JPS6222986B2 - - Google Patents

Description

[Detailed description of the invention] The present invention relates to a heterocyclic compound, a method for producing the same, and a method for producing the same.
Compositions containing them and their use as pharmaceuticals
related. Hydantoin compounds defined below by formula ()
natural prostags in various biological specimens.
A drug that has similar physiological effects to Ranjin.
natural probiotics, as evidenced by
Has pharmacological properties related to staglandins
It was revealed that. In particular, some parts of the expression ()
The compound inhibits the platelet aggregation effect of prostaglandins
It has a strong pseudo effect. formula() [In the formula, Z is hydrogen or alkyl, Z¹Ha-(CH₂)_3-8-COOR (where R is hydrogen or
is alkyl), −CH₂-C・X・C-(CH₂)₃COOH (in the formula)
X represents a triple bond or double bond), long chain
alkyl, 3-oxa-long chain alkyl,
[Formula] (In the formula, R is -COOCH₃Also is −CH₂CH₂COOH) or −(CH₂)_Four−
OCH₂represents COOH, and Z²teeth
[Formula] (wherein X is -(CH₂)_0-6− CH₃, −CR₁R₂−(CH₂)_0-3−CH₃[Here R₁ra
Lukiru and R₂is hydrogen or alkyl
], or −CR₁R₂−CH₂R [Here, R is
Substituted or substituted with lifluoromethyl
is not phenyl, and R₁and
R₂are each alkyl), −
(CH₂)−CR(OH)−(CH₂)_0-6−CH₃(In the formula, R is
hydrogen or alkyl),
[Formula] (In the formula, R is C_4-7alkyl, phenyl, hydrogen or benzyl), -CH₂)₃
−(CH₂)_0~1-OR (wherein R is substituted with alkyl)
phenyl), 3-oxo-long chain aryl
alkyl, long chain alkyl or aralkyl, or
Ha-(CH₂)₆−COOH]. Unless otherwise specified, the formula () and the specification
In other formulas in the book, alkyl groups include methyl, ethyl
tyl, propyl, butyl, pentyl and hexy
and all its isomers.
be. For example, Y¹and Y²Alki in the definition of
The group is preferably a methyl group, and the alkoxycarbonyl group is preferably a methyl group.
〓〓〓〓〓
The alkyl residue in the molecule is preferably a methyl or ethyl group.
Yes. Similarly, aluminum having 2 to 4 carbon atoms
A kylene group is, for example, vinyl. In formula (), the cycloalkyl group is a carbon atom.
It has 3 to 10 children, and the bicycloalkyl group is carbon
It has 4 to 10 elementary atoms, such as adamantyl
There is a ru group. In formula (), the bond of divalent phenylene group is
Can be ortho, meta or para; oxa
Preferably, the group is adjacent to phenylene, and
If X is not phenylene, then¹is −CH₂-O-
CH₂- may be. X²is carboxyl or tetrazolyl
in each case its carboxylic acid and tetrazo
Salts corresponding to Z and also salts when Z is hydrogen
Included in the compounds of formula (). Use as a medicine
Salts of value include pharmaceutically acceptable cations.
salts such as ammonium salts, alkali metal
For example sodium and potassium salts, alkali
Lithium metals such as calcium and magnesium
or organic bases, especially amines, e.g.
It is a salt of tanolamine. accepted as a medicine
Also included within the scope of this invention are salts of cations that do not contain cations.
This is a pharmaceutically acceptable salt of formula () or
Useful as an acid or ester intermediate. Unless specifically instructed otherwise,
Formula () and other formulas herein are represented by
It includes all stereoisomers. Sunawa
enantiomeric form, called racemate
including mixtures and diastereomers thereof.
Ru. In formula (), Z is hydrogen or a carbon atom
Alkyl groups having 1 to 4 such as methyl
Or it is a butyl group, and Z¹and Z²One of the is -
CH₂-X-X¹−X², in which case X and¹
have 3 to 7 carbon atoms, especially 5 carbon atoms.
form alkylene, X²is alkoxycarbony
Z, carboxyl or its salt, Z¹Oyo
BiZ²The other is −Y−Y¹−Y²−Y³And in this place
Combined Y, Y¹and Y²is the same as defined earlier.
R, Y³is hydrogen, having 4 to 7 carbon atoms
Cycloalkyl, phenyl or benzyl
Ru. Compounds of particular interest are prostagranges.
It has a ton-related effect. In this definition, Z is water.
Z¹−CH defined earlier₂-X-X¹−X²
Included are subclasses of compounds that are. Compounds of formula () are synthesized from compounds with similar structures.
It can be synthesized by any known method.
Ru. For example, expression () (In the formula, G is carboxyl or its derivative
amide or ester, especially alkyl ester
Z, Z¹and Z²is defined for the expression ()
Hydantoic acid represented by (synonymous with)
Heating the corresponding derivative of under acidic conditions or alone
It can be produced by cyclization. This reaction is
It can be carried out without a solvent, but an inert solvent may be used if desired.
For example, using hydrocarbons such as petroleum solvents.
Good too. Also, G is alkoxycarbonyl
If the cyclization is carried out using a suitable base such as sodium ethyl
carried out in the presence of an alkoxide such as
You can also do that. A compound of formula () is a compound of formula () (In the formula, G, Z¹and Z²is the same as defined earlier
However, G may also be nitrile)
The indicated amino acid derivatives can be prepared either by Z or hydrogen.
or alkyl, respectively.
or reacting with alkyl isocyanates
It can be manufactured by When using cyanic acid, ionic acid is an alkali
Metal cyanates such as potassium cyanate,
It is convenient to produce it in situ using water and acid.
Ru. This acid is represented by R and X in formula ()²No.1
When one or both are hydrogen, the compound of formula ()
It may be an acid addition salt or a free acid. Also,
by adding an equivalent amount of mineral or organic acid into the reaction medium.
Good too. The reaction may be carried out without solvent, but inert
It is desirable to use a solvent. Polar as a solvent
Solvents such as water or water and acetone, dimethyl fluoride
〓〓〓〓〓
lumamide, dimethyl sulfoxide or
Mixtures with lower alcohols such as tanol are preferred.
Yes. Also hydrocarbons, ethers or halogens
Hydrocarbons such as chloroform can also be used.
Ru. If desired, for example, if the reaction is carried out without a solvent,
In this case, the reaction can be accelerated by heating the reaction mixture.
Can also be done. Similar results apply when using alkyl isocyanates.
Although reaction conditions can be used, acid addition salts or
otherwise adds an equivalent amount of acid into the reaction mixture
There's no need. Alternatives to using cyanates or isocyanates
Then, the compound of formula () is converted into a suitable urea or nitrourea.
Alternatively, it may be reacted with N-alkylurea. melt
A medium is not required, but may be one of the solvents mentioned above.
Inert solvents may be used if desired. reaction
It is best to perform this under heating, for example at 100° to 125°C.
Although preferred, temperatures up to 150°C may be employed.
stomach. In the above synthesis method, the intermediate of formula () is
It is not necessary to isolate it from the reaction mixture and the reaction conditions described above
may be directly converted into a compound of formula (). An intermediate of formula () is a compound of formula ()
It is convenient to produce by reacting with the compound ().
be. Q²−Z² () In the formula, G, Z¹and Z²is defined in terms of expression ()
is synonymous with Q¹and Q²One side is Ami
The other is halide, preferably bromine. reaction
may be used without solvent or with an inert solvent such as ethanol.
This is done by heating in the presence of water. In Eq.²G-Y-Y¹−Y²−Y³and
Y¹is carbonyl, then in the formula Q¹
The formula for an amine in which is amino is CR₂＝CH・CO・Y²・Y³ () (Y in the formula²and Y³is defined in formula ()
(synonymous)) is reacted with
It can also be manufactured. The reaction can be carried out in the presence of an inert solvent or
is carried out without solvent at room temperature or under heat. The hydantoin of the formula () is the formula () (In the formula, Z, Z¹and Z²is defined in terms of expression ()
is synonymous with G¹is carboxyl or its
reactive derivatives such as ethoxycarbonyl
alkoxycarbonyl)
It can also be produced by cyclizing a compound. formula
The compound of () is similar to the compound of formula ()
A method for producing compounds of formula () that can be cyclized under the conditions of
The method includes conventional reaction conditions such that spontaneous cyclization occurs.
It is advantageous to choose. For example, a compound of formula () is a compound of formula ()
can be produced by reacting a compound with a compound of formula ().
Ru. Q²=Z² () 【formula】 In the formula, Q¹and Q²One is preferably halogeno
is chlorine or bromine, the other is amino,
Z, Z¹, Z²and G¹is defined for the expression ()
is synonymous with Reaction involves mixing reaction raw materials
or an inert solvent may be used.
Heat the mixture. A suitable solvent is
Lukanols, ethers, hydrocarbons and halogens
There are carbonated hydrocarbons. The compound of formula () itself is a suitable carbamic acid inducer.
conductors such as alkyl esters,
responded by techniques well known to experts.
can be manufactured separately. A method related to the method described above is that the expression ()
The method for producing hydantoin compounds includes the formula () (Z, Z in the formula¹and Z²is defined for the expression ()
) is a carbonic acid derivative.
There is a way to react. This technology is used for carbonic acid derivatives.
〓〓〓〓〓
Any that is obvious to those skilled in the field is appropriate.
derivatives such as phosgene, diphenyl carbonate or
is an alkyl haloformate, such as ethyl chloroformate.
Can be used. This reaction is performed using a base such as triethyl
like amine or diisopropylethylamine
with an inert aprotic solvent in the presence of a
For example, toluene, dimethylformamide or
For example, in the presence of diethyl ether
is desirable, the reaction can be carried out at room temperature, but if desired
The reaction mixture may be heated further. Intermediates of formula () are used for the production of compounds of formula ()
can be manufactured using a method similar to that described above.
Ru. A hydant in which Z is alkyl in formula ()
Inn is alcohol J³・Reactive ester derivative of OH
With the alkylating agent represented as a conductor, the formula
() (In the formula, J is hydrogen or alkyl, and J¹is hydrogen
or Z¹and J²is hydrogen or Z²and J³teeth
Alkyl, Z¹or Z²It is. However, J, J¹and
J²One type of is hydrogen, J³is J, J¹or J²same as
Not one. J¹,J²and J³Z in the definition of¹oh
Call and Z²are the same as defined in equation (), respectively.
Even if the compound represented by
Can be manufactured. Suitable reactive esters include
loride, bromide, iodide and sul
phonates such as p-toluenesulfonate,
Thanesulfonate and benzenesulfonate
be. Alkylation is considered appropriate in the art.
Using the reaction conditions described above, e.g.
Alkali metal hydrides, alkali metal amides or
is an alkali metal alkoxide, give a typical example.
