JPH0443066B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the general formula In the formula, ^R1 means 1 ^- methyl-2-pyrrolidinyl or the group _-CH2 - ^NR2R3 , where ^R2 and ^R3
each represents C _1-4 alkyl or -NR ² R ³ is the residue of a 5- or 6-membered saturated heterocyclic ring system which may optionally further contain nitrogen or oxygen atoms in the ring, 2-Nitroimidazole and its physiologically acceptable acid addition salts. The invention further relates to processes for the preparation of these new compounds, to pharmaceutical preparations containing them, and to the use of these compounds as medicaments. The C _1-4 alkyl group may be linear or branched; methyl and ethyl are preferred. Examples of 5- or 6-membered heterocyclic ring systems which may optionally contain further nitrogen or oxygen atoms in the ring are pyrrolidine, piperidine, piperazine and morpholin. The method provided by the present invention comprises (a) Eq. In the formula, X represents hydroxy, chlorine, bromine or iodine. In the formula, R ¹ has the above meaning. or (b) 2-halo-α-(1-methyl-2-nitroimidazol-5-yl)-p-acetanisidinde with a compound of formula HNR ² R ³ in which R ² and or ( ^c ) α-(1-methyl-2-nitroimidazole-
5-yl)-p-anisidine is reacted with a compound of the formula R ¹ -COOH or a reactive derivative thereof, in which R ₁ A has the meaning given above, and optionally the resulting compound of the formula is physiologically tolerated. It consists of converting it into a capable acid addition salt. Processes (a), (b) and (c) are carried out according to conventional conditions well known to those skilled in the art, i.e. in a known inert solvent at a temperature between room temperature and the reflux temperature of the reaction mixture and optionally with a condensing agent. This is a condensation reaction that can be carried out in the presence of Formula R ¹ −COOH used in method (c)
As reactive derivatives of the compounds used in the condensation reaction are, for example, acid halides or acid anhydrides. The novel 2-nitroimidazole provided by the present invention exhibits protozoocidal, especially trypanosomicidal, activity. Compared to known compounds that have been found to have good trypanosomicidal activity, such as pentamidine or suramin, the present compound has excellent permeability to fluids (cerebrospinal fluid, i.e. the fluid present in the brain and spine). On the other hand, compared to already known 2-nitroimidazoles with the same activity profile, such as benznidazole or misonidazole, the present compound is more effective against African trypanosomes [e.g. (Trypanosomarhodesiense)] (see Table 1). A preferred field of use of the compounds provided by the present invention is veterinary medicine, ie a field in which trypanosomiasis plays an important role. Equine trypanosomiasis (Nagana) [Trypanosoma congolese (T.
congolense), Trypanosoma vivatucus (T.
vivax), Trypanosoma brucei (T.brucei)
[caused by T. euansi], surra [caused by T. euansi] and dourine
(Trypanosoma equiperdum (T.
equiperdum] is a notable disease of this species.

The compounds provided by the present invention can therefore be used as medicaments, ie for the prevention and treatment of diseases caused by protozoa, in particular trypanosomes, such as bed disease. It can be administered in the form of solid or liquid pharmaceutical preparations in admixture with inert organic or inorganic carrier substances and customary auxiliary substances suitable for oral or parenteral administration. As a dosage guideline for humans, amounts of 1 to 10 mg of active substance/Kg of body weight/day over a treatment period of 1 to 10 days may be possible. Dosage units are conveniently 50-1000 mg. Similar dosages apply for veterinary medicines. The compounds of the formula provided by the present invention can be used in pharmaceutical preparations in the form of acid addition salts with known physiologically compatible acids such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, citric acid or tartaric acid. can exist inside. These salts can be prepared by reacting a compound of the formula with the desired acid by known methods. The following examples illustrate methods of making compounds provided by the present invention. Example 1 78.5 g of 1-methyl-2-nitroimidazole-5-methanol was dissolved in 1.5 g of anhydrous tetrahydrofuran.
