JPS59227847A - N-acyl acidic amino acid diamide, its preparation and antiulcer agent containing the same - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [R<1>-R<4> are H, (substituted) alkyl, etc.; R<5> is (substituted) cycloalkyl, acyl or heterocyclic group; A is bond, (substituted) alkylene, alkenylene, etc.; n is 1-3] and its salt. EXAMPLE:DL-2-( beta-2-Furylacrylamide )-N<5>-methyl-N<1>,N<1>-di-n-propylpentane-1,5-diamide. USE:An antiulcer agent. PREPARATION:The compound of formula I can be prepared by reacting the compound of formula II or its salt with the compound of formula R<5>-A-COOH or its reactive derivative at the carboxyl group. As an alternative method, the reaction of the compound of formula III or its reactive derivative at the carboxyl group with the amine of formula IV gives the compound of formula I .

Description

[Detailed description of the invention]

The present invention relates to N-acyl acidic amino acid diamides represented by the general formula, a method for producing the same, and an antiulcer agent containing them. Conventionally, L-glutamine has been widely used as an antiulcer agent, but in recent years, acylglutamic acid derivatives have been developed as improved versions thereof and have come to be used for the treatment of ulcers. However, the anti-ulcer effect of acyl glutamic acid derivatives is not sufficient, and it has been desired to develop a compound with stronger anti-ulcer effect and higher efficacy rate. Against this background, the present inventors conducted extensive research with the aim of finding the present compound that has a strong anti-ulcer effect, and as a result, the present inventors found that it has a strong anti-ulcer effect and the desired properties. The present invention has been completed by discovering a compound represented by the general formula (I') that satisfies all the objectives and a method for producing the same.The present invention will be described in detail below.In the general formula /I), R ', R2, R' and R4 are, for example, methyl, ethyl, n-7', 1so-propyl, n-butyl, 1
Groups such as so-butyl, see, -butyl, tert, -butyl, pentyl, hexyl, octyl, etc.
Particularly preferred is a C7-4 alkyl group. In addition, as a heterocyclic group formed by R1 and R1, R3 and R4 together with adjacent nitrogen atoms, a heterocyclic group containing at least one nitrogen atom among nitrogen, sulfur, and oxygen atoms is used. Formula groups include, for example, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl groups, and the like. Examples of the cycloalkyl group in R5 include groups such as cyclopropyl, cyclopentyl, cyclohexyl, and cycloheptyl, and examples of the heterocyclic group include a 5-membered ring containing one or more heteroatoms selected from 9 atoms, sulfur, and oxygen atoms. ,6
Heterocyclic groups of the ring and fused ring type, such as chenyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, inthiazolyl, oxazolyl, isoindolyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, tsutrahydrofuryl, etc. a 5-membered heterocyclic group,
6-membered complex flt formulas such as pyranyl, pyridyl, pyrazinyl, pyrimidigol, pyridazinyl, piperazinyl, piperazinyl, morpholinyl, triazinyl, thiazinyl, etc.
, benzochenyl, benzofuryl, isobenzofuryl,
Condensed ring type complex compounds such as indolyl, isoindolyl, benzofuryl, purinyl, quinolyl, isoquinolyl, naphthyridinyl, quinogisazinyl, chromanyl, indolinyl, isoindolinyl, chromenyl, 3,6-epoxy-l-cyclohexenyl, etc. Examples of acyl groups include acetyl, propionyl,
Butyryl 7'l (including any alkanoyl group, an aroyl group such as benzoyl, naphthoyl, a heterocyclic carbonyl group having the above-mentioned heterocyclic group, etc.) and a purkyl group in these R1, R2, R3 and R4. A heterocyclic group formed by combining R2, R3 and R4 with adjacent nitrogen atoms, and R
The cycloalkyl, acyl, and heterocyclic groups in 5 include halogen atoms such as fluorine, chlorine, bromine, and iodine; hydroxyl; amino; carboxyl; methyl, ethyl, 11-propyl, 1so-propyl; , n-butyl, l5o-butyl, sec, -butyl, 1
ert. - Alkyl groups such as butyl, pentyl, hexyl, heptyl, octyl; oxo groups; methoxy, ethoxy, n-
Propoxy, 15o-propoxy, n-butoxy, 1s
o-butoxy, see, -butoxy, tert, -7
) Alkoxy groups such as xy, pentoxy, hexyloxy, heptyloxy, octyloxy; phenyl,
Aryl or halogen-substituted aryl groups such as naphthyl, chlorophenyl; aralkyl or alkoxy-substituted aralkyl groups such as benzyl, 7enethyl, naphthylmethyl, (2,3,4- or 3,4.5- )rimethoxybenzyl; Aminoalkyl groups such as aminomethyl and amineethyl; dialkylaminoalkyl groups such as dimethylaminomethyl and diethylaminoethyl; N-methylpiperazin-1-yltutyl groups; hydroxy-substituted alkyl groups such as hydroxymethyl and hydroxyethyl;
Aralkenylcarbonyl or alkoxy-substituted aralkenylcarbonyl groups such as styrylcarbonyl, 3,4.5-trimethoxystyrylcarbonyl; aralkyloxycarbonylamino groups such as benzyloxycarbonylamino; benzoylamino, 3,4.5-)
1 selected from aroyl amino or alkoxy-substituted aroylamino groups such as rimethoxypenzoylamino ↓ heterocyclic carbonyl alkyl groups such as pyrrolidinylcarbonylmethyl, piperidinylcarbonylmethyl, piperazinylcarbonylmethyl, morpholinylcarbonylmethyl, etc. Examples of the alkylene group substituted with one or more substituents include methylene, ethylene, propylene, and butylene; examples of the alkenylene group include hnylene, Propenylene, butenylene, 2゜4-butadienylene groups; examples of alkagenylene groups include 1,4-butadienylene;
