DD143252A5 - PROCESS FOR PRODUCING NEW UREAS - Google Patents

Description

212404

-Λ-

Process for the preparation of new ureas Field of application of the invention

The invention relates to a process for the preparation of novel 3-0 ^ o ~ cyclopentenyl ~ ureas. The compounds according to the invention have hypotensive action and are used in pharmaceutical preparations as antihypertensives.

Characteristic of the known technical solutions

There is no information as to whether urea compounds having antihypertensive activity are known or methods of preparation of such compounds.

Object of the invention

The object of the invention is to provide a simple process for the production of hypotensive urea compounds having low toxicity and which can be used as antihypertensives.

Explanation of the essence of the invention

The invention has for its object to find suitable starting components and suitable reaction conditions for the preparation of such compounds.

According to the invention, new 3-oxo-cyclopentenylureas of the formula

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(D

wherein cyclopentenyl ring may have another double bond and wherein R 1 is hydrogen or lower alkyl, H p is lower alkyl and E is optionally unsaturated lower alkyl, or R p and R 1 together with the carbon atom connecting them, optionally unsaturated cycloalkyl or R 1, R p and R ~ together with the carbon atom connecting them, optionally substituted phenyl, R ₂ , hydrogen, lower alkyl or optionally substituted phenyl, -S ^ hydrogen, an optionally esterified or amidated carboxy or nitrile group. and R _{6 is} hydrogen or lower alkyl and Y is oxygen, sulfur, imino = 1TH or cyanoimino = H-CH.

212404 -3-

The radicals and compounds referred to herein as "lower" preferably contain from 7 to and most preferably 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 having 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, double or multiple substituted phenyl. Substituents are i.a. Lower alkyl, lower alkoxy, halogen, trifluoromethyl, lower alkylsulfonyl or nitro,

Optionally esterified or amidated carboxy is the carboxy group itself, further Z..B. Lower alkoxycarbonyl such as methoxycarbonyl or phenyl-lower alkoxycarbonyl or carbamoyl, mono- or di-lower alkylcarbaifloyl, especially methyl- or dimethyl-carbamoyl.

Lower alkyl is e.g. n-propyl, isopropyl, η-butyl, isobutyl or tert-butyl, and especially methyl or ethyl.

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

Lower alkynyl is especially propargyl.

Lower alkoxy is e.g. n-propyloxy, n-butyloxy, isopropyloxy or isobutyloxy, and especially methoxy or ethoxy.

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Lower alkylsulfonyl is in particular methylsulfonyl, ethylsulfonyl or propylsulfonyl.

Halogen is preferably halogen with an atomic number of 9 hi to 35 »d.h · fluorine, chlorine or bromine.

The new compounds have valuable pharmacological properties.

In particular, compounds of the formula II

0 E ₁

KH - C - HH - Gr - E ₂

manufactured,

wherein E ^, H ₂ and E, lower alkyl or wherein E ^ is lower alkyl and E ₂ and E ~, together with the C-joining them, are cycloalkyl having 5-7 carbon atoms.

In particular, compounds of formula II are prepared, or in E ^ and E _{2 are} methyl and E _{0 is} lower alkyl having 1-3 carbon atoms or wherein E ^ is methyl and R ₂ and E-, together with the carbon atom connecting them with cycloalkyl 5-7 »in particular mean with 5 carbon atoms.

In the first place compounds of formula II are prepared according to the invention, wherein E ^, E ₂ and B ^ mean methyl «

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Of particular importance are the following compounds which can be prepared by the process according to the invention:

1-tert-Bu tyl-3- (2-cyclopenten-1-on-3-yl) -harnst off 1-tert-Ara3rl-3- (2-cyclopenten-1-on-3-yl) -urea 1-tert-Butyl-3- (2-cyclopenten-1-on-3-yl) thiourea 1-tert-butyl-2-cyano-3- (2-cyclopenten-1-one-3-yl) -guanidine 1-sec-butyl-3- (2-cyclopenten-1-on-3-yl) -urea 1-tert-aniline-2-cyano-3- (2-cyclopenten-1-one-3- yl) guanidine

The novel compounds of the formula I can according to themselves be

21240 4 - «>

knew methods were obtained.