suspended in it. After the addition of 102 g of p-chloroacetylaminophenol and 144 g of triphenylphosphane, the mixture was cooled to 10° C. and a solution of 111 g of diisopropylazodicarboxylate in 750 ml of anhydrous tetrahydrofuran was stirred vigorously and the temperature was lowered with an ice bath. Addition was made within 20 minutes while maintaining the temperature at 10-12°C. The mixture was placed in the refrigerator overnight and the crystalline precipitate was sucked off. After recrystallization from acetonitrile 2, pure 2-
Chlor-α-(1-methyl-2-nitroimidazol-5-yl)-p-acetanisidide 90.9g
(56.6%). To a suspension of 20 g of this anisidide in 500 ml of ethanol was added 32 ml of a 3.68 molar ethanol solution of dimethylamine. The mixture was boiled under reflux for 5 hours, concentrated to dryness under reduced pressure and poured into 1 ml of methylene chloride and 400 ml of water. The mixture was adjusted to pH 7 with sodium bicarbonate. The organic phase was then separated, washed with a little water and evaporated. Crystallization of the residue from 200 ml of isopropanol gives 2-(dimethylamino)-α-(1-methyl-2-nitroimidazol-5-yl)-p-acetanisidide (16.6
g (82%) was obtained. 2-(dimethylamino)-α-(1-methyl-2
-Nitroimidazol-5-yl)-p-acetanisidide (15 g) was dissolved in 300 ml of hot ethanol.
To this was added 12 ml of 4.1N ethanolic hydrochloric acid with stirring, the mixture was cooled in an ice bath and 250 ml of diethyl ether were added. After standing in the refrigerator overnight, the precipitated hydrochloride salt was filtered off, washed with diethyl ether and dried under vacuum. Melting point 193~
2-(dimethylamino)-α-(1
-Methyl-2-nitroimidazol-5-yl)-
16.4 g of p-acetanisidide hydrochloride was obtained. Example 2 2-chloro-α-(1-methyl-2-nitroimidazol-5-yl)-p-acetanisidide 7
g and 3.8 g of pyrrolidine were heated under reflux in 200 ml of ethanol for 5 hours. This mixture is approx.
It was concentrated to 50ml and cooled. By recrystallizing the precipitate from acetonitrile, α-(1-methyl-2-nitroimidazole-5-
yl)-1-pyrrolidine-p-acetanisidide
5.9g (76%) was obtained. α-(1-methyl-2-nitroimidazole-5
15 g of -yl)-1-pyrrolidine-p-acetanisidide was dissolved in 350 ml of hot ethanol. to this
11 ml of 4.1N ethanolic hydrochloric acid are added with stirring, the mixture is cooled in an ice bath and diluted with diethyl ether.
250ml was added. After leaving it in the refrigerator overnight,
The precipitated hydrochloride salt was suctioned off, washed with diethyl ether and dried under vacuum. Melting point 209-210℃
(Decomposition) 15.4 g of α-(1-methyl-2-nitroimidazol-5-yl)-1-pyrrolidine-p-acetanisidide hydrochloride was obtained. Example 3 Piperidine 4.6 was prepared in the same manner as in Example 2.
α-(1-methyl-2-
6.1 g (75%) of nitroimidazol-5-yl)-1-piperidine-p-acetanisidide were obtained. Example 4 Diethylamine was prepared in the same manner as in Example 2.
2-(diethylamino)-α-(1-methyl-2-nitroimidazole-) with a melting point of 106-108°C from 3.95g
5-yl)-p-acetanisidide 5g (64%)
I got it. Example 5 By the same method as in Example 2, 2-chlor-α
α-(1-Methyl-2-nitroimidazol-5-yl)-(1-methyl-2-nitroimidazol-5-yl) with a melting point of 154-156°C (from methanol) from 3.24 g of p-acetanisidide and 2.18 g of morpholin 3.3 g (83%) of 5-yl)-4-morpholin-p-acetanisidide were obtained. Example 6 A suspension of 30 g of 1-methyl-2-nitroimidazole-5-methanol, 22 g of 4-aminophenol and 55 g of triphenylphosphine in 600 ml of anhydrous tetrahydrofuran is heated with diisopropylazoate for 20 minutes with vigorous stirring. Dicarboxylate
It was treated dropwise with a solution of 42.5 g in 300 ml of anhydrous tetrahydrofuran. Cool this mixture externally
The temperature was maintained at 20-24°C. After 2 hours, the resulting clear solution was evaporated under reduced pressure and diluted with methylene chloride.
Boiled briefly with a mixture of 125 ml and ethyl acetate. Crystal α-(1-
Methyl-2-nitroimidazol-5-yl)-p
-24.4 g of anisidine were obtained. A solution of 4.14 g of N-methyl-L-proline and 6.2 g of the above anisidine in 250 ml of acetonitrile was treated with 12.5 ml of triethylamine, followed by 2-fluoro-1
- treated with 8.5 g of methylpyridinium tosylate. The mixture was heated under reflux for 1 hour, the solvent was removed under reduced pressure and the residue was dissolved in 200 ml of ethyl acetate and water.
