JPH0379336B2 - - Google Patents

Description

[Detailed description of the invention] The present invention relates to novel carboxamide derivatives.
Ru. More specifically, against leukotrienes
Antagonism, phospholipase inhibition, and 5α
- Novel carboxyl compound with reductase inhibitory effect
Concerning samide derivatives. 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, abbreviated as LTC, LTD and LTE, respectively.
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), same114, 462 (1980), same.114,866
(1980), same.114, 929 (1980), Modern Medicine,12，
909 (1980), same.12, 1029 (1980), same.12,1065
(1980), same.12, 1105 (1980), etc.
There is. 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
(hydroperoxyeicosatetraenoic acid, hereafter
Abbreviated as HPETE. ) via hydroxyray
Kosatetra Enoitsuku Assist
(hydroxyeicosatetraenoic acid, hereinafter referred to as HETE)
Abbreviated. ) 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 12-HPETE, respectively.
−HPETE or 15−HPETE is generated. These HPETEs are processed by peroxidase.
Hydrogen peroxide group is converted to hydroxyl group, and 5-
Convert to HETE, 12−HETE or 15−HETE
be done. Also, among these HPETEs, 5-
HPETE is LTA by being dehydrated_FourConversion to
be done. In addition, L.T.A._Fouris enzymatically leukotriene B_Four
(hereinafter referred to as LTB_FourIt is abbreviated as ), also glutachio
LTC by N-S-transferase_Fourchanged to
will be replaced. And LTC_Fouris γ-glutamyl transpep
LTD by tidase_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)]. Furthermore, Kellaway et al. perfused sensitized guinea pig lungs.
Sometimes, when sensitized with antigen, SRS-A (Slow
Reacting Substance of Anaphylaxis) is released
The relationship between SRS-A and allergic reactions was shown to be
showed the relationship for the first time [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)
There are many reports such as As mentioned above, SRS is released due to immune reaction.
SRS-A, calcium ionophore
(calcium ionophore) treatment, etc.
Two types are distinguished: SRS and those that are released without
However, there are many similarities between the two and they are identical.
It is thought that there is a strong possibility that it is a substance of 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
is replaced with the pharmacological properties of SRS or SRS-A.
I can think about it. [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, it is important to suppress these leukotrienes.
In mammals including humans, especially humans,
Allergic tracheal and bronchial diseases such as asthma.
Breath, allergic lung disease, allergic symptoms
prevention and/or prevention of various allergic diseases
or effective for treatment. 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 choline) 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) is released by the action of
pathways are generally considered [chemistry and biology]
21, 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(Loukotriene
B_Four) is known to be metabolized into physiologically active substances such as
[See Chemistry and Biology 21154 (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_FourHa, pain
It is a chemical mediator of inflammation such as wind.
In addition, PG has a vasodilatory effect in inflammation,
A chemical that has pain, fever, and white blood cell migration effects.
It is known to be a lumediator.
Xie 20317 (1983), The Lancet 1122 (1982), Katori
See Shin et al., ed. Prostaglandin (1978) Kodansha]. In this way, arachidonic acid is physiologically
As a chemical mediator that plays an important role in
Although these mediators are exchange metabolized,
A number of diseases are caused by the collapse of the
It will be done. The inventors have discovered compounds that antagonize leukotrienes.
substance, or phospholipase (phospholipase A₂
and/or a compound that inhibits phospholipase C)
As a result of extensive research to find compounds,
The carboxamide represented by the general formula () below is
Discovered that the purpose could be achieved and completed the invention
did. The compound of the present invention strongly inhibits phospholipase
and inhibits the release of arachidonic acid from phospholipids.
Therefore, mammals including humans, especially humans,
Rachidonic acid metabolites, e.g. TXA₂, PG, Royco
Prevention and/or treatment of diseases caused by triene
It is effective for therapy. 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 compound of the present invention includes the above-mentioned leukotrium
Use as an ene antagonist and phospholipase inhibitor
In addition, 5α-reductase inhibitors such as
It has also been found useful. 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 inside cells
This effect is enhanced by causing more cell proliferation.
and the onset of benign 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 because the Lumon effect remains as a side effect.
It was hard to say that anything was done. Of course, the compounds of the present invention 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 hyperplasia, alopecia and loci in animals, especially humans
Can effectively prevent and/or treat acne
be. The present invention is based on the general formula [In the formula, R¹() Straight chain with 5 to 15 carbon atoms or
represents a branched alkyl group or alkoxy group.
watermelon, () straight chain or branched chain with 5 to 15 carbon atoms
Alkenyl group or alkenyloxy group
and is bonded to the 2nd or 3rd position of the benzene ring.
or () straight chain with 13 to 15 carbon atoms
or branched alkenyl group or having 5 to 15 carbon atoms
A straight or branched alkenyloxy group with base
It represents that it is bonded to the 4th position of the ring,
R²represents a hydrogen atom or a methyl group, R³is water
Acid group, carboxyl group, carboxymethyl group, carbon
Ruboxymethoxy group, straight chain having 2 to 6 carbon atoms or
Branched alkoxycarbonyl group or number of carbon atoms
3 to 7 linear or branched alkoxycarbonyl
methyl group or alkoxycarbonylmethoxy
represents a group, and X represents -CH= or a nitrogen atom.
, n represents 0, 1 or 2, and the symbol 〓 is double
Join (Eor Z) or a single bond. ] Carboxamide derivatives represented by and their non-toxic salts
and its acid addition salts. In the general formula (), R¹represents a carbon number of 5 to 15
Straight chain or branched in alkyl or alkoxy groups
Branched chain alkyl groups include pentyl group and hexy group.
group, peptyl group, octyl group, nonyl group, decyl group, peptyl group, octyl group,
Ru group, undecyl group, dodecyl group, tridecyl group
groups, tetradecyl groups, and pentadecyl groups and
and their isomers, R¹preferred as
Examples of groups include n-pentyl group and isopentyl group.
group, n-heptyl group, n-decyl group, n-pentyl group
and n-octyloxy groups.
It will be done. In the general formula (), R¹represents a carbon number of 5 to 15
Straight chain in alkenyl or alkenyloxy groups
Or as a branched alkenyl group, pentene
group, pentadienyl group, hexenyl group, hexa
dienyl group, hexatrienyl group, heptenyl group
group, heptadienyl group, heptatrienyl group,
Ctenyl group, octadienyl group, octatrienyl group
group, octatetraenyl group, nonenyl group, nona
dienyl group, nonatrienyl group, nonatetraenyl group
group, decenyl group, decadienyl group, decatrier group
Nyl group, decatetraenyl group, decapentaenyl group
group, undecenyl group, undecadienyl group,
decatrienyl group, undecatetraenyl group,
Ndecapentenyl group, dodecenyl group, dodecadi
enyl group, dodecatrienyl group, dodecatetrae
Nyl group, dodecapentenyl group, dodecahexae
Nyl group, tridecenyl group, tridecadienyl group,
tridecatrienyl group, tridecatetraenyl
group, tridecapentenyl group, tridecahexae
Nyl group, tetradecenyl group, tetradecadienyl
group, tetradecatrienyl group, tetradecatetra
enyl group, tetradecapentenyl group, tetradecapentenyl group
Cahexaenyl group, tetradecaheptaenyl group,
pentadecenyl group, pentadecadienyl group, pen
Tadecatrienyl group, pentadecatetraenyl group
group, pentadecapentenyl group, pentadecahex
saenyl group, pentadecaheptaenyl group and their
The isomers of R¹as a preferred base
1-decenyl group, 1-decenyloxy group,
1-tridecenyl group and 1-tridecenyloxy
An example is a cy group. In the general formula (), R³has 3 to 7 carbon atoms
Straight or branched chain alkoxycarbonylmethyl
group or alkoxycarbonylmethoxy group.
Straight chain or branched chain with a lucoxy group and 2 to 6 carbon atoms
The alkoxy group in the alkoxycarbonyl group of the chain and
methoxy group, ethoxy group, propyloxy group
cy group, butoxy group, pentyloxy group and their
isomers, preferably methoxy groups and
It is an ethoxy group. R³as a preferred group
is hydroxyl group, carboxy group, carboxymethyl
group, carboxymethoxy group, methoxycarbonyl
group, methoxycarbonylmethyl group, methoxycal
Bonylmethoxy group, ethoxycarbonyl group, etho
Oxycarbonylmethyl group, ethoxycarbonylmethyl group
Examples include toxy groups. The compound of the present invention represented by the general formula () has different
The existence of sexual bodies is considered, especially when the symbol 〓 is a double bond.
, this double bondEorZYo
, and the symbol 〓 represents a single bond, and R²is methyl
When representing a group, the carbon to which this methyl group is bonded
The element is an asymmetric carbon, and isomers exist. Matasa
Furthermore, each substituent in general formula () is a branched chain alkali.
Kyl or alkylene groups, as well as groups containing double bonds.
Further isomers may occur. The present invention
Also includes all isomers of and mixtures thereof.
It is something to do. 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?
Therefore, the present invention cannot be easily achieved. for example
Described in Example 2 of JP-A-50-135047
is a compound with a formula and compound number 49 in the specification of JP-A-49-93335.
The formula is a compound written as The compound represented by is one of the objects of the present invention.
Statements suggesting that it antagonizes leukotrienes
there is nothing. Further, these compounds are described herein.
Listed LTD_FourAntagonism and phospholipers
Ze A₂When subjected to a system for measuring the inhibitory effect, the formula (A)
The compound shown is LTD_FourID showing antagonistic action₅₀value
is 30 μM and exhibits phospholipase inhibitory effect.
I C₅₀The value is 100 μM, and the value is expressed by formula (B).
The compound did not show any activity against either.
Ivy. However, the compound of the present invention has the formula Compound and formula represented by The compounds shown are each LTD_Fourantagonistic
I C₅₀Values 14 μM and 16 μM, phospholipase A₂
IC of inhibitory action₅₀Activity with values 22μM and 54μM
In the present invention, the present inventors have shown that R¹phase
Depending on the length of the corresponding carbon chain, LTD_FourIf there is an antagonistic effect
and phospholipase inhibitory effects can be easily inferred.
It is also clear that the more you can't do it, the stronger you become.
I made it. In addition, the present inventors 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 three applications further include
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. The compound represented by the general formula () is the general formula [All symbols in the formula have the same meanings as above.
vinegar. ] Acid chloride and general formula shown by [In the formula, all symbols have the same meaning as above.
vinegar. ] It is produced by reacting the amine shown by
can be done. This reaction is a known reaction, for example, inert
organic solvents, such as methylene chloride, chloroform,
In trahydrofuran, tertiary amines, e.g.
-20°C to 40°C in the presence of thylamine, pyridine, etc.
It is carried out at a temperature of Preferably methylene chloride
medium, in the presence of triethylamine, at 0°C to room temperature.
be exposed. The compound represented by the general formula () is a known compound
For example, the symbol X is −CH=, R³is 2-ka
Compounds expressing a ruboxy group are anthranilic acid and
It is commercially available as
A carboxyl group is located at the 3rd position counting from the ring nitrogen.
R³Compounds substituted as 2-aminoni
It is commercially available as cotinic acid. 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, such as chlorinated
in tyrene, tetrahydrofuran or without solvent
Thionyl chloride, oxalyl chloride, etc.
It is carried out at a temperature of -40°C to 30°C. suitably
was carried out using oxalyl chloride without solvent at room temperature.
It will be held in The carboxylic acid represented by the general formula () is itself
Is it known (e.g. p-amylcinnamic acid is commercially available?
It is. ), or manufactured by a known method.
An example is shown diagrammatically below. The meaning of each symbol in the diagram is as follows.
Other symbols have the same meanings as above. R^1a- Straight or branched chain alkali having 5-15 carbon atoms
Kyl group, alkoxy group or alkenyl group
le group. R^1b- Straight or branched chain alkali having 5-15 carbon atoms
Koxy group or alkenyloxy group. R^1c- Straight or branched chain alkali having 5-15 carbon atoms
Kenyl or alkenyloxy group. R^1d- Straight or branched chain alkali having 5-15 carbon atoms
Kyl group, alkoxy group, alkenyl group
or an alkenyloxy group. R^1e- Straight or branched chain alkali having 5-15 carbon atoms
Kill group or alkoxy group. R^1f- Straight chain or branched alkenes having 5 to 15 carbon atoms
Nyl or alkenyloxy group. R^Four- Straight chain or branched chain hormones having 2-14 carbon atoms
Milalkyl or formyl group. R^Five- Straight chain or branched chain hydrogen having 1 to 14 carbon atoms
loxyalkyl group or hydroxyl group. All reactions in the diagram are known reactions.
