DE3929660A1 - CYCLOALKYL-SUBSTITUTED 4-AMINOPHENYL DERIVATIVES AND METHOD FOR THE PRODUCTION THEREOF - Google Patents

Abstract

A cycloalkyl-substituted 4-aminophenyl derivative of formula (I): <IMAGE> wherein R is C1 - C4 alkyl; R1 is (i) a halogen atom; (ii) a group -OR2, wherein R2 is C1 - C4 alkyl; or (iii) a group -NR3R4, wherein each of R3 and R4, which may be the same or different, is C1 - C4 alkyl; n is an integer of 1 to 5; A is >C=O or -CH2- and B is, independently, -O-, -NH- or -CH2-, and the pharmaceutically acceptable salts thereof; are aromatase inhibitors. The NO2-substituted precursors are also claimed.

Description

The present invention relates cycloalkyl-substituted 4-aminophenyl derivatives, a Process for their preparation, containing them pharmaceutical preparations and the use of Compounds as inhibitors of biosynthesis of Estrogens, especially as aromatase inhibitors. Basic and clinical data indicate that estrogens the hormones are those in pathogenic cellular Changes that come with the growth of some hormone-dependent cancers, such as breast, uterine, Ovarian and pancreatic cancer, are associated, involved.

Estrogens are also involved in the pathogenesis of Involved in prostatic hyperplasia. It was envisaged that an effective inhibition of the biosynthesis of Estrogens, which comes from compounds that are capable are the activity of the enzyme aromatase, which is the Aromatization of the steroid ring A causes, too neutralize, a useful application in the scheme the amount of circulating oestrogens and the estrogen-dependent tumors could have.  

Known non-steroidal substances, one of which is more or less selective aromatase inhibiting activity For example, aminoglutethimide (Ann. Surg. 187, 475 (1978); Lancet, 2, 646 (1978)); 4-cyclohexylaniline (Endocrinology, 114, 2128 (1984)) and 4-pyridyl-3-ethyl-2,6-piperidinediones (J. Med. Chem., 28, 200 (1985)).

The invention provides a new group of non-steroidal Substances with aromatase inhibitory properties, the Cycloalkylsubstituierte 4-aminophenylderivate with the general formula (I)

wherein R is C₁-C₄ alkyl; R₁ (i) is a halogen atom; (ii) an -OR₂ group wherein R₂ is C₁-C₄ alkyl, or (iii) a -NR₃R₄ group wherein each of the substituents R₃ and R₄, which may be the same or different, is C₁-C₄ alkyl; n is a number from 1 to 5; AC = O or -CH₂-, and B is independently -O-, -NH- or -CH₂-.

Also the pharmaceutically acceptable salts of Compounds of the formula (I) are within the scope of the invention including. The salts are the salts with pharmaceutically acceptable acids, both inorganic Acids, such as. As hydrochloric acid and sulfuric acid, as well organic acids, such as. Citric acid, tartaric acid, Maleic acid, malic acid, succinic acid, methanesulfonic acid and ethanesulfonic acid. All possible isomers of the formula (I) are included within the scope of the invention, both separated as well as in mixture. So for example can for  each compound of formula (I) has two distinct optical Isomers, d. H. Enantiomers, according to the configuration of the chiral carbon atom bearing the substituent R, consist. The formula (I) should be understood to mean that they are the two enantiomers, either separated or in Mixture, in particular as a racemic mixture.

Preferred enantiomers according to the invention are those which are represented by the formula (Ia)

wherein R, R₁, n , A and B are as defined above.

In the above formulas (I) and (Ia), a C₁-C₄- Alkyl group preferably methyl or ethyl, in particular Methyl. A halogen atom is preferably fluorine, chlorine or Bromine, with chlorine or fluorine being particularly preferred.

Preferred values for n are 3 and 4, in particular 4.

Preferred salts are the hydrochlorides.  

Examples of specific compounds used in the present invention are the following Compounds, both as individual enantiomers and as Mixtures of enantiomers, especially racemic mixtures:

