temperature, it was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: cyclohexane = 2:3). Dissolve the obtained methyl ester in a mixture of tetrahydrofuran (70 ml) and methanol (30 ml), add 50 ml of 2N aqueous potassium hydroxide solution, stir overnight at room temperature, add 500 ml of water,
Extracted with ethyl acetate. The extract was washed successively with water and saturated saline, dried over anhydrous magnesium sulfate,
After concentration under reduced pressure, the title compound has the following physical properties:
6.44g was obtained. MS: m/Z=218 (M ⁺ ), 175, 161, 144,
115. NMR: δ = 8.50 (s, 1H), 7.78 (d, 1H),
7.47 (d, 2H), 7.21 (d, 2H), 6.40 (d,
1H), 2.63 (t, 2H), 1.40−1.80 (m, 2H),
1.10−1.45 (m, 4H), 0.88 (t, 3H). Reference example 5 p-isobutyl cinnamic acid 8.9g of the compound produced in Reference Example 3(a) was added to pyridine.
Dissolve in 45 ml, piperidine 1 ml and malonic acid
5.7g was added, heated to 120°C, and reacted for 4 hours.
The reaction solution was allowed to cool to room temperature, water was added, the mixture was acidified with hydrochloric acid, and filtered. This was recrystallized from a mixture of n-hexane and benzene to obtain 10.7 g of the title compound having the following physical properties. MS: m/Z = 204 (M ⁺ ), 161, 144, 115. NMR: δ = 7.80 (d, 1H), 7.48 (d, 2H),
7.18 (d, 2H), 6.42 (d, 1H), 2.50 (d,
2H), 1.84 (m, 1H), 0.90 (d, 6H). Reference example 5(a) p-isopentyl cinnamic acid Using 2.7 g of the compound produced in Reference Example 3(a), the same procedure as in Reference Example 5 was carried out to obtain 2.9 g of the title compound having the following physical properties. Note that a recrystallization method (n-hexane-benzene) was used for purification. MS: m/Z = 218 (M ⁺ ), 151, 144, 115. NMR: δ = 7.80 (d, 1H), 7.48 (d, 2H),
7.22 (d, 2H), 6.40 (d, 1H), 2.63 (t,
2H), 1.40-1.80 (m, 3H), 0.92 (t, 6H). Reference example 5(b) p-cyclohexylcinnamic acid Using 8.6 g of the compound produced in Reference Example 3(c), the same procedure as in Reference Example 5 was carried out to obtain 3.0 g of the title compound having the following physical properties. Note that a recrystallization method (chloroform) was used for purification. NMR: δ=7.81 (d, 1H), 7.48 (d, 2H),
7.26 (d, 2H), 7.22 (d, 2H), 6.43 (d,
1H), 2.40-2.80 (m, 1H), 1.60-2.00 (m,
5H), 1.20-1.60 (m, 5H). Reference example 5(c) p-heptylcinnamic acid Using 8.7 g of the compound produced in Reference Example 3(d), the same procedure as in Reference Example 5 was carried out to obtain 9.0 g of the title compound having the following physical properties. MS: m/Z = 246 (M ⁺ ), 161, 144, 115. NMR: δ = 7.80 (d, 1H), 6.41 (d, 1H),
2.63 (t, 2H), 1.40-1.70 (m, 2H), 1.30
(m, 8H), 0.86 (m, 3H). Reference example 5(d) p-decylcinnamic acid Using 1.3 g of the compound produced in Reference Example 3(e), the same procedure as in Reference Example 5 was performed to obtain 1.2 g of the title compound having the following physical properties. TLC: Rf = 0.55 (Chloroform: Methanol =
1:9). MS: m/Z = 288 (M ⁺ ), 161. IR: ν=3400~2300, 1680, 1620, 1605,
1460, 1425, 1310, 1290, 1225, 1180, 980
cm ^-1 . NMR: δ = 7.74 (d, 1H), 7.33 (q, 4H),
6.39 (d, 1H), 2.63 (t, 2H), 0.87 (m,
3H). Reference example 6 p-amylacetophenone After suspending 8.6 g of aluminum chloride in 60 ml of carbon tetrachloride and dropping 4.6 ml of acetyl chloride,
After cooling on ice, a solution of 8 g of amylbenzene dissolved in 30 ml of carbon tetrachloride was added dropwise. After stirring the reaction solution for 2 hours, it was poured into ice water and extracted with ethyl acetate.
The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The concentrate was purified by distillation to obtain 6.6 g of the title compound having the following physical properties. MS: m/Z = 190 (M ⁺ ), 185, 133. NMR: δ = 7.88 (d, 2H), 7.25 (d, 2H),
2.64 (t, 2H), 2.55 (s, 3H), 1.40~1.80
(m, 2H), 1.20-1.40 (m, 4H), 0.87 (t,
3H). Reference example 7 p-amyl-3-methylcinnamic acid 6.6g of the compound produced in Reference Example 6 was added to 50% of toluene.
ml, added 14 g of methoxycarbonyl triphenyl phosphorane, and heated under reflux for 48 hours.
After the reaction, the reaction mixture was allowed to cool, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 1.6 g of methyl ester of the title compound. This was dissolved in a mixture of methanol and tetrahydrofuran (1:1), and 12 ml of 5N potassium hydroxide was added for hydrolysis, acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound 280 having the following physical properties.
