JPS6097946A - Carboxamide derivative, its production and remedy containing said derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (R<1> is 5-15C straight or branched chain alkyl, alkoxy, etc.; R<2> is H or methyl; R<3> is OH, carboxyl, carboxymethyl, etc.; X is -CH= or N; n is 0, 1 or 2; the dotted line is double bond or single bond), its non-toxic salt and non-toxic acid addition salt. EXAMPLE:o-[N-(p-Amylcinnamoyl)amino]phenylacetic acid and its sodium salt. USE:Effective to the various allergic plumonary diseases, shock, etc. caused by leukotriene, and thrombosis, inflammation, etc. e.g. caused by the damage of the endothelium or intima of brain or coronary vessel. PREPARATION:The compound of formula I can be produced by reacting the acid chloride of formula II with the amine of formula III.

Description

[Detailed description of the invention] The present invention relates to novel carboxamide 9 derivatives.

More specifically, the present invention relates to novel carboxami t-"ti derivatives having leukotriene antagonism, phospholipase inhibition, and 5α-reductase inhibition, methods for producing the same, and pharmaceuticals containing these as active ingredients.

Prostaglandin
, hereinafter abbreviated as pc. ) A number of 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. Newly discovered or newly determined P
Among the G-sopharies, PG-endoperoxide (PG) has particularly strong and unique biological activity.
endoperoxides, i.e. PGG2 and PG) I2), thromboxane A2 (Thrombox
ane A2, hereinafter abbreviated as TXA2. ), Prostacyclin (PCI), and leukotrienes C, D, and E (hereinafter abbreviated as LTC, LTD, and LTE, respectively).

) etc. In addition to these compounds, all of the known PG families, including various PGs, are biosynthesized in vivo using arachidonic acid as a common parent, so the metabolic pathway starting from arachidonic acid is The entirety of the arachitooctaphosphate cascade' (Arachi
Donate Ca-Scade').

For a detailed explanation of each route and the pharmacological properties of each product, please refer to History of Medicine, Su 3378 (1980), Ibid.
62 (1980), ibid.

114.866 (1,980), same, 114.929 (
1980), Modern Medicine, 几909 (1980),
□, 1029 (1980), 12.1065 (1
980) and the same.

12, 1105 (1980), etc.

In arachidonic acid cascade 9, cyclooxygenase acts on arachidonic acid to produce PC, c, 2, and further PCI2.
various PCs, such as prostaglandin F2. □(
Hereinafter, it will be abbreviated as PGF2a. ), prostaglandin E
2 (hereinafter abbreviated as P0E2), PGI2, TxA2
etc., and lipoxygenase acts on arachito-nanoic acid to form hydroperoxy-eicosI+t
et, raenoir acid, hereinafter abbreviated as HPETE. ) and then hydroxyeicosatetraenoic acid (hydroxyeicosatetra).
enoic acid.

Hereinafter, it will be abbreviated as HETE. ) or the route leading to leukotrienes.

The former pathway is already well known, so we will not discuss it in detail here. For details, see Shin Katori et al., eds., Prostaglandins (1978).

Please refer to the publication by Kodansha.

Regarding the latter route, it is known that various compounds are produced by the route shown in Scheme I.

Arachidonic acid is metabolized by a well-known pathway, i.e., via PC endoperoxide, and also by lipoxygenase (through another pathway, i.e., arachidonic acid is metabolized by lipoxygenase, e.g. 5-lipoxygenase). , 12-lipoxygenase or 15-lipoxygenase acts, respectively! 5
-HPETE, 12-HPETE or l 5-HP
ETE is produced〇These HPETEs are produced by converting hydrogen peroxide groups into hydroxyl groups by nomo oxidase.
5-HETE, 12-HETE or 15-HETE
is converted to

Furthermore, among these HPETEs, 5-HPETE is converted to LTA by being dehydrated.

Furthermore, LTA4 is enzymatically linked to leukotriene B4 (hereinafter abbreviated as LTB4) K, and also to glutathione-8-
) Converted to LTC4 by transferase.

LTC4 is then converted to LTD4 by γ-glutamyl transpeptidase. LTD4 is further LT
It has recently been revealed that [Bi] is metabolized to E4.
ochem-Bionhys-&s-Commun,,
9].

1266 (1979) and Prostaglandin
s, 19(5), 645 (1980)].

On the other hand, speaking about SR8, SR8 is SlowR
This is an abbreviation for ``acting 5ubstance,'' and this name was used for the substance liberated when Feldberg Laca copra venom is perfused into the lungs or when copra venom is incubated with egg yolk. has been reported to last for a long time (J-Physiol, ,
94°187 (1938)].

Furthermore, Kellaway et al. sensitized 5R8-A (Slow Rea
ctingSubstance of Anaphyl
Quant, -
J, EXD, Physiol, 30.121
(1940)]. Also Broc'klehurst
When the antigen is applied to surgically removed lung sections of bronchial asthma patients for whom the specific antigen is known, histamine and 5.
R8-A is released and strongly contracts bronchial muscles, and this contraction is not relieved by antihistamines, so 5R8-A is an important bronchial constrictor during asthma attacks.
[Progr-Allergy, 6.539 (196
See 2)]. Subsequently, 5R8 obtained from a piece of human lung tissue
- A constricts the bronchial rings in normal humans (Int, A
rch-A], 1ergy AT) T) 1- Immu
Nol., 38.217 (1970)], and when rat 5R8-A is intravenously injected into guinea pigs, an increase in pulmonary airway resistance is observed (J-Clin-Invest, J-Clin-Invest).

53, 1679 (1974)]; 5R8-A, when injected into the skin of guinea pigs, rats, and monkeys, advances the permeability of extraction tubes [Advances in Immuno
logy, 10.105 (1969), J. Alle.
rgy C11n, Immunol, , 62]
t371 (1978), Prostagrandi
ns, 19(5), 779 (1980), etc.).

As mentioned above, SR3 uses 5R8-A, calcium ionophore (ca]-c, which is released as a result of the immune reaction.
There are two types of SR3 and SR3, which are released without any immune reaction such as treatment (Ium 1onophore), but there are many similarities between the two, and it is thought that there is a strong possibility that they are the same substance. ing.

Furthermore, it has become clear that LTC4 and LTD4 are the same substances as SR8 or 5FIS-A, and therefore the pharmacological properties of these leukotrienes are similar to those of SR8 or 5FIS-A.
It can be considered in place of the pharmacological properties of 8 or 5R8-A. [Pro+, Natl, Acad-
8ci-USA, 76, 4275 (1979), Bi
ochem-Biophys-ReB-Commun,
, 91.1266(1,979), prr)c, N
atl-Acad, Sci, USA, 77, 201
4 (1980), Nat.

285, 104 (1980)] Based on the results of many studies such as these, various leukotrienes (LTCLTD and ETE4), which are biosynthesized from arachidonic acid through LTA4,4 and the structure of which will be further determined in the future. Leukotrienes are considered to be important factors involved in the development of allergic tracheal and bronchial or pulmonary diseases, allergic shock, or various types of allergic inflammation.
,do.

Therefore, by suppressing these leukotrienes, allergic tracheal and bronchial diseases such as asthma, allergic lung diseases, allergic shock, and various allergic diseases in mammals including humans, especially humans, can be prevented. It is effective in the prevention and/or treatment of.

In addition, arachidonic acid is phospholipase (phosph-
It is released from phospholipids by the action of
That is, (1) phosphatidyl choline (phosph
atidvl Cholirla) K phospholipase A2 acts and (2) Phosphatidyl boar)
-le (phospbatidyl 1nositol)
) to produce 1,2-diglyceride (1,2-diglyceride), which is further treated with diglyceride 9 lipase (diglyceride 9 lipase).
It is generally thought that a pathway in which the compound is released by the action of monoglyceride lipase) and then by monoglyceride lipase [see Chemistry and Biology Convex 154 (1983)].

The liberated arachidonic acid is further processed by two routes: (1) cyclooxygenase (cvclooxygenase);
ase) metabolic pathway, prostaglandin (PG)
or (2) lipoxygenase (LI).
poxygenase) metabolic pathway, SR8-A (
Slow Reacting Substances o
f Anaphylaxi, s), hyP-roxyeicosatetraenoic acid (I (ETE)) and leukotrief B4 (L
It is known that it is metabolized into physiologically active substances such as oukotriene B4) [Chemistry and Biology 21.154 (
(1983)].

These metabolites include, for example, TxA2, which has strong platelet aggregation and vasoconstriction effects, and 5R8-A, which is a chemical mediator of asthma.
LTB4 is a chemical mediator of inflammation such as gout, and P
C is a vasodilatory effect, a stimulant effect, a fever effect in inflammation,
It is known to be a chemical mediator that has a leukocyte migration effect [Metabolism 20.317 (1983), T
See Lancet 1i22 (1982), Prostaglandin (1978) edited by Makoto Katori et al., Kodansha].

In this way, arachito9anoic acid is converted and metabolized in vivo into chemical mediators that perform physiologically important killing functions, but breakdown of these mediators causes a number of diseases.

The present inventors conducted extensive research to find compounds that antagonize leukotrienes or inhibit phospholipases (phospholipase A2 and/or phospholipase C), and as a result, carboxamides represented by the general formula (1) below were found. Find out how to achieve that purpose,
The invention has been completed.

The compound of the present invention strongly inhibits phospholipase and suppresses the release of arachidonic acid from phospholipids, thereby preventing diseases caused by arachidonic acid metabolites such as TXA2, PG, and leukotrienes in salivary mammals including humans, especially humans. Effective for prevention and/or treatment.

Examples of target diseases include the aforementioned various allergic diseases caused by leukotrienes and thrombosis, such as thrombosis caused by damage to the endothelium and intima of the brain and coronary arteries, and inflammation, such as arthritis and rheumatism. [Circulation Science 1484 (1983) and Pharmacy 34.167 (19
83)].

Furthermore, the compound of the present invention has been found to have the following 5α-reductase inhibitory action in addition to its uses as a leukotriene antagonist and phospholipase inhibitor as described above.

5α-reductase Exists in the endoplasmic reticulum and nucleic acids, and has the effect of converting testosterone ingested into target tissues into the active form of 5α-dihydrotestosterone, which is activated by intracellular receptors. It is said that binding with the drug causes cell proliferation, and when this action progresses, it causes the onset of prostatic hypertrophy, alopecia, or sitting ulcers.

For example, in the case of benign prostatic hyperplasia, conventionally, as drug therapy, estrogen agents, which are female hormones, and gestagen agents, which have anti-androgen effects, have been used.

However, in both cases, the original hormonal effects remain as side effects, so it was difficult to say that sufficient treatment was being provided.

The compound of the present invention, of course, has hormone-specific effects, and moreover, it strongly inhibits 5α-reductase, suppresses the increase in 5α-dihydrotestosterone, and suppresses cell proliferation. It can effectively prevent and/or treat benign prostatic hyperplasia, alopecia, and sitting pain in humans.

The present invention is based on the general formula [wherein R represents (1) a straight chain or branched alkyl group or an alkoxy group having 5 to 15 carbon atoms, or (1) a straight chain or branched chain having 5 to 15 carbon atoms] an alkenyl or alkenyloxy group in the chain, at the 2- or 3-position of the benzene ring
(Iil) A straight-chain or branched alkenyl group having 13 to 15 carbon atoms or a straight-chain or branched alkenyloxy group having 5 to 15 carbon atoms, which is attached to the benzene ring. It means that it is bonded to the 4th position,
R represents a hydrogen atom or a methyl group; R represents a hydroxyl group, a carboxyl group, a carboxymethyl group, a carboxymethoxy group, a straight or branched alkoxycarbonyl group having 2 to 6 carbon atoms, or a straight chain Represents a chain or branched alkoxycarbonylmethyl group or alkoxycarbonylmethoxy group, X represents -CH= or a nitrogen atom, L represents 0°1 or 2, and the symbol 2 is a double bond (匪 or Z) Or represents a single bond. ] The present invention relates to carboxamide derivatives represented by the above, their non-toxic salts and acid addition salts, their production methods, and pharmaceuticals containing them as active ingredients.