So you can produce them, if you have a compound of formula III

(III)

wherein X is optionally esterified or etherified hydroxy, with a compound of formula IV

Y Il

C-NH

-C-

R

(IV)

implements.

An optionally esterified or etherified hydroxy is especially hydroxy, which can also be present as oxo with rearrangement of the double bond in the 2,3-position of the cyclopentenyl radical. Esterified hydroxy is primarily one with strong inorganic or organic acids, e.g. Hydrogen halide or sulfuric acid, or optionally substituted by lower alkyl, lower alkoxy or halogen-substituted benzenesulfonic acid such as p-toluenesulfonic acid or lower alkanesulfonic acid, such as methanesulfonic acid, esterified hydroxy. Etherified hydroxy is in particular lower alkoxy, such as methoxy or ethoxy.

The reaction is preferably carried out under water or acid-cleaving conditions. How to set a connection III

212404 - * -

wherein X is hydroxy, preferably in the presence of a strong acid, such as a sulfonic acid, e.g. p-toluenesulfonic acid or methahsulfonic acid. It is preferable to work in an aprotic solvent such as an aromatic hydrocarbon, e.g. Benzene, toluene or xylene. However, one can also carry out this reaction so that during the reaction, e.g. removed by distillation, the resulting water continuously. The reaction with compounds of formula III wherein X represents esterified or etherified hydroxy is preferably carried out in a solvent such as an alkanol, e.g. Methanol, ethanol or propanol, di-lower alkylformamide, e.g. Dimethylformamide or hexamethylphosphoric triamide, if desired, in the presence of a base, e.g. Alkali or alkaline earth alkoxide or hydride, a nitrogen base such as tri-lower alkylamine, e.g. If the reaction is carried out in an alcohol as the solvent, the corresponding sodium or potassium alcoholate is used as the base. If the reaction is carried out in dimethylformamide, the base used is in the first place an alkali metal or alkaline earth metal hydride, e.g. Sodium or potassium hydride.

The starting materials to be used for this process are known or can be obtained in a manner known per se, e.g. by esterification or etherification of the compound of formula III, wherein X is hydroxy.

The new compounds are also obtained when one is a compound of the formula

(V)

with a compound of formula VI

212404

in which one of the radicals Z and Z_ an amino group and the other group of formula VII

r r

C-N- (VII)

^Y l

where X _{1 is} optionally reactive esterified or etherified hydroxy or mercapto and X "is hydrogen, or X ₁ and X" together represent a bond between C and N, and Y is oxygen, sulfur, imino or cyanimino, with the proviso that if Y _{1 is} imino or cyanimino, X is halogen and X is hydrogen.

A reactive esterified hydroxy or mercapto group X ₁ is, in particular, a hydroxy group esterified by a strong inorganic acid, in particular hydrogen halide, for example hydrobromic or hydrochloric acid. A reactive etherified hydroxy or mercapto group is primarily lower alkoxy such as methoxy or ethoxy or lower alkano mercapto such as methylmercapto.

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

The starting materials are known-or can be prepared in a conventional manner, so the cyclopentenyl, e.g. obtained by Curtius degradation from the 3-oxo-1-cyclopentenecarboxylic acid.

In obtained compounds, wherein Y is the imino group or the

212 4 0 4 -β-

Sulfur atom, these can be converted into the oxygen atom, for example by hydrolysis, preferably in the presence of an acidic agent such as a mineral acid, for example hydrochloric acid. However, it is also possible to convert compounds in which Y is sulfur, for example by reaction with a lower alkyl halide, into the corresponding lower alkyl mercapto compounds and react them, for example with ammonia or cyanamide. In this case, the reaction is carried out in absence or preferably in the presence of a solvent or diluent and, if necessary, with cooling or heating, for example in a temperature range from about 0 ^° C. to 150 ^° C., in a closed vessel and / or in an inert gas atmosphere.

The process also includes those embodiments in which intermediate compounds are used as starting materials and the remaining process steps are carried out with them, or the process is stopped at any stage; furthermore, starting materials may be used in the form of derivatives or formed during the reaction.

Preferably, such starting materials are used and the reaction conditions are selected so that one arrives at the compounds mentioned as being particularly preferred.