Briefly, steps (a) and (n) are formylation
For example, in trifluoroacetic acid, hexame
Performed using tylenetetramine at 50°C to reflux temperature.
be exposed. Steps (b), (j) and (o) are Wittig reactions, e.g.
For example, inert organic solvents (ethyl ether, tetrahedron)
Dorofuran, chloroform, benzene, etc.), phase
React at -78℃ to room temperature using the corresponding Wittig reagent.
This is done by letting When using this reaction
In this case, the product with n=1 or 2 can be obtained.
can. Steps (c), (k) and (p) are based on the Perkin reaction or Deb
For example, in the presence of piperidine,
Malonic acid or malonic acid ester using lysine as a solvent
The reaction can be carried out at 100℃ to reflux temperature using Stell.
This is done by When this reaction is used, the production
The object is n=1, and R²is a hydrogen atom. Steps (d), (l) and (q) are oxidation reactions, e.g.
Bagillons oxidation, Collins oxidation, Swan oxidation
Depending on the technique, it is carried out at temperatures between -20°C and 40°C. child
When using the reaction, the product n=0 is obtained.
can be done. Steps (e) and (u) replace the hydroxyl group with an alkoxy group or
A reaction that converts into an alkenyloxy group, for example, an unaltered
Active organic solvents (ethyl ether, tetrahydrofu
in dimethylformamide or
In the presence of hexamethylphosphamide, etc., anhydrous
such as sodium hydride or potassium carbonate
In the presence of a base, the corresponding alkyl bromide or
or alkenyl bromide at 40°C to reflux.
It is done at temperature. Step (f) is a saponification reaction, e.g.
Organic solvents (tetrahydrofuran, methanol,
(tanol, etc.), potassium hydroxide, sodium hydroxide
aqueous solution of alkali such as aluminum or lithium hydroxide
It is carried out at a temperature of 0°C to 40°C. Steps (g) and (t) are Wittig reactions, and the steps described above
It is carried out similarly to (b), (j) and (o). Step (h) is a reduction reaction, using an inert organic solvent (to
Luene, benzene, ethyl ether, tetrahydride
Lofuran, etc.), diisobutylaluminum high
The reaction is carried out at a temperature of -78℃ using a dryide, or
or using lithium aluminum hydride
The reaction is carried out at 0°C to reflux temperature.
Ru. Steps (i) and (s) are oxidation reactions in which an inert organic solvent is
Medium (methylene chloride, dimethyl sulfoxide, etc.)
Medium and tertiary amines (triethylamine, pyridine
etc.) using oxalyl chloride,
It is carried out at 0°C to 40°C. Steps (m) and (r) are reduction reactions in a hydrogen atmosphere,
Organic solvents (methanol, ethanol, tetrahydride
Lofuran, etc.) in catalysts (palladium-carbon, para
0℃～
This is done by reacting at 40°C. In addition, the carboxamide represented by the general formula ()
Of these, the general formula [In the formula, R^1gis a straight or branched chain with 5 to 15 carbon atoms
represents an alkyl or alkoxy group in the chain;
All other symbols have the same meaning as above.
vinegar. ] The compound represented by has the general formula [In the formula, R^1hStraight chain or branched chain with 5 to 15 carbon atoms
represents an alkenyl group or an alkenyloxy group.
and all other symbols have the same meaning as above.
Was. ] For the reduction reaction of the compound represented by R^1hmiddle two
Heavy bonds and R²reduces the double bond bound to
and by converting each into an ethylene group.
can also be manufactured. This reduction is a known reaction, for example in a hydrogen atmosphere.
under air, organic solvents (methanol, ethanol, tetol)
catalyst (palladium-charcoal) in a catalyst (palladium-charcoal)
presence of metal, palladium, platinum black, nickel, etc.)
This is done by reacting at 0°C to 40°C.
Ru. Furthermore, the compound represented by the general formula ()
General formula [In the formula, R^3ais carboxy group, carboxymethylene
represents a group or a carboxymethoxy group, and its
Other symbols have the same meanings as above. ] The compound represented by has the general formula [In the formula, R^3bis a straight chain or branched chain with 2 to 6 carbon atoms
Alkoxycarbonyl group in chain, straight carbon number 3-7
Chain or branched alkoxycarbonylmethyl
group, or a linear or branched chain atom having 3 to 7 carbon atoms.
Represents a lucoxycarbonylmethoxy group, and other
The symbol represents the same meaning as above. ] By subjecting the compound represented by to a saponification reaction,
You can also get it. Saponification reaction is a well-known reaction, for example, when mixed with water.
compatible solvents, such as methanol, ethanol,
In tetrahydrofuran, an alkaline substance, e.g.
Sodium hydroxide, potassium hydroxide, lithium hydroxide
Using an aqueous solution such as
Preferably, it is carried out at room temperature. Of course, the general formula (_c) is the compound shown by
General formula (_b) to esterify the compound shown in
It can also be obtained by Esterification reaction is a well-known reaction, for example, phase
acid, such as p-toluene, in the appropriate alkanol.
In the presence of sulfonic acid or hydrochloric acid, from 0°C to 40°C, preferably
or at room temperature. Of course, as a solvent
Tetrahydrofuran, methylene chloride that does not participate in the reaction
You may also use something like Also chloride water as acid
An elementary gas may also be used. Furthermore, a compound represented by the general formula ()
Medium, R³is an alkoxycarbonylmethoxy group or
represents a carboxymethoxy group, R³
represents a hydroxyl group in step (e) in the above scheme.
Similar reaction (however, for alkyl bromide)
Then, the corresponding alkoxycarbonyl methyl bromine
If necessary, use sodium iodide etc.
of iodide. ), and if necessary,
It can also be obtained by subjecting it to a saponification reaction.
Ru. 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
In the experiment, the following effects were shown. The compound of the present invention is LTD_FourIn contrast, as shown in the table below
It showed an antagonistic effect. 【table】 The compound of the present invention is a phospholipase A₂For,
It showed inhibitory effects as shown in the table below. 【table】 【table】 The compound of the present invention has the following properties against 5α-reductase:
It showed inhibitory effects as shown in the table below. 【table】 Shows the value in concentration.
LTD of the compound of the present invention_FourThe antagonistic effect on
It was measured using the experimental method. Extracted from 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 the main amount for the contraction at this time.
Add the invented compound at different concentrations and measure the shrinkage height.
So, 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 [see Anal.Biochem., 114, 67 (1981)]
Light]. The inhibition of 5α-reductase by the compounds of the present invention
Harmful effects were evaluated based on the method of J. Shimazaki et al.
5α-results obtained from the nuclear fraction of the prostate gland of Tutu.
This was done using ductase. 5α-reductor
0.09M Hepes (pH7.4), 0.22M
Cane sugar, 5 x 10^-3M NADPH, 5 μM [4-¹⁴C]
Testolone, 5α-reductase and the invention
The reaction was carried out at 37°C for 60 min using a mixture of compounds.
Ivy. To stop the reaction, chloroform-methanol (1/
2), and after centrifugation, transfer the supernatant to silica.
Spotted on a gel thin layer plate and chloroform-
Minute using methanol-acetic acid (99.2:0.6:0.2)
radioactivity of dihydrotestosterone produced
Measurement of enzyme activity inhibition using a TLC scanner
calculated the harm [Endocrinol, Japan., 18, 179]
(1971). ] Salts and acid addition salts are preferably non-toxic.
stomach. Non-toxic salts and acid addition salts are animal tissues.
relatively harmless and necessary for treatment.
A compound represented by the general formula () when using the amount
The effective pharmacological properties of
to ensure that it is not impaired by the side effects caused by the treatment.
means a salt consisting of an anion or a cation.
Ru. Also, it is preferable that the salts and acid addition salts are water-soluble.
Delicious. Suitable salts include, for example, sodium or potassium salts.
salts of alkali metals such as umum, calcium or
Salts of alkaline earth metals such as gnesium, ammonia
salts and pharmaceutically acceptable (non-toxic)
Contains min salt. carboxylic acids and their salts
Suitable amines to form are well known, e.g.
Theoretically, one or more pieces of water in ammonia
Contains amines obtained by replacing elementary atoms with other groups.
will be included. The group has one or more hydrogen atoms substituted.
They can be the same or different when
Alkyl group having 1 to 6 carbon atoms, hydrogen having 1 to 3 carbon atoms
selected from loxyalkyl groups. suitable non-toxic a
Examples of amine salts include tetramethylammonium.
salts of tetraalkylammonium and methyl
Amine salt, dimethylamine salt, cyclopentyl amine salt
Min salt, benzylamine salt, phenethylamine
salt, piperidine salt, monoethanolamine salt, di-
Ethanolamine salt, lysine salt, arginine salt
Examples include organic amine salts such as Suitable acid addition salts include, for example, hydrochloride, bromide
Hydrogenates, Hydroiodides, Sulfates, Phosphates,
Inorganic acid salts such as nitrates, or acetates, lactates, alcohol
phosphate, benzoate, citrate, methanesulfonate
phosphate, ethanesulfonate, benzenesulfone
acid salt, toluenesulfonate, isethionate.
Examples include organic acid salts such as Carboxamine salt represented by general formula ()
The acid represented by the general formula () can be prepared by a known method, e.g.
For example, a suitable base, e.g. an alkali, in a suitable solvent.
Metal or alkaline earth metal hydroxides or
By reacting with carbonates or organic amines
can get. Acidification of carboxamine represented by general formula ()
Salting is carried out by adding a compound represented by the general formula () to a known compound.
method, e.g. in a suitable solvent, a suitable acid, e.g.
Hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphorus
acids, inorganic acids such as nitric acid, or acetic acid, lactic acid, alcohol
Tartaric acid, benzoic acid, citric acid, methanesulfonic acid,
Ethanesulfonic acid, benzenesulfonic acid, toluene
Reacts with organic acids such as sulfonic acid and isethionic acid.
It can be obtained by making it correspond. In mammals including humans, especially humans,
Allergy by suppressing icotriene
Sexual tracheal and bronchial diseases, such as asthma and allergies
–-related lung diseases, allergic shots,
For the prevention and/or treatment of various diseases related to
It is also effective against phospholipase (phospholipase).
-ze A₂and/or inhibit phospholipase C).
Including the above leukotrienes by harming
Diseases caused by arachidonic acid metabolites, such as thrombosis
disease, such as damage to the endothelium or intima of the brain or coronary arteries.
Thrombosis, various inflammations such as arthritis, rheumatism
Effective for prevention and/or treatment. moreover
Inhibiting 5α-reductase can inhibit prostate hyperplasia
Useful for the prevention and/or treatment of acne, alopecia, and acne.
It is effective. A carboxamide represented by the general formula () or
Their non-toxic salts or acid addition salts for the above purposes.
(leukotriene antagonist, phospholipase inhibitor
(as a 5α-sidactase inhibitor)
For each, usually systemic or local
Administered orally or parenterally. Dosage is yearly
Age, weight, symptoms, therapeutic effects, administration method, processing time
It varies depending on the situation, but usually per adult, each
1mg to 1g, preferably 20mg to 200mg at a time
It is administered orally, ranging from once to several times a day, or
or 100 μg of each at a time per adult.
~100mg, preferably in the range of 1mg to 10mg, per day
It is administered parenterally in one to several doses. Of course as mentioned above
The above dosages vary depending on various conditions, so
In some cases, doses lower than the above dosage range may be sufficient;
There may also be cases where it is necessary to administer doses beyond the range.
Ru. Solid compositions for oral administration include tablets,
Includes powders, granules, etc. Such a solid composition
In products, one or more active substances
but at least one inert diluent, e.g.
Lactose, mannitol, glucose, hydroxypro
pill cellulose, microcrystalline cellulose, starch,
Polyvinylpyrrolidone, aluminum metasilicate
Mixed with gnesium. The composition is prepared according to conventional methods.
Additives other than inert diluents, e.g.
Lubricants such as magnesium phosphate and cellulose glue
Contains disintegrants such as calcium conate
Good too. Tablets or pills may be added with white sugar or gelatin if necessary.