In general formula (1), the linear or branched alkyl group in the alkyl group having 5 to 15 carbon atoms or alkoxy group represented by R is a methyl group, hexyl group, heptyl group, octyl group, nonyl group. , decyl group, undecyl group, dodecyl group, tridecyl group, tetradecyl group, and tadecyl group and their isomers. Preferred groups as R include lupentyl group, inpentyl group, leuheptyl group, rudecyl group, rudecyl group, and isomers thereof. Examples include octyloxy group and octyloxy group.

In the general formula (1), the linear or branched alkenyl group in the alkenyl group or alkenyloxy group having 5 to 15 carbon atoms represented by R includes an intenyl group, a bancgenyl group, a hexenyl group, a hexagenyl group, and a hexagenyl group. , hexenyl group, heptagenyl group, hexagenyl group, octenyl group, octagenyl group, octagenyl group, octatetraenyl group, nonenyl group, nonenyl group
, nonatrienyl group, nonatetraenyl group, decenyl group, decagenyl group, decagenyl group, tetradecenyl group, deca-antenyl group, undecenyl group, undecajenyl group, undecajenyl group, undecatetraenyl group, undeca-entenyl group, dodecenyl group, dodecajenyl group, Dodecagenyl group, dodecatetraenyl group, dodeca-entaenyl group, dodecatetraenyl group, tridecenyl group, tridecagenyl group, tridecatrienyl group,
tridecatetraenyl group, tridecatetraenyl group, tridecatetraenyl group, tetradecenyl group, tetradecagenyl group, tetradecajenyl group, tetradecatetraenyl group, tetradeca is ntaenyl group, tetradecahexaenyl group, tetradeca Examples include heptadeenyl group, pentadecenyl group, pentadecagenyl group, interdecatrienyl group, pentadecatetraenyl group, pentadecapentaenyl group, pentadecahexaenyl group, pentadecenyl group and isomers thereof. , R as preferable groups include 1-decenyl group, 1-decenyloxy group, 1-decenyl group, 1-decenyloxy group, 1-decenyl group,
-tridecenyl group and 1-tridecenyloxy group.

In the general formula (1), R represents a straight chain or branched alkoxycarbonylmethyl group having 3 to 7 carbon atoms or an alkoxy group in the alkoxycarbonylmethoxy group and a straight chain or branched chain having 2 to 6 carbon atoms. Examples of the alkoxy group in the alkoxycarbonyl group include methoxy group, ethoxy group, propyloxy group, butoxy group, R-methyloxy group and isomers thereof, and preferably methyl group and ethyl group. Preferred groups as R include hydroxyl group, carboxy group, carboxymethyl group, carboxymethoxy group, methoxycarbonyl group, methoxycarbonylmethyl group, methoxycarbonylmethoxy group, ethoxycarbonyl group, ethoxycarbonylmethyl group, ethoxycarbo,
=rumethoxy group.

The compound of the present invention represented by the general formula (1) is considered to have isomers, and in particular, when the symbol : represents a double bond, the double bond may have a double bond, and the symbol ni may be different. When R represents a single bond and R represents a methyl group, the carbon to which this methyl group is bonded is an asymmetric carbon and isomers exist. Furthermore, if each substituent in the general formula (11) contains a branched alkyl or alkylene group or a double bond, further isomers may occur.The present invention covers all these isomers and their It also includes mixtures.

Although several patent applications containing compounds with structures similar to the compounds of the present invention have been filed, the present invention cannot be easily derived from these patent applications. For example, JP-A-50-1350
The formula of the compound described in Example 2 in the specification of No. 47 and the compound number 52 in the specification of JP-A-49-93335
There is no description suggesting that the compound represented by the formula, which is a compound described as , is antagonistic to leukotrienes, which is one of the objects of the present invention. Furthermore, when these compounds were subjected to the system for measuring LTD4 antagonism and phospholipase A2 inhibition described herein,
The compound represented by formula (A) has a 5° value of 30 μM, which shows LTD4 antagonistic action, and a C5o value of 100 μM, which shows phospholipase inhibitory action. However, it did not show any activity.

However, the compound represented by the formula and the compound represented by the formula, which are the compounds of the present invention, each have an LTD4 antagonistic effect.
5o values of 14 μM and 16 μM, phospholipase A2
In the present invention, the present inventors found that LTD4 antagonism and phospholipase inhibition cannot be easily inferred due to the length of the carbon chain corresponding to H. He also announced that he would make it stronger.

In addition, the present inventors previously disclosed a compound similar to the compound of the present invention in JP-A-57-106651,
Although the purpose is to inhibit leukotriene biosynthesis,
The mechanism of action is to selectively inhibit 5-lipoxygenase to achieve this goal. On the other hand, the gist of the present invention is an action that antagonizes leukotriene itself, and these actions are essentially different.

Furthermore, these three applications do not describe the use as a phospholipase inhibitor or 5α-reductase inhibitor as in the present invention, but rather as an antithrombotic agent, prophylaxis against benign prostatic hyperplasia, alopecia, and acne. The present invention is the first to discover the use of the present invention as a therapeutic agent or treatment, and the present invention cannot be easily deduced from these prior art techniques.

According to the present invention, the compound represented by the general formula (11) is an acid chloride represented by the general formula (all symbols in the formula have the same meanings as defined above) and an acid chloride represented by the general formula (in which all symbols have the same meanings as defined above). It can be produced by reacting the amines shown below.

This reaction is a known reaction, for example, an inert organic solvent,
For example, the reaction is carried out in methylene chloride, chloroform, or tetrahydrofuran in the presence of a tertiary amine such as triethylamine or pyridine at a temperature of -20°C to 40°C.

Preferably it is carried out in methylene chloride in the presence of triethylamine at 06C to room temperature.

The compound represented by general formula (m) is a known compound,
For example, a compound in which the symbol X represents -CH- and R represents a 2-carboxyl group is commercially available as anthranilic acid,
In addition, a compound in which the symbol X represents a nitrogen atom and a carboxyl group is substituted as R3 at the 3rd position counting from the ring nitrogen is 2.
-Commercially available as amine nicotinic acid.

The compound represented by the general formula (IT) is represented by the general formula 1 [wherein all symbols have the same meanings as above]. ] It is produced by converting the carboxylic acid represented by the formula into an acid chloride.

The reaction of converting carboxylic acids to acid chlorides is well known and can be performed using thionyl chloride, thionyl chloride, in an inert organic solvent such as methylene chloride, tetrahydrofuran, or neat.
It is carried out at a temperature of -40°C to 30°C using oxalyl chloride or the like. Preferably, the reaction is carried out using oxalyl chloride without a solvent at room temperature.

Is the carboxylic acid represented by the general formula (■) known per se (for example, p-amylcinnamic acid is commercially available)?
Alternatively, it can be produced by a known method, an example of which is shown in the following scheme (2).

The meaning of each symbol in the diagram (■) is as follows, and the other symbols have the same meanings as above.

R - straight chain or branched alkyl group having 5 to 15 carbon atoms;
Alkoxy or alkenyl group.

b R-C5-15 straight or branched alkoxy or alkenyloxy group.

R - Straight chain or branched alkenyl group or alkenyloxy group having 5 to 15 carbon atoms.

R1d - a linear or branched alkyl group, alkoxy group, alkenyl group or alkenyloxy group having 5 to 15 carbon atoms;

R - Straight chain or branched alkyl group or alkoxy group having 5 to 15 carbon atoms.

R1f - Straight chain or branched chain a/I/ having 5-15 carbon atoms
)7- = group or alkenyloxy group.

R--linear or branched formyl alkyl group or pormyl group having 2 to 14 carbon atoms.

R--linear or branched hydroxyalkyl group or hydroxyl group having 1 to 14 carbon atoms.

In the diagram ①, all reactions are known reactions, but to explain briefly, steps (α) and (n) are formylation reactions, for example, using hexamethylenetetramine in trifluoroacetic acid, 50'C ~Performed at reflux temperature.

Steps 1(5), σ) and (o) are Wittig reactions, for example in an inert organic solvent (ethyl ether, tetrahydrofuran, chloroform, honey, etc.).

The reaction is carried out using the corresponding Wittig reagent at -78°C to room temperature. When using this reaction, products with l=1 or 2 can be obtained.

Steps (C), (A) and (p) are Perkin reaction or Depner reaction, for example, in the presence of pyridine, using pyridine as a solvent, malonic acid or malonic acid ester is used to react at a reflux temperature of 100 ° C. This is done by When using this reaction, the product is of l = 1 and R is a hydrogen atom.

Steps (d), (1) and (, q) are oxidation reactions, and are carried out at a temperature of -20°C to 40°C, for example, by Jones oxidation, Collins oxidation, or Swann oxidation.

When this reaction is used, the product can be obtained with l=0.

Step (g) and (gradation) are reactions that convert hydroxyl groups into alkoxy or alkenyloxy groups, for example in an inert organic solvent (ethyl ether, tetrahydrofuran, etc.), optionally in the presence of dimethylformamide, hexamethylphosphaamide, etc. , using the corresponding alkyl bromide or alkenyl bromide 9 in the presence of sodium hydride under anhydrous conditions at 406 C to reflux.

Process) is a saponification reaction, for example, using an organic solvent (tetrahydrofuran, methanol, ethanol, etc.) that is miscible with water.
medium, using an aqueous alkali solution such as potassium hydroxide, sodium hydroxide or lithium hydroxide, at 0°C to 40°C.
carried out at a temperature of

Steps (q) and (t) are Wittig reactions carried out in the same manner as steps (A), 0) and (O) described above.

The process (Al is a reduction reaction, and the reaction is carried out using diisoptylaluminoid hydride in an inert organic solvent (toluene, ying, ethyl ether, tetrahypyrofuran, etc.) at a temperature of -78°C, or The reaction is carried out using lithium aluminum raminoidolite 9 at a temperature of 0° C. to reflux.

Steps (L) and (=l=1) are oxidation reactions in which oxalyl chloride is reacted in the presence of a tertiary amine (triethylamine, 2-lysine, etc.) in an inert organic solvent (methylene chloride, dimethyl sulfoxide, etc.). It is carried out at 0°C to 40°C.

Steps (-11 and (r)) are reduction reactions in which a catalyst (.ξradium-carbon, .ξradium, platinum black, nickel, etc.) is reacted in an organic solvent (methanol, ethanol, tetrahydrofuran, etc.) under a hydrogen atmosphere. in the presence of 0°C to 40°C
This is done by reacting with

In addition, the carboxamide represented by the general formula (1) [wherein Rlq represents a linear or branched alkyl group or an alkoxy group having 5 to 15 carbon atoms, and all other symbols are as defined above] express the same meaning. It can also be produced by subjecting the compound represented by ] to a reduction reaction, reducing the double bond in R1h and the double bond to which R is bonded, and converting it into an ono-onoethylene group.