Sodium hydride or sodium alkoxa
for example in the presence of sodium methoxide
It will be done. This reaction acts simply as a diluent for the reaction reagents
Inert solvents such as toluene, dioxane,
tel, dimethylformamide, tetrahydrofura
dimethyl sulfoxide or acetonitrile
It is convenient because it can be done in the room. The base is an alkali metal
If it is an alkoxide, the corresponding alkali
Nord can also be used. The intermediate whose odor J is hydrogen is the formula
It is also a compound of () and any of the methods mentioned above
It can also be manufactured by Compound of formula ()
The product can also be used by methods known in the art, such as
For example, Chemical Reviews (1950)46, 403−425
) can also be manufactured. Other methods for producing compounds of formula () include formula
(XI) (Z in the formula³= CR−CH₂−Y¹−Y²−Y³And Z^FourHa-
CH₂-X-X¹−X²or Z³is=CH−
X-X¹−X²And Z^FourHa-Y-Y¹−Y²−Y³And
Ru. R, X or X²and Y or Y³is the expression
(same meaning as defined in parentheses))
The corresponding unsaturated compound is reduced with a suitable reducing agent.
There is a method of manufacturing by starting from scratch. A suitable reducing agent includes stannous chloride. this is the place
Use as an aqueous solution, optionally in the presence of a dilute mineral acid.
Can be used. Also, for example, Ranenikskel, white
of gold, palladium, ruthenium or rhodium
Catalytic hydrogenation may be carried out in the presence of in certain cases
In addition to the selection of the reducing agent in the
The presence of other reactive groups that are themselves susceptible to reduction
Should be considered by nothing. The intermediate of formula (XI) can be prepared by the following series of reactions.
Can be manufactured. 〓〓〓〓〓
In the above formula, Z, Z³, Z^Fourand G are formulas (XI) and
and () respectively.
ri, G³is alkyl, such as n-butyl,
G^Fouris a halogeno, such as bromo. formula(
) for the compound of formula ().
It is carried out in the same manner as ring closure, and the compound of formula () is
It can be prepared using concentrated mineral acids such as hydrochloric acid. Tetrazole of formula () has a group -X²but
[Formula] (X in the formula³and X^Fouris a combination between both Represent (nitrile) or X³is hydrogen or alkyl
and X^Fouris alkoxy (imidoester),
Alkylthio (imidothioester), -NH-
N.H.₂(amidrazone) or amino (amidine)
or X³is hydroxy and X^FourHaa
Equivalents substituted with mino (amidoxime)
It can be produced from compounds that The reaction is polar aprototypical
In aqueous liquids such as dimethylformamide,
Using salts of lazoic acid, e.g. salts of sodium azide
It is preferable to do so. However, X²Gaami
When substituted with zine or amidrazone
A suitable reagent is nitrous acid. Amidine to nitrous
Intermediate nitrosation products if reacted with acid
, with or without isolation, and then
For example, when reduced using sodium amalgam,
The corresponding tetrazole is obtained. Tetrazole
The precursor can be obtained by known methods. For example, nitrile
can be prepared by dehydration of the corresponding amide. In the expression (), X²is hydroxymethylene
Certain alcohols have corresponding acids, esters, and
Appropriate reduction of acids, anhydrides or aldehydes
It can also be obtained by reduction with an agent. Suitable reducing agents are
It depends on the reaction raw materials, but the reducing agents that can be used include
There is sodium in ethanol. Especially carbon
Acids are, for example, ethyl chloroformate and bases.
If treated in the presence of triethylamine, the corresponding
Conversion to mixed anhydride followed by sodium borohydride
It can be reduced to alcohol using um. Similarly,
The ester can be prepared in an inert solvent such as an ether or
in a hydrocarbon such as hexane or benzene
Alcohol using diisobutylaluminum hydride
It can be reduced to This type of alcohol is catalytically reduced.
It can also be manufactured from scratch. Alternatively, in the expression ()²is hydroki
The alcohol that is symethylene is
It can also be produced by hydrolyzing the compound with an appropriate reagent. child
For this purpose, the hydroxide can be
liquid or a suspension of silver oxide in water can be used. Hidan of formula () with a hydroxyl group in the side chain
In the case of toin synthesis, it must be protected during the reaction process.
It is desirable to keep it. Protection is done by known methods.
For example, acyl, aroyl, tetrahydropyran
-2-yl, 1-ethoxyethyl or aral
Killing can be done using a protecting group such as benzyl.
easily done. Removal of protecting groups is well known to those skilled in the art.
For example, acyl groups can be
The benzyl group can be reductively removed by hydrolysis or base hydrolysis.
It can be implemented by solving Furthermore, in equation (), Y¹is carbonyl
Certain ketones can be treated with suitable reducing agents such as borohydride.
Reduced with sodium to the corresponding secondary alcohol
Can be converted. In equation (), Y¹ga-CH
Alcohols that are (OH)- can be prepared using Johns reagent,
acid dichromate or any other suitable reagent
can be oxidized to the corresponding ketone using Similarly, if the compound of formula () is -C≡C- or
If there is a −CH=CH− bond, the penetrating hydrogenation method
For example, using Lindler type or Adams catalysts.
Corresponding ethylenic or saturated
It can also be converted into a compound as appropriate. Hydantoin of formula () is an asymmetric carbon atom at the 5th position
but also Y¹has a hydroxyl group
Another asymmetric center forms in a compound. did
However, this type of alcohol has four isomers.
exist, and this can be done using thin layer chromatography or high
Two types of diastema were detected using fast liquid chromatography.
Can be separated into rheomers. There are two types of each
is a racemic mixture of isomers. diastereo
〓〓〓〓〓
After separating the diastereomers, one diastereomer
by treating it with a base, e.g. an alkali metal hydroxide.
Conversion into a mixture of four isomers and then separation again
two diastereomers can be obtained by
Ru. By repeating this method, one diastereo
This can effectively convert one mer to the other.
Biological activity of one diastereomer compared to the other
Desirable if excellent. There are also four types of isomerism in the alcohol corresponding to formula ().
Body shape exists. If desired, this can be combined with two types of dia.
Split into stereomers and then combine with formula ()
When cyclized into a substance, the configuration is maintained as is.
Ru. In all of the above chemical operations, the reaction reagents are
The selection should also be based on the functional groups present in the substrate.
It must also have an appropriate selectivity effect.
reagents must be used as necessary.
Needless to say. Hydantoin of formula () is a natural prostagran
It has pharmacological properties related to gin. Sunawa
This hydantoin is a prostagrange of each group.
(PG), A, B, C, D, E and F series organisms
It has a pseudo effect or an antagonistic effect on the chemical effect.
do. For example, hydantoin in formula ()
PGE for board₁The anti-aggregation effect of
shows aggregation effect, PGE₂or PGF₂Rat stomach
smooth muscle of rat colon, bird rectum and guinea pig
It antagonizes the contractions induced in the trachea. in general,
The antagonistic action, which is the opposite of the pseudo-action, is due to this hydantoin.
observed when using large doses of Pseudo effect also
compared the antagonistic effects with natural prostaglandins.
Pharmacological characteristics expressed as relative activity
Of course, it differs depending on the hydantoin.
Ru. Due to its prostaglandin-related properties, the formula
() Hydantoin is a natural prostaglandi
to characterize the biological activity of the drug and its receptors.
It is useful for classifying and classifying information. Prostagra
To further clarify the physiological role of
Of course, it is important for research into new and improved therapeutic substances.
Ru. Hydantoin of formula () is also useful as a therapeutic agent.
It is for use. In particular, it has a strong anti-aggregation effect on platelets.
The hydantoins mentioned above as having
If you want to inhibit the aggregation of platelets or the adhesion of platelets.
This is useful when you want to reduce
Can be used to treat or prevent blood clots in mammals.
Ru. For example, this compound is used in the treatment of myocardial infarction and
for the treatment and prevention of blood clots, after surgery.
It promotes the opening of blood vessel connections, and also causes arteriosclerosis.
blood clotting due to arteriosclerosis and hyperlipidemia.
The symptoms and underlying etiology of the disorder are lipid balance disorders.
For the treatment of clinical symptoms associated with hyperlipidemia or hyperlipidemia.
Useful. This type of compound can be used in artificial extracorporeal circulation or
or blood used to perfuse isolated biological parts.
It can also be used as an additive for other liquids. Particularly valuable as a platelet aggregation inhibitor
The compound for which it has been revealed has the formula (),
Z is hydrogen, Z¹does not have 3 carbon atoms in the alkylene part
It is a carboxyalkylene having 9 Z²
is the group -(CH₂)₂−CH(OH)−Y²−³And Y²
The carbon atom adjacent to the hydroxy-substituted carbon is tertiary
is a branched alkylene with Y³is the expression ()
A group of compounds that have the same meaning as defined for
Ru. Among this group of compounds, Z¹is carboxyhexy
Le, Y³has 4 to 7 carbon atoms
Compounds that are alkyl are particularly active
has been revealed. Also, the hydantoin of formula () is prostag
Similar to compounds belonging to the Landin A and E series
This results in relaxation of vascular smooth muscle. This type of compound
Examples include 5-(6-carboxyhexyl)-
1-(3-hydroxy-4,4-dimethyloctyl
) hydantoin and 5-(6-carboxyhexyl)
xyl)-1-(3-hydroxy-4,4-dimethy
-5-phenylpentyl)hydantoin
can be done. Compounds that relax vascular smooth muscle
has antihypertensive effects because it can induce vasodilation.
and lower blood pressure in mammals including humans.
Useful. alone and also β-adrenergic
combination with sex receptor blockers or other antihypertensive drugs.
Together, all types of hypertension, essential, malignant and
It can be used to treat secondary hypertension. 5-(6-carboxyhexyl)-1-(3-hexyl)
Droxy-4,4-dimethyloctyl)hydant
In compounds also inhibit histamine-induced bronchoconstriction.
antagonistic PGE₁Shows an effect similar to that of . this
Hydantoin of the formula () with the properties of bronchial
〓〓〓〓〓
Relieves bronchoconstriction associated with asthma and bronchitis
used to treat or prevent this condition by
can. Hydantoins of formula (), for example 5-(6-
carboxyhexyl)-1-(3-hydroxyoc
hydantoin, 5-(6-carboxyhexyl)
sil)-3-methyl-1-(3-oxooctyl)
Hydantoin, 5-(6-carboxyhexyl)-
1-(3-oxooctyl)hydantoin and
5-(6-carboxyhexyl)-1-(4-phene
Hydantoin (Noxybutyl)
inhibits aspirin-induced gastric acid secretion in rats.
Reduces the formation of gastric lesions and suppresses gastric acid hypersecretion.
and has the effect of reducing or preventing gastrointestinal ulcer formation.
