DE4438021A1 - New N-cyclohexyl-N-phenyl-urea cholesterol biosynthesis inhibitors - Google Patents

Abstract

N1-Cyclohexyl-N3-phenyl-urea or thiourea derivs. of formula (I) and their acid addn. salts are new: X = O or S; R1 = t-Bu or Ph (opt. mono- or disubstd. by 1-3C alkyl, OH or 1-3C alkoxy (opt. substd. in 2- or 3-position by di- 1-3C alkylamino, pyrrolidino, piperidino or hexamethyleneimino)); R2 = H, Me or Et; R3 = 1-3C alkyl; R4 = 1-12C alkyl, 3-12C mono- or polyunsatd. alkenyl or alkynyl opt. monosubstd. by Ph (substd. by R5 and R6), 7-12C cycloalkyl or Ph substd. by R5 and R6; R5, R6 = H, F, Cl, Br, CF3, 1-4C alkyl or alkoxy; or Ph+R5+R6 = naphthyl.

Description

The invention relates to new phenylureas, these verbin containing medicaments and methods for their preparation position.

Numerous phenylureas are described in the literature which are used as herbicides, biocides, growth regulators, Pesticides, fungicides or bactericides can be used see, for example, C.A. 99, 141054b, C.A. 60, 15775h, EP-A-0.066.922, DE-A-32 45 679, DE-A-32 22 622, DE-A-32 21 871, WP-O-81.02156, EP-A-0.028.829).

In addition, in US-A-4,387,105 phenylureas, in an aminocarbonyl group by two identical alkyl or Cycloalkyl substituted, described which a serum cholesterol lowering or antiatherosclerotic Have an effect caused by an inhibition of the enzyme acyl- CoA cholesterol acyltransferase (ACAT) comes about.

It has now been found that the new phenylureas of general formula

and, if R₁ contains a basic group, their acid Addition salts, in particular for pharmaceutical applications Their physiologically acceptable salts with anorgani or organic acids, superior pharmacological Have properties, in particular a strong Hemmwir kung on cholesterol biosynthesis.

In the above general formula
X is an oxygen or sulfur atom,
R₁ is a tert-butyl group or a phenyl group which may be mono- or disubstituted by a hydroxy, alkoxy or alkyl group each having 1 to 3 carbon atoms, wherein the substituents may be the same or different and wherein such alkoxy group in 2- or 3 By a dialkylamino group in which each alkyl moiety may contain 1 to 3 carbon atoms, or may be substituted by a pyrrolidino, piperidino or hexamethyleneimino group,
R₂ is a hydrogen atom or an alkyl group having 1 or 2 carbon atoms,
R₃ is an alkyl group having 1 to 3 carbon atoms,
R₄ is a straight-chain or branched alkyl, alkenyl or alkynyl group, which may also have a radical of the general formula

may be substituted, wherein the alkyl moiety 1 to 12 Koh and the mono- or polyunsaturated Alkenyl or Alkinylteil each 3 to 12 carbon atoms may contain; R₄ can furthermore be a cycloalkyl radical having a total of 7 to 12 carbon atoms or a group the formula

where R₅ and R₆ are the same or different may be a hydrogen, fluorine, chlorine or bromine atom, a trifluoromethyl, alkyl or alkoxy group in which the Alkyl part may contain 1 to 4 carbon atoms, or together with the phenyl ring meaning a naphthyl group th.

The abovementioned radicals in the general formula I can have, for example, the following meanings:
R₁ = tert-butyl, phenyl, 2-methyl-phenyl, 3-methyl-phenyl, 4-methyl-phenyl, 2,3-dimethyl-phenyl, 2,4-dimethyl-phenyl, 2,5-dimethyl-phenyl, 3,4-dimethyl-phenyl, 2-ethyl-phenyl, 3-ethyl-phenyl, 4-ethyl-phenyl, 2,3-diethyl-phenyl, 2,4-dimethyl-phenyl, 2,5-diethyl-phenyl , 3,4-diethyl-phenyl, 4-iso-propyl-phenyl, 3,4-di-n-propyl-phenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2,3- Dihydroxy-phenyl, 2,4-dihydroxyphenyl, 2,5-dihydroxyphenyl, 3,4-dihydroxyphenyl, 2-methoxy-phenyl, 3-methoxy-phenyl, 4-methoxy-phenyl, 2,3- Dimethoxy-phenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 3,4-dimethoxyphenyl, 2-ethoxyphenyl, 3-ethoxy-phenyl, 4-ethoxyphenyl, 2,3 Diethoxyphenyl, 2,4-diethoxy-phenyl, 2,5-diethoxyphenyl, 3,4-diethoxyphenyl, 4-n-propoxyphenyl, 3,4-di-n-propoxy-phenyl, 2-Hydroxy-3-methylphenyl, 2-hydroxy-4-methylphenyl, 2-hydroxy-5-methylphenyl, 3-hydroxy-2-methylphenyl, 3-hydroxy-4-methylphenyl , 3-hydroxy-5-methylphenyl, 2-methoxy-3-methylphenyl, 2-Me thoxy-4-methylphenyl, 2-methoxy-5-methylphenyl, 3-methoxy-2-methylphenyl, 4-methoxy-3-methylphenyl, 3-methoxy-5-methylphenyl, 2 Ethoxy-3-methylphenyl, 3-ethoxy-4-methylphenyl, 2-ethoxy-5-methylphenyl, 4-ethoxy-3-methylphenyl, 3-ethoxy-5-methylphenyl, 4 - (2-N, N-dimethylaminoethoxy) phenyl, 4- (2-N, N-ethylaminoethoxy) phenyl, 4- (2-N, N-di-n-propylaminoethoxy) phenyl, 4- (2-N, N Diisopropylaminoethoxy) phenyl, 4- (2-N-ethyl-N-methylaminoethoxy) phenyl, 4- (3-N, N-dimethylaminopropoxy) phenyl, 4- (3-N, N-diethylamino-propoxy) phenyl, 4- (3-N-Ethyl-N-methylaminopropoxy) phenyl, 4- (2-N, N-dimethylaminoethoxy) -3-methyl-phenyl, 4- (2-N, N-diethylamino-ethoxy) -3-methyl -phenyl, 4- (2-N, N-n-propylaminoethoxy) -3-methylphenyl, 4- (2-N-ethyl-N-methylaminoethoxy) -3-methylphenyl, 4- 3-N, N-dimethylamino-propoxy) -3-methyl-phenyl, 4- (3-N, N-diethylamino-propoxy) -3-methyl-phenyl, 4- (3-N-ethyl-N-methyl-amino-propoxy) 3-methylphenyl, 4- (2-pyrrolidinoethoxy) phenyl, 4- (2-piperidinoethoxy) phenyl, 4 - (2-hexamethylenimino-ethoxy) -phenyl, 4- (3-pyrrolidino-propoxy) -phenyl, 4- (3-piperidino-propoxy) -phenyl, 4- (3-hexamethylene-imino-propoxy) -phenyl, 4- (2- Pyrrolidinoethoxy) -3-methylphenyl, 4- (2-piperidinoethoxy) -3-methylphenyl, 4- (2-hexamethyleneiminoethoxy) -3-methylphenyl, 3-methyl-4- (3 -pyrrolidino-propoxy) phenyl, 3-methyl-4- (3-piperidino-propoxy) -phenyl, 4- (3-hexamethylene-imino-propoxy) -3-methyl-phenyl,
R₂ = hydrogen, methyl, ethyl, wherein methyl, ethyl before given in 2-position,
R₃ = methyl, ethyl, propyl, isopropyl,
R₄ = methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, 3-methyl-n-butyl, 3-methyl-n-pentyl, 3-ethyl-n-pentyl, 4-methyl n-pentyl, n-hexyl, 3-methyl-n-hexyl, 4-methyl-n-hexyl, 3-ethyl-n-hexyl, n-heptyl, 3-methyl-n-heptyl, 3-ethyl n-heptyl, n-octyl, 3-methyl-n-octyl, 3-ethyl-n-octyl, 3,7-dimethyl-n-octyl, 3,7-diethyl-n-octyl, n-nonyl, 3, 7-dimethyl-n-nonyl, 3,7-diethyl-n-nonyl, n-decyl, 3,7-dimethyl-n-decyl, 3,7-diethyl-n-decyl, n-undecyl, n-dodecyl , Allyl, crotyl, 3-butenyl, 3,3-dimethylallyl, 3,3-diethylallyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2-pentenyl, 3-methyl-3-pentenyl, 3 Methyl 4-pentenyl, 3-ethyl-2-pentenyl, 3-ethyl-3-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexyl, 3-methyl-2-hexenyl, 3 Methyl 3-hexenyl, 3-methyl-4-hexenyl, 3-methyl-5-hexenyl, 3-ethyl-2-hexenyl, 3-ethyl-3-hexenyl, 3-ethyl-4-hexenyl, 3-ethyl 5-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 3-methyl-2-heptenyl, 3-methyl-3-heptenyl, 3-methyl-4-heptenyl , 3-methyl-5-heptenyl, 3-methyl-6-heptenyl, 3-ethyl-2-heptenyl, 3-ethyl-3-heptenyl, 3-ethyl-4-heptenyl, 3-ethyl-5-heptenyl, 3-ethyl-6-heptenyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octyl, 6-octenyl, 7-octenyl, 3-methyl-2-octenyl, 3-methyl-3-octenyl, 3 Methyl 4-octenyl, 3-methyl-5-octenyl, 3-methyl-6-octenyl, 3-methyl-7-octenyl, 3-ethyl-2-octenyl, 3-ethyl-3-octenyl, 3-ethyl 4-octenyl, 3-ethyl-5-octenyl, 3-ethyl-6-octenyl, 3-ethyl-7-octenyl, 2,6-octadienyl, 3,7-dimethyl-6-octenyl, 3,7-diethyl 2-octenyl, 3,7-dimethyl-2,6-octadienyl, 3,7-diethyl-2,6-octadienyl, cyclohexylmethyl, phenyl, benzyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, cinnamyl, Pro pargyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3-hexyl in 1, 4-hexynyl, 5-hexynyl,
R₅ and R₆ = hydrogen, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, propyl, butyl, tert-butyl, trifluoromethyl, methoxy, ethoxy, propoxy, butoxy or together the Butadi nylgruppe.

Preferred compounds of general formula I are those in which
R₁ is a tert-butyl group or a phenyl group which may be mono- or disubstituted by a methyl, hydroxy, methoxy or ethoxy group, where the substituents may be the same or different and an ethoxy group in the 2-position by a dimethylamino or diethylamino group can be substituted,
R₂ is a hydrogen atom, R₃ is a methyl or ethyl group,
R₄ is a straight-chain or branched alkyl, alkenyl or alkynyl group which may optionally be substituted by a phenyl radical, wherein the alkyl part contains 1 to 10 carbon atoms, the mono- or di-unsaturated alkenyl part contains 3 to 10 carbon atoms and the alkynyl part contains 3 to 5 carbon atoms can
R₅ and R₆, which may be the same or different, represent a hydrogen, fluorine or chlorine atom, a methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl or methoxy group or
R₅ and R₆ together with the phenyl ring a Naphthylgrup pe and
X represents an oxygen atom, in particular those compounds in which
R₁ is a tert-butyl group or a phenyl group which is substituted in the 4-position by a methoxy, hydroxy or 2- (N, N-dimethylamino) -ethoxy group and may additionally be substituted in the 3-position by a methyl group,
R₂ is a hydrogen atom, R₃ is a methyl group,
R₄ represents an n-propyl, n-butyl, isobutyl, 3-methyl-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-de cyl, allyl, crotyl, 3,3-dimethyl-allyl, propargyl, 3,7-dimethyl-6-octenyl, 3,7-dimethyl-2,6-octadienyl-cyclohexylmethyl, benzyl or phenyl,
R₅ represents a hydrogen, fluorine or chlorine atom, a methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl or methoxy group,
R₆ is a hydrogen, fluorine or chlorine atom, a methyl or ethyl group or
R₅ and R₆ together with the phenyl ring a Naphthylgrup pe and
X represents an oxygen atom, and, if R₁ represents a phenyl group in which an ethoxy group is substituted in the 2-position by a basic group whose Säureaddi tion salts, in particular for the pharmaceutical application of their physiologically acceptable salts with inorganic or organic acids.

