JPH0812672A - Thiadiazinone derivative - Google Patents

Abstract

PURPOSE:To obtain a new derivative, having excellent cardiotonic actions and useful as a cardiotonic agent. CONSTITUTION:This derivative (salt) is expressed by formula I [R<1> is H or a 1-5C alkyl; R<2> is a 5- to 6-membered (substituted)heterocyclic group containing 1-3N atoms and/or one 0 atom or 1-3N atoms and one S atom], e.g. 3,6- dihydro-5-[4-(4-pyridylamino)phenyl]-2H-1,3,4-thiadiazin-2-one. The derivative is obtained by heating a compound of formula II and a compound of the formula R<2>-X (X is a halogen) in an inert solvent such as N,N-dimethylacetamide, as necessary, in the presence of a base such as triethylamine and a catalyst such as metallic copper at 50-200 deg.C for 0.5-10hr.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel thiadiadinone derivative useful as a cardiotonic agent or a salt thereof.

[0002]

2. Description of the Related Art Cardiotonic agents have the effect of directly acting on the heart to increase the contractile force thereof, and various agents have been conventionally used for the treatment of heart failure. For example, pyridazinone derivatives (JP-A-58-8015, JP-A-58-8016, and JP-A-58-14).
No. 0076, No. 58-148865, No. 58-183.
No. 618, No. 58-203978, No. 59-8488.
No. 3, No. 60-87283, No. 60-126282
No. 60-197672, No. 61-183228
No. 63-154670, etc.), pyridazine-
3-thione derivative (JP-A-58-188815, JP-A-5-188815)
8-203977, etc.), pyridine derivative (JP-A-60-197681, etc.), pyridone derivative (JP-A-2-59571, etc.), 2 (1H) -pyrimidinone derivative (JP-A-2-59573, etc.). It is known that pyrazinone derivatives (JP-A-2-59574 and the like), thiazolone derivatives (JP-A-2-59577 and the like) have a cardiotonic action.

[0003]

However, this type of conventionally used cardiotonic drug has an extremely narrow safety margin and causes arrhythmia, or its cardiotonic action is transient and is orally administered. There is a case where it is not suitable for, and it is not always in a sufficiently satisfactory state. This invention has excellent cardiotonic action and a wide safety margin,
The purpose was to provide an easy-to-use cardiotonic drug.

[0004]

Means for Solving the Problems As a result of intensive studies to achieve the above objects, the present inventors have found that a thiadiadinone derivative having a specific heterocyclic group or a salt thereof has an excellent cardiotonic action, The present invention has been completed. That is, the gist of the present invention is the following general formula (I)

[0005]

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(Wherein R ¹ is a hydrogen atom or C ₁ -C
₅ represents an alkyl group, and R ² is each C _{1 to} C ₅
Alkyl group, cyano group, hydroxyl group, C ₁ -C ₅ alkoxy group, amino group, C ₁ -C ₅ alkylamino group, C
Dialkylamino group ₂ -C _6, an acylamino group of C ₂ -C _5, a carboxyl group, have one or more substituents selected from the group consisting of alkoxycarbonyl group and a carbamoyl group of C ₂ -C ₅ 1 to 3 good nitrogen atoms,
Represents a 5-membered or 6-membered heterocyclic group containing one oxygen atom, one sulfur atom, one to three nitrogen atoms and one oxygen atom, or one to three nitrogen atoms and one sulfur atom. . And a thiadiadinone derivative represented by the formula (1) or a pharmacologically acceptable salt thereof, a pharmaceutical composition comprising the compound and a pharmacologically acceptable carrier, and a cardiotonic agent containing the compound as an active ingredient.

