JPS61115022A - Serum lipid depressant - Google Patents

Abstract

NEW MATERIAL:To compound of formula I [A forms a 5-6-membered ring containing S, O or N together with the =C=N- bond, or is -CH=N-R without forming a ring (R is H or group of formula II; R1 is OH, NH2, etc.; R3 is alkylene or phenylene; n is 0 or 1; X is O, S, etc.); B forms a monocyclic group containing -C=C- bond or is R6-CR4=CR5- (R4 and R5 are H, aryl, alkyl, etc.); R6 is OH, mercapto, etc.] and its salt. EXAMPLE:N-2-hydroxymaphyhylmethyleneglycine methyl ester. USE:A serum lipid depressant. It has remarkable serum lipid depressing activity, HDL-cholesterol increasing activity and chelate forming capability, and extremely high safety. PREPARATION:The compound of formula V (a compound of formula I wherein A is thiazoline ring and B is benzene ring) can be prepared in high yield and purity by the deammoniation reaction of 2-hydroxybenzonitrile of formula III with cysteine of formula IV.

Description

[Detailed description of the invention] The present invention relates to novel and useful serum lipid-lowering agents.

Heart disease, particularly coronary artery disease, is the leading cause of death in Western countries. In Japan as well, with the Westernization of dietary habits, coronary artery disease has become a major cause of death and has become a major social problem.

The main causes of coronary artery disease and heart disease are (1) hypertension, (2) hyperlipidemia, and (3) arteriosclerosis. Many drugs and treatments have been developed and put into practical use. However, at present, no effective drugs or treatments have been developed for hyperlipidemia and arteriosclerosis.

In view of this current situation, in order to deal with coronary artery disease, we conducted intensive research to develop an effective serum lipid lowering agent. The present invention was completed after further extensive research was conducted, including compound screening, confirmation of serum lipid-lowering effects, safety checks, and formulation studies.

That is, the present invention is a serum lipid-lowering agent containing a compound represented by the general formula (I) in F, and its salts, esters, and amides as active ingredients.

b) The number of people is 1. Forms a 5- to 6-membered ring containing sulfur, oxygen or nitrogen together with C=N- bond; or does not form a term (represents -CH=N-R; +n C-R1 or +Rus
+1O-R2; I (in the formula, turtle represents a hydroxyl group, alkoxy group, or amino group; in the formula, 2 represents a carbon, sulfur, oxygen, or nitrogen atom; Y represents hydrogen, a hydroxyl group, mercapto, alkyl Base.

Represents an alkoxy group or an alkylthio group.

几represents an alkylene/or phenylene group, n must be 0 or 1.

X represents an oxygen or sulfur atom. )] (9 mouths B
represents a monocyclic or fused aromatic group having a -C=C- bond; or R4R [However, 几4 and islands may be the same or different; Alternatively, it represents an aralkyl group: Horse represents a hydroxyl group, mercapto, alkoxy group or alkylthio group. ” Or, Re is -8°...M/m ・N=C through the metal atom together with the c=N-bond of A.

[However, M represents a metal atom, m represents a natural number, R6 represents the same meaning as defined above, and 10-.

-8-. ] In the active ingredient compound (I) of the present invention, one can
8.0 with N-bond. or 5 containing N atoms
~6-membered ring 19 For example, thiazoline, oxazoline, imidacilline, pyrimidine.

Examples include 4H-1,3-thiazine, 4)1-1.2.5-oxadiazine, etc.Also, humans also represent 10H=N-(Schick's base), but R is + island + nC × In the case of Aya, examples include Aya skeleton or imidacillin.

B represents an aromatic ring having a double bond, such as benzene or naphthalene. It also represents alkyl, aryl, and aralkyl, and examples of f-aryl include phenyl, tolyl, and 7-ethyl groups, and examples of aralkyl groups include benzyl, 7-enethyl, 7/namyl,
Examples of styril fear include OH, 5H.
Examples include 10-alql and S-alkyl groups.

The active ingredient compound of the present invention can be freely obtained in a high yield and in high purity by, for example, the following method.

