JPS63101322A - Thromboxane a2 receptor antagonist - Google Patents

Abstract

PURPOSE:To provide the titled antagonist containing a quinone derivative having bulky group on the alpha-carbon of a side chain or its hydroquinone compound as an active component, resistant to inactivation by metabolism in living body and capable of keeping effective drug concentration in blood over a long period. CONSTITUTION:The objective agent contains a quinone derivative of formula [R<1> and R<2> are methyl, methoxy or together form -CH=CH-CH=CH-; R<3> is (substituted) phenyl, naphthyl or thienyl; R<4> is carboxyl or a group which can be converted to carboxyl group in living body; n is 3-15] or its hydroquinone compound, e.g. 7-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-7-phenylheptanoic acid, as an active component. The agent is useful as a remedy and preventive for diseases caused by the insulfficiency or disorder of the function of circulation system or peripheral circulation system. It is convenient to administer 0.1-20mg/kg weight of the active component once or twice a day in the case of oral administration to an adult patient.

Description

[Detailed Description of the Invention] [Industrial Application Field] The present invention is based on circulatory system and terminal circulatory system dysfunction or disorder in organs such as the brain, heart, lungs, kidneys, liver, stomach, and intestines. This invention relates to non-prostanoid thromboxane A, a receptor antagonist, which has therapeutic and preventive effects on various diseases.

[Prior Art] Among the compounds that antagonize the thromboxane At receptor, many compounds that structurally belong to the prostanoid system are known, but examples of compounds that belong to the non-prostanoid system are extremely limited. Compounds belonging to the former category are generally prostaglandins in structure.

Because it is similar to thromboxane A, the synthesis process is long and complicated, and it is susceptible to inactivation due to metabolism, so it is not fully satisfactory in terms of medicinal efficacy and pharmacology.

On the other hand, non-prostanoid thromboxane A.

Receptor antagonists include, for example, sulfonamide compounds [P
, E. 0sborn, M. A. Wasser
man, Pharmaco-1ogist, 26.1
56 (1984): K., Stegmeier, J.
, Pill.

B., Mueller-Beckmann, F.
Schmidt, E., C., Witte.

II, P. Wolff, Il, I'a
tscheke, Thromb, Res,,
35°379 (1984); ni', Stegmeie
r, J, Pill, B, Mueller-
Beckmann, G., 5poner, H.
, Patschke, Int.

Conf, Leuk, Prost, 1le
a1. Dis, Abstract.

1), 10 (1985)] and tetrahydroisoquinoline compounds [A, Mukhopadhyay, S, S
, Navran, tl., M., Am1n.

S, A, Abdel-aziz, J, Chan
g, D, J, 5ober, D.

D, Miller, D, R, Feller, J
, Pharmacol, Exp.

Ther,, 232. (1985)] is only known.

[Problems to be Solved by the Invention] The present invention provides a novel non-prostanoid thromboxane comprising thromboxane A, a receptor or prostaglandin I-1, a quinone derivative or a hydroquinone derivative that antagonizes the receptor. A. It provides a receptor antagonist.

[Means for Solving the Problems] The present invention is directed to the general formula (wherein R' and R' represent a methyl group or a methoxy group, or R1 and nt are bonded to each other and R1 and R2 are -CH=
CH-CI- (= CH-. R3 is an optionally substituted phenyl, naphthyl or dienyl group, R4 is a carboxyl group or a group that can be converted into a carboxyl group in vivo, and n is 3 to 15 This is a thromboxane A2 receptor antagonist comprising a quinone derivative represented by (indicates an integer of ) or its hydroquinone form as an active ingredient.

In the general formula (Ia), the naphthyl group represented by R3 is 1- or 2-naphthyl, and the chenyl group is 2-
Or 3-chenyl is mentioned.

Phenyl, naphthyl, and dienyl represented by R3 may have 1 to 3 substituents at any position on the ring, and examples of such substituents include methyl, methoxy, methylenedioxy, trifluoro, etc. Methyl, fluor, chlor,
Examples include bromine and hydroxyl groups, among which furor,
Methyl is preferred.

Examples of the hydroxyl group represented by R4 that can be converted into a carboxyl group in vivo include methyl, optionally substituted hydroxymethyl, and optionally esterified or amidated carboxyl group. Examples of optionally substituted hydroxymethyl groups include unsubstituted hydroxymethyl groups, as well as methoxycarbonyl, acetoxymethyl, nitroxymethyl, aminocarbonyloxymethyl, etc., and esterified carboxyl groups include:
Examples of carboxyls in which lower alkoxycarbonyl such as methoxycarbonyl and ethoxycarbonyl may be amidated include aminocarbonyl, hydroxyaminocarbonyl, methylaminocarbonyl,
Examples include trimethylaminocarbonyl.