The present invention will be described in detail below. In the general formula (I), the “5- or 6-membered heterocyclic group containing 1 to 3 nitrogen atoms” in the definition of R ² is a pyridyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group. , S-triazinyl group, as-triazinyl group, pyrrolyl group, imidazolyl group, pyrazolyl group, pyrrolidinyl group, pyrrolinyl group, imidazolidinyl group, imidazolinyl group, pyrazolidinyl group, pyrazolinyl group, piperidyl group, piperazinyl group and the like. Examples of the "5- or 6-membered heterocyclic group containing 1 atom" include furyl group, pyranyl group, tetrahydrofuryl group, tetrahydropyranyl group, and the like, "5-membered ring containing 1 sulfur atom" Examples of the "cyclic or 6-membered heterocyclic group" include a thienyl group and the like, "1 to 3 nitrogen atoms and 1 oxygen atom"
Examples of the "5-membered or 6-membered heterocyclic group containing 1" include an oxazolyl group, an isoxazolyl group, a flazanyl group, a morpholinyl group, and the like, "containing 1 to 3 nitrogen atoms and 1 sulfur atom" Examples of the “5- or 6-membered heterocyclic group” include a thiazolyl group and an isothiazolyl group.

On the ring of the heterocyclic group in the definition of R ² above,
Methyl group, ethyl group, n- propyl group, i- propyl, n- butyl, t- butyl group, an alkyl group of C ₁ -C _5, such as n- pentyl group; a cyano group, a hydroxyl group, a methoxy group, an ethoxy Group, n-propoxy group, i-propoxy group, n-butyloxy group, t-butyloxy group, n-pentyloxy group and other C _{1 to} C ₅ alkoxy groups; amino group; methylamino group, ethylamino group, n -Propylamino group, i-propylamino group, n-butylamino group,
alkylamino group C ₁ -C _5, such as n- pentylamino group, dimethylamino group, methylethylamino group, a dialkylamino group of C ₂ -C ₆ such as a diethylamino group; an acetylamino group, propionylamino group, butyrylamino group an acylamino group of C ₂ -C ₅ and the like; carboxyl group;
Methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, i-propoxycarbonyl group,
It may have one or more substituents selected from C _{2 to} C ₅ alkoxycarbonyl groups such as n-butoxycarbonyl group; and carbamoyl groups.

Further, as the "C ₁ -C ₅ alkyl group" in the definition of R ^1, the same groups as mentioned above can be mentioned. The groups not specifically indicated in the groups in the definition of R ¹ and R ² above can be any combination of the above atoms and groups,
Alternatively, it is selected according to commonly known common sense.

The thiadiadinone derivative of the present invention is a 5-membered or 6-membered heterocyclic ring represented by the general formula (I) in which R ² contains 1 to 3 nitrogen atoms which may have the above-mentioned substituent. The compound which is a group is preferable, and among these, those in which the heterocyclic group is unsubstituted, those containing one nitrogen atom, those having a 6-membered ring are particularly preferable, and the most preferable heterocyclic group in the definition of R ² is Can include a pyridyl group. Further, a compound in which R ¹ is a hydrogen atom or a methyl group is preferable.

The thiadiadinone derivative of the present invention represented by the above general formula (I) can form a pharmacologically acceptable salt. Specific examples of such salts include metal salts such as lithium salt, sodium salt, potassium salt, magnesium salt, calcium salt, or ammonium salt, methylammonium salt, dimethylammonium salt, trimethylammonium when an acidic group is present. Salts, ammonium salts such as dicyclohexyl ammonium salts can be formed, and when basic groups are present, mineral salts such as hydrochloride, hydrobromide, sulfate, nitrate and phosphate, or methanesulfonic acid. Salt, benzene sulfonate, paratoluene sulfonate, acetate, propionate, tartrate,
Can form organic acid salts such as fumarate, maleate, malate, oxalate, succinate, citrate, benzoate, mandelate, cinnamate, lactate etc. .

In the general formula (I), R ¹ is C ₁
While thus an asymmetric carbon is present if an alkyl group -C _5, compounds of the invention are those of (R) body, (S)
Body, (RS) body is included. Specific examples of the compound of the present invention are shown below.

[0013]

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[0014]

[Chemical 4]

[0015]

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[0016]

[Chemical 6]

[0017]

[Chemical 7]

[0018]

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[0019]

[Chemical 9]

Next, a method for producing the compound of the present invention will be described. The thiadiadinone derivative represented by the general formula (I) of the present invention can be produced, for example, by the following route.