This reduction is a known reaction, for example, in a hydrogen atmosphere, in an organic solvent (methanol, ethanol, tetrahydrofuran, etc.), in the presence of a catalyst (palladium-carbon, palladium, platinum black, nickel, etc.) at 00G-40°C. This is done by letting

Furthermore, among the compounds represented by the general formula (11), compounds represented by the general formula [wherein R represents a carboxy group, carboxymethyl group, or carboxymethoxy group, and other symbols have the same meanings as above] is a general formula [wherein R is a straight-chain or branched noalkoxycarbonyl group having 2 to 6 carbon atoms, a straight-chain or branched alkoxycarbonylmethyl group having 3 to 7 carbon atoms, or a straight-chain or branched alkoxycarbonylmethyl group having 3 to 7 carbon atoms; 7 represents a straight-chain or branched alkoxycarbonylmethoxy group, and other symbols have the same meanings as above.] It can also be obtained by subjecting the compound represented by the above to a saponification reaction.

The saponification reaction is a known reaction, for example, using an aqueous solution of an alkaline substance such as sodium hydroxide, potassium hydroxide, lithium hydroxide, etc. in a water-miscible solvent such as methanol, ethanol, tetrahydrofuran.
It is carried out at a temperature of 0°C to 50°C, preferably room temperature.

Of course, the compound represented by the general formula (1,) can also be obtained by esterifying the compound represented by the general formula (Ih).

The esterification reaction is a known reaction, for example, in the corresponding alkanol, an acid such as 7)-) luenesulfonic acid,
It is carried out in the presence of hydrochloric acid at 0°C to 40°C, preferably at room temperature. Of course, solvents such as tetrahydrofuran and methylene chloride, which do not participate in the reaction, may also be used. Further, hydrogen chloride gas may be used as the acid.8 Furthermore, among the compounds represented by the general formula (1), the compounds in which R3 represents an alkoxycarbonylmethoxy group or a carboxymethoxy group are the same as those in which R represents a hydroxyl group as described above. It can also be obtained by subjecting it to the same reaction as step (g) in the scheme, and then subjecting it to a saponification reaction.

The reaction product is 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, column chromatography, or recrystallization. can do. Purification may be performed for each reaction or after completion of several reactions.

As mentioned above, the compound of the present invention has leukotriene antagonistic activity, phospholipase inhibitory activity, and 5α-reductase inhibitory activity, and for example, in laboratory experiments, it exhibited the following effects.

The compounds of the present invention exhibited antagonistic effects against L'rD4 as shown in the table below.

The compounds of the present invention exhibited inhibitory effects on phospholipase A2 as shown in the table below.The compounds of the present invention exhibited inhibitory effects on 5α-reductase as shown in the table below.

The inhibition rate shows the value at a concentration of 2 mbl of the compound of the present invention.

The antagonistic effect of the compound of the present invention on LTD4 was measured by the following experimental method.

The ileum (3cIrL) extracted from a male guinea pig weighing 300 to 400 g was incubated at 37°C with Tyrode's solution and oxygen (
95%) - Carbon dioxide (5%) was suspended in a magmas tube with gas ventilation, and after stabilizing for about 30 minutes, LTD4 was added at a concentration of 10 1/wtl, and the shrinkage at this time was The inventive compound was added at different concentrations and the shrinkage height was measured, from which the engineering C5o value was calculated.

The inhibitory effect of the compounds of the present invention on phospholipase A2 can be determined by using a modified 5hakir method using L-β as a substrate.
-(1-(3)-arachito9yl-α'-stearoyl-phosphatidylcholine) was measured using phospholipase A2 obtained from guinea pig lung as the enzyme (Anal
, Biochem, 114.67 (1981)].

The inhibitory effect of the compounds of the present invention on 5α-reductase was determined using 5α-reductase obtained from rat prostate nuclear fraction, with reference to the method of J. Shimazaki et al. 5α-reductor-synergic fil
i if... ,. 9 M Hep. s'(pH',
7. '4. ), 0.22M sucrose, 5X10-”M
NADPH55μM [42140] Testolone, 5α-
The reaction was carried out at 37° C. for 60 minutes using a mixture of reductase and the compound of the present invention. The reaction was stopped with chloroform-methanol (1/2), and after centrifugation, the supernatant was spotted on a silica gel thin layer plate and chloroform-methanol-acetic acid (99,2:0.6:
The radioactivity of the dihydrotestosterone produced was measured using a TLC scanner, and the enzyme activity inhibition was calculated [: Endocrinol,
See Janon, 18.179 (1971)].

Preferably, the salts and acid addition salts are non-toxic. Here, non-toxic salts and acid addition salts are relatively harmless to animal tissues, and when used in the amount necessary for treatment, the compound represented by the general formula (11) has effective pharmacological properties. It means a salt consisting of an anion or cation that is not impaired by side effects caused by the anion or cation.

It is also preferred that the salts and acid addition salts are water bathable.

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 have 1 to 6 carbon atoms.
alkyl groups, and hydroxyalkyl groups having 1 to 3 carbon atoms. Suitable non-toxic amine salts include tetraalkylammonium salts such as tetramethylammonium, methylamine salts, dimethylamine salts, cyclopentylamine salts, benzylamine salts, phenethylamine salts, lysine salts, monoethanolamine salts, Examples include organic amine salts such as jetanolamine salt, lysine salt, and arginine salt.

Suitable acid addition salts include, for example, inorganic acid salts such as hydrochlorides, hydrobromides, hydroiodides, sulfates, phosphates, nitrates, or acetates, lactates, tartrates, benzoates. salt,
Examples include organic acid salts such as citrate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, and isethionate.

The salt of carfoxamine represented by the general formula (1) can be prepared by adding the acid represented by the general formula (1) to a suitable base, such as an alkali metal or alkaline earth metal hydroxide or Obtained by reaction with carbonates or organic amines.

The acid addition salt of carfoxamine represented by the general formula (1) is
The compound represented by the general formula (1) is prepared by a known method, for example, in an appropriate solvent, using an appropriate acid such as an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, or nitric acid. Alternatively, it can be obtained by reacting with an organic acid such as acetic acid, lactic acid, tartaric acid, benzoic acid, citric acid, methanesulfonic acid, ethanesulfonic acid (fl, 4benzenesulfonic acid, toluenesulfonic acid, isethionic acid).

In mammals including humans, especially humans, suppressing leukotrienes can prevent allergic tracheal and bronchial diseases such as asthma, allergic lung diseases, allergic shock, and various allergic diseases. / or therapeutically effective and also
Diseases caused by arachidonic acid metabolites including the above-mentioned leukotrienes, such as thrombosis, such as thrombosis caused by damage to the endothelium and intima of the brain and coronary arteries, can be prevented by inhibiting phospholipase A2 and/or phospholipase C. ,
It is effective in preventing and/or treating various inflammations such as arthritis and rheumatism. Furthermore, inhibiting 5α-reductase is effective in preventing and/or treating benign prostatic hyperplasia, alopecia, and sitting ulcers.

Carboxamides of general formula (11) or their non-toxic salts or acid addition salts are used for the above purpose (leukoto 1
When used as an enzyme antagonist, vosphorinose inhibitor, or 5α-reductase inhibitor, each is usually administered systemically or locally, orally or parenterally. Dosage depends on age, body weight, symptoms, therapeutic effect, administration method,
Although it varies depending on the processing time etc., it is usually 1m9 to 19cm per adult, preferably 20mm to 200cm at a time.
rn9, administered orally once to several times a day;
Or 100 μg or more of each per adult
Administer parenterally in doses of 100 μl, preferably ITn 9-10 μ, once to several times a day. Of course, as mentioned above, the dosage varies depending on various conditions, so there are cases where it is sufficient to use a smaller amount than the above-mentioned dosage range, and there are also cases where it is necessary to administer the dosage above 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 whey, mannitol, nodotose, hydoxypropyl cellulose, microcrystalline cellulose, starch, polyvinyl pyrrolidone, is mixed with magnesium aluminate metasilicate. The composition is prepared according to a conventional method.
Additives other than inert diluents may be included, such as lubrication agents 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 sucrose, gelatin, hydroxypropyl cellulose, hydroxypropyl methyl cellulose phthalate, etc., or coated with two or more j- You may. 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, this composition may contain adjuvants such as wetting agents and suspending agents, sweetening agents, flavoring agents,
It may contain aromatics 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, and emulsions. Aqueous solution, l! ! Examples of clouding agents 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, Polytrul 80, gum arabic, and sodium alginate. Such compositions may further contain preservatives, humectants,
Auxiliary agents such as emulsifiers and dispersants may also be included. These can be sterilized, for example, by passing through a bacteria-retaining filter, incorporating disinfectants, or by irradiation. They can also be prepared as sterile solid compositions and dissolved in sterile water or sterile injectable solvents before use.

The compositions for parenteral administration include topical solutions, liniments such as ointments, containing one or more active substances and formulated in a manner known per se, for rectal administration. This includes suppositories and intracavitary medicines.

Among the compounds of the present invention represented by general formula (1), preferred compounds include N-(p-amylcinnamoyl)anthranilic acid, N-
(ρ-isoityrsinnamoyl)anthranilic acid, N
-(P-hebutylcinnamoyl)anthranilic acid, N-
(p-decylcinnamoyl)anthranilic acid, N-(m
-decylcinnamoyl)anthranilic acid, N-(7)-
octyloxycinnamoyl)anthranilic acid, N-(P-decyl-2-methylcinnamoyl)anthranilic acid benzoic acid, Honshin Nil Kuipan Mino J phenylacetic acid, venter 2) 4-genoyl]anthranilic acid, nocophenoxyacetic acid , yl)aminocophenoxyacetic acid, N-(p-amylbenzoyl)anthranilic acid, N-(
p-Isopentylbenzoyl)anthranilic acid, N-(
7)-heptylbanzoyl)anthranilic acid, N-(ρ
-decylbenzoyl)anthranilic acid, N-(m-decyl insoyl)anthranilic acid, N-CP-pentyloxybenzoyl)anthranilic acid, N-(P-octyloxybenzoyl)anthranilic acid, 2-1:N-(P
-amylcinnamoyl)aminoconicotinic acid, mino]nicotinic acid, and the corresponding methyl esters, ethyl esters, and non-toxic salts of the above acids, and non-toxic acid addition salts thereof, and o-[NC7'-amyl cinnamoyl)amino]phenol, nol, o-'CN-(p-7''silcinnamoyl)amine]phenol, 0-[N-CP-(1-tridecenyl)cinnamoyl)
[amine]phenol, [yl)amino]phenol, and acid addition salts of the above compounds.

Hereinafter, the present invention will be explained in detail with reference to reference examples and examples.
The present invention is not limited to these examples. In addition, "hP" in Reference Examples and Examples, 1'-TLCJ,
The symbols rIRJ, ``NMRJ and l'''MSJ are
"Boiling point", "Thin layer chromatography", "Infrared absorption spectrum", "Nuclear magnetic resonance spectrum" and "
"Mass spectrometry" and the proportions of solvents listed in the section of separation by chromatography are indicated by volume, volume ratio, [
The solvent in parentheses of TLCJ indicates the developing solvent, and [IRJ
is measured using the KB7 tablet method unless otherwise specified.
MFiJ is deuterated chloroform (unless otherwise specified).
CDC/3) Measured in solution.

Reference Example 1 P-amylbenzaldehyde hexamethylenetetramine 21.9 was added to trifluoro-O vinegar e
The mixture was dissolved in 2nOrul, 150d of amyl was added to the mixture, 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,
The residue was concentrated under reduced pressure and distilled under reduced pressure to obtain the title compound 13.9, which was formed into a shell and had the following physical properties.

HP: 147°C/12-season.

MS: 771/Z=176(M), 147.133
．． 120.119°NMR: δ=9.93 (Office, IH)
, 7.76 (d, 2H), 7.29 (d, 2H),
7.63 (t, 2H), 1.4-1.7 (m.

