GB2222588A - Cycloalkyl-substituted 4-aminophenyl derivatives and process for their preparation - Google Patents
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Description
1 - FC 406 22',,258'u Title 1ICYCLOALKYL-SUBSTITUTED 4-AMINOPHENYL
DERIVATIVES AND PROCESS FOR THEIR PREPARATION" The present invention relates to cycloalkyl-subst-ituted 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 /Ann. Surg.
187, 475 (1978); Lancet,,R, 646 (1978)/; 4-cyclohexylaniline /Endocrinclogy, L14, 2128 (1984)/, and 4-pyridyl-3-ethyl -2,6-piperidinedione /T. Med. Chem., 28, 200 (1985)7.
1 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, (CH R A-B_", 2 n wherein R is C I- c 4 alkyl; R is (i) a halogen atom; (ii) a group -OR 2 ' wherein R 2 is c 1-C 4 alkyl; or (iii) a group -NR 3 R 4' wherein each of R 3 and R 4, which may be the same or different, is C 1-C 4 alkyl; n Is an integer of 1 to S; A is %C=O or-CH- and B is, independently,-0-, -NHor -CH 2 2 Also the pharmaceutically acceptable salts of the compounds of formula (1) 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,7for example, for each compound of-formula (1) two 3.
is 4 distinct optical isomers, i.e. enantiomers, may exist according to the configuration of the chiral carbon atom carrying the R substituent. The formula (1) 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 (1a) NH 2.
H 2) n H A-B (1a) wherein R, R19 n, A and B are as defined above.
In the above formulae(I) and (Ia) a C i- C 4 alkyl group is, preferably, methyl or ethyl, especially methyl. A halogen atom is,preferably, fluorine, chlorine or bronine, most preferably chlorine or fluorine. Preferred values for n are 3 and 4, in particular 4. Preferred salts are the hydrochlorides. 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:
4.
cyclohexyl 2-(31-chloro-41-aminophenyl)propionate; cycl-)hexyl 2-(21chloro-41-aminophenyl)propionate; cyclohexyl 2-(3'-fluoro-41aminophenyl)propionate; cyclohexyl 2-(21-fluoro-41-aminophenyl)propionate; N-cyclohexyl-2-(31-chloro-41-aminophenyl)propanamide; N-cyclohexyl-2-(21chloro-41-aminophenyl)propanamide; N-cyclohexyl-2-(31-fluoro-41aminophenyl)propanamide; -luoro-41-aminophenyl)propanamide; N-cyclohexyl-2-(21--L 1-cyclohexyl-3-(31-chloro-41-aminophenyl)-2-butanone; 1-cyclohexyl-3-(21-chloro-41-aminophenyl)-2-butanone; 1-cyclohexyl-3-(31fluoro-41-aminophenyl)-2-butanone 1-cyclohexyl-3-(21-fluoro-41aminophenyl)-2-butanone 2-(31-chloro-41-aminophenyl)propylcyclohexyl ether; N-cyclohexyl-2-(31-chloro-41-aminophenyl)propylamine; 1-cyclohexyl3-(31-chloro-41-aminophenyl)butane; N-cyclohexyl-2-(31-methoxy-41aminophenyl)propanamide; N-cyclohexyl-2-(21-methoxy-41aminophenyl)propanamide; 1-cyclohexyl-3-(31-methoxy-41-aminophenyl)-2butanone; 1-cyclohexyl-3-(21-methoxy-41-aminophenyl)-2-butanone; 20 Ncyclohexyl-2-(31-dimethylamino-41-aminophenyl)propanamide; N-cyclohexyl-2(2l-dimethylamino-41-aminophenyl)propanamide; 1-cyclohexyl-3-(31dimethylamino-4l-aminophenyl)-2-butanone;and 1-cyclohexyl-3-(21dimethylamino-41-aminophenyl)-2-butanone, and the pharmaceutically acceptable salts thereof especially 25 the hydrochlorides.
1 5.