According to the invention, the novel compounds are obtained according to fol the following procedure:

• a) reaction of a compound of the general formula with a compound of the general formula in which
  R₁ to R₆ are as defined above, one of the radicals U₁ or U₂ is a hydrogen atom and the other of the radicals U₁ or U₂ is a Z₁-CX group in which X is as defined above and
  Z₁ is a nucleophilic leaving group such as a halogen atom, an alkoxy, aryloxy, aralkoxy, alkylthio, arylthio or aralkylthio group, e.g. As a chlorine or bromine atom, a methoxy, ethoxy, phenoxy, methylthio or ethylthio group represents.

The reaction is conveniently carried out in an inert Lö such as ethers, toluene, methylene chloride or di methylformamide and preferably in the presence of a base such as For example, triethylamine, pyridine, potassium carbonate or an excess of the amine used at temperatures between tween -10 ° C and the boiling point of the solvent, be Preferably, however, at temperatures between 0 and 30 ° C Runaway leads.

• b) For the preparation of compounds of general formula I in which X represents an oxygen atom:
  Alkylation of a compound of the general formula in the
  R₁, R₂ and R₅ and R₆ are as defined above, one of the radicals R₃ 'or R₄' is a hydrogen atom and the other of the radicals R₃ 'or R₄' has the meanings mentioned for R₃ or R₄, with a compound of the general formula Z₂-R₇ (V) in the
  R₇ has the meanings mentioned for R₃ or R₄ and, and
  Z₂ is a nucleophilic leaving group such as a halogen atom or a substituted sulphonyloxy group, e.g. As a chlorine, bromine or iodine atom, a methylsulfonyloxy, ethylsulfonyl oxy or p-toluenesulfonyloxy group represents.

The alkylation is conveniently carried out in an inert Lö such as benzene, ether, tetrahydrofuran, glycolime methyl ether or dimethylformamide and preferably in the presence a base such as lithium diisopropylamide, potassium tert-butylate or sodium hydride at temperatures between -10 and 30 ° C executed.

• c) For the preparation of compounds of the general formula I in which R₁ is a phenyl group which is substituted by at least one alkoxy group having 1 to 3 carbon atoms, wherein the alkoxy group in the 2- or 3-position by a Di alkylaminogruppe in which each alkyl part may contain up to 3 carbon atoms, or may be substituted by a pyrrolidino, piperi dino or hexamethyleneimino group, and X represents an oxygen atom:
  Alkylation of a compound of the general formula in the
  R₂ to R₆ are as defined above and
  R₁ 'is a hydroxyphenyl group which may additionally be substituted by a hydroxy, alkoxy or alkyl group each having 1 to 3 carbon atoms, an alkoxy group being in the 2- or 3-position by a dialkylamino group in which each alkyl portion is 1 to 3 carbon atoms may be substituted or may be substituted by a pyrrolidino, piperidino or hexamethylene imino group, means
  with a compound of the general formula Z₃-Alk-R₈ (VII) in the
  Alk is an n-alkylene group having 1 to 3 carbon atoms,
  R₈ represents a hydrogen atom, a pyrrolidino, piperidino, hexamethyleneimino or dialkylamino group in which each alkyl moiety may contain 1 to 3 carbon atoms, and
  Z₃ is a nucleophilic leaving group such as a halogen atom, e.g. As a chlorine, bromine or iodine atom, represent.

The alkylation is conveniently carried out in a solvent or solvent mixture such as acetone, diethyl ether, dimethyl formamide, dimethyl sulfoxide, benzene, tetrahydrofuran or Dioxane preferably in the presence of an acid-binding Mit tels, z. As an alcoholate such as potassium tert.butylat, one Alkali Hydroxide such as sodium or potassium hydroxide, an Al potassium carbonate such as potassium carbonate, an alkali metal such as Na triumamide, an alkali hydride such as sodium hydride, a ter tiary organic base such as triethylamine or pyridine, wherein the latter also serve as a solvent at the same time can, or a reaction accelerator such as potassium iodide, depending on the reactivity of the nucleophile exchangeable Restes expediently at temperatures between 0 and 150 ° C, preferably at temperatures between 50 and 120 ° C, z. B. at the boiling point of the solvent used, carried out.

The reaction can also in a solvent or Lö mixture such as methylene chloride / water, chloroform / Water, benzene / water with the addition of an acid-binding agent such as As sodium hydroxide, potassium hydroxide and a Phasentrans Fer catalyst such as tetrabutylammonium hydrogen sulfate, before preferably at room temperature.

In the reactions described above can give If appropriate, reactive groups such as hydroxy groups are selected protected during implementation by conventional protecting groups will be split off after the implementation.

For example, comes as a protective group for a hydroxy group trimethylsilyl, acetyl, benzoyl, methyl or benzyl group into consideration.  

The optional subsequent cleavage of a use The protective moiety is preferably carried out hydrolytically in one aqueous solvents, for. In water, isopropanol / water, Tetrahydrofuran / water or dioxane / water, in the presence of a Acid such as hydrochloric acid or sulfuric acid or in the presence an alkali base such as sodium hydroxide or potassium hydroxide Temperatures between 25 and 50 ° C. The split of a Ben zyloxyrestes preferably takes place hydrogenolytically, z. B. with Hydrogen in the presence of a catalyst such as palladium / Coal in a solvent such as methanol, ethanol, vinegar acid ethyl ester or glacial acetic acid, if appropriate with addition an acid such as hydrochloric acid at temperatures between 0 and 50 ° C, but preferably at room temperature, and a What hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar, one in the rest R₄ existing double or three can be hydrogenated simultaneously. The spal tion of an alkoxy group is preferably carried out by Bortri bromide in a suitable solvent such as methylene chloride or chloroform at temperatures between -30 and 30 ° C or by reaction with sodium thioethoxide in a solution such as dimethylformamide at temperatures between 100 and 160 ° C, preferably at the boiling temperature of the solution means.

Further, the obtained compounds of the general Formula I, wherein R₁ represents a phenyl group, which through at least one in 2- or 3-position by a dial kylamino, pyrrolidino, piperidino or hexamethyleneimino substituted alkoxy group is substituted in their Acid addition salts, especially for their pharmaceutical Application in their physiologically acceptable acid additions salts with inorganic or organic acids become. As acids in this case, for example, hydrochloric acid, Hydrobromic acid, sulfuric acid, phosphoric acid, vinegar acid, lactic acid, citric acid, tartaric acid, succinic acid, Maleic acid or fumaric acid.  

The compounds used as starting materials of the general NEN formulas II to VII are known from the literature or obtained these by known methods.

The N-alkylcyclohexyl used as starting compounds amines of general formula II are known from the literature [J. Chem. Soc. (C), 1509 (1967)] or can be deduced from the ent speaking cyclohexanones and primary amines by reduk tive amination according to Leuckart-gelding or by means of kataly table excited hydrogen in the presence of a heavy metal produce catalysts such as Raney nickel, or by Reduk tion of the intermediately formed corresponding ketimines with complex metal hydrides such as sodium cyanoborohydride, Na triumborohydride or lithium aluminum hydride or by kata lytically excited hydrogen in the presence of a heavy tallkatalysators such as palladium.

Here, the amines of general formula II as cis / Trans mixtures obtained, where appropriate, according to known Methods by column chromatography on silica gel or Alumina or by fractional crystallization of their Salts with inorganic or organic acids, in the rei nen isomers can be separated.

The carbamoyl compounds used as starting compounds gene of the general formulas II and III are known from the literature or can be obtained from the corresponding amines by reaction with excess phosgene, diphosgene, triphosgene or thio phosgene in inert solvents such as ethyl acetate, Benzene, toluene, chloroform, methylene chloride, hexane, at Tem temperatures between 0 ° C and the boiling point of the solution by means of, preferably at temperatures between 50 and 120 ° C, represent.

The phenylureas used as starting compounds Formula IV can be in a known manner from the corre sponding  secondary amines by reaction with the corre sponding producing isocyanates, the ones for use Isocyanates are either commercially available or by reaction of the corresponding amines with excesses phosgene, diphosgene, triphosgene in inert solvents such as ethyl acetate, benzene, toluene, chloroform, Methylene chloride, hexane, at temperatures between 0 ° C and the Boiling temperature of the solvent, preferably at Tempe temperatures between 50 and 110 ° C can be obtained.

In the event that the compounds of general formula I contain asymmetric carbon atoms and thus in the form of enantiomer or diastereomer mixtures, the compounds obtained can be customary per se Separate method in their optical antipodes.

As already mentioned, the compounds of the Formula I has valuable pharmacological properties, in particular a strong inhibitory effect on the endogenous Choleste rolbiosynthese. Because most of it is in the organism cholesterol is not ingested, son When endogenously synthesized, inhibition of Cho occurs lesterol biosynthesis plays a crucial role in the regula tion of cholesterol metabolism while the above mentioned ACAT inhibitors essentially only with the Affect food intake cholesterol content.

The phenylureas of the present invention are to compounds that promote cholesterol biosynthesis inhibit assets and therefore against structure-like ones known compounds an independent pharmacological Profile.

Due to their excellent inhibiting properties on the Cholesterol biosynthesis and good compatibility are the  Compounds of general formula I in a preferred manner suitable for normalizing cholesterol metabolism and to reduce excessive serum cholesterol levels and thus particularly effective for the prevention and treatment of Hyperlipoproteinämien, atherosclerosis and from the atherosclerotic vascular changes resulting episode diseases, such as myocardial infarction, the Claudicatio intermittens, ischemic heart disease, coronary heart disease and cerebral ischemia.

The biological activity of compounds of the general formula I was determined by determining the ¹⁴C acetate incorporation into the digitonin precipitable steroids according to the following method:
Human hepatoma cells (Hep G2) are stimulated after 3 days of culture for 16 hours in cholesterol-free medium. The substances to be tested (dissolved in dimethyl sulfoxide, final concentration 0.1%) are added during this stimulation phase. Subsequently, after addition of 200 mmol / l of 2-.sup.1 C acetate, it is further incubated for 2 hours at 37.degree. C. in an incubator.

After detachment of the cells and saponification of the cholesterol ester after extraction, cholesterol is precipitated with digitonin brought. The built in cholesterol ¹⁴C-acetate is determined by scintillation measurement.

It has been found that, for example, the compounds
A = N₃-crotyl-N₁- (trans-4-tert-butyl-cyclohexyl) -N₁-methyl-N₃-phenyl-urea,
B = N₁- [trans-4- (4-methoxy-3-methylphenyl) cyclohexyl] - N₁-methyl-N₃-phenyl-N₃-propylurea,
C = N₁- (trans-4-tert-butylcyclohexyl) -N₁-methyl-N₃- (3-methyl-butyl) -N₃-phenyl-urea,
D = N₁- (trans-4-tert-butylcyclohexyl) -N₃- (3,3-dimethyl-allyl) -N₁-methyl-N₃-phenyl-urea,
E = N₁- [trans-4- (4-methoxy-3-methylphenyl) cyclohexyl] - N₃- (3,3-dimethyl-allyl) -N₁-methyl-N₃-phenyl-urea and
F = N₁- (trans-4-tert-butylcyclohexyl) -N₃-hexyl-N₁-methyl-N₃-phenyl-urea
at a test concentration of 10 ^-6 mol / l inhibit ¹⁴C acetate incorporation into cholesterol by at least 50%.

