JPS61137869A - Piperazine derivative - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides compounds of formula (I) in free form or in the form of acid addition or base salts: wherein Ko is hydrogen or formula (II): (wherein R3, R4 and R5 is independently hydrogen, lower alkyl, lower alkoxy, lower) λrogen alkyl,
CN1N02 or halogen), and R2 is hydrogen or lower alkyl.

According to the invention, the compounds of formula (I) and their acid addition and base salts have the following properties: a) When Rr is other than hydrogen, compounds of formula (Ib):
A compound represented by the formula (III) is reacted with a compound represented by R1-X (l[), and b) a compound represented by the formula (■) is converted into a compound represented by the formula (V): YCH2,CO,GOOR2(V). C) The compound represented by the formula (■): f-λ R1--jH (■) is reacted with the compound represented by the formula (■) [where the formula (Ib) and In ([) to (■), K and R2 have the same meanings as above, X, Y, and Z are leaving groups, and λ' is the formula (I
J, which is the group of I), optionally converts the compound in which R2 is lower alkyl to a compound in which R2 is hydrogen, or vice versa, and converts the resulting compound into the free form as appropriate. or by recovering it in the form of an acid addition salt or a base salt.

Step a) consists of dissolving a compound of formula (Ib) in an inert solvent such as a dialkylcarboxylic acid amide, for example dimethylformamide, and converting it to a compound of formula This can be easily carried out by reacting with the compound (I).

Cyclization according to b) involves dissolving or suspending the compound of formula (IV) in an inert solvent, such as an anhydrous lower alkanol, such as anhydrous ethanol, and adding it, preferably at elevated temperature, e.g. at the boiling point of the reaction mixture. This can be easily carried out by reacting with a compound of formula (V), for example, ethyl bromopyruvate.

Step 1 C) comprises, for example, adding a compound of formula (■) to a compound of formula (■) in an inert solvent such as a cyclic ether, for example tetrahydrofuran, preferably at elevated temperature, for example at the boiling point of the reaction mixture.
This can be easily carried out by reacting with a compound.

The product can be isolated and purified by conventional methods.

Leaving groups such as X, Y, Z are leaving groups commonly used in this type of reaction, such as halogens, such as chlorine or bromine. .

The starting materials of formula (IV) in which R1 is other than hydrogen are partially new and can be prepared according to the following reaction scheme: [where λ' and X are as defined above].

B) Ic thus when preparing a compound of formula (IX),
Piperazine hydrate can be used in excess, e.g.
A 10-fold excess, preferably a 7-8 fold excess, is used.

Other starting materials are either known or can be prepared according to known methods.

Compounds of formula (I) in which R2 is hydrogen and compounds of formula (I) in which R2 is lower alkyl can be interconverted by conventional methods.

Compounds of formula (I) in which K□ is hydrogen can be recovered in free form or in the form of acid addition salts. Examples of suitable acids include inorganic acids such as hydrohalic acid or organic acids such as maleic acid.

Compounds of formula (I) in which R2 is hydrogen may be recovered in free form or in the form of a basic salt, such as an alkali or alkaline earth metal salt.

The compounds of the invention exhibit pharmacological, particularly antiviral activity, as shown by their inhibitory action against various viruses, such as picornaviruses and especially rhinoviruses. This inhibitory effect is shown in vitro at various concentrations, for example from 0.0001 to 100 μg/ml. The compounds are therefore indicated for use in medicine, especially as antivirals, for example against respiratory diseases induced by viruses.

The indicated daily doses for the above uses range from about 70 to 350, conveniently administered in 1 to 4 divided doses per day or in controlled release form.

Dosage forms suitable for oral administration consist of 17.5 η to about 350 η of the active ingredient in admixture with a solid or liquid pharmaceutical carrier.

As previously noted, the appropriate daily dosage for a particular compound of the invention will vary depending upon, among other things, its relative degree of activity.

For example, 2-[1-(2,
5-dimethylbenzyl)piperazin-4-yl]-1,
3-thiazole-4-carboxylic acid sodium salt is 0.
It showed an inhibitory effect on rhinovirus at 0001 μg/nl.

The compounds can be used in free form or, when □ is hydrogen, as pharmaceutically acceptable acid addition salts, such as hydrochloride, acid fumarate or naphthalene-1,5-disulfonate. .