2H), 0.85 (m, 3H).

Reference Example 1 (a) The title compound 79 having the following physical property values was obtained by the same operation as in Reference Example 1 using 132 g of P-iavea f zunzaldehyde inbentylinzene.
I got 11.

MS: 7F+/Z=176 (M), 133.13
1.120.92.91°NMR: δ = 9.98 (J, IH), 7.8 (d-,
2H), 7.34 (tL, 2H), 2.7 (m, 2
H), 1.54 (m.

2H), 0.96 (d, 6H).

Reference Example 1 (h) Using P-hebutylbenzamidoheptylbenzene 13 (l), the title compound having the following physical properties was obtained by the same procedure as in Reference Example 1: 65.9
I got it.

b7>: 115°C15+++tHg.

MS: m/Z=204 (M), 175.161.12
0.92.91°NMR: δ = 9.96 (, r, IH), 7.78Cd
, 2H), 7.31(d, 2H), 2.65Ct,
2H), 1.4-1.7 (m, 2)1), 1.27
(m, 8H), o, s 4 (m.

3H).

Reference Example 1 (C) 65 g of the title compound having the following physical properties was obtained in the same manner as in Reference Example 1 using 134 g of p-decyl banzaldehyde.

TLC: Rf÷0.53 (cyclohexane:ethyl acetate=1:9).

NMR: δ = 9.76 (J, IH), 7.4 (dcl
, 4H), 2.7 (t, 2H), 0.88 (m, 3H)
.

Reference Example 2 P-amylcinnamic acid Compound 5.88# produced in Reference Example 1 was dissolved in chloroform 1
16.7 fi of methoxycarbonyl methylidene triphenyl phosphorane was added to the mixture, and the mixture was refluxed for 1.5 hours. 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). The obtained compound was dissolved in a mixture of tetrahydrofuran (70 ml) and methanol (30 m/l), 50 ml of 2N aqueous potassium hydroxide solution was added, the mixture was stirred at room temperature overnight, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the title compound 6.44F having the following physical properties.

MS: m/Z=218 (M), 175.161.14
4.115°NMR: δ = 8.50 (,?, IH),
7.78Cd, IH), 7.47(d, 2H), 7.2
1(d, 2H), e, 4o(d, IH), 2.63(
t, 2H), 1.40-1.80 (7yl, 2H),
1.10-1.45 (m, 4H), 0.88 (t, 3H
).

Reference Example 2 (α) p-amyl-2methylcinnamic acid A compound having the following physical properties was prepared in the same manner as in Reference Example 2 using 2 g of the compound produced in Reference Example 1 and 1-ethoxycarbonylethylidene triphenyl phosphorane 4II. Title compound 1.7. I got li+.

MS: m/Z=232 (M), 175.129.11
5°NMR: δ-7,83 (y, IH), 7.40 (
d, 2H), 7.24 (d, 2H), 2.63 (t,
2H), 2.15(d, 3H3,1,5-1,8(m
, 2H), 1.2-1.4 (m, 4H), 0.88
(t, 3H).

Reference Example 3 Dissolve 0.181 nl of 5-(p-7 milphenyl) bank-2,4-chefic acid diisopropylamine in 1.0 ml of anhydrous tetrahydrofuran, and slowly add 0.80 nl of 1.5 M butyllithium at -78°C. , 15 at the same temperature
Stir for a minute. Next, anhydrous tetrahydrofuran 1.
354 ■ of methoxycarbonylprop-2-enyl jetoxyphosphine oxide dissolved in Oral
It was added slowly at 8°C and stirred at the same temperature for 30 minutes.

A solution of Compound 176 prepared in Reference Example 1 dissolved in 1.5 ml of anhydrous tetrahydrofuran was added dropwise to this at -78°C, stirred at the same temperature for 1 hour, and then heated to 0°C.
The mixture was poured into ice-1N hydrochloric acid and extracted with ethyl acetate. The extract was washed successively with water, saturated 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 (methylene chloride: cyclohexane = 2 = 3),
The title compound 217■ having the following physical properties was obtained.

TLG: Rf=0.45 (benzene).

MS: m/Otsu = 258 (M), 243.227.20
1.199.141.129.115.71°NMR: δ=7.05-7.60 (m, 5H), 6.
60-7. O5Cm, 2H), 5.95(d, IH
), 3.74 (, r.

3H), 2.60 (t, 2H), 1.40-1.80
(m, 2H), 1.10-1.50 (m, 4H),
o, 57(t, 3H).

Reference Example 4 p-Amylbenzoic acid 51'111 Compound 1.33.9 produced in Reference Example 1 was dissolved in acetone 25
-, Jones reagent 8d was added under water cooling, and the mixture was stirred at room temperature for 30 minutes. After the reaction, isoproanol was added, filtered, and the filtrate was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol:chloroform=3:97),
The title compound 1.19 having the following physical property values was obtained, TL
C: Rf=0.60 (chloroform:methanol=9
:1).

IR Niji (cIrL)=3400.2300.168
0.1610.1570.1420.1310.128
0°MS Near 71/2. =192(M), 135°N
MR: δ-12,45 (771, IH), 8.1-7.
2 (dd, 4H), 2.68 (t, 2H), 1.9~
1.48 (m, 2H), 1.87-1.15 Cm,
4H), 0.89Cm, 3H).

Reference Example 4 (a) ρ-denlebenzoic acid Using compound 1.611 produced in Reference Example 1 (C),
By the same operation as in Reference Example 4, 1.52N of the title compound having the following physical properties was obtained.

TLC: Rf-0,52 (chloroform:methanol=
q:N.

IR, ν(cIrL)=3400~2200,168
0,1610°1575.1470.1420.132
0,1290cMS near 71/Z, =262(M),
136°NMR: δ-11,5 (m, IH), 8.05
-7.20 (dd.

4H), 2.19(t, 2H). o, ss (m, 3H)
.

Reference example 5 p-inpentyl cinnamic acid Compound 2.71 produced in Reference example 1 (α) was added to pyridine 1
1 ml of lysine and 3.49 g of malonic acid were added thereto, heated to 120° C., and reacted for 4 hours.

The reaction solution was cooled to room temperature, water was added, acidified with hydrochloric acid, and filtered. Purification was performed by recrystallization using a mixture of rheuhexanes and benzene to obtain 2.9 g of the title compound having the following physical properties.

MS Near 71/Z=218(M), 151.144.
115°NMR: δ=7.80 (d, 2H), 7.2
2(d, 2H), 7.48Cd, IH), 6.4o(
d, IH), 2.63(t, 2H), 1.4-1.
8 (m, 3H), o, c+2 (t, 6H).

Reference Example 5 (α) p-heptylcinnamic acid 9.0 g of the title compound having the following physical property values was obtained by the same operation as in Reference Example 5 using Compound 8.7I produced in Reference Example 1 (h). .

MS Near 71/2. =246(M), 161.144
．． 115°NMR: δ -7,80 (d, IH), 6
．． 41 (d, IH), 2.63 (t, 2H), 1.
4-1.7 (m, 2H), 1.3 (m, 8H), o,
s6(m, 3H).

714 Reference Example 5 (h) P-decylcinnamic acid Using 1.3 g of the compound produced in Reference Example 1 (C), the title compound 1.20. I got a 9.

TLC: Rf=0.55 (chloroform:methanol-
1=9).

Engineering Rniji (crIL-”) = 3400-2300.1
68o, 1620°1605.1460.1425.1
310.1290.1225.1180.980゜MS
Near 11/Z, = 288 (M), 161°NMR: δ
=7.74(d, IH), 7.33(,Y, 4H
), 6.39 (d, IH), 2.63 (t, 2H)
, 0.87 (m, 3H).

Reference example 6 ρ-hydroxycinnamic acid methyl ester p-hydroxycinnamic acid 25.9 methanol 200 ml
After blowing hydrogen chloride gas under water cooling for 30 minutes, the solution was concentrated under reduced pressure. The distillate was subjected to silica gel column chromatography (cyclohexane:ethyl acetate = 10:1
) to obtain the title compound 21 having the following physical properties.

MS Near 71/Z-178 (M), 147.119.
91°NMR: δ-6,88~7.42 (dd, 4H
), 6.3-7.85(g*2H), 3.8(,?
, 3H).

Reference Example 7 p-hentyloxycinnamic acid methyl ester sodium hydride 1.04,9 was added to 15 Tnl of anhydrous tetrahydrofuran
P-hydroxycinnamic acid methyl ester 4.45F (produced in Reference Example 6) was suspended in the solution and cooled in a water bath.
A solution prepared by dissolving . A solution of nityl bromide 4.53.9 dissolved in 10 mA' of anhydrous tetrahydrofuran was added to this 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 to obtain 4.4 g of the title compound having the following physical properties.

MS Near 71/2. =248(M), 217.178
．． 147.109°NMR: δ = 6.9 ~ 7.49 (
dd, 4H), 6.3-7.66 (q.

2H), 3.98 (!, 2H), 3.78 (J, 3H
) 1.6-1.9 (m, 2) 1), 1.2-1.6 (
m*4H) 0.92(t, 3H).

Reference Example 7 (α) p-Octyloxycinnamic acid methyl ester Using 4.5 g of the compound produced in Reference Example 6, the title compound 3.19 having the following physical property values was obtained by the same operation as in Reference Example 7. Ta.・□Pi, MS: m/z=290 (M), 1
78.147J16g. '□NMR: δ-7,17
(dd, 4H), 7.07 (q, 2H), 3.96 (
t, 2H), 3.77 (J?, 3H), 1.6-1.
9 (m, 2H), 1.2-1.6 (m, 10H)
, 0.87 (t, 3)1).

Reference Example 8 p --<Hentyloxycinnamic acid p -Hentyloxycinnamic acid methyl ester (Reference Example 7
Manufactured by. ) 4.4.9 to tetrahedral 90 francs 30
It was dissolved in a mixture of WLl and 30 d of methanol, 15 d of a 4N aqueous potassium hydroxide solution was added, and the mixture was stirred at room temperature for 4 hours. Drained reaction water, ether and concentrated hydrochloric acid were added, and the ether layer was washed successively with water and saturated brine, dried over anhydrous sulfuric acid, and concentrated under reduced pressure. The residue was purified by recrystallization using benzene to obtain 3.86 J/ml of the title compound having the following physical properties.

MS: m/7. -234(M), 217.164.1
47°NMR: 6M6.9-7.5Cdd, 4H),
6,3-7.76 (q.

IH), 3.99 (!, 2H), 1.6-1.9 (m
.

2H), 1.2-1.6 (m, 4H), 0.92
(t.

3H).

Reference Example 8 (α) C3H07 to p-octyloxycinnamic acid O Using 3.1 g of the compound produced in Reference Example 7 (α),
By the same operation as in Reference Example 8, the title compound 3.09 having the following physical property values was obtained.

MS: m now, = 276 (M ), 258.164.14
7°NMR: δ = 7.2 (dd, 4H), 7.0 (q
, 2H), 3.98 (t, 2H), 1.6-1.9 (7
71,2H), 1.2-1.6 (m, 10H), 0.8
7(t, 3H).

Reference Example 9 7)-(1-)Lysocenyl)benzoic acid methyl ester In an aluene gas atmosphere, P-decyltriphenylphosphonium promyelium-'8.6519 was added to anhydrous tetrahedral 90
1. Suspended in Furan 60 and cooled to -78°C.
5N rubyl lithium (n-hexane) solution 8.2
37d was slowly added, stirred for 5 minutes at the same temperature, and 1.48 g of P-formylbenzoic acid methyl ester was added to the mixture at 10 mA of anhydrous tetrahydrone! A solution dissolved in water was slowly added thereto, and the mixture was stirred at the same temperature for 1 hour and 30 minutes and at 0°C for 30 minutes.