The compounds are still characterized by a very good Compatibility. For example, Compound D showed after oral administration of 1000 mg / kg to the mouse no toxic side effects.

For pharmaceutical application, the compounds the general formula I together with one or more inert carriers or diluents in be way known in the usual pharmaceutical preparations shapes, z. In tablets, dragees, capsules or supposito familiarize yourself with The single dose may be given by oral administration between 0.02 to 2 mg, preferably 0.08 to 1 mg per kg Body weight vary according to a daily dose of 5 to 300 mg for a human of 60 kg body weight, taking the daily dose is preferably divided into 1 to 3 individual doses becomes.

The following examples are intended to explain the invention in more detail:
Examples for the preparation of the starting materials:

example A N₁- (trans-4-tert-butyl-cyclohexyl) -N _{1-methyl-N₃-phenyl} urea

2.7 g (16 mmol) of N-methyl-trans-4-tert-butyl-cyclohexylamine are placed in 30 ml of absolute ether and dropwise with stirring and cooling in an ice bath with a solution of 1.9 g (16 mmol) of phenyl isocyanate 20 ml of absolute ether added. After completion of the addition is stirred for 30 minutes, then filtered with suction from the crystalline precipitate formed and washed with ether.
Yield: 3.4 g (75% of theory),
Melting point: 187-188 ° C.

Calc .: C 74.95; H 9,79; N, 9.71;
gef. : C, 74.65; H 9,92; N 9.67.

1 H-NMR spectrum (200 mHz, CDCl₃); Signals at ppm:
0.88 (s, 9H), 0.9-1.95 (m, 9H), 2.87 (s, 3H), 4.07 (m, 1H), 7.02 (m, 1H), 7 , 22-7.45 (m, 4H).

In an analogous manner were obtained:

a.) N₁- (trans-4-tert-butyl-cyclohexyl) -N₃- (3-chloro phenyl) -N₁-methyl-urea

Prepared from (3-chloro-phenyl) isocyanate and N-methyl-trans-4-tert-butyl-cyclohexylamine
Yield: 64% of theory,
Melting point: 172-173 ° C.

Re: C 66.96; H 8,43; N, 8.68;
gef. : C 66.88; H 8,17; N 8,60.

b.) N₁- (trans-4-tert-butyl-cyclohexyl) -N₃- (4-chloro phenyl) -N₁-methyl-urea

Prepared from (4-chloro-phenyl) isocyanate and N-methyl-trans-4-tert-butyl-cyclohexylamine
Yield: 70.2% of theory,
Melting point: 170-171 ° C.

Re: C 66.96; H 8,43; N, 8.68;
gef. : C, 67.05; H 8,70; N 8,77.

c.) N₁- (trans-4-tert-butyl-cyclohexyl) -N₃- (2,6-dichloro) phenyl) -N₁-methyl-urea

Prepared from (2,6-dichloro-phenyl) isocyanate and N-methyl-trans-4-tert-butyl-cyclohexylamine.
Yield: 81.0% of theory,
Melting point: 178-179 ° C.

Calc .: C 60.50; H 7,33; N, 7.84;
gef. : C 60.20; H 7,29; N 7,88.

d.) N₁- (trans-4-tert-butylcyclohexyl) -N₃- (3-methoxy- phenyl) -N₁-methyl-urea

Prepared from (3-methoxy-phenyl) isocyanate and N-methyl-trans-4-tert-butyl-cylohexylamine.
Yield: 91.5% of theory,
Melting point: 161-162 ° C.

Calc .: C, 71.66; H 9,49; N 8,79;
gef. C, 71.45; H 9.43; N 8,68.

e.) N₁- (trans-4-tert-butylcyclohexyl) -N₃- (4-methoxy- phenyl) -N₁-methyl-urea

Prepared from (4-methoxy-phenyl) isocyanate and N-methyl-trans-4-tert-butyl-cyclohexylamine.
Yield: 94.3% of theory,
Melting point: 187-189 ° C.

Calc .: C, 71.66; H 9,49; N 8,79;
gef. : C 71.38; H 9,19; N 8,66.

f.) N₁- (trans-4-tert-butylcyclohexyl) -N₃- (2-methoxy- phenyl) -N₁-methyl-urea

Prepared from (2-methoxy-phenyl) isocyanate and N-methyl-trans-4-tert-butyl-cyclohexylamine.
Yield: 91.8% of theory,
Yield: 117-118 ° C.

Calc .: C, 71.66; H 9,49; N 8,79;
gef. C, 71.67; H 9.53; N 8,72.

g.) N₁- (trans-4-tert-butylcyclohexyl) -N₁-methyl-N₃- (3 methyl-phenyl) -urea

Prepared from (3-methyl-phenyl) isocyanate and N-methyl-trans-4-tert-butyl-cyclohexylamine.
Yield: 79% of theory,
Melting point: 210-211 ° C.

Calc .: C, 75.45; H 10.00; N 9,26;
gef. : C 75.18; H 9,74; N 9,12.

h.) N₁- (trans-4-tert-butyl-cyclohexyl) -N₁-methyl-N₃- (4- methyl-phenyl) -urea

Made of (⁴-methyl-phenyl) isocyanate and N-methyl-trans-4-tert-butyl-cyclohexylamine.
Yield: 82.7% of theory,
Melting point: 214-215 ° C.

Calc .: C, 75.45; H 10.00; N 9,26;
gef. : C, 75.41; H 10,30; N 9,27.

i.) N₁- (trans-⁴-tert-butyl-cyclohexyl) -N₃- (2,6-dimethyl- phenyl) -N₁-methyl-urea

Made of (2,6-dimethyl-phenyl) isocyanate and N-methyl-trans-4-tert-butyl-cyclohexylamine.
Yield: 94.9% of theory,
Melting point; 211-213 ° C.

Calc .: C, 75.90; H 10,19; N, 8.85;
gef. : C, 75.98; H, 10.44; N 8.99.

k.) N₁- (trans-4-tert-butyl-cyclohexyl) -N₃- (2,6-diethyl- phenyl) -N₁-methyl-urea

Prepared from (2,6-diethyl-phenyl) isocyanate and N-methyl-trans-4-tert-butyl-cyclohexylamine.
Outstanding: 93.9% of theory,
Melting point: 223-225 ° C.

Calc .: C 76.69; H 10.53; N 8,13;
gef. : C 76.74; H, 10.76; N 8.09.

1.) N₁- (trans-4-tert-butyl-cyclohexyl) -N₃- (2-isopropyl- 6-methyl-phenyl) -N₁-methyl-urea

Prepared from (2-isopropyl-6-methyl-phenyl) isocyanate and N-methyl-trans-4-tert-butyl-cyclohexylamine.
Yield: 87.7% of theory,
Melting point: 214-216 ° C.

Calc .: C 76.69; H 10.53; N 8,13;
gef. : C, 76.80; H, 10.71; N 8,12.

m.) N₁- (trans-4-tert-butyl-cyclohexyl) -N₃- (2,4-difluoro- phenyl) -N₁-methyl-urea

Prepared from (2,4-difluoro-phenyl) isocyanate and N-methyl-trans-4-tert-butyl-cyclohexylamine.
Yield: 52% of theory,
Melting point: 120 ° C.

Calc .: C, 66.64; H 8.08; N, 8.64;
gef. : C 66.48; H 7,88; N 8.74.

n.) N₁- (trans-4-tert-butyl-cyclohexyl) -N₁-ethyl-N₃- phenyl-urea

Prepared from phenyl isocyanate and N-ethyl-trans-4-tert. butyl-cyclohexylamine.
Yield: 88% of theory,
Melting point: 170-171 ° C.

Calc .: C, 75.45; H 10.00; N 9,26;
gef. : C, 75.42; H 10,33; N 9,13.

o.) N₁- (trans-4-tert-butyl-cyclohexyl) -N₃-phenyl-N₁- propyl-urea

Made from phenyl isocyanate and N-propyl trans-4-tert. butyl-cyclohexylamine.
Yield: 79% of theory,
Melting point: 141 ° C.

Calc .: C, 75.90; H 10,19; N, 8.85;
gef. : C, 75.87; H 10,32; N 8.64.

p.) N₁- (trans-4-tert-butyl-cyclohexyl) -N₁-methyl-N₃- (1-naphthyl) urea

Made of N-methyl-trans-4-tert-butyl-cyclohexylamine and (1-naphthyl) isocyanate.
Yield: 76.4% of theory,
Melting point: 175 ° C.

Calc .: C 78.06; H 8,93; N 8,28;
gef. : C 78.12; H 8,98; N 8,33.

q.) N₁- [trans-4- (4-methoxy-3-methylphenyl) cyclohexyl] - N₁-N₃-methyl-phenyl urea

Prepared from phenyl isocyanate and N-methyl-trans-4- (4-methoxy-3-methylphenyl) cyclohexylamine.
Yield: 86% of theory,
Melting point: 188-189 ° C.

Calc .: C 74.97; H 8.01; N 7.95;
gef. : C, 74.68; H 8.03; N 8,00.
1 H-NMR spectrum (200 mHz, CDCl₃); Signals at ppm:
1.48-2.08 (m, 8H), 2.20 (s, 3H), 2.40 (m, 1H), 2.92 (s, 3H), 3.80 (s, 3H), 4 , 26 (m, 1H), 6.70-7.46 (m, 8H)

The starting material used is N-methyl-trans-4- (4-meth oxy-3-methyl-phenyl) cyclohexylamine is obtained by reaction of Cyclohexane-1,4-dione monoethylene ketal with 4-methoxy-3-methyl- phenyl-lithium to 4-hydroxy-4- (4-methoxy-3-methylphenyl) cyclohexanone ethylene ketal (melting point: 88 ° C), followed by Dehydration to 4- (4-methoxy-3-methylphenyl) cyclohex-3- en-1-one ethylene ketal (m.p .: 69 ° C), subsequent Hy and deketalization to 4- (4-methoxy-3-methyl-phe nyl) cyclohexanone (melting point: 94 ° C), reductive amination with methylamine to give N-methyl-cis / trans-4- (4-methoxy-3-methyl) phenyl) cyclohexylamine and subsequent isomer separation, in crystalline form (melting point: 98 ° C).

Example B N₁- (cis-4-tert-butyl-cyclohexyl) -N₁-methyl-N₃-phenyl- urea

5.08 g (30 mmol) of N-methyl-cis-4-tert-butyl-cyclohexylamine are dissolved in 50 ml of absolute ether and added dropwise with stirring and ice cooling with a solution of 3.6 g (30 mmol) of phenyl isocyanate in 15 ml added to absolute ether. After completion of the addition, stirring is continued for 30 minutes, then concentrated by evaporation and the residue from concentration on silica gel is purified by column chromatography (eluent: methylene chloride).
Yield: 6.0 g (69.5% of theory) -
Melting point: 103-105 ° C.

Calc .: C 74.96; H 9,79; N, 9.71;
gef. : C 74.98; H 9,92; N 9.59.
1 H-NMR spectrum (200 mHz, CDCl₃); Signals at ppm:
0.88 (s, 9H), 1.13-2.0 (m, 9H), 3.01 (s, 3H), 4.23 (m, 1H), 7.01 (m, 1H), 7 , 18-7.45 (m, 4H).

In an analogous manner were obtained:

a.) N1- (cis-4-tert-butyl-cyclohexy) -N₁-methyl-N₃- (4- methyl-phenyl) -urea

Prepared from (4-methylphenyl) isocyanate and N-methyl-cis 4-tert-butylcyclohexyamine
Yield: 86.1% of theory,
Melting point: 150-151 ° C.