I got mg. MS: m/Z = 232 (M ⁺ ), 214, 175, 158. NMR: δ = 7.32 (q, 2H), 6.18 (d, 1H),
2.64 (t, 2H), 2.62 (d, 3H), 1.64 (m,
2H), 1.30-1.40 (m, 4H), 0.90 (t, 3H). Reference example 8 3-heptyldecyl cinnamic acid Dissolve 6g of phenyl heptyldecyl ketone in 30ml of chloroform, add 12.5g of methoxycarbonylmethylidene triphenylphosphorane,
Heating was carried out under reflux for 72 hours. After the reaction, it was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 40:1).
The obtained methyl ester was dissolved in ethanol-tetrahydrofuran, hydrolyzed using an aqueous potassium hydroxide solution, and purified by recrystallization to obtain 430 mg of the title compound having the following physical properties. MS: m/Z = 358 (M ⁺ ), 298, 175, 162. NMR: δ=7.40 (m, 5H), 6.06 (s, 1H),
3.12 (t, 2H), 1.20-1.40 (m, 26H), 0.87
(t, 3H). Reference example 9 p-hydroxycinnamic acid methyl ester p-hydroxycinnamic acid (manufactured in Reference Example 4)
25 g was dissolved in 200 ml of methanol, hydrogen chloride gas was bubbled in for 30 minutes under ice cooling, and the mixture was concentrated under reduced pressure.
By purifying the residue by silica gel column chromatography (cyclohexane:ethyl acetate = 10:1), the title compound 26 having the following physical properties was obtained.
I got g. MS: m/Z = 178 (M ⁺ ), 147, 119, 91. NMR: δ=6.88−7.48 (dd, 4H), 6.30−7.85
(q, 2H), 3.80 (s, 3H). Reference example 10 p-octyloxycinnamic acid 1.04 g of sodium hydride was suspended in 15 ml of anhydrous tetrahydrofuran, cooled on ice, and a solution of 4.5 g of the compound prepared in Subtraction Example 9 dissolved in 10 ml of anhydrous tetrahydrofuran was added dropwise, followed by 10 ml of anhydrous dimethylformamide. A solution of 5.8 g of octyl bromide dissolved in 10 ml of anhydrous tetrahydrofuran was added to this reaction solution, and the mixture was refluxed for 4 hours. After the reaction, 50 ml of ether and 50 ml of water were added, and the organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Dissolve the residue in a mixture of tetrahydrofuran (30 ml) and methanol (30 ml), add 15 ml of 4N aqueous potassium hydroxide solution,
The mixture was stirred at room temperature for 4 hours. After the reaction, water, ether and 5 ml of concentrated hydrochloric acid were added, and the ether layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by recrystallization using benzene to obtain 3.0 g of the title compound having the following physical properties. MS: m/Z = 276 (M ⁺ ), 258, 164, 147. NMR: δ = 7.20 (dd, 4H), 7.00 (q, 2H),
3.98 (t, 2H), 1.60−1.90 (m, 2H), 1.20−
1.60 (m, 10H), 0.87 (t, 3H). Reference example 11 2-[N-(p-amylcinnamoyl)amino]
phenol p-Amylcinnamic acid (produced in Reference Example 4) 308
Add 1 ml of oxalyl chloride to mg, and add 1 ml of oxalyl chloride to
After stirring for an hour, the mixture was concentrated under reduced pressure and 2 ml of chloroform was added. This is o-aminophenol
162 mg and triethylamine 142 mg dissolved in 4 ml of chloroform were added dropwise under ice cooling, and at the same temperature
The mixture was stirred for an hour, water was added, extracted with ethyl acetate, and concentrated under reduced pressure. Add methanol to the residue,
Insoluble matter was filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate:
n-hexane=1:4) to obtain 69 mg of the title compound having the following physical properties. TLC: Rf = 0.60 (ethyl acetate: n-hexane =
1:2). MS: m/Z = 309 (M ⁺ ), 201, 131. IR: ν=1650, 1620, 1600cm ^-1 . NMR: δ = 9.33 (s, 1H), 7.77 (d, 1H),
7.76 (s, 1H), 7.00-7.50 (m, 7H), 6.85
(dt, 1H), 6.57 (d, 1H). Example 1 N-(p-amylcinnamoyl)orthanilic acid p-Amylcinnamic acid (produced in Reference Example 4) 100
Add 1 ml of oxalyl chloride to mg, and add 1 ml of oxalyl chloride to
Stir for an hour, concentrate under reduced pressure, and add 1 ml of methylene chloride.
added. Cool this solution on ice and add 79mg of orthanilic acid.
and triethylamine 92mg in methylene chloride solution (1
ml) and stirred overnight at room temperature. After the reaction,
The mixture was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed successively with diluted hydrochloric acid and water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain 55 mg of the title compound having the following physical properties. TLC: Rf = 0.1 (ethyl acetate). IR: ν=1660, 1630, 1610, ^{1595cm -1} . NMR: δ = 8.42 (d, 1H), 7.88 (d, 1H),
7.68 (d, 1H), 7.10-7.55 (m, 7H), 6.63
(d, 1H). Example 1(a) N-(p-amylcinnamoyl)-3-hydroxyanthranilic acid Using 110 mg of the compound produced in Reference Example 4 and 77 mg of 3-hydroxyanthranilic acid, 52 mg of the title compound having the following physical properties was obtained by the same operation as in Example 1. Note that silica gel column chromatography (ethyl acetate:n-hexane=1:2) was used for purification. TLC: Rf = 0.2 (ethyl acetate) MS: m/Z = 353 (M ⁺ ), 335, 317, 289,
201. IR (liquid film method): ν=1720, 1680, 1620, 1600cm
^-1 . NMR (CDCl ₃ + CD ₃ OD): δ = 6.90−7.70 (m,
8H), 6.30-6.65 (m, 1H). Example 1(b) 2-[N-(p-amylcinnamoyl)amino]
Thiophenol The title compound having the following physical properties was obtained by the same procedure as in Example 1 using 170 mg of the compound produced in Reference Example 4 and 100 mg of 2-aminothiophenol.