However, for ulcers that already exist in the gastrointestinal tract, spontaneous
Even if it is a sexual disease, it may be part of multiple adenoma syndrome.
It exerts a healing promoting effect even in cases of ulcers.
Ru. Part of the hydantoin of formula (), representative compounds
As a substance, 5-(6-carboxyhexyl)-1-
(3-hydroxyoctyl)hydantoin for dogs
When injected intravenously, an increase in urine output has been observed.
This type of compound may be used in humans and other animals.
edema in, for example, heart failure, liver failure or renal failure.
diuretics, including their use in the treatment of edema associated with
It shows the possibility of being used as Hydantoin in formula () is PGE₂and PGE₂〓
It has an effect similar to that of uterine smooth muscle, and is antifertility.
It can also be used as an abortifacient, especially as an abortifacient. the formula required to achieve the desired biological effect
The amount of compounds in parentheses will vary depending on various factors.
It is. For example, specific compounds selected, used
It varies depending on the purpose, route of administration, recipient, etc.
Generally, the daily dose is 1 μg to 20 mg/Kg body weight.
It seems to be within the range. For example, intravenous administration
The dose is 5μg~1mg/Kg, in this case 0.01~
It is convenient to infuse 50 μg/Kg/min. this
The appropriate infusion for the purpose is 0.001 to 100, for example 0.01 to 10
It can contain μg/ml. unit dose drug
The mold contains 10 μg to 100 mg of the compound of formula ().
For example, in the case of an ampoule for injection, 0.01 to 1 mg,
Unit dosage forms for oral administration e.g. tablets or caps
In the case of cells, contain 0.1 to 50 mg, for example 2 to 20 mg.
Ru. More specifically, the compound of formula () is used to induce platelet aggregation.
When used for collection prevention, if it is patient blood
However, even in the case of perfusate, it is generally about 1 μg to 10 mg.
For example, use an appropriate concentration of 10 μg to 1 mg/
is desirable. The above doses are for acids, amides, and esters of formula ().
Also about alcohols, alcohols and tetrazoles
However, when using salt, the dose should be adjusted accordingly.
must be considered on an ion basis. To treat or prevent the various conditions mentioned above,
Dantoin compounds may be used as raw materials, but
Formulated with an acceptable carrier and presented as a pharmaceutical dosage form.
It is preferable to The carrier is, of course, other than the one in the formulation.
It also means that it is compatible with the ingredients of
in the sense that it is not harmful to the recipient
must also be acceptable. The carrier is solid
It can be either body or liquid, which is converted into a hydantoin compound.
Combined with hydantoin compound 0.05 to 95 weight
Formulated in unit dosage form e.g. tablets containing %
It is preferable to As mentioned above, the present invention
Adding other pharmacologically active compounds to the formulation
You can also do that. Hydantoin compounds are acid or
It can be added to formulations in the form of its salt or ester.
The formulation is mainly made by mixing each component.
Manufactured using well-known pharmaceutical technology
can be done. This formulation includes oral, rectal, and topical (buccal)
– e.g. sublingual tablets), parenteral (subcutaneous, intramuscular and
Formulations suitable for intravenous and intravenous administration are included. but
However, the most appropriate route in a particular case is
The severity of the symptoms to be treated, as well as the hydantoin compounds.
It depends on the nature of things. Preparations suitable for oral administration contain a predetermined amount of each
Capsules containing hydantoin compounds, Kashyu
-, discrete units such as lozenges or tablets, powders
powder or granules, solution in water or non-aqueous liquids or
is a suspension, water-in-oil emulsion or oil-in-water emulsion
There is. This type of preparation contains hydantoin compounds.
A carrier and a combination of one or more auxiliary ingredients
By any pharmaceutical method whose main step is combining
Can be manufactured. Generally, hydantoin compounds are
homogeneous with the body or a finely powdered solid carrier or both
and mix intimately, then form into the desired shape if necessary.
It can be manufactured by molding. for example,
〓〓〓〓〓
Tablets contain powder or granules of hydantoin compounds.
If desired, with one or more auxiliary ingredients
Manufactured by compressing or molding. compressed tablets powder
Hydants in the form of powders or granules with good flowability
If necessary, binder, lubricant, inert
Mix with suitable diluents, surfactants or dispersants.
Compress with a suitable machine. Molded tablets are powdered hydantoin
Wet the compound with an inert liquid diluent and place it in a suitable machine.
Mold with a machine. Formulations suitable for sublingual administration include
A flavor base, usually sucrose or
and gum arabic or gum tragacanth
lozenges, or gelatin and glycerin or
or an inert base such as sucrose and gum arabic.
There are pastilles containing hydantoin compounds inside. Formulations of the invention suitable for parenteral administration are preferably
is a hydantoin that is made isotonic with the blood of the subject.
There are sterile aqueous formulations of the compounds. This preparation is administered intravenously
It is preferable to administer the drug by subcutaneous or intramuscular injection.
Shooting is also possible. This type of preparation is hydantoin
Mix the compound with water, deplete the product, and remove it from blood, etc.
It is usually manufactured by making it tonic. Formulations suitable for rectal administration include unit dose suppositories.
preferable. It contains one or more hydantoin compounds.
is a combination of two or more commonly used solid carriers such as cocoa butter and
Mix the hydantoin compounds and use the resulting mixture as
It can be manufactured by molding. As is clear from the above description, the
All novel aspects listed are included in the present invention.
Ru. For example, if you list them as follows:
However, the present invention is not limited to this.
stomach. (a) A novel compound of formula () as defined above. (b) Method for producing the novel compound of formula () above (c) a compound of formula () in a pharmaceutically acceptable carrier;
Pharmaceutical preparations that are mixed with the body and their manufacturing method (d) the compound of formula () is effective and non-hypertensive;
Blood pressure in mammals, including humans, administered toxic doses
Decreasing method (e) an antithrombotic effective and non-toxic amount of a compound of formula ();
mammals, including humans, or
Methods for treating or preventing blood clots in mammalian tissues (f) a vasodilatory effective amount of the compound of formula () and
blood vessels of mammals, including humans, administered toxic doses.
Expansion method (g) in a therapeutically or prophylactically effective amount of a compound of formula ();
and non-toxic doses can be administered to mammals including humans.
How to treat or prevent gastric lesions (h) a bronchodilatory effective amount of a compound of formula () and
Trachea for administering toxic doses to mammals including humans
Support expansion method (i) a prophylactically or therapeutically effective amount of a compound of formula ();
Administer to mammals, including humans, in non-toxic doses.
How to treat or prevent allergic symptoms (j) an abortifacient and nontoxic amount of the compound of formula ();
administration of fetal doses to mammals, including humans.
Abortion method (k) a contraceptively effective and non-toxic amount of a compound of formula ();
Contraceptive methods in which doses are administered to mammals including humans.
law (l) Equation (J, J in the formula¹and J²The two pieces are Z, Z¹and
Z², and the remaining one is hydrogen.
Ru. However, each symbol is defined above for expression ().
Compounds represented by (synonymous with) (m) formula (In the formula, M is 〓C=Z³, 〓CH−CHO or 〓CH
−CH(OG³)₂and Z, Z³, Z^Fourand G³teeth
Define equations () and (XII), respectively.
(synonymous with ) (n) expression (M in the formula¹−Q defined for the expression ()¹And
or −NH−Z²and Z, Z¹, Z²oh
Call and G¹is G¹The formula except that may be hydrogen
〓〓〓〓〓
(same as defined for ))
Compound Example 1 5-(6-carboxyhexyl)-1-(3-hexyl)
Droxy-4,4-dimethyl-5-phenylpene
Production of hydantoin A 2-aminononanedioic acid diethyl ester Acetamidomalonic acid diethyl ester
(16.7g) and ethyl 7-bromoheptanoate
Ester (16.6g) to ethoxide ethanol
Solution (1.51g sodium and absolute ethanol
(prepared from 30 ml) and stirred this mixture for 27 hours.
Reflux. Cool the solution, pour it into ice water, and
Extract the product into ether, dry and evaporate the extract.
Crude acetamide (6-ethoxycarboxylate)
Nylhexyl) malonic acid diethyl ester is
Obtained as a yellow oil. δ2.2(3H,
singlet, −COCH₃), 4.17 (6H, multiplet, 3X
−OCH₂−CH₃). Add this amide to 111ml of concentrated hydrochloric acid.
Reflux for 5.5 hours, cool the solution and dilute with ether.
Wash and decolorize the aqueous layer with activated carbon and evaporate in vacuo.
Dry. Minimum amount of colorless glassy substance left behind
Dissolved in absolute ethanol, absolute ethanol
Cooling of 125 ml and 15.7 g of thionyl chloride (-
10℃) into the mixture under stirring. obtained
The solution was left at room temperature for 1 hour, refluxed for 1.5 hours,
Cool, pour into ice water and adjust pH to sodium hydroxide
Adjust to 9 with aqueous solution. Extract the mixture with ether.
When the extract is dried, concentrated, and distilled,
2-aminononanedioic acid diethyl ester (yield
55%), but with a boiling point of 114-115°/0.02-0.03mm
Obtained as a colored oil. B 2-[(4,4-dimethyl-3-oxo-phene
nylpentyl)amino]nonanedioic acid diethyl ether
Stell 2-Aminononanedioic acid diethyl ester
(5.18g), 4,4-dimethyl-5-phenylene
Lupent-1-en-3-one (3.95g),
Cool and add dropwise while stirring. Bring the mixture to room temperature at 21:00
If left for a while, 2-[(4,4-dimethyl-3-
Oxo-5-phenylpentyl)amino]nona
This yields diethyl diethyl ester. C 2-[(3-hydroxy-4,4-dimethyl-
5-phenylpentyl)amino]nonanedioic acid di
ethyl ester The above crude ketone (5.1g) was dissolved in absolute ethanol.
(70 ml) and stir this solution in an ice bath.
while taking sodium borohydride (380mg)
Add gradually. Leave this solution in an ice bath for another 10 minutes.
Stir for a while and then leave at room temperature for 5 hours. most
Evaporate the alcohol and add water to make the solution.
Acidify to PH6. Insoluble oil with ether
Extract, dry and evaporate the ether solution
and 2-[(3-hydroxy-4,4-dimethyl
-5-phenylpentyl)amino]nonanedioic acid
The diethyl ester remains as a pale yellow oil.
Use as is without further purification. D 5-(6-ethoxycarbonylhexyl)-1
-(3-hydroxy-4,4-dimethyl-5-
(phenylpentyl) hydantoin and equivalent
acid Add the above alcohol (8.45g) to ethanol
(37.6 ml) and 2N hydrochloric acid (18.8 ml).
Stir the solution and add potassium sia while cooling on ice.
