JPS5962578A - Oxadiazine derivative and pharmaceutical composition containing the same - Google Patents

Abstract

NEW MATERIAL:The oxadiazine derivative of formula I (R1 is H, alkyl, phenyl, or halogen-substituted phenyl; R2 is H, alkyl, substituted hydroxyalkyl, or substituted aminoalkyl; R3 is H, alkyl, halogen, nitro, OH, alkoxy, amino, acylamino, 3-isopropylamino-2-hydroxypropoxy, or 2,3-epoxypropoxy). EXAMPLE:Phenyl-3,6-dihydro-1,3,4-oxadiazin-2-one. USE:A drug for circulatory organs such as antithrombotic agent, hypotensor, cardiotonic agent, etc. It has blood platelet coagulation suppressing, hypotensive and cardiotonic activities, etc. PROCESS:A compound of formula I wherein R2 is H can be prepared e.g. by reacting the hydrazine derivative of formula II in the presence of a proper base, and the obtained product is converted if desired to the objective compound of formula I .

Description

[Detailed description of the invention] R, 12 [In the formula, 1 is hydrogen, lower alkyl, phenyl or halogen-substituted phenyl, and t2 is hydrogen, lower-norgyl, substituted hydroxyalkyl, or substituted amino -Nylgyl, 1 (3 is hydrogen, lower alkyl, H Tl)
-7, 21, hydroxy, lower alkoxy/, -no'
i-no, abruamino, 3-isopropylamino-,2-
Human “J Ginpropokin and Dabaa, 3-EvoA/ZoL1
Bogi/not shown. The present invention relates to Ogyzadia//attractant J expressed by: and I-deficient its compositions containing them as active ingredients.

Regarding Ogiza/A7, its chemical and physical 12]
There are several reports regarding ri. Among the several isomers of ogizadia/n, which are related to the present invention, 3. 'l-
For the ogizadiazine no-one derivative i+1, e.g. to 4, I? Studies of its chemical human lJj and thermal isomerization have been reported by C.J., A.mer, Chem., S.
oc, , g3.3g 7'1 ('Otsu3), :
l-1,) i d, -+ g 7+shio 7 no Otsu ('Otsu k
)]. 1, D, G.

There are synthetic reports on oxadiazine derivatives by ``11o1'', a, nd et al. (1Lec, Tra, v,
Ch+em,, gJ, IO'17 ('Otsu 4)). Koshida, C1, Iyumi, Co., Ltd. discloses that oxadiazine derivatives can be used as blowing agents for Atsumachi FV+ organic polymers [JP-A Sho, t, 2-3 Shio Yuogu, Toji Kai. Akishio, 2-3 Otsu 7g]. However, in neither case is the pharmaceutical usefulness of the ogisadiazine derivatives mentioned.

The present inventors have diligently researched the above-mentioned oxadiazine derivatives and have discovered that they are medicinally useful and have arrived at the present invention. That is, as will be detailed later, the compound of the present invention has pharmacological effects such as platelet aggregation inhibiting action, antihypertensive action, and cardiotonic action, and is useful as a cardiovascular agent such as an antithrombotic agent, an antihypertensive agent, and a cardiotonic agent. .

To explain in more detail about the oxa/azine derivative represented by the general formula [■], lower alkyl includes methyl, ethyl, propyl, impropyl, butyl, inobutyl, tertiary butyl, etc. 2, 3. 'Phenyl substituted with fluorine, chlorine, bromine, or iodine at the 1st position is substituted.Substituted hydroxyalkylates include hydroquinemethyl, hydroxyethyl, hydroquinepropyl, benzoyloxyethyl, etc. Norkyl means dinotylamine ethyl, /''nibutylaminoethyl, nobyl, monomethylaminoethyl, monoethylaminoethyl, lower alkoxy, and r.
]-notoki/, engineering/gi/, prohoki/, butogi/nato, and aburamino refers to acetylamino, zo-I pionylamine, etc. Also, regarding the position of the 1 mo 3 substituent, 1, 3 , 1. Includes both places.

