JPS6023673B2 - Pyrimido[4,5-e][1,3,4]thiadiazine derivative and method for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a novel pyrimide [4,5-
e] [1.3.4] Regarding thiadiazine derivatives and methods for producing the same.

More specifically, the present invention relates to the general formula [wherein RI is a hydrogen atom or an alkyl group, R2 is an alkyl group, R3 is a hydrogen atom, an alkyl group, an alkenyl group, a phenyl group, a phenyl group substituted with a halogen, pyrimide [415-
e] [113.4] Related to thiadiazine derivatives and methods for producing the same.

Regarding the above general formula (1), R1, R2, R3 and R4
The alkyl group represented by is preferably a lower alkyl group, especially an alkyl group having 6 or less carbon atoms (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl,
(i-butyl, sec-butyl, t-butyl, n-pentyl, i-bentyl, n-hexyl, i-hexyl), and particularly preferred are alkyl groups having 4 or less carbon atoms.

The alkenyl group represented by R3 is preferably a lower alkenyl group, especially an alkenyl group having 6 or less carbon atoms (
For example, vinyl, allyl, 1-probenyl, isoprobenyl, 2-butenyl groups) are preferred. Examples of the halogen of the halogen-substituted phenyl group represented by R3 include chlorine, fluorine, bromine, and iodine. The phenylalkyl group represented by R3 is preferably a phenylalkyl group whose alkyl moiety has 3 or less carbon atoms, such as a penzyl group or a phenethyl group. R3
The acyl group represented by is preferably a lower alkanoyl group, an optionally substituted penzoyl group, and especially a lower alkanoyl group having 4 or less carbon atoms in the alkyl moiety (e.g., acetyl, propionyl, 2-butyryl, i-butyryl group). , benzoyl group is preferred. As the compound of the above general formula (1), a compound in which RI and R2 are each a lower alkyl group, and a compound in which RI is a hydrogen atom and R2 is a lower alkyl group are preferable.

The compound represented by the above-mentioned single-pronged formula (1) can be produced, for example, by the following new synthetic reaction.

[In the formula, R1, R2, and R3 have the same meanings as above, and R4 represents a hydrogen atom or an alkyl group.] The above reaction is performed on a compound (
By reacting b) with an oxidizing agent, a compound of general formula (la) is obtained.

This reaction is usually carried out in the presence of a solvent, such as halogenated hydrocarbons (e.g. chloroform,
(methylene chloride, etc.), dioxane, benzene, etc. Examples of the oxidizing agent include oxidizing agents with relatively weak oxidizing power such as N-chlorosuccinimide, N-furomosuccinimide, and N-bromoacetamide, with N-chlorosuccinimide being preferred. The amount of the oxidizing agent used is approximately 1 to 4 mol, preferably approximately 1 to 2 mol, per 1 mol of compound (b). The reaction temperature is usually about 0 to 5,030 degrees Celsius, preferably about 20 to 30 degrees Celsius.
The temperature is within the range of about ℃. The reaction time is usually about 0.5
The time is about 1 to 1 hour, preferably about 1 to 3 hours.
The compound of general formula (1) thus produced can be isolated by conventional separation and purification means (eg, recrystallization from an organic solvent, etc.).

In this case, the compound of general formula (1) may be isolated as a suitable salt, for example an addition salt (eg, hydrobromide, hydrochloride, etc.). Pyrimide of the present invention [4.51e] [1.3
・4] Thiadiazine derivative (1) and its salt are heterocyclic compounds having a novel skeleton that has not been described in literature, and c-AM
D (Cyclic Adenosine Monophosphate) Phosphogesterase inhibitory effect, histamine 2-receptor inhibitory effect, and antihypertensive, diuretic, and antihypertensive effects on animals, especially mammals (e.g., humans, dogs, rabbits, rats, and mice).
Shows anti-inflammatory and gastric secretion suppressing effects, such as hypertension,
Antihypertensive agents and diuretics for diseases such as edema and gastric ulcers,
It is not only useful as an anti-inflammatory agent, a therapeutic agent for gastric ulcers, and has antibacterial activity, but also as a reagent for biochemical tests.

When compound (1) and its salts are used as such pharmaceuticals, they can be used by themselves or mixed with appropriate pharmacologically acceptable carriers, excipients, and diluents to form powders, tablets, capsules, and injections. It can be safely administered orally or parenterally in the form of tablets, suppositories, liniments, etc.