Add a solution of nate (3.05 g) in water (5.6 ml) dropwise.
Ru. This mixture was left at room temperature for 18 hours, then
Evaporate the alcohol and add water to remove the insoluble oil
Extract the product with ether. Dry the ether solution
When dried and evaporated, a viscous oil remains. this
When heated on a steam bath for 6 hours, 5-(6-e
Toxycarbonylhexyl)-1-(3-hydro
xy-4,4-dimethyl-5-phenyl pliers
) Hydantoin as a viscous pale yellow oil
can get. This ether is mixed with 2N sodium hydroxide.
(25ml) and water (60ml), add the
The resulting cloudy white solution is left at room temperature for 2 hours. this
Wash the solution with ether to obtain a clear alkaline solution.
Acidify the solution with 2N hydrochloric acid and remove the precipitated oil.
The oil comes out with a ter. Dry the ether solution and evaporate it.
When evaporated, a viscous oil (6.8g) is obtained.
Ru. This was performed using silica gel column chromatography.
When attached to -, 5-(6-carboxyhexyl)-
1-(3-hydroxy-4,4-dimethyl-5
- phenylpentyl) hydantoin is a colorless viscous
Obtained as a thick oil and solidifies. Melting point approx. 115
℃, a diastereomeric mixture that softens from about 90℃.
It is a compound. Ethyl acetate and petroleum ether (boiling point
〓〓〓〓〓
After recrystallizing several times from a mixture of
The other diastereomer is obtained as small needles.
It can be done. Melting point 135-137℃ Example 2 5-(6-carboxyhexyl)-1-(3-hexyl)
Production of (Droxyoctyl) hydantoin A 2-[3-(tetrahydropyran-2-yl-o)
xy)octylamino]nonanedioic acid diethyl ether
Stell Ether (200ml) and hydrogen bromide (26.8g)
Dry ethereal hydrogen bromide prepared at 0°C from
Acrolein was cooled to -25℃ and stirred.
(19.15g) in ether (100ml) dropwise.
do. The mixture was held at this temperature for 1 hour.
Stir and leave to raise temperature to 0℃,
Stir at 0°C for 1 hour, then add 1-bromopene.
Tan (54g), magnesium (8.8g) and
Pentylmagne prepared from ether (120ml)
Add dropwise to an ether solution of sium bromide and
Continue a steady reflux. Saturate the reaction mixture with salt
Decompose with ammonium chloride aqueous solution and remove oil with ether.
When the dried extract is concentrated and distilled, 1
-Bromo-3-hydroxyoctane is a colorless oil
Obtained as an object. Boiling point 68.5-72.5℃/0.08
mm. This bromoalcohol (20.9g) is dihydrated.
Add this solution to ropyran (17.0g) and
Ether of luenesulfonic acid (500 mg) (1
) treated with solution, left at room temperature for 18 hours, heavy carbon
Wash with sodium chloride solution. organic layer,
Pass through silica in 1:9 ether/hexane.
After filtration and removal of the solvent in vacuo, the 1-bromo
-3-(tetrabidropyran-2-yloxy)
c) Octane is obtained as a colorless oil.
δ0.88 (3H, triplet, −CH₃), 4.62 (1H,
broad, -O-CHR-O-). This tetrahydro
Pyranyl intermediate (15.0 g) and 2-amino
Dilute nandiic acid diethyl ester (13.0g) with anhydrous ether.
Take this solution in tanol (100ml) and leave it for 18 hours.
Reflux, remove the ethanol in vacuo, and remove the residue.
Dilute with water containing a small excess of sodium carbonate.
Ru. Extract the mixture with dichloromethane and extract
was dried with Glauber's salt, evaporated, and the residue was diluted with 1:4 hex.
Column chromatography of silica in sun/ether
When purified by filtration, 2-[3-(tetra
Hydropyran-2-yloxy)octylamide
] Nonanedioic acid diethyl ester is colorless and viscous.
Obtained as an oil. δ0.88 (3H, triplet, −
CH₃), 2.28 (2H, triplet, −CH ₂ −CO₂Et),
2.61 (2H, multiplet, −CH ₂ -N), 3.20
(1H, triplet, N-CHR-CO₂et), 4.13
(4H, multiplet, 2X-O-CH ₂ −CH₃), 4.60
(1H, broad, -O-CHR-O-) The amino diesters mentioned above can be prepared by the following alternative method:
It can be manufactured even if 2-Aminononanedioic acid diethyl
Tyl ester (10.40g) and oct-1-ene
-3-one (5.04g) was gradually added at 0°C with stirring.
When mixed and left at room temperature for 3 hours, 2-(3-
oxooctylamino)nonanedioic acid diethyl ether
Stell is obtained as a colorless oil. δ2.3
(4H, multiplet, −CH ₂ −CO₂Et and NCH₂
CH ₂ CO−), 3.16 (1H, triplet, EtO₂C−CHR
-N), 4.11 (2H, quartet, -O-CH ₂ -
CH ₃ ), 4.17 (2H, quartet, -O-CH ₂ -
_CH3 ). While stirring a solution of this ketone (13.5 g) in absolute ethanol (140 ml),
A solution of sodium borohydride (665 mg) in absolute ethanol (70 ml) is added dropwise at °C, then kept at room temperature for 3.5 hours and concentrated in vacuo at 40 °C. Dissolve the residue in water, bring the pH to 5 with N hydrochloric acid, and thoroughly extract with chloroform. The oil extract is washed with water, dried and evaporated to yield 2-(3-hydroxyoctylamino)nonanedioic acid diethyl ester as a colorless oil. Without further purification, this was dissolved in dihydropyran (14.0 ml), treated with ether (10 ml) and then p-
Add toluenesulfonic acid (6.72 g) little by little and leave at room temperature for 18 hours. The reaction solution was diluted with ether, washed with aqueous sodium carbonate and then water, dried, evaporated and the residue purified by column chromatography on silica in 1:4 hexane/ether to give 2-[3-(tetrahydropyran). -2-yloxy)octylamino]nonanedioic acid diethyl ester is obtained.
Identical product (NMR,
IR, mixed TLC). B 5-(6-carboxyhexyl)-1-[3-
(Tetrahydropyran-2-yloxy)octyl)hydantoin〓〓〓〓〓
To a solution of 2-[3-(tetrahydropyran-2-yloxy)octylamino]nonanedioic acid diethyl ester (7.8 g) in ethanol (32 ml) was added potassium cyanate (3.0 g) in water (6.0 g).
ml) solution. The resulting suspension is stirred and cooled, and 2N hydrochloric acid (16.7 ml) is gradually added. The solution is left at room temperature for 22 hours, the ethanol is mostly evaporated, water is added and the undissolved oil is extracted with ether. The ether solution is washed with water, dried over magnesium sulphate and evaporated. The yellow oil thus obtained (8.0 g) was mixed with light oil (boiling point 60-80
The solution was refluxed for 4 hours, evaporated to dryness and the remaining oil heated on a steam bath for 2 hours to give 5-(6-ethoxycarbonylhexyl)-1-[3-(tetrahydro Pyran-2-yloxy)octyl]hydantoin is obtained as a yellow oil (7.3 g). Use as is without further purification. This ester (6.2g) was dissolved in 0.5N sodium hydroxide solution (80ml), the solution was left at room temperature for 2.5 hours, then the solution was washed with ether and the aqueous layer was acidified with 2N hydrochloric acid to precipitate. Extract the oil with ether. The ether extract is washed, dried and evaporated to yield 5-(6carboxyhexyl)-1-[3-(tetrahydropyran-2-yloxy)octyl]hydantoin as a yellow oil. C 5-(6-carboxyhexyl-1-(3-hydroxyoctyl)hydantoin) This tetrahydropyranyloxy compound (3.55 g) was dissolved in tetrahydrofuran (28 ml) and 5N hydrochloric acid (7 ml), and the solution was heated to room temperature for 3.5 hours. Leave to stand and then reflux for 30 minutes. Most of the solvent is evaporated, water is added and the undissolved oil is extracted with ether. The ether solution is washed with water, dried over magnesium sulfate and evaporated to give a viscous 3.15 g of a yellow oil is obtained which is subjected to column chromatography on silica gel, eluting first with chloroform and then with a 19:1 mixture of chloroform and methanol, yielding 5-(6-carboxyhexyl)-1-
(3-Hydroxyoctyl)hydantoin is obtained as an almost colorless, very viscous oil. δ0.89 (3H, triplet, −CH ₃ ), 2.34 (2H,
triplet, _−CH2 − _CO2H ), 2.9−4.2(4H,
complex, - CH ₂ -N, CH -N, CH -OH),
Approximately 5.6 (3H, broad, exchangable, −CO ₂ H, −
OH), about 9.0 (1H, broad, exchangeable,
NH) From the corresponding 2-[3-hydroxyoctyl)amino]nonanedioic acid diethyl ester, and 1 other
The same hydantoin as described above can also be produced by the method described above. D. Separation of diastereomers The viscous oily hydantoin obtained by the above-mentioned method was heated on a silica column using chloroform, methanol, and acetic acid as solvents in a ratio of 97:2.5:0.5.
The mixture is subjected to HPLC and separated into two diastereomers. Both form fine colorless needle-like crystals, with melting points of 76-78℃ and 76-78℃, respectively.
The temperature is 63-65℃. The same diastereomers can also be prepared by cyclization of the corresponding diastereomers of formula (). That is, the 2-
The diastereomeric mixture of [(3-hydroxyoctyl)amino]nonanedioic acid diethyl ester is dissolved in ethanol and an ethereal solution of hydrogen chloride is added. The solution is evaporated to dryness, leaving a mixture of diastereomeric hydrochlorides as a viscous oil, which partially solidifies on standing. Add ether, stir and cool to obtain a crystalline solid. This is collected, washed with ether and dried. When this solid is crystallized from ethyl acetate,
Pure hydrochloride salt as tiny colorless plate crystals, melting point
95-96.5℃ is obtained. This salt is suspended in dilute sodium hydroxide solution, shaken with ether, and the ether solution is separated, washed, dried and evaporated to give one of the 2-[(3-hydroxyoctyl)amino]nonanedioic acid diethyl esters. The diastereomer (A) is obtained as a colorless oil. After collecting the initial solid hydrochloride salt, the remaining ether filtrate is evaporated to leave an oily hydrochloride salt.
When this is converted into a base as described above, 2-
A nearly pure second diastereomer of [(3-hydroxyoctyl)amino]nonanedioic acid diethyl ester is obtained as a colorless oil. By the method described in Example 1, the above diastereomer (A) was prepared as 5-(6-carboxyhexy〓〓〓〓
)-1-(3-hydroxyoctyl)hydantoin into a single diastereomer.