The compound of general CI) can be synthesized, for example, by the following method.
, l and 1mo3 have the same meaning 1 floor as before. ] Zunawa 1), the hydrazone compound expressed by the general formula [■] 5,,+
; Rest J14; ;;';, Example 7 +- Ha,
Dissolved in a suitable solvent such as water, alcohol, ])MFS-acetone, ether, Hensen, etc. in the presence of sodium metal, sodium hydride, tutria hydroxide, sulfur and lithium carbonate, potassium carbonate, sodium bicarbonate, etc. Allow the reaction to proceed. At this time, the reaction temperature is preferably in the range of θ to 100C. The compound [■] thus produced is included in the general formula [■], but when further introducing a substituent for R2 in the general formula [■], first the compound of the general formula ([) It can be obtained by converting a compound into a sodium salt with a sodium salt/hydride, sodium alkoxide, etc., and then reacting it with a corresponding reagent such as ethylene carbonate, diethylamine ethyl chloride, etc. In addition, the general formula CIO
Although the compound itself is a new compound, it can be synthesized by a known method, for example, by the following reaction example.

[In the formula, 1(・J and [also 3 have the same meaning as before,
X y+!・Represents Roken. ] Oxadiazi/1 represented by the general formula CI') of the present invention
, a pharmaceutically acceptable salt, e.g.
11i2 Salts (salts with inorganic acids such as acid salts and nitrates, acetic acid, oxic acid, succinic acid, maleic acid, etc.)
Includes salts with m acids, metal salts with sodium, potassium, cal/rum, etc.

The compound of general formula CI) produced as described in 1-1 below has a hypotensive effect on mammals such as humans, monkeys, dogs, rabbits, rats, etc. It also has platelet aggregation inhibitory effects. Unfortunately, there are also compounds that increase myocardial contractility. From this, the compound of general formula CI) and its "fA" are useful as a cardiovascular drug, but when used as a medicine, they may be used alone or in combination with appropriate pharmacologically acceptable antibodies and excipients. , mixed with diluents to form powders, granules, tablets, capsules,
It can be administered orally or parenterally in the form of an injection. The dosage varies depending on the target disease, symptoms, subject, test method, etc., but when testing hypertension drugs, anticoagulants, cardiotonic drugs, etc. for adults as a cardiovascular drug, it is recommended to use 1] Administration / daily dose / ~: 100m?
For intravenous injection, it is preferable to test 100 mf/day/~) divided into 2 to 3 times.

Hereinafter, the present invention will be explained in more detail with reference to Examples. Some of the compounds described in the Examples are foamed and decomposed by heat and do not exhibit clear melting points, so the melting points of such compounds are not listed.

Example/α-Hydroki/Acetophenone-N-Carboethoxy/Hydrazone, 2. Dissolve g < tg in 30 ml of ethanol and hydrogenate 100 ml of trichloride (5θ aqueous solution)! ! After stirring at room temperature for 7 hours and then at 50C for 7 hours, the solvent was distilled off, and the residue was purified with a 7-hour gel column to obtain a phenyl-phenyl compound with a melting point of 3. Otsu-dihydro/, 3.17-oxadianononion/left g? Obtained.

EXAMPLE Example 1 Nidrason 62I in ethanol:
After adding hydrogenated triuno, (Sθ) ice water solution 7θQ m f, dissolved in
Uchida 3. The solvent was distilled off and water was added to 5me-1,2N
IFj7; After neutralization with acid, methylene chloride 3 Q m
Extract with e, sulfurize the extract anhydrously and dry with l-'Jum! - After that, the solvent was distilled off, and the residue was recrystallized from methylene chloride-hexane to obtain a colorless prism product with a melting point of 2y
q-,2,200 3-Cl1-chlorophenyl)
-3, Otsu-/Hydro'l 3+"-Oxadiazine-
I got 1.2ft of no-on.