Chin, Hydroxypropyl cellulose, Hydroxylene
Stomachs such as cipropyl methylcellulose phthalate
Even if coated with a film of soluble or enteric-coated substances
Alternatively, it may be coated with two or more layers. Sara
capsules of absorbable substances such as gelatin
is also included. Liquid compositions for oral administration are pharmaceutically acceptable
Emulsions, solutions, suspensions, syrups, etc.
Commonly used inert substances, including lixir agents, etc.
diluents such as purified water and ethanol. child
The composition contains wetting agents and suspending agents in addition to inert diluents.
Adjuvants such as sweeteners, flavoring agents, aromatics, and preservatives
It may contain an agent. Other compositions for oral administration include
Contains one or more active substances and as such
Contains sprays formulated by known methods.
Ru. For injections for parenteral administration, sterile water
Including aqueous or non-aqueous solutions, suspensions, and emulsions.
do. Examples of aqueous solutions and suspensions include injections.
Includes distilled water and physiological saline. water insoluble
Solutions and suspensions include, for example, propylene glycol.
Coal, polyethylene glycol, olive oil
vegetable oils such as, alcohols such as ethanol
Polysorbate 80, Gum Arabic, Algin
There are sodium chloride, etc. Such a composition is
In addition, supplements such as preservatives, wetting agents, emulsifiers, and dispersants
It may also contain auxiliary agents. These are, for example, bacteria
Passing through a retention filter, adding disinfectants or
Sterilized by irradiation. These are also sterile
Prepare the solid composition and sterilize it with sterile water or sterilize it before use.
It can also be used by dissolving it in an injection solvent. Other compositions for parenteral administration include:
Contains one or more active substances and is itself
External liquids and soft drinks prescribed by known methods
liniments, suppositories for rectal administration, and
Includes pettu saris for intravaginal administration. Among the compounds of the present invention represented by the general formula (), preferred
As a new compound, N-(p-amylcinnamoyl)anthranilic acid, N-(p-isopentylcinnamoyl)anthra
Nilic acid, N-(p-heptylcinnamoyl)anthranyl
acid, N-(p-decylcinnamoyl)anthranilic acid, N-[p-(1-tridecenyl)cinnamoyl]a
ntranilic acid, N-[m-(1-decenyl)cinnamoyl]ant
Ranilic acid, N-(m-decylcinnamoyl)anthranilic acid, N-(p-pentyloxycinnamoyl)ant
Ranilic acid, N-(p-octyloxycinnamoyl)ant
Ranilic acid, N-(p-amyl-2-methylcinnamoyl)a
ntranilic acid, N-(p-isopentyl-2-methylcinnamoy)
) anthranilic acid, N-(p-heptyl-2-methylcinnamoyl)
anthranilic acid, N-(p-decyl-2-methylcinnamoyl)a
ntranilic acid, N-[p-(1-tridecenyl)-2-methylsin
Namoyl] anthranilic acid, N-[m-(1-decenyl)-2-methylcinnamo
anthranilic acid, N-(m-decyl-2-methylcinnamoyl)a
ntranilic acid, N-(p-pentyloxy-2-methylcinnamo
anthranilic acid, N-(p-octyloxy-2-methylcinnamo
anthranilic acid, m-[N-(p-amylcinnamoyl)amino]an
zoic acid, m-[N-(p-isopentylcinnamoyl)ami
[Benzoic acid] m-[N-(p-heptylcinnamoyl)amino]
benzoic acid, m-[N-(p-decylcinnamoyl)amino]an
zoic acid, m-[N-[p-(1-tridecenyl)cinnamoy
[amino]benzoic acid, m-[N-[m-(1-decenyl)cinnamoyl]
amino] benzoic acid, m-[N-(m-decylcinnamoyl)amino]an
zoic acid, m-[N-(p-pentyloxycinnamoyl)a
Mino]benzoic acid, m-[N-(p-octyloxycinnamoyl)a
Mino]benzoic acid, m-[N-(p-amyl-2-methylcinnamoy)
) amino] benzoic acid, m-[N-(p-isopentyl-2-methylcinna
moyl)amino]benzoic acid, m-[N-(p-heptyl-2-methylcinnamoy)
) amino] benzoic acid, m-[N-(p-decyl-2-methylcinnamoy)
) amino] benzoic acid, m-[N-[p-(1-tridecenyl)-2-methyl
Cinnamoyl [amino] benzoic acid, m-[N-[m-(1-decenyl)-2-methylsin
namoyl[amino]benzoic acid, m-[N-(m-decyl-2-methylcinnamoy
) amino] benzoic acid, m-[N-(p-pentyloxy-2-methylsine
Namoyl)amino]benzoic acid, m-[N-(p-octyloxy-2-methylsin
Namoyl)amino]benzoic acid, o-[N-(p-amylcinnamoyl)amino]ph
enyl acetic acid, o-[N-(p-isopentylcinnamoyl)ami
] Phenyl acetic acid, o-[N-(p-heptylcinnamoyl)amino]
phenyl acetic acid, o-[N-(p-decylcinnamoyl)amino]ph
enyl acetic acid, o-[N-[p-(1-tridecenyl)cinnamoy
[amino]phenylacetic acid, o-[N-[m-(1-decenyl)cinnamoyl]
Amino] phenyl acetic acid, o-[N-(m-decylcinnamoyl)amino]ph
enyl acetic acid, o-[N-(p-pentyloxycinnamoyl)a
Mino] phenyl acetic acid, o-[N-(p-octyloxycinnamoyl)a
Mino] phenyl acetic acid, o-[N-(p-amyl-2-methylcinnamoy)
(amino) phenyl acetic acid, o-[N-(p-isopentyl-2-methylcinna
moyl)amino]phenylacetic acid, o-[N-(p-heptyl-2-methylcinnamoy)
(amino) phenyl acetic acid, o-[N-(p-decyl-2-methylcinnamoy)
(amino) phenyl acetic acid, o-[N-[p-(1-tridecenyl)-2-methyl
cinnamoyl[amino]phenylacetic acid, o-[N-[m-(1-decenyl)-2-methylsin
namoyl[amino]phenylacetic acid, o-[N-(m-decyl-2-methylcinnamoy
(amino) phenyl acetic acid, o-[N-(p-pentyloxy-2-methylsin
Namoyl)amino]phenylacetic acid, o-[N-(p-octyloxy-2-methylsin
Namoyl)amino]phenylacetic acid, N-[5-(p-amylphenyl)penta-2,4
-dienoyl]anthranilic acid, N-[5-(p-isopentylphenyl)penta-
2,4-dienoyl]anthranilic acid, N-[5-(p-heptylphenyl)penta-2,
4-dienoyl]anthranilic acid, N-[5-(p-decylphenyl)penta-2,4
-dienoyl]anthranilic acid, N-[5-[p-(1-tridecenyl)phenyl]
penta]-2,4-dienoyl]anthranilic acid, N-[5-[m-(1-decenyl)phenyl]pen
ter-2,4-dienoyl]anthranilic acid, N-[5-(m-decylphenyl)penta-2,4
-dienoyl]anthranilic acid, N-[5-(p-pentyloxyphenyl)penta
-2,4-dienoyl]anthranilic acid, N-[5-(p-octyloxyphenyl)penta
-2,4-dienoyl]anthranilic acid, N-[5-(p-amylphenyl)-2-methylpe
ter-2,4-dienoyl]anthranilic acid, N-[5-(p-isopentylphenyl)-2-methane
Chirpenta-2,4-dienoyl]anthranil
acid, N-[5-(p-heptuphenyl)-2-methyl
penta-2,4-dienoyl]anthranilic acid, N-[5-(p-decylphenyl)-2-methylpene
ter-2,4-dienoyl]anthranilic acid, N-[5-[p-(1-tridecenyl)phenyl-
2-Methylpenta-2,4-dienoyl]ant
Ranilic acid, N-[5-[m-(1-decenyl)phenyl-2-
Methylpenta-2,4-dienoyl]antrani
Ruic acid, N-[5-(m-decylphenyl)-2-methylpene
ter-2,4-dienoyl]anthranilic acid, N-[5-(p-pentyloxyphenyl)-2-
Methylpenta-2,4-dienoyl]antrani
Ruic acid, N-[5-(p-octyloxyphenyl)-2-
Methylpenta-2,4-dienoyl]antrani
Ruic acid, o-[N-(p-amylcinnamoyl)amino]ph
enoxyacetic acid, o-[N-(p-isopentylcinnamoyl)ami
[n] Phenoxyacetic acid, o-[N-(p-heptylcinnamoyl)amino]
phenoxyacetic acid, o-[N-(p-decylcinnamoyl)amino]ph
enoxyacetic acid, o-[N-[p-(1-tridecenyl)cinnamoy
[amino]phenoxyacetic acid, o-[N-[m-(1-decenyl)cinnamoyl]
Amino] phenoxyacetic acid, o-[N-(m-decylcinnamoyl)amino]ph
enoxyacetic acid, o-[N-(p-pentyloxycinnamoyl)a
Mino] phenoxyacetic acid, o-[N-(p-octyloxycinnamoyl)a
Mino] phenoxyacetic acid, o-[N-(p-amyl-2-methylcinnamoy)
[amino]phenoxyacetic acid, o-[N-(p-isopentyl-2-methylcinna
moyl)amino]phenoxyacetic acid, o-[N-(p-heptyl-2-methylcinnamoy)
[amino]phenoxyacetic acid, o-[N-(p-decyl-2-methylcinnamoy)
[amino]phenoxyacetic acid, o-[N-[p-(1-tridecenyl)-2-methyl
Cinnamoyl [amino] phenoxyacetic acid, o-[N-[m-(1-decenyl)-2-methylsin
namoyl [amino] phenoxyacetic acid, o-[N-(m-decyl-2-methylcinnamoy
[amino]phenoxyacetic acid, o-[N-(p-pentyloxy-2-methylsin
Namoyl)amino]phenoxyacetic acid, o-[N-(p-octyloxy-2-methylsin
Namoyl)amino]phenoxyacetic acid, N-(p-amylbenzoyl)anthranilic acid, N-(p-isopentylbenzoyl)antrani
Ruic acid, N-(p-heptylbenzoyl)anthranilic acid, N-(p-decylbenzoyl)anthranilic acid, N-[p-(1-tridecenyl)benzoyl]an
Tranilic acid, N-[m-(1-decenyl)benzoyl]anthra
Nilic acid, N-(m-decylbenzoyl)anthranilic acid, N-(p-pentyloxybenzoyl)anthra
Nilic acid, N-(p-octyloxybenzoyl)anthra
Nilic acid, 2-[N-(p-amylcinnamoyl)amino]d
cotinic acid, 2-[N-(p-decylcinnamoyl)amino]d
cotinic acid, 2-[N-[m-(1-decenyl)cinnamoyl]
amino] nicotinic acid, 2-[N-(p-pentyloxycinnamoyl)a
Mino] Nicotinic acid, 2-[N-(p-amyl-2-methylcinnamoy)
[amino]nicotinic acid, 2-[N-(p-decyl-2-methylcinnamoy)
[amino]nicotinic acid, 2-[N-[m-(1-decenyl)-2-methylsin
Namoyl [amino] nicotinic acid, 2-[N-(p-pentyloxy-2-methylsin
Namoyl)amino]nicotinic acid, N-[3-(p-amylphenyl)propionyl]
anthranilic acid, N-[3-(p-decylphenyl)propionyl]
anthranilic acid, N-[3-(p-amyl phenyl)-2-methylp
ropionyl]anthranilic acid and N-[3-(p-decylphenyl)-2-methylp
ropionyl anthranilic acid and the corresponding methyl esters of the above acids,
Tyl esters, and non-toxic salts, and their
non-toxic acid addition salts, and o-[N-(p-amylcinnamoyl)amino]ph
enol, o-[N-(p-isopentylcinnamoyl)ami
] Phenol, o-[N-(p-heptylcinnamoyl)amino]
phenol, o-[N-(p-decylcinnamoyl)amino]ph
enol, o-[N-[p-(1-tridecenyl)cinnamoy
[amino]phenol, o-[N-[m-(1-decenyl)cinnamoyl)
amino]phenol, o-[N-(m-decylcinnamoyl)amino]ph
enol, o-[N-(p-pentyloxycinnamoyl)a
Mino] phenol, o-[N-(p-octyloxycinnamoyl)a
Mino] phenol, o-[N-(p-amyl-2-methylcinnamoy)
[amino]phenol, o-[N-(p-isopentyl-2-methylcinna
moyl)amino]phenol, o-[N-(p-heptyl-2-methylcinnamoy)
[amino]phenol, o-[N-(p-decyl-2-methylcinnamoy)
[amino]phenol, o-[N-[p-(1-tridecenyl)-2-methyl
cinnamoyl)amino]phenol, o-[N-[m-(1-decenyl)-2-methylsin
namoyl [amino] phenol, o-[N-(m-decyl-2-methylcinnamoy
[amino]phenol, o-[N-(p-pentyloxy-2-methylsin
Namoyl)amino]phenol, o-[N-(p-octyloxy-2-methylsin
Namoyl)amino]phenol, 2-[N-(p-amylcinnamoyl)amino]-
3-hydroxypyridine, 2-[N-(p-decylcinnamoyl)amino]-
3-hydroxypyridine, 2-[N-[m-(1-decenyl)cinnamoyl]
amino]-3-hydroxypyridine, 2-[N-(p-pentyloxycinnamoyl)a
[mino]-3-hydroxypyridine, 2-[N-(p-amyl-2-methylcinnamoy)
) amino]-3-hydroxypyridine, 2-[N-(p-decyl-2-methylcinnamoy)
) amino]-3-hydroxypyridine, 2-[N-[m-(1-decenyl)-2-methylsin
namoyl]amino]-3-hydroxypyridine, 2-[N-(p-pentyloxy-2-methylsin
Namoyl)amino]-3-hydroxypyridine, 2-[N-(p-amylcinnamoyl)amino-6
-hydroxypyridine, 2-[N-(p-decylcinnamoyl)amino]-
6-hydroxypyridine, 2-[N-[m-(1-decenyl)cinnamoyl]
amino]-6-hydroxypyridine, 2-[N-(p-pentyloxycinnamoyl)a
[mino]-6-hydroxypyridine, 2-[N-(p-amyl-2-methylcinnamoy)
) amino]-6-hydroxypyridine, 2-[N-(p-decyl-2-methylcinnamoy)
) amino]-6-hydroxypyridine, 2-[N-[m-(1-decenyl)-2-methylsin
namoyl]amino]-6-hydroxypyridine, and 2-[N-(p-pentyloxy-2-methylsin
namoyl)amino]-6-hydroxypyridine, and acid addition salts of the above compounds. Hereinafter, the present invention will be explained in detail with reference to reference examples and examples.