A quinone compound means a compound represented by the general formula (in the formula, each symbol has the same meaning as above).

The compounds represented by formulas (Ia) and (Ib) according to the present invention can be produced by any of the methods described in JP-A No. 61-44840, for example, by using the following reaction steps. Can be done.

+10 (II) ([) Acid catalyst
Oxidation -> (1b) -> (Ia) (In the formula, each symbol has the same meaning as above.) The above formula (I
The quinone derivative represented by a) has the formula (I b) in vivo.
These compounds can be biochemically interconverted with the hydroquinone derivatives represented by , and these compounds can be considered to be equivalent in both physiological and pharmacological senses.

In order to discover the receptor antagonism of thromboxane A in an in vitro experimental system, it is essential that R4 be a free carboxyl group, whereas in an in vivo experimental system, Now, R4
If is a carboxyl group or a group that is converted to a carboxyl group by oxidation (e.g., ω-oxidation, β-oxidation) or hydrolysis reaction in vivo, thromboxane A, receptor antagonism shows.

In the above compound (I a) or (Ib), R3 is phenyl, 3- or 4-methylphenyl, 3- or 4
-fluorophenyl, 2-chenyl, 3--! -Enil,
Compounds in which R4 is a carboxyl group or hydroxymethyl and the number (n) of methylene groups is an integer from 5 to 9 are more preferred as the object compounds of the present invention.

In living organisms, thromboxane A is biosynthesized mainly in platelets or leukocytes from arachidonic acid via prostaglandin H1. Thromboxane A.

The physiological effects of prostaglandin H1 include strong platelet aggregation and vascular or bronchial smooth muscle contraction at extremely low concentrations. For example, it is well known that thromboxane A production is generally increased in patients with thrombosis, myocardial infarction, cerebral infarction, arteriosclerosis, diabetic hypertension, asthma, etc. . Therefore thromboxane A
Compounds that antagonize the receptors for , or prostaglandin H, may inhibit, for example, vasoconstriction, vasospasm, platelet aggregation,
Antithrombotic agents, antivasoconstrictor agents, antihypertensive agents, antihypertensive agents for the treatment and prevention of various diseases based on thrombosis, airway constriction, etc.
It is thought to be used as an anti-asthmatic agent and an anti-arteriosclerotic agent.

The compounds according to the invention inhibit platelet aggregation caused by arachidonic acid, collagen, adenosine diphosphate (ADP), platelet activating factor (PAF), etc., and also thromboxane A.

or U-440, a prostaglandin H3 analog known as a substance that causes platelet aggregation, airway narrowing, and vasoconstriction through prostaglandin H2 receptors.
69 or U-46619.

In addition, it shows an improvement effect on the occurrence of arrhythmia and infarction in a rat cardiac ischemia-reperfusion model. Furthermore, it shows an effect of improving pre-ischemic function in rats and an effect of improving cerebral ischemic attack in spontaneously hypertensive rats.

The compounds of the present invention have low toxicity and can be used as is or in pharmaceutical compositions mixed with known pharmaceutically acceptable carriers, excipients, etc. [e.g., tablets, capsules (including soft capsules and microcapsules), liquid preparations, injections] It can be safely administered orally or parenterally as a drug or suppository.

The dosage varies somewhat depending on the subject, administration route, symptoms, etc., but for example, when orally administered to an adult patient, the usual dose is about 0.1 mg/kg to 20 mg/kg.
mg/kg body weight, preferably 0, 1 mg/
It is convenient to administer about 10 mg/kg body weight about 1 to 2 times a day.

Compounds (Ia) and (Ib) of the present invention have a bulky group at the alpha (α) carbon position of the side chain of the quinone nucleus or hydroquinone nucleus, and have an asymmetric center. The action of thromboxane A or prostaglandin H2 receptor antagonism is particularly strong in one of the optical isomers due to this asymmetric center. Since the optical isomer, which does not exhibit receptor antagonism, does not exhibit any effects similar to those of thromboxane A or prostaglandin Hz, racemic compounds pose no particular problem in terms of their medicinal efficacy.

The structure of the compound of the present invention has a bulky group at the alpha carbon position of the side chain, making it less susceptible to inactivation reactions due to in vivo metabolism. It exhibits excellent medicinal efficacy with low medicinal value. .

[Experimental Examples] The test compounds in the following experimental examples are those listed in Table 6.