The new compounds show a hypotensive effect, as shown in animal experiments, e.g. at i.v. Administration in doses of 1 to 30 mg / kg to the anesthetized cat, as well as an antihypertensive effect as found in the renal hypertensive rat at doses of about 10 to about 100 mg / kg / day p.o. show. They are less toxic than comparable, known compounds. The new compounds can therefore be used as antihypertensive agents and as antihypertensives.

The novel compounds of the present invention may be, e.g. used for the preparation of pharmaceutical preparations containing an effective amount of the active ingredient together or in admixture

212 4 0 4

with inorganic or organic, solid or liquid, pharmaceutically acceptable excipients which are suitable for enteral or parenteral administration. Thus, tablets or gelatin capsules containing the active ingredient together with diluents, e.g. Lactose, dextrose, sucrpex, mannitol, sorbitol, cellulose and / or glycine, and lubricants, e.g. Silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol; Tablets also contain binders, 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, disintegrants, e.g. Starches, agar, alginic acid or a salt thereof, such as sodium alginate, and / or effervescent mixtures, or adsorbents, dyes, flavorings and sweeteners. Furthermore, the novel pharmacologically active compounds in the form of injectable, e.g. use intravenously or with infusion solutions. Such solutions are preferably isotonic aqueous solutions or suspensions, e.g. from lyophilized preparations containing the active ingredient alone or together with a carrier material, e.g. Mannitol, can be prepared before use. The pharmaceutical preparations may be sterilized and / or adjuvants, e.g. Preservatives, stabilizers, wetting agents and / or emulsifiers, solubilizers, salts for regulating the osmotic pressure and / or buffers. The present pharmaceutical preparations which, if desired, may contain further pharmacologically active substances, are prepared in a manner known per se, for example B. by means of conventional mixing, granulating, coating, dissolving or lyophilization processes, and containing from about 0.1% to 100%, in particular from about 1% to about 50%, lyophilizates up to 100% of the active substance.

The dosage may depend on various factors, such as route of administration, species * age and / or individual condition. The daily dose to be administered by oral administration is between about 10 mg and about 1000 mg for warm-blooded animals weighing

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of about 70 kg.

Pie invention "also relates ax as an obtainable isothioureas of the formula VIII

S - E ₇ 1

(Viii)

 N = G - KH - C

in which R 1 to R 7 have the abovementioned meaning and represents lower alkyl, especially methyl *

- Explanatory note

The invention will be explained in more detail below on some embodiments

 Temperatures are given in degrees centigrade. ,

21 2 40 4., Ι-

Example 1; 9.8 g of 1,3-cyclopentadione, 11.6 g of tert-butyl urea, 0.2 g of p-toluenesulfonic acid are heated in 300 ml of benzene-toluene (1: 1) for 6 hours on a water separator. The organic phase is separated off, the residue is suspended in 200 ml of hot ethyl acetate and filtered off from insoluble resin. The filtrate is concentrated, treated with ether and cooled. The precipitated crystals are filtered off and washed with a little ethyl acetate. The filtrate is combined with the above-separated organic phase, evaporated and chromatographed on silica gel in a mixture of ethyl acetate-methanol-ammonia (70: 30: 1). By subsequent sublimation still existing t-butyl harsh material is separated. The 1-tert-butyl-3- (2-cyclopenten-1-on-3-yl) urea has a mp. 193-195 °.

Similarly, the 1-tert-amyl-3- (2-cyclopenten-lon-3-yl) urea, m.p. 208-209 °, can be prepared.

Example 2: 0.5 g of 1-amino-cyclopentene-1D-one-O), 5 ml of t-butyl isocyanate and 5 ml of dimethylformamide are heated in a bomb tube at 140 ° for 18 hours. It is cooled, added methanol, filtered and the filtrate evaporated to dryness. The residue is boiled with ethyl acetate, filtered off from a carbonaceous product and the filtrate was evaporated and chromatographed on silica gel in ethyl acetate-methanol (8: 2). The l-tert-butyl-3- (2-cyclopentenl-on-3-yl) urea is recrystallized from isopropanol ether. He has a mint of 193-195 °.