[0021]

[Chemical 10]

(In the formula, R ¹ and R ² are as defined above, and X represents a halogen atom such as a chlorine atom or a bromine atom.)

That is, in the above reaction scheme, the compound of formula (II) and the compound of formula (III) are placed in an inert solvent such as N, N-dimethylformamide, N, N-dimethylacetamide or N-methyl-2-pyrrolidone. 50-200 ° C
Then, the desired thiadiadinone derivative of the formula (I) can be synthesized by heating for 0.5 to 10 hours. An organic base such as triethylamine or DBU (1,8-diazabicyclo [5.4.0] -7-undecene) or an inorganic base such as potassium carbonate or sodium carbonate may be added as the base. Further, a copper compound such as metallic copper, copper oxide or cuprous chloride may be used as the catalyst. The compound of formula (II) used as a starting material can be synthesized by the following route.

[0024]

[Chemical 11]

(Wherein R ¹ is as defined above, Q is an amino group substituted with a protecting group such as an acetyl group or a benzyloxycarbonyl group; or a substituent capable of being converted into an amino group such as a nitro group. And Y represents a halogen atom such as a chlorine atom or a bromine atom.)

That is, in the above reaction formula, when Q of the haloketone derivative of the formula (IV) represents an amino group substituted with a protective group such as an acetyl group or a benzyloxycarbonyl group, a proton such as a commonly used hydrochloric acid or sulfuric acid is used. Room temperature to 100 in methanol or ethanol containing acid
The anilino haloketone compound of formula (V) easily deprotected can be synthesized by heating at 0 ° C. or under the reflux temperature of the solvent for 0.5 to 20 hours. When Q represents a substituent capable of being converted into an amino group such as a nitro group,
A reduction method of the formula (V) is used, which is a commonly used reduction method, for example, using stannous chloride under acidic conditions such as hydrochloric acid and heating at room temperature to 100 ° C. or at a reflux temperature of the solvent for 0.5 to 10 hours. Anilino haloketone compounds can be synthesized.

The thus obtained anilinohaloketone compound of the formula (V) and the thiocarbazic acid derivative of the formula (VI) are heated from room temperature to 100 ° C. or a solvent reflux in an inert solvent such as ethanol, THF or acetonitrile. By heating at a temperature for 0.5 to 10 hours, the compound of formula (II), which is an intended intermediate, can be obtained.
Incidentally, in the reaction, a protic acid such as hydrochloric acid, sulfuric acid, p-toluenesulfonic acid or trifluoroacetic acid may be added. Further, the thiadiadinone derivative of the formula (I) can be produced by the route shown below.

[0028]

[Chemical 12]

(In the formula, R ¹ and R ² are as defined above, and Z represents a halogen atom such as a chlorine atom or a bromine atom.)

That is, in the above reaction formula, the haloketone derivative of the formula (VII) and the thiocarbazic acid derivative of the formula (VI) are heated from room temperature to 100 ° C. or under the reflux temperature of the solvent in an inert solvent such as ethanol, THF or acetonitrile. By heating for 0.5 to 10 hours, the target thiadiadinone derivative of the formula (I) can be synthesized. In this reaction, a protic acid such as hydrochloric acid, sulfuric acid, P-toluenesulfonic acid or trifluoroacetic acid may be added. The compound of formula (VII) used as a starting material can be synthesized by the route shown below.

[0031]

[Chemical 13]

(In the formula, R ¹ , R ² and Z are as defined above, and D represents a halogen atom such as a chlorine atom or a bromine atom. Here, Z and D may be the same or different. )

That is, in the above reaction formula, the formula (VIII)
And an acyl halide compound of formula (IX) in the presence of a Lewis acid such as anhydrous aluminum chloride, anhydrous aluminum bromide or anhydrous tin chloride in an inert solvent such as dichloromethane, dichloroethane, nitromethane or trichlorobenzene. Under heating from ice-cooling temperature to 100 ° C. or solvent reflux temperature for 0.5 to 10 hours, the compound of formula (VII), which is the target intermediate, is obtained.
Can be synthesized.