In the active ingredient compound of the present invention (IJ), for example, when B forms a thiazoline ring and B forms a benzene ring, for example, by removing ammonia from 2-hydroxybenzonitrile and cysteine, R is reduced. Compound CI in which 〇〇もで几 is -OH)
is obtained. When R1 is a lower alkoxy group, the compound CIJ is obtained by esterification with the corresponding alcohol. When the compound is a -CO island, the compound CI,l is obtained by a coupling reaction between the compound obtained by the formula [I] and the amino acid or thiazolidine carboxylic acid corresponding to R1.

When the ring is a thiazoline ring and B is 10=C-, the compound CI,1 can be obtained by deammonifying the imino ether represented by the formula R4all LIJ and cysteine ester or Seri/ester in a solvent.

When R is 100R, a compound obtained from an imino ether and a 7-stein ester or a serine ester may be ester-hydrolyzed by a conventional method, and then a stone may be coupled by a conventional peptide synthesis method. A cysteine derivative to which islets have been coupled in advance may be used to react with an iminoether.

Alternatively, the compound Lij can also be obtained by deanomonizing a nitrile represented by the formula (I[j) and cysteine.

When IJ forms a thick base and B forms a benzene ring, the compound (IJ
is obtained.

Compounds obtained using amino acids or their esters (
I) is -a3-CO, but -R3-COR.

In order to obtain compound CI), it is preferable to synthesize a compound represented by j) NH, -R5-COR, in advance by a conventional peptide synthesis method, and then dehydrate and condense this with salicylaldehyde.

The active ingredient compound (I) of the present invention obtained as described above
J can be isolated from the reaction solution using conventional separation methods such as extraction, condensation, filtration, recrystallization, and column chromatography.

Compounds (when IJ is 10H) can also be isolated in the form of alkali gold PA clay, alkaline earth gold M salt, ammonium salt, triethylamine salt, etc.

The compound (IJ) may exist in 2 to 4 optical isomers depending on the amino acid used as a synthetic material.

Both of these individual isomers and mixtures thereof are included in the compounds of the present invention, and can be isolated individually if necessary. For example, a method of reacting by limiting amino acids, which are synthetic materials, to a single isomer, a conventional separation method for isomer mixtures, a method of generating salts with optically active acids or optically active bases, a column chromatography fractional crystallization method, etc. There are various methods of separating each isomer.

When the active ingredient compound LIJ of the present invention takes the enol form, two forms and eight forms exist depending on the position of the substituent, but as a serum lipid lowering agent, the two forms having a strong quint-forming ability are preferred.

In the present invention, compounds useful as serum lipid-lowering agents include those described below, such as the following.