When R2 is hydrogen, the compound is in the form of a pharmaceutically acceptable base salt, such as the IJium or potassium salt,
Preferably, it can also be used in the former form.

The compounds can be administered enterally, eg, orally, or parenterally, eg, as an injection.

Pharmaceutical compositions containing compounds of the invention can be prepared according to standard pharmaceutical techniques, eg, in admixture with conventional pharmaceutically acceptable diluents, carriers or other excipients.

Such formulations are made up in conventional manner, eg, into tablets or capsules, or into dosage forms suitable for injection. Other dosage forms include, for example, ointments, sprays, aerosols, nasal drops, and tinctures.

In accordance with the above, the invention further provides a compound of the invention as defined above for use in medicine, in particular as an antiviral agent. In a further aspect, the invention also provides a method of treating a viral disease in a subject in need thereof, the method comprising administering an effective amount of a compound of the invention as defined above.

In yet another aspect, the invention also provides a pharmaceutical composition comprising a compound of the invention as defined above together with a pharmaceutically acceptable diluent or carrier thereof.

Lower alkyl preferably has 1 to 4 carbon atoms, especially methyl or ethyl. Halogenalkyl is, for example, CF a, CCz 3 or CHF2, especially
This is CF3.

The significance of specific substituents is λ□=a) Formula (II), b) benzyl, C) mono- or di- or trialkylbenzyl, R2=　a　　) Hydrogen b) C1-4 alkyl @ Combinations of these are particularly preferred.

An example of a particularly suitable group of compounds is where kl is a group of the formula CI, where R3, R4 and R5 are independently lower alkyl, and R2 has the same meaning as defined above, or R1 is hydrogen or a group represented by formula (II) [where R
4 is hydrogen, lower alkyl, lower alkoxy, CF3 or halogen], R5 is hydrogen, lower alkyl or lower alkoxy, and R3 and λ2 have the same meanings as above, or λ1 is hydrogen or ): [wherein R3, R4 and R5 are hydrogen, lower alkyl,
Lower alkoxy, CF3. NO2 or halogen], and R2 is hydrogen or lower alkyl.

A particularly preferred compound is the free form, sodium salt form or ethyl ester of 2-[1-(2,5-dimethylbenzyl)piperazin-4-yl]-1,3-thiazole-4-carboxylic acid.

The following examples illustrate the invention, in which temperatures are given in degrees Celsius.

Example 1 2-[1-(2,5-dimethylbenzyl)piperazin-4-yl J-1.3-thiazole-4-carboxylic acid ethyl ester (method b) 1-(2,5-dimethylbenzyl)-4 -thiocarbamoyl-piperazine 14
0 g is suspended in 2000 rnl of absolute ethanol, 70 g of ethyl brompyruvate is added, and the mixture is refluxed for 30 minutes with stirring. Insoluble solids are removed by hot suction,
Cool the Oki liquid with ice water and aspirate and filter it again. The mother liquor is concentrated by evaporation and the residue obtained is recrystallized from ethanol. The collected crystals were suspended in chloroform at 150°,
Treated with 100 g of potassium carbonate and 800 g of water, 30 g
Stir for a minute. The organic phase is shaken once with sat. The residue is digested with 500 g of petroleum ether, evacuated with suction and dried. Concentrate the mother liquor and add chloroform 200rn
Silica gel 60 (particle size 0.040~
0.063 m) 2.5 kg is subjected to chromatography. The corresponding fractions are concentrated and combined with the residue obtained above.

M, p, ss ~89° (HClm, P, 210 ~
220°).

Example 2 2-(I-(2,5-dimethylbenzyl)piperazin-4-yl)-1,3-thiazole-4-carboxylic acid sodium salt 2-(I-(2,5-dimethylbenzyl)piperazine-
146 g of ethyl ester (4-yl)-1,3-thiazole-4-carboxylate are dissolved in 25:00 rJ of methanol, 10,001 nl of caustic soda are added, and the mixture is stirred overnight and concentrated. The residue was dissolved in 2j of water, shaken once with chloroform 500°C, the solvent-free aqueous solution was adjusted to pH 5 with dilute HC/(I/1), and the precipitated material was filtered with suction. dry.

The mother liquor was concentrated and dissolved in 0.5N caustic soda 200-
Adjust the pH to 5 again, filter with suction and dry.

