NO791348L - PROCEDURE FOR PREPARING NEW URINE SUBSTANCES - Google Patents

Description

Procedure for the production of new

urine substances.

The invention relates to new 3-oxo-cyclopentenylurin substances with the formula:

whose cyclopentenyl ring may have an additional double bond and wherein means hydrogen or lower alkyl, R2 means lower alkyl and R^ means optionally unsaturated lower alkyl, or R2 and R3 together with the C atom connecting them optionally means unsaturated cycloalkyl or R-^, R2 and R^ together mean The C atom connecting them optionally substituted phenyl, R4 means hydrogen, lower alkyl or optionally substituted phenyl, R5 means hydrogen, an optionally esterified or amidated carboxy or nitrile group and Rg means hydrogen or lower alkyl and Y means oxygen, sulphur, the imino group =NH or the cyanoimino group = N-CH, as well as methods for their preparation, further pharmaceutical preparations containing these compounds and their use preferably in the form of pharmaceutical preparations.: Those in connection with the present invention with "lower" termed residues and compounds preferably contain up to 7 and primarily up to 4 carbon atoms.

An optionally unsaturated lower alkyl is preferably a lower alkyl, but also lower alkenyl or lower alkynyl.

An optionally unsaturated cycloalkyl is preferably a cycloalkyl with 5-7 ring carbon atoms, e.g. cyclopentyl, cyclohexyl or cycloheptyl, but also a cycloalkenyl with 5-7 ring carbon atoms, for example cyclopentenyl, cyclohexenyl or cycloheptenyl, whose double bond is located primarily in the 1-position.

A substituted phenyl is e.g. single, twice

or also multiple substituted phenyl. Substituents are i.a. lower alkyl, lower alkoxy, halogen, trifluoromethyl, lower alkylsulfonyl or nitro..

Possibly esterified or amidated carboxy is the carboxy group itself, further e.g. lower alkoxycarbonyl such as methoxycarbonyl or phenyl lower oxycarbonyl or carbamoyl, mono- or diloweralkylcarbamoyl, primarily methyl or dimethylcarbamoyl.

Lower alkyl is e.g. n-propyl, isopropyl, n-butyl,

isobutyl or tert-butyl and in the first row methyl or ethyl.

Lower range alkenyl is e.g. vinyl, allyl, 2- or 3-methallyl or 3,3-dimethylallyl.

Low real akinyl is especially propargyl.

Low-area coke is e.g. n-propyloxy, n-butyloxy, isopropyloxy or isobutyloxy and primarily methoxy or ethoxy.

Lower alkylsulfonyl is particularly methylsulfonyl,

ethylsulfonyl or propylsulfonyl.

Halogen is preferably halogen with atomic number from

9 to 35, i.e. fluorine, chlorine or bromine.

The new compounds have valuable pharmacological properties

properties;.

The invention relates in particular to connections with

formula II

in which R-jy R2 and R^ means lower alkyl or in which R-^ means lower alkyl and R 2 and R^ together with the C atom connecting them means cycloalkyl with 5-7 carbon atoms.

The invention relates above all to compounds of formula II, in which R 2 and R 2 are methyl and R 2 is lower alkyl with 1-3 carbon atoms or in which R 2 is methyl and R 2 and R 2 together

with the C atom connecting them means cycloalkyl with 5-7, especially<1>with 5 carbon atoms.

Primarily, the invention relates to compounds

of formula II, in which R 1 , R 2 and R 2 are methyl.

In particular, the invention relates to the new compounds mentioned in the examples.

The new compounds of formula I can be obtained by methods known per se.

Thus, they can be prepared when a compound of formula III

in which X means optionally esterified or etherified hydroxy, is reacted with a compound of formula IV

An optionally etherified or esterified hydroxy is above all hydroxy, which during rearrangement of the double bond in the 2,3-position of the cyclopentenyl residue can also exist as oxo. Esterified hydroxy is primarily a hydroxy esterified with strong inorganic or organic acids, e.g. halogen hydrogen or sulfuric acid, or optionally in the case of lower alkyl, lower alkoxy or halogen substituted benzenesulfonic acids such as p-toluenesulfonic acid or lower alkanesulfonic acid, such as methanesulfonic acid, Ethered hydroxy is especially lower alkoxy, such as methoxy or ethoxy.