(1) N-2-hydroxynaphthylmethyleneglycine methyl ester (2) N-2-methoxybenzylidene glycine methyl ester + 3) N-2-ethoxybenzylidene glycine methyl ester (41N-2-propoxybenzylidene glycine methyl ester + 5) N -2-Methylthiobenzylideneglycine ethyl ester + 6) N-2-ethylthiobenzylideneglycinoethyl ester +91N-2-hydroxybenzylideneaminodithioacetic acid tllN-2-hydroxybenzylideneaminothio-8
-acetic acid liυ N-2-hydroxybenzylidene aminothio-
8-Acetate ethyl ester 11JN-2-Hydroxybenzylidene glycinamide t13N-2-Hydroxybenzylidene triglycinamide/V 141N-2-hydroxybenzylidene/Zylidene glycinamide/L-
Methylproline methyl ester u! 19N-2-hydroxybenzylidenecrisyl-L
-Mercaptoproline methyl ester 16) N-2-Hydroxybenzylidene glycol L-methoxyproline methyl ester u7) N-2-Hydroxybenzylidene glycol L-ethylthioproline methyl ester 11
~ N-2-Hydroxybenzylidenegly/ru-L-virolidine-4-carboxylic acid methyl ester 1ilN-2-hydroxy/penzylideneglyne-ruthiazolidine-4-carboxylic acid methyl ester 1A N-2
-Hydroxy 7 penzylidene glycol imidazoline-5
-Carboxylic acid methyl ester 11DN-2-hydroxybenzylidenethiocarbamoyl-L-prolinemethylnisder4 N-2-hydroxybenzylidenecarbamoyl-L-proline methyl ester (c) N-(2-(α-benzyl7-enacyl)thiazoline -4-Sword Rubonyl]-L-Pro9/(To) 2- (
2'-hydroxyphenyl)oxazoline-4-carboxylic acid 1252-(2'-hydroxyphenyl)imidacilline-4-carboxylic acid (c) 2-(2'-hydroxyphenyl)pyrimidine-4-carboxylic acid 2-( 2'-Hydroxyphenyl)4H-1゜3
-Thiasia 4-carboxylic acid 3-(2'-hydroxyphenyl)4H-1゜2
．． 5-Oxadiazine-4-carboxylic acid 1212-(2
'-Methoquinophenyl)thiazoline-4-Bonba... 2-(2'-Hydroxyphenyl)thiazoline-
5-carboxylic acid + 311 2- (2'-hydroxyphenyl) imidacillin-5-carboxylic acid 04 bisacetonylthiazoline zinc-dihys(2-
(2'-Hydroxykphenyl)thiazoline-4-carboxylic acid methylnisder] Zinc (b) 2-(α-methyl 7ena/Lunthiazoline-4-carboxylic acid sodium) 2-7enacylthiazoline-4-carboxylic acid ( -N-(2-(2'-Hydroxycuphenyl)thiazoline-4-carbonyl)-L-hydroxyproline The serum lipid-lowering agent of the present invention can be administered either orally or parenterally.Orally. In the case of administration, it can be administered in the form of soft or hard capsules, tablets, granules, fine granules, or powders, and in the case of parenteral administration, it can also be administered in the form of injections, drops, and suppositories. can do.

When administering the active ingredient according to the present invention to humans, the dosage varies depending on the type of compound, symptoms, and dosage form, but the appropriate daily dose is 920 to 2,000 #Ip91 and usually 50 to
A suitable value is 800 Da.

The lipid-lowering agent of the present invention has low toxicity and extremely high safety, with a content of 5%. That is, 500~io
No abnormalities were observed in rats even after oral administration of oo and da/ro.

+: @Meika@- To formulate the active ingredients of the proboscis, surfactants, excipients, lubricants, flavoring agents, deodorants, layer colorants, flavoring agents, preservatives, and gold are added. Use sticting agents, wetting agents, film-forming substances, coating aids, and other adjuvants as appropriate.

Next, a test method for confirming the lipid-lowering activity of the compound of the present invention will be described.

Test Example 1 Effect of acetonylthiazoline and acetonylthiazoline-4-carboxylic acid on serum lipids in normal rats. @ Before and after saline Wistar 5 Kondo rats were used. Rats were given free access to food and water, and drugs were administered once a day at a dose of 500·d9/#.

Oral administration was continued for 2 weeks. Two hours after the final administration, the rats were decapitated and their serum lipids were measured.As shown in Table 1, acetonylthiazoline lowered serum cholesterol, triglycerides, and free fatty acids to 83.6° of the normal rat values. It was confirmed that acetonylthiazoline has a lipid-lowering effect. Also, as is clear from Table 2, acetonylthiazoline-4-carboxylic acid has a significant effect on serum cholesterol,
HDL-Cho, which is said to significantly reduce triglycerides and free fatty acids and has anti-arteriosclerotic effects.
l t - significantly elevated.

Similarly, the following compounds were confirmed to have a significant wA lipid-lowering effect.