Got 70mg. For purification, silica gel column chromatography (cyclohexane:ethyl acetate =
5:1) was used. TLC: Rf=0.7 (cyclohexene:ethyl acetate=3:1). MS: m/Z=325 (M ⁺ ), 323, 306, 290,
266, 201, 161. NMR: δ = 8.49 (d, 1H), 8.10 (s, 1H),
7.63 (d, 1H), 7.47 (d, 2H), 7.21 (d,
2H), 7.1-7.4 (m, 2H), 6.98 (t, 1H),
6.19 (d, 1H), 2.64 (t, 2H) 1.65 (m,
2H), 1.32 (m, 4H), 0.9 (t, 3H). Example 1(c) N-(p-amylcinnamoyl)-4-nitroanthranilic acid The title compound having the following physical properties was obtained by the same procedure as in Example 1 using 172 mg of the compound produced in Reference Example 4 and 143 mg of 4-nitroanthranilic acid.
Obtained 164 mg. Purification is by recrystallization method (ethyl acetate)
I did it at TLC: Rf = 0.1 (ethyl acetate). MS: m/Z=382 (M ⁺ ), 364, 201, 161,
152. IR: ν=1710, 1670, 1615, 1595 ^{cm -1} . NMR (CDCl ₃ + CD ₃ OD): δ = 9.73 (d, 1H),
8.28 (d, 1H), 7.90 (dd, 1H), 7.76 (d,
1H), 7.15-7.60 (m, 4H), 6.54 (d, 1H). Example 1(d) N-(p-amylcinnamoyl)-4-chloroanthranilic acid The same procedure as in Example 1 was performed using 130 mg of the compound produced in Reference Example 4 and 102 mg of 4-chloroanthranilic acid to obtain 130 mg of the title compound having the following physical properties. Note that a recrystallization method (ethyl acetate:n-hexane=1:1) was used for purification. TLC: Rf = 0.2 (ethyl acetate). MS: m/Z = 371 (M ⁺ ), 353, 201. IR: ν=1705, 1670, 1600, ^{1570cm -1} . NMR (CDCl ₃ + CD ₃ OD): δ = 8.96 (d, 1H),
8.05 (d, 1H), 7.73 (d, 1H), 7.15−7.55
(m, 4H), 7.07 (dd, 1H), 6.56 (d, 1H). Example 1(e) N-(p-amylcinnamoyl)-5-methylanthranilic acid The title compound having the following physical properties was obtained by the same procedure as in Example 1 using 170 mg of the compound produced in Reference Example 4 and 118 mg of 5-methylanthranilic acid.
Obtained 172 mg. Note that a recrystallization method (ethyl acetate-n-hexane) was used for purification. TLC: Rf = 0.30 (ethyl acetate: n-hexane =
1:1). IR: ν=1680, 1620, 1590, 1520cm ^-1 . NMR: δ = 8.77 (d, 1H), 7.96 (d, 1H),
7.75 (d, 1H), 7.43 (dd, 1H), 7.15−7.55
(m, 4H), 6.55 (d, 1H), 2.38 (s, 3H). Example 1(f) N-(p-amylcinnamoyl)-5-chloroanthranilic acid The title compound having the following physical properties was obtained by the same procedure as in Example 1 using 150 mg of the compound produced in Reference Example 4 and 118 mg of 5-chloroanthranilic acid.
Obtained 170 mg. TLC: Rf = 0.30 (ethyl acetate). MS: m/Z=371, 353, 201, 144. IR: ν=1680, 1620, 1600, 1580, 1510 ^{cm -1} . NMR (CDCl ₃ + CD ₃ OD): δ = 8.82 (d, 1H),
8.08 (d, 1H), 7.72 (d, 4H), 7.50 (dd,
1H), 7.15-7.60 (m, 4H), 6.55 (d, 1H). Example 1(g) N-(p-amylcinnamoyl)-3-chloroanthranilic acid The title compound having the following physical properties was obtained by the same procedure as in Example 1 using 165 mg of the compound produced in Reference Example 4 and 135 mg of 3-chloroanthranilic acid.