Calc .: C, 75.45; H 10.00; N 9,26;
gef. : C 75.34; H 10.08; N 9,18.

b.) N₁- (cis-4-tert-butylcyclohexyl) -N₃-2,6-dimethyl- phenyl) -N₁-methyl-urea

Prepared from (2,6-dimethyl-phenyl) isocyanate and N-methyl-cis-4-tert-butyl-cyclohexylamine
Yield: 88.6% of theory,
Melting point 199-201 ° C.

Calc .: C, 75.90; H 10,19; N, 8.85;
gef. : C, 75.87; H 10,27; N 8,81.

c.) N₁- (cis-4-tert-butyl-cyclohexyl) -N₃- (2-methoxy- phenyl) -N₁-methyl-urea

Prepared from (2-methoxy-phenyl) isocyanate and N-methyl-cis-4-tert-butyl-cyclohexylamine.
Yield: 77.2% of theory,
Melting point: 58-60 ° C.

Calc .: C, 71.66; H 9,49; N 8,79;
gef. : C 71.96; H 9.57; N 8,93.

d.) N₁- (cis-4-tert-butylcyclohexyl) -N₃- (3-methoxy- phenyl) -N₁-methyl-urea

Prepared from (3-methoxy-phenyl) isocyanate and N-methyl-cis-4-tert-butyl-cyclohexylamine.
Yield: 66% of theory,
Melting point: 140-142 ° C.

Calc .: C, 71.66; H 9,49; N 8,79;
gef. : C 71.98; H 9.57; N 9.03.

e.) N₁- (cis-4-tert-butylcyclohexyl) -N₃- (2,6-dichloro) phenyl) -N₁-methyl-urea

Prepared from (2,6-dichloro-phenyl) isocyanate and N-methyl-cis-4-tert-butyl-cyclohexylamine.
Yield: 86.6% of theory,
Melting point: 174-176 ° C.

Calc .: C 60.50; H 7,33; N, 7.84;
gef. : C 60.28; H 7,16; N 7,76.

f.) N₁- (cis-4-tert-butyl-cyclohexyl) -N₃- (3-chloro phenyl) -N₁-methyl-urea

Prepared from (3-chloro-phenyl) isocyanate and N-methyl-cis-4-tert-butyl-cyclohexylamine.
Yield: 83.8% of theory,
Melting point: 139-141 ° C.

Re: C 66.96; H 8,43; N, 8.68;
gef. : C 66.99; H 8,53; N 8,73.

g.) N₁- (cis-4-tert.-butyl-cyclohexyl) -N₃- (2,4-difluoro- phenyl) -N₁-methyl-urea

Prepared from (2,4-difluoro-phenyl) isocyanate and N-methyl-cis-4-tert-butyl-cyclohexylamine.
Yield: 85.6% of theory,
Melting point: 98-100 ° C.

Calc .: C, 66.64; H 8.08; N, 8.64;
gef. : C 66.57; H 8,14; N 8,81.

h.) N₁- (cis-4-tert-butylcyclohexyl) -N₁-ethyl-N₃- phenyl-urea

Made from phenyl isocyanate and N-ethyl-cis-4-tert. butyl-cyclohexylamine.
Yield: 84% of theory,
Melting point: 98 ° C.

Calc .: C, 75.45; H 10.00; N 9,26;
gef. : C 75.51; H 10,13; N 9.35.

i.) N₁- (cis-4-tert-butyl-cyclohexyl) -N₁-methyl-N₃- (1-naphthyl) urea

Made of N-methyl-cis-4-tert-butyl-cyclohexylamine and (1-naphthyl) isocyanate.
Yield: 94.7% of theory,
Melting point: 178 ° C.

Calc .: C 78.06; H 8,93; N 8,28;
gef. : C 78.36; H 9.11; N 8,13.

Examples of the preparation of the end products:

Example 1 N₃-benzyl-N₁- (trans-4-tert-butyl-cyclohexyl) -N₁- methyl-N₃-phenyl-urea

144 mg (6 mmol) of sodium hydride are suspended in 20 ml of absolute Di methylformamide and then with 1.11 g (3.8 mmol) of N₁- (trans-4-tert-butyl-cyclohexyl) -N₁-methyl-N₃-phenyl- urea added. After 1 hour of stirring at 40 to 50 ° C is cooled to room temperature and treated dropwise with 680 mg (4 mmol) of benzyl bromide. After stirring overnight, it is decomposed with ice-cold 2N hydrochloric acid and extracted with ether. The extracts are dried over magnesium sulfate, concentrated by evaporation and the residue from concentration on silica gel is purified by column chromatography (eluent: petroleum ether / ethyl acetate 10: 1).
Yield: 1.3 g (86% of theory),
Melting point: 93 ° C.

Re: C, 79.32; H 9.05; N, 7.40;
gef. : C, 79.53; H 9,31; N 7.28.

1 H-NMR spectrum (200 mHz, CDCl₃); Signals at ppm:
0.82-1.85 (s + m, 18H), 2.47 (s, 3H), 3.90 (m, 1H), 4.84 (s, 2H), 7.03-7.35 ( m, 10H).

In an analogous manner were obtained:

a.) N₁- (trans-4-tert-butyl-cyclohexyl) -N₁-methyl-N₃- phenyl-N₃-propyl-urea

Prepared from N₁- (trans-4-tert-butylcyclohexyl) -N₁-methyl-N₃-phenylurea and propylbromide.
Yield: 91% of theory,
Melting point: oil.

Re: C 76.31; H 10.37; N 8,48;
gef. : C, 76.62; H, 10.63; N 8.36.

1 H-NMR spectrum (200 mHz, CDCl₃); Signals at ppm:
0.81-1.85 (s + t + m, 23H), 2.40 (s, 3H), 3.56 (m, 2H), 3.83 (m, 1H), 7.06-7, 30 (m, 5H).

b.) N₁- (trans-4-tert-butylcyclohexyl) -N₃-hexyl-N₁- methyl-N₃-phenyl-urea

Prepared from N₁- (trans-4-tert-butylcyclohexyl) -N₁-methyl-N₃-phenylurea and hexylbromide.
Yield: 60% of theory,
Melting point: oil.

Re: C 77.37; H, 10.82; N, 7.52;
gef. : C, 77.31; H, 10.96; N 7,22.

1 H-NMR spectrum (200 mHz, CDCl₃); Signals at ppm:
0.83-1.85 (s + m, 29H), 2.40 (s, 3H), 3.57 (m, 2H), 3.83 (m, 1H), 7.06-7.25 ( m, 5H).

c.) N₁- (trans-4-tert-butylcyclohexyl) -N₃- (3,3-dimethyl- allyl) -N₁-methyl-N₃-phenyl-urea

Prepared from N₁- (trans-4-tert-butylcyclohexyl) -N₁-methyl-N₃-phenylurea and 3,3-dimethylallyl-bromide.
Yield: 82% of theory,
Melting point: 78-80 ° C.

Re: C 77.48; H 10,18; N, 7.86;
gef. : C 77.60; H, 10.42; N 7.64.

1 H-NMR spectrum (200 mHz, CDCl₃); Signals at ppm:
0.81-1.85 (3s + m, 24H), 2.41 (s, 3H), 3.85 (m, 1H), 4.18 (d, 2H), 5.32 (m, 1H) , 6.98-7.35 (m, 5H).

d.) N₃-Allyl-N₁- (trans-4-tert-butyl-cyclohexyl) -N₁- methyl-N₃-phenyl-urea

Prepared from N₁- (trans-4-tert-butylcyclohexyl) -N₁-methyl-N₃-phenylurea and allyl bromide.
Yield: 69% of theory,
Melting point: oil.

Re: C 76.78; H 9,82; N 8,53;
gef. : C 76.78; H 9,91; N 8,31.

1 H-NMR spectrum (200 mHz, CDCl₃); Signals at ppm:
0.82-1.85 (s + m, 18H), 2.43 (s, 3H), 3.87 (m, 1H), 4.23 (d, 2H), 5.1 (m, 2H) , 5.97 (m, 1H), 7.0-7.35 (m, 5H).

e.) N₁- (trans-4-tert-butylcyclohexyl) -N₃-crotyl-N₁- methyl-N₃-phenyl-urea

Prepared from N₁- (trans-4-tert-butylcyclohexyl) -N₁-methyl-N₃-phenylurea and crotylbromide.
Yield: 72% of theory,
Melting point: oil.

Re: C 77.14; H 10.01; N 8,18;
gef. : C, 76.83; H 9,86; N 7.95.

1 H-NMR spectrum (200 mHz, CDCl₃); Signals at ppm:
0.83-1.83 (s + m, 21H), 2.42 (s, 3H), 3.86 (m, 1H), 4.15 (d, 0.8H), 4.25 (d, 0.2H), 5.55 (m, 1H), 7.0-7.35 (m, 5H).

f.) N₁- (trans-4-tert-butylcyclohexyl) -N₃-cinnamyl-N₁- methyl-N₃-phenyl-urea

Prepared from N₁- (trans-4-tert-butylcyclohexyl) -N₁-methyl-N₃-phenylurea and cinnamylbromide.
Yield: 51% of theory,
Melting point: 105 ° C.

Ber .: C 80.15; H 8,97; N, 6.92;
gef. : C 80.37; H 8,97; N 6.84.

1 H-NMR spectrum (200 mHz, CDCl₃); Signals at ppm:
0.81-1.86 (s + m, 18H), 2.45 (s, 3H), 3.89 (m, 1H), 4.39 (d, 2H), 6.39 (s, 1H) , 7.0-7.4 (m, 10H).

g.) N₁- (trans-4-tert-butylcyclohexyl) -N₁-methyl-N₃- (3-methyl-butyl) -N₃-phenyl-urea

Prepared from N₁- (trans-4-tert-butylcyclohexyl) -N₁-methyl-N₃-phenylurea and 3-methylbutylbromide.
Yield: 38% of theory,
Melting point: 63 ° C.

Calc .: C 77.04; H, 10.68; N, 7.81;
gef. : C, 77.08; H 11.02; N 7,87.

1 H-NMR spectrum (200 mHz, CDCl₃); Signals at ppm:
0.82-1.85 (s + d + m, 27H), 2.38 (s, 3H), 3.6 (m, 2H), 3.84 (m, 1H), 7.0-7, 36 (m, 5H).

h.) N₁- (trans-4-tert-butyl-cyclohexyl) -N _3- (3,3-dimethyl-allyl) -N₃- (2,6-dimethyl-phenyl) -N₁-methyl-urea

Prepared from N₁- (trans-4-tert-butylcyclohexyl) -N₃- (2,6-dimethyl-phenyl) -N₁-methyl-urea and 3,3-dimethyl-allylbromide.
Yield: 70.2% of theory,
Melting point: oil.

Calc .: C, 78.07; H, 10.48; N 7.28;
gef. : C 78.25; H, 10.71; N 7.11.

1 H-NMR spectrum (200 mHz, CDCl₃); Signals at ppm:
0.78-1.77 (3s + m, 24H), 2.23 (s, 6H), 2.38 (s, 3H), 3.43 (m, 1H), 3.98 (d, 2H) , 5.46 (m, 1H), 7.03 (s, 3H).

i.) N₁- (trans-4-tert-butyl-cyclohexyl) -N₃- (2,6-diethyl- phenyl) -N₃- (3,3-dimethyl-allyl) -N₁-methyl-urea

Prepared from N₁- (trans-4-tert-butylcyclohexyl) -N₃- (2,6-diethyl-phenyl) -N₁-methyl-urea and 3,3-dimethyl-allylbromide.
Yield: 91.8% of theory,
Melting point: oil.

Calc .: C 78.59; H 10.75; N 6.79;
gef. : C 78.29; H, 10.88; N 6.63.