The compounds of formula (I) may be prepared by a process comprising (1) reacting a compound of formula (II) NH 2 R1 H _ COOH R is (II) wherein R and R 1 are as defined above, or a reactive derivative thereof, with a compound of formula (III) X_<_li (CH) n (III) wherein n is as defined above and X is OH or NH 2' so obtaining a compound of formula (I) wherein R, R 1 and 1.
n are as defined above, A is ' C=0 and B is -0- or -NH- respectively; or (2) reducing a compound of formula (I) wherein R, R 1 and n are as defined above and A is -C-0 and B is -0-, -NH- or -CH J' so obtaining a corresponding compound of formula (I) wherein A is -CH 2- and B is -0-, -NH- or -CH 2-; or 6.
(3) reducing a compound of formula (IV) NO 2 -- R 1 H -B (CH 2)n R <j (IV) wherein R, R1.9 n, A and B are as defined above,so obtaining a corresponding compound of formula (I) wherein R, Rly n, A and B are as defined above; andp 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 J) into the single isomers.
The intermediate compounds of the above formulae (II) and (IV) and of the following formula M 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.
a 7.
Preferably the reaction between a compound of formula (II) and a compound of formula (111) 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 1% .0 C=0 and B is -0- or -NH- may be carried out in presence of a reducing agent such as, e.g., LiA1H 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 400C and about 1200C for a reaction time varying approximately in the range of 4-48 hours.
8.
The reduction of a compound of formula (1) wherein A Is C=0 and B Is -CH 2- Is preferably carried out by transforming 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 20'C and about SO0C 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 lOO0C, for a reaction time of about 1-3 hours.
Optionally, the carbonyl group in the compound of formula (1) may be transformed Into the corresponding 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 409C 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_ 9.
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 1006C 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. The optional salification of a compound of formula (I) 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 diasteroisor6eric 10.
salts which are separated by means of, e.g., fractional crystallization or chromatography. From each separated diastereoisomeric salt; the single enantiomer of formula (1) may be then recovered in a conventional way.
The compounds of fQrmula (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 "'C=O and B is -0- or -NH- can be prepared reacting a compound of formula (V) NO 2 I H... COOH R (V) wherein R, and R I are as defined above or, preferably, a reactive 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 (II) and a compound of formula (III).
z 0 1 0 11.
A compound of formula (IV) wherein A Is C=0 and B is -CH 2- may be Preparei, e.g., reacting a compound of formula (V), or a reactive derivative thereof as herein before define'd, with a compound of formula (VI) (C2)n L:;- CH 2 MY (V1) wherein n is as defined above, M is a metal,priferably 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.
By virtue of their ability to inhibit arom atase and, consequently, to f the invention can find e reduce estrogen levels, the compounds c us in the treatment and prevention of various estrogen dependent diseases, e.g. estrogen dependent tLm.rs, for instance breast, endometrial, Ovarian and pancreatic cancers; gynecomastia; benign breast disease; endometriosis; polycystic ovarian disease, and precocious puberty.
Another application of the compounds of the invention is in the therapeutic and/or prophylactic treatment of prostatic hypexrplasia, a disease of the estrogen dependent straaal tissue. The compounds of the invention can be useful also for the treatment of male infer tility associate with oligospernda and for fer,-kale fertility control, 12.
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 aromiatase 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, which method corrprises administering to the patient an effec tive amomt of a coapound 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; pren terally, 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 com positions 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.
13.
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, methyleellulose, carboxymethy1cellulose 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 bep 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 14.
example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethyleellulose, 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 they 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 ester 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.
15.
Example 1 Cyclohexyl 2-(31-chloro-41-aminophenyl)propionate 11, R=-CH R1i= 31-Cl, A= %.-'C=O, B=-0-, n=4].
To a stirred suspension of 2-(31-chloro-41-aminophenyl)pro- pionic acid (2.0 g, 10 mmole) in dry benzene (25 ml) is added thionyl chloride (2.9 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 (20 ml) is then added dropwise to a stirred solution of cyclohexanol (1.0 g, 10 mmole) and triethylamine (7.0 ml, 50 mmole) in dry benzene (50 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.-b.p. 145-70 (0.1-0.05 mm Hg). There are obtained 1.90 g (yield 67%) of the title compound, 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 (CDC1 3' 1.44 (3H,d) 25 3.55 (1HM 3.50 (Mbr) 4.74 (1H,m) 6.70 (1H,d) 7.00 (1H,dd) 7.20 (1H,d) 16.