Obtained 135 mg. TLC: Rf = 0.30 (ethyl acetate). MS: m/Z=371, 353, 336, 201. IR: ν=1690, 1655, 1620, 1510 ^{cm -1} . NMR (CDCl ₃ + CD ₃ OD): δ = 7.89 (dd, 1H),
7.72 (d, 1H), 7.62 (dd, 1H), 7.40−7.55
(m, 2H), 7.15-7.30 (m, 3H). Example 1(h) 2-[N-(p-amylcinnamoyl)amino]
-4-nitrophenol Using 138 mg of the compound produced in Reference Example 4 and 97 mg of 2-amino-4-nitrophenol, 130 mg of the title compound having the following physical properties was obtained by the same operation as in Example 1. Note that a recrystallization method (n-hexane-ethyl acetate) was used for purification. TLC: Rf = 0.60 (ethyl acetate: n-hexane =
1:1). MS: m/Z=354, 201, 131. IR: ν=1670, 1620, 1595, 1540 ^{cm -1} . NMR (CDCl ₃ + CD ₃ OD): δ = 8.75 (d, 1H),
7.93 (dd, 1H), 7.75 (d, 1H), 7.45−7.55
(m, 2H), 7.15-7.30 (m, 2H), 6.95 (d,
1H), 6.64(d, 1H). Example 1(i) 2-[N-(p-amylcinnamoyl)amino]
benzotrifluoride Using 125 mg of the compound produced in Reference Example 4 and 92 mg of 2-aminobenzotrifluoride, 55 mg of the title compound having the following physical properties was obtained by the same operation as in Example 1. In addition, recrystallization method (n
-hexane) was used. TLC: Rf = 0.40 (ethyl acetate: n-hexane =
1:1). MS: m/Z=361, 342, 304, 256, 201,
144, 131. IR: ν=1660, 1625, 1590, 1530 ^{cm -1} . NMR: δ = 8.36 (d, 1H), 7.74 (d, 1H),
7.4-7.7 (m, 4H), 7.15-7.30 (m, 3H),
6.47 (d, 1H). Example 1(j) N-(p-amylcinnamoyl)-3,5-dichloroanthranilic acid 128 mg of the compound produced in Reference Example 4 and 3,5
The same procedure as in Example 1 was performed using 121 mg of -dichloroanthranilic acid to obtain 65 mg of the title compound having the following physical properties. In addition, recrystallization method (n
-hexane-ethyl acetate). TLC: Rf = 0.20 (ethyl acetate). MS: m/Z=407, 405, 389, 387, 332,
330, 218, 201, 189, 187. IR: ν=1700, 1645, 1615, ^{1600cm -1} . NMR (CDCl ₃ + CD ₃ OD): δ = 7.86 (d, 1H),
7.69 (d, 1H), 7.61 (d, 1H), 7.15−7.55
(m, 4H), 6.60 (d, 1H). Example 1(k) 3-[N-(p-amylcinnamoyl)amino]
salicylic acid Using 150 mg of the compound produced in Reference Example 4 and 105 mg of 3-aminosalicylic acid, 67 mg of the title compound having the following physical properties was obtained by the same procedure as in Example 1.
I got it. Note that preparative TLC (ethyl acetate:methanol=4:1) was used for purification. TLC: Rf = 0.30 (methyl acetate: methanol =
4:1). MS: m/Z = 353 (M ⁺ ), 309, 290, 201. IR: ν=1650, 1620, 1600, 1520 ^{cm -1} . NMR (CD ₃ OD): δ = 8.21 (dd, 1H), 7.63
(dd, 1H), 7.41 (d, 1H), 7.15−7.55 (m,
4H), 6.92 (d, 1H), 6.76 (t, 1H). Example 1(l) 2-[N-(p-amylcinnamoyl)amino]
Terephthalic acid The title compound 89 having the following physical properties was prepared in the same manner as in Example 1 using 170 mg of the compound produced in Reference Example 4 and 141 mg of 2-aminoterephthalic acid.
I got mg. TLC: Rf = 0.20 (ethyl acetate: n-hexane =
1:1). MS: m/Z=365, 347, 219, 144, 137,
131. NMR: δ = 8.88 (d, 1H), 8.15 (dt, 1H),
7.62 (dt, 1H), 7.1-7.6 (m, 4H), 7.12 (t,
1H), 6.56 (d, 1H). Example 1(m) N-(p-amylcinnamoyl)-4-methoxyanthranilic acid Using 218 mg of the compound prepared in Reference Example 4 and 250 mg of 4-methoxyanthranilic acid, 225 mg of the title compound having the following physical properties was obtained by the same operation as in Example 1. Note that silica gel column chromatography (chloroform:methanol=40:1) was used for purification. TLC: Rf=0.56 (ethyl acetate:methanol=
10:1). MS: m/Z=367 (M ⁺ ), 349, 292, 201,
167, 161, 144, 131, 115, 43. IR: ν=3100, 2930, 2860, 1680, 1610,
1585, 1525, 1460, 1395, 1335, 1220,
1140, 1035, 1005 ^{, 970cm -1} . NMR (CD ₃ OD): δ = 8.29 (d, 1H), 8.02 (d,
1H), 7.61 (d, 1H), 7.51 (d, 2H) 7.19
(d, 2H), 6.57 (d, 1H), 6.62 (dd, 1H),
3.83 (s, 3H), 2.61 (t, 2H), 1.61 (m,
2H), 1.20-1.45 (m, 4H), 0.89 (t, 3H). Example 1(n) 4-chloro-N-(p-isobutylcinnamoyl)anthranilic acid The title compound having the following physical properties was obtained by the same procedure as in Example 1 using 239 mg of the compound produced in Reference Example 5 and 201 mg of 4-chloroanthranilic acid.