1 H-NMR spectrum (200 mHz, CDCl₃); Signals at ppm:
0.78-1.75 (3s + m + t, 30H), 2.40 (s, 3H), 2.58 (m, 4H), 3.33 (m, 1H), 3.97 (d, 2H), 5.44 (m, 1H), 7.08-7.30 (m, 3H).

k.) N₁- (trans-4-tert-butyl-cyclohexyl) -N₃- (3,3-dimethyl- allyl) -N₃- (2-isopropyl-6-methyl-phenyl) -N₁-methyl- urea

Prepared from N₁- (trans-4-tert-butylcyclohexyl) -N₃- (2-isopropyl-6-methyl-phenyl) -N₁-methyl-urea and 3,3-dimethyl-allylbromide.
Yield: 97.3% of theory,
Melting point: 80-82 ° C.

Calc .: C 78.59; H 10.75; N 6.79;
gef. : C 78.60; H, 10.79; N 6,710.

1 H-NMR spectrum (200 mHz, CDCl₃); Signals at ppm:
0.80-1.80 (3s + dd + m, 30H), 2.27 (s, 3H), 2.43 (s, 3H), 3.08 (m, 1H), 3.38 (m, 1H), 3.98 (d, 2H), 5.46 (m, 1H), 6.97-7.17 (m, 3H).

l.) N₁- (trans-4-tert-butyl-cyclohexyl) -N₃- (3,3-dimethyl- allyl) -N₁-methyl-N₃- (4-methyl-phenyl) -urea

Prepared from N₁- (trans-4-tert-butylcyclohexyl) -N₁-methyl-N₃- (4-methylphenyl) urea and 3,3-dimethylallyl bromide.
Yield: 84% of theory,
Melting point: oil.

Calc .: C 77.79; H 10,33; N, 7.56;
gef. C, 77.44; H 10,38; N 7,50.

1 H-NMR spectrum (200 mHz, CDCl₃); Signals at ppm:
0.82-1.84 (3s + m, 24H), 2.31 (s, 3H), 2.38 (s, 3H), 3.85 (m, 1H), 4.14 (d, 2H) , 5.31 (m, 1H), 6.93 (d, 2H), 7.07 (d, 2H)

m.) N₁- (trans-4-tert-butyl-cyclohexyl) -N₃- (3,3-dimethyl- allyl) -N₁-methyl-N₃- (3-methyl-phenyl) -urea

Prepared from N₁- (trans-4-tert-butylcyclohexyl) -N₁-methyl-N₃- (3-methylphenyl) urea and 3,3-dimethylallyl bromide.
Yield: 79.5% of theory,
Melting point: 49-50 ° C.

Calc .: C 77.79; H 10,34; N, 7.56;
gef. : C, 78.01; H 10.55; N 7.57.

¹ H-NMR spectrum (200 mHz, CDCl₃); Signals at ppm:
0.82-1.84 (3s + m, 24H), 2.30 (s, 3H), 2.42 (s, 3H), 3.87 (m, 1H), 4.17 (d, 2H), 5 , 32 (m, 1H), 6.86 (m, 3H), 7.14 (m, 1H)

n.) N₁- (trans-4-tert-butyl-cyclohexyl) -N₃- (3,3-dimethyl- allyl) -N₃- (2-methoxy-phenyl) -N₁-methyl-urea

Prepared from N₁- (trans-4-tert-butylcyclohexyl) -N₃- (2-methoxy-phenyl) -N₁-methyl-urea and 3,3-dimethyl-allylbromide.
Yield: 80.1% of theory,
Melting point: 125-127 ° C.

Calc .: C 74.57; H 9,91; N 7.25;
gef. : C, 74.44; H 9.68; N 6.98.

1 H-NMR spectrum (200 mHz, CDCl₃); Signals at ppm:
0.81-1.80 (3s + m, 24H), 2.36 (s, 3H), 3.18 (m, 1H), 3.88 (s, 3H), 4.04 (d, 2H) , 5.38 (m, 1H), 6.80-7.25 (m, 4H)

o.) N₁- (trans-4-tert-butyl-cyclohexyl) -N₃- (3,3-dimethyl- allyl) -N₃- (3-methoxy-phenyl) -N₁-methyl-urea

Prepared from N₁- (trans-4-tert-butylcyclohexyl) -N₃- (3-methoxy-phenyl) -N₁-methyl-urea and 3,3-dimethyl-allylbromide.
Yield: 95.6% of theory,
Melting point: oil.

Calc .: C 74.57; H 9,91; N 7.25;
gef. : C, 74.42; H 10,10; N 7.04.

1 H-NMR spectrum (200 mHz, CDCl₃); Signals at ppm:
0.82-1.88 (3s + m, 24H), 2.44 (s, 3H), 3.77 (s, 3H), 3.90 (m, 1H), 4.19 (d, 2H) , 5.32 (m, 1H), 6.57-6.7 (m, 3H), 7.12-7.30 (m, 1H)

p.) N₁- (trans-4-tert-butyl-cyclohexyl) -N₃- (3,3-dimethyl- allyl) -N₃- (4-methoxy-phenyl) -N₁-methyl-urea

Prepared from N₁- (trans-4-tert-butylcyclohexyl) -N₃- (4-methoxy-phenyl) -N₁-methyl-urea and 3,3-dimethyl-allylbromide.
Yield: 98.2% of theory,
Melting point: 90-91 ° C.

Calc .: C 74.57; H 9,91; N 7.25;
gef. : C, 74.44; H 10.09; N 7.09.

1 H-NMR spectrum (200 mHz, CDCl₃); Signals at ppm:
0.82-1.85 (3s + m, 24H), 2.39 (s, 3H), 3.78 (s, 3H), 3.80 (m, 1H), 4.10 (d, 2H) , 5.32 (m, 1H), 6.82 (d, 2H), 6.98 (d, 2H)

q.) N₁- (trans-4-tert-butyl-cyclohexyl) -N₃- (2,6-dichloro) phenyl) -N₃- (3,3-dimethyl-allyl) -N₁-methyl-urea

Prepared from N₁- (trans-4-tert-butylcyclohexyl) -N₃- (2,6-dichloro-phenyl) -N₁-methyl-urea and 3,3-dimethyl-allylbromide.
Yield: 84.7% of theory,
Melting point: 138-140 ° C.

Re: C 64.93; H 8.05; N, 6.58;
gef. : C 65.25; H 7,89; N 6,44.

1 H-NMR spectrum (200 mHz, CDCl₃); Signals at ppm:
0.81-1.80 (3s + m, 24H), 2.40 (s, 3H), 3.55 (m, 1H), 4.15 (d, 2H), 5.49 (m, 1H) , 7.05-7.40 (m, 3H)

r.) N₁- (trans-4-tert-butyl-cyclohexyl) -N₃- (2,4-difluoro- phenyl) -N₃- (3,3-dimethyl-allyl) -N₁-methyl-urea

Prepared from N₁- (trans-4-tert-butylcyclohexyl) -N₃- (2,4-difluoro-phenyl) -N₁-methyl-urea and 3,3-dimethyl-allylbromide.
Yield: 85.3% of theory,
Melting point: 102-104 ° C.

Calc .: C, 70.38; H 8,73; N 7,14;
gef. : C 70.39; H, 8.65; N 7.04.

1 H-NMR spectrum (200 mHz, CDCl₃); Signals at ppm:
0.76-1.85 (3s + m, 24H), 2.40 (s, 3H), 3.71 (m, 1H), 4.04 (d, 2H), 5.34 (m, 1H) , 6.74-7.12 (m, 3H)

s.) N₁- (trans-4-tert-butyl-cyclohexyl) -N₃- (3,3-dimethyl- allyl) -N₁-ethyl-N₃-phenyl-urea

Prepared from N₁- (trans-4-tert-butylcyclohexyl) -N₁-ethyl-N₃-phenylurea and 3,3-dimethyl-allylbromide.
Yield: 84% of theory,
Melting point: oil.

Calc .: C 77.79; H 10,34; N, 7.56;
gef. : C 77.94; H 10.36; N 7.54.

1 H-NMR spectrum (200 mHz, CDCl₃); Signals at ppm:
0.75-1.85 (3s + t + m, 27H), 2.96 (q, 2H), 3.67 (m, 1H), 4.14 (d, 2H), 5.34 (m, 1H), 7.0-7.15 (m, 3H), 7.2-7.35 (m, 2H)

t.) N₁- (trans-4-tert-butyl-cyclohexyl) -N₃- (3,3-dimethyl-allyl) -N₃-phenyl-N ₁ -propyl-urea

Made of N₁- (trans-4-tert.butyl-cyclohexyl) -N₃-phenyl-N₁-propyl-urea and 3,3-dimethyl-allyl bromide.
Yield: 78% of theory,
Melting point: oil.

Calc .: C, 78.07; H, 10.48; N 7.28;
gef. : C 78.20; H 10.70; N 7,13.

1 H-NMR spectrum (200 mHz, CDCl₃); Signals at ppm:
0.65-1.85 (3s + t + m, 29H), 2.81 (m, 2H), 3.65 (m, 1H), 4.14 (d, 2H), 5.33 (m, 1H), 7.0-7.26 (m, 5H)

u.) N₁- (cis-4-tert-butylcyclohexyl) -N₃- (3,3-dimethyl- allyl) -N₁-methyl-N₃-phenyl-urea

Prepared from N₁- (cis-4-tert-butylcyclohexyl) -N₁-methyl-N₃-phenylurea and 3,3-dimethyl-allylbromide.
Yield: 56% of theory,
Melting point: oil.

Re: C 77.48; H 10,18; N, 7.86;
gef. : C 77.13; H 10,14; N 7,96.

1 H-NMR spectrum (200 mHz, CDCl₃); Signals at ppm:
0.83-1.95 (3s + m, 24H), 2.50 (s, 3H), 4.07 (m, 1H), 4.20 (d, 2H), 5.32 (m, 1H) , 7.0-7.15 (m, 3H), 7.20-7.35 (m, 2H)

v.) N₁- (cis-4-tert-butylcyclohexyl) -N₁-methyl-N₃- phenyl-N₃-propyl-urea

Prepared from N₁- (cis-4-tert-butylcyclohexyl) -N₁-methyl-N₃-phenylurea and propylbromide.
Yield: 92% of theory,
Melting point: oil.

Re: C 76.31; H 10.37; N 8,48;
gef. : C 76.51; H 10.55; N 8,28.

1 H-NMR spectrum (200 mHz, CDCl₃); Signals at ppm:
0.82-1.95 (s + t + m, 23H), 2.48 (s, 3H), 3.58 (m, 2H), 4.04 (m, 1H), 7.1 (m, 3H), 7.29 (m, 2H)

w.) N₁- (cis-4-tert-butyl-cyclohexyl) -N₃-hexyl-N₁- methyl-N₃-phenyl-urea

Prepared from N₁- (cis-4-tert-butylcyclohexyl) -N₁-methyl-N₃-phenylurea and hexylbromide.
Yield: 70% of theory,
Melting point: oil.

Re: C 77.37; H, 10.82; N, 7.52;
gef. : C 77.41; H 11.20; N 7,34.

1 H-NMR spectrum (200 mHz, CDCl₃); Signals at ppm:
0.83-1.95 (s + m, 29H), 2.48 (s, 3H), 3.59 (m, 2H), 4.03 (m, 1H), 7.09 (m, 3H) , 7.29 (m, 2H)

x.) N₁- (cis-4-tert-butyl-cyclohexyl) -N₃- (2,4-difluoro- phenyl) -N₃- (3,3-dimethyl-allyl) -N₁-methyl-urea

Prepared from N₁- (cis-4-tert-butylcyclohexyl) -N₃- (2,4-difluoro-phenyl) -N₁-methyl-urea and 3,3-dimethyl-allylbromide.
Yield: 96.8% of theory,
Melting point: oil.

Calc .: C, 70.38; H 8,73; N 7,14;
gef. : C 70.28; H 8,86; N 6.95.