Alkyl groups such as ethyl, propyl, butyl; hydroxyl groups; aryl groups such as phenyl, naphthyl, etc. may be substituted (... Also, since the compound of general formula (I) has an asymmetric carbon atom, However, when it has a double bond, there are cis-trans isomers, tautomers, etc., but these specific forms and mixtures thereof are also Also included in the present invention are hydrates and solvates of the compound of general formula (I).In addition, the compound of general formula (I) has a carboxyl group, a hydroxyl group; When the bitroxyl group has a protecting group (・, it may be protected with a protecting group known in the art (・). Here, the protecting group for the bitroxyl group can normally be used as a protecting group for the hydroxyl group. including all groups,
For example, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,
4-Dimethquinepenzyloxycarbonyl, 4-(phenylaso)benzyloxycarbonyl, 4-(4-methoxyphenylazo)benzyloxycarbonyl, tpr
t,-butoxycarbonyl, 1,1-dimethylpropoxycarbonyl, impropoxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2,2.2-) IJ dibromotoxycarbonyl, 2-furfuryloxycarbonyl , 1-adamantyloxycarbonyl, 1-cyclopropylethoxycarbonyl, 8-quinolyloxycarbonyl or trifluoroacetyl; and benzyl, trityl, methoxymethyl, 0-nitrophenylsulfenyl, 2,4 -dinitrophenylsulfenyl group and the like. In addition, protecting groups for amino groups include all groups that are normally used as amine protecting groups, such as )! J r'loethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyl, methanesulfonyl, benzenesulfonyl, p-toluene/sulfonyl, p-nitrobenzyloxycarbonyl, 0-bromobenzyloxycarbonyl, (
(7-no, di, tri) chloroacetyl, trifluoroacetyl, acetyl, formyl, tert, -amyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, 2-cyanoethoxycarbonyl, tert, -butoxycarbonyl, methoxymethoxycarbonyl, acetyl Methoxycarbonyl, p-methoxybenzyloxycarbonyl, phenyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 4-(phenylaso)benzyloxycarbonyl, 4-(4-methoxyphenylazo)benzyloxycarbonyl, pyridine-1-
Oxide-2-yl-methoxycarbonyl, 2-furyloxycarbonyl, diphenylmethoxycarbonyl, 1
, 1-dimethylgloboxycarbonyl, ingloboxycarbonyl, 1-cyclopropylethoxycarbonyl,
Phthalo4, succinyl, 1-adamantyloxycarbonyl, 8-quinolyloxycarbonyl, benzoyl,
p-nitrobenzoyl, p-jert, -butylbenzoyl, etc. Phenyl, benzylthia, p-=)lobensyritene, 2-hydroxyhensyritene, 2-hydroxy-5-chlorobenzilitine, 2-hydroxy-1-naphthylmethylene, 3
-Hydroxy-4-pyridylmethylene, 2-(1-ethoxycarbonyl-1-propenyl), 2-(1-(1-
morpholino) carbonyl-1-propenyl L2-(1-
diethylaminocarbonyl-1-propenyl), 1-methoxycarbonyl-2-propyritine, 1-ethoxycarbonyl-2-propyritine, 3-nitoxycarbonyl-2-butylidene, 1-acetyA/-2-10 pyligine, l-benzoyl -2-propyritine, 1-[:N-(
2-methoxyphenyl)carbamoyl]-2-7'rohyritene, 1-(N-(4-methoxyphenyl)carbamoyl]-2-glopylidene, 2-ethoxycarbonylcyclohexylidene, 2-ethoxycarbonylcyclopentylidene, 2- Acetylcyclohexylidene, 3,3-
Examples include easily leaving groups such as dimethyl-5-oxycyclohexylidene and protecting groups for amine groups such as di- or tri-alkylsilyl groups. Furthermore, the carboxyl group-protecting group includes all groups that can be used as ordinary carboxyl group-protecting groups, such as methyl, ethyl, n-propyl, 1so-propyl, te
rt, -butyl, n-butyl, phenyl, indanyl,
Benzyl, diphenylmethyl, trityl, p-nitrobenzyl, p-methoxybenzyl, benzoylmethyl, acetylmethyl, p-nitrobenzoylmethyl, p-bromobenzoylmethyl, p-methanesulfo! -rubenzoylmethyl, phthalimidomethyl, trichloroethyl, 1
．． Adimethyl-2-probeni/L-11,1-dimethylpropyl, acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl, 1-acetylethyl,
1-pivaloyloxyethyl, 1-pivaloyloxy-
n-propyl, acetylthiomethyl, pino(loylthiomethyl, 1-acetylthioethyl, ]-pivaloylthioethyl, methoxymethyl, ethoxymethyl, propoxymethyl, impropoxymethyl, .-methoxymethyl,
Methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, tert, -butoxycarbonylmethyl, 1-methoxycarbonyloxy-ethyl, 1-ethoxycarbonyloxy-ethyl, 1-improvoxycarbonyloxyethyl, phthalidyl, 2-(phthalidylidene)-ethyl , 2-(5-fluoro7taldylidene)
-Ethyl, 2-(6-chlorophthalisylidene)-ethyl, 2-(6-medoxyphthalidylidene)-ethyl, 5-
Methyl-2-oxo-1,3-dioxo-iI/-4-
yl, 5-ethyl-2-oxo-11,(-dioquine-
4-yl, 5-propyl-2-oxo-1,3-dioxo-4-yl, 1,1-dimethyl-2-propenyl, 3-methyl-3-butynyl, succinimidomethyl, 1-chloropropyl ethyl, methylthiomethyl, phenine

[・Thiomethyl, dimethylaminomethyl, quinoline-nioxide-2-yl-methyl, pyridine-1-
Oxid-2-yl-methyl, bis(p-7toxyphenyl)methylnato groups are not mentioned, and when the carboxyl group is protected with a nonmetallic compound such as titanium tetrachloride, and JP-A-46-7073 For example, as described in Dutch Publication No. 7105259, the carboxyl group is protected with a silyl compound such as dimethylchlorosilane. Further, when the compound of general formula (I) has an acidic group or a basic group capable of forming a salt, the salt thereof is also included in the compound of the present invention. Here, as salts in acidic groups, alkali metal atoms such as sodium and potassium salts; magnesium,
Alkaline earth metal atoms such as calcium; ammonia;
Zorokin, Shihenzylamine, N-benzyl-β-f, Enethylamine, 1-Efenamine, N. N-dibenzylethylenediamine, triethylamine,
Examples include salts with nitrogen-containing bases such as trimethylamine, tributylamine, pyridine, diethylamine/, N-methylpiperidine, N-methylmorpholine, diethylamine, and dicyclohexylamine. Examples of salts with basic groups include hydrochloric acid and bromide. Mineral acids such as hydrogen acid and sulfuric acid; oxalic acid, succinic acid, formic acid, trichloroacetic acid, l-refluoro? Organic carboxylic acids such as +f acid; methanesulfonic acid, ethanesulfonic acid, benzenesulfone p, +-toluene-2-sulfonic acid, toluene-4-sulfonic acid, menthylenesulfonic acid (2,4,6-) IJ methylbenzenesulfonic acid ), naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid, phenylmethanesulfonic acid, benzene-1,3-disulfonic acid, toluene-3,5-disulfonic acid, naphthalene-1,5-disulfonic acid , naphthalene-2,6-disulfonic acid, naphthalene-2