However, the present invention is not limited to these examples.
It's not. In addition, in reference examples and examples
"bp", "TLC", "IR", "NMR" and "MS"
The symbols for ``boiling point'' and ``thin layer chromatography''
"infrared absorption spectrum", "nuclear magnetic resonance spectrum"
chromatography” and “mass spectrometry”.
Solvents listed for separation using graphs
The percentage indicates the volume ratio, and the percentage in the "TLC" cutlet is
Solvent indicates the developing solvent, and “IR” indicates no special description.
If not, measure using the KBγ tablet method, and use “NMR” as a special method.
If there is no description, use heavy chloroform (CDCl).₃) melt
Measured with liquid. Reference example 1 p-Amylbenzaldehyde Hexamethylenetetramine 21g trifluoro
Dissolve in 200ml of acetic acid and add 150ml of amylbenzene.
Yes, I stirred it at 90℃ overnight. Concentrate the reaction solution under reduced pressure
Then add 50ml of ice water and stir for 30 minutes to dissolve hydrogen carbonate.
Add sodium aqueous solution and ethyl acetate to separate the liquids.
Ta. The organic layer was washed with water and saturated saline, and washed with anhydrous sulfuric acid solution.
Dry with magnesium, concentrate under reduced pressure and use vacuum distillation.
13g of the title compound having the following physical properties was purified by
Obtained. 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), 1.4~1.7 (m,
2H), 0.85 (m, 3H). Reference example 1(a) p-Isopentylbenzaldehyde Reference example using 132g of isopentylbenzene
By the same operation as in 1, a standard with the following physical property values was obtained.
79 g of the title compound was obtained. MS: m/Z=176 (M⁺), 133, 131, 120, 92,
91. NMR: δ = 9.98 (s, 1H), 7.8 (d, 2H),
7.34 (d, 2H), 2.7 (m, 2H), 1.54 (m,
2H), 0.96 (d, 6H). Reference example 1(b) p-heptylbenzamide Using 130g of heptylbenzene, reference example 1 and
By the same operation, a title with the following physical property values is created.
65g of compound was obtained. 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), 1.4~1.7 (m,
2H), 1.27 (m, 8H), 0.84 (m, 3H). Reference example 1(c) p-decylbenzaldehyde Same as Reference Example 1 using 134g of decylbenzene.
Through similar operations, the title compound with the following physical properties was obtained.
Obtained 65g of material. TLC: Rf=0.53 (cyclohexane: ethyl acetate
=1:9). NMR: δ=9.76 (s, 1H), 7.4 (dd, 4H), 2.7
(t, 2H), 0.88 (m, 3H). Reference example 2 p-amylcinnamic acid 5.88g of the compound produced in Reference Example 1 was added to chloroform.
Dissolve methoxycarbonyl methylide in 150ml of
Add 16.7g of triphenyl phosphorane for 1 hour.
Semi-refluxed. After cooling to room temperature, concentrate under reduced pressure to remove the residue.
Silica gel column chromatography (methychloride)
It was purified using cyclohexane (2:3). profit
The resulting compound was added to tetrahydrofuran (70 ml).
Dissolve in a mixture of tanol (30ml) and 2N hydric acid.
Add 50ml of potassium chloride aqueous solution and stir at room temperature overnight.
Rice and 500 ml of water were added, and the mixture was extracted with ethyl acetate.
Wash the extract with water and saturated saline, and pour into an anhydrous sulfuric acid mug.
After drying with sodium chloride and concentrating under reduced pressure, it has the following physical properties.
6.44 g of the title compound 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 2(a) p-amyl-2methyl cinnamic acid 2g of the compound produced in Reference Example 1 and 1-eth
Oxycarbonylethylidene triphenyl phos
Using 4g of Horan, follow the same procedure as in Reference Example 2.
1.7 g of the title compound having the following physical property values was obtained. MS: m/Z=232 (M⁺), 175, 129, 115. NMR: δ = 7.83 (q, 1H), 7.40 (d, 2H),
7.24 (d, 2H), 2.63 (t, 2H), 2.15 (d,
3H), 1.5-1.8 (m, 2H), 1.2-1.4 (m,
4H), 0.88(t, 3H). Reference example 3 5-(p-amylphenyl)penta-2,4-
Dienic acid Diisopropylamine 0.18ml in anhydrous tetrahydride
Dissolve in 1.0ml of Lofuran and store at -78℃ to 1.5M butyl chloride.
Slowly add 0.80ml of thium and leave at the same temperature for 15 minutes.
I was bored. Next, 1.0ml of anhydrous tetrahydrofuran
Methoxycarbonylprop-2-ene dissolved in
354 mg of diethoxyphosphine oxide -
Add slowly at 78℃ and stir at the same temperature for 30 minutes.
Ta. 176 mg of the compound produced in Reference Example 1 was added to anhydrous tetamine.
A solution dissolved in 1.5 ml of lahydrofuran was heated to -78℃.
Add drops to this and stir at the same temperature for 1 hour, then 0℃
After raising the temperature to
Extracted with chill. Add the extract to water and saturated sodium bicarbonate.
Wash sequentially with sodium chloride solution and saturated saline solution, and then wash with anhydrous sulfuric acid.
It was dried over magnesium and concentrated under reduced pressure. residue
Silica gel column chromatography (methylene chloride
cyclohexane = 2:3) and the following
217 mg of the title compound having physical properties was obtained. TLC: R=0.45 (benzene). MS: m/Z=258 (M⁺), 243, 227, 201,
199, 141, 129, 115, 71. NMR: δ=7.05-7.60 (m, 5H), 6.60-7.05
(m, 2H), 5.95 (d, 1H), 3.74 (s, 3H),
2.60 (t, 2H), 1.40~1.80 (m, 2H), 1.10~
1.50 (m, 4H), 0.87 (t, 3H). Reference example 4 p-Amylbenzoic acid 1.33g of the compound produced in Reference Example 1 was added to 25g of acetone.
ml, add 8 ml of Jones reagent under water cooling.
Well, I stirred it for 30 minutes at room temperature. Isopro after reaction
Add panol, filter, and dilute the filtrate with anhydrous sodium sulfate.
and concentrated under reduced pressure. Remove the residue from silica
Gel column chromatography (methanol: chromatography)
Purified with roform = 3:97) and has the following physical properties.
The title compound 1.19 was obtained. TLC: R=0.60 (chloroform:methanol=
9.1). IR: ν(cm^-1)=3400, 2300, 1680, 1610,
1570, 1420, 1310, 1280. MS: m/Z=192 (M⁺), 135. NMR: δ=12.45 (m, 1H), 8.1−7.2 (dd,
4H), 2.68 (t, 2H), 1.9-1.48 (m, 2H),
1.87-1.15 (m, 4H), 0.89 (m, 3H). Reference example 4(a) P-decylbenzoic acid Using 1.6g of the compound produced in Reference Example 1(c),
By the same operation as in Example 4, a material with the following physical property values was obtained.
1.52 g of the title compound was obtained. TLC: R=0.52 (chloroform:methanol=
9:1). IR: ν(cm^-1)=3400~2200, 1680, 1610,
1575, 1470, 1420, 1320, 1290. MS: m/Z=262 (M⁺), 136. NMR: δ=11.5 (m, 1H), 8.05−7.20 (dd,
4H), 2.19(t, 2H). 0.88 (m, 3H). Reference example 5 p-isopentyl cinnamic acid 2.7g of the compound produced in Reference Example 1(a) was added to 15% of pyridine.
ml, piperidine 1 ml and malonic acid 3.4 g
was added, heated to 120°C, and reacted for 4 hours. reaction
Cool the liquid to room temperature, add water, and make it acidic with hydrochloric acid.
It was cleaned and filtered. n-hexane-benzene mixture
It was purified by recrystallization using liquid, and the following physical properties were obtained.
Obtained 2.9 g of the title compound. MS: m/Z=218 (M⁺), 151, 144, 115. NMR: δ = 7.80 (d, 1H), 7.22 (d, 2H),
7.48 (d, 2H), 6.40 (d, 1H), 2.63 (t,
2H), 1.4-1.8 (m, 3H), 0.92 (t, 6H). Reference example 5(a) p-heptyl cinnamic acid Reference using 8.7g of the compound produced in Reference Example 1(b)
By the same operation as in Example 5, it has the following physical property values.
9.0 g of the title compound was obtained. MS: m/Z=246 (M⁺), 161, 144, 115. NMR: δ = 7.80 (d, 1H), 6.41 (d, 1H),
2.63 (t, 2H), 1.4-1.7 (m, 2H), 1.3 (m,
8H), 0.86 (m, 3H). Reference example 5(b) p-decyl cinnamic acid Using 1.3g of the compound produced in Reference Example 1(c),
By the same operation as in Example 5, a product with the following physical property values was obtained.
1.20 g of the title compound was obtained. TLC: R = 0.55 (chloroform: methanol =
1:9). IR: ν(cm^-1)=3400~2300, 1680, 1620,
1605, 1460, 1425, 1310, 1290, 1225,
1180, 980. MS: m/Z=288 (M⁺), 161. 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-hydroxycinnamic acid methyl ester 25g of p-hydroxycinnamic acid and 200ml of methanol
Dissolve in water and blow hydrogen chloride gas under ice cooling for 30 minutes.
Thereafter, it was concentrated under reduced pressure. Dab the residue with silica gel
Muchromatography (cyclohexane: ethyl acetate)
By purifying with 10:1), the following physical properties can be obtained.
Obtained 26 g of the title compound having a value of . MS: m/Z=178 (M⁺), 147, 119, 91. NMR: δ=6.88~7.42 (dd, 4H), 6.3~7.85
(g, 2H), 3.8 (s, 3H). Reference example 7 p-pentyloxycinnamic acid methyl ester 1.04g of sodium hydride in anhydrous tetrahydrofuride
P-
Hydroxycinnamic acid methyl ester 4.45g (Reference example 6
Manufactured by. ) to 10 ml of anhydrous tetrahydrofuran.
After dropping the dissolved solution, add anhydrous dimethylform.
10 ml of Muamide was added. Add pentyl chloride to this solution.