Obtained 230mg. In addition, for purification, recrystallization method (n-
Hexane:ethyl acetate=10:1) was used. TLC: Rf = 0.20 (ethyl acetate: n-hexane =
2:1). MS: m/Z=359, 357, 340, 187. IR: ν=1700, 1670, 1600, 1570, 1500cm ^-1 . NMR (CDCl ₃ + CD ₃ OD): δ = 8.93 (d, 1H),
8.03 (d, 1H), 7.73 (d, 1H), 7.1−7.6 (m,
4H), 7.07 (dd, 1H), 6.55 (d, 1H). Example 1(o) 4-chloro-N-(p-isopentylcinnamoyl)anthranilic acid 211 mg of the compound produced in Reference Example 5(a) and 4-
The same procedure as in Example 1 was carried out using 166 mg of chloroanthranilic acid to obtain 227 mg of the title compound having the following physical properties. In addition, recrystallization method (n-
Hexane-ethyl acetate) was used. TLC: Rf = 0.20 (ethyl acetate: n-hexane =
2:1). MS: m/Z=374, 372, 353, 201. IR: ν=1700, 1670, 1600cm ^-1 . NMR (CDCl ₃ + CD ₃ OD): δ = 8.95 (d, 1H),
8.03 (d, 1H), 7.70 (d, 1H), 7.1−7.5 (m,
4H), 7.06 (dd, 1H), 6.55 (d, 1H). Example 1(p) 4-chloro-N-(p-cyclohexylcinnamoyl)anthranilic acid 219 mg of the compound produced in Reference Example 5(b) and 4-
The same procedure as in Example 1 was carried out using 164 mg of chloroanthranilic acid to obtain 206 mg of the title compound having the following physical properties. Note that a recrystallization method (ethyl acetate) was used for purification. TLC: Rf = 0.20 (ethyl acetate: n-hexane =
2:1). MS: m/Z=385, 383, 365, 213. IR: ν=1700, 1670, 1625, 1600, 1580 ^{cm -1} . NMR (CDCl ₃ + CD ₃ OD): δ = 8.89 (d, 1H),
8.03 (d, 1H), 7.89 (d, 1H), 7.2−7.6 (m,
4H), 7.06 (dd, 1H), 6.55 (d, 1H). Example 1(q) N-(p-amyl-3-methylcinnamoyl)-
4-chloroanthranilic acid The title compound having the following physical properties was obtained by the same procedure as in Example 1 using 275 mg of the compound produced in Reference Example 7 and 305 mg of 4-chloroanthranilic acid.
Obtained 72 mg. Note that a recrystallization method was used for purification. TLC: Rf = 0.20 (ethyl acetate). MS: m/Z = 385, 367, 215, 145, 115, 43. IR: ν=3150, 2930, 2860, 1690, 1675,
1600, 1580, 1510, 1415, 1380, 1190,
1145, 1100, 915cm ^-1 . NMR: δ=11.00 (s, 1H), 8.80 (d, 1H),
8.02 (d, 1H), 7.41 (d, 2H), 7.19 (d,
2H), 7.05 (dd, 1H), 6.16 (s, 1H), 3.50
(s, 1H), 2.64 (s, 3H), 2.62 (t, 2H),
1.62 (m, 2H), 1.20−1.45 (m, 4H) 0.89
(t, 3H). Example 1(r) N-(p-amylcinnamoyl)-4-fluoroanthranilic acid Using 155 mg of the compound produced in Reference Example 4 and 100 mg of 4-fluoroanthranilic acid, 71 mg of the title compound having the following physical properties was obtained by the same operation as in Example 1. Note that a recrystallization method was used for purification. TLC: Rf = 0.20 (ethyl acetate). MS: m/Z=355, 337, 310, 201, 145,
131, 115, 43. IR: ν=3110, 2930, 2860, 1710, 1675,
1605, 1525, 1450, 1430, 1390, 1340,
1280, 1210, 1130, 1005, 990, 970, 905,
810 cm ^-1 . NMR: δ=11.32 (s, 1H), 8.71 (dd, 1H),
8.16 (dd, 1H), 7.75 (d, 1H), 7.48 (d,
2H), 7.18 (d, 2H), 6.81 (m, 1H), 6.53
(d, 1H), 4.40 (s, 1H), 2.61 (t, 2H),
1.60 (m, 2H), 1.20−1.45 (m, 4H) 0.88
(t, 3H). Example 1(s) 4-chloro-N-(p-heptylcinnamoyl)
anthranilic acid 184 mg of the compound produced in Reference Example 5(c) and 4-
The same procedure as in Example 1 was carried out using 129 mg of chloroanthranilic acid to obtain 145 mg of the title compound having the following physical properties. Note that a recrystallization method (ethyl acetate-n-hexane) was used for purification. TLC: Rf = 0.20 (ethyl acetate: n-hexane =
2:1). MS: m/Z=401, 399, 381, 229, 189,
144, 131. IR: ν=1700, 1670, 1600, 1570, 1520,
1505cm ^-1 . NMR: δ = 9.00 (d, 1H), 8.05 (d, 1H),
7.75 (d, 1H), 7.15−7.55 (m, 4H) 7.10 (dd,
1H), 6.53(d, 1H). Example 1(t) 4-chloro-N-(p-decylcinnamoyl)
anthranilic acid 182 mg of the compound produced in Reference Example 5(d) and 4-
The same procedure as in Example 1 was carried out using 109 mg of chloroanthranilic acid to obtain 133 mg of the title compound having the following physical properties. Note that a recrystallization method (methanol) was used for purification. TLC: Rf = 0.30 (ethyl acetate: n-hexane =
2:1). MS: m/Z=443, 441, 423, 296, 271. IR: ν=1700, 1670, 1595, 1565, 1510 ^{cm -1} . NMR: δ = 9.00 (d, 1H), 8.07 (d, 1H),
7.76 (d, 1H), 7.15-7.60 (m, 4H) 7.11
(dd, 1H), 6.54 (d, 1H). Example 1(u) 4-chloro-N-(p-octyloxycinnamoyl)anthranilic acid The title compound having the following physical properties was obtained by the same procedure as in Example 1 using 191 mg of the compound produced in Reference Example 10 and 119 mg of 4-chloroanthranilic acid.