Example 3 The following compound (Example 3
~//)was gotten. , t-(4j-bromophenyl)
-4-methyl-, l, A-dihydro-/, 3. ll-
Ogizadiazinoeuon: Melting point/Ototsu~/OtsugC Example q 3-(t,1-fluorophenyl)-4-methyl-3
, Otsu-Dihythro/, 3.1%-Oxadiazine-
2-one Example 5 (3-chlorophenyl) -Mail-3
゜゜O-dihytot''-/, 3,1l--oxadia/Nonion Example Otsu, 5--(,2-bromophenyl)-4-methyl-3゜O-dihyto-t''-/, 3.1I--oxazi Anone-non-one Example 7 S-(V-acetaminphenyl)-3,O-dihythro/,3.11-oxadiazin-1-one: Melting point, 2
Gu flood~! 11. qC (decomposition) fruitful Kaede fil g 5- (g-acetaminophenyl)-ot-methyl-3
, Otsu-Nhidoro/, 3. g-Oxadiazi/-neon: Melting point, 2/g~, 2/, ffC (decomposition) Example 9, t-(3-acetaminophenyl)-Otsuichimethyl-3
．． 3.17-Oxadianeru-no-on Actual Example 10, ff-(ll-hydroxyphenyl)-3, 3. 'l-Oxadiazine-Uon:
1. Il! Point. 2 3 3 'C (minute angle A) Example // S-(Z-7 Toki/Phenyl)-3, Otsu-Dihito rJ-
/, 3.17-oxadiazine-euon: toto: small point /q ot ~ / gua C Example /, 2 ω1.2-dihydroquinacetophenone-N-carboethoxy/hydrazone 102 to ethanol 30■17? Add potassium carbonate, 200mf,
', de/ I-jlf, j 11' L, ta. Precipitated crystal; b! After washing with ethanol and water and drying at low temperature, it has a melting point of 155°C (discretion angle TC). t-(,2-hydroxophenyl)-3゜O-dihydro-/, 3. ll
-Oxadiazine Uon 0. /21 was obtained.

Example/3 By the same reaction as in Example/2, 5-(3-hydroquinophenyl)-M-3. A->Hydro-
/, 3.1%-oxadiazinone was obtained.

Example/lit m-Nitro-ω-hydroquinoacetophenone-N-carboethoxyhydrazone 9-2 was dissolved in 30me of ethanol, and 200ml of thorium hydride (So) was added thereto, followed by heating under reflux for 3 hours. Cooling. Thereafter, the precipitated crystals were recrystallized from methylene chloride-ethanol to give 3-(3-nitrophenyl)-3,2-(decomposed) with a melting point of 93 to 90°C (decomposition).
) 49 St of hydro-/, 3.41-oxa diazine-neone was obtained.

Example 15 By the same reaction as in Example 1, 1. t-(<z-nitrophenyl)-3,4-dihydro-/, 3. ll-oxadiazine-call was obtained. Melting point 2Q3'C (
Decomposition) Example/Otsu, Goo (J-1--1・11 phenyl)-3, Otsu-7 human+1-/, j', Gooxadiazinoyuon//
1/to・dry・1seiko1)・I i” :l Q m
Dissolve in 1 liter of diethylamino-1-bulk ``Iride hydrochloride'' and add 5 q of water to
(60 width aqueous solution) Guda 0m/l
The reaction mixture was poured into ice water at a temperature of 1330 m/?
Extracted with. The extract was dried, then evaporated, and the remaining residue was dissolved on a licage gel bottle.
5-(3-nitrophenyl)-J of ff'C? -(N
, N-diethyl-7mi/:L-chill)-3, Otsu-dihythrow/, 3. I; 7-Ogiza N'ajinoyuon is 7.20 m.