Dissolve 4.53g of Mide in 10ml of anhydrous tetrahydrofuran.
The cooled solution was added and the mixture was refluxed for 4 hours. After the reaction,
Add 50 ml of water and 50 ml of water, and immerse the organic layer in water until saturated.
Wash with Japanese saline solution and then with anhydrous magnesium sulfate.
After drying, concentrate under reduced pressure to obtain a title with the following physical properties:
4.4 g of compound was obtained. MS: m/Z=248 (M⁺), 217, 178, 147,
109. NMR: δ = 6.9-7.49 (dd, 4H), 6.3-7.66
(q, 2H), 3.98 (t, 2H), 3.78 (s, 3H)
1.6-1.9 (m, 2H), 1.2-1.6 (m, 4H) 0.92
(t, 3H). Reference example 7(a) p-octyloxycinnamic acid methyl ester Using 4.5g of the compound produced in Reference Example 6,
By the same operation as Example 7, it has the following physical property values.
3.1 g of the title compound was obtained. MS: m/Z=290 (M⁺), 178, 147, 109. NMR: δ = 7.17 (dd, 4H), 7.07 (q, 2H),
3.96 (t, 2H), 3.77 (s, 3H), 1.6~1.9 (m,
2H), 1.2-1.6 (m, 10H), 0.87 (t, 3H). Reference example 8 p-pentyloxycinnamic acid p-pentyloxycinnamic acid methyl ester (reference)
Manufactured in Example 7. ) 4.4g of tetrahydrofuran
Dissolve in a mixture of 30 ml and 30 ml of methanol,
Add 15ml of normal potassium hydroxide aqueous solution and leave in room for 4 hours.
Stir warm. After the reaction water, ether and concentrated
Add 5 ml of hydrochloric acid, and dilute the ether layer with water and saturated saline.
Wash sequentially, dry with anhydrous sodium sulfate, and reduce pressure
Concentrated. The residue was recrystallized using benzene.
The title compound was purified by
Obtained 3.86g. MS: m/Z=234 (M⁺), 217, 164, 147. NMR: δ = 6.9 ~ 7.5 (dd, 4H), 6.3 ~ 7.76 (q,
1H), 3.99 (t, 2H), 1.6-1.9 (m, 2H),
1.2-1.6 (m, 4H), 0.92 (t, 3H). Reference example 8(a) p-octyloxycinnamic acid Using 3.1g of the compound produced in Reference Example 7(a),
By the same operation as in Example 8, a product with the following physical property values was obtained.
3.0 g of the title compound was obtained. MS: m/Z=276 (M⁺), 258, 164, 147. NMR: δ=7.2 (dd, 4H), 7.0 (q, 2H), 3.98
(t, 2H), 1.6-1.9 (m, 2H), 1.2-1.6 (m,
10H), 0.87 (t, 3H). Reference example 9 Methyl p-(1-tridecenyl)benzoate
Tell Dodecyltriphenyl in an argon gas atmosphere
8.65g of phosphonium bromide was dissolved in anhydrous tetrahedron.
Suspended in 60ml of Dorofuran and cooled to -78℃,
1.5N n-butyllithium (n-hexane) solution
Slowly add 8.23ml of liquid and stir at the same temperature for 5 minutes.
In addition, p-formylbenzoic acid methyl ester
Dissolve 1.48g of water in 10ml of anhydrous tetrahydrofuran.
Add the solution slowly and leave at the same temperature for 1 hour and 30 minutes.
The mixture was stirred at 0°C for 30 minutes. Dilute the reaction solution with ammonium chloride.
Pour into aqueous solution of sodium chloride, extract with ethyl acetate, and concentrate under reduced pressure.
Shrunk. The residue was dissolved in ethyl acetate-cyclohexane.
(5:1), filtered, and concentrated under reduced pressure. Residue
The distillate was subjected to silica gel column chromatography (acetic acid
Purify with ethyl:cyclohexane=1:20) and
2.95 g of the title compound having the following physical property values was obtained. TLC: R=0.40 (ethyl acetate: cyclohexane
= 1:10). MS: m/Z=316 (M⁺), 285, 257, 162, 131, 115, 91. NMR: δ = 8.00 (d, 2H), 7.32 (d, 2H),
6.44 (d, 1H), 5.76 (dt, 1H), 3.90 (s,
3H), 2.30 (m, 2H), 1.05-1.80 (m, 18H),
0.88 (t, 3H). Reference example 10 p-(1-decenyl)benzyl alcohol The chemical produced in Reference Example 9 in an argon gas atmosphere
Dissolve 2.91 g of the compound in 60 ml of anhydrous toluene and cool at -78°C.
1.76 mol/l of diisobutyl
Aluminum hydride (toluene) solution
Slowly add 8.90ml and incubate at the same temperature for 5 minutes at 0℃.
Stir for 20 minutes. After cooling the reaction solution to -20℃,
Add methanol and then 4 ml of water and stir vigorously.
dropwise to stop the reaction, then leave at room temperature for another 30 minutes.
I stirred it vigorously. Filter the reaction solution and reduce the filtrate.
It was concentrated under pressure. Add toluene to the residue and azeotropically
After removing water and drying under reduced pressure, it has the following physical properties.
2.54 g of the title compound was obtained. TLC: R = 0.27 and 0.33 (ethyl acetate: cyclo
Hexane = 1:3). MS: m/Z=288 (M⁺), 270, 257, 134, 129, 117, 105, 91. NMR: δ=7.28 (s, 4H), 6.40 (d, 1H),
5.66 (dt, 1H), 4.63 (s, 2H), 2.30 (m,
2H), 2.00 (s, 1H), 1.05-1.70 (m, 18H),
0.88 (t, 3H). Reference example 11 p-(1-tridecenyl)benzaldehyde Oxalyl chloride 1.05ml methylene chloride 15
ml at −78 °C under an argon gas atmosphere.
1.42 ml of dimethyl sulfoxide and 5 ml of methylene chloride
Slowly add ml of the mixture and leave at the same temperature for 20 minutes.
I was bored. In addition, the compound produced in Reference Example 10
A solution of 2.54g dissolved in 10ml of methylene chloride was heated to -78℃.
and stirred at the same temperature for 30 minutes. Sara
6.3ml of triethylamine was added dropwise to the solution at the same temperature.
After stirring for 5 minutes, raise the temperature to room temperature and stir for 5 minutes.
I poured it into the water. Extract with methylene chloride.
Wash the liquid with saturated saline and add anhydrous magnesium sulfate.
The mixture was dried under vacuum and concentrated under reduced pressure. Silica gel residue
Column chromatography (methylene chloride: cyclo
Purified with hexane = 1:3) and has the following physical properties.
2.48 g of the title compound was obtained. TLC: R=0.35 (ethyl acetate: cyclohexane
=1:3). MS: m/Z=286 (M⁺), 268, 257, 132,
117, 91. NMR: δ = 9.98 (s, 1H), 7.84 (d, 2H),
7.42 (d, 2H), 6.44 (d, 1H), 5.80 (dt,
1H), 2.30 (m, 2H), 1.05-1.70 (m, 18H),
0.88 (t, 3H). Reference example 12 p-(1-tridecenyl)cinnamate methyl ester
le 2.48g of the compound produced in Reference Example 11 was added to methyl chloride.
Dissolve in 30ml of methoxycarbonyl methylide.
Add 2.9g of triphenylphosphorane and reflux for 2 hours.
It flowed. After the reaction, cool to room temperature and concentrate under reduced pressure.
Ta. Silica gel column chromatography of the residue
- (methylene chloride: cyclohexane = 2:3)
3.42g of the purified title compound having the following physical properties:
I got it. TLC: R = 0.45 and 0.55 (benzene). MS: m/Z=342 (M⁺), 311, 201, 188,
169, 157, 141, 115. NMR: δ = 7.69 (d, 1H), 7.49 (d, 2H), 7.28 (d, 2H), 6.42 (d, 1H), 6.39 (d, 1H), 5.72 (dt, 1H), 3.80 (s, 3H), 2.30 (m, 2H), 1.05-1.70 (m, 18H), 0.88 (t, 3H). Reference example 13 p-(1-tridecenyl)cinnamic acid 2.81g of the compound produced in Reference Example 12 was added to methanol.
(15ml) - tetrahydrofuran (7ml) mixture
Dissolve and add 22.5ml of 1N lithium hydroxide aqueous solution.
Well, I stirred it all day and night at room temperature. 150ml of water after reaction
was added, neutralized with 1N hydrochloric acid, and extracted with ethyl acetate.
I put it out. Wash the extract sequentially with water and saturated saline,
Dry over anhydrous magnesium sulfate, concentrate under reduced pressure, and
2.24 g of the title compound having the following physical property values was obtained. TLC: R=0.40 (ethyl acetate: cyclohexane
=1:1). MS: m/Z=328 (M⁺), 311, 300, 187,
174, 169, 161, 141, 128, 115, 91. NMR: δ = 7.68 (d, 1H), 7.51 (d, 2H), 7.30 (d, 2H), 6.41 (d, 1H), 6.39 (d, 1H), 5.72 (dt, 1H), 4.37 (s, 1H), 2.30 (m, 2H), 1.05-1.65 (m, 18H), 0.86 (t, 3H). Reference example 14 3-Hydroxymethylbenzonitrile 3g of 3-cyanobenzoic acid in tetrahydrofuran
The solution dissolved in 5 ml was cooled on ice and diluted with ethyl chloroacetate.
2.43g was added dropwise and stirred for 20 minutes. This and water
Add 2.26g of sodium borohydride and stir for 30 minutes.
Rice and water were added, and the mixture was extracted with ethyl acetate. extraction
After drying the liquid with anhydrous sodium sulfate, it was concentrated under reduced pressure.
The residue was subjected to silica gel column chromatography (vinegar
Purify with ethyl acid: n-hexane = 3:7) and
1.7 g of the title compound having the following physical property values was obtained. IR (liquid film method): ν (cm^-1) = 3400, 2230. NMR: ν=4.53 (s, 4H), 7.50 (m, 4H). Reference example 15 3-(2-tetrahydropyranyloxy methi
) Benzonitrile 1.7g of the compound produced in Reference Example 14 was added to methylene chloride.
It was dissolved in 30 ml and cooled on ice. This dihydropyran
Add 2.14 g and p-toluenesulfonic acid catalyst amount.
Well, I made it react. After the reaction, add triethylamine.
washed with water, dried with anhydrous sodium sulfate, and reduced.
It was concentrated under pressure. Silica gel column chromatography of the residue
Graphi (ethyl acetate: n-hexane = 2:8)
2.0g of the title compound purified by
I got it. IR (liquid film method): ν (cm^-1)=2230. Reference example 16 3-(2-tetrahydropyranyloxymethyl)
benzaldehyde 2.7g of the compound produced in Reference Example 15 was added to 10ml of toluene.
diisobutyl, cooled to -78°C, diisobutyl
After adding 5.47ml of aminium hydride, 0
After heating to ℃ and stirring for 10 minutes, methane was heated to -78℃.
Added rules. Add water to this, filter, and ethyl acetate.
Wash the precipitate with tartaric acid aqueous solution, and remove the filtrate.
Wash with water, dry with anhydrous sodium sulfate,
It was concentrated under reduced pressure. Chroma the residue on a silica gel column.
Tography (ethyl acetate: n-3 hexane = 1:
The title compound purified by 9) and having the following physical properties
Obtained 2.56g. IR (liquid film method): ν (cm^-1)=1730. NMR: δ=9.60 (s, 1H). Reference example 17 1-[3-(2-tetrahydropyranyloxime
(chill)phenyl]dec-1-ene Triphenylnonylphosphine bromide at room temperature
Prepare 6.60g of hexamethylphosphamide
After adding 2 ml, the compound produced in Reference Example 16
2.56g was added at once and reacted at room temperature for 3 hours.
After the reaction, water was added, extracted with ethyl acetate, and extracted with anhydrous sulfur.
After drying with sodium chloride, it was concentrated under reduced pressure. residue
Silica gel column chromatography (ethyl acetate
1: n-hexane = 1:9), and the following
Obtained 2.87 g of the title compound having a specific value. NMR: δ=7.05 (m, 4H), 6.26 (d, 1H), 5.50 (dt, 1H), 4.55 (q, 2H). Reference example 18 1-(3-hydroxymethylphenyl)deca-
1-en 2.87g of the compound produced in Reference Example 17 was added to methanol.