, 7-disulfonic acid, benzene-1,3,5=trisulfonic acid, benzene-1,2,4-t! According to the invention of J.S.
1. For example, a novel compound represented by the general formula (■) useful as an anti-ulcer agent can be obtained by the production method described below. That is, the compound of the present invention can be produced by manufacturing method 1: a method in which a compound represented by the general formula or a salt thereof is reacted with a compound not represented by the general formula %() or a reactive derivative thereof in the carboxyl group; A method of reacting a compound represented by the formula % or its reactive derivative in the carboxyl group pressure with an amine represented by the general formula, production method 3 A compound represented by the general formula or its reactive derivative in the carboxyl group, and the general Method of reacting amines represented by the formula, and production method 4 Reacting a compound represented by the general formula % formula % () or a reactive derivative in its carboxyl group with an amine represented by the general formula (V) It can be produced by a method of obtaining a compound represented by the general formula %. The starting compounds of the general formulas (II), (rV), (Vl) and (%'), which are the raw material compounds in the above-mentioned production methods 1.2.3 and 4, can be prepared, for example, by the following reaction route. It can be produced by: Method for producing compounds of general formula (II) Protection of amino group (IX) (X) (
XI ) HR HR (Xllll') H2 (n) (■) (■) 0' (XIV) (IV) (in ■+)
(XVI) (xI′x) As the carboxyl protecting group for
Preferred are alkyl groups such as terl and -butyl, and aralkyl groups such as benzyl and fuyunegle. ShitaR
Examples of the amino protecting group include those mentioned above. Examples of the salt in general formula (11) include acid addition salts with hydrochloric acid, hydrobromic acid, and the like. Next, the manufacturing method and raw material manufacturing process for the Aζ-emitting compound will be explained in more detail. Production method 1 Normal bebutide synthesis using the compound of general formula (IX) (aspartic acid when n=1, glutamic acid when n=2 and aminoadipic acid when 1-3) as a starting material amine protecting groups in, for example, benzyloxycarbonyl, substituted benzyloxycarbonyl,
The amine group of the compound of general formula (■) is protected with a tosyl group or the like to obtain a compound of general formula (X). The reaction is promoted by using chloroform, 1,1.2-) chloride hydrocarbons, aromatic hydrocarbons such as benzene and toluene as a solvent, and p-) luene sulfo/acid, sulfuric acid, etc. The compound of the general formula (xi) is obtained by dehydration condensation with paraformaldehyde in the presence of a reaction accelerator. (Volume/Volume @) The degree of slenderness is preferable, and this reaction differs slightly depending on the solvent used, but it is generally completed in several hours. In this way, 11) et al. The amine T:Q''g of O1) is reacted to obtain a compound of general formula (XII). In this reaction, the usability of amines of general formula (■) is For example, the solvent may be about 2.5 times the mole of chloroform, halogenated hydrogen ash such as 1°1.2-) dichloroethane, esters such as ethyl acetate, butyl acetate, etc. tetrahydrofuran,
You can use ethers such as dioxane, aromatics such as benzene, toluene, etc. that do not involve reaction in a hydrocarbon furnace, but do not use excessive amines as reaction reagents or use them as solvents. Moyo-・. As amines of general formula (■),
For example, methylamine, ethylamine, n-7' lobylamine, 1so-propylamine, n-butylamine, dimethylamine, di(β-hydroxyethyl)amine, diethylamine, di-n-propylamine, di-n
Examples thereof include C5-4-mono- or dialkylamines such as -butylamine, and heterocyclic amines such as bicollidine, piperidine, morpholine, and N-methylpiperazine. If the compound of the general formula (XII) obtained in step 1-A is not allowed to react with the amine of the general formula (V), a compound of the general formula (xrtt) is obtained. When a compound of general formula (xn) is subjected to a reaction, it is reacted with an amine of general formula (V) in the presence of a condensing agent such as dicyclohexylcarbodiimide, carbonyldiimidazole, or Woodward's reagent; When a reactive derivative containing a carboxyl group K t, of the compound of formula (XII) is subjected to a reaction, it is reacted with a carbonic acid monoalkyl ester such as ethyl chlorocarbonate to form a conventional compound such as a mixed acid anhydride or an acid azide. Known reactive derivatives can be expressed by the general formula (V
) is reacted with an amine to form ω-amidation, which gives the general formula (
A compound of Xllll) is obtained. Furthermore, this 7. When the general formula (V