The compound produced in the above reaction can be separated and purified from the reaction mixture by a commonly used method known per se, for example, extraction, recrystallization, chromatography and the like. When the compound represented by the general formula (I) of the present invention is used as a medicine, it is formulated into various forms as a composition containing a commonly used suitable pharmacologically acceptable carrier or excipient. It can be administered by a suitable oral or parenteral administration method. In this case, the dosage form provided is for oral administration,
For example, powders, granules, tablets, dragees, pills, capsules,
Liquid preparations, etc., for parenteral administration, for example, suppositories,
Suspensions, solutions, emulsions, ampoules, injections and the like can be mentioned. Of course, a combination of these may be provided.

The above-mentioned various dosage forms can be produced by a commonly used method known per se using a solid or liquid carrier or excipient. Examples of the solid carrier used in the preparation include lactose, white clay (kaolin), sucrose, crystalline cellulose, corn starch, talc, agar, pectin, stearic acid, magnesium stearate, lecithin, sodium chloride and the like. As the liquid carrier, for example, glycerin, peanut oil, polyvinylpyrrolidone, olive oil,
Examples thereof include ethanol, benzyl alcohol, propylene glycol, water and the like.

The dose is, age, sex, body weight, sensitivity difference,
It is determined by the doctor in consideration of the administration method, the time and interval of administration, the degree of medical condition, the physical condition, the nature of the pharmaceutical preparation, the preparation, the type and the type of the active ingredient. For example, in the case of oral administration, a dose of about 0.1 to 10 mg per 1 kg of body weight per day is selected, but it is not limited to this.

[0037]

The present invention will be described in more detail with reference to the following examples, but the invention is not limited to the following examples as long as the gist of the present invention is not exceeded. Reference Example 1 3,6-dihydro-5- (4-aminophen
Nil) -2H-1,3,4-thiadiazin-2-one
Synthesis (A) Synthesis of 4-acetylaminophenacyl chloride

[0038]

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10 g of acetanilide and 30 g of aluminum chloride were suspended in 50 ml of 1,2,4-trichlorobenzene, and 6.5 ml of chloroacetyl chloride was added dropwise under heating and stirring at 70 ° C. After completion of dropping, the reaction temperature is set to 80 ° C
And stirred at the same temperature for 1 hour. The reaction mixture was added to ice water 5
Then, 100 ml of hexane was added, and the precipitated solid was collected by filtration. The solid is ethyl acetate / THF = 5 /
2) Dissolved in about 700 ml, dried over anhydrous sodium sulfate, and filtered through a silica gel layer. The filtrate was concentrated under reduced pressure to give the title compound (14.14 g, yield: 90.3%).

¹ H-NMR (250 MHz, DMSO-
d ₆ ) δ: 10.3 (1H, s) 7.94 (2H, d)
7.73 (2H, d) 5.12 (2H, s) 2.09
(3H, s) (B) Synthesis of 4-aminophenacyl chloride

[0041]

[Chemical 15]

4-Acetylaminophenacyl chloride 8.00 g, methanol 100 ml and 6N-sulfuric acid 100
The mixture with ml was heated and stirred under reflux for 2.5 hours. After completion of the reaction, methanol was distilled off under reduced pressure, the concentrate was diluted with about 300 ml of water, and saturated aqueous sodium carbonate solution was added to make the mixture weakly basic. The precipitated solid was collected by filtration and dried to obtain 7.32 g (yield: quantitative) of the title compound.

¹ H-NMR (250 MHz, CDCl
₃ ) δ: 7.81 (2H, d) 6.65 (2H, d)
4.61 (2H, s) 4.23 (2H, s) (C) 3,6-dihydro-5- (4-aminophenyl)
Of 2H-1,3,4-thiadiazin-2-one

[0044]

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4-Aminophenacyl chloride 1.53
g, trifluoroacetic acid 0.69 ml, thiocarbazic acid O
-Methyl ester 1.05 g acetonitrile 40 ml
The solution was heated and stirred under reflux for 4 hours. After the reaction was completed, the reaction mixture was cooled, diluted with approximately 200 ml of water, and saturated aqueous sodium carbonate solution was added to this solution to make it weakly basic. The precipitated viscous substance was extracted with ethyl acetate and then purified by silica gel column chromatography (solvent: chloroform → 8% THF / chloroform) to obtain 0.79 g (yield: 42.3%) of the title compound.

