DK141287B - Analogous process for the preparation of 5-nitro-imidazole carbamates or acid addition salts thereof. - Google Patents

Description

(φΝ (ID no. 141287 DENMARK »') intci.'c 07 d 233/94 f (2t) Application No. 3 ^ -88 / 66 (22) Filed on 6 * Jul 1966 (23) Running Dec 6 1966 (44) The application presented and the subpoena published on 1 Feb 198Ο

DIRECTORATE OF

PATENT AND TRADEMARKET (30) Priority granted from, on

July 7. 1965, 470239s US

May 18, 1966, 550952, US

(71) MERCK & CO. INC., Rahway, New Jersey, US.

(72) Inventor: John Alan Carlson, 175 Chestnut Street, Cambridge, Massac® House, US: Dale Richard Hoff, 172 Hillcrest Avenue, Cranford, New Jer® sey, US: Clarence Stanley Ifooney, 1110 Cambridge Lane, Bridgewater Township, New Jersey, US.

(74) Plenipotentiary in the course of proceedings:

Hofman-Bang & Boutard Engineering Company.

(64) Analogous process for the preparation of 5-nitro-imidazole carbamates or their acid additives salts.

The present invention relates to an analogous process for the preparation of novel therapeutically active 5-nitro-imidazole carbamates of the general formula set forth in the preamble to the claim, as well as the acid addition salts thereof, which is characterized by the characterizing portion of the claim. These compounds exhibit antiparasitic activity, especially against trichomoniasis and enterohepatitis. The compounds are also active against amoebiasis and trypanosomiasis as well as against chronic respiratory diseases of poultry caused by PPLO organisms.

Danish Patent Specification No. 88653 discloses 5-nitroimidazole compounds which contain at the 2-position an alkyl or aralkyl group and at one nitrogen atom are substituted with an alkylene oxy or alkylenacyloxy group.

2 t41287

Furthermore, N-alkyl-2-hydroxymethyl-5-nitroimidazoles or 2-acylated derivatives thereof are known from the specification of Danish Patent No. 107,618.

These known compounds possess antiparasitic activity, but to a significantly lesser extent than the compounds prepared by the process of the invention.

The present 5-nitro-imidazole carbamates have a surprisingly high activity against the aforementioned parasites and microorganisms.

Thus, they are effective against Thrichomoniasis, which is caused by infections of the vagina with Trichomoniasis vaginalis.

For the treatment of said diseases, the active compounds are administered either orally or topically. For this purpose, the usual dosage forms, such as capsules, tablets, solutions, ointments or suspensions containing the active substance in admixture with diluents, carriers and additives of various kinds may be used.

in

The effective dose size is 25 - 1000 mg in a single dose or divided into several doses per day. day.

The invention further encompasses the preparation of acid addition salts of these imidazole carbamates. The salt may be of an inorganic acid such as the hydrochloride, hydrobromide, phosphate, nitrate or sulfate, or of an organic acid, e.g. citrate, tartrate, adipate, methanesulfonate, p-toluenesulfonate. Non-toxic acid addition salts tolerated by the host animal in the amounts used are used when the carbamates are to be used in their salt form as an antiparasitic agent.

Hereinafter, a more detailed description of various embodiments of the process for preparing the compounds of the present invention is given.

3 141287 I. Isocyanate and the isothlocyanate process

One method of preparing the carbamates comprises reacting an appropriate isocyanate or isothiocyanate with a 1-substituted-2-hydroxyalkyl-5-nitroimidazole or 1-substituted-2-mercaptoalkyl-5-nitroimidazole in accordance with the reaction scheme: J- M + r3 -N = C = K- »° 2" θ- [o] -AI-NHR3 2 tt 1 "5 where Q, A, M, R and R have the above meaning.

The isocyanate reaction is conveniently carried out by mixing the imidazole and a substituted isocyanate (or isothiocyanate), preferably in aquimolar amounts or with a slight molar excess of isocyanate (or isothiocyanate), in an inert solvent at a temperature of 20 - 120 ° C. Aromatic hydrocarbons such as benzene and toluene or halogenated aliphatic hydrocarbons, e.g. dichloro or tetrachloroethane, are examples of suitable solvents. It is preferred to add a small amount of base, such as a tertiary amine, e.g. pyridine or triethylamine, or even a stronger base such as an alkali metal alkoxide, e.g. sodium methoxide or potassium ethoxide since the reaction is catalyzed by base.

z

The method can also be used to prepare carbamates where R is hydrogen and M is oxygen, in which case the cyanic acid reagent is preferably formed in situ from an alkali metal cyanate, such as by the addition of acetic acid or trifluoroacetic acid to the reaction mixture. It should be noted that unsubstituted carbamates can be more satisfactorily prepared in other ways and that the specific reaction described does not lend itself to the preparation of x unsubstituted thionecarbamates wherein R 2 in the formula is hydrogen and M is sulfur.