The amines in ) include those similar to the amines in general formula (■). In the above reaction (when a condensing agent is used, the reaction conditions can be the same as those for normal amidation reactions), using a halogenated hydrocarbon such as methylene chloride as a solvent. It is preferable to carry out the reaction at around 0°C. Furthermore, when the reaction is carried out by successively using a mixed acid anhydride or azide, the reaction is carried out under approximately the same conditions. The removal of the amine protecting group of the compound of the general formula (XIII) that could not be obtained can be done by using (・ Although the removal conditions differ depending on the protecting group used, ( For example, when the protecting group is benzyloxycarbonyl, it is easily removed by adding hydrogen bromide in an acid-resistant environment or by bringing it into contact, yielding the compound of general formula (n). Then, the compound of general formula (II) ) and the compound of general formula (m) to obtain the target compound of general formula (I). In this case, a condensing agent such as dicyclohexylcarbodiimide may be used. Instead of the compound, a J-responsive derivative thereof at the carboxyl When using mixed acid anhydrides) or acids (・As a solvent for reaction (2. Reaction 1) (・All things, for example, halogenated hydrocarbons such as methylene chloride, ether nitrile such as tetrahydrofuran, dioxane, etc. It is preferable to use nitriles of f1..b.The reaction temperature varies depending on the compound used, but from -20 to
When using an acid halide, which is a conductor packed with 4'1°, the reaction at the carboxyl group of the compound (Tll) is generally carried out at 50°C, at room temperature in the presence of a deoxidizing agent such as triethylamine or pyridine. When a mixed acid anhydride is used, it is preferably maintained at -20 to 0°C, and when a carboxylic acid is used, it is preferably maintained at around 0°C in the presence of a condensing agent. This reaction is completed in approximately several minutes to several tens of hours. In addition, in the series of reactions in the above-mentioned production method, as the amino acid of the general formula (IX) which is the starting material, if the DL form is used, the target product of the DL form will be obtained, but if the L form is used (if the L form is used, the target product of the L form will be If you use 9 objects again, you will have 9 objects.l)
I don't get 1. Production method 2 Reaction of the compound of general formula (■) and the compound of general formula (IIT) +j-? A derivative Schotten-Baumann (Scho
tten-Baumann) reaction, the general formula (■
) is heated with a carboxylic acid anhydride such as anhydride 11' [acid] to give the general formula (xr
After forming an intramolecular anhydride of the compound of v), the general formula (
(2) The amines of (2) are reacted in water, aqueous acetone or aqueous dioxane, preferably water at -5 to 5 DEG C. to obtain a compound of general formula (IV). At this time, in addition to the α-amide form, some ω-amide forms may also be produced, but these can be easily separated by pH separation or the like. Then, the compound of general formula (IV) or its carboxyl group reactive derivative and the amine of general formula (V) are added to the compound of general formula (Xn) of production method 1. Similar to the method for deriving the compound of formula ('Xll+), the compound of general formula (I) can be obtained by ζ-reaction. 5-Here, the carboxylic group VL' of the compound of the general formula Qv) is an example of a reactive derivative such as a mixture which is reacted (e) with monocarbonic acid 7/lekyl esters such as ethyl chlorocarbonate. Commonly known reactive derivatives such as FHtM hydrate or acid azide are mentioned, and according to the above-mentioned production method, "C1-" general formula (■
) During the process of obtaining a compound of general formula (IV) from a compound of general formula (IV), racemization may occur, and the desired product may be obtained as a DL form.Production method 3 In a compound of general formula (VO) If R1 and R2 are hydrogen atoms, amino-5-carbamoylvaleric acid is subjected to the same Schotten-Baumann (F) reaction as described above with a reactive derivative of the compound of general formula (m), the corresponding reaction is obtained. The compound of general formula (■) can be converted into ().Also, when ζ1 and R2 are other than hydrogen atoms, the α-carbogicyl group of aspartic acid, glutamic acid or 2-aminoadipic acid and the α-amino -2i1
．． The above-mentioned standards for use in the relevant field are maintained at 9 units. Preferably, protecting groups include a number of different carboxyl-protecting groups and amino-protecting groups, such as tert.-butyl and penzyloxycarbonyl groups, benzyl and tert,-butyloxy. 411 such as carbonyl group
These protecting groups are used to protect the compound of the general formula (XV), and then this compound and the amines of the general formula (■) are reacted in the same manner as in the amidation reaction of Production Method 1. The compound of the general formula (X'v'T) is obtained by performing the procedure externally. Next, the α-carboxyl protecting group and the α-aζ protecting group are simultaneously removed to obtain a compound of general formula (XVlr), or α-a? Only 7 groups are eliminated to obtain a compound of general formula (xVN), and these and compound A of general formula The acylation reaction is carried out under the same conditions as in the reaction to obtain a compound of general formula (Vl) or CXIX). The compound of general formula (XIX) can be led to a compound of general formula (Vl) by removing the α-carboxyl protecting group by a conventional method. The compound of the general formula (Ml) thus prepared or its reactive derivative at the carboxyl group and the amines of the general formula (■) are prepared in Production Method 2.