Experimental Example I Thromboxane A, receptor antagonism Suppressive effect on U-44069 contraction of rabbit aorta piece Experimental method, spiral strip of rabbit thoracic aorta (width 2-3
mm, length 3 cm), 95% 0. -25 Krebs -Hen5ele saturated with 5% CO gas mixture
A load of 2 g was applied and suspended in the IT solution. A prostaglandin that has the same effect as thromboxane A.
1. Analogs U-44069 (5Z, 9a, Ila.

13E,I5S)-15-hydroxy-9,11-
The inhibitory effect of 30 minutes pretreatment with the test compound on the contraction reaction of vascular strips caused by the addition of 10-'M of (epoxymethano)brostar 5.13-dienoic acid (manufactured by Upjohn, USA) was investigated.

The experimental results are shown in Table 1 in terms of inhibition rate.

Table 1 Experimental Example 2 Thromboxane A, receptor antagonism (inhibition of U-44069 aggregation of guinea pig platelets) Experimental method: Blood was collected from male guinea pigs by cardiac puncture. When blood was collected, 3.15% citric acid (10% of the blood volume was added to the syringe in advance) was used as a blood coagulation inhibitor. Blood was centrifuged at 300 Or, p, m, for 5 seconds to separate platelet-rich plasma (PRP), and then centrifuged at 300
r, p, m, centrifuge for 10 minutes to remove platelet plasma (I)P
P) was isolated. PRP was diluted with PPP and the platelet count was 4.
The temperature was adjusted to 50,000 μC-'. PRP
Born's method [Nature,
194.927 (1962)] L: The aggregation ability was examined using a Catch platelet aggregometer (Rika Denki). U-44069 (3XIO''7~10-'M) as aggregation inducing agent
, arachidonic acid (0,6mM), :] lagen (1-7
μg/form) and ADP (0.3μ to 3M) were used.

The sample was added in two directions to which these inducing agents were added, and the inhibition rate against aggregation was determined.

The experimental results are shown in Table 2. Compound number 5 is U-
44069 aggregation was inhibited by lo-6 to 3XIO-7M, and arachidonic acid and collagen aggregation were similarly inhibited. In addition, secondary aggregation caused by ADP was carefully suppressed.

Table 2 Experimental example 3 using various aggregation-inducing agents for guinea pig platelets
Inhibitory effect of ['l-1]-〇-46619 on the specific binding of platelet thromboxane A to its receptor Experimental method: Using a syringe containing 0.315% citric acid at a final concentration, guinea pigs and human Blood was drawn.

The blood was centrifuged at 3000° r, p, m, for 5 seconds to separate platelet-rich plasma (PRP), and the two aliquots were further centrifuged at 300° r, p, m, for 5 minutes to separate platelet pellets. It was diluted with 25mM Tris-HCl buffer solution and adjusted so that the platelet count was 660,000 μQ'' for guinea pigs and -1,40,000 μQ'' for humans. This 460μ was fractionated into a tube, and a fixed concentration of the specimen (20μQ) was added thereto and reacted at 25°C for 6 minutes (only 20μQ of buffer was added to the control group). Then [
3■] Cor U-46619, manufactured by New England Nuclear Co., USA, 20 μe.

After adding 60,000 to 140,000 dpm) and reacting for another 6 minutes, vacuum filtration was performed using a glass filter, the filter was thoroughly washed, and the radioactivity on the filter was measured using a scintillation counter. Nonspecific binding of ['H]-U-46619 to platelets was determined from binding in the presence of 10''M unlabeled U-46619.

Experimental results: Shown in Table-3. In guinea pig platelets, compound-5 dose-dependently inhibited the specific binding of [3H-co-U-46619 at 1O-9 to 10''8 M, and its I
Cs. The value (analyte concentration that inhibits binding by 50%) is 7.4
It was XIO″″9M. On the other hand, compound-5 showed 75% inhibition at 10-''M in human platelets.

Table 3: Specific binding of [3H]-U-46619 Experimental example 4 Improving effect on ischemic renal function in rats Experimental method: The unilateral renal artery of rats paralyzed with pendoparbital (50 mg/kg, intraperitoneal injection) was The cells were tied for 1 hour to induce ischemia, blood flow was resumed, blood was collected 24 hours later, and plasma creatinine and plasma urea nitrogen, which are indicators of renal function, were measured using commercially available measurement kits.

Samples were taken 1 hour before renal artery ligation and 20 hours after blood resumption.
It was administered orally in divided doses.

Experimental Results 2 Table 4 shows the results of Compound-5.