¹ H-NMR (250 MHz, DMSO-d ₆ ) δ: 11.29 (1 H, s) 7.52 (2 H, d)
6.58 (2H, d) 5.64 (2H, s) 4.0
7 (2H, s) Example 1 3,6-dihydro-5- [4- (4-pyri
Dilamino) phenyl] -2H-1,3,4-thiadia
Synthesis of gin-2-one

[0047]

[Chemical 17]

5- (4-aminophenyl) -2H-1,
To a solution of 3,7-thiadiazin-2-one (0.27 g) in N-methyl-2-pyrrolidone (3 ml) was added triethylamine (90 μl) and 4-chloropyridine hydrochloride (0.20 g) successively while heating and stirring at 100 ° C. Stirring was continued for hours. After cooling the reaction mixture, 10 ml of acetone and 15 ml of ether were added and the precipitated crystals were collected by filtration. After air-drying, the crystals were dissolved in 50 ml of warm water and the pH was adjusted with saturated potassium carbonate solution.
= 8. The precipitated solid is collected by filtration and purified by silica gel column chromatography to give the desired product (0.26 g)
(Yield: 70.3%) was obtained.

Melting point: 222-225 ° C. (decomposition) ¹ H-NMR (250 MHz, DMSO-d ₆ ) δ: 11.5 (1H, s) 9.10 (1H, s)
8.25 (2H, d) 7.79 (2H, d) 7.27
(2H, d) 7.00 (2H, d) 4.20 (2
H, s) Reference Example 2 1- [4- (4-pyridylamino) phenyl
]]-2-Chloropropanone Synthesis

[0050]

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4-pyridylaminobenzene (9.00 g) and aluminum chloride (21 g) were suspended in 1,2,4-trichlorobenzene (45 ml), and 2-chloropropionic acid chloride (5.7 ml) was stirred at 70 ° C. under stirring to about 1 ml.
Dropped in minutes. After the dropping was completed, the temperature was raised to 80 ° C. and the reaction was carried out at the same temperature for 1 hour. After completion of the reaction, the reaction mixture was diluted with 500 ml of dichloromethane. Then, about 20m of ice water
1 was added carefully and stirred well, after which anhydrous potassium carbonate was added until tack free and the solution was dried. After the desiccant was filtered off, the product was concentrated under reduced pressure to obtain a crude product, which was then purified by silica gel column chromatography (solvent: chloroform → 5% methanol / chloroform).
34 g (yield: 89.5%) was obtained.

¹ H-NMR (250 MHz, DMSO-
d ₆ ) δ: 9.41 (1H, s) 8.33 (2H, d)
8.00 (2H, d) 7.30 (2H, d) 7.10
(2H, d) 5.71 (1H, q) 1.61 (3
H, d) Example 2 3,6-dihydro-5- [4- (4-pyri
Dilamino) phenyl] -6-methyl-2H-1,3
Synthesis of 4-thiadiazin-2-one

[0053]

[Chemical 19]

0.50 g of 1- [4- (4-pyridylamino) phenyl] -2-chloropropanone was added to ethanol 5
ml and 1N-hydrochloric acid 2.2 ml, and after adding thiocarbazic acid O-methyl ester 0.23 g, the mixture was heated under reflux for 2 hours. After the reaction was completed, the reaction solution was diluted with water and then adjusted to pH 8 with a saturated potassium carbonate solution. The precipitated viscous substance was extracted with dichloromethane and then purified by silica gel column chromatography (solvent: chloroform → 5% methanol / chloroform) 0.30 g of the title compound (yield: 5
1%) was obtained.