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-butyl urea are added with stirring and heated to 60 ° for 15 minutes. Subsequently, 19.9 g of 1-ethoxy-cyclopenten- (I) -one- (3) are added dropwise in 25 ml of absolute ethanol for 5 minutes and the clear solution heated under reflux for 10 hours. Then it is dripped to dryness, the residue dissolved in 100 ml of water and extracted 5 times with 150 ml of ethyl acetate. The organic phases are combined, dried and evaporated. The residue is recrystallized from isopropanol ether.

212 40 4

- -13-

Siert. The tert-butyl-S-C-C-cyclopenten-1-one-S-yD-urea has a mp of 193-195 °.

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

Example 4: 7.5 g of 1-aniino-cyclopenten- (1) -one- (3) are mixed in 150 ml of absolute dimethylformamide with 8.6 g of potassium tert-butoxide and, under nitrogen and with stirring for 1 hour at 90 ° heated. The light brown, thick suspension is cooled and 11.1 g of tert-butyl thiocyanate in 35 ml of absolute dimethylformamide are added dropwise with ice cooling. The resulting solution is stirred for 15 hours at room temperature. It is then neutralized with 77 ml of 1N hydrochloric acid, evaporated to dryness and the adhering moisture is removed by evaporation with toluene. The residue is suspended in 250 ml of warm 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 crystals are then chromatographed on silica gel in ethyl acetate-methanol 8: 2. This is then treated with charcoal in methanol, the filtrate is evaporated to dryness and dried with toluene. The residue is recrystallized from isopropanol. The 1-tert-butyl-3-yl) thiourea has a mp of 198-200 °

Example 5: A mixture of 2.26 g of 1-tert-butyl-3- (2-cyclopenten-3-yl) -S-methyl-thiourea, 0.6 g of finely pulverized cyanamide and 10 ml of absolute dimethylformamide , is stirred for 48 hours at room temperature with the addition of 3 drops of N, N-diisopropyl-ethylamine. Thereafter, it is evaporated under reduced pressure. The residue is chromatographed on 100 silica gel, using a mixture of chloroform-methanol (9: 1) as egg mixture. After recrystallization of the purified product from ethyl acetate-petroleum ether gives the l-tert-But3 ' ^r l-2-cyano-3 ^ra (2-cyclopenten-l-on ™ 3-

21240 4 _; - · * · -

yl) -guanidine of mp = 211-214 °.

The 1-tert-butyl-3- (2-cyclopenten-1-on-3-yl) -S-methyl-thiourea used as starting material can be prepared in the following manner:

To a mixture of 1.05 g of 1-tert-butyl-3- (2-cyclopenten-3-yl) thiourea, 0.7 g of potassium carbonate in 25 ml of absolute ethyl alcohol, is added dropwise with stirring, a solution of 0 , 37 ml of methyl iodide in 5 ml of absolute ethyl alcohol. Stirring is continued for 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 freed by treatment with toluene of still adhering moisture. After trituration of the residue with diethyl ether is obtained as a crystalline product, the l-tert-butyl-3- (2-cyclopenten-1-on-3-yl) -S-methyl-thiourea from 80-84 ° F.

Example 6: 7.5 g of 1-amino-cyclopenten- (I) -one- (3) are added in 150 ml of absolute dimethylformamide with 8.6 g of potassium tert-butoxide and under nitrogen and stirring for 1 hour at 90 ° heated. The light brown, thick suspension is cooled and added dropwise with ice cooling 9.5 g of sec-butyl isocyanate 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 1N hydrochloric acid, evaporated to dryness and the adhering moisture is rubbed off with toluene. The residue is suspended in 250 ml of warm 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 crystals are then chromatographed on silica gel in ethyl acetate-methanol 8: 2. The mixture is then treated with charcoal in methanol, the filtrate is evaporated to dryness and dried with toluene. The residue is recrystallized from isopropanol. This gives the 1-sec-butyl-3- (2-cyclopenten-1-one-3-yl) urea.