The dosage varies depending on the target disease, symptoms, subject, administration method, etc., but for example, for lowering blood pressure for hypertension in adults,
When administered as a diuretic, oral administration is approximately 0.3 to 1 female/kg (body weight) per dose, and the daily dose is approximately 1 to 1.
Preferred dosages are approximately 9/k9 (body weight) of 4. Furthermore, the compound (1) of the present invention and its salts are useful as intermediates for the synthesis of new pharmaceuticals. For example, the compound of general formula (ld) can be led to a new compound (blood) having the same action and use as the compound of the present invention by the following reaction. [In the formula, RI' and R2' represent an alkyl group, and R5 represents an acyl group] In the above single-pronged formula, R5
An acyl group as represents a lower alkanoyl group.

The above acylation reaction can be carried out using a conventional acylating agent (eg, acid anhydride, acid halide, etc.).
Usually, the reaction is preferably carried out in a suitable solvent (eg, pyridine, etc.) at room temperature for about 1* to 3 hours. Furthermore, the compound of general formula (le) can provide antipyretic, analgesic, and
Useful as an anti-inflammatory agent [1, 2, 3) Thiadiazolo [4]
・51d] Pyrimidine derivative [JP-A-52-10519
4 (Tokubuta No. 51-21512)].

[In the formula, R1, R2 and R3 have the same meaning as shown in general formula (1)] The above reaction involves reacting the compound (le) with an oxidizing agent (an oxidizing agent with relatively strong oxidizing power such as bromine). A compound of general formula (W) is obtained by the following steps.

This reaction is usually preferably carried out in a solvent (eg, chloroform, methylene chloride, etc.) at room temperature for about 1 to 3 hours.
The raw material compound (0) used in the production of the compound (1) of the present invention can be produced, for example, by the following reaction [JP-A-52-105194 (Tsubakiisosho 51-2)
No. 1512)].

[In the formula, R1, R2, R3 and R4 have the same meanings as above]
In method 'a-' above, first add compound (W) to compound (V).
to obtain compound (b).

This reaction is usually allowed to proceed by heating in the presence of a solvent. Such solvents include, for example, polar aprotic solvents (e.g. dimethylformamide, dimethylsulfoxide, pyridine, ethyl acetate, acetone, etc.)
and other aprotic solvents (eg, dioxane, benzene, etc.). The reaction temperature is usually about 2 to 10
The temperature is about 00C, preferably about 50 to 8000C. The reaction time is usually about 1 to 1 feeding time, preferably about 1 to 4 hours. The amount of compound (W) to be used is about 1 to 5 mol, preferably about 1 to 2 mol, per 1 mol of compound (V). When R3 is a hydrogen atom, by generating thiocyanic acid in the reaction solution (for example, by reacting a thiocyanate such as ammonium thiocyanate or potassium thiocyanate with hydrochloric acid) and reacting it with compound (V). A compound (0) in which R3 is a hydrogen atom can be obtained. This reaction is usually allowed to proceed by heating in the presence of a solvent. Examples of such solvents include water, cellosolve, and the like. The reaction temperature is usually about 80-12
The reaction time is preferably about 0 qo and the reaction time is about 1 to 5 hours.
The amount of thiocyanate used is about 1 to 3 moles per 1 mole of compound (V). Also, R3 and R4
Compound (0) in which is a hydrogen atom can also be obtained in good yield by the following reaction.

[In the formula, RI and R2 have the same meanings as above.] The above method {b' is for obtaining the compound of the general formula (b') by reacting the compound (W) with thiosemicarbazide.

This reaction is usually allowed to proceed by heating in the presence of a solvent. Examples of such solvents include methyl cellosolve and ethyl cellosolve. The reaction temperature is usually around the boiling point of the solvent, and the reaction time is preferably about 3 to 6 hours. The amount of thiosemicarbazide used is approximately 1 to 3 moles per mole of the compound (blood).
The compound of general formula (0) thus produced is preferably isolated from the reaction solution by conventional separation and purification means (eg, crystallization from alcohol, etc.) and then subjected to the next reaction. The compound of the above formula (0) is a new compound, and the synthesis of the compound (1) of the present invention or other heterocyclic compounds [Special Seki No. 52-105194 (Samurai Buta No. 51-121512)]
It is an extremely useful compound.

The present invention provides a novel compound useful as such an intermediate (0
) is also provided. In addition, the above [a',
The raw material uracil derivative used in the method of 'b) is, for example, Annalen der Heko-(value n.Chem.), 6
Vol. 12, p. 158 (1958), Journal of Praktschechemy (J.Prakt.Chem)
．． ), vol. 32, p. 47 (1966), or according to the method described therein.

Reference Example 1 1,3-dimethyl-6-hydrazinouracil (7 days) was suspended in dimethylformamide (40 days), ethyl isothiocyanate (10 days) was added, and the mixture was heated at 50-60 degrees Celsius.
It lights up for 3 hours.