1 H-NMR spectrum (200 mHz, CDCl₃); Signals at ppm:
0.83 (s, 9H), 1.0-1.9 (2s + m, 15H), 2.51 (s, 3H), 3.95 (m, 1H), 4.07 (d, 2H) , 5.32 (m, 1H), 6.72-6.92 (m, 2H), 6.96-7.13 (m, 1H)

y.) N₁- (cis-4-tert-butylcyclohexyl) -N₃- (3,3-dimethyl- allyl) -N₁-methyl-N₃- (4-methyl-phenyl) -urea

Prepared from N₁- (cis-4-tert-butylcyclohexyl) -N₁-methyl-N₃- (4-methylphenyl) urea and 3,3-dimethylallyl bromide.
Yield: 95.4% of theory,
Melting point: oil.

Calc .: C 77.79; H 10,33; N, 7.56;
gef. C 77.66; H, 10.56; N 7.48.

1 H-NRM spectrum (200 mHz, CDCl₃); Signals at ppm:
0.83 (s, 9H), 1.0-1.95 (2s + m, 15H), 2.31 (s, 3H), 2.49 (s, 3H), 4.04 (m, 1H) , 4.17 (d, 2H), 5.32 (m, 1H), 6.95 (d, 2H), 7.08 (d, 2H)

z.) N₁- (cis-4-tert-butylcyclohexyl) -N₃- (3,3-dimethyl- allyl) -N₃- (2,6-dimethyl-phenyl) -N₁-methyl-urea

Prepared from N₁- (cis-4-tert-butylcyclohexyl) -N₃- (2,6-dimethyl-phenyl) -N₁-methyl-urea and 3,3-dimethyl-allylbromide.
Yield: 89.9% of theory,
Melting point: oil.

Calc .: C, 78.07; H, 10.48; N 7.28;
gef. : C 78.15; H, 10.65; N 7.25.

1 H-NMR spectrum (200 mHz, CDCl₃); Signals at ppm:
0.82 (s, 9H), 0.95-1.72 (2s + m, 15H), 2.22 (s, 6H), 2.46 (s, 3H), 3.72 (m, 1H) , 4.0 (d, 2H), 5.44 (m, 1H), 7.02 (s, 3H)

aa.) N₁- (cis-4-tert-butyl-cyclohexyl) -N₃- (3,3-dimethyl- allyl) -N₃- (2-methoxy-phenyl) -N₁-methyl-urea

Prepared from N₁- (cis-4-tert-butylcyclohexyl) -N₃- (2-methoxy-phenyl) -N₁-methyl-urea and 3,3-dimethyl-allylbromide.
Yield: 93.1% of theory,
Melting point: oil.

Calc .: C 74.57; H 9,91; N 7.25;
gef. : C 74.32; H 10.08; N 7,31.

1 H-NMR spectrum (200 mHz, CDCl₃); Signals at ppm:
0.77-1.90 (3s + m, 24H), 2.43 (s, 3H), 3.85 (s, 3H), 3.97 (m, 1H), 4.05 (d, 2H) , 5.38 (m, 1H), 6.8-7.02 (m, 3H), 7.1-7.23 (m, 1H)

.) N₁- (cis-4-tert-butyl-cyclohexyl) -N₃- (3,3-dimethyl- allyl) -N₃- (3-methoxy-phenyl) -N₁-methyl-urea

Prepared from N₁- (cis-4-tert-butylcyclohexyl) -N₃- (3-methoxy-phenyl) -N₁-methyl-urea and 3,3-dimethyl-allylbromide.
Yield: 96.5% of theory,
Melting point: oil.

Calc .: C 74.57; H 9,91; N 7.25;
gef. : C 74.50; H 10,10; N 7,19.

1 H-NMR spectrum (200 mHz, CDCl₃); Signals at ppm:
0.82 (s, 9H), 1.0-1.93 (2s + m, 15H), 2.54 (s, 3H), 3.77 (s, 3H), 4.11 (m, 1H) , 4.19 (d, 2H), 5.31 (m, 1H), 6.57-6.72 (m, 3H), 7.12-7.28 (m, 1H)

ac.) N₁- (cis-4-tert-butyl-cyclohexyl) -N₃- (2,6-dichloro phenyl) -N₃- (3,3-dimethyl-allyl) -N₁-methyl-urea

Prepared from N₁- (cis-4-tert-butylcyclohexyl) -N₃- (2,6-dichloro-phenyl) -N₁-methyl-urea and 3,3-dimethyl-allylbromide.
Yield: 88.1% of theory,
Melting point: oil.

Re: C 64.93; H 8.05; N, 6.58;
gef. : C, 65.07; H 8.11; N 6,48.

1 H-NMR spectrum (200 mHz, CDCl₃); Signals at ppm:
0.82 (s, 9H), 1.02-1.72 (2s + m, 15H), 2.50 (s, 3H), 3.81 (m, 1H), 4.07 (d, 2H) , 5.48 (m, 1H), 7.04-7.38 (m, 3H)

ad.) N₁- (cis-4-tert-butyl-cyclohexyl) -N₃- (3-chloro-phe nyl) -N₃- (3,3-dimethyl-allyl) -N₁-methyl-urea

Prepared from N₁- (cis-4-tert-butylcyclohexyl) -N₃- (3-chloro-phenyl) -N₁-methyl-urea and 3,3-dimethyl-allylbromide.
Yield: 93.3% of theory,
Melting point: oil.

Calc .: C, 70.65; H 9.02; N 7,17;
gef. : C 70.53; H 9.04; N 7,14.

1 H-NMR spectrum (200 mHz, CDCl₃); Signals at ppm:
0.83 (s, 9H), 1.0-1.97 (2s + m, 15H), 2.56 (s, 3H), 4.10 (m, 1H), 4.19 (d, 2H) , 5.28 (m, 1H), 6.90-7.29 (m, 4H)

ae.) N₁- (cis-4-tert-butylcyclohexyl) -N₃- (3,3-dimethyl- allyl) -N₁-methyl-N₃- (1-naphthyl) urea

Prepared from N₁- (cis-4-tert-butylcyclohexyl) -N₁-methyl-N₃- (1-naphthyl) urea and 3,3-dimethyl-allyl bromide.
Yield: 97.2% of theory,
Melting point: oil.

Re: C, 79.76; H 9,42; N, 6.89;
gef. : C, 79.47; H 9,50; N 7.03.

1 H-NMR spectrum (200 mHz, CDCl₃); Signals at ppm:
0.60-1.82 (3s + m, 24H), 2.35 (s, 3H), 4.02 (m, 1H), 4.16 (d, 2H), 5.50 (m, 1H) , 7,10-8,15 (m, 7H)

af.) N₁- (trans-4-tert-butyl-cyclohexyl) -N₃- (3,3-dimethyl- allyl) -N₁-methyl-N₃- (1-naphthyl) urea

Prepared from N₁- (trans-4-tert-butylcyclohexyl) -N₁-methyl-N₃- (1-naphthyl) urea and 3,3-dimethyl-allyl bromide.
Yield: 73.8% of theory,
Melting point: oil.

Re: C, 79.76; H 9,42; N, 6.89;
gef. : C, 79.93; H 9,69; N 6.89.

1 H-NMR spectrum (200 mHz, CDCl₃); Signals at ppm:
0.55-1.70 (3s + m, 24H), 2.30 (s, 3H), 3.72 (m, 1H), 4.16 (d, 2H), 5.50 (m, 1H) , 7,10-8,13 (m, 7H)

ag.) N₁- (trans-4-tert-butyl-cyclohexyl) -N₃- (3-chloro-phe nyl) -N₃- (3,3-dimethyl-allyl) -N₁-methyl-urea

Prepared from N₁- (trans-4-tert-butylcyclohexyl) -N₃- (3-chloro-phenyl) -N₁-methyl-urea and 3,3-dimethyl-allylbromide.
Yield: 97.2% of theory,
Melting point: oil.

Calc .: C, 70.65; H 9.02; N 7,17;
gef. : C, 70.85; H 9,10; N 7.11.

1 H-NMR spectrum (200 mHz, CDCl₃); Signals at ppm:
0.82-1.89 (3s + m, 24H), 2.45 (s, 3H), 3.85 (m, 1H), 4.18 (d, 2H), 5.29 (m, 1H) , 6.85-7.29 (m, 4H)

ah.) N₁- (trans-4-tert-butyl-cyclohexyl) -N₃- (4-chloro-phe nyl) -N₃- (3,3-dimethyl-allyl) -N₁-methyl-urea

Prepared from N₁- (trans-4-tert-butylcyclohexyl) -N₃- (4-chloro-phenyl) -N₁-methyl-urea and 3,3-dimethyl-allylbromide.
Yield: 97.2% of theory,
Melting point: 75-76 ° C.

Calc .: C, 70.65; H 9.02; N 7,17;
gef. C, 70.66; H 8,82; N 7,14.

1 H-NMR spectrum (200 mHz, CDCl₃); Signals at ppm:
0.80-1.88 (3s + m, 24H), 2.42 (s, 3H), 3.84 (m, 1H), 4.15 (d, 2H), 5.29 (m, 1H) , 6.97 (d, 2H), 7.24 (d, 2H)

ai.) N₁- (trans-4-tert-butylcyclohexyl) -N₃-heptyl-N₁- methyl-N₃-phenyl-urea

Prepared from N₁- (trans-4-tert-butylcyclohexyl) -N₁-methyl-N₃-phenylurea and heptylbromide.
Yield: 86% of theory,
Melting point: oil.

Calc .: C, 77.67; H 10.95; N 7.25;
gef. : C 77.51; H, 10.92; N 7.23.

1 H-NMR spectrum (200 mHz, CDCl₃); Signals at ppm:
0.75-1.84 (s + m, 31H), 2.39 (s, 3H), 3.57 (m, 2H), 3.84 (m, 1H), 6.98-7.13 ( m, 3H), 7,22 {, 35 (m, 2H)

ak.) N₁- (trans-4-tert-butylcyclohexyl) -N₁-methyl-N₃- nonyl-N₃-phenyl-urea

Prepared from N₁- (trans-4-tert-butylcyclohexyl) -N₁-methyl-N₃-phenylurea and nonylbromide.
Yield: 80% of theory,
Melting point: oil.

Calc .: C 78.20; H 11,18; N 6.76;
gef. : C 78.33; H, 10.98; N 6,90.

1 H-NMR spectrum (200 mHz, CDCl₃); Signals at ppm:
0.77-1.87 (s + m, 35H), 2.40 (s, 3H), 3.57 (m, 2H), 3.83 (m, 1H), 6.98-7.13 ( m, 3H), 7.21-7.37 (m, 2H)

al.) N₁- (trans-4-tert-butyl-cyclohexyl) -N₃-decyl-N₁- methyl-N₃-phenyl-urea

Prepared from N₁- (trans-4-tert-butylcyclohexyl) -N₁-methyl-N₃-phenylurea and decylbromide.
Yield: 88.6% of theory,
Melting point: oil.

Calc .: C, 78.45; H 11,29; N, 6.53;
gef. : C 78.17; H 11.11; N 6.45.

¹NMR spectrum (200 mHz, CDCl₃); Signals at ppm:
0.77-1.85 (s + m, 37H), 2.40 (s, 3H), 3.57 (m, 2H), 3.83 (m, 1H), 6.98-7.13 ( m, 3H), 7.21-7.37 (m, 2H)

am.) N₁- (trans-4-tert-butyl-cyclohexyl) -N₃-cyclohexyl- methyl-N₁-N₃-methyl-phenyl urea

Prepared from N₁- (trans-4-tert-butylcyclohexyl) -N₁-methyl-N₃-phenylurea and cyclohexylmethylbromide.
Yield: 57% of theory,
Melting point: oil.

Calc .: C, 78.07; H, 10.48; N 7.28;
gef. : C 78.12; H, 10.68; N 7.08.