IR (CHCl., cm -1): 3480, 3380, 2920, 2840, 1715, 1615, 1590, 1495. In analogous fashion one can prepare the single enantiomers of the above title compound as well as the following comas racemates and as single enantiomers: 2-(21-chloro-41-aminophenyl)propionate; 2-(31-fluoro-41aminophenyl)propionate; 2-(21-fluoro-41-aminophenyl)propionate; 2-(31chloro-4-aminophenyl)propionate 2-(21-chloro-4-arr,inophenyl)propionate; 2-(31-fluoro-4-aminophenyl)propionate; and 2-(21-fluoro-4aminophenyl)propionate pounds both cyclohexyl cyclohexyl cyclohexyl cyclopentyl cyclopentyl cyclopentyl cyclopentyl 1 17.
Example 2 N-cyclohexyl-2-(31-chloro-41-aminophenyl)-Propanamide rl, R=CH39 R 31-Cl, A= \C=O, B=-NH-, n=4] The acyl chloride, prepared from 2.0 g Of 2-(31-chloro-41- aminophenyl)proplonic acid and 2.9 ml of thionyl chloride as reported in the Example 1, Is dissolved In dry benzene (20 ml) and added dropwise to a stirred solution of cyclohexylamine (4.0 g, 40 mmole) In dry benzene (50 ml) at 5-100C. After 3 hours of additional stirring at room tempera10 ture the reaction mixture is worked up as reported in the Example 1. The crude product is purified by repeated 0.5 N HCl extraction and Na 2 C0 3 neutralization. There are obtained 1.50 g 53% yield of the title compound, as a glassy product. Elemental analysis (as hydrochloride): calculated % (found %) C 56.78 (56.19) H 6.99 ( 6.98) Cl 22.35 (22.42) N 8.83 (8.73) NMR (DMSO,vr): 1.24 (3H,d) 3.50 (2H,m) 7.08 (2HM 7.28 (1H,br 7.78 (Mbr 5) d) IR (KBr, cm-'): 3300, 3050, 2920, 2940, 3000-1900, 1630, 1600, 1530, 1490.
18.
is In analogous fashion one can prepare the single enantiomers of the above title compound as well as the following com- pounds both as racemates and as single enantiomers:
N-cyclohexyl-2-(21-chloro-41-aminophenyl)propanamide; N-cyclohexyl-2-(31fluoro-41-aminophenyl)propanamide;_ N-cyclohexyl-2-(21-fluoro-41aminophenyl)propanamide; N-cyclopentyl-2-(31-chloro-41-aminophenyl)propanamide; N-cyclopentyl-2(21-chloro-41-aminophenyl)propanamide; N-cyclopentyl-2-(31-fluoro-41aminophenyl)propanamide; N-cyclopentyl-2-(21-fluoro-41aminophenyl)propanamide; N-cyclohexyl-2-(31-chloro-41aminophenyl)butanamide; N-cyclohexyl-2-(21-chloro-41aminophenyl)butanamide; N-cyclohexyl-2-(31-fluoro-41aminophenyl)butanamide; N-cyclohexyl-2-(21-fluoro-41aminophenyl)butanamide; N-cyclohexyl-2-(21-methoxy-41aminophenyl)propanamide; N-cyclohexyl-2-(31-methoxy-41aminophenyl)propanamide; N-cyclopentyl-2-(31-methoxy-41aminophenyl)propanamide; N-cyclopentyl-2-(21-methoxy-41aminophenyl)propanamide; N-cyclohexyl-2-(31-methoxy-41aminophenyl)butanamide; N-cyclohexyl-2-(21-methoxy-41aminophenyl)butanamide; N-cyclohexyl-2-(21-dimethylamino-41aminophenyl)propanamide; N-cyclohexyl-2-(31-dimethylamino-41aminophenyl)propanamide; N-cyclopentyl-2-(31-dimethylamino-41aminophenyl)propanamide N-cyclopentyl-2-(21-dimethylamino-41aminophenyl)propanamide; N-cyclohexyl-2-(31-dimethylamino-41aminophenyl)butanamide;and N-cyclohexyl-2-(21-dimethylamino-41aminophenyl)butanamide.
z 19.