The amidation reaction was carried out under the same conditions as the amidation reaction of t.
A compound of general formula (r) can be obtained. Production method 4 The amino acid of the general formula (IX) and the compound of the general formula (If) or its reactive derivative at the jylboxyl group are reacted under the same conditions as described in the production procedure to obtain the compound of the general formula (1). Amidation reaction moxibustion was carried out in the same manner as described in Production Method 1, except that the amines of general formula (V) were used at least twice the mole of the compound of general formula (■) or its reactive derivative in the carboxyl group. In this case, the compound of the general formula (Ia) is obtained by reacting the compound of the general formula (II) or its reactive derivative at the carboxyl group with the amine of the general formula (V). In addition, in each of the above-mentioned production methods (*), the amines of general formula (V) or (■) can be used for the amidation by using the same amines or caeca amines once a month, depending on the purpose. It can be amidated.Next & CS The pharmacological effects* of the representative compounds of the present invention are explained below.1 Anti-ulcer effect (1124 hours fasted Wistar rats (male), body weight 180-220 g The compound of the present invention or progelamide was administered to a group of 8 animals on a good day, and 25 mq/Kq of indomethacin (registered KH4'2) was orally administered 1 hour later.On the other hand, a control group was orally administered only indomethacin on the same day. After 5 hours, the stomach was removed and the length of the ulcer surface was determined as j + ilj > E L, the sum of which was 50% of the control group.
The dosage of the compound of the present invention and progelamide (ED
5° value) was determined. The results are shown in Table IK. (Left below) (2124-hour fasted Wistar rats (female,
The compound of the present invention or progelamide was intraperitoneally administered at 50 μl/Kq to mice weighing 180 to 220 F/group, and 1 hour later, 25 μ/Kq of Indomesacin (registered trademark) was orally administered. On the other hand, the same amount of indomesacin alone was administered orally to the control group. After 5 hours, the stomach was removed and the total length of the ulcer surface was measured.
The inhibition rate was calculated by comparing with the control group. Table 2 shows the results.
Shown below. (Left below) 2. Acute gastric dd'Y mouse (2 males, body weight 23±21. 10 mice per group)
K, compound of drug Na3-6 was administered intraperitoneally (L I)
When I calculated the lo values, they were all 600 to 9.
It was two. As described above, it can be seen that the compound of the present invention has an extremely strong anti-ulcer effect compared to the commercially available anti-ulcer agent glogulumide. The compounds of the present invention can be used for the treatment of ulcers in humans and animals, and are used for this purpose in dosage forms commonly used in the field, such as tablets, tablets, granules, etc., and for the preparation thereof. Various additives, such as excipients, lubricants, sugars, etc., may be added in order to
The method and frequency of administration are appropriately selected depending on the symptoms, but in general, the dosage is 1 to 1000 per person per day for adults.
~ may be orally administered once to several times. Next, Examples and Formulation Examples of the compounds of the present invention will be described, but the present invention is not limited thereto. 487 and p-toluenesulfonic acid monohydrate x2y were added to toluene ItK and azeotropically dehydrated for 1 hour. After the reaction was completed, the toluene was distilled off under reduced pressure and the oily substance was extracted with 500 ml of ethyl acetate.
rnl, washed with water, dried over anhydrous magnesium sulfate, and distilled off the solvent under reduced pressure to obtain oily DL-3.
-benzyloxycarbonyl-4-(2-carboxyethyl)oxazolidin-5-one is obtained. This is 600ml of toluene! and azeotropically dehydrated by adding di-n-propylamine 42o2. After the reaction is completed, the solvent is distilled off under reduced pressure, and 500% of ethyl acetate is added to the residue. Add this liquid to dilute hydrochloric acid.
After cleaning with TE (Ah), add 10% aqueous sodium chloride solution and shake thoroughly, then divide the aqueous layer by 1 (v). Then, adjust this to 16 K with dilute salt N. 1
After adding 500% of ethyl acid and thoroughly shaking, the organic layer is separated. After drying this solution over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain DL-N2-benzyloxycarbonyl-Nl, which had a melting point of 108~0°C.