The turnover is preferably carried out under water or acid-cleaving conditions. Thus, a compound of formula III, in which X means hydroxy, is reacted, preferably in the presence of a strong acid, such as a sulphonic acid, e.g. p-toluenesulfonic acid or methanesulfonic acid. Thereby, one preferably works in an aprotic solvent, such as an aromatic hydrocarbon, e.g. benzene, toluene, or xylene. However, you can also carry out this turnover so that during the reaction, e.g. by distillation constantly removes mixed water. The reaction with a compound of formula III, in which X means esterified or etherified hydroxy, is preferably carried out in a solvent, such as an alkanol, e.g. methanol/ethanol or propane, dilave alkylformamide, e.g. dimethylformamide or hexamethylphosphoric acid triamide, if desired in the presence of a base, e.g. alkali or alkaline earth alcoholate or hydride, a nitrogen base, such as trilower alkylamine, e.g., trimethylamine, as well as pyridine or piperidine. If you work in an alcohol as a solvent, you use primarily the corresponding sodium or potassium alcoholate as a base, if you work in dimethylformamide, an alkali or alkaline earth hydride is used as a base, e.g. sodium or potassium hydride.

Starting materials used for this method

is known or can be produced in a known manner, e.g. by esterification or etherification of the compound of formula III, in which X means hydroxy.

The new compounds are also obtained when a compound with formula

is reacted with a compound of formula VI in which one of the residues Z-^ and Z2 represents an amino group and the other group corresponds to formula VII

in which X-^ means any reactive esterified or etherified hydroxy or mercapto and X2 means hydrogen, or X.^and X2 together means a bond between C and N and means oxygen, sulphur, imino or cyanimino, with the precaution that if Y-^ means imino or cyanimino, X^ means halogen, and X2 hydrogen.

A reactive esterified hydroxy or mercapto group X-^ is in particular a hydroxy group esterified with a strong inorganic acid, especially hydrohalic acid, e.g. bromic or hydrochloric acid^A reactive. etherified hydroxy or mercapto group is primarily lower alkoxy, such as -.methoxy or ethoxy or, lower alkyl mercapto, such as methyl mercapto.

This reaction is preferably carried out in an inert organic solvent, such as benzene, dioxane, toluene or xylene at room temperature or a slightly elevated temperature.

The starting materials are known or can be prepared in a manner known per se, thus cyclopentenyl can be obtained, e.g. by Curtius degradation of 3-oxo-1-cyclopentenecarboxylic acid.

In compounds formed, in which Y means the imino group or the sulfur atom .,. can one transfer these into an oxygen atom, e.g. by means of hydrolysis, preferably in the presence of an acidic agent,

as a mineral acid, e.g. hydrochloric acid.. However, compounds can also be transferred, in which Y means sulphur, e.g. by reaction with a lower alkyl halide to the corresponding lower alkyl mercapto compounds, and these are reacted e.g. with ammonia or cyanamide. Thereby, one works in the absence' or preferably in the presence of a solvent or diluent, and if necessary during cooling or heating, e.g. in a temperature range from approx. 0°C to 150°C in a closed vessel and/or<:>in an inert gas atmosphere.

The method also includes the embodiments according to which compounds formed as intermediates are used as starting materials and the remaining method steps are carried out with these or the method is interrupted at one or another step, further can; starting materials are used in the form of derivatives or formed during the reaction.

Such starting materials are preferably used and the reaction conditions are chosen in such a way that one reaches the compounds listed at the outset which are particularly highlighted.

The new compounds show a blood pressure-lowering effect, as can be shown in animal experiments, by e.g. intravenous administration in doses from 1-30 mg/kg in anesthetized cats, as well as an antihypertensive effect as can be shown in renal hypertensive rats in doses from approx. 10 to approx. 100 mg/kg/day p.o.

They are less toxic than comparable known compounds.

The new compounds can therefore be used as blood pressure-lowering agents and as antihypertensives.

The new compounds produced according to the invention can e.g. used for the production of pharmaceutical preparations containing an effective amount of the active substance together or in admixture with inorganic or organic, solid or liquid, pharmaceutically usable carriers suitable for enteral or parenteral administration. Thus, tablets or gelatin capsules are used, which contain the active substance together with diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine, and lubricant e.g. silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol. Tablets also contain the binder, e.g. magnesium aluminum silicate, starches, such as corn, wheat, rice or arrowroot starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidine, and if desired explosive, e.g. starch, agar, alginic acid or a salt thereof, such as sodium alginate and/or fizzy mixes or adsorbents, colourings, flavorings and sweeteners. Furthermore, the new pharmacologically active compounds can be used in the form of injectables, e.g. preparations that can be administered intravenously, or of infusion solutions. Such solutions are preferably isotonically aqueous solutions or suspensions, as these e.g. can be produced from lyophilized preparations, which contain the active substance alone or together with a carrier material, e.g. mannitol, before use. The pharmaceutical preparations may be sterilized and/or contain excipients, e.g. preservatives, stabilisers, wetting and/or emulsifying agents, solubility mediators, salts for regulating the osmotic pressure and/or buffers. The present pharmaceutical preparations, which if desired may contain additional pharmacologically active substances, are produced in a manner known per se, e.g. by means of usual mixing, granulating, coating, dissolving or lyophilization methods, and contains from approx. 0.1% to: 100%, especially from approx. 1% to approx. 50%, lyophilisates up to 100% of the active substance.