02-(2'-hydroxyphenyl)thiazoline-4-
Carboxylic acid (m, l), 126.6-127.8℃) N −
(2-(2'-hydroxyphenyl)thiazoline-4-
Carbonyl J-L-proline (diastereomer A: m
, p, :ca94℃, [α scale=-224,9°(C:I
CHCA,) diastereomer B:rn, j, :c
a55℃Cab”:=+sy,s°(C=I CHC
1j3)), N-(2-(2'-hydroxyphenyl)thiazoline-4-carbonyl)-L-thiazolidine-4-carboxylic acid (m, p, : ca92°C Ca)":=-s 3.19° (C: ICHCL
'3) )ON -(2-(2'-Hydroxy2enylthiazoline-4-carbonyl)-L-hydroxyproline methyl ester (diastereomer A: (a) p=-++s 1.29° (C =I DM80
) Diastereomer B: (αJi,'=-124.41°(C=I DM, 9
0))ON-(2-(α-methyl7-enacyl)thiacyly/-4-carbonylno-L-proline (m,p,:17
2 to 175℃ [α]y=+1s, a° (C2 1.01N NaOH)
)OL-N-(2-acetonylthiazoline-4-carbonyl)-L-proline (m, p, : 159-162°C (dec, )
) Test Example 2 Effect of acetonylthiazoline and acetonylthiazoline-4-carboxylic acid on serum lipids of triton hyperlipidemic rats The animals used were male Wistar and Kinun-type rats weighing approximately 120 J. Rats were allowed free access to food and water. The drug was orally administered once a day for two consecutive weeks at a dose of 500 da/9. 2 hours after the final dose, Dryde 7-wR-13
39 was injected into the jugular vein at a dose of 400 rnglk4), and 6 hours later, the rats were sacrificed at the stump and serum lipids were measured.

The results are shown in Tables 6 and 4.

Tatsu 6 Cho in serum lipids of Triton hyperlipidemia rats
l(InIIVdl TG(+119/dA Triton group 241°5±11.5 26151
．． 7±265.0 Azoline group Kushi II umbrella p<0.01, Kushi umbrella umbrella p<0.001 V
S Triton group () is a 4-cent table when the Triton group is set as 100.
lOf/d#) TG (In9/dAr) Triton-182.4±12.6"" 1842.5±56
7.5”f Setonirchi (79,7)
(72,7)Azoline-4 Monocarboxylic acid group p<0.02, p<0.01 VS
) As shown in Table 3, the percentages in the Rydon group () are based on the Triton group as 100, acetonylthiazoline had the effect of lowering serum cholesterol and triglyceride even in Triton hyperlipidemia rats. Furthermore, as is clear from Table 4, a similar effect was confirmed for acetonylthiacyly/-4-carboxylic acid. From the above results, it was revealed that the compound of the present invention has a remarkable serum lipid-lowering effect and has an effect of increasing HDL-cholesterol, which has an anti-arteriosclerotic effect. Furthermore, the knowledge that arteriosclerosis can be prevented by preventing the deposition of Ca2+ on the arterial wall (
Scie%ce213 1511-1512.1981
) and the strong chelate formation f@ of this compound, the application of the compound of the present invention to arteriosclerosis can be expected.

Test Example 5 In the same manner as Test Example 1, the effectiveness of the following compounds as serum lipid lowering agents was confirmed.

ON-(2-(2'-hydroxy7phenyl)thiaso I
J-4-carbonyl)-L-proline methyl ester (A: m-p-145, 6-148.6°C (αJ"j
=-201,3℃(C=5,C)(CA3)B
: m, p, 104.0-109.2℃ α] Sweet+36.1℃ (C=5, CHCl,))ON -[
2-(2'-Hydroxyphenyl)thiazoline-4-carbonyl)-L-thiazolidine-4-carboxylic acid methyl ester (m, I) -100.8-105.0°C (aJ%'=
-22,06° (C=1, CHCl5) ON
-(2-(α-Methyl 7-enaflu)thiazoline-4-carbonyl)-L-proline methyl ester (keto form: enol form = 1:1 m, p. 166-167°C [α] kidney = +L5.77° (C=0.58.chloroform))OL-N-(2-acetonylthiacylino-4-carbonyl)-L-proline methyl ester (m, p, 1
77.4-181.5℃ [αJ Amase-250.97° (C=1, CHsOH
) ON-2-Hydroxybenzylidene glycine-methyl ester (m, p, 58-40°C) ON-2-hydroxybenzylidene glycyl-L-hydroxyproline methyl ester (m, p, 128-12
9°C) -N-2-hydroxybenzylideneglycyl-L-7'
Loline methyl ester (m, p, 98-101°C) -N-(2-hydroxybenzylidene)-6-aminopropionic acid (m, p, 133.0-155.0°C) -N-(2-hydroxybenzylidene) )-2-Aminebenzoic acid (m, p, 185.0-190.8°C) Examples of the present invention are shown below.