1 H-NMR spectrum (200 mHz, CDCl₃); Signals at ppm:
0.77-1.87 (s + m, 29H), 2.41 (s, 3H), 3.45 (d, 2H), 3.87 (m, 1H), 6.98-7.12 ( m, 3H), 7.20-7.35 (m, 2H)

An.) N₁- (trans-4-tert-butyl-cyclohexyl) -N₃-butyl-N₁- methyl-N₃-phenyl-urea

Prepared from N₁- (trans-4-tert-butylcyclohexyl) -N₁-methyl-N₃-phenylurea and butylbromide.
Yield: 77.4% of theory,
Melting point: oil.

Calc .: C 76.69; H 10.53; N 8,13;
gef. : C, 76.80; H, 10.69; N 7,90.

1 H-NMR spectrum (200 mHz, CDCl₃); Signals at ppm:
0.75-1.88 (s + t + m, 25H), 2.38 (s, 3H), 3.58 (m, 2H), 3.83 (m, 1H), 6.98-7, 14 (m, 3H), 7.21-7.37 (m, 2H)

ao.) N₁- (trans-4-tert-butyl-cyclohexyl) -N₁-methyl-N₃- phenyl-N₃-propargyl-urea

Prepared from N₁- (trans-4-tert-butylcyclohexyl) -N₁-methyl-N₃-phenylurea and propargylbromide.
Yield: 73.50% of theory,
Melting point: 89 ° C.

Calc .: C 77.26; H 9,26; N 8,58;
gef. C 77.14; H 9,39; N 8,33.

1 H-NMR spectrum (200 mHz, CDCl₃); Signals at ppm:
0.78-1.84 (s + m, 18H), 2.18 (t, 1H), 2.44 (s, 3H), 3.87 (m, 1H), 4.33 (d, 2H) , 7.09-7.23 (m, 3H), 7.24-7.41 (m, 2H)

ap.) N₁- (trans-4-tert-butyl-cyclohexyl) -N₁-methyl-N₃- pentyl-N₃-phenyl-urea

Prepared from N₁- (trans-4-tert-butylcyclohexyl) -N₁-methyl-N₃-phenylurea and pentylbromide.
Yield: 89.2% of theory,
Melting point: oil.

Calc .: C 77.04; H, 10.68; N, 7.81;
gef. : C 77.18; H, 10.83; N 7.54.

1 H-NMR spectrum (200 mHz, CDCl₃); Signals at ppm:
0.77-1.85 (s + t + m, 27H), 2.40 (s, 3H), 3.58 (m, 2H), 3.83 (m, 1H), 6.98-7, 13 (m, 3H), 7.22-7.36 (m, 2H)

aq.) N₁- (trans-4-tert-butylcyclohexyl) -N₃-isobutyl-N₁- methyl-N₃-phenyl-urea

Prepared from N₁- (trans-4-tert-butylcyclohexyl) -N₁-methyl-N₃-phenylurea and isobutylbromide.
Yield: 56% of theory,
Melting point: 101 ° C.

Calc .: C 76.69; H 10.53; N 8,13;
gef. : C 77.00; H, 10.62; N 7.99.

1 H-NMR spectrum (200 mHz, CDCl₃); Signals at ppm:
0.75-1.84 (s + d + m, 24H), 1.95 (m, 1H), 2.43 (s, 3H), 3.43 (d, 2H), 3.87 (m, 1H), 6.98-7.12 (m, 3H), 7.20-7.37 (m, 2H)

ar.) N₁- (trans-4-tert-butyl-cyclohexyl) -N₃- (trans-3,7- dimethyl-2,6-octadienyl) -N₁-methyl-N₃-phenyl- urea

Prepared from N₁- (trans-4-tert-butylcyclohexyl) -N₁-methyl-N₃-phenylurea and trans-3,7-dimethyl-2,6-octa-dienyl-bromide.
Yield: 39% of theory,
Melting point: oil.

Ber .: C 79.19; H, 10.44; N 6.60;
gef. : C, 79.28; H, 10.56; N 6,55.

1 H-NMR spectrum (200 mHz, CDCl₃); Signals at ppm:
0.77-2.10 (4s + m, 31H), 2.41 (s, 3H), 3.84 (m, 1H), 4.20 (d, 2H), 5.03 (m, 1H) , 5.34 (m, 1H), 6.98-7.12 (m, 3H), 7.20-7.34 (m, 2H)

as.) N₁- [trans-4- (4-methoxy-3-methylphenyl) cyclohexyl] - N₁-N₃-methyl-phenyl-N₃-propyl-urea

Prepared from N₁- [trans-4- (4-methoxy-3-methyl-phenyl) -cyclohexyl] -N₁-methyl-N₃-phenyl-urea and propyl bromide.
Yield: 76% of theory,
Melting point: oil.

Calc .: C 76.10; H 8,69; N 7,10;
gef. C, 75.96; H, 8.63; N 6,96.

1 H-NMR spectrum (200 mHz, CDCl₃); Signals at ppm:
0.9 (t, 3H), 1.34-2.0 (m, 10H), 2.20 (s, 3H), 2.32 (m, 1H), 2.45 (s, 3H), 3 , 57 (m, 2H), 3.79 (s, 3H), 4.00 (m, 1H), 6.68-7.39 (m, 8H)

at.) N₃- (3,3-dimethyl-allyl) -N₁- [trans-4- (4-methoxy-) 3-methyl-phenyl) cyclohexyl] -N₁-methyl-N₃-phenyl- urea

Prepared from N₁- [trans-4- (4-methoxy-3-methyl-phenyl) -cyclohexyl] -N₁-methyl-N₃-phenylurea and 3,3-di-methyl-allylbromide.
Yield: 89% of theory,
Melting point: oil.

Calc .: C 77.10; H, 8.63; N, 6.66;
gef. : C 76.97; H 8,56; N 6,41.

1 H-NMR spectrum (200 mHz, CDCl₃); Signals at ppm:
1.34-2.05 (2s + m, 14H), 2.20 (s, 3H), 2.31 (m, 1H), 2.45 (s, 3H), 3.80 (s, 3H) , 4.01 (m, 1H), 4.20 (d, 2H), 5.34 (m, 1H), 6.69-7.37 (m, 8H)

au.) N₁- (trans-4- (4-methoxy-3-methylphenyl) cyclohexyl- N₁-methyl-N₃- (3-methyl-butyl) -N₃-phenyl-urea

Prepared from N₁- [trans-4- (4-methoxy-3-methylphenyl) cyclohexyl] -N₁-methyl-N₃-phenylurea and 3-methylbutyl bromide.
Yield: 95% of theory,
Melting point: oil.

Re: C 76.74; H 9.06; N, 6.63;
gef. : C 77.00; H 9,34; N 6,51.

1 H-NMR spectrum (200 mHz, CDCl₃); Signals at ppm:
0.83-2.00 (d + m, 17H), 2.19 (s, 3H), 2.32 (m, 1H), 2.43 (s, 3H), 3.62 (m, 2H) , 3.80 (s, 3H), 3.99 (m, 1H), 6.67-7.39 (m, 8H)

example 2 N₁- (trans-4-tert-butyl-cyclohexyl) -N₁, N₃-dimethyl-N₃- phenyl-urea

340 mg (2 mmol) of N-methyl-trans-4-tert-butyl-cyclohexylamine and 0.5 ml (2.9 mmol) of N-ethyl-diisopropylamine are dissolved in 30 ml of absolute methylene chloride and dropwise at room temperature with a solution Of 340 mg (2 mmol) of N-methyl-N-phenyl-carbamic acid chloride in 10 ml of methylene chloride. After completion of the addition, the mixture is refluxed for 2 hours, then cooled and treated with dilute Salzsäu re. After extraction with methylene chloride is dried over magnesium sulfate and concentrated. The concentration residue is purified by column chromatography on silica gel
(Eluant: petroleum ether / ethyl acetate = 8: 1).
Yield: 334 mg (58% of theory),
Melting point: 60-61 ° C.

Calc .: C, 75.45; H 10.00; N 9,26;
gef. : C, 75.30; H 10.08; N 9,15.

1 H-NMR spectrum (200 mHz, CDCl₃); Signals at ppm:
0.83-1.84 (s + m, 18H), 2.43 (s, 3H), 3.19 (s, 3H), 3.35 (m, 1H), 7.08 (m, 3H) , 7.27 (m, 2H)

Analog was produced:  

a.) N₁- (trans-4-tert-butyl-cyclohexyl) -N₃, N₃-diphenyl- N₁-methyl-urea

Made of N, N-diphenyl-carbamic acid chloride and N-methyl-trans-4-tert-butyl-cyclohexylamine.
Yield: 73.1% of theory,
Melting point: 103-105 ° C.

Calc .: C, 79.08; H, 8.85; N, 7.69;
gef. : C 79.24; H 8,83; N 7.82.

1 H-NMR spectrum (200 mHz, CDCl₃); Signals at ppm:
0.78-1.88 (s + m, 18H), 2.62 (s, 3H), 3.97 (m, 1H), 6.97-7.17 (m, 6H), 7.22 7.38 (m, 4H)

example 3 N₁- (cis-4-tert-butyl-cyclohexyl) -N₁-methyl-N₃, N₃-di phenyl-urea

1.02 g (6.0 mmol) of N-methyl-cis-4-tert-butyl-cyclohexylamine are dissolved in 20 ml of absolute ethyl acetate and phosgene at 60 ° C to a stirred solution of 1.78 g (6 mmol) Tri added dropwise in 20 ml of ethyl acetate. After completion ter addition is stirred for 3 hours at 80 ° C, then concentrated in a water jet vacuum and cooled abge to room temperature. The N-methyl-N- (cis-4-tert-butylcyclohexyl) carbamic acid chloride obtained in this case is dissolved in 25 ml of methylene chloride and, with ice cooling, to a stirred solution of 1.01 g (6 mmol) of diphenylamine and 2.07 ml (12 mmol) of N-ethyl-diisopropylamine. After stirring for 2 hours, it is decomposed with ice-cold 2N hydrochloric acid, extracted with methylene chloride, dried and concentrated. The oily residue is purified by column chromatography on silica gel
(Eluant: petroleum ether / ethyl acetate = 5: 1).
Yield: 320 mg (14.6% of theory),
Melting point: 90-92 ° C.

Calc .: C, 79.08; H, 8.85; N, 7.69;
gef. : C 78.79; H 9.02; N 7.59.

1 H-NMR spectrum (200 mHz, CDCl₃); Signals at ppm:
0.8-0.95 (2s, 9H), 1.02-2.07 (m, 9H), 2.72 (s, 0.8H), 2.76 (s, 0.2H), 3, 77 (m, 0.2H), 4.19 (m, 0.8H), 6.98-7.18 (m, 6H), 7.21-7.37 (m, 4H)

example 4 N₃- (3,3-dimethyl-allyl) -N₁- [trans-4- (4-hydroxy-3-methyl- phenyl) cyclohexyl] -N₁-methyl-N₃-phenyl-urea

0.6 g (1.4 mmol) of N₃- (3,3-dimethyl-allyl) -N₁- [trans-4- (4-methoxy-3-methylphenyl) cyclohexyl] -N₁-methyl-N₃-phe Nyl-urea and 0.3 g (3.57 mmol) of sodium thioethanolate are refluxed in 1.5 ml of dimethylformamide for 3.5 hours. It is then cooled, acidified with 2N hydrochloric acid and extracted with ether. The extracts are dried, concentrated and purified by column chromatography on silica gel
(Eluant: toluene / ethyl acetate = 6: 1).
Yield: 470 mg (82% of theory),
Melting point: 130-131 ° C.

Calc .: C, 76.81; H 8,43; N, 6.89;
gef. : C 76.60; H 8,48; N 6,83.