The dosage may depend on various reasons, such as method of application, type, age and/or individual condition. The daily dose to be administered lies between approx. 10 mg and approx. 1000 mg for warm-blooded animals, with a weight of approx. 70 kg.

The invention also relates to the isothioureas with formula VIII which can be obtained as intermediates:

wherein R 1 to R 8 have the above meaning and R 1 means lower alkyl, especially methyl.

The invention will be explained in more detail with the help of some examples.

Example 1

9.8 g of 1,3-cyclopentadione, 11.6 g of t-butylurea, 0.2 g of p-toluenesulfonic acid are heated in 300 ml of benzene-toluene (1:1)

for 6 hours under water separator. The organic phase is separated, the residue is suspended in 200 ml of hot acetic acid and the insoluble resin is filtered off. The filtrate is evaporated, mixed with ether and cooled. The precipitated crystallisate is filtered off and washed with a little vinegar. The filtrate is combined with the organic phases separated above, evaporated and chromatographed on silica gel in a mixture of acetic ester-methaneql-ammonia (70:30:1). During subsequent sublimation, any t-butylurea that is still present is separated. 1-tert.-Butyl-3-(2-cyclopenten-1-on-3-yl)-urea has a m.p. 193-195°C;

In the same way, 1-tert.-amyl-3-(2-cyclopenten-1-on-3-yl)-urea can be prepared, m.p. 208-209°C.

Example 2

0.5 g of 1-amino-cyclopentene-(1)-one-(3), 5 ml of t-butyl isocyanate and 5 ml of dimethylformamide are heated in a bomb tube for 18 hours at 140°C. It is cooled, methanol is added, filtered and the filtrate is evaporated to dryness. The residue is boiled off with ethyl acetate, filtered off from a charcoal-like product and the filtrate is evaporated and chromatographed on silica gel in ethyl acetate-methanol (8:2). 1-tert.-butyl-

3-(2-Cyclopenten7l-on-3-yl)urea is recrystallized from isopropanol ether. It has a melting point of 193-195°C.

Example 3

To a sodium alcoholate solution prepared from 4.6 g of sodium and 300 ml of absolute ethanol, 18.4 g of t-butylurea are added while stirring and heated for 15 minutes at 60°C. Then 19.9 g of 1-ethoxy-cyclopentene-(1)-one-(3) in 25 ml of absolute ethanol are added dropwise over the course of 5 minutes, and the clear solution is heated for 10 hours under reflux. The residue is then evaporated to dryness, dissolved in 100 ml of water and extracted 5 times with each time, 150 ml vinegar. The organic phases are combined, dried and evaporated. The residue is recrystallized from isopropanol-ether. 1-tert-butyl-3-(2-cyclopenten-1-on-3-yl)-urea has a melting point of 193-195°C.

In the same way, 1-tert.-butyl-3-(2-methyl-2-cyclopenten-1-on-3-yl)-urea, m.p. 216-220°C and 1-(1-methyl- 1-cyclopentyl)-3(2-cyclopenten-1-on-3-yl)-urea, m.p. 182-183°C.

Example 4

7.5 g of 1-amino-cyclopentene-(1)-one-(3) are mixed in 150 ml of absolute dimethylformamide with 8.6 g of potassium tert.-butylate and heated under nitrogen and stirred for 1 hour at 90°C. The light brown, thick suspension is cooled and, under ice cooling, 11.1 g of tart are added dropwise. butyl thiocyanate in 35 ml of absolute dimethylformamide. The resulting solution is stirred for 15 hours at room temperature. It is then neutralized with 77 ml of 1-1 hydrochloric acid, evaporated to dryness and the adhering moisture is driven off with toluene. The residue is suspended in 250 ml of hot methanol, filtered off and washed with methanol and ether. The methanol filtrate is evaporated to dryness, the residue is boiled with 250 ml of ether and filtered off. The crystallisate is then chromatographed on silica gel in ethyl acetate-methanol 8:2. Then treated in methanol with animal charcoal, the filtrate is evaporated to dryness and dried with toluene. The residue is recrystallized* from isopropanol. 1-tert.-'-butyl-3-yl)-thiourea has a m.p. at 198-200°C.