When crystallized from a mixture of ethyl acetate and light oil (boiling point 60°-80°), it forms fine colorless needle-shaped crystals.
It has a melting point of 63-65°. Similarly, the above diastereomer (B),
When converted to the second diastereomer of 5-(6-carboxyhexyl)-1-(3-hydroxyoctyl)hydantoin and crystallized from ethyl acetate-gas oil (boiling point 60-80°), it forms fine colorless needles. It is crystalline and has a melting point of 76-78°. E Interconversion of diastereomers 5-(6-carboxyhexyl)-1-(3-
Hydroxyoctyl) hydantoin (melting point 76−
The 78° diastereomer, 100 mg) was dissolved in N sodium hydroxide solution (3 ml) and heated to room temperature at 19°C.
Leave it for a while. The solution was acidified, extracted with ether, the ether extract was washed with water, dried,
Evaporation leaves a viscous oil. When this oil was separated into two diastereomers of 5-(6-carboxyhexyl)-1-(3-hydroxyoctyl)hydantoin by high-performance liquid chromatography, a diastereomer with the same melting point as the starting material, 76-78°C, was obtained. Approximately 40 mg of the teleomer and 40 mg of a substance identical to the diastereomer (A) described above with a melting point of 63-65° C. are obtained. Similarly, the diastereomer with a melting point of 63-65° is converted to a nearly equal mixture of itself and the diastereomer with a melting point of 76-78°C, which is isolated to the pure diastereomer by high-performance liquid chromatography. It can be done. Examples 3-27 By reactions similar to those described in Example 1, the following compounds can be prepared from the appropriate vinyl ketones as starting materials. (3a) 2-[(3-oxopentyl)amino]nonanedioic acid diethyl ester (4a) 2-[(3-oxo-4,4-dimethylpentyl)amino]nonanedioic acid diethyl ester (5a) 2-[(3 -oxo-4-methylpentyl)
Amino]nonanedioic acid diethyl ester (6a) 2-[(3-oxononyl)amino]nonanedioic acid diethyl ester (7a) 2-[(3-oxo-4-methyloctyl)
Amino]nonanedioic acid diethyl ester (8a) 2-[(3-oxodecyl)amino]nonanedioic acid diethyl ester (9a) 2-[(3-oxo-4,4-dimethyloctyl)amino]nonanedioic acid diethyl ester (10a) 2-[(3-oxo-4-ethylhexyl)amino]nonanedioic acid diethyl ester (11a) 2-[(3-cyclobutyl-3-oxopropyl)amino]nonanedioic acid diethyl ester (12a) 2-[(3-cyclopentyl) -3-oxopropyl)amino]nonanedioic acid diethyl ester (13a) 2-[(3-oxo-4,4-dimethyl-
5-(3-Trifluoromethylphenyl)pentyl)amino]nonanedioic acid diethyl ester (14a) 2-[(3-cyclohexyl-3-oxopropyl)amino]nonanedioic acid diethyl ester (15a) 2-[(3- Cycloheptyl-3-oxopropyl)amino]nonanedioic acid diethyl ester (16a) 2-[(3-oxo-3-phenylpropyl)amino]nonanedioic acid diethyl ester (17a) 2-[(3-oxo-4- Phenylbutyl)amino]nonanedioic acid diethyl ester (18a) 2-[(3-oxooctyl)amino]pentanedioic acid diethyl ester (19a) 2-[(3-oxooctyl)amino]undecanedioic acid diethyl ester (20a) 2-[ (3-oxooctyl)amino]-3
-(3-Ethoxycarbonylmethoxyphenylpipropionic acid ethyl ester (21a) 2-[(3-oxo-4,4-dimethylpentyl)amino]-3-(3-ethoxycarbonylmethoxyphenylpropionic acid ethyl ester ( 22a) 2-(3-oxopentylamino)-3-
[3-(2-ethoxycarbonylethyl)phenyl]propionate ethyl ester (23a) 2-(3-cyclobutyl-3-oxopropylamino)-3-[3-(2-ethoxycarbonylethyl)phenyl]ethyl propionate Ester (24a) 2-(3-cyclopentyl-3-oxop〓〓〓〓〓
2-(3-cyclohexyl-3-oxopropylamino)-3-[3-(2-ethoxycarbonylethyl) Phenyl] propionic acid ethyl ester (26a) 2-(3-oxooctylamino)-7-
Oxanonanedioic acid diethyl ester and (27a) 2-(3-cyclopentyl-3-oxopropylamino)-7-oxanonanedioic acid diethyl ester This is converted to the corresponding hydroxy compound below. (3b) 2-[(3-hydroxypentyl)amino]
Nonanedioic acid diethyl ester (4b) 2-[(3-hydroxy-4,4-dimethylpentyl)amino]nonanedioic acid diethyl ester (5b) 2-[(3-hydroxy-4-methylpentyl)amino]nonanedioic acid diethyl ester (6b) 2-[(3-hydroxynonyl)amino]nonanedioic acid diethyl ester (7b) 2-[(3-hydroxy-4-methyloctyl)amino]nonanedioic acid diethyl ester (8b) 2-[(3-hydroxy Decyl)amino]nonanedioic acid diethyl ester (9b) 2-[(3-hydroxy-4,4-dimethyloctyl)amino]nonanedioic acid diethyl ester (10b) 2-[(3-hydroxy-4-ethylhexyl)amino]nonanedioate Acid diethyl ester (11b) 2-[(3-cyclobutyl-3-hydroxypropyl)amino]nonanedioic acid diethyl ester (12b) 2-[(3-cyclopentyl-3-hydroxypropyl)amino]nonanedioic acid diethyl ester (13b) 2-[(3-hydroxy-4,4-dimethyl-5-(3-trifluoromethylphenyl)
Pentyl)amino]nonanedioic acid diethyl ester (14b) 2-[(3-cyclohexyl-3-hydroxypropyl)amino]nonanedioic acid diethyl ester (15b) 2-[(3-cycloheptyl-3-hydroxypropyl)amino]nonanedioate Acid diethyl ester (16b) 2-[(3-hydroxy-3-phenylpropyl)amino]nonanedioic acid diethyl ester (17b) 2-[(3-hydroxy-4-phenylbutyl)amino]nonanedioic acid diethyl ester (18b) 2-[(3-hydroxyoctyl)amino]pentanedioic acid diethyl ester (19b) 2-[(3-hydroxyoctyl)amino]undecanedioic acid diethyl ester (20b) 2-[(3-hydroxyoctyl)amino]-3- (3-Ethoxycarbonylmethoxyphenyl)propionic acid ethyl ester (21b) 2-[(3-hydroxy-4,4-dimethylpentyl)amino]-3-(3-ethoxycarbonylmethoxyphenyl)propionic acid ethyl ester ( 22b) 2-(3-hydroxypentylamino)-
3-[3-(2-ethoxycarbonylethyl)phenyl]propionic acid ethyl ester (23b) 2-(3-cyclobutyl-3-hydroxypropylamino)-3-[3-(2-ethoxycarbonylethyl)phenyl]propion Acid ethyl ester (24b) 2-(3-cyclopentyl-3-hydroxypropylamino)-3-[3-(2-ethoxycarbonylethyl)phenyl]propionate ethyl ester (25b) 2-(3-cyclohexyl-3- hydroxypropylamino)-3-[3-(2-ethoxycarbonylethyl)phenyl]propionic acid ethyl ester (26b) 2-(3-hydroxyoctylamino)-
7-Oxononanedioic acid diethyl ester and (27b) 2-(3-cyclopentyl-3-hydroxypropylamino)-7-oxanonanedioic acid diethyl ester Hydantoins of formula () are obtained from the above compounds, and when separated by HPLC, the melting point is Two diastereomers are obtained as shown. (3c) 5-(6-carboxyhexyl)-1-(3
-Hydroxypentylhydantoin, colorless oil〓〓〓〓〓
diastereomers 71−73° and 56−58
゜(4c) 5-(6-carboxyhexyl)-1-(3
-hydroxy-4,4-dimethylpentyl)hydantoin, diastereomers 114-115° and 144-146°(5c) 5-(6-carboxyhexyl)-1-(3
-Hydroxy-4-methylpentyl)hydantone, melting point approximately 70-80°, diastereomer 73-
76° and 110−111° (6c) 5-(6-carboxyhexyl)-1-(3
-hydroxynonyl)hydantoin, viscous oil (7c) 5-(6-carboxyhexyl)-1-(3
-hydroxy-4-methyloctyl)hydantoin, viscous oil (8c) 5-(6-carboxyhexyl)-1-(3
-hydroxydecyl) hydantoin, viscous oil, diastereomers 68-70° and 82-83
゜(9c) 5-(6-carboxyhexyl)-1-(3
-hydroxy-4,4-dimethyloctyl)hydantoin, colorless crystals, melting point 90-98°, one diastereomer isolated by crystallization from ethyl acetate. Melting point 103-104゜(10c) 5-(6-carboxyhexyl)-1-(3
-hydroxy-4-ethylhexyl)hydantoin, melting point 70-80°, diastereomer 82-
84° and 120−122° (11c) 5-(6-carboxyhexyl)-1-(3
-cyclobutyl-3-hydroxypropyl)hydantoin, diastereomers 114-116° and 103-105°(12c) 5-(6-carboxyhexyl)-1-(3
-cyclopentyl-3-hydroxypropyl)
Hydantoin, diastereomers 116-117° and 97-99° (13c) 5-(6-carboxyhexyl)-1-(3
-Hydroxy-4,4-dimethyl-5-m-trifluoromethylphenyl)hydantoin, diastereomers 118-120° and 145-147°(14c) 5-(6-carboxyhexyl)-1-(3
-cyclohexyl-3-hydroxypropyl)
Hydantoin, diastereomers 96-98° and 124-126° (15c) 5-(6-carboxyhexyl)-1-(3
-cycloheptyl-3-hydroxypropyl)
Hydantoin, melting point approximately 70-76°, diastereomers 107-109° and 107-109° (16c) 5-(6-carboxyhexyl)-1-(3
-hydroxy-3-phenylpropyl)hydantoin, both diastereomers are colorless viscous oils (17c) 5-(6-carboxyhexyl)-1-(3
-hydroxy-4-phenylbutyl)hydantoin, diastereomers 102-104° and 61
-63゜(18c) 5-(3-carboxypropyl)-1-(3
-hydroxyoctyl)hydantoin, both diastereomers are colorless viscous oils (19c) 5-(8-carboxyoctyl)-1-(3
-hydroxyoctyl)hydantoin, diastereomers 57-60° and 69-71° (20c) 5-(3-carboxymethoxybenzyl)
-1-(3-hydroxyoctyl)hydantoin, colorless melange-like (21c) 5-(3-carboxymethoxybenzyl)
-1-(3-hydroxy-4,4-dimethylpentyl)hydantoin, diastereomer of the corresponding ethyl ester: mp 100-103° and 151-154° (22c) 5-[3-(2-carboxyethyl ) benzyl]-1-(3-hydroxyoctyl)hydantoin, one diastereomer 82-86°(23c) 5-[3-(2-carboxyethyl)benzyl]-1-(3-cyclobutyl-3- hydroxypropyl)hydantoin, one diastereomer 118-121°(24c) 5-[3-(2-carboxyethyl)benzyl]-1-(3-cyclopentyl-3-hydroxypropyl)hydantoin, one diastereomer Ohmer melting point 140-143° (25c) 5-[3-(2-carboxyethyl)benzyl]-1-(3-cyclohexyl-3-hydroxypropyl)hydantoin (26c) 5-(4-carboxymethoxybutyl) −
1-(3-hydroxyoctyl)hydantoin and 〓〓〓〓〓
(27c) 5-(4-carboxymethoxybutyl)-
1-(3-Cyclopentyl-3-hydroxypropyl)hydantoin All of these can be obtained via the corresponding ethyl ester. The starting material used in the above operation can be produced by the following method. A Example 18 and 19 Using the method described in Example 1A, 2-aminopetanedioic acid diethyl ester boiling point 93-96°/
0.02 mm, n ²⁴ _D 1.4425 and 2-aminoandecanedioic acid diethyl ester boiling point 160°/0.1 mm are obtained. These are used in Examples 18 and 19, respectively. B 2-Amino-3-(3-ethoxycarbonylmethoxyphenyl)propionic acid ethyl ester Acetamidomalonic acid diethyl ester (2.60 g) and 3-(chloromethyl)phenoxyacetic acid ethyl ester (Robertson, J.Chem.