The reaction solution was concentrated, water was added to the resulting syrup, and the precipitate was reconsolidated from methanol (140') to give colorless crystals of 1,3-dimethyl-6-(4-ethylthiosemicarbazide)uracil, 8.59 get. Melting point 204-20 is ○ Ultraviolet absorption spectrum: Contains methanol 267, 24 times Elemental analysis value Calculated value: C9 days, C (%) days (%) N (%) as 5N502S 42.01 5.88 27.22 Actual measurement value:
41.66 5.77 27.18 Reference example 2
3-isobutyl-6-hydrazinouracil (melting point 135
Suspend -140qo, 5 nights) in dimethylformamide (30), add isobutyl isothiocyanate (5) and heat at 70-80qo for 4 hours.

Add water (100 mm) to the reaction solution, dissolve the precipitate in dimethyformamide (60 mm), and add water (10 mm) to the precipitate.
is added to give 6.5 kg of colorless crystals of 3-isobutyl-6-(4-isobutylthiosemicarbazide)uracil. Melting point 242-24 ○ Calculated elemental analysis value: C, 3 days As 22N502S C (%) days (%) N (%) 49.98 7.10 22.42 Actual value: 4
9.81 7.30 22.70 Reference example 3-
19 According to the methods of Reference Examples 1 and 2, the compounds shown in Table 1 are obtained by the following reaction.

Table 1 Example 1 1,3-diethyl-6-(4-ethylthiosemicarbazide) uracil (4.0%) was suspended in chloroform (40%) and N-chlorosuccinimide (2.0%) was suspended in chloroform (40%).
) was added little by little over about 2 hours.

After reacting for an additional hour, the pale green reaction solution was concentrated and dissolved in methanol (10 ships), and water was added to obtain yellow crystals. When reconstituted from methanol, 2-ethylamino-5
・7-diethylpyrimide [4.5-e] [1.3.4]
Yellow crystals (2.5 hours) of thiadiazine-6.8(hu.7H)-dione are obtained. *Melting point: 190-200℃ (decomposed) Ultraviolet absorption spectrum: Contains methanol 356, 26 Elemental analysis value: C,. C (%) Day (%) N (%) S (%) 46.68 6.05 24.72 11.31 Actual value: 46.30 6.03 24.57 11.4
6 Examples 2-15 According to the method of Example 1, the compounds shown in Table 2 are obtained by the following reaction.

NCS: N-Chlorosuccinimide Table 2 Reference Example 20 1,3-dimethyl-6-chlorouracil (3.0 m) was dissolved in methyl cellosolve (15 m), thiosemicarbazide (3.0 m) was added, Heat at 1300-135°C and react.

After reacting for 5 hours, when the mixture is left to cool, a cold-colored powder is precipitated.

When collected by filtration and reconsolidated from dimethylformamide-water, 1.
Colorless crystals (2.0 min.) of 3-dimethyl-6-thiosemicarbazidouracil are obtained. Melting point 178-180qC Ultraviolet absorption spectrum: Methanol 2, 241n Elemental analysis calculated value C7 days. C (%) Day (%) N (%) S (%) as N502S 36.67 4.84 30.55 13.99 Actual value 36.46 4.96 30.70 13.6
Example 1 161.3-Dimethyl-6-thiosemicarbazidouracil (2.0 ml) was suspended in chloroform (20 ml) and N-bromosuccinimide (2.0 ml) was suspended while stirring.
0) in small portions over about 2 hours.

After reacting for another 1 hour, the precipitate was suspended in water and made slightly alkaline with dilute ammonia water, and the yellow precipitate was collected by filtration.
Gently warm and dissolve in dimethylformamide (40'), add water (20') and leave to cool to yield 2-amino-5,7-dimethylpyrimide [4,5-e] [1,3
・4] Obtain 1.5 yellow crystals of thiadiazine-6.8(7H)n dione. Melting point 190-200qo (decomposition) Ultraviolet absorption spectrum: Methanol 356, 25
Enemy mass spectrum: m/e227 (molecular ion peak)
Elemental analysis value calculation value C (%) day (%) N (%) S (%) as C7 rat day 502S 36.99 3.99 30.82 14.11 Actual value 36. Muscle 3. Carp 30. Spot 14.67 Example 211.3-diethyl-6-(1-methylhydrazino)uracil (3.0 ml) was dissolved in dimethylformamide (1
Ethylysothiocyanate (2.0
Add [) and react at 100 qo for 3 hours.

The syrup obtained by concentration is crystallized from alcohol to obtain 3.0 g of 1,3-ethyl-6-(1-methyl-4-ethylthiosemicarbazide)uracil. Kuzu & Dot
170-17chi0 Mass spectrum: m/e299 (molecular ion peak) Ultraviolet absorption spectrum: Input methanol 274 nm elemental analysis calculated value C, 2 days 2, C (%) days (%) N (%) as N502S )S (%) 48.14 7.07 23.39 10.71 Actual value 48.27 7.01 23.71 10.6
2 Reference Examples 22-24 According to the method of Reference Example 21, the compounds shown in Table 3 are obtained by the following reaction.