Obtained 150 mg. Note that a recrystallization method (n-hexane) was used for purification. TLC: Rf = 0.20 (ethyl acetate: n-hexane =
1:1). MS: m/Z=429, 411, 299, 259, 147. IR: ν=1680, 1660, 1590, 1565, 1500cm ^-1 . NMR (CDCl ₃ + CD ₃ OD): δ = 8.91 (d, 1H),
8.02 (d, 1H), 7.66 (d, 1H), 7.4−7.6 (m,
2H), 7.04 (dd, 1H), 6.8−7.0 (m, 2H),
6.44 (d, 1H). Example 1(v) 4-chloro-N-(3-pentadecylcinnamoyl)anthranilic acid The title compound having the following physical properties was obtained by the same procedure as in Example 1 using 154 mg of the compound produced in Reference Example 8 and 74 mg of 4-chloroanthranilic acid.
Got 100mg. Note that a recrystallization method (ethyl acetate-n-hexane) was used for purification. TLC: Rf = 0.20 (ethyl acetate: n-hexane =
2:1). MS: m/Z=511, 493, 341 IR: ν=1690, 1670, 1620, 1595, 1565,
1510cm ^-1 . NMR (CDCl ₃ + CD ₃ OD): δ = 8.69 (d, 1H),
7.89 (d, 1H), 7.15-7.40 (m, 5H), 6.96
(dd, 1H), 5.99 (s, 1H). Example 1(w) 6-acetyl-2-[N-(p-amylcinnamoyl)amino]phenol Using 1.13 g of the compound produced in Reference Example 4 and 1.09 g of the compound produced in Reference Example 2, the title compound having the following physical properties was obtained by the same procedure as in Example 1.
Obtained 547 mg. In addition, silica gel column chromatography (ethyl acetate-n-hexane) was used for purification.
was used. TLC: Rf = 0.40 (ethyl acetate: n-hexane =
1:2). MS: m/Z = 351 (M ⁺ ), 201, 151, 131. NMR: δ=12.96 (s, 1H), 8.77 (dd, 1H),
8.02 (s, 1H), 7.74 (d, 1H), 7.48 (m,
3H), 7.20 (d, 2H), 6.94 (t, 1H), 6.56
(d, 1H), 2.64 (t, 2H), 2.63 (s, 3H),
1.10−1.80 (m, 6H), 0.90 (t, 3H). Example 2 2-(p-amylcinnamoyl)aminophenyl diethyl phosphate Under an argon atmosphere, 0.16 ml of diethoxyphosphonic chloride was slowly added to a mixture of 0.38 ml of triethylamine and 3 ml of anhydrous chloroform at 0°C, and the mixture was stirred for 5 minutes. Reference example 11 to this
A solution (3 ml) of anhydrous chloroform containing 113 mg of the compound prepared above was slowly added at 0°C, and the mixture was incubated at the same temperature for 30 minutes.
The mixture was further stirred at room temperature for 1 hour. After the reaction, ethyl acetate and dilute hydrochloric acid were added, the layers were separated, and the organic layer was diluted with water and
The mixture was washed successively with an aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: cyclohexane = 2:5) to obtain 106 mg of the title compound having the following physical properties. TLC: Rf=0.25 (ethyl acetate:cyclohexane=1:2). MS: m/Z=445 (M ⁺ ), 416, 400, 374,
290, 245, 227, 201, 131, 115, 43. IR: ν=3310, 2980, 2950, 2920, 2850,
1685, 1630, 1605, 1525, 1480, 1445,
1340, 1275, 1255, 1185, 1160, 1105,
1050, 1030, 970cm ^-1 . NMR: δ = 8.64 (s, 1H), 8.36 (d, 1H),
7.74 (d, 1H), 7.48 (d, 2H), 7.18 (d,
2H), 7.15-7.30 (m, 20H), 7.06 (t, 1H),
6.55 (d, 1H), 4.13 (m, 4H), 2.62 (t,
2H), 1.62 (m, 2H), 1.34 (dt, 6H), 1.20−
1.50 (m, 4H), 0.89 (t, 3H). Example 3 N-(p-amylcinnamoyl)-4-hydroxyanthranilic acid p-Amylcinnamic acid (produced in Reference Example 4) 109
Add 1 ml of oxalyl chloride to mg, and add 1 ml of oxalyl chloride to
The mixture was stirred for an hour, concentrated under reduced pressure, and 1 ml of methylene chloride was added. This solution was cooled on ice, a mixture of 77 mg of 4-hydroxyanthranilic acid, 0.21 ml of triethylamine and 2 ml of chloroform was added, stirred at the same temperature for 30 minutes and at room temperature for 1 hour and 30 minutes, poured into 20 ml of 0.5N hydrochloric acid, and diluted with ethyl acetate. Extracted. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Dissolve the concentrate in a mixture of methanol (2.5 ml) and tetrahydrofuran (2.5 ml), and add 2 ml of 1N aqueous sodium hydroxide solution.
ml and stirred overnight. After the reaction, add 3 ml of 1N hydrochloric acid and 10 ml of water, extract with ethyl acetate,
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:methanol=10:1) to obtain 58 mg of the title compound having the following physical properties. TLC: Rf=0.23 (chloroform:methanol=
10:1). MS: m/Z=353 (M ⁺ ), 335, 309, 278,
201, 161, 131, 115, 43. IR: ν=3100, 2930, 2860, 1660, 1605,
1550, 1450, 1410, 1325, 1250, 1145,
1000, 975, 870, 770 cm ^-1 . NMR (CDCl ₃ + CD ₃ OD): δ = 8.24 (d, 1H),
7.99 (d, 1H), 7.65 (d, 1H), 7.49 (d,
2H), 7.20 (d, 2H), 6.60 (d, 1H), 6.56
(dd, 1H), 2.64 (t, 2H), 1.64 (m, 2H),
1.20−1.45 (m, 4H), 0.90 (t, 3H). Example 4 6-acetyl-2-[N-(p-amylcinnamoyl)amino]phenoxyacetic acid methyl ester Dissolve 305 mg of the compound prepared in Example 1 (w) in 10 ml of methyl ethyl ketone, and add sodium iodide.