The reaction solution was poured into an aqueous ammonium chloride solution, extracted with ethyl acetate, and concentrated under reduced pressure. The residue was suspended in ethyl acetate-cyclohexane (5:1), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:
Cyclohexane = 1 = 20) to obtain 2.95 g of the title compound having the following physical properties.

TLC: Rf=0.40 (ethyl acetate:cyclohexane=1:10).

MS: m/Otsu = 316 (M), 285.257.16
2.131.115.91°NMR: δ -8,00 (d, 2H), 7.32 (d
, 2H), 6.44Cd, IH), 5.76(dt, I
H), 3.90 (-t, 3H), 2.30 (m, 2H)
, 1.05-1.80 (m, 18H), 0.88 (t
.

3H).

Reference Example 10 1-(p-hydroxyphenyl)tridec-1-ene In an argon gas atmosphere, the compound produced in Reference Example 9, 2.
91.9 was dissolved in anhydrous toluene 60 mA' and heated to -78°C.
To the solution cooled to
1 Ll was slowly added and stirred at the same temperature for 5 minutes and at 0°C for 20 minutes. After cooling the reaction solution to -20°C, methanol and then 4 d of water were added dropwise with vigorous stirring.
The reaction was stopped and the mixture was vigorously stirred at room temperature for 30 minutes. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. Toluene was added to the residue, water was removed by azeotropy, and the residue was dried under reduced pressure to obtain 2.54 fl of the title compound having the following physical properties.

TLC: Rf-0,27 and 0.33 (ethyl acetate:
cyclohexane-1:3).

MS: m/2. -288(M), 270.257.1
34.129.117, ] 05.91° NMR: δ = 7.28 (!, 4H), 6.40 (d,
IH), 5.66 (dt, IH), 4.63 (J',
2H), 2.30 (m.

2H), 2.00 (-?, IH), 1.05-1.70
(m.

18H), 0.88(', 3H).

Reference Example 11 p-(1-)lysocenyl)induldehyde oxalylchloride)”1.05TnA! was added to 15ml of methylene chloride.
After dissolving K, a mixture of 1.42 ml of dimethyl sulfoxy and 5-methylene chloride was slowly added at −78° C. under an argon gas atmosphere, and the mixture was stirred at the same temperature for 20 minutes. In addition to this, the compound produced in Reference Example 10 was 2.541!
A solution prepared by dissolving 10 d of methylene chloride was added dropwise at -78°C, and the mixture was stirred at the same temperature for 30 minutes. Furthermore, 5.3 ml of triethylamine was added dropwise at the same temperature, stirred for 5 minutes, heated to room temperature, stirred for 5 minutes, and poured into water.

Extract with methylene chloride, wash the extract with saturated saline,
It was dried over anhydrous magnesium sulfate and concentrated under reduced pressure.

The residue was purified by silica gel column chromatography (methylene chloride: cyclohexane = 1:3) to obtain the title compound 2.48.9 having the following physical properties.

TLC: Rf=0.35 (ethyl acetate:cyclohexane=1:3).

MS: m/z, = 286 (M), 268.257.1
32.117.91°NMR: δ = 9.98 (S, IH), 7.84 (d,
2H), 7.42 (d, 2H), 6.44 (d, IH)
, 5,80 (tit, iH), 2.30 (771,2
HS, 1.05-1.70 (771, 18H), 0.8
8 (1', 3H).

Reference Example 12 p-(1-)lysocenyl)cinnamic acid methyl ester 2.48 g of the compound produced in Reference Example 11 was added to 30 g of methylene chloride.
2.9 g of methoxycarbonyl methylidene triphenylphosphorane was added to the mixture, and the mixture was refluxed for 2 hours. After the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride:cyclohexane-2=3) to obtain the title compound 3.421! having the following physical properties. I got it.

TLC: Rf-0,45 and 0.55 (-!Nzen).

MS: m/z, = 342 (M), 311.201.1
88.169.157.141.115°NMR: δ = 7.69 (d, IH), 7.49 (d,
2H), 7.28(d, 2H), 6.42(d, 1)I
), 6.39 (d, IH), 5.72 (di, IH),
3.80(,?, 3H), 2.30(m, 2)1)
, 1.05-1.70(m, tel(), 0.88(
t.

3H).

Reference Example 13 7)-(1-)lysocenyl)cinnamic acid Compound prepared in Reference Example 12 2.81. ! i' was dissolved in a mixture of methanol (15 m/) and tetrahydrofuray (7 m), 225 d of a 1N aqueous lithium hydroxide solution was added, and the mixture was stirred at room temperature overnight. 150 ml of reaction water was added, neutralized 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 concentrated under reduced pressure to obtain the title compound 2.24.9 having the following physical properties.

TLC: Rf=0.40 (ethyl acetate:cyclohexane-1:1).

MS: m72F328 (M), 311.300.18
7.174.169.161.141.128.115
．． 91°NMR: δ = 7.68 (c7.LH), 7.
51 (d, 2H), 7.30 (Cj, 2H), 6.41
(d, IH), 6.39 (d, IH), 5.72 (dt
, IH), 4.37 (-1', tH), 2.30 (m,
2H), 1.05-1.65 (m, 18H), 0.86
(1!

3H).

Reference Example 14 3-Hydroxymethylbenzonitrile A solution of 3 g of 3-cyanobenzoic acid dissolved in 5 ml of tetrahydrofuran was cooled with ice, and 2.439 g of ethyl chloroacetate was added dropwise thereto, followed by stirring for 20 minutes. 2.26 # of sodium borohydride was added to this, stirred for 30 minutes, water was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: rL-hexane = 3 nia) to obtain the title compound 1.7 having the following physical properties.
I got g.

IR (liquid film method); ν(α)-3400,2230°N
MR Niji = 4.53 (, r, 4H), 7.50 (m
, 4H).

Reference Example 15 1.7 g of the compound produced in Reference Example 14 was added to 3 methylene chloride.
The solution was dissolved in 0ml and cooled on ice. This is dihydrohyde 572.
14,! i"#, J: A catalytic amount of hip-toluenesulfonic acid was added to react. After the reaction, triethylamine was added, washed with water, dried over 11 um of anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified with silica gel. - Purification by chromatography (ethyl acetate: Ruhexane = 2:8) to obtain 2.0 g of the title compound having the following physical properties.

IR (liquid film method) CcrFt) = 2230° Reference Example 1
6 2.7 g of the compound produced in Reference Example 15 was added to toluene xom
After cooling the mixture to -78°C and adding 5.471 Ll of diisobutylaminium hydrate,
After raising the temperature to 0°C and stirring for 10 minutes, methanol was added at -78°C. Water was added thereto, filtered, diluted with ethyl acetate, the precipitate was washed with an aqueous tartaric acid solution, combined with the filtrate, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:
n-hexane (1:9) to obtain the title compound 2.56.9 having the following physical properties.

IR (liquid film method) rainbow (cm ) = 1730°NMR: δ
Category 9.60(,?,xH).

Reference Example 17 Triphenylnonylphosphine bromine) at room temperature 6.
After preparing 60.9 and adding hexamethylphosphaamide 2-resistant, compound 2.56.9 produced in Reference Example 16
was added all at once and reacted at room temperature for 3 hours. After the reaction, water was added, extracted with ethyl acetate, dried over anhydrous sulfuric acid, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate = n-hexane = 1:9) to obtain the title compound 2.07.9 having the following physical properties.
I got it.

NMR: δ-7,05(m, 4)I), 6.26(d
, LH), 5.50 (di!, IH), 4.55 (
q, 2H).

Reference Example 18 1-(3-Hydroxymethylphenyl)dec-1-ene Compound 2.87F produced in Reference Example 17 was dissolved in methanol 4
0ml, add 1 drop of p-toluenesulfonic acid,
The mixture was stirred at room temperature for 2 hours. Triethylamine was added to the reaction solution, concentrated under reduced pressure, and the residue was dissolved in ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, and then subjected to silica gel column chromatography (ethyl acetate: n-hexane-1-9).
2.1 g of the title compound having the following physical properties were obtained.

NMR: δ = 7.05 (771,4H), 6.3Cd,
IH), 5.50 (dt, IH), 4.42 (S,
2H).

Reference Example 19 3-(1-decenyl)-? 2.1 g of the compound produced in Reference Example 18, 1.3 g of dimethyl sulfoxide
4#,) ethylamine 4,9d and methylene chloride 5
Cool 0 ml of the mixture on ice, and add oxalylchloride F'1.
64 g was added dropwise and left for 1 hour. The reaction solution was washed with water, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (ethyl acetate = n-hexane - 5:95) to obtain the title compound 1.84.1i having the following physical properties.
got '.

■R Niji (cIrL) = 1725° MS: m/2=244 (M).

NMR: δ-9,81(-1", IH), 7.1-7
．． 7 (m, 4H), 6.33 (d,, IH), 5
．． 65 (dt, IH).

Reference Example 20 3-(1-7”cenyl)cinnamic acid methyl ester Reference Example 1
Compound 5007Q prepared in step 9, methoxycarbonyl methylidene triphenylphosphorane 1.26. A mixture of li' and 2011 L of benzene was stirred at room temperature for 15 hours and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:L-hexane 1:9) to obtain the title compound 550■ having the following physical properties.

Engineering R Niji (閤-') -1690,1640゜MS:m/
Z, -300 (M), 258.243°NMR: δ=
7.7-7.1 (m, 5H), 6.3 (d, IH
), 6.29(d, IH), 5.7Cdt, IH),
3.6 (#, 3H).

Reference Example 21 3-(1-decenyl)cinnamic acid A mixture of 300 ml of the compound prepared in Reference Example 20, 3 ml of 1N aqueous sodium hydroxide solution, and 5 d of methanol was refluxed for 3 hours. After the reaction, the reaction mixture was concentrated under reduced pressure, acidified with 1N hydrochloric acid, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Residue and silica gel column chromatography (ethyl acetate/l/: n-hexane = 3 nia)
The title compound 3001n was purified by
l/ was obtained.

MS: m/2=244 (M).

NMR: δ = 10.0 (,?, IH), 7.66 (d
, IH), 7.2 (m, 4H), 6.35 (d, IH)
, 6.30 (d, If-1), 5.6 (dt, tH),
2.3 (m.

2H).

Reference example 22 1-(3-hydroxymethylphenyl)tecan 1oH2
1 A mixture of the compound 100Tn produced in Reference Example 18, 9.10% palladium-carbon, 10 ml, and methanol (5 ml) was stirred at room temperature under a hydrogen atmosphere for 4 hours.

The reaction solution was filtered and concentrated under reduced pressure to obtain the title compound 92■ having the following physical properties.

MS Near 71/Z, = 288° Reference Example 23 3-decylbenzaldehyde Using Compound 92■ produced in Reference Example 22, Reference Example 1
9 By the same operation, the title compound 80Tv having the following physical properties was obtained.

■R Niji(crrL)-17(10°NMR: δ-9,7(,?, IH),'1.7(m,
2H), 7.3 (m, 2H), 2.5 (bt, 2H)
.

Reference Example 24 3-decylcinnamic acid methyl ester Using the compound 80■ produced in Reference Example 23, Reference Example 2
By the same operation as in Example 0, the title compound 901Q having the following physical properties was obtained.

Engineering Rniji (am) = 1690.1640°MS: m/
2r298 (M).