II. The alkali metal cyanate or thiocyanate / acid method

Certain 1-substituted imidazol-2-ylalkyl carbamates and thiocarbamates can be obtained by another process whereby the corresponding 1-substituted-2-halo methyl (or 2-alkyl or arylsulfonyloxymethyl), 1A1287 4 imidazolyl is reacted with an alkali metal cyanate or thiocyanate to give a 1-substituted-2-cyanatomethyl or 2-thiocyanatomethylimidazole which is treated with a mineral acid, preferably sulfuric acid. However, it is preferred to use this method to prepare thiocarbamates instead of carbamates because the cyan atom intermediate can be rearranged into an isocyanate derivative. This problem is of no practical importance if it is a thiocyanato intermediate. The reaction can be diagrammatically illustrated as follows;

0 n ~ 1 J- / 0 / -X + NaACN-> 0 £ Ν l JL / q7ACN

2 IT II

l1 R1 I

1H + -FX / - / · 02N-1y) - [3 / -AC. NH 2 wherein R 1 and Q have the above meaning and X is halogen, alkylsulfonyloxy or phenylsulfonyloxy, suitably chlorine, mesyl, tosyl or bromine.

It is preferred to carry out the reaction with thiocyanate in a solvent such as a lower alkanol, e.g. methanol or ethanol, dimethylformamide, a lower alkanoyl nitrile, such as acetonitrile, at a temperature between 15 ° C and 100 ° C. Thereby, a 1-substituted-2-thiocyano-5-nitroimidazole is formed, e.g. a 1-alkyl or 1-acyloxy-alkyl-2-thiocyano-5-nitroimidazole, such as a 1-methyl, 1-ethyl or 1-acetoxyethyl-2-thiocyano-5-nitroimidazole. A similar product is obtained when a starting material is used a 2-alkylsulfonyloxymethyl or 2-arylsulfonyloxymethylimidazole such as 2-p-toluenesulfonyloxymethyl-5-nitroimidazole in place of the 2-halo-methyl-imidazole, such as the corresponding 2- chloro- or 2-bromo-methyl-5-nitroimidazole.

The conversion of the 1-substituted-k'-thiocyanoalkyl or 2-cyanoalkyl-5-nitroimidazole to the thiocarbamate or carbamate out is conveniently effected by treatment with an excess of strong acid, preferably concentrated sulfuric acid in the cold, e.g. between 0 ° C and 15 ° C. The reaction is stopped by water addition to precipitate the thiocarbamate.

III. Imidazol-halogencarbonatprocessen

Another embodiment of the preparation of carbamates consists in a reaction of the halogen carbonate or halogen ion carbonate ester of 1-substituted-2-hydroxyalkyl- (or 2-mercaptoalkyl) -5-nitroimidazole with a primary or secondary amine. The reaction can be illustrated by the following scheme: - w M ^ ° 2N \ tf ~ A-C-X_) 02N_l / V-A-C-N ^ k hnr3r4 lx r4

K R

1 4 where Q, A, M, R, R and R have the above meaning and X is halogen.

The two reagents are mixed in an inert solvent such as dioxane, tetrahydrofuran or an aromatic hydrocarbon such as benzene at a temperature of 0 - 75 ° C. Excess amine reagent is usually used and good results are obtained with 2.0 - 5.0 moles of amine per liter. mole of halogenated carbonate ester, such as chlorocarbonate ester, at reaction temperatures of 10 - 40 ° C for most amines. It is noted that the ester is frequently called haloformate or halogenothione formate ester of 1-substituted-2-hydroxyalkyl (or mercaptoalkyl) -5-nitro-imidazole.

A molar excess of amine is desirable as it is advantageous to use 1 mole of amine (in addition to the mole required by the reaction) as an acid binding agent to neutralize the acid formed. The halogen formate used as starting material can be introduced into the reaction in the form of an acid addition salt and it is necessary to have another mole of amine to neutralize this salt.

6 U1287

Amines which are suitable in this reaction are in addition to ammonia e.g. methylamine or dimethylamine.