260mg, 2-bromoacetic acid methyl ester 0.83ml,
and 731 mg of potassium carbonate were added, and the mixture was heated under reflux all day and night. The mixture was allowed to cool to room temperature and filtered, and the filtrate was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=
1:5) to obtain 285 mg of the title compound having the following physical properties. TLC: Rf = 0.25 (ethyl acetate: n-hexane =
1:3). MS: m/Z=423 (M ⁺ ), 397, 392, 366,
364, 351, 334, 223, 201, 144, 131, 115. NMR: δ=9.84 (s, 1H), 8.76 (dd, 1H),
7.75 (d, 1H), 7.52 (d, 2H), 7.35 (dd,
1H), 7.20 (t, 1H), 7.18 (d, 2H), 6.75
(d, 1H), 4.62 (s, 2H), 3.84 (s, 3H),
2.63 (t, 2H), 2.60 (s, 3H), 1.62 (m,
2H), 1.20-1.45 (m, 4H), 0.88 (t, 3H). Example 5 6-acetyl-2-[N-(p-amylcinnamoyl)amino]phenoxyacetic acid 280 mg of the compound produced in Example 4 was dissolved in a mixture of methanol (3 ml) and tetrahydrofuran (3 ml), 2 ml of a 1N aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature overnight, followed by the addition of 3 ml of 1N hydrochloric acid and 15 ml of water. , extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by recrystallization method (ethyl acetate-n-hexane),
131 mg of the title compound having the following physical properties was obtained. TLC: Rf=0.30 (ethyl acetate:methanol=
5:1). MS: m/Z=409 (M ⁺ ), 391, 351, 334,
259, 209, 201. IR: ν=3270, 3120, 2930, 2850, 1740,
1680, 1660, 1615, 1600, 1540, 1435,
1410, 1350, 1270, 1160, 1120, 1050, 975
cm ^-1 . NMR: δ = 9.70 (s, 1H), 8.70 (d, 1H),
7.70 (d, 1H), 7.00-7.55 (m, 6H), 6.65
(d, 1H), 4.39 (s, 2H), 2.57 (s, 3H),
2.55 (t, 2H), 1.56 (m, 2H), 1.20−1.45
(m, 4H), 0.87 (t, 3H). Example 6 N-(p-amylcinnamoyl)-4-methoxyanthranilic acid sodium salt 85 mg of the compound produced in Example 1 (m) was dissolved in 5 ml of methanol, 0.23 ml of 1N aqueous sodium hydroxide solution was added, concentrated under reduced pressure, and dried in a desiccator to obtain 86 mg of the title compound having the following physical properties. . NMR (CD ₃ OD): δ = 8.28 (d, 1H), 7.62 (d,
1H), 7.53 (d, 2H), 7.21 (d, 2H), 7.00
(d, 1H), 6.87-7.12 (m, 3H), 4.44 (s,
2H), 2.63 (t, 2H), 1.64 (m, 2H), 1.25−
1.45 (m, 4H), 0.90 (t, 3H). Example 7 The same operation as in Example 6 was performed to obtain Example 1(c),
1(d), 1(e), 1(f), 1(g), 1(l), 1(r), 1
(n), 1(o), 1(p), 1(s), 1(t), 1
(q)
The corresponding sodium salts of compounds No. 3 and No. 3 were prepared. The monosodium salt of the compound of Example 1(l) was prepared. Example 8 N-(p-amylcinnamoyl)orthanilic acid 5g, cellulose calcium gluconate (disintegrant)
200mg, Magnesium Stearate (Lubricant) 100
mg and 4.7 g of microcrystalline cellulose were mixed in a conventional manner and tableted to obtain 100 tablets each containing 50 mg of active ingredient.