NMR: δ=7.7-7.1 (7F+, 5H), 6.
3 (d, IH), 2.3 (m, 2H).

Reference Example 25 3-decylcinnamic acid Compound 9oTn9 produced in Reference Example 24 was used in the same manner as in Reference Example 21 to obtain the title compound 85Tn9 having the following physical properties.

NMR: δ-11,5 (j', IH), 7.65 (d
, IH), 7.2 (m, 4H), 6.33 (d, ],
IH, 2, 3 (m, 2H).

Reference Example 26 3-(1-decenyl)benzoic acid Compound 5oom9 produced in Reference Example 19 was aceto720
ml, cooled to -20°C, and Jones reagent was added dropwise. The reaction was confirmed by TLC, and when there were no unreacted substances, isopropyl alcohol was added. Extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated under reduced pressure,
Silica gel column chromatography (ethyl acetate=I
The product was purified using L-hexane (3 nia) to obtain 210 ml of the title compound having the following physical properties.

Engineering R Niji (crrL-1)-3400~2800.16
900M5 near 71/2. =260(M+).

NMR: δ=7.3-8.0 (771,4H), 6.3
5 (d, IH), 5.65 (4, IH).

Reference Example 26 (α) m-decylbenzoic acid Using Compound 20 prepared in Reference Example 23, Reference Example 2
By the same operation as in 6, the title compound 16Iv having the following physical properties was obtained.

IR:l/(cIIL)=3400~270G, 17
00M5: m/z; = 262 (M).

NMR: δ-11,5 (m, IH), 7.7 (m, 2H
), 7.25 (m, 2H), 2.6 (y+1.2H)
, 2.25 (m.

16H), 0.90 (m, 3H”).

Example 1 N-(p-amylcinnamoyl)anthranilic acid and its sodium salt'-C5H1l 1 ml of oxalyl chloride was added to 218 cm of p-amylcinnamic acid (produced in Reference Example 2), and the mixture was diluted with 1 ml of oxalyl chloride at room temperature.
After stirring for an hour, the mixture was concentrated under reduced pressure.

Anthranilic acid 137q and triethylamine 30:lI
The above concentrate was added dropwise to a solution of 9 in 2 d of methylene chloride under water cooling, and the mixture was stirred at room temperature for 1 hour, then 3 ml of 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was purified using silica gel column chromatography (methylene chloride:ether-5:1) and recrystallized using a mixture of methanol-hexane to obtain the title compound (acid) 125~ having the following physical properties. .

TLC: Rf-0,3 (methylene chloride:ether=2:
1).

MS: m/z, -337 (M+), 319.201° D0ν (c7rL): 1695.1665.16o5
．． 1580°] 515.1450° NMR: δ-8,92 (dd, LH), 8.17 (dd
, IH), 7.77 (d, IH), 7.65Cdt, I
H), 7.51Cd, 2H), 7.21(d, 2H),
7.14 (d, t, IH), 6.57 (d, IH).

Suspend the above acid in methanol and 1N hydroxide)
An equivalent amount of an aqueous solution of IJum was added dropwise and concentrated under reduced pressure to obtain the corresponding sodium salt (pale yellow crystals).

Example 1 (21-1) The following compound was obtained from the corresponding starting material by the same procedure as in Example 1.

Example 1 (α) Starting material: p-decylcinnamic acid 233m9 (Reference example 5 (h
). ).

Purification method Nisilica gel column chromatography (methylene chloride:ether = 5:1).

Yield [acid 1145 ■.

TLC (acid): R,7''-0,3 (methylene chloride:ether = 3:1).

IR[Salt]Niji(n)=1670.16201159
0.1510.1440.1380゜MS (acid) Near 71/22-407 (), 389.27
1°NMR (acid): δ = 8.92Cdd, IH), 8
．． 17 (dd, IH), 7.77Cd, IH), 7
．． 65 (tit, IH), 7.51 (d, 2H), 7.
21Cd, 2H), 7.14Cdt, IH), 6.57
(d, IH).

Salt form: pale yellow crystals.

Example 1 (h) Starting material: P-amylbenzoic acid 100 Iv (Reference example 4
Manufactured by. ).

Purification method: Preparation TLC (ethyl acetate:Ruhexane=1:1).

Yield [acid]: 29 Tv TLC [:acid:]: Rf=0.3 (ethyl acetate:rL-hexane-1:1).

IR[acid]Ccrn)-1690,1650,1
610,1585°MS [acid]: m/i31HM),
293.175°NMR [acid]: δ-8,86 (dd,
IH), 8.14 (dd, IH), 7.94 (d,
2H), '1.59Cdt, IH), 7.29(d
, 2H), 7.12 (dt, IH).

Form of salt: light brown crystals.

Example 1 (C) (102) Starting material: P-decylbenzoic acid 236■ (Reference example 4 (
α). ).

Purification method: Preparative TLC (ethyl acetate:luhexane-1:1).

Yield [acid] = 40■.

TLC [acid]: Rf-0,3 (ethyl acetate: rL-
Hexane = 1 = 1).

IR [acid]: L/(cm ) = 1690.165o, 1
610.1590°MS [acid 1:m/2. =381(M
), 363.245°NMR [acid]: δ = 8.98 (
dd, IH), 8.17 (dd, IH), 7.96
Cd, 2H), 7.67Cdt, IH), 7.32Cd
, 2H), 7.16Cdt, IH).

Salt form: pale yellow crystals.

Example 1(d) (103) Starting material: m-(1-decenylbenzoic acid 103Lrv
/ (produced in Reference Example 26).

Purification method: Preparative TLC (ethyl acetate y+-; luhexane=11).

Yield [acid]; 10~.

TL, G [acid]: Rf = 0.3 (ethyl acetate; luhexane = 1; 1).

IR (acid) di(cm) = 1680.1665.16
10.1590.1530.1450°MS (acid): m/22-379(), 361.334.
267.243°NMR [acid]: δ = 8.9'1Cdd, IH), 8.
67 (dd, LH), 7.8-8.05 (1'n, 2
H), 7.67 (d, t.

IH”l, 7.2-7.6 (7y+, 2H), 7,3
7 (d, t, IH), 6.47 (CL, 1) I),
5.7'1Cdt, IH).

Salt form: brown crystals.

Example 1(e) N-(m-decylbenzoyl)anthranilic acid and its sodium salt Starting material: m-decylbenzoic acid 69 da (Reference Example 26 (
Manufactured with al. ).

n Manufacturing method: Preparative TLC (ethyl acetate: luhexane = 1:2).

Yield [acid]; 51n9° TLC [acid]: Rf-0,3 (ethyl acetate=FL-hexane=1:1).

IR [acid] (liquid film method) Niji ([-”) = 1680.16
1o, 1590.1530°MS [acid]: m/2j-381,363,301,
245°NMR [acid]: δ-8,95 (dd, i!H
), 8.15 (cLd, IH), 7.75-7.95
(m, 2H), 7.64 (dt.

IH"), 7.30-7.50 (71, 2H), 7.1
3 (dt, IH).

Salt form: pale yellow crystals.

(104) Example 1 (J) N-Cm-(1-decenyl)cinnamoyl]anthranilic acid and its sodium salt Starting material Nia 7l-(1-decenyl)cinnamic acid 1301
n9 (manufactured in Reference Example 21).

Purification method: Preparatape TL0 2 times development (ethyl acetate:
rL-hexane = 1:2).

Yield [acid]: 421 Da.

TLC (acid): Rf-0,3 (ethyl acetate: rL-
hexa/=1:1).

IR [acid] (liquid film method) CcIrL)-1680,
1605°MS [acid]: 771/2. =405.3
87.269°NMR [acid]: δ = 8.89 (d, I
H), 8.14Cdd, 1f-1), 7.76(d,
IH), 7.62Cdt, IH)1, 7.2-7.5(
m, 4H), 7.13 (t, IH), 6.58Cd, I
H), 6.40 (IIM, IH).

Salt form: pale yellow crystals.

(106) (105) Example 1(g) N-(m-decylcinnamoyl)anthranilic acid and its sodium salt RuC□. H2□ Starting material: m-decylcinnamic acid 1051n9 (Reference example 2
5. ).

Purification method: Recrystallization method (ethyl acetate-ruhexane).

Yield [acid]: 60 Da.

TLC [: acid): Rf = 0.4 (ethyl acetate: r
L-hexay=1:1).

IR (acid) (liquid film method) CIIL = 1680.
1605.1590°MS [acid]: m/ or 407.389.271°NMR[
Acid]: δ = 8.88 (d, IH), 8.11 (dd, I
H), 7.72 (d, IH), 7.60dl! , IH
').

7.2-7.5 (711, 4H), 7.11 (t, IH
), 6.58 (', IH).

Salt form: white crystals.

(107) Example 1(h) Starting material 2p-amy-2-methylcinnamic acid 230Tn9
(Produced in Reference Example 2 (α)).

Purification method: Recrystallization method (Tojosan: Ethyl acetate = 10:1)
.

Yield [acid]: 254■.

TLC [acid:]: Rf=0.3 (ethyl acetate:ruhexane=2:i).

Engineering R [acid] nitrogen (crrL) = 1660.1610.1
600.1580.1520°MS (acid) near 71/21=351.333,215.
187.145°NMR [acid]: δ = 8.80 (d,
IH), s, os(dd, IH), 7.56Cdt,
IH), 7.54(,?,IH'), 7.1-7.4(
771,4H), 7.07(t, IH), 2.23(d
, IH).

Form of salt - white crystals.

Example 1 (t,+ Starting material: p-<1-) I+decenyl)cinnamic acid 1881 ng (produced in Reference Example 13).

Purification method Nisilica gel column chromatography (ethyl acetate:cyclohexane-1=3→2:1).

Yield [acid] = 105Tn9° TLC [acid]: Rf = 0.20 (ethyl acetate:cyclohexane 1:1).

IR[acid]nid(c++t)=2940.2860.
1685.1625.1605.1585.1520.
1450.1400.1220,835.755.65
5.520°MS [acid 1: m/2r447.429.311.1
69.157.141.137.129.115°NMR [salt] (CD30D): δ = 8.6Hd,
IH), 8.08 (cl.

1H), 7.50-7.70Cm, 3H), 7.25-
7.50 (m, 2H), 7.06 (t, IH), 6.7
2Cd, IH), 6.3-6.50 (m, 1.5H
), 5.72 (dt, 0.5H), 2.15-2.42
(m, 2H), 1.15-1.60 (m, 18H), 0
．． 90 (1!, 3H).

Salt form: brown solid.

Example 10) Starting material vL: p-inpentyl cinnamic acid 267'In
g (produced in Reference Example 5).

Purification method - Recrystallization method (ethyl acetate: luhexane = 1:
10).

Yield [acid]: 215# TLC [acid']: Rf = 0.6 <Ethyl acetate:
rL-hexay=2:1).

(110) IR[acid]nid(cML)=1680.1620.1
600.1580.1510°MS [acid 1:m/2I=2337.319.201.1
37.131°NMR (acid): δ = 8.91 (d,
IH), 8.18 (ldt, IH), 7.77Cd
, IH), 7.64 (dt, IH), 7.2-7.6 (
771, 4H), 7.14 (1!, IH), 6.57 (
d, IH).

Two white crystals in the form of salt.

Example 1(k) Starting material: p-pentyloxycinnamic acid 290Iv (prepared in Reference Example 8).

Purification method: Recrystallization method (chloroform-ruhexane).

Yield [acid]: 269■ ・　,21′・ν″・”゛ TLC [acid]: Rf-0,40 (chilled acetic acid).