Melting point: 195 to 198 ° C. (decomposition) ¹ H-NMR (250 MHz, DMSO-d ₆ ) δ: 11.6 (1H, s) 9.10 (1H, s)
8.24 (2H, d) 7.77 (2H, d) 7.26
(2H, d) 6.99 (2H, d) 4.71 (3
H, d) 1.47 (3H, d)

[0056]Test example Usefulness of the thiadiadinone derivative of the present invention as a cardiotonic action
Of guinea pig isolated papillary muscle samples for pharmacological studies showing sex
The method was followed. A male model weighing 400-600g
Strike the occipital region of the lumot and immediately remove the right ventricular papillary muscle.
Krebs-Henslight solution 30 that was put out and kept warm at 32 ° C
It was fixed at the bottom of an organ bath filled with ml. Ku in the organ bath
95% O for Levus Henslite solution ₂ And 5% CO
₂ The mixed gas consisting of and was aerated. Attach the thread to the papillary muscle
And connect the other end of the thread to the transducer to make isometric tension.
The force was measured. A static tension of 0.5 g was applied to the specimen.
Connect the sample via two platinum electrodes 1 ms, threshold
A rectangular wave with 1.2 times the voltage is applied once every two seconds.
Driven by the air. Allow the sample to stabilize for 30 minutes and then melt it.
The compound dissolved in the medium was added to the organ bath and the reaction was recorded.
Was. The rate of increase in the papillary muscle contraction force is shown in Table 1 below.

[0057]

[Table 1]

[0058]

The compound of the present invention has an excellent cardiotonic action and is useful as a cardiotonic agent.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Office reference number FI Technical display location C07D 417/12 239 251 263 277 307 333 A61K 31/54 ABP

Claims (11)

[Claims] 1. A compound represented by the following general formula (I) (In the formula, R ¹ represents a hydrogen atom or a C _{1 to} C ₅ alkyl group, and R ² is each a C _{1 to} C ₅ alkyl group, a cyano group, a hydroxyl group, and a C _{1 to} C ₅ alkoxy group. , An amino group, a C ₁ -C ₅ alkylamino group, a C ₂ -C ₆ dialkylamino group, a C ₂ -C ₅ acylamino group, a carboxyl group, a C ₂ -C ₅ alkoxycarbonyl group, and a carbamoyl group. 1 to 3 nitrogen atoms optionally having one or more substituents selected from the group, 1 oxygen atom
, 1 sulfur atom, 1 to 3 nitrogen atoms and 1 oxygen atom
Or a 5-membered or 6-membered heterocyclic group containing 1 to 3 nitrogen atoms and 1 sulfur atom. ) A thiadiadinone derivative represented by the formula) or a pharmacologically acceptable salt thereof. 2. R ² is a C ₁ -C ₅ alkyl group, a cyano group, a hydroxyl group, a C ₁ -C ₅ alkoxy group, an amino group,
It is selected from the group consisting of a C _{1 to} C ₅ alkylamino group, a C _{2 to} C ₆ dialkylamino group, a C _{2 to} C ₅ acylamino group, a carboxyl group, a C _{2 to} C ₅ alkoxycarbonyl group, and a carbamoyl group. The compound according to claim 1, which is a 5-membered or 6-membered heterocyclic group containing 1 to 3 nitrogen atoms which may have one or more substituents. 3. The compound according to claim 2, wherein the heterocyclic group is a 5-membered or 6-membered heterocyclic group containing 1 to 3 nitrogen atoms which does not have a substituent. 4. The compound according to claim 2, wherein the heterocyclic group is a 5-membered or 6-membered heterocyclic group containing one nitrogen atom. 5. The compound according to claim 2, wherein the heterocyclic group is a 6-membered heterocyclic group containing 1 to 3 nitrogen atoms. 6. The heterocyclic group is a pyridyl group as claimed in claim 3.
5. The compound according to any of 5. 7. The compound according to claim 1, wherein R ¹ is a hydrogen atom or a methyl group. 8. The compound according to claim ¹ , wherein R ² is a pyridyl group and R ¹ is a hydrogen atom. 9. The compound according to claim ¹ , wherein R ² is a pyridyl group and R ¹ is a methyl group. 10. A pharmaceutical composition comprising the compound according to any one of claims 1 to 9 and a pharmacologically acceptable carrier. 11. A cardiotonic agent comprising the compound according to any one of claims 1 to 9 as an active ingredient.