(1933) 492, U.S. Pat. No. 3,933,895)
(2.39 g) is dissolved in ethanolic ethoxide (prepared from 230 mg of sodium and 10 ml of absolute ethanol) and the mixture is refluxed for 19 hours.
The solution is cooled and poured into ice water, the product is extracted with ether, the extract is dried and evaporated. The remaining gum is crystallized from ether/hexane to give acetamido(3-ethoxycarbonylmethoxyphenyl)malonic acid diethyl ester as white prismatic crystals with a melting point of 98.5-101.5°. This derivative (1.90g)
Reflux with 10% aqueous hydrochloric acid (25 ml) for 3.5 hours, cool and evaporate to dryness in vacuo. The remaining white solid was dissolved in a minimum amount of absolute ethanol and mixed with a stirred mixture of absolute ethanol (15 ml) and thionyl chloride (1.64 g), cooled (-10
℃) into the solution. The resulting solution was left at room temperature for 18 hours, refluxed for 1 hour, cooled, poured into ice water, and brought to a pH of 9-9 with aqueous sodium hydroxide.
Adjust to 10. The mixture was extracted with ether and the extract was dried and concentrated to give 2-amino-3-
(3-ethoxycarbonylmethoxyphenyl)
Propionic acid ethyl ester is obtained as a colorless oil. This is used in Examples 20 and 21 without further purification. C 2-Amino-3-[3-(2-ethoxycarbonylethyl)phenyl]propionic acid ethyl ester Diisopropylamine (4.04 g) and butylithium (25 ml, 1.60 M in hexane) were taken up in dry tetrahydrofuran (40.0 ml) and this The solution was stirred at -78° under dry nitrogen and acetic acid t-butyl ester (4.64 g) was added over 5 minutes.
Add α・α′-dibromo-m to this solution for 5 minutes.
- Add a solution of xylene (11.60 g) and dry hexamethylphosphoramide (1.42 g) in dry tetrahydrofuran (8.0 ml). The resulting yellow solution was stirred at -78° for 0.5 hour, then the temperature was raised to room temperature over a period of 3 hours. Add excess ice water;
The mixture was extracted with ether and the extract was washed with N-hydrochloric acid (60 ml) and then with water. The extract is dried and concentrated in vacuo to give a yellow oil. Purification by column chromatography on silica gel, eluting with 1:1 ether-hexane yields 3-(3-bromoethyl phenyl).
Propionic acid t-butyl ester is obtained as a colorless oil. Using the method described at the end of the previous paragraph, this can be converted into the desired diethyl esters, which are used in Examples 22 to 25, respectively. D 2-Amino-7-oxanonanedioic acid diethyl ester This can be obtained from 4-bromobutoxyacetic acid ethyl ester (Merck, DE 2354085) by a reaction similar to that described in B above.
Obtained as a colorless oil, boiling point 120-121°/0.005 mm. Used in Examples 26 and 27. Example 28 Preparation of 5-(6-carboxyhexyl)-1-(3-oxooctyl)hydantoin 2-(3-oxooctylamino)nonanedioic acid diethyl ester (7.7 g) prepared by the method described in Example 1B was When treated with potassium cyanate and hydrochloric acid, 5-(6-ethoxycarbonylhexyl)-1
-(3-oxooctyl)hydantoin is obtained. Hydrolysis of this ester using sodium hydroxide solution gives 5-(6-carboxyhexyl)-1-(3-oxooctyl)hydantoin as a viscous oil that crystallizes and has a low melting point. Becomes a solid. 〓〓〓〓〓
Example 29 Production of 5-(6-carboxyhexyl)-1-(5-phenylpentyl)hydantoin 2-aminononanedioic acid diethyl ester (25.9
g) and 5-phenylpentyl bromide (22.7
The mixture of g) is heated in a bath to 100° C. for 3 hours. After cooling, ether (100 ml) is added to the mixture and then left at 0°C for 2 hours. A crystallized colorless solid (21.95 g) is collected and dried. This 2-[(5-phenylpentyl)amino]nonanedioic acid diethyl ester hydrobromide has a melting point of 70-72°C. This hydrobromide (4.86 g) was mixed with ethanol (20
ml) and 2N hydrochloric acid (5 ml), this solution is cooled on ice, and while stirring it is gradually added to a solution of potassium cyanate (1.62 g) in water (5 ml), and the solution is left at room temperature for 18 hours. . The alcohol is evaporated, water is added, the insoluble oil is extracted with ether, the ether extract is dried and evaporated leaving a pale yellow oil. Heat this on a steam bath for 6 hours,
5-(6-ethoxycarbonylhexyl)-1-
(5-phenylpentyl)hydantoin is obtained. Hydrolysis of the above ester by treatment with dilute sodium hydroxide solution and purification of the product by chromatography on silica gel yields 5-(6-carboxyhexyl)-1-(5-phenylpentyl).
Hydantoin is obtained. Crystallization from ethyl acetate gas oil (boiling point 60-80°C) gives colorless prismatic needles, melting point 90-92°. Examples 29-35 Using the appropriate alkyl halide and reacting as described in Example 28, the following compounds are obtained. (29a) 2-Octylaminononanedioic acid diethyl ester (30a) 2-(4-propoxybutyl)aminononanedioic acid diethyl ester (31a) 2-(4-phenoxybutyl)aminononanedioic acid diethyl ester (32a) 2-(4-m) -trifluoromethylphenoxybutyl)aminononanedioic acid diethyl ester (33a) 2-(3-m-triloxypropyl)aminononanedioic acid diethyl ester (34a) 2-(3-hydroxypropyl)aminononanedioic acid diethyl ester, and (35a) ) 2-(3-Hydroxy-3-methyloctyl)aminononanoic acid diethyl ester These are converted to the desired hydantoins. (29b) 5-(6-ethoxycarbonylhexyl)
-1-octylhydantoin, melting point 46-48° (29b) 5-(6-carboxyhexyl)-1-octylhydantoin, melting point 88-89° (30b) 5-(6-carboxyhexyl)-1-(4
-Propoxybutyl)hydantoin, melting point 72-
74゜(31b) 5-(6-carboxyhexyl)-1-(4
-Phenoxybutyl)hydantoin, melting point 88-
90゜(32b) 5-(6-carboxyhexyl)-1-(4
-m-trifluoromethylphenoxybutyl)
Hydantoin, melting point 51-54° (33b) 5-(6-carboxyhexyl)-1-(3
-m-tolyloxypropyl)hydantoin,
Colorless viscous oil (34b) 5-(6-carboxyhexyl)-1-(3
-hydroxypropyl)hydantoin, melting point
111−113° and (35b) 5-(6-carboxyhexyl)-1-(3
-Hydroxy-methoxyoctyl)hydantoin, viscous oil Example 36 Preparation of 1-(6-carboxyhexyl)-5-octylhydantoin A mixture of absolute ethanol (70 ml) and thionyl chloride (6 ml) was cooled to -10°C. While stirring, add 2-aminodecanoic acid (J, Am.Chem.Soc.
(1946) 68 , 450) (16.0g) little by little.
The resulting solution is left at room temperature for 2 hours, refluxed for 1 hour, cooled, poured into ice water and the pH is adjusted to 9 with aqueous sodium hydroxide. The mixture was extracted with ether and the extract was dried, concentrated and distilled to give 2-aminodecanoic acid ethyl ester (75
%) as a colorless oil with a boiling point of 82-4°C/0.2mm. A solution of the above amino ester (18 g) and 7-bromoheptanoic acid ethyl ester (20 g) in absolute ethanol (50 ml) was refluxed for 24 hours, and then ethanol was added.
evaporate. Addition of ether precipitates the hydrobromide salt, mp 98°C. Dissolving in a small amount of dichloromethane, adding an equivalent amount of triethylamine, washing thoroughly with water, drying and removing the solvent gives 2-
(6-Ethoxycarbonylhexylamino)decanoic acid ethyl ester (52%) has a boiling point of 142-4
Obtained as a colorless viscous oil of °C/0.001 mm. When 2-(6-ethoxycarbonylhexylamino)decanoic acid ethyl ester (7.4 g) is reacted with potassium cyanate and hydrochloric acid, 1-
(6-Ethoxycarbonylhexyl)-5-octylhydantoin is obtained. Light oil (boiling point 60-80
℃) to form colorless crystals with a melting point of 68-70℃. Hydrolysis of this ester with sodium hydroxide solution yields 1-(6-carboxyhexyl)-5-
Octylhydantoin is obtained. Crystallization from a mixture of ethyl acetate and light oil (boiling point 60-80°) gives colorless needles with a melting point of 65-66°C. Example 37 5-(6-carboxyhexyl)-3-methyl-
Preparation of 1-octylhydantoin A solution of 2-octylaminononanedioic acid diethyl ester (742 mg) and methyl isocyanate (120 mg) in dry ether (7.5 ml) was allowed to stand at room temperature for 48 hours, and then the ether was evaporated to give a pale yellow color. An oil (800 mg) is obtained. This oil is heated on a steam bath for 2 hours to yield 5-(6-ethoxycarbonyl)-3-methyl-1-octylhydantoin as a yellow oil. This ester (650 mg) was mixed with ethanol (2.4 ml).