Compound-5 significantly suppressed increases in plasma creatinine and plasma urea nitrogen that occur after ischemia-reperfusion by oral administration of 20 mg/8.2 times.

Experimental Example 5 Compound-5 or water was orally administered to spontaneously hypertensive rats (male, 23-24 weeks old) at a dose of 5 d/kg, and 1 hour later the rats were anesthetized with bendoparbital (50 mg/kg, intraperitoneal injection). did. Immediately after bilateral common carotid arteries were ligated, the time until seizures (spasticity, jumping, etc.) occurred was measured, and the incidence of seizures up to 3 hours after ligation was determined.

Experimental Results 2 Tables 5 to 5 show the results of Compound-5.

Oral administration of Compound-5 at 3 and 20 mg/kg significantly prolonged the time until onset of cerebral ischemic attack and completely suppressed the attack incidence.

(): Number of cases; vs. control group *p<0.05゜*$p
<0.010 Reference example 1 7-hydroxy-7-phenylhebutanoic acid (42.2g
, 0.190 mol) and 2.3.5-trimethylhydropenzoquinone (28.9 g, 0.190 mol) were added with dry toluene (570 d) and stirred at 60°C. This was added to trifurinated diethyl ether (8.1 g,
0.19 x 0.3 mol) was added dropwise over 20 minutes, and then 6
Stirring was continued for 2.5 hours at 0°C. The solvent was removed under reduced pressure;
Dissolve the residue in tetrahydrofuran (300rrf),
Ferric chloride (102.6g, 0.190X2mol),
A water (300%) solution was added, and the mixture was stirred at room temperature for 30 minutes.

Tetrahydrofuran was removed under reduced pressure, and the resulting ethyl acetate layer was thoroughly washed with saturated brine and dried over magnesium sulfate. Silica gel (Merck, Art, 7734.19
0g) and eluted with ethyl acetate (570ml). The desired yellow fraction was collected, and after the solvent was evaporated, the yellow-orange precipitated crystals were washed with isopropyl ether (250d) to give the crude product (49g, 73ml). %) was obtained, which was mixed with ethanol (25%).
07J) to obtain 7-(3,5,6-drimedyl-1,4-benzoquinon-2-yl)-7-phenylhebutanoic acid (Compound 5,43, 1 g, 64%).

The physicochemical constants are shown in Table-6.

Reference Example 2 7-Hydroxy7-(4-fluorophenyl)hebutanoic acid (2.4 g, IO, Ommol) and 2-methylhydronaphthoquinone (1,74 g, IO, OrIImo
Dry toluene (31) was added to l) and stirred at 60°C.

To this was added p-1-luenesulfonic acid-hydrate (0.57 g).

30 mmol) was added thereto, and stirring was further continued at 60° C. for 3 hours. After the reaction, it was cooled in air and tetrahydrofuran (
30d) and ferric chloride (5.4g, 20ml1lol)
A water (30%) solution was added, and the mixture was stirred at room temperature for 30 minutes.

The organic solvent was removed under reduced pressure, and an ethyl acetate layer was added to the residue for extraction. The organic layer was thoroughly washed with saturated brine and dried over magnesium sulfate. Silica gel (manufactured by Merck & Co., Ltd., Art,
7734.20g) and eluted with ethyl acetate (70d). The desired yellow fractions were collected, and after the solvent was removed, the yellow-orange precipitated crystals were washed with isopropyl ether (25d) to obtain a crude product (2.5 g). Add this to ethanol (
Recrystallize from 7.20d). -(3-methyl-1,4-
Naphthoquinon-2-yl)-7-(4-fluorophenyl)heptanoic acid (compound-3, 2, 25 g, 57%) was obtained. The physicochemical constants are shown in Table-6.

Reference Example 3 According to Reference Example 1 or 2 above, Compound No. 1.2.
Compound No. 12 was synthesized from Compound No. 4 and Compound No. 6.

The physicochemical constants are shown in Table-6.

(Margin below)

Claims (1)

[Claims] General formula▲ Numerical formula, chemical formula, table, etc.▼ (In the formula, R^1 and R^2 represent a methyl group or a methoxy group, or R^1 and R^2 are bonded to each other.) R^1 and R^2
represents -CH=CH-CH=CH-. R^3 represents an optionally substituted phenyl, naphthyl or thienyl group, R^4 represents a carboxyl group or a group that can be converted into a carboxyl group in vivo, and n represents an integer of 3 to 15. Thromboxane A_2 comprising a quinone derivative represented by ) or its hydroquinone form as an active ingredient
Receptor antagonist.