, ``IR[acid]nid(crrL)=1660,1600.
1580°('l'l'l')' 1525.1510°MS [acid:] Near 71/2=353(M), 335.
264.217.208.147°NMR [#]: δ = 8.90 (d, IH), 8.15 (
d, IH), 7.72 (d, 2H), 7.62 (dt,
IH), 7.45-7.60 (m, 2H), 7.12 (
t.

IH), 6.80-6.95 (7F+, 2H), 6.4
6 (d, IH), 3.96 (t, 2H).

Salt form: pale yellow solid.

Example 1 (1) Starting material: P-octyloxycinnamic acid 285Tng (
Produced in Reference Example 8 (α). ).

Purification method - recrystallization method (methanol-ruhexane).

Yield [acid]: 210■.

TLC (acid 1: Rf-0,40 (ethyl acetate).

IR [Salt] Niji (cIrl) = 1660.1600.1
590.1505°MS [acid 1:m/2J=395(M), 377.25
9.147°NMR [acid] (CDC13+CD30D)
: δ=8.81 (d, IH), 8.10 (1s,
1m) H), 7.68 (d, IH), 7.56 (dt,
IH), 7.09Ct, IH), 7.45-7.60 (
771, 2H), 6.85-7.00 (m, 2H), 6
．． 47 ('d, IH), 3.98 (t, 2H).

Salt form: pale yellow solid.

Example 1 (m) Starting material: ρ-amylcinnamic acid 130I solution (produced in Reference Example 2) and anthranilic acid methyl ester 901n9° Purification Method Nisilica gel column chromatography (ethyl acetate: rL-hexane = 1:20) .

Yield = 89m9° TLC: Rf-0,70 (ethyl acetate: n-hexane =
1:4).

Engineering Rniji (cIrL) = 1680.1620.1600
．． 1580.1520°MS 2m/Otsu =351.336.320.201.
151°131° NMR: δ = 8.87 (d, IH), 8.05 (d,
IH), 7.74 (d, IH), 7.58Ct, IH)
, 7.2-7.55 (m, 4H), 7.08 (t,
IH) 6.57Cd, IH), 3.95 (J', 3H)
.

Example 1 (rLl Starting material: p-amylcinnamic acid 146Tny (Reference example 2
Manufactured by. ) and 0-aminophe(114) nylacetic acid 101j719° Purification method Nisilica gel column chromatography (ethyl acetate:rL-hexane-1:2).

Yield [acid]: 951n9° TLC (acid 1: Rf = 0.30 (ethyl acetate).

IR[acid]nid(,)=1690.1650.16J5
゜MS [acid]: ”m/2-351.333.307.2
01.151.131°NMR [acid]: δ = 7.90L5', IH), 7.7
4(d, LH), 7.1-7.6Cm, 8H), 6.6
0 (d, IH), 3.65 (-? delirium 2H).

Salt form: pale yellow solid.

Example 1 (O) m-CN-Cp-amylcinnamoyl)amino]benzoic acid and its sodium salt Starting material: ρ-amylcinnamic acid 12! W (produced in Reference Example 2) and m-aminobenzoic acid (115) 791 ng.

Yield [salt]: 52■.

TLG (salt): Rf=0.30 (ethyl acetate: r
L-hexane = 1:1).

IR [salt] Niji (Confucian) = 1680.1650.162
0, '1585.1535°MS [salt']: m/z = 337 (M), 201.13
1°NMR [salt] (CD30D): δ=7.8O-82
0 (771, 2H), 7.40-7.80 (7y+, 4
H), 7.20-7.40 (m.

3H), 6.74(d, IH).

Salt form: pale yellow solid.

Example 1 (P) N-(p-hebutylcinnamoyl)anthranilic acid and its sodium salt Starting material Ninohe-heptylcinnamic acid 224■ (Reference example 5 (
α). ).

Purification method Niji 11 Kagel column chromatography (ethyl acetate: rL-hexane = 1:10).

Yield [acid 1: 1601n9゜TL (3 [acid]: Rf = 0.20 (ethyl acetate: rL-
Hexane = 1 = 1).

IR (Salt) Niji Ccrft)-1605,1585,1
500,1435,1380°MS [acid 1: m/z, = 365.347.219.
144.137.131°NMR [acid]: δ=s, 5s (d, IH), 8.15 (
dt, IH), 7.62Cdt, IH), 7.1-7.
6 (r, 4H) 7.12 (t, IH), 6.56 (d,
IH).

The form of the salt is a two-white solid.

Example 1 (q) Starting material: P-amylcinnamic acid 308Tng (Reference Example 2
Manufactured by. ) and O-aminophenol 1621n9° purification method Niji 11 Kagel column chromatography (ethyl acetate: rL-hexane = 1:4'').

Yield: 69 Da.

TLC: Rf-0,60 (x tyl acetate: n-hex f
y=1=2).

Engineering Rniji (cIrL) = 1650.1620,1600
゜MS: m/Z = 309 (M), 201.131゜N
MR: δ = 9.33 (#, IH), 7.77 (d,
IH), 7.76 (, r, IH), 7.00-7.50
(7F+, 7H), 6.85 (dt, IH), 6.57
(d, IH).

Example 1(r) 2-(N-(ρ-amylcinnamoyl)aminonicotinic acid and its sodium salt Starting materials: 110 μm of p-decylcinnamic acid (produced in Reference Example 2) and 2-aminonicotinic acid 77 ■.

(118) Purification method Niji 11 gel column chromatography (ethyl acetate: rL-hexane = 1:2).

Yield [acid]: 52 Da.

TLC [acid']: Rf-0,10 (ethyl acetate), IR
[Acid] Niji (my ') = 1680.1630, J600
．． 1550MS [acid]nia 71/2. -338 (M)
, 319.310.291.201°NMR [salt] (CD30D): δ-8,43 (dd,
11(), 8.40Cm, IH), 7.72(d, IH
), 7.50-7.60 (m, 2H), 7.20-7.
30 (m, 2H), 7.12Cdd, IH), 6.7
8 (d.

IH).

Salt form: pale yellow solid.

Example 1 (S) (119) Starting material: P-amylcinnamic acid 6251n9 (Reference example 2
Manufactured by. ) and 2-amino-3-hydroxypyridine 100 ■.

Purification method Nisilica gel column chromatography (ethyl acetate: cyclohexane-1:2) Yield: 80 ■.

TLC: Rf=0.22C ethyl acetate:cyclohexane=1=1).

Engineering R Niji (crIL)=3520,3440.329
0,3130°2920.2850.1775.163
0-1650.1605.1565.1515.147
5.1450.1415.1370.1305.120
5.1180.1145.1100.960.845.
825.810.755.555.500°MS: m/Z-310CM), 266.253.20
1.173.157.144.131.115.110
．． 103°NMR: δ -7,95 (dtL, IH), 7.86
(d, 1) 1), 7.48 (d, 2H), 7.37 (
d, cL, IH), 7.22 (d, 2H), 6.69 (
dd, IH), 6.57 (d, IH), 4.65 (S,
2H), 2.64 (t, 2H), 1.62 (m, 2H)
, 1.20-1.50 (m, 4H), 0.90 (t, 3
H＞.

Example 1(t) Starting material: P-amylcinnamic acid 654Tng (Reference Example 2
Manufactured by. ) and 2-amino-6-hydroxypyridine 110■.

Purification method Nisilica gel column chromatography (M ethyl: cyclohexane = 1:3).

Yield: 164■.

The: Rf = 0.25 (ethyl acetate: cyclohexane = 1: IIR di(cIn) = 3435.33
20.3310,2930.2855.1710.16
40.1605.1550.1480.1435.12
50°1195.1175.1125.1055.10
00.975.910,815.795°765.62
0,505°MS: m/z=310(M), 282.265.2
53.225.201.173.157.144.33
1.115.110.103°NMR: δ -7,86 (d, IH), 7.52 (t,
IH), 7.48 (d, 2H), 7.21 (d, 2
H), 6.56 (d, IH), 6.49 (d, IH),
6.39 (d, IH), 4.52 (#, 2H), 2.
64 (t, 2H), 1.83 (m, 2H), 1.2
0-1.50 (m, 4H), 0.90 (t.

3H).

Example 2 (22) Add 1.4 ml of 5-(p-peptylphenyl) oxalylchloride to 110~ of 2.4-dienoic acid (produced in Example 3), After stirring at room temperature for 30 minutes, it was concentrated.The obtained yellow solid was dissolved in 2 ml of anhydrous methylene chloride, and 121 μm of anthranilic acid methyl ester dissolved in 3 ml of anhydrous methylene chloride and 0.11 g of triethylamine was added to the solution at 0°C. The mixture was added dropwise at the same temperature for 30 minutes and then stirred at room temperature for 1 hour.

To this was added 20 g of 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid, water, an aqueous sodium bicarbonate solution, and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform:cyclohexane=1:
1) and further washed with luhexane to obtain the title compound 90Iv having the following physical properties.

MS: m/, 7377 (m”), 362.346.31
9.242.227.170.161.141.115
°NMR: δ = 11.24 (,9, IH), 8.86 (
d, ll-1), (123) 8.02 (dd, IH), 7.00-7.70 (m, 7
H) 6.80-7.00 (m, 2H), 6.15Cd,
IH), 3.92 (J', 31 (), 2.60 (1,
2H), 1.10-1.80 (771,6H), 0.8
8(t, 3H).

Example 3 89 ml of the methyl ester produced in Example 2 was dissolved in 2 d of tetrahydrofuran and 3 ml of methanol, and 0.35 m/2 N aqueous potassium hydroxide solution was added thereto, followed by stirring at room temperature for 3 days. 1N hydrochloric acid 11R1 was added to this, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The concentrate was washed with roohexane to obtain the title compound [
Acid] 79μ was obtained. Further, 76 ml of this acid was dissolved in 21 nl of methanol, 1N hydroxide was added, and 0.21 d of an aqueous solution of IJ was added and concentrated under reduced pressure to obtain 781n9 of the corresponding sodium 11ium salt (yellow).

TLC [acid]: Rf=0.30 (ethyl acetate:cyclohexane=2:1).

IR[acid]nid(cnL)=3010.2920.2
850°1675.1645.1600.1520.1
4801445.1415.1385.1280.12
101160.1135.995.830.800.7
55.695.650.530°MS [acid 1 nia 71/, z=363(M), 345.
306.288.274.242.227.198.1
70,161.157.141.129.115°NMR [salt] (CD30D): δ = 8.59 (d, IH
), 8.08 (d, IH), 7.30-7.55 (m,
4H), 7.16 (d, 2H), 6.85-7.12 (
m, 3) (), 6.25 (d, IH), 2.60 (f
! , 2H), 1.62 (m, 2H), 1.33 (77+
, 4H), 0.90 (t.

3H).

Example 4 0-[N-(711-7 milcinnamoyl)amino]phenoxyacetic acid ethyl ester 0-[N-(p-amylcinnamoyl)amine]phenol (Example 1 (prepared in ql)) 180~ to methyl ethyl ketone 】 □ml, 90ml of sodium iodide, 100ml of potassium carbonate, and 67μ of ethyl 2-bromoacetate were added, and the mixture was refluxed for 2 days and filtered.The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography and mucochromatography. Purified with (chloroform:rL-hexane-6:1),
The title compound 140171& having the following physical properties was obtained.

MS: m/υ395 (M), 350.338.309
．． 201195, ]31, ]15.43°NMR: δ=8.70(,?, IH), 8.56(r
id, IH), 7.76(d, IH”l, 7.49(
d, 2H), 7.19(d, 2H), 6.80-7.
15 (yl, 3H), 6.64 (d, IH), 4.
68 (J', 2H), 4.27 (126) (q, 2H), 2.62 (t, 2H), 1.60
(m.

