JPS59206359A - 2-butene compound - Google Patents

Abstract

NEW MATERIAL:A 2-butene compound shown by the formula I (R is H, or CH3) or its acid addition salt. EXAMPLE:trans-1,4-Bis[(2,6-dichlorophenyl-2-imidazolin-2-yl)amino]-2-b utene. USE:A drug acting on circulatory organs. Useful as a preventive and remedy especially for cardiac incompetence, diseases of coronaria, or arrhythmia of heart, and an antiphlogistic. A does is 0.01-10mg/weight kg/day. PREPARATION:A 1,4-dihalo-2-butene compound shown by the formula II (Hal is halogen of Cl, Br, or I) is reacted with 2-(2,6-dichlorophenyl)aminoimidazoline (2) in a reaction solvent in the presence or absence of a dehydrohalogenating agent at 10-100 deg.C for 3-50hr to give a compound shown by the formula I .

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel 2-butene compound having the general formula (where B represents a hydrogen atom or a methyl group). In the present invention, the 2-butene compound represented by formula (I) may be either a cis form or a trans form. These may be in the form of addition salts with physiologically acceptable acids.

The compound of the present invention is useful as a drug that acts on the circulatory system, and is particularly useful as a prophylactic/therapeutic agent for heart failure or coronary artery disease or cardiac arrhythmia. It can also be usefully used as an anti-inflammatory agent.

Compounds of formula (I) may, for example, have the general formula aal! -an2a-auau2-Haf
(n) a 1,4-dihalo-2-butene compound [in the formula, Hal represents a halogen atom such as a chlorine atom, a bromine atom, or an iodine atom, and R has the same meaning as defined in formula (1)]; It can be obtained by reacting 2-(2,6-cyclophenylinaminoimidazoline (2)) in the presence or absence of a dehalogenating agent.

To explain the above reaction in more detail, the reaction solvent is:
alcohol such as methanol or ethanol],
A non-aqueous polar solvent such as tetrahydrofuran is suitable, and an alkali metal carbonate, bicarbonate, etc. can be used as the dehydrogenating agent. The reaction temperature is preferably 100C to 100C, but considering the by-products of colored substances, it is better to keep it in the range of 20C to 50"C.The reaction time is determined by the reaction temperature, dehalogenating agent Depending on the presence or absence or the type of sybaride used, 3 o'clock to 1
It varies from 4 to 50 hours.

When the above reaction method is followed, a compound in which the cybaride is substituted with the bridging nitrogen atoms of the imidacilline compound is obtained.

Any compound of general formula (I) of the present invention can be converted into a physiologically acceptable acid addition salt according to a conventional method. Suitable acids for salt formation include mineral acids such as hydrochloric, hydrobromic, hydroiodic, hydrofluoric, sulfuric, phosphoric or nitric acids, or mineral acids such as oxalic, malonic, succinic, glutamate, etc. /l/acid, maleic acid, fumaric acid, lactic acid,
tartaric acid, citric acid, malic acid, gluconic acid, benzoic acid,
Organic acids such as phthalic acid, cinnamic acid or ascorbic acid.

In addition, when the product of the above reaction is collected in the form of a salt of halogenated water, this salt is reacted with an appropriate acid among the above without desalting, and other It can lead to salt.

The compounds of the present invention can be administered to animals and humans either neat or together with conventionally known pharmaceutical carriers. The dosage unit form is not particularly limited and may be appropriately selected and used as required. Examples of such dosage forms include oral preparations such as tablets, capsules, granules, and various oral liquid preparations, and parenteral preparations such as injections and suppositories. The amount of the active ingredient to be administered is not particularly limited and may be appropriately selected from a wide range, or the amount of the active ingredient to be administered may be 1.
A daily body? It is preferable to use 0.01 to 10 vIg per a I Kli. Also, 0.1% of the active ingredient in dosage unit form.
It is preferable to contain up to 500 μm. Regarding these dosages, depending on the type of the disease and the patient's condition, it is possible to increase the therapeutic effect of the active ingredient of the present invention by using other drugs in combination as necessary.