Nl-di-n-propyl-α-glutamylamide 27
2y (yield 7o%) is obtained. (2+ D L -N''-benzyloxycarbonyl-NINl-di-n-propyl-α-glutamylamide 36.4f 44M, +' f L' 7500 m
e I/C dissolution Susume -20=-15°C 25.2y of tidoethylamine and 122y of hydrochloroethyl carbonate were added dropwise, and after stirring for 30 minutes, 7.41y of methylamine hydrochloride was added in portions. Then, after IMI stirring for 2 hours at the same temperature, the reaction solution was mixed with 100 ml of dilute hydrochloric acid, 100 ml of dilute alkali, and io water. Wash sequentially with me. If this is dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure, the DL-2-beni/
Zyloxycarbonylamino-N5-methyl-N', H
+-see n, oral pill pentane-1,5-diamide 35
．． 82 (yield 95%) is obtained. (3) Dissolve 9.32 g of D L -2-benzylreoxylponylamino N5-methyl-Nl, Nl-di-n-propylpentane-1,5-diamide in 50 me of isopropyl alcohol, and dissolve 2.3 g of UA hydrochloric acid. Add 2 ml of 10% paradiuno and 0.51 carbon, and perform catalytic reduction at normal pressure. After the reaction is complete, palladium on carbon is removed by filtration, and IJX is distilled off from the filtrate under reduced pressure to obtain DL-2-amino-N5, which has a melting point of 125-127°C.
-Methyl-Nl, Nl-di-n-propylpentane-1
, 5-diamide jl to acid salt 6,7 f' (yield c+
75Vt). (4) 2-furan acrylic rF! , 5r was dissolved in 75m of methylene chloride, and to this was added 2.7f of triethylamine and 1.7f of ethyl chlorocarbonate at -25 to -20C.
DL-2-7 minnow N5 after 30 minutes.
-Methi, Roux Natsu, Tot1-Di-n-phyllobylpentane-1,5-diamide salt r18-9 salt 32 is added,
Let react for 1 hour. After the reaction is complete, dilute the reaction solution with 30-1 IJ amino aqueous solution, 30-1 dilute hydrochloric acid and 3-3 water.
After sequentially washing with 0+++/, drying with anhydrous magnesium sulfate (7) and distilling off the solvent under reduced pressure, the melting point is 112-1.
DL-2-(β-2-furylacrylamide)-N5-methyl-N',N'-di n-furovirpentane-1,5-diamide showing 13°C 3.12 (yield 80%)
get. Elemental analysis value (CIQ H2ON3 o4) C (to)
H (to) N (to) Note, value 62,78 8.04 11.56 Actual value 62,85 8,23 11.62NMR (C
DCl, )δ value; 0.85 (3H,t, -CH,), 0.97 (
3H,t, -c)I3). 1.25~2.60 (8H+rnCH2
X4), 2.87 (3H, d. -C1l, ), 3.05-3.90 (4n,
m, ;cH2x 2 ), 5.15(H(, m,
→CH), 6.45~6.67 (2H, m, 7
Run J Town (N2), 6.66 (IH, d, -C
H= ), 7.05-7.45 (1)1. m,
'; NH), '7.54 (IH, d, -CH=)
. 7.57 (If(, S, furan ring H), 7.83
(IH, d, > NH) I R (KB r )
cm-'; νNH3300 νc=Q 1635. 1615 Example 2 2-furanacrylic acid 1,7r'4; methylene chloride 75
+nI! , and triethylamine was then added dropwise at -25 to -20°C to obtain DL-2-amino-N',N'-dimethyl obtained in substantially the same manner as in Example 1 (1) to (3). -Nl
, N'-di-n-propylpenkune-1,5-diamide hydrochloride 42 was added, and the reaction was allowed to proceed for 1 hour. Then, by post-processing in the same manner as in Example 1 (4), the melting point is 1.
DL-2-(β-2-furylacrylamide) N5,N5-dimethyl-Nl, N
l-di-n-propylpentane-1,5-diamide 3,
5y (yield 76%). Elemental analysis value (C20 N31 N3 04 ) C (To) H% 8% Subtraction value 63,63 8.28 11.13 Actual value Li 3,43 8,38 11.08 NM. R
(Cl)CL, )δ value; o, 85 (3fl, t, -CH3>, 0.9
9 (3H, t, -C13). 1, 25-2.70 (8H, m, ;CH,
4), 2.95 (6H.s, -CH,N2), 3.10''-4,95 (
4H, nl, 〉CH2X2 )+5,19 (i
ll, u+, ”; CH ), 6.41-
6.57 (2H, m. Furan ring 11X2 L 6.62 (LH, d
, -CH= ), 7.46( IH, d, -
C) i-), 7.48 (IH, s, 7 run ring n). 8,07 (III, d, ;NH)IR(KBr
) cm-'; Cito, 3370 Cico 1665, 1645. 1610 Example (1) DL--glutamic acid 6.52 to water 75tn
1. After adding 5.27 g of sodium hydroxide and cooling to -10 to -7°C, a solution of 6 g of 2-furanacrylic acid chloride dissolved in 75 g of diethyl ether was added for 1 hour. Drop the required L2. After dripping, 5
After reacting at the same temperature for a period of time, the aqueous layer is separated and adjusted to pH 5.5 by adding dilute hydrochloric acid. Add this to ethyl acetate 50+++/! Extract twice with
Separate the aqueous layer. After adjusting the pH of this solution to 2 with dilute hydrochloric acid, the extraction tank was poured with 100+1 ml of ethyl acetate, and 41 layers were separated. If this is dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure, the melting point is 174.5-175.5.
DL-N-(β-2-furyl acryloyl)glutamic acid 5.5 y (yield 52%) was obtained. (21DL-N-(β-2-furyl acryloyl)glutamic acid 52 to methylene chloride 100rn!.9D?
After IA, add 7 ml of triethylamine to dissolve the melt. The solution was cooled to -20 to -15°C, 4.61 ml of ethyl chlorocarbonate was added dropwise, and after reacting for 30 minutes, 3.12 ml of dimethylamine hydrochloride was added, and at the same temperature. Let react for 2 hours. After the reaction is completed, the reaction solution is diluted with hydroxide)
IJum water soluble i9.50d, dilute salt vi, 50rn1.
and 50 bottles of water, dried over anhydrous magnesium sulfate, and then distilled off the solvent under reduced pressure.