Example 5

A mixture of 2.26 g of 1-tert.-butyl-3-(2-cyclopenten^l-on-3-yl)-S-methyl-thiourea, 0.6 g of finely powdered cyanamide and 10 ml of absolute dimethylformamide is stirred under addition of 3 drops of N,N-diisopropyl-ethylamine for 48 hours at room temperature. It is then evaporated under reduced pressure. The residue is chromatographed on 100 silica gel, using a mixture of chloroform-methanol (9:1) as elution mixture. After recrystallization of the purified product from acetic acid ethyl ester-petroleum ether, 1-tert.-butyl1-2-cyano-3-(2-cyclopenten-1-oh-3-yl)-guanidine is obtained with m.p. 2U-214°C.

The 1-tert.-hutyl-3-(2-cyclopenten-1-on-3-yl)-S-methyl-thiourea used as starting material can be prepared in the following way: To a mixture of 1.05 g of 1-tert. -butyl-3-(2-cyclo-penten-1-on-3-yl)-thiourea, 0.7 g potassium carbonate in 25 ml absolute ethyl alcohol, a solution of 0.37 ml methyl iodide in 5 ml absolute ethyl alcohol is added dropwise while stirring ethyl alcohol. It is left to stir for a further 20 hours at room temperature and then evaporated under reduced pressure. The residue is suspended in 50 ml of chloroform and filtered over "Hyflo". The filtrate is evaporated under reduced pressure, and the residue is liberated by treatment with toluene for still clinging moisture. After expelling the residue with diethyl ether, the following crystalline product is obtained: 1-tert-butyl-3(2-cyclopenten-1-on-3-yl)-S-methyl-thiourea with m.p. 80-84°C.

Example 6

7.5 g of 1-amino-cyclopentene-(1)-one-(3) are mixed in 150 ml of absolute dimethylformamide with 8.6 g of potassium tert.-butylate and heated under nitrogen and stirring for 1 hour at 90°C. The light brown thick suspension is cooled and, under ice cooling, 9.5 g of sec.butyl isocyanate are added dropwise in 35 ml of absolute dimethylformamide. The resulting solution is stirred for 15 hours at room temperature. It is then neutralized with 77 ml of 1-1 hydrochloric acid, evaporated to dryness and the remaining moisture is removed with toluene. The residue is suspended in 250 ml of hot methanol, filtered off and washed with methanol and ether. The methanol filtrate is evaporated to dryness, the residue is boiled with 250 ml of ether and filtered off. The crystallisate is then chromatographed

silica gel in ethyl acetate-methanol 8:2. It is then treated with animal charcoal in methanol, the filtrate is evaporated to dryness and dried with toluene. The residue is recrystallized from isopropanol. One thus obtains 1-sec-butyl-3-(2-cyclopenten-1-on-3-yl)-urea.

Example 7

4.7 g of potassium tert.-butylate is present in 100 ml absolute. dimethylformamide with stirring. To this, 4.9 g of N"-cyano-N'-tert.-butyl-

guanidine and stirs the mixture for 2 hours at 50°C reaction temperature. A solution of 4.4 g of 1-ethoxy-cyclopentane-(1)-one-(3) in 50 ml of absolute dimethylformamide is then added dropwise over the course of 30 minutes and stirred for a further 3 hours at 50°C. It is then cooled, neutralized with 42 ml 1-1 hydrochloric acid and evaporated to dryness. The residue is dissolved in chloroform and washed with water. After drying

of the combined organic phases, decolorize with "Florisil" and evaporate. The residue is recrystallized from isopropyl alcohol-diethyl ether and 1-tert.-butyl-2-cyano-3-(2-cyclo-pentene-1) is obtained as a white crystal. -on-3-yl)-guanidine, m.p. 211-214°C.

In the same way, tert-amyl-2-cyano-3-(2-cyclopenten-1-on-3-yl)-guanidine can be obtained, m.p. 135.5-137.5°C.