Example/7 Ni-(3-21・[j-phenyl)-3, O-dihytou-
/, J+Googizadiazin-2-one//l・:・
Q, l・731) Dissolved in 8・11-, sodium hydride (60% aqueous solution), 200m? was added, and further 550 mg of ethylene (-Bonnet) was added, and the reaction solution was poured into ice water and extracted with 10 liters of water. was dried and then distilled off, and the residue/rt was 7 lica gel carato 0, left-(3-nitrophenyl)-3-(,2-hydroquinethyl)-3', and 2-dihydro-1.3.

320ml of Goo Oxadiazine-Nion? Obtained.

Example ig 3-(3-nitrophenyl)-3,1. -dihydro-/,3,ll-oxadiazin-one; 1. ．． 2
Dissolve /7g in methanol/θQml, S-paragraph 7
After adding 300 mf of palladium on carbon, hydrogenation was carried out at normal pressure in a hydrogen atmosphere, and the reaction was stopped when 70 g of hydrogen had been consumed, the palladium on carbon was removed by filtration, and the mother liquor was concentrated to dryness. Allow to solidify, and purify the residue using a 7-layer gel column.
Melting point/73'O (min 4 Ifr) CD! ;-(, J'-7
1 and 2 # of (minophenyl)-3,o-dihydro-/,3,g-oxadiazinoeuon were obtained.

Example/9 3-(g-aminophenyl)-3,A-dihydro-/, 3. 4! - Vice Gieson Azino-on was obtained.

Fruit//fti example-〇ll-rJrJhenzoin-N no noboetkinhitoshizono,! i near j/ ethanol/ 3 Q m
Hydrogenated uno dissolved in /' (40% aqueous solution) 1
00 ml was added, and the mixture was heated to reflux. The solvent was distilled off, and the residue was extracted with ethyl 1-'1 acid, washed with water, and dried. -)-(41-chlorophenyl)-3゜Et-Nhitrono, 3.Hiro-Oxasia Jinyuo/392 were obtained.

By the same reaction as in Example 2 and Example 20, Shio, Otsuji (3-
The compound chromophenyl)-3,A-dihydro-13 was obtained.

Example: 12 By the same reaction as in Example/A, 3-(diethylaminoethyl)-5, O-di(g-chlorophenyl-3, Otsu-1, Nhitro/, 3,47-oxadipdine-coone) Melting point //g~/I'7 Example, 2.7 By the same reaction as in Example/7, 1.?-(,2-hydroquinethyl)-, !i-, A-c( ψ-chlorophenyl)-3, O-dihydro-/, 3.1%-oxacyazin-2-one was obtained. -hydroxyethyl)-3,O-di(g-chlorophenyl)-3,1v-2hydro-/.

3, q-oxadiazine-neon 73ff:, 20m
benzoyl chloride Q
,! rg, I-ethylamine 03 t, force 11, l
The mixture was heated under reflux for 6 hours. The reaction solution was dried to dryness under reduced pressure, extracted with ethyl acetate, washed with water, dried, and purified on a force gel column. = ) v ) − 3, Otsu-ichijihito o-/, j'.

Gookizadiazinoyuon. 2Q Qm? Obtained.

Example. 25 3(GuchtrJki7phenyl)-3,O-dihydro-
/,J,ll-oxanoazi7~''-one 102 to methyl ethyl ketone. :), Om 7? and 0: I)
Dissolved in a mixed heart medium of Ml・” / O Ille,
Nibromohydrin/θ2 and Thylium carbonate 7 2
After adding 0 mg, the mixture was stirred at goC/1]. The precipitated salt was filtered off, and the j:J solution was dried under reduced pressure, crystallized from alcohol, and 1ii1! Point/l&. 2 ~/q4'c
of. t- [4! - (, 2.3-x Bogi/PrJ Bogin) phenyl]-3, O-dihito r1-no, 3, /1
．． -Ohe--Nasiazin-a-one is o. q-g i))
Rareda 3, Example A, Example B. By a reaction similar to 25, t-4:ll-(
2, 3--r-hoki/propoquine)phenyl)-4-meguru, ? ,Otsuji Hydro/,3,l
1-Okylydia/noeuon was obtained.