In the present invention, oral preparations such as tablets, capsules, and oral liquid preparations are manufactured according to conventional methods. That is, tablets are prepared by mixing the compound of the present invention with pharmaceutical excipients such as gelatin, starch, lactose, magnesium stearate, talc, and gum acacia. Capsules are prepared by mixing the compound of the present invention with an inert pharmaceutical filler or diluent, and filling the mixture into hard gelatin capsules, soft capsules, or the like. When molding into a suppository, a wide range of conventionally known materials can be used as the phase, such as polyethylene C-glycol, cacao 11, higher alcohols, esters of higher alcohols, gelatin, and semi-synthetic materials. You can open glycerides, etc. If EJA is manufactured as an injection, '1
The GI agent and suspension agent are preferably sterilized and isotonic with blood, and when forming these into the form of a powder, emulsion, or suspension, a diluent commonly used in this field may be used. All can be used, such as water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated instearyl alcohol, and polyoxyethylene sorbitan fatty acid esters. 2. In this case, the preparation may contain a sufficient amount of salt, glucose, or glycerin to make an isotonic solution, and the usual solubilizing agents, buffers, soothing agents, etc. may be added. You may. Further, if necessary, coloring agents, preservatives, perfumes, flavoring agents, sweeteners, etc. are added.The present invention will be explained below with reference to Examples.

Example 1 7.5 g of trans-1,4-bis[(2,6-cyclophenyl-2-imidacylin-2-yl]amino]-2-butene of 2-(2,6-dichlorophenyl)aminoimidase Phosphorus (20 liters of ethanol solution containing 21
．． A 20 me ethanol solution containing trans-1,4-dibromo-2-butene of No. 66 was added, and the mixture was reacted at room temperature for 500 hours. After removing the ethanol by evaporation, 50% water
mε was added and extracted with 100 mg of ether.

When the raffinate solution (saturated sodium bicarbonate solution was added and the pH was adjusted to 10, white crystals were precipitated. This was separated, dried, and recrystallized from a hexane-methanol mixture, and the above compound was purified by thin layer chromatography. 2: '2, 'obtained.

The melting point and spectral data of the above substance are shown below.

Melting point i 95-98°C NMR spectrum (CD30D, p range; 3.45
('I MN,':A, 8H, N)ノ4.15
(Multiplet, 4H, 0H8) 5.64 (Multiplet, 2H, -0H-) R spectrum (KBr, am) +1618
, 790 Mass spectrum (E, m/s; 51015121514 (M”).

229 (base peak) Example 2 cis-1,4-bis[(2,6-cyclophenyl-2
-imidacillin-2-ylnoamino]-2-butene hydrochloride 5.0 g (7) 2-(2,6-cyclophenylene 1
Lt) Ethanol solution containing aminoimidacyline (2) 40 times Schiff, -1,4-di90o-2-butene 3 times
．． 0OfI was added, and the mixture was reacted at room temperature for 46 hours. After removing the ethanol by evaporation, the residue was washed with ether four times and the remaining colorless crystals were recrystallized from an ether-methanol mixture, yielding 1.6 g of the above compound that was pure in terms of thin layer chromatography. Ta.

The subpoints and spectral data of the above compound are shown below.

Melting point (°C, l; 211-213 NMR spectrum (CD30D, ppm); 3.84 (singlet, 8H
,N)) 4.40 (2i-line, 4H,0H2) 5.84 (multiplet, 2H, -0H-) R spectrum (KBr, am).

1615.785 Example 3 trans-1,4-bis[(2,6-cyclophenyl-2-imidacillin-2-ylnoamino]-2-methy/
I/-2-Butene hydrobromide In a similar manner to Example 2, 5.0 g of 2-(2,6-dichlorophenyl)amino-imidacillin (2) and 2.72. When 1,4-dibromo-2-methyl-2-butene was reacted in 30 g of methanol, the pure above compound was determined by thin layer chromatography. I got Q.

The point and spectrum data of the above ≠I compound are shown below.

Melting point (℃) i 192-194 NMR spectrum (CD30D, 1) Tono; 1.75
(Single line, 3H, aa3) OH3 4,25 (Single line, 2H, -0-0 degrees,) 4.44
(2!i, 2H, -0H-OH2)5.54
(Triple line, in, =OH-) engineering R spectrum (K
Br, am) +1610.790 Mass spectrum (E engineering, m/li; 5241526
(M”).

52315251527 (M-1 Ha296 (Pacebeakts Test Example-1 Cardiac Activity [Experimental Method] Male guinea pigs weighing 300 to 400 g were killed by exsanguination, and atrial specimens were prepared according to a conventional method. 95%02+5
KrebeHen kept at 37°C under %C02 saturation.
The tube was suspended in a Magnus tube filled with Selsit solution.

The reagents to be tested were suspended in a 0.2% OMO solution or dissolved in a nutrient solution and applied.

〔result〕

Table 11 shows the inotropic effect when I x 10-'M was applied.

Table 1 Test Example-2 Acute toxicity test by intravenous administration [Test method] DDY male mice, 5 mice per group, were used. The test drug was 0.
Dissolve in 1N acidic acid, 0.1ml! /10. After intravenous administration for 10 seconds, the progress was observed for 7 days, and the estimated LD
The 5o value was determined.

[Results] The LD5o value of the compound of Example 1 was 6.25 .

Continued from page 1 ■Applicant: Mitsui Pharmaceutical Industries, Ltd. 3-12-2 Nihonbashi, Chuo-ku, Tokyo Procedural Amendment Commissioner: Mr. Kazuinu Wakasugi, Commissioner of the Patent Office 1, Indication of the case, Patent Application No. 82277, filed in 1982, 2, Name of the invention 2-1 Thene compound 3, relationship to the amended case Patent applicant address 1-4 Teppocho, Sakai City, Osaka Prefecture Agent 530 Address 1-3 Quarter, 5-chome Nishitenma, Kita-ku, Osaka City・
One Pill 8, related to any ministerial cases involving amendments other than those mentioned above Patent applicant address: 3-12-28 Nihonbashi, Chuo-ku, Tokyo Name:
Mitsui Pharmaceutical Co., Ltd. Representative Waken Mizuno 1. Correct "dehalogenating agent" to "dehydrohalogenating agent" in the 8th line from the bottom of page 2 of the specification.

2. "Dehalogenating agent 1c" in the 9th line from the top of page 3 of the circular
r dehydrohalogenating agent" [Correction 08, same book, page 5, lines 5 to 8 from the top [i.e., the tablet contains the compound of the present invention as gelatin, starch, lactose, magnesium stearate,
It is mixed with pharmaceutical excipients of talc and gum arabic and shaped. For example, tablets may contain the compound of the present invention, excipients (lactose, sucrose, glucose, starch, microcrystalline cellulose, etc.), binders (starch paste solution, gum arabic solution, gelatin solution, glucose solution, tragacanth solution, CMC liquid, sodium alginate liquid, etc.), disintegrants (starch, calcium carbonate, etc.), lubricants (magnesium stearate,
Purified talc, etc.) may be appropriately selected, mixed, tableted, and then coated. ” is corrected.

4. The following Test Example-8 is added after "The LD5 value of the compound of Example 1 was 6.25 rtqy/Kf" in the fourth to fifth lines from the top of page 12 of the same book.

"Test Example-8 @ Pain Activity [Experimental Method] After fasting overnight, 5-week-old aay male mice were orally administered the test ring, and 1 hour later, 0.1 d of o, os% phenylbenzoquinone was administered per body weight IQy. The drug was administered intraperitoneally. 5 minutes later, the number of nutrettings was counted for 10 minutes to determine the inhibition rate relative to the untreated group.

Table 2

Claims (1)

[Claims] (1) A 2-butene compound having the general formula [wherein R represents a hydrogen atom or a methyl group] or an acid addition salt thereof.