Z When ammonia is used to form carbamates in which R and both are hydrogen, a large excess is usually used and liquid ammonia is frequently used as the reaction medium. If the process is carried out with ammonia, the reaction temperature can be from -35 ° C (corresponding to the boiling point of ammonia) to about room temperature. At higher temperatures, a pressure vessel must be used or the ammonia must be dissolved in an organic solvent such as chloroform, ethanol or methanol.

IV. Carbamylhalogenid / Alkyl carbamate-process

In yet another embodiment, imidazolyl alkyl carbamates are prepared by reacting a 1-substituted-2-hydroxyalkyl (or 2-mercaptoalkyl) -5-nitro-imidazole with the carbamyl halide or alkyl oarbamate in question. This process can be illustrated by the following scheme: Μ M, i — f i / Ϊ — Ϊ II / R · ° 2N JI | _Zq / -ah ♦ b-c-n ^ 4 —- I J_fa / -Ac <R4 f i ίχ

R1 R

15 where R, Q, A, M, R and R are as defined above and B is halogen or alkoxy.

It will be appreciated that when B is chlorine, carbamyl chloride will react with the 2-substituted imidazole and when B is alkoxy, the reagent is an alkyl carbamate.

To prepare imidazolylalkylthione carbamates, i.e. where M in the above formula is sulfur, a thiocarbamyl chloride is used.

By the carbamyl chloride method, the two reagents are brought together in a suitable inert solution medium such as benzene, toluene, tetrahydrofuran or dioxane. It is preferred to use a low molar excess, e.g. 1 - 15% of carbamyl halide, and having an acid binding agent in the medium as acid is formed during the reaction.

When this process is used to form unsubstituted carbamates or thionecarbamates (where and both are hydrogen), the carbamyl chloride reagent is developed in the reaction medium as it is a very unstable compound. The disubstituted carbamyl chlorides are stable and added directly to the reaction mixture.

When the imidazole is treated with an alkyl carbamate, for example, ethyl or methyl carbamate, the two reagents are brought together in equimolar amounts in the presence of a strong base, preferably an alkali metal alkoxide such as sodium ethoxide, sodium methoxide or potassium isopropoxide in an inert solvent such as 1,2-dimethoxyethane.

A number of typical compounds prepared by the process of the invention have been tested for biological activity by the following test:

Mice with a mean weight of approx. 20 g were grafted intraperitoneally with 1 ml of a 48 h culture of Trichomonas fetus immediately after the mice were given an oral dose of the test compound. Similar doses were administered once a day for an additional three consecutive days.

The activity is expressed by the formula: A = 4 x (mg of test compound / kg body weight / day), adding to the formula the smallest amount of weight of the test compound exhibiting activity against the disease, i.e. enable the mice to survive. The lowest numbers are therefore the greatest activity of the compound.

In comparison, "Flagyl®1 (2-methyl-5-nitroimidazole-1-ethanol), prepared as disclosed in the specification of Danish Patent No. 88653, and" Emtryl "(1,2-dimethyl-5- nitro-1B-imidazole), known from Danish Patent Specification No. 107618.

The results are shown in the following table: 0 141287

ISLAND

TABLE

Compounds of formula y

09N -IL 3-R

* Y

R1

Compound R1 RA mg / kg No. 6 1 CH 2 CH 2 CO 2 NH 2 3.5 2 CH 3 CH 2 OCONHCH 2 8 CH3 CH20CSNH2 10 9 CH3 CH20CONH2 10 10 CH2CH3 ch2oconh2 10

Comparative compounds:

Compound A mg / kg

Flagyl® '60' Emtryl '60

The process according to the invention will be explained in more detail below by means of some examples.

EXAMPLE 1 1-Methyl-5-nitro-imidazol-2-ylmethylcarbamate 3.12 g of 1-methyl-2-hydroxymethyl-5-nitroimidazole are dissolved in 100 ml of methylene dichloride and cooled to 0 ° C. 2.64 g of sodium cyanate and 4.5 g of trifluoroacetic acid are added. The flask is sealed tightly and the mixture is stirred for 24 hours at 0 ° C. 200 ml of methylene chloride are added and the mixture is washed with saturated potassium hydrogen carbonate solution. The methylene chloride solution is evaporated to dryness in vacuo to give 1-methyl-5-nitro-2-imidazolyl-methylcarbate. This substance is recrystallized from a minimal volume of ethyl acetate to give practically pure 1-methyl-5-nitroimidazol-2-ylmethylcarbamate, mp: 166-170 ° C.