Example 3
2-(31-chlorO-41-aminophenyl)propyi cyclohexyl_ether FI, R=CH39 R 1 =3'-Cl, A=-CH 2-' B=-O-, n='j To a stirred suspension of lithium aluminum hydride (2.5 g) in anhydrous tetrahydrofuran (50 ml) is added a mixture of cyclohexyl 2-(31-chloro-41-aminophenyl)prop i onate (4-21 9, 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 water, 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 2.6 g of the title compound.
IR (CHCl 3' cm 3440, 3360, 3080 3020, 2920, 2840, 1610, 1510, 1175, 1130, 1075.
1 Example 4
20.
N-cyclohexyl-2-(31-chloro-4,-aminophenyl)propylamine bis hydrochloride /I, R=-CH..jR, =31-Cl, A=-CH,,79 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-(31 chloro-41-aminophenyl)propanamide (0.560 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 recrystalliz ed from methanol: isopropanol 1:2. There are obtained 0.605 g of the title compound as bis hydrochloride.
IR (KBr, cm- I): 3100-2300, 2920, 2840, 1610, 1505, 1450, 1375.
21.
Example 5
1-cyclohexyl-3-(31-chloro-41-aminophenyl)-butane /I R,=31-Cl, A=B=-CH 2-' n= R=-CH 3.1.
To a solution of 1-cyclohexyl-3-(31-chloro-41-aminophenyl)-2-butanone(2.79 9, 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 and evaporated in vacuc. The crude thioketal so obtained (3.25 g) i s 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 1.60 g of the title compound, IR (CHCl., Cm- 3440, 3360, 3080, 3020, 2920, 2840, 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-(21-chloro-41-aminophenyl)butane; 1-cyclohexyl-3-(31-fluoro-41-aminophenyl)butane; and 1-cyclohexyl-3-(21-fluoro-41-aminophenyl)butane.
22.
Example 6
1-cyclohexyl-3-(31-chloro-41-nitrophenyl)-2-butanone /'V' R=CH32-31. = 3'-Cl, A= "C=O, B=-CH 2-' n=4 To a stirred solution of cyclohexylmethyl magnesium Iodide (prepared from 7.5 g of cyclohexylmethyl iodide and 0.7 g 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-chloro-41-nitrophenyl)propionyl chloride (prepared from 4.60g, 20 mmole, of 2-(3'-chloro 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 times), the combined extracts are dried over Na 2 so 4' filtered and concentrated in vacuo. There are obtained 4.7 g of the crude title compound, IR (CHCl 3' em -1: 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-(21-chloro-41-nitrophenyl)-2-butanone; 1-cyc lohexyl-3- (3 1 -f luoro-4 1 -nitrophenyl) -2-butanone; 23.
1-cyclohex1-3-(21-fluoro-41-nitrophenyl)-2-butanone; 1-cyclopentyl-3-(31-chloro-41-nitrophenyl)-2-butanone; 1-cyclopentyl-3(21-chloro-41-nitrophenyl)-2-butanone 1-eyclopentyl-3-(31-fluoro-41-nitrophenyl)-2-butanone; 1-cyclopentyl-3(21-fluoro-41-nitrophenyl)-2-butanone; 1-cyclohexyl-3-(31-chloro-41nitrophenyl)-2-pentanone; 1-cyclohexyl-3-(21-chloro-41-nitrophenyl)-2pentanone; 1-cyclohexyl-3-(31-fluoro-41-nitrophenyl)-2-pentanone; 1eyclohexyl-3-(21-fluoro-41-nitrophenyl)-2-pentanone; 1-cyclohexyl-3-(21methoxy-41-nitrophenyl)-2-butanone; 1-cyclohexyl-3-(31-methoxy-41nitrophenyl)-2-butanone; 1-cyclopentyl-3-(31-methoxy-41-nitrophenyl)-2butanone; 1-cyclopentyl-3-(21-methoxy-41-nitrophenyl)-2-butanone; 1cyclohexyl-3-(31-methoxy-41-nitrophenyl)-2-pentanone; 1-cyclohexyl-3-(21methoxy-41-nitrophenyl)-2-pentanone; 1-cyclohexyl-3-(21-dimethylamino-41nitrophenyl)-2-butanone; 1-cyclohexyl-3-(3l-dimethylamino-41-nitrophenyl)2-butanone; 1-cyclopentyl-3-(31-dimethylamino-41-nitrophenyl)-2-butanone; 1-cyclopentyl-3-(21-dimethylamino-41-nitrophenyl)-2-butanone; 1cyclohexyl-3-(31-dimethylamino-41-nitrophenyl)-2-penta- none; and 1-cyclohexyl-3-(21-dimethylamino-41-nitrophenyl)-2-pentanone.
