JPH0529032B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the general formula (In the formula, R is a hydrogen atom or a lower alkyl group, n
represents an integer from 1 to 3) and its salt. (Industrial Application Field) The compound of the general formula () of the present invention has thromboxane A ₂ (hereinafter referred to as TXA ₂ ) synthesis inhibiting action,
It is useful for the prevention and treatment of diseases involving TXA ₂ , such as angina pectoris, ischemic diseases such as myocardial infarction, cerebrovascular disorders, and thrombosis. (Prior Art) TXA ₂ is a physiologically active substance that is biosynthesized from arachidonic acid in vivo. To explain in more detail, arachidonic acid is converted into prostaglandin G ₂ (hereinafter referred to as PGG ₂ ) and prostaglandin H ₂ (hereinafter referred to as PGH ₂ ) by cyclooxygenase. This PGG ₂ ,
PGH ₂ is converted into prostacyclin (hereinafter PGI ₂ ) and prostaglandin E ₂ (hereinafter referred to as PGI 2 ) by various enzymes.
PGE ₂ ), prostaglandin F ₂ α (hereinafter referred to as PGF ₂ α)
and TXA ₂ etc. are produced. Regarding the physiological activities of TXA ₂ , it is known that it has a strong platelet aggregation promoting effect and vasoconstricting effect, and it is known that TXA ₂ production is accelerated in some patients with angina pectoris during an angina attack. (M. Tada et al., Circulation,
64, No. 6, 1107, 1981) Drugs that suppress TXA ₂ production include cyclooxynagase inhibitors such as aspirin and indomethacin, and dazoxiben (4-(2-(1-
_Two TXA inhibitors are known, represented by (imidazolyl)ethoxy)benzoic acid hydrochloride and the like. The former cyclooxygenase inhibitor suppresses the production of TXA ₂ and at the same time inhibits TXA ₂ such as PGI ₂ and PGE ₂ .
It also suppresses the production of other prostaglandins. PGI ₂ has physiological activities that are contradictory to TXA ₂ , namely, strong platelet aggregation inhibition and vasodilation, so suppressing PGI ₂ production is beneficial for diseases such as angina pectoris and myocardial infarction. I can't say that. On the other hand, TXA ₂ synthetase inhibitors suppress the production of TXA ₂ , but rather increase the production of PGI ₂ and PGE ₂ , so the latter is more preferable for ischemic diseases. However, dazoxiben, a known TXA ₂ synthesis inhibitor, also exhibits cyclooxygenage inhibitory effects at higher concentrations. Therefore, more selective
TXA ₂ synthesis inhibitors are desired. The present inventors completed the present invention as a result of intensive studies aimed at improving these drawbacks of conventional TXA ₂ synthesis inhibitors. That is, the present invention relates to a compound of general formula () and a salt thereof. Examples of salts include acid addition salts with inorganic acids such as hydrochloric acid, sulfuric acid, and nitric acid, and organic acids such as fumaric acid, tartaric acid, maleic acid, succinic acid, oxalic acid, benzenesulfonic acid, toluenesulfonic acid, and methanesulfonic acid;
When R is a hydrogen atom, examples thereof include alkali metal salts of the carboxyl group such as sodium and potassium, and alkaline earth metal salts such as calcium and magnesium. The compound of the present invention can be produced by various methods, and representative examples thereof include those shown by the following reaction formula. (In the formula, R' represents a lower alkyl group, X represents a halogen atom or a toluenesulfonyloxy group, and n
is the same as above. ) That is, the compound of formula () is converted into 1H-1,2,4-
By reacting with triazole, a compound of formula () in which triazole is substituted at the 1-position and R is a lower alkyl group can be obtained. Further, at this time, the compound of formula () is obtained as the main product, but it is also possible to obtain a compound substituted with triazole at the 4-position. This compound can be separated by silica gel column chromatography. By hydrolyzing the obtained compound of formula () using an alkali such as sodium hydroxide, a compound of formula () in which R is a hydrogen atom can be obtained. (Effect of the invention) The compound of formula () of the present invention has an excellent TXA ₂ synthesis inhibitory effect, and its activity is known to be
It is more active than the TXA ₂ synthesis inhibitor dixiben, and also has superior selectivity in its inhibitory action against TXA ₂ synthase. The present invention will be explained below with reference to Examples and Test Examples. Example 1 5,6,7,8-tetrahydro-6-(1H-
1,2,4-triazol-1-ylmethyl)
-2-Naphthalenecarboxylic acid ethyl 0.15 g of 50% sodium hydride is suspended in 20 ml of dimethylformamide. Cooled on ice for 1 hour - 1, 2, 4
- After adding 0.19 g of triazole, stir for 0.5 hour. Then 5,6,7,8-tetrahydro-6-
Add 0.97 g of ethyl (p-toluenesulfonyloxymethyl)-2-naphthalenecarboxylate and leave at room temperature.