The combined crystals are dissolved in IN caustic soda 382.2 and lyophilized. I'', P, = 180' (decomposition).

Example 3 2-(I-, Piperazinyl)-1,3-thiazole-4-carboxylic acid ethyl ester (Method b) 0.25 g of 1-thiocarbamoylpiperazine was dissolved in 10 of absolute ethanol with 0.0 of ethyl brompyruvate. .36g
and leave at room temperature for 2 hours. The mixture was then concentrated to a volume of 1A and 10% diethyl ether. nl, evacuated and dried under reduced pressure with NaOH at room temperature for 18 hours. M, p, (dihydrochloride) 236-239'.

Example 4 2-(I-benzylpiperazin-4-yl)
-1,3-thiazole-4-'carboxylic acid ethyl ester (method a) 2-(I-piperazinyl)-1,3-thiazole-4-
9.5 g of carboxylic acid ethyl ester/HBr was dissolved in 10-dimethylformamide, and then 2CO3 fine powder 1
g and 0.2 g of benzyl chloride and stirred at room temperature for 24 hours.
Stir for an hour. The inorganic salts were then removed and the solution was evaporated under rotation and ethyl acetate.

50-, washed with water and saturated NaC/M
Dry over g S 04 and evaporate under reduced pressure under rotation.

This material is distilled (I, 33 x 10 milJ bar/
170°). m, p.

107~109° (HClm, P, 206~209°
).

Example 5 2-(I-benzylpiperazin-4-yl)
-1,3-thiazole-4-carboxylic acid ethyl ester (Method C) 4 g of N-benzylpiperazine was added to 15 g of tetrahydrofuran.
2-bromo-1,3-thiazole-4-
Treat with carboxylic acid ethyl ester and reflux for 2 hours. The solvent is removed by evaporation, the residue is triturated with 8% NaHCO3 and extracted with ethyl acetate. The organic phase was diluted with concentrated NaC/1
Mouth shaken Mg dried with SO4 and evaporated under rotation at 16 mbar (m.p. 107-109', HC
tm. p. 206-209°).

Similarly, the following compound of formula (I) can be produced.

K□=Formula (Il) l-(2.5-dimethylbenzyl)-4-thiocarbamoyl-piperazine, which is essential as a starting material, can be produced as follows.

a) 1-(2.5-dimethylbenzyl)-4-t-butoxy-carbonylpiperazine 159 g of 1-t-butoxycarbonylpiperazine was mixed with N,
Dissolve 1000 m7J of N-dimethylformamide and add 60 g of finely powdered potassium carbonate, 2.

32 g of 5-dimethylbenzyl chloride is added dropwise while cooling. Stir this mixture overnight at room temperature (gas will evolve)
, remove the salt, and concentrate the liquid in a rotary evaporator. The residue was taken up in 2000 ml of ethyl acetate/water (3/1), shaken once with saturated Na (J), and dissolved in M g S
Drying at 0.04 °C and concentration on a rotary evaporator gives the title product as a yellowish oil.

b) l-(2.5-dimethylbenzylon 1-(2.5-dimethylbenzyl)-4-t-bu) +
C fy /I/bonylpiperazine 2 60 g
After 1 hour, the mixture was treated with ethanolic HC/1500-- (which generated a lot of gas) under water cooling, and after 1 hour was concentrated using a rotary evaporator.
0+/, suction-filtered and dried. The crystals are taken up in dichloromethane and, while cooling, gaseous ammonia is bubbled through until saturation. The resulting thick suspension is sucked off, washed well, and the P solution is concentrated on a rotary evaporator to give the title product as white crystals. m, p, 59
~63°0 l-(2,5-dimethylbenzyl)piperazine also cannot be obtained directly from piperazine. 2. 10 g of 5-dimethylbenzyl chloride was added to 10 Qr of anhydrous ethanol.
It is added dropwise to a solution of 38.2 g of piperazine (without water) in nl with stirring at 10-15° over a period of 30 minutes. After reacting for 3 hours at room temperature, the solvent was removed under reduced pressure,
The residue was extracted repeatedly with diethyl ether, and the residue after concentration under reduced pressure was subjected to silica gel chromatography (M7734
, open column, φ=5 al, ! = 1 m, eluent CHCl3/CH30H/33%NH3=85/1
5/2). The crude extract can also be separated from residual piperazine by fractional vacuum distillation.