Distributed between 200ml. The aqueous phase was adjusted to pH 10 with sodium hydroxide and added 100 ml each of ethyl acetate.
Extracted twice. The extracts were combined and evaporated. The residue was filtered through 28 g of silica gel using acetone/toluene (volume ratio 1/1). (2S)-1-Methyl-α-(1-
8.1 g of methyl-2-nitroimidazol-5-yl)-pyrrolidine-carboxy-p-anisidide were obtained in the form of an oily crude product. 2.5 g (27%) of pure product was obtained by recrystallization from ether. Melting point 106-107℃, [α] ²⁵ _D = -66.5゜ (c = 1
% in methanol). Example 7 A solution of 22 g of 1-methyl-2-nitroimidazole-5-methanol in 300 ml of tetrahydrofuran and 150 ml of dimethylformamide was added with a solution of lithium diisopropylamine (2.2 g of butyl lithium).
(Made from 14.5 g of diisopropylamine in 65 ml of molar hexane solution and 150 ml of tetrahydrofuran)
was added dropwise over a period of 15 minutes at a temperature of -60°C.
The mixture was stirred at -60°C for 30 min and p-toluenesulfonyl chloride in 150 ml of tetrahydrofuran was added.
Treated with 28g. After removing the cooling means, warming to room temperature and adding 300 ml of ice/water, the mixture was extracted three times with 300 ml each of ethyl acetate. The combined extracts were washed with 150 ml of saturated sodium chloride solution and evaporated under reduced pressure. This residue was purified from 800 g of silica gel using ethyl acetate/dichloromethane (1:3 by volume). A pre-run of 1.5 followed by 1.5 was collected and evaporated. By recrystallizing from 70 ml of toluene, 5-
12 g (50%) of (chloromethyl)-1-methyl-2-nitroimidazole was obtained. Add 2.9 ml of a 1.98 molar toluene solution of sodium tert-amylate to 10 ml of dimethylformamide.
Medium 4'-hydroxy-pyrrolidine-acetanilide
Added to 1.26g of solution at -10°C. Then 5-
1 g of (chloromethyl)-1-methyl-2-nitroimidazole was added and the mixture was stirred at -10°C for 3 hours. The product was separated by adding 100 ml of water.
The product was recrystallized from 13 ml of acetonitrile to give α-(1-methyl-2
0.42 g (21%) of -nitroimidazol-5-yl)-1-pyrrolidine-p-acetanisidide was obtained. Example 8 A suspension of 0.14 g of 1-methyl-2-nitroimidazole-5-methanol, 0.22 g of 4'-hydroxy-1-pyrrolidine-acetanilide and 0.26 g of triphenylphosphane in 3 ml of anhydrous tetrahydrofuran was cooled with ice. While stirring vigorously, 0.17 g of diethyl azodicarboxylate in 1.5 ml of tetrahydrofuran was added dropwise. Mixture at room temperature
Stirred for an hour and the resulting clear solution was evaporated under reduced pressure. The crude product was purified by chromatography on silica gel. The by-products were first eluted with ethyl acetate and the main product was obtained by eluting with dichloromethane/methanol (9:1 by volume). Evaporation of the solvent mixture and crystallization from 1 ml of acetonitrile yielded 0.115 g (36%) of α-(1-methyl-2-nitroimidazol-5-yl)-1-pyrrolidine-p-acetanisidide, melting point 140-142°C.
I got it. The following examples illustrate pharmaceutical preparations containing compounds of formula and their physiologically acceptable acid addition salts. Example A Tablet 2-dimethylamino)-α-(1-methyl-2-
Nitroimidazol-5-yl)-p-acetanisidide hydrochloride 100mg Lactose 192mg Corn starch 80mg Hydrolyzed corn starch 20g Calcium stearate 8mg 400mg Example B Tablet α-(1-methyl-2-nitroimidazole- 5
-yl)-1-pyrrolidine-p-acetanilide hydrochloride 50 mg Lactose 194 mg Pre-latinized corn starch 150 mg Calcium stearate 6 mg 400 mg Example C Injection solution 2-(dimethylamino)-α-(1 per ml of drug) -methyl-2
-nitroimidazol-5-yl)-p-acetanisidide 5.1 mg Propylene glycol 0.4 ml Benzyl alcohol (benzaldehyde free) 0.015 ml Ethanol (anhydrous) 0.10 ml Sodium benzoate 48.8 mg Benzoic acid 1.2 mg Water (for injection) Total amount Up to 1.0ml

Claims (1)

[Claims] 1. General formula In the formula, ^R1 means 1 ^- methyl-2-pyrrolidinyl or the group _-CH2 - ^NR2R3 , where ^R2 and ^R3
each represents C _1-4 alkyl or -NR ² R ³ is the residue of a 5- or 6-membered saturated heterocyclic ring system which may optionally further contain nitrogen or oxygen atoms in the ring, 2-nitroimidazoles and physiologically acceptable acid addition salts thereof. 2 General formula In the formula, ^R1 means 1 ^- methyl-2-pyrrolidinyl or the group _-CH2 - ^NR2R3 , where ^R2 and ^R3
each represents C _1-4 alkyl or -NR ² R ³ is the residue of a 5- or 6-membered saturated heterocyclic ring system which may optionally further contain nitrogen or oxygen atoms in the ring, The compound according to claim 1, which is 2-nitroimidazole. 3 α-(1-methyl-2-nitroimidazole-
5-yl)-N-(1-methyl-2-pyrrolidinylcarbonyl)-p-anisidide. 4 2-(dimethylamino)-α-(1-methyl-
The compound according to claim 1, which is 2-nitroimidazol-5-yl)-p-acetanisidide. 5 2-(dimethylamino)-α-(1-methyl-
The compound according to claim 1, which is 2-nitroimidazol-5-yl)-p-acetanisidide hydrochloride. 6 2-(diethylamino)-a-(1-methyl-
2-Nitroimidazol-5-yl)-p-acetanisidideal Compound according to claim 1. 7 α-(1-methyl-2-nitroimidazole-
5-yl)-1-pyrrolidine-p-acetanisidide. 8 α-(1-methyl-2-nitroimidazole-
The compound according to claim 1, which is 5-yl)-1-pyrrolidine-p-acetanisidide hydrochloride. 9 α-(1-methyl-2-nitroimidazole-
5-yl)-1-piperidine-p-acetanisidide. 10. The compound according to claim 1, which is α-(1-methyl-2-nitroimidazol-5-yl)-4-morpholin-p-acetanisidide. 11 formula In the formula, X represents hydroxy, chlorine, bromine or iodine. In the formula, ^R1 means 1 ^- methyl-2-pyrrolidinyl or the group _-CH2 - ^NR2R3 , where ^R2 and ^R3
each represents C _1-4 alkyl or -NR ² R ³ is the residue of a 5- or 6-membered saturated heterocyclic ring system which may optionally further contain nitrogen or oxygen atoms in the ring, and, if desired, converting the resulting compound into a physiologically acceptable acid addition salt. A method for producing 2-nitroimidazoles and physiologically acceptable acid addition salts thereof, wherein R ¹ has the above-mentioned meaning. 12 2-Halo-α-(1-methyl-2-nitroimidazol-5-yl)-p-acetanisidide with the formula HNR ² R ³ where R ² and R ³ each represent C _1-4 alkyl or - NR ² R ³ is the residue of a 5- or 6-membered saturated heterocyclic ring system which may optionally further contain nitrogen or oxygen atoms in the ring, and optionally the obtained General formula characterized by converting a compound into a physiologically acceptable acid addition salt A method for producing 2 ^- nitroimidazoles and physiologically acceptable acid addition salts thereof, wherein R ² and R ³ have the above-mentioned meanings. 13 α-(1-Methyl-2-nitroimidazol-5-yl)-p-acetanisidide with the formula R ¹ -COOH where R ¹ is 1-methyl-2-pyrrolidyl or the group -CH ₂ -NR ² R ³ , where R ² and R ³ each represent C _1-4 alkyl or -NR ² R ³ represents a 5- or 6-membered ring which optionally further contains nitrogen or oxygen atoms in the ring. or a reactive derivative thereof, which is the residue of a saturated heterocyclic ring system, and optionally converts the resulting compound into a physiologically acceptable acid addition salt. A method for producing 2 ^- nitroimidazoles and physiologically acceptable acid addition salts thereof, wherein R ¹ has the above meaning. 14 General formula In the formula, ^R1 means 1 ^- methyl-2-pyrrolidinyl or the group _-CH2 - ^NR2R3 , where ^R2 and ^R3
each represents C _1-4 alkyl or -NR ² R ³ is the residue of a 5- or 6-membered saturated heterocyclic ring system which may optionally further contain nitrogen or oxygen atoms in the ring, A trypanosomicidal agent characterized by containing 2-nitroimidazole or a physiologically acceptable acid addition salt thereof as an active ingredient.