DL-2-(β-2-furylacrylamide) + Nl, Nl, N5°N5-7") exhibiting 180°C
3.5 y of lamethylpentane-1,5-diamide (yield 55%) is obtained. Elemental analysis value (c,, H2S N3 o, )C(to)
H (to) N% Calculated value 59,79 7.21 13.08 Actual value 5
9,93 7.3213.09NMR(CDCIB)δ
Value; 1.5-2.7 (4H, m, >CH2X2),
2.93 (6H, 8°-CH, K2), 3,00 (
3H,S, -CH5)+3.24(3H1s,
-CH3), 5.16 (IH, m, CH),
6.34-6.52 (2H, n), Furan + pHX
2), 6.55 (IH, d, -CH=)
, 7.34 (IH, d, -C, HF ・)+
7.41 (IHI S + furaso ring H), 7,7
4 (1) (, a, NH) IR (KBr) on-'
: 'NH3310 SI:=Q 1660. 1640. 1615 Example 4 T'1T (1) 6.5f of L-glutamine was dissolved in 45ml of IN-sodium hydroxide aqueous solution and 50ml of diethyl ether, and stirred vigorously at -10 to -15°C. 9 g of acrylic acid chloride was mixed with 25 g of diethyl ether.
Solution dissolved in step 1 and IN-sodium hydroxide aqueous solution 60
mfl was added dropwise at the same time in 1 hour. After the dropwise addition is completed, the reaction is allowed to proceed for 1 hour, and the aqueous layer is separated. This was adjusted to pH 5.5 with 6N hydrochloric acid, washed three times with 50 ml of ethyl acetate, adjusted to pH 4.5 with 6 N salt r2, and washed with 50 ml of ethyl acetate. The solution is then adjusted to plI 2 with 6N acid and extracted twice with 50me of ethyl acetate. 1()) After drying several layers over anhydrous magnesium sulfate, the melt is distilled off under reduced pressure, and the melting point is 163-164°C.
L-N-(β-2-furyl acryloyl)glutamine 3
zr (yield 10%) is obtained. (21L-N-(β-2-furyl acryloyl)glutamine 1,1 f was dissolved in anhydrous methylene chloride 27,5 td and triethylamine 0.69 ml!, -15
Add 0.44 me of ethyl chlorocarbonate at ~-20°C. After reacting at the same temperature for 1 hour, 0.68 yd of di-n-propylamine was added, and the reaction was continued at the same temperature for 1 hour and at room temperature for 2 hours.
Allow time to react. After the reaction is complete, pour the reaction solution into water 10m/,
After washing with 10 tons of 0.5N hydrochloric acid, 10 tons of saturated sodium bicarbonate aqueous solution, and 10 tons of saturated brine, and drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain a melting point of 152. D indicating 5-153℃
I, -2-(β-2-furylacrylamide) Nl
, Nl-di-n-propylpentane-1,5-diamide 0,25y (yield 17X) is obtained. NMR (CDCIA) δ value; o, 56 (3rt, t, -CH3), 0.93 (
3H,t, -CH5Ll, 20-2-65 (sII
, m, >CH,, K4), 2.65-3.85
(411, m, ; CH2X2 ) + 5.20 (
IH, m, 9CH). 8.11 (IH, d, NH) I R (K13
r) cm-'; νNI,, 3400,3
260.3190 C engineering 01670. 1630 Example 5 (1) DL-N-(β-2-furyl acryloyl) glutamic acid dissolved in 20πe of acetic anhydride! let 15
The mixture is heated at 100° C. for minutes and excess acetic anhydride is distilled off under reduced pressure to obtain DL-N-(β-2-furyl acryloyl)glutamic anhydride. This was added to a mixture of 5 ml of di-n-propylamine and 5 nIe of water under water cooling, and reacted for 2 hours. When the reaction is complete, the reaction solution is adjusted to pH 4 with diluted hydrochloric acid, extracted twice with 20% of ethyl acetate, and the organic layers are combined and dried over anhydrous sulfuric acid. When the solvent is distilled off under reduced pressure, DL-N? exhibits a melting point of 30 to 131°C. -(β-2-Furyl acryloyl) -Nl, N1-Jeep I: +piru α-glutamylamide 42 (yield 62%) was converted to 1-1. (21DL-N2-(β-2-furyl acryloyl)-
N', Nl-di-n-propyl-α-glutamylamide 4y was dissolved in methylene chloride 100-, and ~
Triethylamine 1.32 and chloroethyl carbonate 1.42 were sequentially added dropwise at 25 to -20°C, and after reacting for 30 minutes, diethylamine 17 was added dropwise at the same temperature, and further 1.
Allow time to react. Then, when post-treated in the same manner as in Example 1-(4), DL-2 having a melting point of 117 to 117.5°C is obtained.