24.
Example 7
1-cyclohexyl3-(31-chloro-41-aminophenyl)-2-butanone R=-CH R=3'-Cl, A= C=O, B=-CH n=4] 3' 2-' is A stirred mixture of 4.4 g of crude 1-cyclohexyl-3-(3'- -chloro-41-nitrophenyl)-2-butanone and 400 mg of 10%.Pd/C catalyst in 75 ml of 95% ethanol and 15 ml of 1N HC1 aqueous solution 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 1.31 g of the title compound. IR (CHCI;,, 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-(21-chloro-41-aminophenyl)-2-butanone; 1-cyclohexyl-3-(31fluoro-41-aminophenyl)-2-butanone; 1-cyclohexyl-3-(21-fluoro-41aminophenyl)-2-butanone; 1-cyclopentyl-3-(31-chloro-41-aminophenyl)-2butanone; 1-cyclopentyl-3-(21-chloro-41-aminophenyl)-2-butanone; 1cyclopentyl-3-(31-fluoro-41-aminophenyl)-2-butanone; 1-cyclopentyl-3-(21fluoro-41-aminophenyl)-2-butanone; 1-cyclohexyl-3-(31-chloro-41aminophenyl)-2-pentanone; 1-cyclohexyl-3-(21-chloro-41-aminophenyl)-2pentanone; 1-cyclohexyl-3-(31-fluoro-41-aminophenyl)-2-pentanone 1-cyclohexyl-3-(21-fluoro-41-aminophenyl)-2-pentanone 1-cyclohexyl-3-(21methoxy-41-aminophenyl)-2-butanone 1-cyclohexyl-3-(31-methoxy-41aminophenyl)-2-butanoiie; 25.
I-Cyclopentyl-3-(31-methoxy-4'-aminophenyl)-2-butanone; 1-cyclopentyl-3(21-methoxy-41-aminophenyl)-2-butanone; 1-cyclohexyl-3-(31-methoxy-41aminophenyl)-2-pentanone; 1-cyclohexyl-3-(21-methoxy-41-aminophenyl)-2pentanone; 1-cyclohexyl-3-(21-dimethylamino-41-aminophenyl)-2-butanone; 1-cyclohexyl-3-(31-dimethylamino-41-aminophenyl)-2-butanone; 1-cyclopentyl-3-(31-dimethylamino-41-aminophenyl)-2-butanone; 1-cyclopentyl-3-(21-dimethylamino-41-aminophenyl)-2-butanone; 1-cyclohexyl-3-(31-dimethylamino-41-aminophenyl)-2-pentanone;anr-1 1cyclohexyl-3-(21-dimethylamino-41-aminophenyl)-2-pentanone.
Example 8
Tablets, each weighing 0.150 g and containing 25 mg of th active substance, can be manufactured as follows:
Composition (for 10,000 tablets) N-cyclohexyl-2-(31-chloro-41-aminophenyl)pro- panamide 250 g Lactose 800 g Corn starch 415 g Talc powder 30 g Magnesium stearate 5 g The N-cyclohexyl-2-(31-chloro-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, tale and magnesium stearate, is added, carefully mixed and processed Into tablets.
26.