and 5N hydrochloric acid (0.6 ml) and left at room temperature for 3 hours. The ethanol was evaporated and the acidic product was isolated by extraction with ether and purified by chromatography on silica gel to yield 5-(6-carboxyhexyl)-3-methyl-1-octylhydantoin as a colorless oil. Obtained as an object. Example 38 5-(6-carboxyhexyl)-3-methyl-
Preparation of 1-(3-hydroxyoctyl)hydantoin When 2-[(3-oxooctyl)amino]nonanedioic acid diethyl ester (Example 28) is reacted with methyl isocyanate as described in Example 37, 5
-(6-ethoxycarbonylhexyl)-3-methyl-1-(3-oxooctyl)hydantoin is obtained. When this is hydrolyzed, it becomes 5-(6-carboxyhexyl)-3-methyl-1-(3-oxooctyl)hydantoin, a colorless oil. This keto acid (1.23 g) is dissolved in 0.25N sodium hydroxide solution (15 ml), and while stirring the solution in an ice bath, sodium borohydride (63 mg) is added. After stirring for 3 hours at room temperature, the solution is acidified and extracted with ether. The ether extract is washed, dried and evaporated leaving an oil. This was purified by chromatography on a silica column using a 50:1 mixture of chloroform and methanol as the eluent, yielding 5-(6-carboxyhexyl)-3-methyl-1-(3-hydroxyoctyl)hydantoin. Obtained as a colorless viscous oil. Example 39 1-(6-carboxyhexyl)-3-methyl-
Preparation of 5-octylhydantoin 1-(6-ethoxycarbonylhexyl)-3-methyl-5-octyl 2-(6-ethoxycarbonylhexylamino)decanoic acid ethyl ester (Example 36) was prepared by the method described in Example 37. When converted to hydantoin and then hydrolyzed, 1-(6-
Carboxyhexyl-3-methyl-5-octylhydantoin is isolated as a colorless oil. Example 40 3-butyl-5-(6-carboxyhexyl)-
Production of 1-octylhydantoin Add 5-(6-ethoxycarbonylhexyl)- to a solution of sodium (308 mg) in ethanol (40 ml).
Add 1-octylhydantoin (see Example 29b) followed by butyl bromide (1.8g),
This solution is refluxed for 24 hours. Evaporate the solvent, add water and extract the undissolved oil with ether. Washing, drying, and evaporating the ether extract yields 3-
Butyl-5-(6-ethoxycarbonylhexyl)-1-octylhydantoin is obtained. Add this ester (3.2g) to ethanol (15ml)
and dissolved in 2N sodium hydroxide (15ml),
Leave at room temperature for 1 hour. The acidic product is isolated by extraction with ether and purified by column chromatography on silica gel to yield 3-butyl-5-
(6-carboxyhexyl)-1-octylhydan〓〓〓〓〓
Toin is obtained as a colorless oil. Example 41 3-Butyl-1-(6-carboxyhexyl)-
Production of 5-octylhydantoin By the method of Example 40, 1-(6-ethoxycarbonylhexyl)-5-octylhydantoin (e.g.
36) to 3-butyl-1-(6-ethoxycarbonylhexyl)-5-octylhydantoin, which is then hydrolyzed to produce 3-butyl-1
-(6-carboxyhexyl)-5-octylhydantoin is obtained as a colorless oil. Example 42 5-(6-carboxyhex-2-ynyl)-
Preparation of 1-(3-hydroxyoctyl)hydantoin Acetamidomalonic acid diethyl ester and 7-bromohepta-
When 5-ynoic acid methyl ester is reacted, acetamide-(6-methoxycarbonylhex-2
-inyl) malonic acid diethyl ester is obtained as a yellow oil. This crude product was hydrolyzed by boiling with 5N hydrochloric acid, and the product was re-esterified to yield 2-aminonona-4-indic acid diethyl ester, boiling point 116
A colorless oil of ゜/0.01 mm is obtained. n ¹⁷ _D 1.4703 The above amino compound is converted into oct-1-ene-3-
When reacted with 2-[(3-oxooctyl)
Amino]nona-4-indic acid diethyl ester is obtained and reduced with sodium borohydride to obtain 2-[(3-hydroxyoctyl)aminonona-4-indic acid diethyl ester. When this compound is treated with potassium cyanate and hydrochloric acid and the resulting hydantoin ester is hydrolyzed, a pale brown oil is obtained. Purification by chromatography using a 30:1 mixture of chloroform and methanol as eluent on a silica column yields colorless 5-(6-carboxyhex-2-ynyl)-1-(3-hydroxyoctyl)hydantoin. oil (diastereomeric mixture)
obtained as. When developed on a thin silica plate with a 90:5:5 mixture of chloroform, methanol and acetic acid, two spots with Rf 0.38 and 0.44 are seen. Using HPLC, one diastereomer (TLC: Rf 0.38) is obtained as a colorless oil.
NMR ( _CDCl3 ) δ0.89 (3H, triplet, _-CH3 ), 2.2
−2.4(6H, multiplet, − CH ₂ C=C− CH ₂ +−
_CH2 − _CO2H ), 3.54(2H, triplet, >N− _CH2
−), approx. 3.6 (1H, multiplet, > CH OH), 4.11
(1H, triplet, >NCHCO−). This compound was then catalytically hydrogenated to give the corresponding 5-(6-carboxyhex-2-enyl)-1-(3-hydroxyoctyl)hydantoin, followed by a saturated compound identical to the title compound of Example 2. can get. Example 43 A 2-(dibutoxymethyl)glycine ethyl ester N-formylglycine ethyl ester
Harman & Hutchinson method (J.Org.
Chem. (1975) 40 , 3474) and the resulting compound was subjected to C-formylation according to HClark et al.
al. “Chemistry of Penicillin (Princetown
University Press, New Jersey, 1949)
Converted to 2-(dibutochimimethyl)glycine ethyl ester using the method described on page 517. B A mixture of 1-(6-carboxyhexyl)hydantoin-5-carboxaldehyde 2-(dibutoxymethyl)glycine ethyl ester (2.0 g) and 7-bromoheptanoic acid ethyl ester (1.82 g) was heated at 100 g under a nitrogen stream. When heated for 3 hours in a bath at ℃, the crude 7-
[(2,2-dibutoxy-1-ethoxycarbonylethyl)amino]heptanoic acid ethyl ester hydrobromide is obtained. This hydrobromide
Dissolve 3.28g of ethanol in 13ml of ethanol,
While cooling with ice water and stirring, treat with a solution of potassium cyanate (1.34 g) in water (4 ml), then add 2N aqueous hydrochloric acid (3.63 ml). Remove the cooling bath and continue stirring at room temperature for 22 hours. The ethanol is evaporated in vacuo, the residue is shaken with water and ether, the ether solution is separated, washed with water, dried over magnesium sulfate (MgSO ₄ ) and the ether removed leaving an oil. This is heated to 100° C. for 3 hours under nitrogen to give 5-dibutoxymethyl-1-(6-ethoxycarbonylhexyl)hydantoin (2.94 g). This was dissolved in water (48 ml) and N in ether (6 ml).
Chamber with aqueous sodium hydroxide solution (24.9ml)〓〓〓〓〓
Stir at room temperature for 1.5 hours and add ether (50
ml), the aqueous phase was separated, cooled with ice water, stirred with fresh ether and diluted with aqueous N-hydrochloric acid.
Make Congo red acidic. The ethereal solution of the carboxylic acid was washed three times with water, dried (MgSO ₄ ) and evaporated to give 1-(6-carboxyhexyl)-
5-dibutoxymethylhydantoin (2.15g)
is obtained as a rubbery material. This 1.89 g was cooled with ice water, stirred with concentrated hydrochloric acid (8.5 ml), and when the resulting solution was allowed to stand, colorless crystals were suspended. This suspension was left at room temperature for 1.5 hours, then diluted with water (10 ml).
The crystals were collected, washed with water, dried in vacuo, suspended in ether (3 ml) and collected again to give 1-(6-carboxyhexyl)hydantoin-5-carboxaldehyde (0.74 mL). g) is obtained. Melting point 223.5−225℃
(Calculated as C ₁₁ H ₁₆ N ₂ O ₅ C51.56, H6.29,
N10.93%, analysis value C51.86, H6.66, N10.62%)
In dimethyl sulfoxide- _d6 , this compound exists in a larger proportion as maskaldehyde, 1-(6-carboxyhexyl)-5-hydroxymethylenehydantoin. C 1-(6-carboxyhexyl)-5-((E)-
3-oxooctylidene)hydantoin 1-(6-carboxyhexyl)hydantoin-5-carboxaldehyde (20 mg) and 2-
Oxoheptylidene-triphenylphosphorane (59 mg) (see J.Org.Chem (1972) 32 , 1818)
and 1 drop of benzene is heated to 100° C. for 35 minutes under nitrogen and the resulting gum is taken up in ethyl acetate. The product is extracted into dilute aqueous sodium bicarbonate, the extract is washed with ethyl acetate, acidified with N aqueous hydrochloric acid and the liberated carboxylic acid is extracted into ether. The ether solution was washed with water, dried (MgSO ₄ ), and evaporated to give a gum (25 mg). This is the NMR spectrum [characteristic signal, δ5.72 (1H, triplet, = CH
−), 3.93 (2H, double, = CH− CH ₂ −CO):
J7.1 Hz in CDCl ₃ ) and identified as 1-(6-carboxyhexyl)-5-((E)-3-oxooctylidene)hydantoin. D 1-(6-carboxyhexyl)-5-((E)-
3-Hydroxyoctylidene)hydantoin 1-(6-carboxyhexyl)-5-((E)-
3-oxooctylidene) hydantoin (20
mg) in water (1.5 ml) is added with a small excess of sodium bicarbonate and, with stirring, treated with sodium borohydride (5 mg). After 60 minutes, the solution is acidified with N-hydrochloric acid, the liberated carboxylic acid is extracted into ethyl acetate, and the ethyl acetate solution is washed three times with water and dried (MgSO ₄ ). Evaporation of ethyl acetate gives a pale yellow gum (14 mg)
remains. This is an NMR spectrum [characteristic signal: δ5.61 (1H, triplet, = CH−, J7.1Hz),
(in CDCl ₃ ) and identified as 1-(6-carboxyhexyl)-5-((E)-3-hydroxyoctylidene)hydantoin. E 1-(6-carboxyhexyl)-5-(3-
Hydroxyoctyl)hydantoin When the product described in C above is reduced, 1-
(6-Carboxyhexyl)-5-(3-oxooctyl)hydantoin is obtained and the title compound is identified as the title compound of Examples 28 and 2. Example 44 5-(6-carboxyhex-2Z-enyl)
-Production of 1-(3-cyclohexyl-3-hydroxypropyl)hydantoin Examples of cis-7-bromohept-5-enoic acid methyl ester (produced by the method of UK No. 1355991) and acetamidomalonic acid diethyl ester
When reacted under the conditions described in 1A, acetamido-(6-methoxycarbonylhex-2-enyl)malonic acid diethyl ester is obtained as a yellow oil. The crude product is hydrolyzed by boiling with 5N hydrochloric acid and the product is esterified as described in Example 1A to give 2-aminonona-4-enedioic acid diethyl ester as a colorless oil. Boiling point 118-123°/0.05mm, ^{n 19} . ⁵ _D 1.4620 This amino compound is reacted with 1-cyclohexylprop-2-enone analogously to Example 2B,
The resulting 2-[(3-cyclohexyl-3-oxopropyl)amino]non-4-enedioic acid diethyl ester was reduced with sodium borohydride as in Example 2C to give 2-[(3-cyclohexyl-3-cyclohexyl-3 -hydroxypropyl)amino]nona-2-
Endic acid diethyl ester is obtained. This compound was treated with potassium cyanate and hydrochloric acid.