2H), 1.27(t, 3H), 1.15-1.45
(m.

4H), 0.88 (t, 3H).

Example 5 Ethyl ester produced in Example 4] 401n9 was dissolved in a mixture of methanol (2 ml) and tetrahydrofuran (2 mJ), and! 11゛Normal Sodium Hydroxide 1.06
ml was added and stirred at 40°C overnight. To this was added 1.5 d of 1N hydrochloric acid, and the mixture was extracted with ethyl acetate.

The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1 = 1 → ethyl acetate) to give the following physical properties. 871 ng of the title compound (acid) having the following formula was obtained.

Pale yellow solid. Furthermore, add 851 ng of acid to 5 ml of methanol.
(127) dissolved in 1N hydroxide) +1um aqueous solution 0.23
ml was added, concentrated under reduced pressure, and dried to obtain the corresponding sodium salt.

TLC [acid 1:Rf=0.20 (ethyl acetate:methanol=5=1).

IR (acid) Ccrrt = 3360.2930.
2860.1740.1655.1605.1590.
15301480, ]450.1350, ]250, ]
1901120.1070.980.745°MS [acid]: m/2J=B367(M), 349.323.3
10°292.282.276.259.201.16
7.144.131,115.43°NMR [salt] (CD30D): δ = 8.2s (d, ]
H), 7.62 (cl, IH), 7.53Cd, 2H
), 7.2Hd.

2H), 7.00 (d, IH), 6.88-7.12 (
m.

3H), 4.45 (J', 2H), 2.63 (t,
2H), 163(m, 2)(), 1.25-1.45
(m, 4I(), 0.90(t, 3H).

Example 6 N-[3-(7)-decylphenyl)propionyl]anthranilic acid and its sodium-11um salt Example 1(a)
Compound 500 +II& prepared in methanol (IO
#l1)-Ethyl acetate<1ml) dissolved in a mixed solution,
After catalytic reduction was performed at room temperature for 2 hours using 10% palladium-carbon in a hydrogen atmosphere, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in methanol 10711JK, a 2N aqueous solution of sodium hydroxide (3,6-) was added thereto, and the mixture was stirred at room temperature for 5 hours. After adjusting to T)H3 with dilute hydrochloric acid, the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the resulting white 1 ml product was purified by silica gel column chromatography (ethyl acetate:rL-hexane-1:2) to obtain 1200 mg of the title compound [acid] having the following physical properties.

TLC: Rf=0.30 (ethyl acetate:rL-hexane=1:1).

Engineering Rniji (cnL) = 1690. -1670.160
0.1580.1520°MS:m=409.39], 365.244°NM
R: δ = 8.74 (d, IH), 8.08Cdd, I
H), 7.58<dt, 1H), 7.05-7.2(
m, 5H).

Example 7 5 g of N-(7)-cinnamoyl)anthranilic acid 20 (19) calcium gluconate (disintegrant), 1007 V of fibrillar magnesium stearate (lubricant) and 5.7 g of microcrystalline cellulose were mixed and tableted in a conventional manner. Thus, 100 tablets containing 501v of active ingredient in each tablet were obtained.

Representative Patent Attorney (8107) Kiyotaka Sasaki (3 others) (130)

Claims (1)

[Scope of Claims] 1) General formula [wherein R represents (1) a linear or branched alkyl group or alkoxy group having 5 to 15 carbon atoms, or (!1)
It represents a linear or branched alkenyl group or alkenyloxy group having 5 to 15 carbon atoms and is bonded to the 2- or 3-position of the benzene ring, or II) a straight-chain or branched alkenyl group having 5 to 15 carbon atoms. It represents a straight-chain or branched alkenyl group or a straight-chain or branched alkenyloxy group having 5 to 15 carbon atoms, which is bonded to the 4-position of the benzene ring, and R represents a hydrogen atom or a methyl group. R is a hydroxyl group, a carboxyl group, a carboxymethyl group, a carboxymethoxy group, a straight-chain or branched alkoxycarbonyl group having 2 to 6 carbon atoms, or a straight-chain or branched alkoxycarbonyl group having 3 to 7 carbon atoms. It represents a methyl group or an alkoxycarbonylmethoxy group, X represents 10H= or a nitrogen atom, L represents 0.1 or 2, and the symbol - represents a double bond (-3- or i) or a single bond. ] A carboxamide derivative, a non-toxic salt thereof, or a non-toxic acid addition salt thereof. 2) The compound according to claim 1, wherein R is a linear or branched alkyl group or alkoxy group having 5 to 15 carbon atoms. 3) The compound according to claim 1, wherein R is a linear or branched alkenyl group or alkenyloxy group having 5 to 15 carbon atoms, which is bonded to the 2- or 3-position of the benzene ring. Compound. 4) R is a straight chain or branched alkenyl group having 13 to 15 carbon atoms or a straight chain or branched alkenyloxy group having 5 to 15 carbon atoms, and these are bonded to the 4-position of the hanzen ring. A compound according to claim 1. 5) The compound according to claim 2, 3 or 4, wherein R is a carboxyl group or a non-toxic salt thereof. 6) Claims 2, 3, or 4 in which R is a carboxymethyl group, a nontoxic salt thereof, a methoxycarbonylmethyl group, or an ethoxycarbonylmethyl group.
Compounds described in Section. 7) The compound according to claim 2, 3, or 4, wherein R is a carboxymethoxy group, a methoxycarbonylmethoxy group, an ethoxycarbonylmethoxy group, or a hydroxyl group. 8) The compound according to claim 1, which is N-(p-amylcinnamoyl)anthranilic acid or its sodium salt. 9) The compound according to claim 1, which is N-(7)-7'silcinnamoyl)anthranilic acid or its sodium salt. 10) The compound according to claim 1, which is N-(P-amyl indiyl) anthranilic acid or its salt. 11) The compound according to claim 1, which is N-<p-decylbenzoyl)anthranilic acid or its sodium salt. 12) The compound according to claim 1, which is N-(m-(1-decenyl)benzoyl)anthranilic acid or its sodium salt. 1.3) N-(m-decylbenzoyl)anthranilic acid or its sodium salt. The compound according to claim 1, which is a salt. 14) The compound according to claim 1, which is N-[nia7l-(1-decyl)cinnamoylphanthranilic acid or its sodium salt. 15) The compound according to claim 1, which is N-(m-decylcinnamoyl)anthranilic acid or its sodium salt. 16) The compound according to claim 1, which is N-(p-amyl-2-methylcinnamoyl)anthranilic acid or its IJium salt. 17) The compound according to claim 1, which is N-(7)-(1-)lysocenyl)cinnamoylphanthranilic acid or its sodium salt. 18) The compound according to claim 1, which is N-(7)-isopentylcinnamoyl)anthranilic acid or its sodium salt. 19) The compound according to claim 1, which is N-(7)-amyloxycinnamoyl)anthranilic acid or its sodium salt. 20) The compound according to claim 1, which is N-(p-octyloxycinnamoyl)anthranilic acid or its sodium salt. 21) The compound according to claim 1, which is N-(p-amylcinnamoyl)anthranilic acid methyl ester. 22) The compound according to claim 1, which is o-[N-(p-amylcinnamoyl)amyl phenylacetic acid or its sodium salt. 23) The compound according to claim 1, which is p-C(p-amylcinnamoyl)amino]benzoic acid or its IJium salt. 24) The compound according to claim 1, which is N-(71)-hebutylcinnamoyl)anthranilic acid or its IJium salt. 25) The compound according to claim 1, which is 0-(N-(p-amylcinnamoyl)amine)phenol. 26) 2-(N-(p-amylcinnamoyl)amine)nicotinic acid or its 27) The compound according to claim 1, which is a sodium salt. 27) The compound according to claim 1, which is 2-CN-(p-amylcinnamoyl)aminoco-3-hydroxypyridine. 28) The compound according to claim 1, which is 2-(N-(P-amylcinnamoyl)amine-6-human90oxypyridine. 29) N-[5-(7)-amylphenyl)-? The compound according to claim 1, which is phth-2,4-dienoyl]anthranilic acid methyl ester. 30) N-[5-(p=niamylphenyl-!'n4
The compound according to claim 1, which is -2,4-genoyl]anthranilic acid or its sodium salt. 31.) The compound according to claim 1, which is 0-CN-(ρ-amylcinnamoyl)amine]phenoxyacetic acid ethyl ester. 32) The compound according to claim 1, which is o-CN-(,p-amylcinnamoyl)amine]phenoxyacetic acid or its sodium salt. 33) The compound according to claim 1, which is N-(p-decylcinnamoyl)anthranilic acid or its sodium salt. 34) General formula [wherein R represents a straight chain or branched alkyl group or alkoxy group having 5 to 15 carbon atoms, or (11) a straight chain or branched chain having 5 to 15 carbon atoms] represents an alkenyl group or alkenyloxy group bonded to the 2- or 3-position of the benzene ring, or (ilt)
It represents a linear or branched alkenyl group or alkenyloxy group having 13 to 15 carbon atoms, which is bonded to the 4-position of the Hanzene ring, R represents a hydrogen atom or a methyl group, and R represents a hydrogen atom or a methyl group. It represents 0.1 or 2, and the symbol 22 represents a double bond (雈 or k) or a single bond. Acid chloride represented by the general formula [wherein R is a hydroxyl group, a carboxy group, a carboxymethyl group, a carboxymethoxy group, a straight chain or branched alkoxycarbonyl group having 2 to 6 carbon atoms, or a C 3 to 7 represents a straight or branched chain alkoxycarbonylmethyl group or alkoxycarbonylmethoxy group, and X is -C
H= or represents a nitrogen atom. [In the formula, all symbols have the same meanings as above.] [In the formula, all symbols have the same meaning as above. ] A method for producing a carboxamide derivative, a non-toxic salt thereof, or a non-toxic acid addition salt thereof. 35) General formula [wherein R represents (1) a straight or branched alkyl group or alkoxy group having 5 to 15 carbon atoms, or (11) a straight or branched chain having 5 to 15 carbon atoms In the alkenyl group or alkenyloxy group)) represents that =< is bonded to the 2- or 3-position of the ring, or (il
t) a straight chain or branched alkenyl group having 13 to 15 carbon atoms or a straight chain or branched alkenyloxy group having 5 to 15 carbon atoms, which is bonded to the 4-position of the benzene ring; R represents a hydrogen atom or a methyl group; R represents a hydroxyl group, a carboxyl group, a carboxymethyl group, a carboxymethoxy group, a straight or branched alkoxycarbonyl group having 2 to 6 carbon atoms, or a straight chain represents a chain or branched alkoxycarbonylmethyl group or alkoxycarbonylmethoxy group, X represents -CH- or a nitrogen atom, L represents 0.1 or 2, and the symbol 2= represents a double bond (EJ or 2) or represents a single bond. ] A leukotriene antagonist comprising a carboxamide derivative represented by the following, a non-toxic salt thereof, or a non-toxic acid addition salt thereof as an active ingredient. [In the formula, all symbols have the same meaning as described in claim 35. ] A phospholipase inhibitor characterized by containing a carboxamide derivative represented by the above, a non-toxic salt thereof, or a non-toxic acid addition salt thereof as an active ingredient. 37) General formula [In the formula, all symbols have the same meaning as described in claim 35. ] A 5α-reductase inhibitor comprising a carboxamide derivative represented by the following, a non-toxic salt thereof, or a non-toxic acid addition salt thereof as an active ingredient.