C) 1-(2,5-dimethylbenzyl)-4-cyanopiperazine N,N-dimethylformamide 1-(2,
50 g of pulverized potassium carbonate are added to 5-dimethylbenzyl, and 63 g of bromine cyanide in 200 N,N-dimethylformamide are gradually added with stirring. Stirring was continued overnight at room temperature, the organic salts were sucked out, and the furnace solution was reduced to zero.

Evaporate at 13 mbar/30° and take up the residue in 21 ml of ethyl acetate/water (3/1). Saturate the organic phase with NaC
Wash once with J'59-, dry with MgSO4, and concentrate on a rotary evaporator.

This oily residue was then digested with petroleum ether (from 40″
60°), crystallization begins. The resulting crystals are digested with petroleum ether (60-80'), filtered under suction, and dried to give the title compound as pale yellowish crystals. , m. p. 56-60°.

d) 1-(2,5-Dimethylbenzyl)-4-thiocarbamoyl-piperazine 70 g of hydrogen sulfide and 35 g of ammonia in 350 methanol are condensed in a pressurized vessel at 120" to give 1-(2
．． 5-dimethylbenzyl)-4-cyanopiperazine 12
Add 5 g at room temperature and shake the mixture until a clear solution forms. The next day, the mixture was concentrated and diluted with diethyl ether 1
000 m/, digestion, suction displacement and drying to give the title compound as white crystals. m. P. 176
~180°.

The remaining compounds of formula (IV) can be obtained analogously.

Claims (1)

[Claims] 1. Formula (
I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R_1 is hydrogen or Formula (II): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) R_5 is independently hydrogen, lower alkyl, lower alkoxy, lower halogenalkyl, CN, NO_2 or halogen), and R_2 is hydrogen or lower alkyl. 2, a) R_1 is a group represented by formula (II) [wherein R_3, R_4 and R_5 are independently lower alkyl], and R_2 is as defined in claim 1; , b) R_1 is hydrogen or a group represented by the formula (II) [wherein R_4 is hydrogen, lower alkyl, lower alkoxy, CF_3 or halogen, and R_5 is hydrogen, lower alkyl or lower alkoxy], A compound according to claim 1, wherein R_3 and R_2 are as defined in claim 1. 3. R_1 is hydrogen or formula (II): ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (II) [In the formula, R_3, R_4 and R
_5 is hydrogen, lower alkyl, lower alkoxy, CF_3
, NO_2 or a halogen], and R_2 is hydrogen or lower alkyl. 4,2-[1-(2,5-dimethylbenzyl)piperazin-4-yl]-1,3-thiazole-4-carboxylic acid. 5. The compound according to claim 1 in the form of a sodium salt or ethyl ester. 6. A pharmaceutical composition containing a compound of formula (I) according to claim 1 in free form or in the form of a pharmaceutically acceptable acid addition salt or base salt, together with a pharmaceutical diluent or carrier. 7. Compounds of formula (I) according to claim 1 in free form or in the form of pharmaceutically acceptable acid addition salts or base salts for use in the manufacture of drugs. 8. A compound of formula (I) according to claim 1, in free form or in the form of a pharmaceutically acceptable acid addition salt or base salt, for use in the manufacture of antiviral drugs. 9, a) If R_1 is other than hydrogen, the formula (I b)
：▲There are mathematical formulas, chemical formulas, tables, etc.▼A compound represented by (I b) is reacted with a compound represented by formula (III): R'_1-X(III), b) Formula (IV): ▲Math. , chemical formulas, tables, etc.▼(I
V) The compound represented by formula (V): YCH_2・CO・COOR_2(V) is cyclized together with the compound represented by formula (V), c) Formula (IV): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I
V) React the compound represented by formula (VII): ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (VII) [Here, in formulas (I b) and (III) to (VII), , R_1 and R_2 are as defined in claim 1, and X, Y
, Z is a leaving group, and R'_1 is a group of formula (II)]
, optionally, R_2 is lower alkyl.
_2 is hydrogen, or vice versa, and the compound thus obtained is recovered in free form or in the form of an acid addition or base salt, as appropriate. A method for producing the compound according to item 1. 10. Formula: ▲ Numerical formula, chemical formula, table, etc. ▼ (IVa) [In the formula, R'_1 is as defined in claim 9] A compound represented by the following.