GB2222589A - Cycloalkyl-substituted 4-aminophenyl derivatives and process for their preparation - Google Patents
Cycloalkyl-substituted 4-aminophenyl derivatives and process for their preparation Download PDFInfo
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Description
2222589 FC 405 Title 1ICYCLOALKYL-SUBSTITUTED 4-AMINOPHENYL DERIVATIVES
AND PROCESS FOR THEIR PREPARATION" The present invention relates to cycloallwl-subsitituted 4-aminophenyl derivatives, to a process for their prepara tion, to pharmaceutical compositions containing them and to the use of said compounds as inhibitors of the biosyn thesis of estrogens, particularly as aromatase inhibitors.
Basic and clinical data indicate that estrogens are the hormones involved in the pathogenic cellular changes associated with the growth of some hormone-dependent cancers such as breast, endometrial, ovarian and pancreatic carcinoma.
Estrogens are also involved in the pathogenesis of prostatic h y p e r p 1 a s i a. It has been envisaged that an effective inhibition of the biosynthesis of estrogens, better if resulting from compounds able to neutralize the activity of the enzyme aromatase which performs the aromatisation of the steroidic ring A, may have useful application for controlling the amount of circulating estrogens, and estrogen-dependent tumors.
Non-steroidal known substances which have been reported to be endowed with a more or less selective aromatase-inhibi ting action are, for example, aminoglutethimide /Inn. Surg.
187, 475 (1978); Lancet,.Z, 646 (1978)/; 4-cyclohexylaniline /indocrinology, 114, 2128 (1984)7, and 4-pyridyl-3-ethyl-2,6-piperidinedione Med. Chem., 28, 200 (1985)7.
2.
The invention provides a new group of non-steroidal substances having aromatase-inhibiting properties, which are cycloalkyl-substituted 4aminophenyl derivatives having the general formula (I) 2 R R, A-B' 2 (CH 2) n (I) wherein R-is C I-C 4 alkyl: R 1 is C I- c 4 alkyl unsubstituted or substituted by 1 to A halogen atoms and R 2 is, independently, hydrogen or C I-C 4 alkyl unsubstitutedor substituted by 1 to 4 halogen atoms; n is an integer of 1 to S; A is %C=0 or-CH and B is, independently,-0-, -NH- or -CH 2- 2_ Also the pharmaceutically acceptable salts of the compounds of formula (I) are included within the scope of the invention. The said salts are the salts with pharmaceutically acceptable acids, both inorganic acids, such as, e.g., hydrochloric and sulfuric, and organic acids such as, e.g., citric, tartaric, maleic, malic, succinic, methanesulfonic and ethanesulfonic.
All the possible isomers of formula (I) are included within the scope of the invention, both separately and in mixture. Thus, for example, for each compound of formula (I) two 3.
distinct optical isomers, i.e. enantiomers, may exist according to the configuration of the chiral carbon atom carrying the R substituent. The formula (I) is meant to cover both the enantiomers, either separately or in mixture, in particular racemic mixture.
Preferred enantiomers according to the invention are those represented by the formula (Ia) NH 2 2 (CH 2 A-B< (Ia) wherein R, Rly R 2' n, A and B are as defined above.
In the above formulae(I) and (Ia) a C 1-C 4 alkyl group is, preferably, methyl or ethyl, especially methyl. A halogen atom is,preferably, fluorine, chlorine or bromine, most preferably fluorine. A C 1-C 4 alkyl group substituted by 1 to 4 halogen atoms is, preferably, a methyl or ethyl group substituted by 1 to 3 halogen atoms such as, for instance, a mono-, di- or tri- halomethyl group, or a 1-halo-,2-halo-, 1,2-dihalo-p2,2-dihalo-or 2,2,2-trihaloethyl groW,in particular fluoromethyl, difluoromethyl, trifluoromethyl, I-fluoroethyl, 2-fluoroethyl; 1,2-difluoroethyl; 2,2- difluoroethyl or 2,2,2-trifluoroethyl. Preferred values for n are 3 and 4, in particular 4. Preferred saltd are the hydrochlorides.
4.
Examples of specific compounds preferred under this invention are the following compounds both as single enantiomers and as mixtures of enantiomers, in particular racemic mixtures:
cyclohexyl 2-(31-methyl-41-aminophenyl) propionate; cyclohexyl 2-(31,51-dimethyl-41-aminophenyl) propionate; N-cyclohexyl-2-(21-methyl-41-aminophenyl) propanimide; N-cyclohexyl-2-(31-methyl-41-aminophenyl) propanamide; N-cyclohexyl-2-(21,31-dimethyl-41-aminophenyl) propanamide; N-cyclohexyl-2-(21,51-dimethyl-41-aininophenyl) propanamide; N-cyclohexyl-2-(31,51-dimethyl-41-aminophenyl) propanamide; N-cyclohexyl-2-(21,61-dimethyl-41-aminophenyl) propanamide; N-cyclohexyl-2-(21-trifluoromethyl-41-aminophenyl) propanamide; N-cyclohexyl-2-(31-trifluoromethyl-41-aminophenyl) propanamide 2-(31-methyl-41-aminophenyl) propylcyclohexyl ether; N-cyclohexyl-2-(31-methyl-41-aminophenyl) propylamine; 1-cyclohexyl-3-(31-methyl-41-aminophenyl)-2-butanone; and 1-cyclohexyl-3-(31-methyl-41-aminophenyl) butane; and the pharmaceutically acceptable salts thereof especially the hydrochlorides.
The compounds of formula (1) may be prepared by a process comprising (1) reacting a compound of formula (11) NH 2 Ri R 2 H '0 COOH R (II) 5.
wherein R, R I and R 2 are as defined above, or a reactive derivative thereof, with a compound of formula (III) ( H 2) n X--<j (III) wherein n is as defined above and X is OH or NH 2' so obtaining a compound of formula (I) wherein R, R19R 2 and or -NH- n are as defined above, A is C=0 and B is respectively; or (2) reducing a compound of formula (I) wherein R, R,, R 2 and n are as defined above and A is.C=O and B is -0-, -NH- or -CH 2-' so obtaining a corresponding compound of formula (I) wherein A is -CH 2- and B is -0-, -NH- or -CH 2-; or (3) reducing a compound of formula (IV) NO 2 R H -BI (CH 2)n R <i (IV) wherein R, R,, R 2, n, A and B are as defined abovegso obtaining a corresponding compound of formula (1) wherein R, Rly R 2' n, A and B are as defined above; and,, if desired, salifying 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 the single isomers.
6.
The intermediate compounds of the above formulae (II) and (IV) and of the following formula (V) may be, as the compounds of formula (I), either single enantiomers or mixtures of enantiomers.
A reactive derivative of an aminoacid of formula (II) may be, e.g., an acyl halide, in particular the chloride, of the acid, or the anhydride thereof. Preferably the reaction between a compound of formula (II) and a compound of formula (III) is performed using a reactive derivative of the compound (II), e.g. of the kind previously specified, and then the reaction is preferably carried out in an inert organic solvent such as, for instance, anhydrous benzene or toluene, in the presence of a base, either an organic base such as, e.g., triethylamine or pyridine, or an inorganic base such as, e.g., an alkali metal, e.g. sodium or potassium, hydroxide, carbonate or bicarbonate. Usual procedures described in organic chemistry for esterification and amidation reactions may be followed. The reduction of a compound of formula (I) wherein A is C=O and B is -0or--NH- may be carried out in presence of a reducing agent such as, e.g., LiAIH 4 or B 2 H 6 in an inert solvent such as tetrahydrofuran, dioxane, diglyme and similar solvents, preferably at a temperature ranging between about 4011C and about 12011C for a reaction time varying approximately in the range of 4-48 hours.
7.
The reduction of a compound of formula (I) wherein A is C=0 and B is -CH is preferably carried out by transform2 ing the carbonyl group Into the corresponding 1,3-dithiolane according to generally known methods, and then reducing the latter derivative, e.g. by the action of an alkali metal, such as, e.g., lithium or sodium, or calcium, in liquid ammonia, according to known procedures.
Alternatively, the 1,3-dithiolane derivative may be reduced by RaneyNickel in an inert solvent, such as, e.g., ethanol, dioxane, acetone, at a temperature ranging between about 200C and about 801C for a reaction time of about 0.5-4 hours, or also by tributyl tin hydride in an inert aprotic solvent, preferably benzene, at a temperature ranging between about 600C and about 1000C, for a reaction time of about 1-3 hours.
Optionally, the carbonyl group in the compound of formula (I) may be transformed into the cor responding tosylhydrazone by general methods and the derivative so obtained may be reduced by the action of hydrides, for instance with lithium aluminium hydride or bis(benzoyloxy)borane, operating In an Inert, aprotic solvent such as, e.g., diethylether, dioxane, tetrahydrofuran, diglyme, chloroform or methylene chloride, at a temperature ranging between about OOC and around 400C and for reaction times of about 0.5-4 hours; or with sodium cyanoborohydride operating In a protic solvent such as, e.g., methanol, ethanol, or propanol, at a temperature ranging 8.
between around 400C and around 1000C for a reaction time of about 1-24 hours. The reduction of a compound of formula (IV) may be carried out, for instance, by stannous chloride in an inert solvent such as, e.g., methanol, ethanol or ethyl acetate at a temperature ranging between about 400C and about 1000C for a reaction time of about 0.5-3 hours; or by ammonium formate in presence of a hydrogenation catalyst, preferably 10% Pd/C operating in a suitable solvent such as, e.g., an aliphatic alcohol, e.g. methanol or ethanol, preferably at a temperature ranging between about 200C and about 500C in a reaction time of from about 0.5 hour to about 1 hour; or by hydrogenation in presence of a catalyst, preferably 10% Pd/C, in a solvent such as, e.g., an aliphatic alcohol, in particular methanol or ethanol, at a temperature ranging between about 200C and about 500C and at a pressure ranging approximately between the atmospheric pressure and 50 psi.
ion of a compound of formula (I) The optional salfficat and the preparation of a free compound of formula (1) from a salt thereof may be performed by conventional known methods. Standard procedures may be followed also for separating a mixture of isomers into the single isomers. In particular, for example, for separating a racemic mixture into the single enantiomers, the mixture may be, e.g., reacted with an optically active acid to give a mixture of diasteroisomeric It- salts which are separated by means of, e.g., fractional crystallization or chromatography. From each separated diastereoisomeric salt, the single enantiomer of formula (I) may be then recovered in a conventional way.
The compounds of formula (II) and (III) are either known compounds or may be prepared by known methods from known compounds. Also the compounds of formula (IV) are either known compounds or can be prepared from known compounds following methods and procedures known in the organic chemistry In particular, for example, a compound of formula (IV) wherein A is and B is -0- or -NH- can be prepared reacting a compound of formula (V) NO 2 1 R 2 11, COOH R (V) wherein R, R 1 and R 2 are as defined above or, preferably, a react.1ve derivative thereof such as, for instance, a corresponding acyl halide, e.g. chloride, or the anhydride thereof, with a compound of formula (III) as previously defined. The reaction may be performed under conditions analogous to those reported before in this specification for the reaction between a compound of formula (11) and a compound of formula (III).
10.
A compound of formula.(IV) wherein A is,C=0 and B is -CH 2- may be prepared, e.g., reacting a compound of formula (V), or a reactive derivative thereof as herein before defined, with a compound of formula (VI) (C'2)n CH 2 MY (VI) wherein n is as defined above, M is a metal, prif erably Mg, suitable to give a Grignard reagent, and Y is a halogen, preferably bromine, iodine or chlorine. The reaction may be carried out in the usual conditions described in the organic chemistry for the Grignard reactions. The compounds having the formulae (V) and (VI) are known compounds or may be prepared' by known methods from known compounds. The compounds of the invention show aromatase inhibiting activity. I By virtue of their ability to inhibit arom.atase and, consequently, to reduce estrogen levels, the compounds of the invention can find use in the treatment and prevention of various estrogen dependent diseases, e.g. estrogen dependent tumors, for instance breast, endcmetrial, ovarian and pancreatic cancers; gynecanastia; benign breast disease; endcm,etriosis; polycystic ovarian disease, and precocious puberty.
Another application of the conpounds of the invention is in the therapeutic and/or prophylactic treatnent of prostatic hyperplasia, a disease of the estrogen dependent stromal tissue. The compounds of the invention can be useful also for the treatment of male infertility associated with oligospermia and for female fertility I 11.
contrcl, by virtue of their ability to inhibit ovulation and egg nidation. Accordingly, object of the invention is also a method of producing inhibition of the enzyme aromatase and, consequently, because of inhibition of estrogen biosynthesis, a method of treating estrogen dependent deseases, e.g. those mentioned above, in a patient in need of it, wtiich method comprises administering to the patient an effective amount of a compound of the invention or a pharmaceutical composition containing it. The compounds of the invention can be administered in a variety of dosage forms, e.g., orally, in the form of tablets, capsules, sugar of film coated tablets, liquid solutions or suspensions; rectally, in the form of suppositories; parenterally, e.g. intramuscularly, or by intravenous injection or infusion. The dosage depends on the age, weight, conditions of the patient and administration route; for example the dosage adopted for oral administration to adult humans may range from about 10 to about 400 mg pro dose, from 1 to 5 times daily. As already said the invention includes pharmaceutical compositions comprising a compound of the invention in association with a pharmaceutically acceptable excipient (which can be a carrier or diluent). The pharmaceutical compositions containing the compounds of the invention are usually prepared following conventional methods and are administered in a pharmaceutical suitable form.
12.
For example, the solid oral forms may contain, together with the active compound, diluents, e.g.,-lactose, dextrose, saccharose, cellulose, corn starch or potato starch; lubricants, e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents, e.g. starches, arabic gums, gelatin, methylcellulose, carboxymethyleellulose or polyvinyl pyrrolidone; disaggregating agents, e.g. a starch, alginic acid, alginates or sodium starch glycolate; effervescing mixtures; dyestuffs; sweeteners; wetting agents, such as lecithin, polysorbates, laurylsulphates; and, in general, non-toxic and% pharmacologically inactive substances used in pharmaceutical formulation. Said pharmaceutical preparations may be manufactured in known manner, for example, by means of mixing, granulating, tabletting, sugar-coating, or film-coating processes.
The liquid dispersions for oral administration may be, e.g., syrups, emulsions and suspensions. The syrups may contain as carrier, for example, saccharose or saccharose with glycerine and/or mannitol and/or sorbitol; in particular a syrup to be administered to diabetic patients can contain as carriers only products not metabolizable to glucose, or metabolizable in very small amount to glucose, for example sorbitol. The suspensions and the emulsions may contain as carrier, for y 13.
example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethy1cellulose, or polyvinyl alcohol.. The suspensions or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and if desired, a suitable amount of lidocaine hydrochloride. The solutions for intravenous injections or infusions may contain as carrier, for example, sterile water or preferably 10they may be in the form of sterile, aqueous, isotonic saline solutions. The suppositories may contain together with the active compound a pharmaceutically acceptable carrier, e.g. cocoa-butter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid 15ester surfactant or lecithin. The following examples illustrate but do not limit the invention. When the configuration is unspecified, the compounds are meant to be racemic compounds, i.e. racemates.
14.
Example 1
Cyclohexyl 2-(3'-methyl-41-aminophenyl) propionate /-I, R=-CH3.L 1..
=-H, R 3'-CH, R 9 A=,C=O, B=-0-, n=4/.
R, 2= - To a stirred suspension of 2-(31-methyl-41-aminophenyl) propionic acid (8.95 g, 50 mmole) In dry benzene (100 ml) Is added thionyl chloride (30 ml). The resulting mixture is refluxed for 4 hours, cooled and evaporated in vacuo to yield a brown oil.
The acyl chloride so obtained, dissolved in dry benzene (50 ml) is then added dropwise to a stirred solution of cyclohexanol., (5 g, 50 mmole) and triethylamine (35 ml, 250 mmole) in dry benzene (100 ml) at 5-100C. After 3 hrs of additional stirring at room temperature, the reaction mixture is poured into a cold 10% Na 2 CO 3 aqueous solution, the organic phase is separated, washed with water, dried over Na 2 so 4' filtered and concentrated in vacuo. The resulting residue is purified by fractional distillation. There are obtained 7.75 g of the title compound. IR (CHC139 cm- 1): 3460, 3380,3100, 2980, 2940, 2860, 1720, 1620, 1510. In analogous fashion one can prepare the single enantiomers of the above title compound as well as the following compounds both as racemates and as single enantlomers: cyclohexyl 2-(31,51-dimethyl-41- aminophenyl) propionate; cyclohexyl 2-(31-trifluoromethyl-41-aminophenyl) propionate.; and cyclopentyl 2-(31, 51-dimethyl-41-aminophenyl) propionate.
15.
Example 2
N-eyclohexyl-2-(31-methyl-41-aminophenyl) propanamide.LI, R=-CH., R1=-H, R.=31-CH., A= C=O, B=-NH-, n=4/ The acyl chloride, prepared from 1.50 g of 2-(41-aminophenyl) propionic acid and 6 ml of thionyl chloride as reported In the Example 1, is dissolved in dry benzene (15 ml) and added dropwise to a stirred solution of cyclohexylamine (3 g, 30 mmole) in dry benzene (30 ml) at 5-100C. After 3 hrs of additional stirring at room temperature the reaction mixture- is worked up as reported in the Example 1. The crude product is purified by flash column chromatography on silica gel eluting with chloroform: methanol 98:2 and by recrystallisation from benzene: n-hexane 1:1. There are obtained 1.05 g of the title compound.
IR (KBr, cm- 1): 3600-3100, 3040, 3010, 2920, 2840, 1635. In analogous fashion one can prepare the single enatiomers of the above title compound as well as the following compounds both as racemates and as single enantiomers: N-cyclohexyl-2-(21-methyl-41-aminophenyl) propanamide; N-cyclohexyl-2-(21,31-dimethyl-41-aminophenyl) propanamide; N-eyclohexyl2-(21,51-dimethyl-41-aminophenyl) propanamide; N-cyclohexyl-2-(31,51dimethyl-41-aminophenyl) propanamide; N-cyclohexyl-2-(21-61-dimethyl-41aminophenyl) propanamide;N-eyclohexyl-2-(21-trifluoromethyl-41aminophenyl) propanamide N-cyclohexyl-2-(31-trifluoromethyl-41aminophenyl) propanamide.
an( 16.
Example 3
2-(31-methyl-41-aminophenyl)propy1 cyclohexyl ether R=CH 3' Rl=-H, R2=3 'CH., A=-CH -, B=-O-, n=4/ To a stirred suspension of lithium aluminum hydride (2.5 g) in anhydrous tetrahydrofuran (50 ml) is added a mixture of cyclohexyl2- (31-methyl-41-aminophenyl)propionate (3.90 g, 15 mmole), prepared as described in the Example 1, and borontrifluoride etherate (30 ml) in anhydrous tetrahydrofuran (50 ml) dropwise with external cooling. After 3 hrs at 450C, the reaction mixture is carefully decomposed by adding wateF, followed by a 23% hydrochloric acid solution. Most of the organic solvent is evaporated in vacuo, the aqueous solution is brought to pH 9bY adding a concentrated sodium hydroxide solution and extracted with diethyl ether (3 times). The combined extracts are washed with water to neutral, dried over Na 2SO4 and evaporated in vacuo. The resulting residue is purified by column chromatography on silica gel eluting with benzene:ethyl acetate 95:5 and by fractional distillation. There are obtained 2.2 g of the title compound.
IR (CHC1 3' Cm -1): 3440, 3360, 30803020, 2920, 2840, 1610, 1510, 1175, 1130, 1075.
1 7.
Example 4
N-cyclohexyl-2-(31-methyl-41-am.inophenyl)propylamine bis hydrochloride /1, R=-CH =-H, R -CH A=-CHp-, B=-NH-, n=4/.
To a stirred suspension of lithium aluminum hydride (0.4 g) in anhydrous diglyme (10 ml) is added N-cyclohexyl 2-(31methyl-41aminophenyl)propanamide (0.510 g, 2 mmole), prepared as described in the Example 2, dissolved in anhydrous diglyme (5 ml) dropwise and under nitrogen atmosphere.
The reaction mixture is then heated at 85-950C for 6 hrs. After cooling, the excess of lithium aluminum hydride is decomposed by the careful addition of a mixture of methanol, t-butylmethylether and water. The organic phase is separated, washed with water, dried over Na 2 so 4 and filtered.
The filtrate is saturated with anhydrous hydrogen chloride and the resulting precipitate is filtered off and recrystallized from methanol:isopropanol 1:2. There are obtained 0.510 g of the title compound as bis hydrochloride.
IR (KBr, cm- 3100-2300, 2920, 2840, 1610, 1505, 1450, 1375.
18.
Example 5 i-eyclohexyl-3-(31-methyl-41-aminophenyl)-butane R=-CH 3-1. RI=-H, R2 =3'- CH,., A=B=-CH,,-, To a solution of 1-cyclohexyl-3-(31-methyl-41-aminophenyl)-2-butanone(2. 60 g, 10 mmole) In methylene chloride (50 ml) there are added ethanedithiol (2 ml) and boron trifluoride etherate (2 ml). The mixture is stirred at room temperature during 2 hours, then it is washed with water, a 8% NaHCO 3 aqueous solution and water, then dried over CaCl 2' filtered 10 and evaporated in vacuo. The crude thioketal so obtained (3.25 g) is dissolved in anhydrous tetrahydrofuran (30 ml) and stirred in presence of Raney nickel (10 g) (prepared according to Org. Synth., 3, 181) for 2 hours at room tempe rature. The catalyst is filtered off and washed with methylene chloride.
The combined filtrate and washings are evaporated in vacuo to yield a residue which is purified by fractional distillation.
There are obtained 1.45 g of the title compound, IR (CHCl 3' cm- 3440, 3360, 3080, 3020, 2920, 284Q, 1610, 1510.
In analogous fashion one can prepare the single enantiomers of the above title compound as well as the following compounds both as racemates and as single enantiomers:
1-cyclohexyl-3-(31,51-dimethyl-41-aminophenyl)butane, and 1-cyclohexyl-3-(39-trifluoromethyl-41-aminophenyl) butane.
19.
Example 6
LIV, R=CH3. RI=H,,=3 1 -CH A= C=O, B=CH 2 To a stirred solution of cyclohexylmethyl magnesium iodide (prepared from 7.5 g of cyclohexylmethyl Iodide and 0.7 9 of magnesium turnings) In anhydrous diethyl ether (30 ml) cooled at OOC there is added pulverized anhydrous cadmium chloride (2.6 g) in small portions over a period of 45 min. After one hour of additional atirring at room temperature, the resulting solution is cooled at -70OV and treated with the dropwise addition of 2-(31-methyl-41-nitrophenyl)propionyl chloride (prepared from 4.18 g, 20 mmole, of 2-(31-methyl-41-nitrophenyl)-propionic acid and 8.0 ml of thionyl chloride) In anhydrous diethyl ether (10 ml). After one hour of addi- tional stirring, the reaction mixture is carefully decomposed by the dropwise addition of 50 ml of water. The organic phase Is separated, the aqueous phase is extracted with diethylether (3 tin.es), the combined extracts are dried over Na 2 so 4' filtered and concentrated in vacuo. There are obtained 4.5 g of the crude title compound, IR (CHCl., em-I): 1715, 1520, 1350.
In analogous fashion one can prepare the single enantiomers of the above title compound as well as the following compounds both as racemates and as single enantiomers:
1-cyclohexyl-3-(31,51-dimethyl-41-nitrophenyl)-2-butanone; and 1cyclohexyl-3-(31-trifluoromethyl-41-nitrophenyl)-2-butanone.
20.
Example 7
1-cyclohexyl-3-(31-methyl-41-aminoRhenyl)-2-butanone R=-CH R,=-H, R -CH32 A=" 3' 2 3' _,C=O, B=-CH 2-, n=l/ A stirred mixture of 4.0 g of crude 1-cyclohexyl-3-(31-methyl-41- nitrophenyl)-2-butanone and 400 mg of 10% Pd/C catalyst in 75 ml of 95% ethanol is hydrogenated in a Brown-type hydrogenator at room temperature till the uptake of hydrogen ceases. The catalyst is filtered off and the filtrate is evaporated in vacuo.
The resulting residue is purified by fractional distillation. There are obtained 1.22 g of the title compound.
IR (CHC1,, cm- 1): 3460, 3380, 3015, 1710, 1620, 1510.
In analogous fashion one can prepare the single enantiomers of the above title compound as well as the following compounds both as racemates and as single enantiomers: 1-cyclohexyl-3-(31,51dimethyl-41-aminophenyl)-2-butanone; and 1-cyclohexyl-3-(31trifluoromethyl-41-aminophenyl)-2-butanone.
Example 8
Tablets, each weighing 0.150 g and containing 25 mg of the active substance, can be manufactured as follows:
4 21.
Composition (for 10,000 tablets) N-cyclohexyl-2-(31-methyl-41-aminophenyl) propanamide Lactose Corn starch Talc powder Magnesium stearate 250 g 800 g 415 g 30 g 5 g The N-cyclohexyl-2-(31-methyl-41-aminophenyl)propanamide, the lactose and half the corn starch are mixed; the mixture is then forced through a sieve of 0.5 mm mesh size.
Corn starch (10 g) is suspended in warm water (90 ml) and the resulting paste is used to granulate the powder.
The granulate is dried, comminuted on a sieve of 1.4 mm mesh size, then the remaining quantity of starch, talc and magnesium stearate, is added, carefully mixed and processed into tablets.
a 22.
Claims (1)
1) A cycloalkyl-substituted 4-aminophenyl derivative of formula (I) 2 R1 H, 2 (CH 2)n R A-B-<:
(I) wherein R is C 1-C 4 alkyl:
R 1 is C 1-C 4 alkyl unsubstituted or substituted by 1 to 4 halogen atoms and R 2 is, independently, hydrogen or C 1-C 4 alkyl unsubstitutedor substituted by I to 4 halogen atoms; n is an integer of I to 5; A is 'C=o or-CH - and B is, independently,-O-, -NH- or -CH 2 2 and the pharmaceutically acceptable salts thereof.
2) A compound according to claim 1, wherein the cycloalkyl- -substituted 4-aminophenyl derivative is the enantiomer having the formula (Ia) NH H A -in H 2) n A B < (Ia) wherein R, R R, n, A and B are as defined in claim 1. 1' 2 3) A compound according to claim 1 or 2, wherein n is 3 or 4.
23.
A compound, either as single enantiomer or as racemic mixture, selected from the group consisting of:
cyclohexyl 2-(31-methyl-41-aminophenyl) propionate; cyclohexyl 2-(31,51-dimethyl-41-aminophenyl) propionate; N-cyclohexyl-2-(21-methyl-41-aminophenyl) propanimide; N-cyclohexyl-2-(31-methyl-41-aminophenyl) propanamide; N-cyclohexyl-2-(21,31-dimethyl-41-aminophenyl) propanamide; N-cyclohexyl-2-(21,51-dimethyl-41-aminophenyl) propanamide; N-cyclohexyl-2-(31,51-dimethyl-41-aminophenyl) propanamide; N-cyclohexyl-2-(21,61-din.ethyl-41-aminophenyl) propanamide; N-cyclohexyl-2-(21-trifluoromethyl-41-aminophenyl) propanamide; N-cyclohexyl-2-(31-trifluoromethyl-41-aminophenyl) propanamide; 2-(31-methyl-41-aminophenyl) propylcyclohexyl ether; N-cyclohexyl-2-(31-methyl-41-aminophenyl) propylamine; 1-cyclohexyl-3-(31-methyl-41-aminophenyl)-2-butanone; and 1-cyclohexyl-3-(31-methyl-41-aminophenyl) butane; and the pharmaceutically acceptable salts thereof.
5) A salt of a compound of claim 4 wherein the salt is the hydrochloride.
205) A process for the preparation of a compound of formula (1) or a salt thereof, according to claim 1, the process comprising:
(1) reacting a compound of formula (II) NH 2 Ri R 2 H""' COOH R (il) - 1 24.
wherein R, R 1 and R 2 are as defined in claim 1,or a reactive derivative thereof, with a compound of formula (III) (CH 2) n X_<j (III) wherein n is as defined in claim 1 and x is OH or NH 2' so obtaining a compound of formula (1) wherein R, RI9R 2 and n are as defined in claim 1; A is C=0 and B is -Q- or -NH respectively; or reducing a compound of formula (1) wherein R, R,, R 2 and n are as defined in claim 1 and A is %.IC=0 and B is -0-, -NH- or -CH 2-' so obtaining a corresponding compound of formula (I) wherein A is -CH 2- and B is -0-, -NH- or -CH 2-; or (3) reducing a compound of formula (IV) NO 2 TR H. -B- (CH 2) n R < (IV) wherein R, R1p R 2' n, A and B are as defined in claim 1, so obtaining a corresponding compound of formula (I) wherein R, R 1' R2, n, A and B are as defined In claim 1; wid, if desired, salifying the compound of formula (I) or obtaining a free compound of formula (1) from a salt thereof andlor, if desired, separating a mixture of isomers of formula (I) into the single isomers.
k 7. A pharmaceutical composition comprising an inert carrier and/or diluent and, as active substance, a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof.
8. A compound of formula (I) or a salt thereof according to claim 1 for use as an aromatase inhibitor.
9. A compound of formula (I) or salt thereof according to claim 8 for use in the treatment of a hormone dependent tumor or of prostatic hyperplasia.
10. A compound of formula (I) or salt thereof according to claim 8 or 9 in the form of a pharmaceutical composition also comprising an inert carrier and/or diluent.
11. The 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. The use according to claim 11 wherein the pharmaceutical composition is for use in the treatment of a hormone-dependent tumor or prostatic hyperplasia.