Stir for 20 hours. The reaction solution was concentrated under reduced pressure, and the residue was extracted with chloroform. The extract was washed with water, dried, and concentrated under reduced pressure. The resulting oil was purified using silica gel column chroma to obtain 0.6 g of the title compound as an oil. NMR (CDCl ₃ ) δ: 1.40 (3H, t, −COOCH ₂ CH ₃ ) 1.6−2.9 (7H, m) 4.21 (2H, d, −CH ₂ −N=) 4.37 (2H, q, −COOCH ₂ CH ₃ ) 7.05-7.2 (2H, m) 7.7-8.2 (3H, m) Example 2 5,6,7,8-tetrahydro-6-(1H-
1,2,4-triazol-1-ylmethyl)
-2-Naphthalenecarboxylic acid monohydrochloride 0.3 g of the ester obtained in Example 1 was heated under reflux for 5 hours with 8 ml of concentrated hydrochloric acid and 8 ml of water. The reaction solution was concentrated under reduced pressure, and the resulting powder was recrystallized from ethanol to obtain 0.45 g of colorless crystals of the title compound. Melting point 194-199℃ NMR (DMSO-D ₆ ) δ: 1.3-2.9 (7H, m) 4.31 (2H, d, -CH ₂ -N=) 7.0-7.1 (1H, m) 7.6-7.7 (2H, m ) 8.36 (1H, s) 9.09 (1H, s) Test example In vitro platelet TXA ₂ production inhibition test Preparation of PRP (platelet rich plasma) Cardiac puncture from male Wistar Kondo rats weighing 280 to 320 g under pentobarbital anesthesia Citrate-added blood (1 volume of 3.13% sodium citrate was added to 9 volumes of blood) was collected at room temperature and centrifuged at 230xg for 7 minutes. PPP the obtained supernatant (PRP)
(platelet-poor plasma) to increase the platelet count to 5x10 ⁸
The sample was prepared at a concentration of 500 mg/ml and used in the following tests. As PPP, the residue after PRP separation was centrifuged at 1500xg for 10 minutes, and the supernatant was used. TXA ₂ and PGE ₂ production reaction and its measurement Add 90μ of the above PRP to 10μ of the sample solution, shake for 1 minute, then take 90μ of this mixture, combine with 10μ of 5mM sodium arachidonic acid solution, and shake at room temperature. did. After shaking for 5 minutes, 10μ of this mixture was added to 90μ of a 100μM flurbiprofen solution to stop the reaction.
After the reaction, the reaction was centrifuged at 1000xg for 5 minutes, and the concentrations of thromboxane B ₂ (stable decomposition product of TXA ₂ , hereinafter referred to as TXB ₂ ) and PGE ₂ in the supernatant were measured using the radioimmunoassay method (Prostaladins 21) of Morris et al. , 771, 1981)
Measured according to. Each specimen and reagent was dissolved in saline or methanol to form a concentrated solution, diluted with saline to an appropriate concentration, and used. The TXA ₂ synthesis inhibition rate was calculated using the following formula, and the TXA ₂
The synthesis inhibitory activity was expressed as the concentration of the sample exhibiting a 50% inhibition rate (IC ₅₀ ). Inhibition rate = 100 - (TXB ₂ concentration at the time of sample addition / TXB ₂ concentration in control x 100) In platelets, inhibition of cyclooxygenase suppresses the production of not only TXB ₂ but also PGE ₂ and PGF _2a (Hamberg et al., Proc. Nat.
Acad.Sci.USA. 71 , 3824, 1974), conversely, TXA ₂
PGE ₂ , PGF _2a due to deficiency or inhibition of synthetic enzymes
and increased production of PGD ₂ (Defreyn et al.
Brot. J. Haematol. 49 , 29, 1981) is known. Therefore, the selectivity index for inhibition of TXA ₂ synthesis was calculated using the following formula, and the relationship between the effects on both TXA ₂ synthase and cyclooxygenase was shown. Selectivity index of TXA ₂ synthesis inhibition = PGE ₂ production amount when sample is added - PGE ₂ production amount of control / TXB ₂ production amount of control - TXB ₂ production amount when sample is added The larger this number is, the more TXA ₂ synthesis is suppressed. It means that the action is strong and the cyclooxygenase inhibitory action is weak. The IC ₅₀ value of the compound obtained in Example 2 is
The activity was 1.5x10 ^-6 M, which was higher than that of dazoxiben, a known TXA ₂ synthesis inhibitor, at 1.1x10 ^-5 M. Furthermore, the selectivity index of this compound was 1.13, which was higher in activity than that of dazoxiben, which was 0.68.

[Claims]

1 A 2-amino-3-halo-1,4-naphthoquinone compound is reacted with a sulfide in an inert gas atmosphere in the presence of an inert water-soluble polar solvent, and then the resulting 2-amino-3- Mercapto-1,4
- Naphtho[2.3-d]thiazole-4,9 characterized by reacting a reaction mixture containing a naphthoquinone compound with an aldehyde in the presence of an acid catalyst.
-Production method of dione compound. 2. The method according to claim 1, wherein the 2-amino-3-halo-1,4-naphthoquinone compound is 2-amino-3-chloro-1,4-naphthoquinone. 3 An inert water-soluble polar solvent is a water-soluble N,N-
2. The method according to claim 1, which is a dialkyl-substituted acid amide, an N,N-dialkyl-substituted phosphoric acid triamide, an alcohol, a sulfoxide or an ether. 4. The method according to claim 1, wherein the sulfide is a compound capable of substituting a halo group of a 2-amino-3-halo-1,4-naphthoquinone compound. 5. The method according to claim 1, wherein the sulfide is an alkali metal sulfide, an alkali metal hydrosulfide, or ammonium sulfide. 6. The method according to claim 1, wherein the acid catalyst is Brønsted acid. 7. The method according to claim 1, wherein the acid catalyst is a carboxylic acid.