Cyclohexyl 2- (3'-chloro-4'-aminophenyl) propionate;
Cyclohexyl 2- (2'-chloro-4'-aminophenyl) propionate;
Cyclohexyl 2- (3'-fluoro-4'-aminophenyl) propanamide;
Cyclohexyl 2- (2'-fluoro-4'-aminophenyl) propanamide;
N-cyclohexyl-2- (3'-chloro-4'-aminophenyl) propanamide;
N-cyclohexyl-2- (2'-chloro-4'-aminophenyl) propanamide;
N-cyclohexyl-2- (3'-fluoro-4'-aminophenyl) propanamide;
N-cyclohexyl-2- (2'-fluoro-4'-aminophenyl) propanamide;
N-cyclohexyl-3- (3'-chloro-4'-aminophenyl) propanamide;
1-cyclohexyl-3- (3'-chloro-4'-aminophenyl) -2-butanone;
1-cyclohexyl-3- (2'-chloro-4'-aminophenyl) -2-butanone;
1-cyclohexyl-3- (3'-fluoro-4'-aminophenyl) -2-butanone;
1-cyclohexyl-3- (2'-fluoro-4'-aminophenyl) -2-butanone;
propylcyclohexylether 2- (3'-chloro-4'-aminophenyl);
N-cyclohexyl-2- (3'-chloro-4'-aminophenyl) propylamine;
1-cyclohexyl-3- (3'-chloro-4'-aminophenyl) butane;
N-cyclohexyl-2- (3'-methoxy-4'-aminophenyl) propanamide;
N-cyclohexyl-2- (2'-methoxy-4'-aminophenyl) propanamide;
1-cyclohexyl-3- (3'-methoxy-4'-aminophenyl) -2-butanone;
1-cyclohexyl-3- (2'-methoxy-4'-aminophenyl) -2-butanone;
N-cyclohexyl-2- (3'-dimethylamino-4'-aminophenyl) propanamide;
N-cyclohexyl-2- (2'-dimethylamino-4'-aminophenyl) propanamide;
1-cyclohexyl-3- (3'-dimethylamino-4'-aminophenyl) -2-butanone;
1-cyclohexyl-3- (2'-dimethylamino-4'-aminophenyl) -2-butanone;

and the pharmaceutically acceptable salts thereof, especially the hydrochlorides.  

The compounds of formula (I) can be prepared by a process to be made that

• (1) the reaction of a compound of formula (II) wherein R and R₁ are as defined above, or a reactive derivative thereof, with a compound of the formula (III) wherein n is as defined above and X is OH or NH₂, to give a compound of formula (I) wherein R, R₁ and n are as defined above, AC = O and B is -O- or -NH-; or
• (2) the reduction of a compound of formula (I) wherein R, R₁ and n are as defined above and AC = O and B is -O-, -NH- or -CH₂- to give a corresponding compound of Formula (I) wherein A is -CH₂- and B is -O-, -NH- or -CH₂-; or
• (3) the reduction of a compound of formula (IV) wherein R, R₁, n , A and B are as defined above to obtain a corresponding compound of formula (I) wherein R, R₁, n , A and B are as defined above; and, if desired, salting the compound of formula (I) or obtaining a free compound of formula (I) from a salt thereof, and / or, if desired, separating a mixture of isomers of formula (I) into includes single isomers.

The intermediate compounds of the above formulas (II) and (IV) and the following formula (V) may be like the Compounds of the formula (I) either individual enantiomers or mixtures of enantiomers.

A reactive derivative of an amino acid of the formula (II) can z. As an acyl halide, especially the chloride, the Acid or the anhydride thereof.

Preferably, the reaction between a compound of the formula (II) and a compound of the formula (III) using a reactive derivative of the compound (II), e.g. B. the previously specified type, performed, and then the reaction is preferably in an inert organic solvents, such as. B. anhydrous benzene or toluene, in the presence of a base, either one organic base, such as. Triethylamine or pyridine, or an inorganic base, such as. An alkali metal, for example, sodium or potassium, hydroxide, carbonate or bicarbonate.

Common methods used in organic chemistry for the Esterification and amidation are described consequences. The reduction of a compound of the formula (I) where A is C = O and B is -O- or -NH-, in the presence of  a reducing agent, such as LiAlH₄ or B₂H₆, in an inert solvent, such as Tetrahydrofuran, dioxane, diglyme and the like Solvents, preferably at a temperature in Range of about 40 ° C and about 120 ° C at a Reaction time, which is approximately in the range of 4 to 48 Hours varied, be carried out.

The reduction of a compound of formula (I) wherein A C = O and B is -CH₂-, is preferably by Transform the carbonyl group into the corresponding one 1,3-dithiolane according to well-known methods and subsequently by reduction of the latter derivative, e.g. B. by the action of an alkali metal, such as. As lithium or Sodium, or calcium, in liquid ammonia according to carried out known methods.

Alternatively, the 1,3-dithiolane derivative may be Raney nickel in an inert solvent such. B. Ethanol, dioxane, acetone, at a temperature in the range from about 20 ° C and about 80 ° C at one Reaction time of about 0.5 to 4 hours or too by tributyltin hydride in an inert aprotic Solvent, preferably benzene, at a temperature in the range of about 60 ° C and about 100 ° C at a Reaction time of about 1 to 3 hours reduced become. Optionally, the carbonyl group in the Compound of formula (I) in the corresponding Tosylhydrazone converted by general methods be, and the derivative thus obtained by action of hydrides, e.g. B. with lithium aluminum hydride or to (benzoyloxy) borane, reducing, while in one inert aprotic solvents, such as. B. diethyl ether, Dioxane, tetrahydrofuran, diglyme, chloroform or  Methylene chloride, at a temperature in the range of about 0 ° C and about 40 ° C and at a reaction time from about 0.5 to 4 hours; or it can with Sodium cyanoborohydride can be reduced, taking in a protic solvent, such as. For example, methanol, ethanol or propanol, at a temperature in the range of about 40 ° C and about 100 ° C at a reaction time from about 1 to 24 hours working.

The reduction of a compound of formula (IV) may be for Example with tin chloride in an inert solvent, such as As methanol, ethanol or ethyl acetate, at a Temperature in the range of about 40 ° C and about 100 ° C at a reaction time of about 0.5 to 3 hours; or by ammonium formate in the presence of a Hydrogenation catalyst, preferably 10% Pd / C, wherein in a suitable solvent, such as. B. one aliphatic alcohol, e.g. Methanol or ethanol, preferably at a temperature of about 20 ° C and about 50 ° C at a reaction time of about 0.5 to about 1 hour works; or by hydrogenation in Presence of a catalyst, preferably 10% Pd / C, in a solvent, such as. As an aliphatic alcohol, especially methanol or ethanol, at a temperature in the range of about 20 ° C and about 50 ° C and at a pressure ranging from about atmospheric pressure to 50 psi are performed.

The possible salt formation of a compound of the formula (I) and the preparation of a free compound of the formula (I) from a salt of it can be known by usual Procedures are performed. Standard methods can also for the separation of a mixture of isomers in the individual isomers follow. In particular, z. B. for the  Separation of a racemic mixture into the individual Enantiomers the mixture for example with an optical active acid are reacted to a mixture of diastereoisomeric salts obtained, for example, with Help a fractionated crystallization or by means Chromatography be separated. From each severed diastereoisomeric salt may be the single enantiomer of Formula (I) are then recovered in the usual way.

The compounds of formulas (II) and (III) are either known compounds or they may have known Process be prepared from known compounds. Also, the compounds of formula (IV) are either known compounds, or they may be known Compounds according to methods and methods described in organic chemistry are known to be produced. In particular, z. B. a compound of formula (IV), where A is C = O and B is -O- or -NH-, prepared be prepared by reacting a compound of formula (V)

wherein R and R₁ are as defined above, or preferably, a reactive derivative thereof, such as. B. a corresponding acyl halide, eg. B. chloride, or the Anhydride thereof, with a compound of formula (III), the previously defined.

The reaction can be carried out under conditions analogous to those who are previously in the description of the reaction between a compound of formula (II) and a Compound of formula (III) have been described are.  

A compound of formula (VI) wherein A is C = O and B -CH₂- can, for example, be prepared by a compound of formula (V) or a reactive A derivative thereof, as defined above, with a Compound of the formula (VI)

wherein n is as defined above, M is a metal, preferably Mg, capable of yielding a Grignard reagent, and Y is a halogen, preferably bromine, iodine or chlorine.

The reaction can be carried out under the usual conditions in of organic chemistry for the Grignard reaction described are performed. The connections with the formulas (V) and (VI) are known compounds or they may be known by known methods Connections are made.

The compounds of the invention show Aromataseinhibierungswirkungen.

Because of their ability to inhibit aromatase and Accordingly, to reduce the estrogen content, can the compounds of the invention are used in the Treatment and prevention of various estrogen dependent diseases, e.g. B. estrogen-dependent Tumors, z. Breast, uterine, ovarian and Pancreatic cancer; gynecomastia; benign Breast disease; Endometriosis; polycystic Ovarian disease and early puberty. A another application of the compounds of the invention is included  therapeutic and / or prophylactic treatment of prostatic hyperplasia, a disease of the estrogen-dependent stromal tissue. The connections of the Invention can also be used in the treatment of male Infertility associated with oligospermia, and at the female fertility control due to her Ability to ovulation and egg performance too be used. Accordingly, one is Object of the invention, a method for generating the Inhibition of the enzyme aromatase and, accordingly, due to the inhibition of estrogen biosynthesis Method of treating estrogen-dependent diseases, z. As the above-mentioned, in need of such Patients, the method comprising the administration of a effective amount of a compound of the invention or a containing pharmaceutical composition on the Patients included.

The compounds of the invention can be used in a variety of ways of dosage forms, e.g. B. orally in the form of tablets, Capsules, sugar- or film-coated tablets, liquid solutions or suspensions; rectally in the form of suppositories; parenteral, e.g. B. intramuscularly or by intravenous injection or infusion.

The dosage depends on the age, weight, the condition of the Patients and the mode of administration; for example The dosage may be for oral administration adult persons is suitable, from about 10 to about 400 mg per dose, ranging from 1 to 5 times daily.

As already said before, the invention concludes pharmaceutical preparations containing a compound of Invention together with a pharmaceutical  compatible drug carrier (the carrier or a Extender can be) include.

The pharmaceutical preparations containing the compounds According to the invention, are in the usual manner according to customary processes and in a pharmaceutical administered appropriate form.

For example, the solid oral forms can be combined with the active compound extender, z. Lactose, dextrose, Sucrose, cellulose, corn starch or potato starch; Lubricants, for example silica, talc, stearic acid, Magnesium or calcium stearate and / or polyethylene glycols; Binders, for example starches, Gum arabic, gelatin, methylcellulose, Carboxymethyl cellulose or polyvinyl pyrrolidone; Release agent, for. As starch, alginic acid, alginates or sodium; Aufschäummischungen; dyes; Sweetener; Wetting agents such as lecithin, polysorbates, laurylsulphates; and in general non-toxic and pharmacologically inactive substances that are involved in pharmaceutical formulations are used, contain. These pharmaceutical preparations can known manner for example by mixing, granulating, Tabletting, sugar coating or film coating getting produced.

The liquid dispersions for oral administration For example, syrups, emulsions and suspensions his.

The syrups can be used as carriers for example sucrose or Sucrose with glycerine and / or mannitol and / or sorbitol contain; especially a syrup that is diabetic  Patients should be administered as a carrier only Contain products that are not too glucose or just in very small amount are metabolized to glucose, for Example sorbitol.

The suspensions and the emulsions can be used as carriers for Example a natural gum, agar, sodium alginate, Pectin, methylcellulose, carboxymethylcellulose or Polyvinyl alcohol included.

The suspensions or solutions for the intramuscular Injections, together with the active component one pharmaceutically acceptable carriers, for example sterile Water, olive oil, ethyl oleate, glycols, e.g. B. Propylene glycol, and, if desired, an appropriate amount Contain on lidocaine hydrochloride.

The solutions for intravenous injection or infusions may contain as carrier, for example, sterile water, or they are preferably in the form of a sterile, aqueous, isotonic saline solution.

The suppositories can together with the active component one pharmaceutically acceptable carriers, for example Cocoa butter, polyethylene glycol, a Polyoxyethylene sorbitan fatty acid ester surfactant or Containing lecithin.

The following examples illustrate the invention, however, do not limit it. If the configuration is not is described in more detail, then the compounds as racemic compounds, d. H. as a racemate, to understand.

Example 1 Cyclohexyl 2- (3'-chloro-4'-aminophenyl) propionate (I, R = -CH₃-, R₁ = 3'-Cl, A = C = O, B = -O-, n = 4)

To a stirred suspension of 2- (3'-chloro-4'-aminophenyl) propionic acid (2.0 g, 10 mmol) in dry benzene (25 ml) is added thionyl chloride (2.9 ml) given. The resulting mixture is allowed to stand for 4 hours refluxed, cooled and evaporated in vacuo, taking one gets a brown oil.

The resulting acyl chloride dissolved in dry benzene (20 ml) is then added dropwise to a stirred solution of cyclohexanol (1.0 g, 10 mmol) and triethylamine (7.0 ml, 50 mmol) in dry benzene (50 ml) at 5 to 10 ° C given. After 3 hours of additional stirring Room temperature, the reaction mixture in a cold 10% Na₂CO₃ aqueous solution, the organic Phase is separated, washed with water, over Na₂SO₄ dried, filtered and in vacuo concentrated. The residue obtained is purified fractional distillation. Boiling point 145-7 ° (0.1-0.05 mm Hg). There are 1.90 g (yield 67%) of Title compound obtained as a colorless oil.

Elemental analysis:
Calculated% (found%): C 63.93 (64.00) H 7,15 (7.24) Cl 12.58 (12.44) N 4.97 (4.92)
NMR (CDCl₃, δ ): 1.44 (3H, d) 3.55 (1H, q), 3.50 (2H, br), 4.74 (1H, m), 6.70 (1H, d) , 7.00 (1H, dd), 7.20 (1H, d)
IR (CHCl₃, cm ^-1 ): 3460, 3380, 2920, 2840, 1715, 1615, 1590, 1495.

In an analogous way one can see the individual enantiomers of the  above title compound as well as the following compounds both as racemates and as individual enantiomers produce:

Cyclohexyl 2- (2'-chloro-4'-aminophenyl) propionate;
Cyclohexyl 2- (3'-fluoro-4'-aminophenyl) propionate;
Cyclopentyl 2- (2'-fluoro-4'-aminophenyl) propionate;
Cyclopentyl 2- (3'-chloro-4-aminophenyl) propionate;
Cyclopentyl 2- (2'-chloro-4-aminophenyl) propionate;
Cyclopentyl 2- (3'-fluoro-4-aminophenyl) propionate;
Cyclopentyl 2- (2'-fluoro-4-aminophenyl) propionate.

example 2 propanamide N-cyclohexyl-2- (3'-chloro-4'-aminophenyl) (I, R = -CH₃, R₁ = 3'-Cl, A = C = O, B = -NH-, n = 4)

The acyl chloride, prepared from 2.0 g of 2- (4'-chloro-4'-aminophenyl) propionic acid and 2.9 ml Thionyl chloride as reported in Example 1 is described in U.S. Pat dissolved dry benzene (20 ml) and dropwise to a stirred solution of cyclohexylamine (4.0 g, 40 mmol) in dry benzene (50 ml) at 5 to 10 ° C. After three Hours of additional stirring at room temperature will be the Reaction mixture worked up as in Example 1. The Crude product is obtained by repeated 0.5 N HCl extraction and Na₂CO₃ neutralization purified. It will be 1.50 g (Yield 53%) of the title compound as a glassy product receive.

Elemental analysis:
Calculated% (found%): C 56.78 (56.19) H 6.99 (6.98) Cl 22.35 (22.42) N 8.83 (8.73)
NMR (CDCl₃, δ ): 1.24 (3H, d) 3.50 (2H, m), 7.08 (2H, m), 7.28 (1H, br s) 7.78 (1H, br )
IR (KBr, cm ^-1 ): 3300, 3050, 2920, 2940, 3000-1900, 1630, 1600, 1530, 1490.

In an analogous way one can see the individual enantiomers of the above title compound as well as the following compounds both as racemates and as individual enantiomers produce:

N-cyclohexyl-2- (2'-chloro-4'-aminophenyl) propanamide;
N-cyclohexyl-2- (3'-fluoro-4'-aminophenyl) propanamide;
N-cyclohexyl-2- (2'-fluoro-4'-aminophenyl) propanamide;
N-cyclopentyl-2- (3'-chloro-4'-aminophenyl) propanamide;
N-cyclopentyl-2- (2'-chloro-4'-aminophenyl) propanamide;
N-cyclopentyl-2- (3'-fluoro-4'-aminophenyl) propanamide;
N-cyclopentyl-2- (2'-fluoro-4'-aminophenyl) propanamide;
N-cyclohexyl-2- (3'-chloro-4'-aminophenyl) butanamide;
N-cyclohexyl-2- (2'-chloro-4'-aminophenyl) butanamide;
N-cyclohexyl-2- (3'-fluoro-4'-aminophenyl) butanamide;
N-cyclohexyl-2- (2'-fluoro-4'-aminophenyl) butanamide;
N-cyclohexyl-2- (2'-methoxy-4'-aminophenyl) propanamide;
N-cyclohexyl-2- (3'-methoxy-4'-aminophenyl) propanamide;
N-cyclopentyl-2- (3'-methoxy-4'-aminophenyl) propanamide;
N-cyclopentyl-2- (2'-methoxy-4'-aminophenyl) propanamide;
N-cyclohexyl-2- (3'-methoxy-4'-aminophenyl) butanamide;
N-cyclohexyl-2- (2'-methoxy-4'-aminophenyl) butanamide;
N-cyclohexyl-2- (2'-dimethylamino-4'-aminophenyl) propanamide;
N-cyclohexyl-2- (3'-dimethylamino-4'-aminophenyl) propanamide;
N-cyclopentyl-2- (3'-dimethylamino-4'-aminophenyl) propanamide;
N-cyclopentyl-2- (2'-dimethylamino-4'-aminophenyl) propanamide;
N-cyclohexyl-2- (3'-dimethylamino-4'-aminophenyl) butanamide;
N-cyclohexyl-2- (2'-dimethylamino-4'-aminophenyl) butanamide.

example 3 2- (3'-methyl-4'-aminophenyl) propyl cyclohexyl ether (I, R = CH₃, R₁ = 3'-Cl, A = -CH₂-, B = -O-, n = 4)

To a stirred suspension of lithium aluminum hydride (2.5 g) in anhydrous tetrahydrofuran (50 ml) becomes a Mixture of cyclohexyl 2- (3'-chloro-4'-aminophenyl) Propionate (4.21 g, 15 mmol), prepared as in Example 1, and boron trifluoride etherate (30 ml) in anhydrous Tetrahydrofuran (50 ml), dropwise with external cooling added. After 3 hours at 45 ° C is the Reaction mixture is carefully decomposed by adding water and then adding 23% hydrochloric acid solution. The most of the organic solvent is in a vacuum evaporated, the aqueous solution is brought to a pH of 9 set by focusing one Sodium hydroxide solution added, and with diethyl ether (3 times) extracted. The combined extracts are with Washed neutral water, dried over Na₂SO₄ and evaporated in vacuo. The residue obtained is Column chromatography on silica gel, using Benzene: ethyl acetate 95: 5 eluted, and by fractional Purified distillation. It will be 2.6 g of Title compound obtained.

IR (CHCl₃, cm ^-1 ): 3440, 3360, 3080, 3020, 2920, 2840, 1610, 1510, 1175, 1130, 1075.

example 4 N-cyclohexyl-2- (3'-chloro-4'-aminophenyl) propylamine bis hydrochloride (I, R = -CH₃, R₁ = 3'-Cl, A = -CH₂-, B = -NH-, n = 4)

To a stirred suspension of lithium aluminum hydride (0.4 g) in anhydrous diglyme (10 ml) becomes N-cyclohexyl 2- (3'-chloro-4'-aminophenyl) propanamide (0.560 g, 2 mmol), prepared as in Example 2, dissolved in anhydrous Diglyme (5 ml), dropwise under nitrogen atmosphere added.

The reaction mixture is then heated to 85-95 ° C six Heated for hours. After cooling, the excess with lithium aluminum hydride with careful addition of a Mixture of methanol, t-butyl methyl ether and water decomposed. The organic phase is separated off, with water washed, dried over Na₂SO₄ and filtered.

The filtrate is washed with anhydrous hydrogen chloride saturated, and the resulting precipitate is filtered off and from methanol: isopropanol 1: 2 recrystallized. It 0.605 g of the title compound is hydrogen chloride receive.

IR (KBr, cm ^-1 ): 3100-2300, 2920, 2840, 1610, 1505, 1450, 1375

example 5 1-cyclohexyl-3- (3'-chloro-4'-aminophenyl) butane (I, R = -CH₃, R₁ = 3'-Cl, A = B = -CH₂-, n = 4)

To a solution of 1-cyclohexyl-3- (3'-chloro-4'-aminophenyl) -2-butanone (2.79 g, 10 mmol) in methylene chloride (50 mL) Ethanedithiol (2 ml) and boron trifluoride etherate (2 ml) added. The mixture is at room temperature 2 Stirred for hours, then it becomes with water, one 8% NaHCO₃ aqueous solution and washed with water,  then dried over CaCl₂, filtered and im Vacuum evaporated. The crude thioketal thus obtained (3.25 g) is dissolved in anhydrous tetrahydrofuran (30 ml) and in the presence of Raney nickel (10 g) (prepared according to Org. Synth., 3, 181) for two hours at room temperature touched. The catalyst is filtered off and washed with Washed methylene chloride.

The combined filtrates and washings are in Vacuum evaporated to give a residue, the is purified by fractional distillation. It will 1.60 g of the title compound.

IR (CHCl₃, cm ^-1 ): 3440, 3360, 3080, 3020, 2920, 2840, 1610, 1510

In an analogous way one can see the individual enantiomers of the above title compound as well as the following compounds both as racemates and as individual enantiomers produce:

1-cyclohexyl-3- (2'-chloro-4'-aminophenyl) butane;
1-cyclohexyl-3- (3'-fluoro-4'-aminophenyl) butane;
butane 1-cyclohexyl-3- (2'-fluoro-4'-aminophenyl).

example 6 1-cyclohexyl-3- (3'-chloro-4'-nitrophenyl) -2-butanone (IV, R = CH₃, R₁ = 3'-Cl, A = C = O, B = CH₂-, n = 4)

To a stirred solution of Cyclohexylmethylmagnesium iodide (prepared from 7.5 g Cyclohexylmethyl iodide and 0.7 g of magnesium turnings) in anhydrous diethyl ether (30 ml), cooled to 0 ° C powdered, anhydrous cadmium chloride (2.6 g) in  small amounts over a period of 45 minutes added. After one hour of additional stirring Room temperature, the resulting solution to -70 ° C. cooled and with dropwise addition of 2- (3'-chloro-4'-nitrophenyl) propionyl chloride (prepared from 4.60 g, 20 mmol 2- (3'-chloro-4'-nitrophenyl) -propionic acid and 8.0 ml Thionyl chloride) in anhydrous diethyl ether (10 ml) treated. After one hour of additional stirring, the Reaction mixture carefully by dropwise addition of 50 ml of water decomposes. The organic phase becomes separated, the aqueous phase with diethyl ether (3 times) extracted, the combined extracts are over Na₂SO₄ dried, filtered and in vacuo concentrated. There are 4.7 g of the tubes title compound receive.

IR (CHCl₃, cm ^-1 ): 1715, 1520, 1350

In an analogous way one can see the individual enantiomers of the above title compound as well as the following Compounds, both as racemates and as individual Enantiomers, produce:

1-cyclohexyl-3- (2'-chloro-4'-nitrophenyl) -2-butanone;
1-cyclohexyl-3- (3'-fluoro-4'-nitrophenyl) -2-butanone;
1-cyclohexyl-3- (2'-fluoro-4'-nitrophenyl) -2-butanone;
1-cyclopentyl-3- (3'-chloro-4'-nitrophenyl) -2-butanone;
1-cyclopentyl-3- (2'-chloro-4'-nitrophenyl) -2-butanone;
1-cyclopentyl-3- (3'-fluoro-4'-nitrophenyl) -2-butanone;
1-cyclohexyl-3- (2'-fluoro-4'-nitrophenyl) -2-pentanone;
1-cyclohexyl-3- (2'-methoxy-4'-nitrophenyl) -2-butanone;
1-cyclohexyl-3- (3'-methoxy-4'-nitrophenyl) -2-butanone;
1-cyclopentyl-3- (3'-methoxy-4'-nitrophenyl) -2-butanone;
1-cyclopentyl-3- (2'-methoxy-4'-nitrophenyl) -2-butanone;
1-cyclohexyl-3- (3'-methoxy-4'-nitrophenyl) -2-pentanone;
1-cyclohexyl-3- (2'-methoxy-4'-nitrophenyl) -2-pentanone;
1-cyclohexyl-3- (2'-dimethylamino-4'-nitrophenyl) -2-butanone;
1-cyclohexyl-3- (3'-dimethylamino-4'-nitrophenyl) -2-butanone;
1-cyclopentyl-3- (3'-dimethylamino-4'-nitrophenyl) -2-butanone;
1-cyclopentyl-3- (2'-dimethylamino-4'-nitrophenyl) -2-butanone;
1-cyclohexyl-3- (3'-dimethylamino-4'-nitrophenyl) -2-pentanone;
1-cyclohexyl-3- (2'-dimethylamino-4'-nitrophenyl) -2-pentanone

example 7 1-cyclohexyl-3- (3'-chloro-4'-aminophenyl) -2-butanone (I, R = -CH₃, R = 3'-Cl, A = C = O, B = -CH₂, n = 4)

A stirred mixture of 4.4 g of crude 1-cyclohexyl-3- (3'-chloro-4'-nitrophenyl) -2-butanone and 400 mg of 10% Pd / C catalyst in 75 ml of 95% ethanol and 15 ml of 1N HCl aqueous solution is in a Brown hydrogenation unit hydrogenated at room temperature until the Uptake of hydrogen ends. The catalyst is filtered off, and the filtrate is evaporated in vacuo.

The residue obtained is fractionated Purified distillation. There are 1.31 g of Title compound obtained.

IR (CHCl₃, cm ^-1 ): 3460, 3380, 3015, 1710, 1620, 1510

In an analogous way one can see the individual enantiomers of the above title compound as well as the following Compounds, both as racemates and as Enantiomers, produce:

1-cyclohexyl-3- (2'-chloro-4'-aminophenyl) -2-butanone;
1-cyclohexyl-3- (3'-fluoro-4'-aminophenyl) -2-butanone;
1-cyclohexyl-3- (2'-fluoro-4'-aminophenyl) -2-butanone;
1-cyclopentyl-3- (3'-chloro-4'-aminophenyl) -2-butanone;
1-cyclopentyl-3- (2'-chloro-4'-aminophenyl) -2-butanone;
1-cyclopentyl-3- (3'-fluoro-4'-aminophenyl) -2-butanone;
1-cyclopentyl-3- (2'-fluoro-4'-aminophenyl) -2-butanone;
1-cyclohexyl-3- (3'-chloro-4'-aminophenyl) -2-pentanone;
1-cyclohexyl-3- (2'-chloro-4'-aminophenyl) -2-pentanone;
1-cyclohexyl-3- (3'-fluoro-4'-aminophenyl) -2-pentanone;
1-cyclohexyl-3- (2'-fluoro-4'-aminophenyl) -2-pentanone;
1-cyclohexyl-3- (2'-methoxy-4'-aminophenyl) -2-butanone;
1-cyclohexyl-3- (3'-methoxy-4'-aminophenyl) -2-butanone;
1-cyclopentyl-3- (3'-methoxy-4'-aminophenyl) -2-butanone;
1-cyclopentyl-3- (2'-methoxy-4'-aminophenyl) -2-butanone;
1-cyclohexyl-3- (3'-methoxy-4'-aminophenyl) -2-pentanone;
1-cyclohexyl-3- (2'-methoxy-4'-aminophenyl) -2-pentanone;
1-cyclohexyl-3- (2'-dimethylamino-4'-aminophenyl) -2-butanone;
1-cyclohexyl-3- (3'-dimethylamino-4'-aminophenyl) -2-butanone;
1-cyclopentyl-3- (3'-dimethylamino-4'-aminophenyl) -2-butanone;
1-cyclopentyl-3- (2'-dimethylamino-4'-aminophenyl) -2-butanone;
1-cyclohexyl-3- (3'-dimethylamino-4'-aminophenyl) -2-pentanone;
1-cyclohexyl-3- (2'-dimethylamino-4'-aminophenyl) -2-pentanone

example 8

Tablets each weighing 0.150 g and 25 mg of the Active compound can be prepared as follows become:

Composition (for 10000 tablets) N-cyclohexyl-2- (3'-chloro-4'-aminophenyl) -propanamide | 250 g lactose 800 g corn starch 415 g talcum powder 30 g magnesium stearate 5 g

N-cyclohexyl-2- (3'-chloro-4'-aminophenyl) -propanamide, the lactose and half of the corn starch are mixed; The mixture is passed through a sieve with a mesh size of 0.5 mm. Cornstarch (10 g) is served in warm Water (90 ml) is suspended, and the resulting paste is used to granulate the powder. The granules will dried, on a sieve with a mesh size of 1.4 mm crushed, and then the remaining amount Starch, talc and magnesium stearate added, carefully mixed and processed into tablets.

Claims (16)

1. Cycloalkyl-substituted 4-aminophenyl derivatives having the general formula (I) wherein R is C₁-C₄ alkyl; R₁ (i) is a halogen atom; (ii) an -OR₂ group, wherein R₂ is C₁-C₄ alkyl; or (iii) an -NR₃R₄ group, wherein each of R₃ and R₄, which may be the same or different, is C₁-C₄ alkyl; n is a number from 1 to 5; AC = O or -CH₂-, and B is independently -O-, -NH- or -CH₂-, and the pharmaceutically acceptable salts thereof. A compound according to claim 1, wherein the cycloalkyl-substituted 4-aminophenyl derivative is the enantiomer of formula (Ia) wherein R, R₁, n , A and B are as defined in claim 1. 3. A compound according to claim 1 or 2, wherein n is 3 or 4. 4. Compound, either as a single enantiomer or as a racemate mixture, selected from the series:
Cyclohexyl 2- (3'-chloro-4'-aminophenyl) propionate;
Cyclohexyl 2- (2'-chloro-4'-aminophenyl) propionate;
Cyclohexyl 2- (3'-fluoro-4'-aminophenyl) propanamide;
Cyclohexyl 2- (2'-fluoro-4'-aminophenyl) propanamide;
N-cyclohexyl-2- (3'-chloro-4'-aminophenyl) propanamide;
N-cyclohexyl-2- (2'-chloro-4'-aminophenyl) propanamide;
N-cyclohexyl-2- (3'-fluoro-4'-aminophenyl) propanamide;
N-cyclohexyl-2- (2'-fluoro-4'-aminophenyl) propanamide;
N-cyclohexyl-2- (3'-chloro-4'-aminophenyl) propanamide;
1-cyclohexyl-3- (3'-chloro-4'-aminophenyl) -2-butanone;
1-cyclohexyl-3- (2'-chloro-4'-aminophenyl) -2-butanone;
1-cyclohexyl-3- (3'-fluoro-4'-aminophenyl) -2-butanone;
1-cyclohexyl-3- (2'-fluoro-4'-aminophenyl) -2-butanone;
propylcyclohexylether 2- (3'-chloro-4'-aminophenyl);
N-cyclohexyl-2- (3'-chloro-4'-aminophenyl) propylamine;
1-cyclohexyl-3- (3'-chloro-4'-aminophenyl) butane;
N-cyclohexyl-2- (3'-methoxy-4'-aminophenyl) propanamide;
N-cyclohexyl-2- (2'-methoxy-4'-aminophenyl) propanamide;
1-cyclohexyl-3- (3'-methoxy-4'-aminophenyl) -2-butanone;
1-cyclohexyl-3- (2'-methoxy-4'-aminophenyl) -2-butanone;
N-cyclohexyl-2- (3'-dimethylamino-4'-aminophenyl) propanamide;
N-cyclohexyl-2- (2'-dimethylamino-4'-aminophenyl) propanamide;
1-cyclohexyl-3- (3'-dimethylamino-4'-aminophenyl) -2-butanone;
1-cyclohexyl-3- (2'-dimethylamino-4'-aminophenyl) -2-butanone;
and the pharmaceutically acceptable salts thereof. 5. A salt of a compound according to claim 4, wherein the salt the hydrochloride is. 6. A process for the preparation of a compound of formula (I) or a salt thereof according to claim 1, wherein the process

• (1) the reaction of a compound of formula (II) wherein R and R₁ are as defined in claim 1, or a reactive derivative thereof, with a compound of formula (III) wherein n is as defined in claim 1 and X is OH or NH₂, to give a compound of formula (I) wherein R, R₁ and n are as defined in claim 1, AC = O and B is -O- or -NH - is; or
• (2) the reduction of a compound of formula (I) wherein R, R₁ and n are as defined in claim 1 and AC = O and B is -O-, -NH- or -CH₂- to give a corresponding one A compound of formula (I) wherein A is -CH₂- and B is -O-, -NH- or -CH₂-; or
• (3) the reduction of a compound of formula (IV) wherein R, R₁, n , A and B are as defined in claim 1 to obtain a corresponding compound of formula (I) wherein R, R₁, n , A and B are as defined in claim 1; and, if desired, salting the compound of formula (I) or obtaining a free compound of formula (I) from a salt thereof, and / or, if desired, separating a mixture of isomers of formula (I) the individual Isomers include.

7. A pharmaceutical preparation comprising an inert Carrier and / or extender, and, as an active substance, a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof. 8. A compound of the formula (I) or a salt thereof according to claim 1 for use as Aromatase. 9. A compound of the formula (I) or a salt thereof Claim 8 for use in the treatment of a hormone-dependent tumor or prostate hypertrophy or hyperplasia. 10. A compound of the formula (I) or a salt thereof Claim 8 or 9 in the form of a pharmaceutical Composition, which is also an inert carrier and / or extender.   11. Use of a compound of formula (I) or a Salt thereof according to claim 1 in the preparation of a pharmaceutical composition for use as an aromatase inhibitor. 12. Use according to claim 11, wherein the pharmaceutical Composition for use in the treatment a hormone dependent tumor or the Prostate hypertrophy or hyperplasia. 13. A compound of formula (I) according to claim 1, as it described hereinbefore except for one connection according to claim 4. 14. A process for the preparation of a compound of the formula (I) according to claim 1 or a pharmaceutical acceptable salt thereof, the process being in essentially as before in any of Examples 1 to 5 and 7 is. 15. Pharmaceutical composition, which is substantially as previously described in Example 8. 16. A compound of the formula (IV) which is defined in claim 6 is described.