13. A compound of formula (I) as defined in claim 1 hereinbefore specified other than a compound claimed in claim 4.
14. A process for the preparation of a compound of formula (I) as defined in claim 1 or a pharmaceutically 1 acceptable salt thereof, said process being substantially as hereinbefore described in any one of Examples 1 to 5 and 7 15. A pharmaceutical composition substantially as hereinbefore described in Example 8.
16. A compound having the formula (IV) reported in claim 6.
Published 1990 a&Th@P&t4ntOMC.StB1e Houm.601"? I!r4h HOIbLirn. London WCIR4TP. Purtharr-opies mVbo obtuned from Th.PwArkt CMes. S&LU branch. St M227 Cr&Y- OrPLMOOZI. K2nt 1395 3RD. Printed by Muluplex toobniques W4 St Mary Cray. Kenu Con, 1:87
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8821137A GB2222589B (en) | 1988-09-09 | 1988-09-09 | Cycloalkyl-substituted 4-aminophenyl derivatives and process for their preparation |
| IT8921600A IT1231933B (en) | 1988-09-09 | 1989-09-04 | DERIVATIVES 4 AMINOPHENYL CYCLALALKYL SUBSTITUTED AND PROCESS FOR THEIR PREPARATION. |
| JP1231336A JPH02121954A (en) | 1988-09-09 | 1989-09-06 | Cycloalkyl-substituted 4- aminophenyl derivative and its production |
| DE3929631A DE3929631A1 (en) | 1988-09-09 | 1989-09-06 | CYCLOALKYL-SUBSTITUTED 4-AMINOPHENYL DERIVATIVES AND METHOD FOR THE PRODUCTION THEREOF |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8821137A GB2222589B (en) | 1988-09-09 | 1988-09-09 | Cycloalkyl-substituted 4-aminophenyl derivatives and process for their preparation |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| GB8821137D0 GB8821137D0 (en) | 1988-10-12 |
| GB2222589A true GB2222589A (en) | 1990-03-14 |
| GB2222589B GB2222589B (en) | 1991-03-06 |
Family
ID=10643296
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB8821137A Expired - Fee Related GB2222589B (en) | 1988-09-09 | 1988-09-09 | Cycloalkyl-substituted 4-aminophenyl derivatives and process for their preparation |
Country Status (4)
| Country | Link |
|---|---|
| JP (1) | JPH02121954A (en) |
| DE (1) | DE3929631A1 (en) |
| GB (1) | GB2222589B (en) |
| IT (1) | IT1231933B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5583128A (en) * | 1991-04-24 | 1996-12-10 | Ciba-Geigy Corporation | Contraception in female primates without affecting the menstrual cycle |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TR28930A (en) * | 1992-05-07 | 1997-07-21 | Zeneca Ltd | Nitrotoluene derivatives with alkyl substituents |
| GB9209872D0 (en) * | 1992-05-07 | 1992-06-24 | Ici Plc | Alkyl substituted nitrotoluene derivatives |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0215601A2 (en) * | 1985-09-06 | 1987-03-25 | FARMITALIA CARLO ERBA S.r.l. | Cycloalkyl-substituted 4-aminophenyl derivatives and processfor their preparation |
-
1988
- 1988-09-09 GB GB8821137A patent/GB2222589B/en not_active Expired - Fee Related
-
1989
- 1989-09-04 IT IT8921600A patent/IT1231933B/en active
- 1989-09-06 DE DE3929631A patent/DE3929631A1/en not_active Withdrawn
- 1989-09-06 JP JP1231336A patent/JPH02121954A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0215601A2 (en) * | 1985-09-06 | 1987-03-25 | FARMITALIA CARLO ERBA S.r.l. | Cycloalkyl-substituted 4-aminophenyl derivatives and processfor their preparation |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5583128A (en) * | 1991-04-24 | 1996-12-10 | Ciba-Geigy Corporation | Contraception in female primates without affecting the menstrual cycle |
Also Published As
| Publication number | Publication date |
|---|---|
| GB2222589B (en) | 1991-03-06 |
| IT8921600A0 (en) | 1989-09-04 |
| JPH02121954A (en) | 1990-05-09 |
| IT1231933B (en) | 1992-01-15 |
| DE3929631A1 (en) | 1990-03-22 |
| GB8821137D0 (en) | 1988-10-12 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PCNP | Patent ceased through non-payment of renewal fee |
Effective date: 19920909 |