Dissolve in 40ml and add 1 drop of p-toluenesulfonic acid.
Yes, I stirred it at room temperature for 2 hours. Add Trie to the reaction solution.
Add thylamine, concentrate under reduced pressure, and dissolve the residue in acetic acid ethyl chloride.
Dissolve in chill, wash with water, and dry with anhydrous magnesium sulfate.
After drying, silica gel column chromatography (acetic acid ethyl chloride)
Purify with chill:n-hexane=1:9) to obtain the following:
Obtained 2.1 g of the title compound having a specific value. NMR: δ=7.05 (m, 4H), 6.3 (d, 1H), 5.50 (dt, 1H), 4.42 (s, 2H). Reference example 19 3-(1-decenyl)benzaldehyde 2.1g of the compound produced in Reference Example 18, dimethyl sulfate
Phoxide 1.34g, triethylamine 4.9ml and salt
Cool a mixture of 50 ml of methylene chloride on ice, and add
1.64 g of loride was added dropwise and left for 1 hour. reaction
Wash the solution with water, dry with anhydrous sodium sulfate, and
Kagel column chromatography (ethyl acetate: n
- hexane = 5:95), and the following physical properties were obtained.
1.84 g of the title compound was obtained. IR: ν(cm^-1)=1725. MS: m/Z=244 (M⁺). NMR: δ=9.81 (s, 1H), 7.1-7.7 (m,
4H), 6.33 (d, 1H), 5.65 (dt, 1H). Reference example 20 3-(1-decenyl)cinnamic acid methyl ester 500 mg of the compound produced in Reference Example 19, methoxyca
Rubonyl methylidene triphenylphosphorane
A mixture of 1.26g and 20ml of benzene was heated at room temperature for 15 hours.
The mixture was stirred for a while and concentrated under reduced pressure. Silicage the residue
column chromatography (ethyl acetate: n-helical
It is purified with xane=1:9) and has the following physical properties.
550 mg of the title compound was obtained. IR: ν(cm^-1) = 1690, 1640. MS: m/Z=300 (M⁺), 258, 243. NMR: δ = 7.7-7.1 (m, 5H), 6.3 (d, 1H), 6.29 (d, 1H), 5.7 (dt, 1H), 3.6 (s, 3H). Reference example 21 3-(1-decenyl)cinnamic acid 300 mg of the compound produced in Reference Example 20, 1N hydric acid
3 ml of sodium chloride aqueous solution and 5 ml of methanol
The mixture was refluxed for 3 hours. After the reaction, concentrate under reduced pressure for 1 time.
Acidified with constant hydrochloric acid, extracted with ethyl acetate, and extracted with anhydrous sulfuric acid.
It was dried over magnesium chloride and concentrated under reduced pressure. residue and
Silica gel column chromatography (ethyl acetate
1: n-hexane = 3:7), and the following
Obtained 300 mg of the title compound having a specific value. MS: m/Z=286 (M⁺). NMR: δ=10.0 (s, 1H), 7.66 (d, 1H), 7.2 (m, 4H), 6.35 (d, 1H), 6.30 (d, 1H), 5.6 (dt, 1H), 2.3 (m, 2H). Reference example 22 1-(3-hydroxymethylphenyl)decane 100mg of the compound produced in Reference Example 18, 10% paradi
A mixture of 10 mg of carbon and 5 ml of methanol is mixed with hydrogen.
The mixture was stirred at room temperature under atmosphere for 4 hours. reaction solution
Filter and concentrate under reduced pressure to obtain a title with the following physical properties:
92 mg of compound was obtained. MS: m/Z=288. Reference example 23 3-decylbenzaldehyde Using 92 mg of the compound produced in Reference Example 22,
Example 19 By the same operation, a standard with the following physical property values was obtained.
80 mg of the title compound was obtained. IR: ν(cm^-1)=1700. NMR: δ=9.7 (s, 1H), 7.7 (m, 2H), 7.3 (m, 2H), 2.5 (bt, 2H). Reference example 24 3-decyl cinnamic acid methyl ester Using 80 mg of the compound produced in Reference Example 23,
By the same operation as Example 20, it has the following physical property values.
90 mg of the title compound was obtained. IR: ν(cm^-1) = 1690, 1640. MS: m/Z=298 (M⁺). NMR: δ = 7.7-7.1 (m, 5H), 6.3 (d, 1H), 2.3 (m, 2H). Reference example 25 3-decyl cinnamic acid Using 90 mg of the compound produced in Reference Example 24,
By the same operation as Example 21, it has the following physical property values.
85 mg of the title compound was obtained. NMR: δ=10.5 (s, 1H), 7.65 (d, 1H),
7.2 (m, 4H), 6.33 (d, 1H), 2.3 (m, 2H). Reference example 26 3-(1-decenyl)benzoic acid 500 mg of the compound produced in Reference Example 19 was added to 20 mg of acetone.
ml, cooled to -20°C, and added Jones's reagent.
dripped. Confirm the reaction with TLC and check that there are no unreacted substances.
When it becomes thick, add isopropyl alcohol.
Ta. Extracted with ethyl acetate and anhydrous sodium sulfate.
Dry, concentrate under reduced pressure, and chromatograph on silica gel column.
Graphie (ethyl acetate: n-hexane = 3:
The title compound purified by 7) and having the following physical properties
Obtained 210 mg. IR: ν(cm^-1)=3400~2800, 1690. MS: m/Z=260 (M⁺). NMR: δ=7.3~8.0 (m, 4H), 6.35 (d,
1H), 5.65 (d, 1H). Reference example 26(a) m-decylbenzoic acid Using 20 mg of the compound produced in Reference Example 23,
By the same operation as Example 26, it has the following physical property values.
16 mg of the title compound was obtained. IR: ν(cm^-1)=3400~2700, 1700 MS: m/Z=262 (M⁺). NMR: δ=11.5 (m, 1H), 7.7 (m, 2H),
7.25 (m, 2H), 2.6 (m, 2H), 2.25 (m,
16H), 0.90 (m, 3H). Example 1 N-(p-amylcinnamoyl)anthranyl
Acids and their sodium salts p-Amylcinnamic acid (produced in Reference Example 2) 218
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. Anthranilic acid 137mg and triethylamine 303mg
Dissolve the above concentrate in 2 ml of methylene chloride.
was added dropwise under ice cooling and stirred at room temperature for 1 hour.
Then, add 3 ml of 1N hydrochloric acid and extract with ethyl acetate.
Ta. After drying the extract over anhydrous sodium sulfate, reduce the pressure.
Concentrated. Concentrate on silica gel column chromatograph
Using Raffy (methylene chloride: ether = 5:1)
Purify the methanol-n-hexane mixture.
The title compound was recrystallized using
125 mg of acid was obtained. TLC: R = 0.3 (methylene chloride: ether =
2:1). MS: m/Z=337 (M⁺), 319, 201. IR: ν(cm^-1): 1695, 1665, 1605, 1580, 1515, 1450. NMR: δ=8.92 (dd, 1H), 8.17 (dd, 1H), 7.77 (d, 1H), 7.65 (dt, 1H), 7.51 (d, 2H), 7.21 (d, 2H), 7.14 (dt.1H), 6.57 (d, 1H). Suspend the above acid in methanol and add 1N hydroxide.
Drop an equivalent amount of sodium chloride aqueous solution and concentrate under reduced pressure.
Possibly the corresponding sodium salt (pale yellow crystals)
crystal) was obtained. Example 1(a)-1(t) Corresponding starting material by a similar procedure as in Example 1
The following compound was obtained from Example 1(a) N-(p-decylcinnamoyl)anthranyl
Acids and their sodium salts Starting material: 233 mg p-decyl cinnamic acid (Reference Example 5(b)
Manufactured by. ). Purification method: Silica gel column chromatography (salt
methylene chloride:ether=5:1). Yield [acid]: 145 mg. TLC [acid]: Rf = 0.3 (methylene chloride: ether =
3:1). IR [salt]: ν (cm^-1) = 1670, 1620, 1590, 1510, 1440, 1380. MS [acid]: m/Z=407 (M⁺), 389, 271. NMR [acid]: δ = 8.92 (dd, 1H), 8.17 (dd, 1H), 7.77 (d, 1H), 7.65 (dt, 1H), 7.51 (d, 2H), 7.21 (d, 2H), 7.14 (dt, 1H), 6.57 (d, 1H). Salt form: pale yellow crystals. Example 1(b) N-(p-amylbenzoyl)anthranilic acid
and its sodium salt Starting material: p-amylbenzoic acid 100mg (reference example
4. ). Purification method: Preparative TLC (ethyl acetate: n-
Hexane = 1:1). Yield [acid]: 29mg TLC [acid]: R = 0.3 (ethyl acetate: n-hexane
=1:1). IR [acid]: ν (cm^-1) = 1690, 1650, 1610, 1585. MS [acid]: m/Z=311 (M⁺), 293, 175. NMR [acid]: δ = 8.86 (dd, 1H), 8.14 (dd, 1H), 7.94 (d, 2H), 7.59 (dt, 1H), 7.29 (d, 2H), 7.12 (dt, 1H). Form of salt: light brown crystals. Example 1(c) N-(p-decylbenzoyl)anthranilic acid
and its sodium salt Starting material: p-decylbenzoic acid 236 mg (reference example
4(a). ). Purification method: Preparative TLC (ethyl acetate: n-
Hexane = 1:1). Yield [acid]: 40 mg. TLC [acid]: R = 0.3 (ethyl acetate: n-hexane
=1:1). IR: ν(cm^-1) = 1690, 1650, 1610, 1590. MS [acid]: m/Z=381 (M⁺), 363, 245. NMR [acid]: δ = 8.98 (dd, 1H), 8.17 (dd, 1H), 7.96 (d, 2H), 7.67 (dt, 1H), 7.32 (d, 2H), 7.16 (dt, 1H). Salt form: pale yellow crystals. Example 1(d) N-[m-(1-decenyl)benzoyl]ant
Ranilic acid and its sodium salt Starting material: m-(1-decenylbenzoic acid 103mg
(Produced in Reference Example 26). Purification method: Preparative TLC (ethyl acetate: n-
Hexane = 1:1). Yield [acid]: 10 mg. TLC [acid]: R = 0.3 (ethyl acetate: n-hexane
=1:1). IR [acid]: ν (cm^-1) = 1680, 1665, 1610, 1590, 1530, 1450. MS [acid]: m/Z=379 (M⁺), 361, 334, 267, 243. NMR [acid]: δ = 8.97 (dd, 1H), 8.67 (dd, 1H), 7.8−8.05 (m, 2H), 7.67 (dt, 1H), 7.2-7.6 (m, 2H), 7.37 (dt, 1H), 6.47 (d, 1H), 5.77 (dt, 1H). Salt form: brown crystals. Example 1(e) N-(m-decylbenzoyl)anthranilic acid
and its sodium salt Starting material: m-decylbenzoic acid 69 mg (Reference example 26
Manufactured in (a). ). Purification method: Preparative TLC (ethyl acetate: n-
Hexane = 1:2). Yield [acid]: 5 mg. TLC [acid]: R = 0.3 (ethyl acetate: n-hexane
=1:1). IT [acid] (liquid film method): ν (cm^-1)=1680, 1610, 1590, 1530. MS [acid]: m/Z = 381, 363, 301, 245. NMR [acid]: δ = 8.95 (dd, 1H), 8.15 (dd, 1H), 7.75−7.95 (m, 2H), 7.64 (dt, 1H), 7.30-7.50 (m, 2H), 7.13 (dt, 1H). Salt form: pale yellow crystals. Example 1(f) N-[m-(1-decenyl)cinnamoyl]an