1 H-NMR spectrum (200 mHz, CDCl₃); Signals at ppm:
1.25-2.00 (2s + m, 14H), 2.23 (s, 3H), 2.30 (m, 1H), 2.43 (s, 3H), 4.02 (m, 1H) , 4.20 (d, 2H), 5.34 (m, 1H), 6.68-7.37 (m, 8H)

example 5 N₁- [trans-4- [4- (2-N, N-diethylamino-ethoxy) -3-methyl-phe nyl] cyclohexyl] -N₃- (3,3-dimethyl-allyl) -N₁-methyl-N₃- phenyl-urea

0.4 g (1 mmol) of N₃- (3,3-dimethyl-allyl) -N₁- [trans-4- (4-hydroxy-3-methylphenyl) cyclohexyl] -N₁-methyl-N₃-phe nyl- urea are dissolved in 30 ml of methylene chloride and after addition of 4.2 ml (4.2 mmol) 1N sodium hydroxide solution, 5 ml of water, 390 mg (2.25 mmol) of 2- (N, N-diethylamino) ethyl chloride hydrochloride and 10 mg of tetrabutylammonium hydrogen sulfate stirred for 48 hours at room temperature. It is then extracted with methylene chloride and purified by column chromatography on concentrating the Extrak te on silica gel (Fließmit tel: toluene / ethyl acetate / methanol / ethanol saturated with ammonia gas = 8: 2: 1: 0.2).
Yield: 310 mg (61% of theory),
Melting point: oil.

Calc .: C 76.00; H 9,37; N, 8.31;
gef. : C 76.27; H 9.51; N 8,37.

1 H-NMR spectrum (200 mHz, CDCl₃); Signals at ppm:
1.07 (t, 6H), 1.30-2.00 (2s + m, 14H), 2.20 (s, 3H), 2.30 (m, 1H), 2.45 (s, 3H) , 2.65 (q, 4H), 2.90 (t, 2H), 4.02 (t + m, 3H), 4.20 (d, 2H), 5.34 (m, 1H), 6, 67-7.36 (m, 8H).

In the following, the preparation of pharmaceutical Applic described using some examples:

example I Tablets containing 5 mg of N₁- (trans-4-tert-butylcyclohexyl) - N₃- (3,3-dimethyl-allyl) -N₁-methyl-N₃-phenyl-urea

composition 1 tablet contains: active substance 5.0 mg lactose 148.0 mg potato starch 65.0 mg magnesium stearate  2.0 mg 220.0 mg

production method

Potato starch is used to produce a 10% slime by heating. The active substance, lactose and the remaining potato starch are mixed and granulated with the above mucus through a sieve of mesh size 1.5 mm. The granules are dried at 45 ° C, again by the above screen ben siege, mixed with magnesium stearate and pressed ver to tablets.
Tablet weight: 220 mg
Stamp: 9 mm

example II Drag'es with 5 mg of N₁- (trans-4-tert-butylcyclohexyl) - N₃- (3,3-dimethyl-allyl) -N₁-methyl-N₃-phenyl-urea

The tablets prepared according to Example I are coated according to any known method with a shell which consists in wesent union of sugar and talc. The finished Drag'es are polished using beeswax.
Drag'e weight: 300 mg

example III Suppositories with 5 mg of N₁- (trans-4-tert-butylcyclohexyl) - N₃- (3,3-dimethyl-allyl) -N₁-methyl-N₃-phenyl-urea

composition 1 suppository contains: active substance 5.0 mg Suppository mass (eg Witepsol W 45®) 1695.0 mg 1700.0 mg

production method

The finely pulverized active substance is suspended in the molten suppository mass which has been cooled to 40.degree. Pour the mass at 37 ° C in slightly pre-cooled suppository forms.
Suppository weight 1.7 g.

example IV Capsules with 5 mg N₁- (trans-4-tert-butylcyclohexyl) - N₃- (3,3-dimethyl-allyl) -N₁-methyl-N₃-phenyl-urea

composition 1 capsule contains: active substance 5.0 mg lactose 82.0 mg Strength 82.0 mg   magnesium stearate  1.0 mg 170.0 mg

production method

The powder mixture is mixed thoroughly and on a cape Self-filling machine in size 3 hard gelatin capsule filled, with the final weight is checked continuously.

Claims (8)

1. phenylureas of the general formula in the
X is an oxygen or sulfur atom,
R₁ is a tert-butyl group or a phenyl group which may be mono- or disubstituted by a hydroxy, alkoxy or alkyl group each having 1 to 3 carbon atoms, wherein the substituents may be the same or different and wherein such alkoxy group in 2- or 3 By a dialkylamino group in which each alkyl moiety may contain 1 to 3 carbon atoms, or may be substituted by a pyrrolidino, piperidino or hexamethyleneimino group,
R₂ is a hydrogen atom or an alkyl group having 1 or 2 carbon atoms,
R₃ is an alkyl group having 1 to 3 carbon atoms,
R₄ is a straight-chain or branched alkyl, alkenyl or alkynyl group, which may also have a radical of the general formula wherein the alkyl moiety may contain 1 to 12 carbon atoms and the mono- or polyunsaturated alkenyl or alkynyl moiety may each contain 3 to 12 carbon atoms,
R₄ may further be a cycloalkyl group having a total of 7 to 12 carbon atoms or a group of the formula in which R₅ and R₆, which may be identical or different, are a hydrogen, fluorine, chlorine or bromine atom, a trifluoromethyl, alkyl or alkoxy group in which the alkyl moiety may contain in each case 1 to 4 carbon atoms, or together with the phenyl ring is a naphthyl group,
and, if R₁ contains a basic radical whose acid addition salts. 2. phenylureas of the general formula I according to claim 1, in which
R₁ is a tert-butyl group or a phenyl group which may be mono- or disubstituted by a methyl, hydroxy, methoxy or ethoxy group, where the substituents may be the same or different and an ethoxy group in the 2-position by a dimethylamino or diethylamino group can be substi tuted
R₂ is a hydrogen atom, R₃ is a methyl or ethyl group,
R₄ is a straight-chain or branched alkyl, alkenyl or alkynyl group which may optionally be substituted by a phenyl radical, wherein the alkyl part contains 1 to 10 carbon atoms, the mono- or di-unsaturated alkenyl part contains 3 to 10 carbon atoms and the alkynyl part contains 3 to 5 carbon atoms can
R₅ and R₆, which may be the same or different, represent a hydrogen, fluorine or chlorine atom, a methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl or methoxy group or
R₅ and R₆ together with the phenyl ring a Naphthylgrup pe and
X represents an oxygen atom, and, if R₁ contains a basic radical, their acid addition salts. 3. phenylureas of the general formula 1 according to claim 1, in which
R₁ is a tert-butyl group or a phenyl group which is substituted in the 4-position by a methoxy, hydroxy or 2- (N, N-diethylamino) -ethoxy group and may additionally be substituted in the 3-position by a methyl group,
R₂ is a hydrogen atom, R₃ is a methyl group,
R₄ represents an n-propyl, n-butyl, isobutyl, 3-methyl-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-de cyl, allyl, crotyl, 3,3-dimethyl-allyl, propargyl, 3,7-dimethyl-6-octenyl, 3,7-dimethyl-2,6-octadienyl, cyclohexylmethyl, benzyl or phenyl group,
R₅ represents a hydrogen, fluorine or chlorine atom, a methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl or methoxy group,
R₆ is a hydrogen, fluorine or chlorine atom, a methyl or ethyl group or
R₅ and R₆ together with the phenyl ring a Naphthylgrup pe and
X represents an oxygen atom, and, if R₁ contains a basic radical, their acid addition salts. 4. As phenylureas of the general formula according to claim 1, the following compounds:
N₃-crotyl-N₁- (trans-4-tert-butylcyclohexyl) -N₁-methyl-N₃-phenyl-urea,
N₁- [trans-4- (4-methoxy-3-methylphenyl) cyclohexyl] -N₁-methyl-N₃-phenyl-N₃-propylurea
N₁- (trans-4-tert-butylcyclohexyl) -N₁-methyl-N₃- (3-methyl-butyl) -N₃-phenyl-urea
N₁- (trans-4-tert-butylcyclohexyl) -N₃- (3,3-dimethyl-allyl) -N₁-methyl-N₃-phenyl-urea,
N₁- [trans-4- (4-methoxy-3-methylphenyl) cyclohexyl] -N₃- (3,3-dimethyl-allyl) -N₁-methyl-N₃-phenylurea and
N₁- (trans-4-tert-butylcyclohexyl) -N₃-hexyl-N₁-methyl-N₃-phenyl-urea. 5. Physiologically acceptable acid addition salts of Ver Compounds according to claims 1 to 3 with inorganic or organic acids. 6. Medicaments containing a compound of the general Formula I according to claims 1 to 4 or its physiological gically acceptable acid addition salt according to claim 5 in addition one or more inert carriers and / or diluents planning agents. 7. A process for the preparation of a medicament according to An claim 6, characterized in that non-chemical Ways a compound according to claims 1 to 4 or their Physiologically acceptable acid addition salt according to claim 5 in one or more inert carriers and / or diluents is incorporated. 8. A process for the preparation of the new phenylureas according to claims 1 to 5, characterized in that

• a) a compound of the general formula with a compound of the general formula in which
  R₁ to R₆ are as defined in at least one of claims 1 to 4, one of the radicals U₁ or U₂ is a hydrogen atom and the other of the radicals U₁ or U₂ is a Z₁-CX group in which
  X as defined in at least one of claims 1 to 4
  and
  Z₁ represents a nucleophilic leaving group, is reacted or
• b) for the preparation of compounds of the general formula I according to claim 1, in which X represents an oxygen atom, a compound of the general formula in the
  R₁, R₂, R₅ and R₆ are as defined in at least one of claims 1 to 4, one of R₃ 'or R₄' is a hydrogen atom and the other of R₃ 'or R₄' is R₃ or R₄ in at least one of the claims Has 1 to 4 mentioned meaning obligations, with a compound of the general formula Z₂-R₇ (V) in the
  R₇ has the meanings mentioned for R₃ or R₄ in at least one of claims 1 to 4 and
  Z₂ represents a nucleophilic leaving group, is alkylated or
• c) for the preparation of compounds of general formula I according to claim 1, in which R₁ is a phenyl group which is substituted by at least one alkoxy group having 1 to 3 carbon atoms, wherein the alkoxy group in 2- or 3-Stel ment by a dialkylamino group, in the each alkyl moiety may contain 1 to 3 carbon atoms, or may be substituted by a pyrrolidino, piperidino or hexamethyleneimino group, and X represents an oxygen atom, a compound of the general formula in the
  R₂ to R₆ are defined as at least one of claims 1 to 4 and
  R₁ 'is a hydroxyphenyl group which may additionally be substituted by a hydroxy, alkoxy or alkyl group each having 1 to 3 carbon atoms, an alkoxy group being in the 2- or 3-position by a dialkylamino group in which each alkyl portion is 1 to 3 carbon atoms may be substituted, or may be substituted by a pyrrolidino, piperidino or hexamethylene imino group, with a compound of the general formula Z₃-Alk-R₈ (VII) in the
  Alk is an n-alkylene group having 1 to 3 carbon atoms,
  R₈ represents a hydrogen atom, a pyrrolidino, piperidino, hexamethyleneimino or dialkylamino group in which each alkyl moiety may contain 1 to 3 carbon atoms, and
  Z₃ represent a nucleophilic leaving group, is reacted and
  if necessary, subsequently a protective group used during the reactions a) to c) for the protection of reactive groups, such as a hydroxy group, is split off and / or
  if desired, subsequently a compound of the general formula I in which R₁ contains a basic radical is converted into its acid addition salts, in particular into its physiologically tolerated acid addition salts with inorganic or organic acids.