Claims (1)

[Claims] 1. General formula [In the formula, R ¹ is (i) a linear or branched alkyl group or alkoxy group having 1 to 15 carbon atoms, or 2 carbon atoms;
~15 linear or branched alkenyl group or alkenyloxy group, (ii) unsubstituted phenyl group or benzyl group, or hydrogen atom, or (iii) C4-7 cyclo represents an alkyl group, R ² and R ² ' each independently represents a hydrogen atom or a straight or branched alkyl group having 1 to 20 carbon atoms, and R ³ represents (i) a carboxy group, a carboxymethyl group; or represents a carboxymethoxy group, a linear or branched alkoxycarbonyl group having 2 to 6 carbon atoms, a linear or branched alkoxycarbonylmethyl group having 3 to 7 carbon atoms, an alkoxycarbonylmethoxy group, or a hydroxyl group. , or (ii) represents a mercapto group, a sulfo group, a diethoxyphosphonoyl group, or a trifluoromethyl group, and R ⁴ and R ⁵ each independently represent a hydrogen atom, a halogen atom, a straight chain having 1 to 4 carbon atoms, or represents a branched alkyl group or alkoxy group, carboxy group, straight or branched alkoxycarbonyl group having 2 to 6 carbon atoms, hydroxyl group, acetyl group or nitro group, n represents 0, 1 or 2; Symbol 〓 is a double bond (E, Z or EZ mixture)
Or represents a single bond. However, when R ³ falls under (i) above, R ⁴ and R ⁵ are not hydrogen atoms at the same time. ] An aniline derivative or a non-toxic salt thereof. 2. The compound according to claim 1, wherein the symbol 〓 represents a double bond, and n is 1. 3. The compound according to claim 1 or 2, wherein R ¹ is an amyl group. 4 R ³ is a carboxy group, a carboxymethyl group,
Carboxymethoxy group, methoxycarbonyl group,
The compound according to claim 1, 2, or 3, which is a methoxycarbonylmethyl group, a methoxycarbonylmethoxy group, or a hydroxyl group. 5 Claims 1, 2, 3, or 4, wherein R ⁴ is a halogen atom or a nitro group.
Compounds described in Section. 6. The compound according to claim 1, 2, 3, or 4, wherein R ⁴ is a carboxy group or a hydroxyl group. 7. The compound according to claim 1, 2, 3, or 4, wherein R ⁴ is a methyl group, a methoxy group, or an acetyl group. 8. The compound according to claim 1, 2, or 3, wherein R ³ is a sulfo group, a mercapto group, a trifluoromethyl group, or a diethoxyphosphonoyl group. 9. The compound according to claim 1, 2, 3, or 8, wherein R ⁴ and R ⁵ are both hydrogen atoms. 10. The compound according to claim 1 or 2, wherein R ¹ is an isobutyl group, an isopentyl group, a heptyl group, a decyl group, an octyloxy group, or a cyclohexyl group. 11. The compound according to claim 1, 2, or 10, wherein R ³ is a carboxy group or a methoxycarbonyl group. 12. The compound according to claim 1, 2, 10 or 11, wherein R ⁴ is a halogen atom. 13. The compound according to claim 1, which is N-(p-amylcinnamoyl)orthanyl acid. 14 N-(p-amylcinnamoyl)-3-hydroxyanthranilic acid Claim 1
Compounds described in Section. 15. The compound according to claim 1, which is 2-[N-(p-amylcinnamoyl)amino]thiophenol. 16. The compound according to claim 1, which is 16 N-(p-amylcinnamoyl)-4-nitroanthranilic acid or its sodium salt. 17. The compound according to claim 1, which is N-(p-amylcinnamoyl)-4-chloroanthranilic acid or its sodium salt. 18. The compound according to claim 1, which is N-(p-amylcinnamoyl)-5-methylanthranilic acid or its sodium salt. 19. The compound according to claim 1, which is N-(p-amylcinnamoyl)-5-chloroanthranilic acid or its sodium salt. 20 The compound according to claim 1, which is N-(p-amylcinnamoyl)-3-chloroanthranilic acid or its sodium salt. 21 The compound according to claim 1, which is 2-[N-(p-amylcinnamoyl)amino]-4-nitrophenol. 22 The compound according to claim 1, which is 2-[N-(p-amylcinnamoyl)amino]benzotrifluoride. 23 N-(p-amylcinnamoyl)-3,5-
The compound according to claim 1, which is dichloroanthranilic acid. 24 The compound according to claim 1, which is 3-[N-(p-amylcinnamoyl)amino]salicylic acid. 25. The compound according to claim 1, which is 2-[N-(p-amylcinnamoyl)amino]terephthalic acid or its sodium salt. 26. The compound according to claim 1, which is N-(p-amylcinnamoyl)-4-methoxyanthranilic acid or its sodium salt. 27 The compound according to claim 1, which is 4-chloro-N-(p-isobutylcinnamoyl)anthranilic acid or its sodium salt. 28. The compound according to claim 1, which is 4-chloro-N-(p-isopentylcinnamoyl)anthranilic acid or its sodium salt. 29. The compound according to claim 1, which is 4-chloro-N-(p-cyclopentylcinnamoyl)anthranilic acid or its sodium salt. 30 The compound according to claim 1, which is N-(p-amyl-3-methylcinnamoyl)-4-chloroanthranilic acid or its sodium salt. 31 The compound according to claim 1, which is N-(p-amylcinnamoyl)-4-fluoroanthranilic acid or its sodium salt. 32 The compound according to claim 1, which is 4-chloro-N-(p-heptylcinnamoyl)anthranilic acid or its sodium salt. 33 The compound according to claim 1, which is 4-chloro-N-(p-decylcinnamoyl)anthranilic acid or its sodium salt. 34 The compound according to claim 1, which is 4-chloro-N-(p-octyloxycinnamoyl)anthranilic acid. 35 The compound according to claim 1, which is 4-chloro-N-(3-pentadecylcinnamoyl)anthranilic acid. 36 The compound according to claim 1, which is 6-acetyl-2-[N-(p-amylcinnamoyl)amino]phenol. 37 The compound according to claim 1, which is 2-(p-amylcinnamoyl)aminophenyl diethyl phosphate. 38 The compound according to claim 1, which is N-(p-amylcinnamoyl)-4-hydroxyanthranilic acid or its sodium salt. 39 The compound according to claim 1, which is 6-acetyl-2-[N-(p-amylcinnamoyl)amino]phenoxyacetic acid or its methyl ester.