Example 2D
Hydrolysis in the same manner as above yields 5-(6-carboxyhex-2Z-enyl)-1-(3-cyclohexyl-3-hydroxypropyl)hydantoin as a yellow oil. It has a tendency to solidify.
When this compound is separated into diastereomers using HPLC, one has minute colorless prismatic crystals, melting point 95-97°, and the other has colorless prismatic crystals, melting point 108°.
-110° is shown. In the examples below, the hydantoin compounds are numbered as follows: Compound 2: 5-(6-carboxyhexyl)-1-
(3-hydroxyoctyl)hydantoin compound 4:5-(6-carboxyhexyl)-1-
(3-Hydroxy-4,4-dimethylpentyl)hydantoin compound 6:5-(6-carboxyhexyl)-1-
(3-hydroxynonyl)hydantoin compound 9:5-(6-carboxyhexyl)-1-
(3-hydroxy-4,4-dimethyloctyl)hydantoin compound 11:5-(6-carboxyhexyl)-1-
(3-Hydroxy-3-cyclobutylpropyl)hydantoin compound 12:5-(6-carboxyhexyl)-1-
(3-hydroxy-3-cyclopentylpropyl)hydantoin compound 14:5-(6-carboxyhexyl)-1-
(3-hydroxy-3-cyclohexylpropyl)hydantoin compound 38:5-(6-carboxyhexyl)-3-
When a methyl-1-(3-oxooctyl)hydantoin diastereomer is used, it is indicated by its melting point. Example A: Cardiovascular effects in rats Male normotensive Wistar (Charles River) rats (250-350 g) were anesthetized with chloroform, a cannula was inserted into the left femoral vein, and chloralose (60 g) was inserted into the left femoral vein.
mg/Kg) intravenously to maintain anesthesia. Pulsatile pressure was transferred from the left femoral artery with an electrical transducer (Bell &
Howell 4-327 L221 model), and the cumulative heart rate was measured using a cardiac tachometer from the arterial pressure wave. Test compounds are administered through the femoral cannula as a saline solution. Wait between consecutive doses until the recorded response returns to pre-injection levels. No reduction in blood pressure was observed with the same volume of vehicle used to administer the drug. Table Example B Platelet Aggregation Inhibition The aggregation of platelets in 1 ml of fresh human platelet-rich plasma (PRP) was studied in a Born aggregometer. The test compound was added to the PRP at the desired concentration, and the resulting mixture was incubated at 37°C for 1 min.
Platelet aggregation was stimulated by the addition of 5 μM adenosine diphosphonate (ADP). The anti-aggregation effect of the compound was expressed as a percentage of inhibition of platelet aggregation when the compound was added to that when the compound was not added. [Table] Using such a comparison method, the following relative intensities were determined for PGE ₁ . Compound 2 (melting point 76-78
゜) 12.5X, Compound 4 (144-146゜) 0.05X, Compound 11 (114-116゜) 5.2X, Compound 12 (116-
117°) 12.5X, Compound 14 (96-98°) 16X Example C Compound 38 reduces the development of aspirin-induced gastric ulcers in rats. Inhibition rate is 80 with oral administration of 1mg/Kg
It was %. Example D 〓〓〓〓〓
Intravenous injection of Compound 2 at a dose of 30 μg/Kg completely inhibits pentagastrin-induced gastric acid production in rats. Example E Intravenous injection (50 μg/Kg) of compound 9 completely antagonizes histamine-induced bronchoconstriction in anesthetized guinea pigs. Example F Compound 2 (melting point 76-78℃) 250μ intravenously
Infusion at a dose of g/min reduces the incidence of electrically induced arterial thrombosis in anesthetized rabbits. Example G Compound 14 (melting point 96-98°C) was given to 5 mice.
No animals died when administered intravenously at a dose of 200 mg/Kg. Therefore, the LD ₅₀ of this compound is
It is considered that the value exceeds 200mg/Kg. Example H Tablet Compound 12 in 1 tablet (melting point 116-117°) 5.0 mg Lactose (BP) 82.0 Starch (BP) 10.0 Povidone (BPC) 2.0 Magnesium stearate 1.0 Compound 12 is mixed with lactose and starch to purify povidone. Granulate the powder using an aqueous solution. The granules are dried, magnesium stearate is added and compressed to produce tablets each weighing 100 mg. Example I Capsule Compound 12 (melting point 116-117°) in 1 capsule 10mg Lactose 79 Starch 10 Magnesium stearate 1 Mix the powders in a powder blender to obtain the content in 1 capsule.
Fill hard gelatin capsules to 100 mg. Example J 1 μg/ml Injection Compound 12 (melting point 116-117°) 100 μg Purified water for injection Make the total volume 100 ml Dissolve compound 12 in purified water for injection, and filter this solution through a membrane funnel with a pore size of 0.22 μm. Sterilize and
The solution is filled into sterile glass ampoules at a rate of 1 ml/ampule under aseptic conditions. Fuse and seal the glass. Example K 10 μg/ml Injection Compound 12 (melting point 116-117°) 1 mg Ethyl alcohol 10 ml Propylene glycol 30 ml Purified water for injection Make the total volume 100 ml. Compound 12 is dissolved in ethyl alcohol, propylene glycol is added, and diluted to volume with purified water for injection. The solution is filtered through a 0.22 μm pore size membrane funnel and the filtrate is collected in a sterile container. Under sterile conditions, 10
Fill sterile vials with this solution at the rate of ml/vial. Stopper with a sterile rubber stopper and seal with an aluminum collar. Example L 100 μg Single dose injection (lyophilized) Compound 12 (melting point 116-117°) 10.0 mg Mannitol 2.5 mg N/10 sodium hydroxide solution Purified water for injection until pH 10.0 Dilute to 100 ml Compound 12 Suspend in approximately 20 ml of water. Add enough sodium hydroxide solution to reach a pH of 10 to dissolve compound 12. Add mannitol to dissolve and dilute to the desired dose with purified water for injection. The solution was sterilized by filtering through a membrane filter with a pore size of 0.22 μm, and aseptically placed into a sterile vial.
Fill at the rate of ml/vial. The solution is lyophilized and aseptically sealed with a rubber stopper. Each vial contains 100 μg of compound 12 as the lyophilized sodium salt. Example M Suppository compound 12 (melting point 116-117°) 3 mg Massa Esterinum C 2 mg Melt the suppository base at about 40°C. Gradually add fine powder of Compound 12 and mix until homogeneous. Pour into a suitable mold and set aside. Massa Esterinum C is a commercially available suppository base composed of mono-, di- and triglycerides of saturated vegetable fatty acids - Henkel International,
Sold by Dusseldorf. 〓〓〓〓〓

Claims (1)

[Claims] 1 Formula () [In the formula, Z is hydrogen or alkyl, Z ¹ is -(CH ₂ ) _3~8 -COOR (in the formula, R is hydrogen or alkyl), -CH ₂ -C・X・C—(CH ₂ ) ₃ COOH (in the formula
X represents a triple bond or double bond), long chain alkyl, 3-oxa-long chain alkyl,
[Formula] (wherein R is -COOCH ₃ or -CH ₂ CH ₂ COOH) or -(CH ₂ ) ₄ -
_{OCH 2 COOH} , and _Z ² _{is [} Formula _] ( _{wherein , 1} is alkyl and R ₂ is hydrogen or alkyl], or -CR ₁ R ₂ -CH ₂ R [where R is phenyl substituted or unsubstituted with trifluoromethyl, and R ₁ and R ₂
are alkyl], −(CH ₂ ) ₂
-CR(OH)-( _CH2 ) _{0~ 6 -CH3} (wherein R is hydrogen or alkyl), [formula] (wherein R is C4 _~7 alkyl, phenyl, hydrogen or benzyl) , -( _CH2 ) _3- ( _CH2 ) _0-1- OR (wherein R is phenyl substituted with alkyl), 3-oxo-long chain alkyl, long chain alkyl or aralkyl, or -( CH ₂ ) ₆ −COOH
A compound represented by 2 Z is hydrogen or an alkyl group having 1 to 4 carbon atoms, 〓〓〓〓〓
Claim 1 wherein Z ¹ is -(CH ₂ ) _3~8 -COOR (wherein R is hydrogen or alkyl) and Z ² has the same meaning as defined in Claim 1. Compounds described in Section. Claim 1, wherein 3 Z ¹ is -(CH ₂ ) ₅ -COOR (wherein R is hydrogen or alkyl)
A compound according to any one of Items 1 and 2. 4 Claims 1 to 3 in which Z is hydrogen
A compound as described in any one of the paragraphs. 5 5-(6-carboxyhexyl)-1-(3-
hydroxyoctyl)hydantoin, 5-(6-carboxyhexyl)-1-(3-hydroxy-4,4-dimethylpentyl)hydantoin, 5-(6-carboxyhexyl)-1-(3-hydroxynonyl)hydantoin, 5 -(6-carboxyhexyl)-1-(3-hydroxy-4,4-dimethyloctyl)hydantoin, 5-(6-carboxyhexyl)-1-(3-hydroxy-3-cyclobutylpropyl)hydantoin, 5- (6-carboxyhexyl)-1-(3-hydroxy-3-cyclopentylpropyl)hydantoin, 5-(6-carboxyhexyl)-1-(3-hydroxy-3-cyclohexylpropyl)hydantoin, or 5-(6- carboxyhexyl)-3-methyl-
The compound according to claim 1, which is 1-(3-oxooctyl)hydantoin or a salt or ester thereof.