Claims (20)

1. Process for the preparation of new 3-oxo-cyclopentenyl-ureas of formula I whose cyclopentenyl ring may have an additional double bond and in which R-^ means hydrogen or lower alkyl, R 2 means lower alkyl and R^ means optionally unsaturated lower alkyl, or R 2 and R^ means together with the C atom connecting them optionally unsaturated cycloalkyl or R-^ , R 2 and R^ mean together with the C atom connecting them substituted phenyl, R4 means hydrogen, lower alkyl or optionally substituted phenyl', R5 means hydrogen, an optionally esterified or amidated carboxy or nitrile group and Rg means hydrogen or lower alkyl, and Y means oxygen, sulphur, the imino or cyanimino group, characterized in that a connection with . formula III in which X means optionally esterified or etherified hydroxy, if- is added with- a compound of formula IV or a compound of formula V is reacted with a compound of formula VI in which one of the residues Z-1 and Z2 represents an amino group and the other corresponds to the group VII in which X^ optionally means reactive esterified or etherified hydroxy or mercapto and X2 means hydrogen, or X-^ and X2 together mean a bond between C and N, and Y^ means oxygen, sulphur, imino or cyanimino, with the precaution that if Y-^ means imino or cyanimino, X-^ means halogen and X2 hydrogen, and if desired transfer the compounds formed, in which Y means the imino group or S these to the oxygen atom. 2. Method according to claim 1, characterized in that it is assumed that a compound is formed as an intermediate in one or other step of the method and the missing method steps are carried out or the method is interrupted at one or other step. 3. Method according to claim 1 or 2, characterized in that a starting substance is formed under the reaction conditions or where a reaction component is possibly present in its form. salts. 4. Procedure according to ex. 1-5. 5. Procedure according to Ex. 6-7. 6. Compounds obtained with the method according to claims 1-5. 7. Compounds obtained with the method according to ex. 1-6. 8. Compounds produced by the method according to ex. 6 and 7. ?. 3-oxo-cyclopentenyl urea of formula (I) whose cyclopentenyl ring may have an additional double bond and in which R-^ means hydrogen or lower alkyl, R 2 means lower alkyl and R^ means optionally unsaturated lower alkyl, or R 2 and R^ together with the C-at<p> met that connects them means optionally unsaturated cycloalkyl or R-^ , R 2 and R^ together with the C atom connecting them means optionally substituted phenyl, R^ means hydrogen, lower alkyl or optionally substituted phenyl, R^ means hydrogen, an optionally esterified or amidated carboxy or nitrile group and Rg means hydrogen or lower alkyl and Y means oxygen, sulphur, the imino or cyanimino group. 10. 3-oxo-cyclopentenyl-urea with formula (II).. in which R-^, R 2 and R^ mean lower alkyl or in which R-^ means lower alkyl and R 2 and R 3 together with the C atom connecting them means cycloalkyl with 5-7 carbon atoms. 11. 3-oxo-cyclopentenyl-ureas with the formula II specified in claim 10, in which R1 and R2 mean methyl, and Rj means lower alkyl with 1-3 carbon atoms, or in which R1 means methyl, and R2 and R3 mean together with The C atom that connects them cycloalkyl with 5-7 carbon atoms. 12. 1-tert-butyl-3-(2-cyclopenten-1-on-3-yl)-urea. 13. 1-tert-amyl-3-(2-cyclopenten-1-on-3-yl)-urea. 14. 1-tert-butyl-3-(2-cyclopenten-1-on-3-yl)-thiourea. 15. 1-tert-butyl-2-cyano-3-(2-cyclopenten-1-on-3-yl)-guanidine. 16. 1-sec-butyl-3-(2-cyclopenten-1-on-3-yl)-urea. 17. 1-tert.-amyl-2-cyano-3-(2-cyclopenten-1-on-3-yl)-guanidine, 18. Pharmaceutical preparations containing one of the compounds specified in claims 9-17. 19. Use of one of the compounds specified in claims 9-17. 20. New compounds mentioned in the description. 21. isothioureas with formula: whose cyclopentenyl ring may have an additional double bond and wherein is hydrogen or lower alkyl, R 2 is lower alkyl and R^ means optionally unsaturated lower alkyl, or R2 and R^ together with the C atom which connects them optionally means unsaturated cyclo- alkyl or R^ , R2 and R^ together with the C atom that connects them to each other means optionally substituted phenyl, R4 means hydrogen, lower alkyl or optionally substituted phenyl, R^ means hydrogen, an optionally esterified or amidated carboxy or nitrile group and Rg means hydrogen or lower alkyl. 22. 1-tert-butyl-3-(2-cyclopenten-1-on-3-yl)-S-methyl-thiourea f.