-(β-2-furylacrylamide) N5, N
5-diethyl-Nl. Nl-zyl n-furobylpentane-t,s-diamide 3,2y (yield 70%) is obtained. Elemental analysis value (C22H3, N304) C (to) H (to) N (to) Division value 65.16 8,70 10.36 Actual value
65,45 8,85 10.42NMR (CDCI
g) δ value; 0.60-1. ,10 (12H,m, -CH5X4
), 1.40-2.70 (8H, m, n CI (2
X4), 2.70-4.40 (8H, m.>CH, N4), 5.20 (IH, m, 9cn),
6.52-6.65 (2H, m, Furan 1Iix2
), 6.59 (IH, d. -CH=), 7.52 (n+, d, -CH=)
, 7.57 (IH.i, Francff1H), 7.65 (IH,d,NH)IR(KBr)cm-'; The following compounds in Table 3 were obtained using Production Methods 1 to 4. Me: methyl group, Et: ethyl group, n-Pr: n-
Propyl group, n-+3u: n-butyl group, Ph: phenyl group, 2: benzyloxycarbonyl group (blank below) Formulation Example I DL-2-(2-furan acrylamide) Nl. Nl, N', N'-tetramethylpentane-1
, 5-diamide 10y1 lactose 140 f , starch 4
52 and Talc 52 are mixed to produce 1000 capsules. Formulation example 2 DL-2-(2-benzofuran acrylamide) N
5, %-dimethyl-N', N'-di-n-propylpentane-1,S-diamide 10%, cornstarch 25v, crystalline cellulose 10f, lactose Zo. 2 and 1.52 of magnesium stearate,
1000 tablets, patent applicant featuring tablets Toyama Chemical Industry Co., Ltd. C07C103/84 737
5-4HC07D 211156
7138-4C2111587138-4C 2131567138-4C 213/81 7138-4
C231/12 6779-4
C2411046970-4C 2791067330-4C 295/10 6917-4
C295/20 6917-4
C3071546640-4C 307/79 6640-4
C309/38 7169-4
C311/12 7169-
4 C333/24 8214
-4 C333/38 821
4-4 C333/60 82
14-4 CI/C07D 233/64
7133-4C2611067166-
4C 263/30 7166-4
C2751027330-4C 277/20 7330-4
C0 Inventor Hirai Dobe 4-33-3 Tabatashinmachi, Toyama City 0 Inventor Takuya Kodama 1-6-2 Shimookui, Toyama City 0 Inventor Hiroshi Hirano 4-21 Chuocho, Oyabe City 0 Inventor Yasuo Kiba 35-42 Shimotomii, Toyama City 0 authors Mikio Kurobe Kata Fabric 226 0 authors Tatsuya Miyaura 212-6 Mizuhashidatecho, Toyama City 0 authors Yasuyuki Suzuki 476-9 Nunoichi, Toyama City Procedures Corrections Showa July 7, 1959 Commissioner of the Japan Patent Office 1 Indication of the case Patent Application No. 101711 of 1981 2 Name of the invention N-acyl acidic amino acid diamide liquor and its manufacturing method, and anti-ulcer agent containing them 6 Make amendments Relationship with the case Patent applicant address: 3-2-5-4 Nishi-Shinjuku, Shinjuku-ku, Tokyo 160
Amendment Order 1-1 Attachment 6 Contents of Amendment CI) Amendment to the bucket of “Detailed Description of the Invention” in Mei Po 111 (Remei 4+11, page 60, 2nd line from the bottom “n-Bu:n
-butyl group," was changed to "1-pr: 1so-propyl group, n-Bu:n-butyl group, 1-Bu:1so-
Butyl group, t-Bu: tert-butyl group, n-A
m: n-7 mil group, l-Am: 1so-y mil group,
n-Hex: n-hexyl group,” is corrected. (2) Add the following table to the end of Table 6 on page 68.

Claims (1)

[Scope of Claims] (1) N-acyl acidic amino acid diamides represented by the general formula and salts thereof. (21R' and R2 are the same or different and are a hydrogen atom or an alkyl group (N-acyl acidic amino acid diamides and salts thereof according to claim 11). N-acyl acidic amino acid diamides and salts thereof according to claim 1 or 2, which are hydrogen atoms or alkyl groups. N-acyl acidic amino acid diamides and salts thereof according to claim (1) or (2), which are a polycyclic heterocyclic group having or having a nitrogen atom where 51R' and R4 are adjacent N-acyl acidic amino acid diamides according to claim (4), which together with a substituent (.pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl group). (6) A is N-acyl acidic amino acid diamides according to any one of claims (1) to (5), which are alkenylene groups with or without substituents. N-acyl acidic amino acid diamides according to claim (6). (Claims (1) to (1) in which 81R5 is a heterocyclic group with or without a substituent) N-acyl acidic amino acid diamides according to claim 1. (9) N-acyl acidic amino acid diamides according to any one of claims 1 to 8, wherein n is 2. (4) General formula N-acyl acidic amino acid diamides represented by the general formula %, characterized in that the compound represented by the general formula % or its salt is reacted with the compound represented by the general formula % or its reactive derivative in the carboxyl group. (11) A method for producing a compound represented by the general formula %, which is characterized by reacting a compound represented by the general formula % or a reactive derivative of its carboxyl group with an amine represented by the general formula %. A method for producing N-acyl acidic amino acid diamides. 02 A method for producing N-acyl acidic amino acid diamides, characterized by reacting a compound represented by the general formula or its reactive derivative at the carboxyl group with an amine represented by the general formula. - A method for producing acyl acidic amino acid diamides. (L3) A method for producing acyl acidic amino acid diamides, characterized by reacting a compound represented by the general formula % or a reactive derivative thereof in the carboxyl group with an amine represented by the general formula. A method for producing N-acyl acidic amino acid diamides expressed by the formula %. (14) An anti-ulcer agent containing an N-acyl acidic amino acid diamide represented by the general formula %.