EXAMPLE 2 1-Methyl-5-nitroimidazol-2-ylmethylthiolcarbamate 1.35 g of 1-methyl-2-chloromethyl-5-nitroimidazole is dissolved in 25 ml of dry ethanol at room temperature and 1.11 g of callumthiocyanate are added to the solution. The resulting mixture is boiled for 2 hours and then allowed to stand at room temperature for approx. 12 hours. It is heated to approx. 75 ° C on a steam bath and the solid is filtered off. The filtrate is diluted with the same volume of water and the resulting solution is cooled and scraped to initiate crystallization. The resulting substance is filtered off, washed with ice water and dried. It consists of 1-methyl-2-thiocyanomethyl-5-nitroimidazole; mp: 87-88 ° C. This product is recrystallized from a minimal volume of benzene containing a trace of hexane to give yellow crystals of 1-methyl-2-thiocyanomethyl-5-nitroimidazole; mp: 87.5-88 ° C.

5 g of 1-methyl-2-thiocyanomethyl-5-nitroimidazole are added portionwise over 15 minutes to 25 ml of cold concentrated sulfuric acid. The resulting solution is maintained at 0 ° C for approx. 14 hours and then poured on excess ice crushed. The solution is adjusted to a pH of 6 with saturated potassium hydrogen carbonate solution. The solid is filtered off and washed with ice water. Then it is extracted with approx. 10 ml of ethyl acetate and the extract is dried over sodium sulfate and then evaporated to dryness. A small volume of hexane is added to the residue and the solid 1-methyl-5-nitro-2-imidazolylmethyl-thiol carbamate is filtered off. The yield is 4.34 g of 1-methyl-5-nitroimidazol-2-ylmethylthiolcarbamate; mp: 138-140 ° C.

EXAMPLE 3 1-Methyl-5-nitroimidazol-2-ylmethylcarbamate 1-methyl-5-nitroimidazol-2-ylmethyl chloroformate is cooled to 0 ° C and 25 ml of liquid ammonia is added. The resulting mixture is stirred for 10 minutes in the cold and then an additional 25 ml of liquid ammonia is added. The mixture is then allowed to stand at room temperature and stirred until excess ammonia evaporates. The residue is dissolved in 100 ml of water and the aqueous solution is extracted with three 100 ml portions of ethyl acetate. The ethyl acetate extracts are combined, washed back with 25 ml of water and then dried over sodium sulfate. Evaporate ethyl acetate to dryness in vacuo to give a residue of 1-methyl-5-nitroimidazol-2-ylmethyl carbamate. The product is recrystallized from ethyl acetate and then from water, whereupon the substance melts at 172-173 ° C.

Preparation of the starting material; 3.12 g of 1-methyl-2-hydroxymethyl-5-nitroimidazole are dissolved in a mixture of 4.3 ml of dimethylaniline and 20 ml of dioxane. Drizzle this solution to 30 ml of phosgene. The resulting dispersion is stirred for 2 hours at 0-5 ° C and then for 2 hours at room temperature. The solvent is evaporated by dry nitrogen for 2 hours to give an oily residue.

Example 4 1-Methyl-5-nitroimidazol-2-ylmethyl carbamate.

3.1 g (0.02 mol) (1-methyl-2-hydroxymethyl) -5-nitroimidazole are dissolved in 100 ml of benzene and 25 ml of pyridine. 1.9 g (0.022 mole of gaseous carbamyl chloride are introduced with stirring and the solution is left at 15 ° C for 8 hours and then evaporated under reduced pressure. The residue is taken up in ethyl acetate, washed with ice water and the ethyl acetate extract is dried over sodium sulfate. reduced pressure is recrystallized from acetone or ethyl acetate to give 1-methyl-5-nitroimidazol-2-ylmethyl carbamate; mp: 166-170 ° C.

H 141287 EXAMPLE 5 1-Methyl-5-nitroimidazol-2-ylmethyl-thioloarbamate 3.5 g (0.02 mol) of 1-methyl-2-mercapto-methyl-5-nitroimidazole are dissolved in 100 ml of benzene and 25 ml of pyridine under nitrogen. 1.9 g (0.22 mol) of gaseous carbamoyl chloride are introduced into the solution with stirring. The solution is left at 15 ° C for 8 hours and then evaporated at reduced pressure. The residue is taken up in ethyl acetate, washed with ice water and the ethyl acetate extract dried over sodium sulfate. Upon evaporation of the solution, reduced pressure is obtained, the residue is recrystallized from acetone or ethyl acetate to give 1-methyl-5-nitroimidazol-2-ylmethyl-thiol carbamate; mp: 138-140 ° C.