Actual h11j example. 27 Example. By a reaction similar to 2, left-(, 2-(, 2
．． 3-Epoxyfluoropoxy)phenyl-methyl-3,ethyl-onehydro/,3,j-okylydiazin-2-one was obtained.

Example. 2g, t-(g-<,2.3-epoxypropoxy)phenyl]-3,O-Nhydro/,3,Googisadiazinone o9t was dissolved in 30ml of methanol, and inopropylamine was added. , 2 m/ was added and then heated under reflux for 2 hours. The reaction solution was dried under reduced pressure, and the residue was purified on a Nori gel column to a melting point of ~/5
/'O3-(ll-(3-inopropylamino-)
-Hitrogi/Furoboki7) Phenyl]-3, Otsu-dihydro-/, ,? , 1. t-Ogizan Ajinosuo/
was obtained as 06.2.

EXAMPLES By the same reaction as in Example 2g, shio-[di(3-inzolopylaminohydro-7proboxy)phenyl]-methyl-3,o-dihydro-/,3,II-oxadiazi7-ion was obtained. It's a good deal.

Example 3θ Actual JjfI example, 5-(,1
-(3-isozol'lbilamino-nohydroquineproboxy7)noenyl]-ot-methyl-3. Otsu-jihitoro/, 3. II-oxaneazin-a-one! I'
/3 Example 3/ The pharmacological effects of the compounds of the present invention were tested, for example, by the following method.

I. Inhibition of Collagen-Induced Platelet Aggregation A healthy Tamoto albino rabbit was fixed in a dorsal position without anesthesia, and blood was collected by inserting a cannula into the carotid artery. Blood was collected directly from the cannula into a solution containing 3 g of triurium enoate, and platelet-rich plasma (PRP) was collected by centrifugation. To measure platelet aggregation, an aggregometer manufactured by 13ryston was used, and a fixed molar amount of the compound of the present invention or aspirin as a control drug was added to a fixed amount of PRP and a buffer solution for a fixed period of time. ) The entire solution was added to a mixed solvent of M and F, and a certain amount of collagen was added to induce platelet aggregation. The strength of the aggregation inhibitory effect is shown in Table/ζ. Please write 1: The following 〇 represents the taste.

”-0 1, less than aspirin; 10; about aspirin.

-]] Published -; Aspiri's i to 10 i sounds.

"H+: 70 to 100 times aspirin 2 Antihypertensive effect Male rats (SHR) with spontaneous hypertension after the onset of hypertension, aged 20 weeks or older, were used after fasting for 7 hours. Systolic blood pressure in the caudal artery was recorded non-invasively before and after drug administration without anesthesia.

Measurements were taken after q, o and 2j hours. Hydralazine was still used as a control drug. Systolic blood pressure is / 9 Q m
m, I-I 1 or more 3-S rats were included, and the subjects were 0. ．． It was dissolved or suspended in a 2% CMC solution and administered orally. Some of the results are shown in Table 7.

Claims (2)

[Claims] (1) general formula CI) , t3 represents hydrogen, lower alkyl, halogen, 21, hydroxy, lower alcogine, amine, acylamino, 3-isobrobylamino-euhydroxyproboxyzo, and -23-epoxypropoxy.] Oxadiazine derivatives. (2) General formula CI) 1(11 [In the formula, R1 is hydrogen, lower alkyl, phenyl or halogen-substituted phenyl, R2 is hydrogen, lower alkyl, substituted hydroxyalkyl or substituted aminoalkyl, 1
(3 is hydrogen, lower alkyl, halogen, hydroxy, lower alkokino, amine, acylamino, 3-
Inzolopylamino--hydroxyproboxy or a,3-epoxypropoxy. ] A pharmaceutical composition containing an oxadiazine derivative represented by: