IL33462A - Thiazole derivatives,their manufacture and pharmaceutical compositions containing them - Google Patents

Description

33462/2 - »-i»».jni f-ns»* ,^ιτκ'η ηισττι nnVm New thiazole derivatives, their manufacture and pharniaceutical compositions containing them CIBA-GEIGY AG 33462/2 This invention relates to new thiazole derivatives of the formula in which R represents a thiomorpholino residue which is substi a tuted at least/one carbon atom by a lower alkyl or an alkoxy-lower alkyl group end /or is oxidized at the sulfur atom, and a process for manufacturing same.

Thiomorpholino residues oxidized at the sulfur atom are S-mono-oxidized and S , S-dioxidized thiomorpholino residues Examples of suitable lower alkyl groups are methyl, ethyl, propyl or isopropyl, or linear or branched butyl, pentyl.or hexyl residues which may be linked in any desired position.

Lower alkoxy-lower alkyl groups are, for example, lower alkoxy-lower alkyl groups derived from the lower alkyl groups indicated above such as methoxymethyl, ethoxymethyl, n-propoxymethyl or n-butoxymethyl or -ethyl residues.

Said substituents of the thiomorpholine ring that are characterized as "lower" are preferably such as contain - - not more than 6 carbon atoms.

The new compounds possess valuable pharmacological properties; inter alia, they display an amoebicidal action, as can be shown by animal experiments, for example on hamsters infected with E. histolytica. Furthermore, they act against Schistosomae, especially S. mansoni and S. japonicum, as can be shown in experiments on mice or hamsters infected with Schistosomae. — ■ t The new compounds, therefore, are useful; as anti-parasitary agents, especially as chemotherapeutics against Schistosomae and amoebal infections. The new compounds have also antibacterial activity, especially against gram-negative bacteria, for example salmonellae. Accordingly, the new compounds are useful as antibacterial agents, too. The new compounds are also valuable intermediates for the manufacture of other useful substances, especially of pharmacologically active compounds.

Specially valuable are compounds of the formulae in which n = 1 or 2 and R and R each represents a lower o x alkyl residue, especially a methyl residue, or a lower alkoxy-alkyl residue, in the first place a methoxymethyl residue, and the residue Rx may also represent hydrogen, and in the first place the compounds of the formulae in which n = 1 or 2, and R' and R" each represents a lower alkyl residue, for example a methyl residue.

Of special value are 4-[N- (5-nitro-2-thiazolyl)-formimidoyl] -thiomorpholine-l, 1-dioxide of the formula 3- (methoxymethyl ) - - [N- (5-nitro-2-thiazolyl ) -formimidoyl ] i thiomorpholine-l, 1-dioxide of the formula cis-2, 6-dimethyl-4-[N-(5-nitro-2-thiazolyl) -formimidoyl] thiomorpholine-l, 1-dioxide of the formula and more especially cis-2, 6-dimethyl-4- [N- (5-nitro-2-thia-zolyl)- ormimidoyl ]-thiomorpholine of the formula which, for example in mice and hamsters infected with S. mansoni, displays a distinct schistosomicidal action on oral or subcutaneous administration of 100 mg/kg.

The new compounds are manufactured by methods known per se . Thus, for example, an amine of the formula HR is reacted with a compound of the formula R having the meaning given above and X standing for an alkoxy group or a dialkylamino group.

An alkoxy group is, for example a. lower alkoxy group such as an ethoxy or methoxy group; a dialkylamino group is, for example a di-lower alkylamino group, such as the dimethyl-amino group.

Another process for the production of the new compounds consists in reacting 2-amino-5-nitrothiazole with a compound of the formula R-C0-C1, in which R has the meaning indicated, in dimethylformamide . In this operation, an N,N-dimethyl-formamidinium chloride is formed intermediately, the N' -nitrogen atom of which belongs to the residue R, and which then reacts further with the 2-amino-5-nitro-thiazole .

The new compounds are also obtained when 2-amino- Specially suitable acetals are those in which the alcohol component is a lower alkanol, for example the dimethylacetal of a formamide of the formula HCOR.

A suitable process for producing the mono- and dioxide of -[N-(5-nitro-2-thiazolyl) -formimidoyl ] -thiomor-pholine consists in oxidizing the non-oxidized compound.

The oxidation can be carried out in known manner, for example by reaction with a peracid, especially peracetic acid, a per-benzoic acid or monoperphthalic acid which may be substituted, for example by halogen atoms. When this reaction is carried out at alow temperature, that is to say with good cooling, or when only one mol equivalent of the oxidant is used, the monoxides are obtained, while heating and/or use of at least 2 mol equivalents of oxidant gives the dioxides.

Resulting unoxidized compounds can be converted into the S-monoxides or S, S-dioxides, and resulting S-monoxi-des into S,S-dioxides . These oxidations can be carried out in the manner described above.

The above-mentioned reactions can be carried out in the usual manner in the presence or absence of diluents and/or catalysts, at room temperature or with heating or cooling, if desired under superatmospheric pressure and/or under an inert gas.

Depending on the starting materials and reaction conditions used the final products are obtained in the free form or in form of their salts, wh±h are likewise included in the present invention. The salts of the final products can be converted into the free bases in known manner, for example which are capable of forming therapeutically acceptable salts they yield salts. As such acids there may be mentioned, for example, hydrohalic, sulfuric or phosphoric acids, nitric or perchloric acid; aliphatic or aromatic sulfonic acids such as methanesulfonici ethanesulfonic, hydroxyethanesulfonic, ethylenesulfonic acid; halobenzenesul onic, toluenesulfonic or naphthalenesulfonic acids.

These or other salts of the new compounds, for example their picrates, may also be used for purifying the resulting bases by converting the bases into salts, isolating the salts and separating the bases again from the salts. In view of the close relationship between the bases in free form and in form of their salts what has been said above and hereinafter with reference to the bases concerns also the corresponding salts wherever this is possible and useful.

The invention includes also any variant of the present process in which an intermediate obtainable at any stage of the process is used as starting material and any remaining process step(s) is/are carried out or in which a starting material is formed under the reaction conditions or is used in the form of a salt and/or isomer or racemate mixture or of their constituents.

Thus, for example, in the first -named process the iminoethers of the N-formyl compounds may be formed in situ; for example, it is possible to react 2-amino-5-nitro-thia- zole with orthoformic acid triethyl ester and to allow the N- (5-nitro-2-thiazolyl) -formic acid-iminoether formed as intermediate product to react with an amine of the formula H-R, in which R has the meaning indicated, to obtain the desired end product.

' ' Depending ~"on~ the degree of substitution in the thio-morpholine ring the new compounds may be in the form of cis-and trans-isomers or possibly of racemates or optical antipodes. The resulting racemates or isomer mixtures can, if desired, be resolved in the usual manner.

Mixtures of isomers or racemates can be resolved on the basis of the physico-chemical differences of the constituents in known manner into the pure isomers or pure racemates, for example by chromatography and/or fractional crystallization.

Pure racemates can likewise be resolved into the optical antipodes by known methods, for example by recrystaUi-zation from an optically active solvent, or with the aid of microorganisms, or by reaction with an optically active acid capable of forming salts with the racemic compound and separation of the salts thus obtained, for example on the basis or their different solubilities, to form the diastereomers from which the antipodes can be liberated by treatment with suitable agents. Particularly frequently used optically active acids are, for example, the D- and L-forms of camphorsul-fonic acid. Preferably, the more active of the constituents is isolated.

The final products of this invention may also be obtained in the form of the cis- or trans-isomers, racemates or optical antipodes, when the starting materials containing the substituted thiomorpholine ring are used in form of the cis- or trans-isomers, racemates or optical antipodes respectively.

The reactions of this invention are preferably per-formed with the use of starting materials that give rise to the preferred compounds mentioned above.

The starting materials are known or can be obtained by known methods.

The new compounds can be used as medicaments in the form of pharmaceutical or veterinary-medicinal preparations which contain the new compounds in the free form or in form of their salts, especially the therapeutically useful acid addition salts, in admixture or conjunction with organic or c ic l i s bl Suitable excipients are substances that do not react with the new compounds, for example water, gelatin, lactose, starches, stearyl alcohol, magnesium stearate, talcum, vegetable oils, benzyl alcohols, gums, polyalkyleneglycols, white petroleum jelly, cholesterol or other known medicinal excipients. The pharmaceutical preparations may be, for example, tablets, dragees, capsules or suppositories, or in liquid form solutions (for example elixirs or syrups), suspensions or emulsions. They may be sterilized and/or contain assistants such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure or buffers. They may also contain further, therapeutically valuable substances. The preparations are formulated by convention methods.

The following Examples illustrate the invention.

Example 1 A solution of 1 .5 g of 2-amino-5-nitro-thiazole in 300 ml of absolute dioxan is added to a solution of 23.3 g of 2, 6-cis-dimethyl- -formyl-thiomorpholine -diethylacetal in 50 ml of absolute dioxan. The mixture is thereafter boiled for hours under reflux and the clear solution is then evaporated in vacuo. The evaporation residue is first re-cr stallized from 150 ml of methanol and. then again from 70 ml of isopropanol. The 2,6-cis-dimethyl-4-[N-(5-nitro-2-thiazolyl) formimidoyl]-thiomorpholine of formula having a melting point of ll6-117°C is thus obtained.

The 2, 6-cis-dimethyl- -formyl-thiomorpholine-di-ethyl-aeetal used as the starting material can be manufactured as follows: 131 g of cis-2, 6-dimethyl-thiomorpholine and 200 g of dimethylformamide -diethylacetal are stirred for 3 hours at an oil bath temperature of about l40°C. About 50 ml of low-boiling constituents distill, off during the first hour. After 3 hours' stirring the reaction mixture is subjected to a fractional distillation. The 2, 6-cis-dimethyl- -formyl-thiomorpholine -diethylacetal of boiling point 112-117°C/ 8 mm Hg is thus obtained.

Example 2 1 .5 g of 2-amino-5-nitro-thiazole, 28.2 g of cis-2, 6-dimethyl-thiomorpholine- -carboxylic acid chloride and 100 ml of absolute dimethylformamide are boiled for 1 hour under reflux. The reaction mixture is subsequently evaporated to dryness in vacuo (finally at about 0.1 mm Hg) . The evaporation residue is first triturated with 60 ml of methanol and the solid product thus obtained is then chromatographed on a 35-fold quantity of silica gel. Elution is carried out with a toluene-chloroform mixture (10:1). The homogeneity of the resulting fractions is controlled by means of thin layer chromatography. The fractions having an Rf-value of about 0.6 (system: chloroform-acetone, 4:1) are combined and recrystallized from 35 ml of isopropanol.

The 2,6-cis-dimethyl- -[N-(5-nitro-2-thiazolyl)-formimidoyl ]-thiomorpholine of melting point Ιΐδ-ΐΐγ0^ which The cis-2, 6-dimethy1-thiomorpholine - -carboxylic acid chloride used as the starting material can be manufactured from cis-2,6-dimethyl-thiomorpholine and phosgene. It represents a water-clear oil of boiling point 90-93°θ/θ·35 mm ¾.

Example 3 A solution of 1.0 g of Ν,Ν-dimethyl-N' - (5-nitro-2-thiazolyl) -formamidine and 1.3 g of cis-2, 6-dimethyl-thio-morpholine in 0 ml of dimethylformamide is boiled for 1 hour under reflux. The reaction mixture is thereafter evaporated to dryness in vacuo (finally about 0.1 mm Hg) and the evaporation residue is chromatographed on a 50-fold quantity of silica gel. Elution is carried out with a toluene-chloroform mixture (10 : 1). The homogeneity of the resulting fractions is checked by means of thin layer chromatography. The fractions having an Rf-value of about 0.6 (system: chloroform-acetone, 4:1) are combined and recrystal-lized from .'. . isopropanol. The 2, 6-cis-dimethyl-4- [N-(5-nitro-2-thiazolyl) -formimidoyl ] -thiomorpholine of melting point 116-117°C (after two recrystallizations from isopropanol) which is identical with the products obtained in examples 1 and 2, is thus obtained.

Example 4 A solution of 9·0 g of m-chloroperbenzoic acid of 85$ strength in 250 ml of methylenechloride is stirred within 0 minutes at 20 to 25°C dropwise into a solution of 5· 7 g of cis-2, 6-dimethyl-4- [N- (5-nitro-2-thiazolyl ) -formimidoyl ] -thiomorpholine in 100 ml of methylenechloride. The batch is then stirred for 3 hours at room temperature and the clear with 2 x 50 ml of water. The methylenechloride solution is dried with anhydrous magnesium sulphate and evaporated. The residue is recrystallized from 75 ml of 2-ethoxyethanol, to yield cis-2, 6-dimethyl- - [N- (5-nitro-2-thiazolyl) -formimi-doyl] -thiomorpholine-1, 1-dioxide of the formula melting at 228-229°C.

Example 5 A solution of 10.0 g of m-chloro-perbenzoic acid in 300 ml of methylene chloride is added dropwise, while stirring at 20-25°C to a solution of 12.9 g of -[N- (5-nitro 2-thiazolyl) -formimidoyl ] -thiomorpholine in 250 ml of methyl ene chloride. The reaction mixture is stirred overnight at room temperature and then agitated with 150 ml of N-aqueous sodium bicarbonate solution. The solid product formed as a suspension is filtered off with suction, washed and dried. - [N- (5-nitro-2-thiazolyl) -formimidoyl ] -thiomorpholine-1-oxide of the formula melting at 259°C (with decomposition) is obtained.

The -[N-(5-nitro-2-thiazolyl) -formimidoyl ]-thio-morpholine used as starting material can be prepared as formamide -dimethyl acetal are stirred for 4 hours, the temperature of the oil bath being gradually raised from 120 to 150°C. During the first hour, 110 ml of low-boiling constituents distill over. When the reaction mixture has been stirred for 4 hours it is subjected to fractional distillation. 4-Formyl-thibmorpholine-dimethylacetal is obtained which boils at lll-ll6°C under a pressure of 15 mm of Hg.

A solution of 47.0 g of 2-amino-5-nitro-thiazole in 1000 ml of absolute dioxan is added to a solution of 57· 2 g of 4-formylthiomorpholine-dimethylacetal in 100 ml of absolute dioxan. The reaction mixture is then boiled for 5 hours under reflux and the solution evaporated. The residue is recrystallized first from 350 ml of toluene and then from 250 ml of 2-ethoxyethanol, to yield 4-[N-(5-nitro-2-thiazolyl)-formimidoyl ]-thiomorpholine of the formula melting at 168 - 170°C.

Example 6 A solution of 12. 9 g of . - [N- (5-nitro-2-thiazolyl) formimidoyl ] -thiomorpholine in 250 ml of methylene chloride is added dropwise at 17-32°C in the course of 10 minutes to a 'solution of 25 of m-chloro-perbanzDic acid in 500 ml of methylene chloride. The mixture is then stirred at room temperature for j5 hours, after which the excess peracid is destroyed by the dropwise addition of sodium meta-bisulfite, and the reaction mixture is then extracted with 300 ml of •ate N-aqueous sodium bicarbon^ solution, - and filtered with suction and the filter residue is washed and dried. The resulting crude product is recrystallized from 75 ml of dimethyl-formamide, then again from O ml of dimethylformamide, and -[N- (5-nitro-2-thiazolyl) -formimidoyl ] -thiomorpholine -1, 1-dioxide of the formula melting at 267°C (with decomposition) obtained.

Example 7 1^ . g of 2-amino-5-nitro-thiazole and 75 ml of orthoformic acid triethyl ester are stirred for 2 hours at an external temperature (oil bath) of 120°C. The resulting alcohol is at the same time distilled off. When the reaction mixture has cooled somewhat, it is treated with 13.1 g of cis-2,6-dimethyl-thiomorpholine, and stirred for another 2 hours at 100°C. The reaction mixture is then evaporated to dryness in a rotary evaporator, the residue triturated with methanol, and then recrystallized from 110 ml of isopropanol. Pure cis-2, 6-dimethyl- (4- [N- (5-nitro-2-thiazolyl ) -formimidoyl ]' thiomorpholine melting at ll6-117°C is thus obtained which is identical with the product obtained according to Example 1.

Example 8 A mixture of 14.5 g of 2-amino-5-nitrothiazole and 75 ml of orthoformic acid triethyl ester is stirred for 2 hours at an oil bath temperature of about 120°C, while distilling off the dthanol which forms. The reaction mixture is allowed to cool somewhat before a solution of 17· 9 g of 3-methoxymethyl-thiomorpholine-1, 1-dioxide in 25 ml of ortho-formic acid triethyl ester is added. The mixture is stirred for 5 to 10 minutes at an oil bath temperature of 100°C, the product crystallizing out. The batch is filtered with suction, then recrystallized from 500 ml of 2-ethoxy-ethanol, then from 420 ml of 2-ethoxy-ethanol. 3- (Methoxymethyl) -4- [N- (5-nitro-2-thiazolyl ) -formimidoyl ] -thiomorpholine -1,1-dioxide of the formula mel in at 22 -228°C is b aine . used as starting material can be prepared for example by condensing 3- (methoxymeth l) -thioxan-1, 1-dioxide with ammonia.

Example 9 Tablets containing 500 mg of cis-2, 6-dimethyl-4-[N- (5-nitro-2-thiazolyl) -formimidoyl ] -thiomorpholine may be prepared with the following ingredients: Per tablet cis-2, 6-dimethyl-4-[N-(5-nitro-2-thiazolyl) -formimidoyl ] -thiomorpholine 500.0 mg Wheat starch 70.0 mg Colloidal silicic acid with hydrolyzed starch 30.0 mg Magnesium stearate 6.0 mg Talc 19.O mg 625.Ο mg Method Half of the wheat starch is pasted with 'four times the quantity of water on a water-bath. The active substance is kneaded with the paste to form a plastic mass. The collo-idal silicic acid with hydrolyzed starch is then worked in in portions. The plastic mass is passed through a sieve having a 4-5 mm mesh and dried at 45°C. The dried granulate is passed through a sieve of 0.8 - 1.4 mm mesh and the remaining disinte rating and lubrication agents are then added. After further homogenization tablets having a diameter of II.5 mm and weighing 625 mg are compressed in the conventional manner.

Claims (4)

1. WHAT WE CLAIM IS: 1. A thiazole derivative of the formula wherein R represents a thlomorpholino residue which is sub- by a lower alkyl or an alkoxy-lower alkyl group stituted at at least one carbon atom/and/or is oxidized at the sulfur atom.
2. 2. A compound of the formula in which R represents an S-oxidized thlomorpholino residue.
3. 3. A compound of the formula wherein n rep^resents 1 or 2 and Ro and Rx stand for lower alkyl residues or lower alkoxyalkyl residues, and the residue R may also represent hydrogen.
4. 4. A compound of the formula wherein n represents 1 or 2 and RT and R" stand for lower alkyl residues. 5· 4-[N- (5-Nitro-2-thiazolyl) -formimidoyl ]-thiomor-pholine-1, 1-dioxide . 33462/2 - 18 - iraldoyl]-thiomorpholine-1,1-dioxide. 7. 2,6-Dimeth 1-4-LN-(5-nitro-2-thiazolyl)-formimidoyl]-thiomorpholine-1, 1-dioxide. 8· cis-2,6-Diraethyl-4-[N-(5-nitro-2-thiazolyl)~formimidoyl]· thiomorpholine-1,1-dioxide. 9* 4-[N-(5- tro-2-thiazolyl)-formimidoyl]-thiomorpholine-l-jpxide. 10. A compound of the formula wherein R represents a C-alkylated and/or C-oxa-alkylated thiomorpholino residue. 11· A oompound of the formula wherein R and R stand for lower alkyl residues or lower alkoxyalkyl residues and the residue may also xspresent hydrogen. 12. A compound of the formula wherein R* and Rn represent lower alkyl residues. 13. 2,6-Dimethyl-4-[H-*(5-nitro-2-thiazolyl)-formimidoyl]-thiomorpholine· 33462/2 - 19 - ¾*· 14. cis-2,6-Dime hyl-4-ίN-(5-nitro-2-thlazolyl)-formimidoyl]-thiomorpholine· 15. A compound described in any one of Claims 2 to 7 having at least 2 eubstituents in the thiomorpholine ring, in the form of a pure isomer* 16. A compound described in any one of Claims 10 to 13» having at least 2 eubstituents in the thiomorpholine ring, in the form of a pure isomer* 17. n optically active compound described in any one of Claims 2 to 8 in the form of an optical antipode. 18 An optically active compound described in any one of Claims 10 to 14 in the form of an optical antipode. 19· A compound described in any one of the Examples herein* 20. A compound described in either of Claims 1 and 9 in the free form. 21. A compound described in any one of Claims 2 to 8, 15 and 17 in the free form. 22. A compound described in any one of Claims 10 to 14, 16 and 1 in the iree form; 23· A salt of a compound described in either of Claims 1 and 9* 24» A salt of a compound described in any one of Claims 2 to 8, 15 and 17» 25. A salt of a compound described in any one of Claims 10-14, 16 and 18. 26. A therapeutically acceptable s alt of a compound described in either of Claims 1 an<¾9. 27· therapeutically acceptable salt of a compound described in any one of Claims 2 to 8, 15 and 17. 28 A thaapeutically acceptable salt of a compound described in any one of Claims 10 to 14, 16 and 18. 29· A pharmaceutical preparation containing a compound as claimed in any one of Claims 1, 9» 20 and 26 in admixture or conjunction with a carrier material. 30, A pharmaceutical preparation containing a compound as claimed in any one of Claims 2 to 8, 15* 17, 21 and 27 in admixture or conjunction with a carrier material. 31· A pharmaceutical preparation containing a compound as claimed in any one of Claims 10 to 14, 16, 18, 22 and 28 in admixture or conjunction with a carrier material. 32· A process for the manufacture of thiazole derivatives of the formula wherein R represents a thiomorpholino residue which is substituted at at least one carbon atom by a lower alkyl or an alkoxy-lower alkyl group and/or is oxidized at the sulfur atom, wherein an aoine of the formula HR is reacted with a compound of the formula R having the meaning given above and X standing for analkoxy group or a dialkylamino^=roupt or 2-amino*5-nitro-thiazole is reacted with a compound of the formula R-C0-C1, in which R has the meaning indicate above, in dimeth lformamide, or 2-amino->5-nitrothiazol© is reacted amide of the formula HCOR in which R has the meaning indicated above, or -[N- (5-nitro-2-thiazolyl ) -formimidoyl ] -thio-morpholine is oxidized. 3 32 ly. A process as claimed in claim i>4, wherein 2-amino- 5-ntrothiazole is reacted with orthoformic acid triethylester and the N- (5-nitro-2-thiazolyl) -formic acid-iminoether formed is further reacted with an amine of the formula H-R, in which 32 R has the meaning indicated. in claim 14. 34 ¾5. A process for the manufacture of thiazole derivatives of the formula in which R represents an S-oxidized thiomorpholino residue, wherein an amine of the formula HR is reacted with a compound of the formula R having the meaning given above and X standing for an alkoxy group or a dialkylamino group, or 2-amino-5-nitro-thiazole is reacted with a compound of the formula R-C0-C1, in which R has the meaning indicated above, in dimethylformamide., or 2-amino-5-nitrothiazole is reacted with an acetal of a form- amide of the formula HCOR in which R has the meaning indicated above, or -[N-(5-nitro-2-thiazolyl)-formimidoyl]-thio-morpholine is oxidized. 35 3 fctl. A process as claimed in claim ffy, wherein 2-amino- 5-nitrothiazole is reacted with orthoformic acid triethylester - 22 is further reacted with an amine of the formula H-R, in which of the formula wherein R represents a thiomorpholino residue substituted at at least one carbon atom by a lower alkyl or an alkoxy-lower alkyl group, wherein an amine of the formula HR is reacted with a compound of the formula \ R having the meaning given above and X s tanding for an alkoxy group or a dialkylamino group, or 2-amino-5-nitro-thiazole is reacted with a compound of the formula R-C0-C1, in which R has the meaning indicated above, in dimeth Iformamide, or 2-amino-5-nitrothiazole is reacted with an ajetal of a formamide of the formula HCO in which R has the meaning indicated above. 37. A process as claimed in Claim 36, wherein 2-amino-5-nitrothlazole is reacted with orthoformic acid triethylester and the IT-(5-nitro-2-thiazolyl)-formic acid-iminoethor formed is further reacted with an amine of the formula H-R, in which R has the meaning indicated in Claim 36. PC:BH