Example 6 1-Methyl-5-nitroimidazol-2-ylmethyl ethyl carbamate 1> 57 g (0.01 mole) of 1-methyl-2-hydroxymethyl-5-nitroimidazole, 0.1 g sodium ethoxide, 10 g ethyl carbamate and 20 ml benzene heated under reflux for 2 hours. The solution is evaporated to obtain reduced pressure and the residue is stirred with 10 ml of water. The mixture is extracted with ethyl acetate. The ethyl acetate fraction is dried over sodium sulfate and evaporated to give 1-methyl-5-nitroimidazol-2-ylmethyl-ethylcarbamate, mp: 166-170 ° C.

EXAMPLE 7 1-Methyl-5-nitrolimidazol-2-ylmethyl methylcarbamate 6 g of 1-methyl-2-hydroxymethyl-5-nitroimidazole and 3.5 ml of methyl isocyanate are added to 200 ml of benzene containing 0.5 ml of pyridine. The resulting mixture is boiled until the solution is complete. Evaporating the solution gains reduced pressure. The partially crystalline material is recrystallized from 12 ml of water to give 1.14 g of 1-methyl-5-nitro-imidazol-2-ylmethyl methylcarbamate; mp: 99-101 ° C.

EXAMPLE 8 1-Methyl-5-nitroimidazol-2-ylmethyl methylthiocarbamate 0.5 g of 1-methyl-2-hydroxymethyl-5-nitroimidazole and 0.28 g of methyl isothiocyanate are added to 20 ml of benzene containing 0.54 ml triethyl amine. The resulting mixture is boiled for 23 hours. It is then evaporated to dryness in vacuo and the solid is filtered off. The product is 1-methyl-5-nitroimidazol-2-ylmethyl methylthioncarbamate; mp: 133.5-135 ° C. It is recrystallized from water to give the melting point of 135.5-136 ° C.

EXAMPLE 9 1- Methyl-5-nitroimidazol-2-ylmethyl-NN-dimethylcarbamate 7.8 g of dimethylamine is added to a solution of 1-methyl-5-nitroimidazol-2-ylmethyl chloroformate prepared from 11.0 g of 1-methyl-2-hydroxymethyl-5-nitroimidazole as described in Example 4. The temperature of the reaction mixture is raised to approx. 24 ° C. The mixture is stirred under cooling for 1 hour and evaporated to dryness Tander reduced pressure. 100 ml of water and 800 ml of ethyl acetate are added to the residue. The ethyl acetate layer is separated and the aqueous layer is extracted with two 200 ml portions of ethyl acetate. The ethyl acetate extracts are combined and evaporated to dryness. After adding 10 ml of ethyl acetate to the residue, 1-methyl-5-nitroimidazol-2-ylmethyl-N, N-dimethylcarbamate crystallizes which is filtered off to give 5.3 g; mp: 91-94 ° C. After recrystallization from a benzene-hexane mixture the pure substance is obtained, mp: 92-94 ° C.

Claims (1)

Patent Claims: Analogous Process for Preparation of 5-Nitro-Imidazole Carbamates of the General Formula: YYaJU ^ Y Rx wherein A and M are oxygen or sulfur, R1 is an alkyl group having 1-6 7 hours of carbon atoms and R is hydrogen , alkyl or halogen substituted alkyl groups having 1-6 carbon atoms, and Q is an alkylene group having 1-4 carbon atoms, or acid addition salts thereof, characterized in: a) a compound of the formula: 1- ¥ Q0N _Q-Aff v A1 wherein Q, A and R1 have the above meaning, reacted with a compound of the formula: r3_N = C = M where R and M have the above meaning, or b) a compound of the formula: O ^ N - R1 where R1 and Q have the above meaning, and X is hydroxyl, halogen, alkylsulfonyloxy or phenylsulfonyloxy, is reacted with an alkali metal cyanate or thiocyanate, whereupon the reaction product of formula: N o2n-J-QA-CN \ r 41 wherein A has the above meaning is treated with an acid or c) a compound of the formula: And N1 ^^ LQ-ACX k1 where r \ Q, A and M have the above meaning and X is halogen is reacted with an amine of the formula: HNR3 R4 x 4 where R and R have the above meaning, d) or that a compound of the formula: Ir ° 2N \ YQ_AH Y where R 1, Q and A have the above meaning, are reacted with a compound of the formula:! B — C — NT \ r4