212 4 0 4

Example 7: 4.7 g of potassium tert-butoxide are introduced into 100 ml of absolute dimethylformamide with stirring. Are added to slightly exothermic reaction to 35 ° C, 4.9 g of N ¹ 'cyano-N'-tert-butyl-guanidine and the mixture is stirred for 2 hours at 50 ⁰ C reaction temperature. Then, a solution of 4.4 g of 1-ethoxy-cyclopentane- (I) -one- (3) in 50 ml of absolute dimethylformamide is added dropwise within 30 minutes and stirred at 50 ⁰ C for a further 3 hours. It is then cooled, neutralized with 42 ml of 1N hydrochloric acid and evaporated to dryness. The residue is dissolved in chloroform and washed with water. After drying the combined organic phases decolorized with Florisil and evaporated. The residue is recrystallized from isopropyl alcohol-diethyl ether to give, as a white crystallizate, the 1-tert.-butyl-2-cyano-3- (2-cyclopenten-1-on-3-yl) -guanidine, m.p. 214 ° C.

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

Claims (3)

18.9.1979 'ΑΡ. C 07 G / 212 4-04 21 2 404 - Λ (° - 55 invention sanction. 1. A process for the preparation of novel 3 ~ 02co-cyclopentenylureas of the formula I. γ - ^ ^ it E ₄ ^ ~ ^S HH - G - HH.- GE ₂ (I) E ₃ whose cyclopentenyl ring may have a much wider double bond and? jorin S ,, hydrogen or lower alkyl, Rp lower alkyl and E, optionally unsaturated lower alkyl, or Eg and E ^ together with the carbon atom connecting them, optionally unsaturated cycloalkyl or E ^, E2 and E- together with the carbon atom connecting them, optionally substituted phenyl, E ^ hydrogen, lower alkyl or optionally substituted phenyl, E _c hydrogen, an optionally esterified or amidated carboxy or nitrile group and Rg represent hydrogen or lower alkyl and I is oxygen, sulfur , the imino or the cyanoimino group, characterized- characterized in that a compound of formula III  R_ H- wherein X is optionally esterified or etherified hydroxy, with a compound of formula IV : 18.9.1979 AP C 07 G / 212 404 212404 - 1+ '55 333/11 I! / ¹ H ₀ N - C - Ml - CR ₀ · (IV) 2 _χ 2 or that a compound of formula V with a compound of formula VI (VI) in which one of the radicals Z ^ and Zp of an amino group and the other of the group VII XYJ Xp C -. N - (VII) , wherein X ^, where appropriate, reactive esterified or etherified P ^ droxy or mercapto, and X is ₀ is hydrogen, or X ^ and Xg susainmen a bond between C and N represent and means Y ^ j oxygen, sulfur, Inino or Cyanj.mino, with with the proviso that if Y is lsino or cyanimino, X * 21 2 40 4 - ^ Halogen and X _{2 represent} hydrogen, and, if desired, in resulting compounds in which Y represents the imino group or S ", converts them into the oxygen atom · %. Process according to item 1, characterized in that 3-0xo-cyclopentenylureas of the formula (II) 0 IL Il / ^Λ ITH-C-KH-G E ₂ (II) are prepared wherein E ^, B ₉ and E ~ is lower alkyl or wherein B is lower alkyl and ~ together with the linking oxygen atom cycloalkyl E ₂ and E having 5-7 carbon atoms · 3 »process according to item Λ _}, characterized in that 3-0xo-cyclopentenyl ~ ureas of the formula II according to point % _} fourdenden, wherein E ^ and B _p methyl and 18,9.1979
AP C Ο? C / 212th 404
21 2 40 4 --19- 55 333/11 R is lower alkyl having 1-3 carbon atoms, or wherein It is methyl and Sp and H- together with the G atom linking them are cycloalkyl having 5-7 carbon atoms
means. 4 ·· Process according to item 1 _f, characterized in that 1-tert-butyl-3- (2-cyclopenten-1-on-3-yl) urea is produced. 5. Procedure according to point 1; characterized in that 1-tert-i-methyl-3- (2-cyclopenten-1-one-3-yl) urea is prepared. 6. The method according to item 1, characterized in that 1-tert-butyl-3 ~ (2-cyclopenten-1-on-3-yl) ~ tbiourea is produced » ?. The method of item 1, characterized _s that 1-tert-butyl-2-cyano-3- (2-cyclopenten-1-on-3-yl) ~ guanidine is prepared. B, method according to item 1, characterized in that 1-sec-butyl-3 ~ (2-cyclopenten-1-on-3-yl) urea is prepared, ". 3, Method according to item 1, characterized in that 1-tort-amyl-2-cyano-3- (2-cyclopenten-1-on-3-yl) -. guanidine is produced.