Tranilic acid and its sodium salt Starting material: m-(1-decenyl)cinnamic acid 130mg
(Produced in Reference Example 21.) Purification method: Preparative TLC development (ethyl acetate)
n-hexane = 1:2). Yield [acid]: 42 mg. TLC [acid]: Rf = 0.3 (ethyl acetate: n-hexane
=1:1). IR [acid] (liquid film method): ν (cm^-1) = 1680, 1605. MS [acid]: m/Z = 405, 387, 269. NMR [acid]: δ = 8.89 (d, 1H), 8.14 (dd, 1H), 7.76 (d, 1H), 7.62 (dt, 1H), 7.2−7.5 (m, 4H), 7.13 (t, 1H), 6.58 (d, 1H), 6.40 (d, 1H). Salt form: pale yellow crystals. Example 1(g) N-(m-decylcinnamoyl)anthranyl
Acids and their sodium salts Starting material: m-decyl cinnamic acid 105 mg (Reference example 25
Manufactured by. ). Purification method: Recrystallization method (ethyl acetate-n-hexane). Yield [acid]: 60 mg. TLC [acid]: Rf = 0.4 (ethyl acetate: n-hexane
=1:1). IR [acid] (liquid film method): ν (cm^-1)=1680, 1605, 1590. MS [acid]: m/Z = 407, 389, 271. NMR [acid]: δ = 8.88 (d, 1H), 8.11 (dd, 1H), 7.72 (d, 1H), 7.61 (dt, 1H), 7.2−7.5 (m, 4H), 7.11 (t, 1H), 6.58 (d, 1H). Salt form: white crystals. Example 1(h) N-(p-amyl-2-methylcinnamoyl)
Anthranilic acid and its sodium salt Starting material: 230 mg p-amyl-2-methyl cinnamic acid
(Produced in Reference Example 2(a).) Purification method: Recrystallization method (n-hexane: ethyl acetate =
10:1). Yield [acid]: 254 mg. TLC [acid]: Rf = 0.3 (ethyl acetate: n-hexane
=2:1). IR [acid]: ν (cm^-1) = 1660, 1610, 1600, 1580, 1520. MS [acid]: m/Z = 351, 333, 215, 187, 145. NMR [acid]: δ = 8.80 (d, 1H), 8.08 (dd, 1H), 7.56 (dt, 1H), 7.54 (s, 1H), 7.1−7.4 (m, 4H), 7.07 (t, 1H), 2.23 (d, 1H). Salt form: white crystals. Example 1(i) N-[p-(tridecenyl)cinnamoyl]an
Tranilic acid and its sodium salt Starting material: 188 mg p-(1-tridecenyl)cinnamic acid
(Produced in Reference Example 13.) Purification method: silica gel column chromatography (Ethyl acetate: cyclohexane = 1:3 →
2:1). Yield [acid]: 105 mg. TLC [acid]: Rf = 0.20 (ethyl acetate: cyclohexane
(=1:1). IR [acid]: ν (cm^-1) = 2940, 2860, 1685, 1625, 1605, 1585, 1520, 1450, 1400, 1220, 835, 755, 655, 520. MS [acid]: m/Z=447, 429, 311, 169, 157, 141, 137, 129, 115. NMR [acid] (CD₃OD): δ = 8.61 (d, 1H), 8.08
(d, 1H), 7.50-7.70 (m, 3H), 7.25 −7.50 (m, 2H), 7.06 (t, 1H), 6.72 (d, 1H), 6.3−6.50 (m, 1.5 H), 5.72 (dt, 0.5H), 2.15−2.42 (m, 2H), 1.15-1.60 (m, 18H), 0.90 (t, 3H). Salt form: brown solid. Example 1(j) N-(p-isopentylcinnamoyl)ant
Ranilic acid and its sodium salt Starting material: p-isopentyl cinnamic acid 267 mg (reference)
Manufactured in Example 5. ). Purification method: Recrystallization method (ethyl acetate: n-hexane =
1:10). Yield [acid]: 215mg TLC [acid]: Rf = 0.6 (ethyl acetate: n-hexane
=2:1). IR [acid]: ν (cm^-1) = 1680, 1620, 1600, 1580, 1510. MS [acid]: m/Z = 337, 319, 201, 137, 131. NMR [acid]: δ = 8.91 (d, 1H), 8.18 (dd, 1H), 7.77 (d, 1H), 7.64 (dt, 1H), 7.2−7.6 (m, 4H), 7.14 (t, 1H), 6.57 (d, 1H). Salt form: white crystals. Example 1(k) N-(p-pentyloxycinnamoyl)an
Tranilic acid and its sodium salt Starting material: p-pentyloxycinnamic acid 290mg
(Produced in Reference Example 8). Purification method: Recrystallization method (chloroform-n-hexane
hmm). Yield [acid]: 269mg TLC [acid]: Rf = 0.40 (ethyl acetate). IR [acid]: ν (cm^-1) = 1660, 1600, 1580, 1525, 1510. MS [acid]: m/Z=353 (M⁺), 335, 264, 217, 208, 147. NMR [acid]: δ = 8.90 (d, 1H), 8.15 (d, 1H), 7.72 (d, 2H), 7.62 (dt, 1H), 7.45−7.60 (m, 2H), 7.12 (t, 1H), 6.80−6.95 (m, 2H), 6.46 (d, 1H), 3.96 (t, 2H). Salt form: pale yellow solid. Example 1(l) N-(p-octyloxycinnamoyl)an
Tranilic acid and its sodium salt Starting material: p-octyloxycinnamic acid 285mg
(Produced in Reference Example 8(a).) Purification method: Recrystallization method (methanol-n-hexane). Yield [acid]: 210mg. TLC [acid]: Rf = 0.40 (ethyl acetate). IR [Salt] ν (cm^-1) = 1660, 1600, 1590, 1505. MS [acid] m/Z = 395 (M⁺), 377, 259, 147. NMR [acid] (CDCl₃＋CD₃OD): δ=8.81(d,
1H), 8.10 (d, 1H), 7.68 (d, 1H), 7.56 (dt, 1H), 7.09 (t, 1H), 7.45-7.60 (m, 2H), 6.85-7.00 (m, 2H), 6.47 (d, 1H), 3.98 (t, 2H). Salt form: pale yellow solid. Example 1(m) N-(p-amylcinnamoyl)anthranyl
acid methyl ester Starting material: p-amylcinnamic acid 130mg (Reference example 2
Manufactured by. ) and methyl anthranilate
Tel 90mg. Purification method: Silica gel column chromatography (vinegar
ethyl acid: n-hexane = 1:20). Yield: 89mg. TLC: Rf = 0.70 (ethyl acetate: n-hexane =
1:4). IR: ν(cm^-1) = 1680, 1620, 1600, 1580, 1520. MS: m/Z=351, 336, 320, 201, 151, 131. NMR: δ = 8.87 (d, 1H), 8.05 (d, 1H), 7.74 (d, 1H), 7.58 (t, 1H), 7.2−7.55 (m, 4H), 7.08 (t, 1H), 6.57 (d, 1H), 3.95 (s, 3H). Example 1(n) o-[N-(p-amylcinnamoyl)amino]
Phenylacetic acid and its sodium salt Starting material: p-amylcinnamic acid 146 mg (Reference example 2
Manufactured by. ) and o-aminophenyl acetic acid
101 mg. Purification method: Silica gel column chromatography (vinegar
ethyl acid: n-hexane = 1:2). Yield [acid]: 95 mg. TLC [acid]: Rf = 0.30 (ethyl acetate). IR [acid]: ν (cm^-1) = 1690, 1650, 1615. MS [acid]: m/Z=351, 333, 307, 201, 151, 131. NMR [acid]: δ = 7.90 (s, 1H), 7.74 (d, 1H), 7.1−7.6 (m, 8H), 6.60 (d, 1H), 3.65 (s, 2H). Salt form: pale yellow solid. Example 1(o) m-[N-(p-amylcinnamoyl)amino]
Benzoic acid and its sodium salt Starting material: p-amylcinnamic acid 125mg (Reference example 2
Manufactured by. ) and m-aminobenzoic acid 79 mg. Yield [salt]: 52 mg. TLC [salt]: Rf = 0.30 (ethyl acetate: n-hexane
=1:1). IR [salt]: ν (cm^-1) = 1680, 1650, 1620, 1585, 1535. MS [salt]: m/Z=337 (M⁺), 201, 131. NMR [salt] (CD₃OD): δ=7.80−8.20(m, 2H),
7.40− 7.89 (m, 4H), 7.20−7.40 (m, 3H), 6.74 (d, 1H). Salt form: pale yellow solid. Example 1(p) N-(p-heptylcinnamoyl) anthrani
Ruic acid and its sodium salt Starting material: p-heptylcinnamic acid 224mg (reference example
5(a). ). Purification method: Silica gel column chromatography
(Ethyl acetate:n-hexane=1:10). Yield [acid]: 160 mg. TLC [acid]: Rf = 0.20 (ethyl acetate: n-hexane
=1:1). IR [salt]: ν (cm^-1) = 1605, 1585, 1500, 1435, 1380. MS [acid]: m/Z=365, 347, 219, 144, 137, 131. NMR [acid]: 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). Salt form: white solid. Example 1(q) o-[N-(p-amylcinnamoyl)amino]
phenol Starting material: p-amylcinnamic acid 308mg (Reference example 2
Manufactured by. ) and o-aminophenol 162
mg. Purification method: Silica gel column chromatography (vinegar
ethyl acid: n-hexane = 1:4). Yield: 69mg. TLC: Rf = 0.60 (ethyl acetate: n-hexane =
1:2). IR: ν(cm^-1) = 1650, 1620, 1600. MS: m/Z=309 (M⁺), 201, 131. 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(r) 2-[N-(p-amylcinnamoyl)amino]
Nicotinic acid and its sodium salt Starting material: p-decyl cinnamic acid 110 mg (Reference example 2
Manufactured by. ) and 77 mg of 2-aminonicotinic acid. Purification method: Silica gel column chromatography (vinegar
ethyl acid: n-hexane = 1:2). Yield [acid]: 52 mg. TLC [acid]: Rf = 0.10 (ethyl acetate), IR [acid]: ν (cm^-1) = 1680, 1630, 1600, 1550 MS [acid]: m/Z=338 (M⁺), 319, 310, 291, 201. NMR [salt] (CD₃OD): δ = 8.43 (dd, 1H), 8.40 (m, 1H), 7.72 (d, 1H), 7.50− 7.60 (m, 2H), 7.20-7.30 (m, 2 H), 7.12 (dd, 1H), 6.78 (d, 1H). Salt form: pale yellow solid. Example 1(s) 2-[N-(p-amylcinnamoyl)amino]
3-hydroxypyridine Starting material: p-aminocinnamic acid 625mg (Reference example 2
Manufactured by. ) and 2-amino-3-hydroxy
Cypyridine 100mg. Purification method: Silica gel column chromatography (vinegar
ethyl acid: cyclohexane = 1:2). Yield: 80mg. TLC: Rf = 0.22 (ethyl acetate: cyclohexane =
1:1). IR: ν(cm^-1) = 3520, 3440, 3290, 3130, 2920, 2850, 1775, 1630− 1650, 1605, 1565, 1515, 1475, 1450, 1415, 1370, 1305, 1205, 1180, 1145, 1100, 960, 845, 825, 810, 755, 555, 500. MS: m/Z=310 (M⁺), 266, 253, 201, 173, 157, 144, 131, 115, 110, 103. NME: δ = 7.95 (dd, 1H), 7.86 (d, 1H), 7.48 (d, 2H), 7.37 (dd, 1H), 7.22 (d, 2H), 6.69 (dd, 1H), 6.57 (d, 1H), 4.65 (s, 2H), 2.64 (t, 2H), 1.62 (m, 2H), 1.20 -1.50 (m, 4H), 0.90 (t, 3H). Example 1(t) 2-[N-(p-amylcinnamoyl)amino]
-6-hydroxypyridine Starting material: p-amylcinnamic acid 654 mg (Reference Example 2
Manufactured by. ) and 2-amino-6-hydroxy
Cypyridine 110mg. Purification method: Silica gel column chromatography (vinegar
ethyl acid: cyclohexane = 1:3). Yield: 164mg. TLC: Rf = 0.25 (ethyl acetate: cyclohexane =
1:2) IR: ν(cm^-1) = 3435, 3320, 3310, 2930, 2855, 1710, 1640, 1605, 1550, 1480, 1435, 1250, 1195, 1175, 1125, 1055, 1000, 975, 910, 815, 795, 765, 620, 505. MS: m/Z=310 (M⁺), 282, 265, 253, 225, 201, 173, 157, 144, 131, 115, 110, 103. NMR: δ = 7.86 (d, 1H), 7.52 (t, 1H), 7.48 (d, 2H), 7.21 (d, 2H), 6.56 (d, 1H), 6.49 (d, 1H), 6.39 (d, 1H), 4.52 (s, 2H), 2.64 (t, 2H), 1.83 (m, 2H), 1.20−1.50 (m, 4H), 0.90 (t, 3H). Example 2 N-[5-(p-amylphenyl)penta-2,
4-Dienoyl]anthranilic acid methyl ester
le 5-(p-peptylphenyl)penta-2,4
- Add 110 mg of dienoic acid (produced in Reference Example 3) to
Add 1.4ml of salyl chloride and leave at room temperature for 30 minutes.