Table 3 Example 17 1,3-dimethyl-6-(1-methyl-4-ethylthiosemicarbazide)uracil (4.
Dissolve the N-bromoacetamide (4.0 μm) in chloroform (50 μm) and add portionwise N-bromoacetamide (4.0 μm).

After further stirring for 1 hour, the brown syrup obtained by concentration was crystallized from methanol-water, resulting in 2-ethylamino-4.
・5,7-trimethylpyrimide [4.51e] [1.3
・4] Obtain 2.5 days of pale yellow crystals of thiadiazine-6,8(7H)-dione. Melting point 261-26 turtle○ Ultraviolet absorption spectrum: ^ Methanol milk lnm elemental analysis calculated value C, rainbow, bu 502S as C (%) day (%) N (%) S (%) 44.59 5.61 26 .01 11.91
Actual value 44.62 5.46 26.17 11.
66 Examples 18-20 According to the method of Example 17, the compounds shown in Table 4 are obtained by the following reaction.

Table 4 Reference Example 24 2-Amino-5,7-dimethylpyrimide [4,5-e][1,3,4]thiadiazine-6 obtained in Example 2
8 (Group/7H) - dione (2.0 evening) with pyridine (30
Suspend in [), add acetic anhydride (6.0 I), and react at room temperature for about 2 hours.

When the syrup obtained by concentrating the reaction solution is resuspended from methanol, pale yellow crystals of 2-acetylimino-3-acetyl-5,7-dimethylpyrimide [4,5-e] [1,3] are obtained.
・4] Thiadiazine-6,8 (spot 7H)-dione 1
．． Get 0 nights. Melting point 140-14300 Mass spectrum: mnoe311 (molecular ion peak) Ultraviolet absorption spectrum: ^ Methanol 295, 221n Elemental analysis calculated value C,. C (%) Day (%) N (%) S (%) 42.25 4.72 20.52 9.39 Actual value 41.96 4.74 20.70 9.44
Reference example 252-methylamino-5,7-dimethylpyrimide [4.51e] (1.3.4) Thiadiazine-6.
8(spot・7H)-dione (0.3) in chloroform (
Add bromine (1 secretion) while suspending it in [) of 5.

After reacting at room temperature for 3 hours, the syrup obtained by concentration is crystallized from methanol to obtain pale yellow crystals. When reconstituted from methanol again, pale yellow crystals of 4,6-dimethyl-[1.2.3]thiadiazolo[4.
5-d] Pyrimidine-5,7-(Princess/Bait)-Zion is 0
．． You can get 1 ta. Melting point 133-13zu○ Ultraviolet absorption spectrum: ^ Ax Winter Nord 33o, 2-breast Elemental analysis value Calculated value: C6 ratio N402S C (%) day (%) N (%) S (%) 36.30 3. 09 28.50 16.32
Actual value: 36.31 3.05 28.79 16.
10 Experimental Examples 1 PDE (phosphogesterase) inhibitory effect From the cerebral crude mitochondrial fraction of 5 SD rats,
The M3 fraction was obtained based on the method of Robertis [Journal of Neurochemistry, Vol. 9, p. 23 (1962)].

Table 5 shows the results of measuring the 50% inhibitory concentration (15o) of a representative example of compound (1) against crude M3-PDE using c-AMP as a substrate. For comparison, 15o of theophylline, a typical known PDE inhibitor, was measured. Table 5

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R^1 is a hydrogen atom or an alkyl group, R^2
represents an alkyl group, R^3 represents a hydrogen atom, an alkyl group, an alkenyl group, a phenyl group, a halogen-substituted phenyl group, a phenyl-alkyl group, or an acyl group; R^4 represents a hydrogen atom or an alkyl group] A pyrimido[4,5-e][1,3,4]thiadiazine derivative or a salt thereof. 2 General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^1 is a hydrogen atom or an alkyl group, R^2
represents an alkyl group, R^3 represents a hydrogen atom, an alkyl group, an alkenyl group, a phenyl group, a halogen-substituted phenyl group, a phenyl-alkyl group, or an acyl group; R^4 represents a hydrogen atom or an alkyl group] A general formula characterized by reacting an oxidizing agent with a compound represented by ▲ mathematical formula,
There are chemical formulas, tables, etc. ▼ Pyrimide [4.5-e] [1.3] [In the formula, R^1, R^2, R^3 and R^4 have the same meanings as above]
-4] Method for producing a thiadiazine derivative or a salt thereof.