4 Example 1 Tablet + 1) Acetonylthiazoline 50g (2) Milk $90. @ (3) Corn starch 29g (4) Magnesium stearate 1g 1000 tablets 170.
@ (1) 12) and 17.9 corn starch were mixed together and granulated with starch made from 7y of corn starch, 59 corn starch and (4) were added to the granules, and the mixture was compressed with a tablet machine. Compressed tablet per tablet D(t)
Example 2 Injection (1) Acetonylthiacyly/-4-carvone #R1
0, @ (2) Sodium chloride 9J (3) Chlorobutanol 5g (4) Sodium hydrogen carbonate 1y All ingredients were dissolved in 1000 g of distilled water, and dispensed 1 g each into 1000 brown nozzles,
The entire process of purging with nitrogen gas and sealing is performed under aseptic conditions.

Examples 6 to 9 fl) The following compounds 200 sou each (2
) Lactose 100J (3) Corn starch 80I (4)
Crystalline cellulose ゛ 10011i:i)
Polyvinylpyrrolidone 15g (6) Magnesium stearate 5J1000 tablets 50
0I Mix the above ingredients according to the usual method, make it into granules, compression mold, and make one tablet 500 yen! Prepare 1000 n9 tablets each.

(2) 2-(2'-hydroxyphenyl)imitasoline-5-carboxylic acid (5) Zinc bisacetonylthiazoline.

(Q his(2-(2'-hydroxyphenyl)thiazoline-4-carboxylic acid methyl ester) zinc (6)
N-2-hydroxynaphthylmethylenoglycne methyl ester + 12-(2'-hydroxyphenyl)pyrimidine-4
-Carboxylic acid (1; 52-(2'-hydroxyphenyl) 4H-1゜5-thiazine-4-carboxylic acid (G13-(2'-hydroquinophenyl) 4H-1
.

2.5-Oxadiazine-4-carbon relative Example 10
Capsule il+ 2-(2'-hydroxyphenyl)theazoline-4-carvone cR200p(2) Lactose 1
50g (3) Corn starch 100g (4) Crystalline cellulose 40gt5) Light anhydrous silicone 5I (6) Magnesium stearate 5Jiooo1vA soog According to the material method, the above ingredients were mixed and granulated into 1000 capsules. Nihikotenshi, 111i! ! 5 Q
Prepare capsules of Q hv.

Claims (1)

[Scope of Claims] A serum lipid-lowering agent characterized by containing a compound represented by the following general formula [I] and salts thereof. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [I] In the formula, (a) A forms a 5- to 6-membered ring containing sulfur, oxygen, or nitrogen together with the >C=N- bond; or forms a ring. (In the formula, R_1 is a hydroxyl group, Represents an alkoxy group or an amino group, and R_2 represents the formula shown by ▲There are mathematical formulas, chemical formulas, tables, etc.▼ In the formula, Z represents carbon, sulfur, oxygen, or nitrogen atom; Y represents hydrogen or hydroxyl group , mercapto, an alkyl group, an alkoxy group, or an alkylthio group, R_3 represents an alkylene or phenylene group, n is 0 or 1, and X represents an oxygen or sulfur atom.)] (b) B represents a monocyclic or condensed aromatic ring having a -C=C- bond; or represents ▲a mathematical formula, chemical formula, table, etc.▼ without forming a ring; [However, R_4, R_5 are They may be the same or different and represent hydrogen, an aryl group, an alkyl group, or an aralkyl group; R_6 represents a hydroxyl group, merkabuto, an alkoxy group, or an alkylthio group. ] Or (c) R_6 forms a chelate represented by -R_6...M/m...N=C< together with the >C=N- bond of the A ring via a metal atom. [However, M represents a metal atom, m represents a natural number, and R_6 represents the same meaning as defined above, and further represents -O- or -S-. ]