After stirring, the mixture was concentrated under reduced pressure. The resulting yellow solid
Dissolve the body in 2 ml of anhydrous methylene chloride, add anhydrous
Dissolved in 3 ml of methylene chloride and 0.11 ml of triethylamine.
121 mg of dissolved anthranilic acid methyl ester was added to 0
Dropped at ℃, kept at the same temperature for 30 minutes, and then at room temperature for 1 hour.
I stirred for a while. Add 20ml of 1N hydrochloric acid to this, and add ethyl acetate.
Extracted. The extract was dissolved in 1N hydrochloric acid, water, and sodium bicarbonate.
Wash with thorium aqueous solution, saturated saline, and anhydrous sulfuric acid.
It was dried over magnesium and concentrated under reduced pressure. residue
Silica gel column chromatography (chloroform
cyclohexane = 1:1), and further
After washing with n-hexane, a standard with the following physical properties was prepared.
90 mg of the title compound was obtained. MS: m/Z=377 (M⁺), 362, 346, 319, 242, 227, 170, 161, 141, 115. NMR: δ=11.24 (s, 1H), 8.86 (d, 1H), 8.02 (dd, 1H), 7.00−7.70 (m, 7H), 6.80=7.00 (m, 2H), 6.15 (d, 1H), 3.92 (s, 3H), 2.60 (t, 2H), 1.10−1.80 (m, 6H), 0.88 (t, 3H). Example 3 N-[5-(p-amylphenyl)penta-2,
4-Dienoyl]anthranilic acid and its sodium
thorium salt 89 mg of the methyl ester produced in Example 2 was
Dissolved in 2 ml of lahydrofuran and 3 ml of methanol,
Add 0.35ml of 2N potassium hydroxide aqueous solution and bring to room temperature.
I stirred it for 3 days. Add 1ml of 1N hydrochloric acid to this.
and extracted with ethyl acetate. Extract with water, saturated
Wash with saline and dry with anhydrous magnesium sulfate
and concentrated under reduced pressure. Wash the concentrate with n-hexane
Then, 79 mg of the title compound [acid] having the following physical property values was added.
Obtained. Furthermore, dissolve 76 mg of this acid in 2 ml of methanol.
Dissolve and add 0.21ml of 1N sodium hydroxide aqueous solution.
Then, concentrate under reduced pressure to obtain the corresponding sodium salt (yellow).
Obtained 78mg. TLC [acid]: Rf = 0.30 (ethyl acetate: cyclohexyl
Sun = 2:1). IR [acid]: ν (cm^-1)=3010, 2920, 2850, 1675, 1645, 1600, 1520, 1480 1445, 1415, 1385, 1280, 1210 1160, 1135, 995, 830, 800, 755, 695, 650, 530. MS [acid]: m/Z=363 (M⁺), 345, 306, 288, 274, 242, 227, 198, 170, 161, 157, 141, 129, 115. NMR [salt] (CD₃OD): δ = 8.59 (d, 1H),
8.08 (d, 1H), 7.30−7.55 (m, 4H), 7.16 (d, 2H), 6.85−7.12 (m, 3H), 6.25 (d, 1H), 2.60 (t, 2H), 1.62 (m, 2H), 1.33 (m, 4H), 0.90 (t, 3H). Example 4 o-[N-(p-amylcinnamoyl)amino]
Phenoxyacetic acid ethyl ester o-[N-(p-amylcinnamoyl)amino]
180 mg of phenol (produced in Example 1(q)) was added to
Sodium iodide dissolved in 10 ml of thyl ethyl ketone
90mg of potassium carbonate, 100mg of potassium carbonate, 2-bromoacetic acid
67 μl of chill was added, and the mixture was refluxed for 2 days and filtered. filtrate
Concentrate under reduced pressure and chromatograph the residue on a silica gel column.
Graphi (chloroform: n-hexane = 6:
The title compound purified by 1) and having the following physical properties
Obtained 140mg. MS: m/Z=395 (M⁺), 350, 338, 309, 201 195, 131, 115, 43. NMR: δ=8.70 (s, 1H), 8.56 (dd, 1H), 7.76 (d, 1H), 7.49 (d, 2H), 7.19 (d, 2H), 6.80−7.15 (m, 3H), 6.64 (d, 1H), 4.68 (s, 2H), 4.27 (q, 2H), 2.62 (t, 2H), 1.60 (m, 4H), 0.88(t, 3H). Example 5 o-[N-(p-amylcinnamoyl)amino]
Phenoxyacetic acid and its sodium salt 140 mg of ethyl ester produced in Example 4 was
Tanol (2ml) - Tetrahydrofuran (2ml)
Dissolved in a mixture of 1N sodium hydroxide 1.06
ml and stirred at 40°C overnight. 1 for this
1.5 ml of normal hydrochloric acid was added and extracted with ethyl acetate.
Wash the extract with water and saturated saline, and pour into an anhydrous sulfuric acid mug.
Dry with nesium and concentrate under reduced pressure.
column chromatography (ethyl acetate: n-helical
xane: 1:1 → ethyl acetate), and the following
87 mg of the title compound (acid) having physical properties was obtained. pale
Yellow solid. Furthermore, dissolve 85 mg of acid in 5 ml of methanol.
Then add 0.23ml of 1N sodium hydroxide aqueous solution.
Concentrate under reduced pressure and dry to obtain the corresponding sodium salt.
Ta. TLC [acid]: Rf = 0.20 (ethyl acetate: methanol
=5:1). IR [acid]: ν (cm^-1)=3360, 2930, 2860, 1740, 1655, 1605, 1590, 1530 1480, 1450, 1350, 1250, 1190 1120, 1070, 980, 745. MS [acid]: m/Z=367 (M⁺), 349, 323, 310, 292, 282, 276, 259, 201, 167, 144, 131, 115, 43. NMR [acid] (CD₃OD): δ = 8.28 (d, 1H),
7.62 (d, 1H), 7.53 (d, 2H), 7.21 (d, 2H), 7.00 (d, 1H), 6.88−7.12 (m, 3H), 4.45 (s, 2H), 2.63 (t, 2H), 1.63 (m, 2H), 1.25-1.45 (m, 4H), 0.90 (t, 3H). Example 6 N-[3-(p-decylphenyl)propioni
]Anthranilic acid and sodium salt 500 mg of the compound produced in Example 1(a) was added to methanol.
Dissolved in a mixed solution of (10 ml) and ethyl acetate (1 ml).
10%-palladium-carbon under hydrogen atmosphere
After carrying out catalytic reduction for 2 hours at room temperature using
It was filtered and the filtrate was concentrated under reduced pressure. methanol residue
Dissolve in 10 ml of 2N sodium hydroxide, and add 2N sodium hydroxide.
Add 3.6ml of aqueous solution and stir at room temperature for 5 hours.
Ta. After adjusting the pH to 3 with dilute hydrochloric acid, extract with ethyl acetate.
Ta. The extract was concentrated under reduced pressure, and the resulting white solid was filtered through the sieve.
Lyca gel column chromatography (ethyl acetate:
Purified with n-hexane = 1:2) and obtained the following physical properties.
Obtained 200 mg of the title compound [acid] having the following values. TLC: Rf = 0.30 (ethyl acetate: n-hexane =
1:1). IR: ν(cm^-1) = 1690, 1670, 1600, 1580, 1520. MS: m/Z=409, 391, 365, 244. NMR: δ = 8.74 (d, 1H), 8.08 (dd, 1H), 7.58 (dt, 1H), 7.05-7.2 (m, 5H). Example 7 N-(p-amylcinnamoyl)anthranyl
Acid 5g Cellulose Calcium Gluconate (Disintegrant) 200
mg Magnesium stearate (lubricant) 100 mg
and 5.7 g of microcrystalline cellulose were mixed in a conventional manner,
Compressed tablets containing 50 mg of active ingredient per tablet
Got 100 tablets.

Claims (1)

[Claims] 1. General formula [In the formula, R ¹ represents () a straight chain or branched chain alkyl group or an alkoxy group having 5 to 15 carbon atoms, or () a straight chain or branched chain alkenyl group or alkenyl having 5 to 15 carbon atoms. It represents an oxy group bonded to the 2- or 3-position of the benzene ring, or () a straight or branched alkenyl group having 13 to 15 carbon atoms, or a straight or branched alkenyl group having 5 to 15 carbon atoms.
represents a straight-chain or branched alkenyloxy group bonded to the 4-position of the benzene ring, R ² represents a hydrogen atom or a methyl group, and R ³
is 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 or branched alkoxycarbonylmethyl group having 3 to 7 carbon atoms; represents an alkoxycarbonylmethoxy group, X represents -CH= or a nitrogen atom, n represents 0, 1 or 2, and the symbol
represents a double bond ( E or Z ) 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 R1 is a linear or branched alkyl group or alkoxy group having 5 to 15 carbon atoms. 3 R ¹ 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, according to claim 1. Compound. 4 R ¹ is a linear or branched alkenyl group having 13 to 15 carbon atoms or a linear or branched alkenyloxy group having 5 to 15 carbon atoms, and these are bonded to the 4-position of the benzene ring. A compound according to claim 1. 5. The compound according to claim 2, 3 or 4, wherein R ³ is a carboxyl group or a non-toxic salt thereof. 6 Claim 2, wherein R ³ is a carboxymethyl group, a non-toxic salt thereof, a methoxycarbonylmethyl group, or an ethoxycarbonylmethyl group
A compound according to item 1, 3 or 4. 7. The compound according to claim 2, 3, or 4, wherein ^R3 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-(p-decylcinnamoyl)anthranilic acid or its sodium salt. 10. The compound according to claim 1, which is N-(p-amylbenzoyl)anthranilic acid or its sodium 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. 13. The compound according to claim 1, which is N-(m-decylbenzoyl)anthranilic acid or its sodium salt. 14. The compound according to claim 1, which is 14 N-[m-(1-decyl)cinnamoyl]anthranilic 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 16 N-(p-amyl-2-methylcinnamoyl)anthranilic acid or its sodium salt. 17. The compound according to claim 1, which is 17 N-[p-(1-tridecenyl)cinnamoyl]anthranilic acid or its sodium salt. 18. The compound according to claim 1, which is N-(p-isopentylcinnamoyl)anthranilic acid or its sodium salt. 19. The compound according to claim 1, which is N-(p-amyloxycinnamoyl)anthranilic acid or its sodium salt. 20 N-(p-octyloxycinnamoyl)
The compound according to claim 1, which is anthranilic acid or its sodium salt. 21 Claim 1 which is N-(p-amylcinnamoyl)anthranilic acid methyl ester
Compounds described in Section. 22. The compound according to claim 1, which is o-[N-(p-amylcinnamoyl)amino]phenylacetic acid or its sodium salt. 23 p-[(p-amylcinnamoyl)amino]
The compound according to claim 1, which is benzoic acid or its sodium salt. 24. The compound according to claim 1, which is N-(p-heptylcinnamoyl)anthranilic acid or its sodium salt. 25. The compound according to claim 1, which is o-[N-(p-amylcinnamoyl)amino]phenol. 26. The compound according to claim 1, which is 2-[N-(p-amylcinnamoyl)amino]nicotinic acid or its sodium salt. 27 The compound according to claim 1, which is 2-[N-(p-amylcinnamoyl)amino]-3-hydroxypyridine. 28 The compound according to claim 1, which is 2-[N-(p-amylcinnamoyl)amino]-6-hydroxypyridine. 29 N-[5-(p-amylphenyl)penta-
The compound according to claim 1, which is 2,4-dienoyl]anthranilic acid methyl ester. 30 N-[5-(p-amylphenyl)penta-
The compound according to claim 1, which is 2,4-dienoyl]anthranilic acid or its sodium salt. 31. The compound according to claim 1, which is o-[N-(p-amylcinnamoyl)amino]phenoxyacetic acid ethyl ester. 32. The compound according to claim 1, which is o-[N-(p-amylcinnamoyl)amino]phenoxyacetic acid or its sodium salt. 33. The compound according to claim 1, which is N-(p-decylcinnamoyl)anthranilic acid or its sodium salt.