Claims (16)
1) A cycloalkyl-substituted 4-aminophenyl derivative of formula (I) H 2 1 R1 JA-IB (CH 2) n R < (1) wherein R is C I-C 4 alkyl; R, is (i) a halogen atom; (ii) a group -OR 2 ' wherein R 2 is C 1 -C 4 alkyl; or (iii) a group -NR 3 R 4, wherein each of R 3 and R 4, which may be the same or different, is C 1-C 4 alkyl; n is an integer of 1 to 5; A is 'C=0 or-CH 2 - and B is, independently,-0-, -NH- or -CH 2 and the pharmaceutically acceptable salts thereof.
2) A compound according to claim 1, wherein the cycloalkyl-substituted 4aminophenyl derivative is the enantiomer having the formula (1a) NH 2 1 H 2) n A A-B-< (Ia) wherein R, R, 9 n, A and B are as defined in claim 1.
27.
4 1 1 i 1 N 3) A compound according to claim 1 or 2, wherein n is
3 or 4.
4) A compound, either as single enantiomer or as racemic mixture, selected from the group consisting of:
cyclohexyl 2-(31-chloro-41-aminophenyl)propionate; cyclohexyl 2-(21chloro-41-aminophenyl)propionate; cyclohexyl 2-(31-fluoro-41aminophenyl)propionate; cyclohexyl 2-(21-fluoro-41-aminophenyl)propionate; N-cyclohexyl-2-(31-chloro-41-aminophenyl)propanamide; N-cyclohexyl-2-(21chlorc-41-aminophenyl)propanamide; N-cyclohexyl-2-(31-fluoro-41aminophenyl)propanamide; N-cyclohexyl-2-(21-fluoro-41aminophenyl)propanamide; 1-cyclohexyl-3-(31-chloro-41-aminophenyl)-2butanone; 1-cyclohexyl-3-(21-chloro-41-aminophenyl)-2-butanone; 1cyclohexyl-3-(31-fluoro-41-aminophenyl)-2-butanone; 1-cyclohexyl-3-(21fluoro-41-aminophenyl)-2-butanone; 2-(31-chloro-41aminophenyl)propylcyclohexy1 ether; N-cyclohexyl-2-(31-chloro-41-aminophenyl)propylamine; 1-cyclohexyl-3-(31chloro-41-aminophenyl)butane; N-cyclohexyl-2-(31-methoxy-41-aminophenyl)propanamide; N-cyclohexyl-2-(21-methoxy-41-aminophenyl)propanamide; 1-cyclohexyl-3-(31methoxy-41-aminophenyl)-2-butanone; 1-cyclohexyl-3-(21-methoxy-41aminophenyl)-2-butanone; N-cyclohexyl-2-(31-dimethylamino-41-aminophenyl)propanamide; N-cyclohexyl-2-(2l-dimethylamino-41-aminophenyl)propanamide; 1-cyclohexyl3-(31-dimethylamino-4l-aminophenyl)-2-butanone;and 1-cyclohexyl-3-(21dimethylamino-41-aminophenyl)-2-butanone, and the pharmaceutically acceptable salts thereof..
28. - 5) A salt of a compound of claim 4 wherein the salt is the hydrochloride.
6) P. 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 (jj) NH 2 R, W- COOH R (I1) laim 1 wherein R and R 1 are as defined in oe a reactive derivative thereof, with a compound of formula (III) X, I(H 2) n ---e (III) claim 1 wherein n is as defined in/ and X is OH or NH 2' so obtaining a compound of formula (I) wherein R, R 1 and claim 1; n are as defined in/ A is C=0 and B is -0- or -NH- respectively; or (2) reducing a compound of formula (I) wherein R, R 1 and n are as defined in claim 1 and A is C-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.-; or 1 1 (3) reducing a compound of formula (iv) NO 2 -'R 1 'R H _B_< ( HA R (IV) wherein R, Rl, n, A and B are as defined in claim 1, so obtaining a corresponding compound of foxmula (I) wherein R, Rl, n, A and B are as defined in claim 1; 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 mixturie of isomers of formula (I) into the single isomers.
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 (1) or a salt thereof according to claim 1 for use as an aromatase inhibitor.
9. A compound of formula (2) 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 (1) or salt thereof according to claim 8 or 9 in the form Df a pharmaceu tical composition also comprising an inert cairier and/or diluent.
- 30
11. The use of a compound of formula M 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 acceptable salt thereof, said process being substantially as hereinbefore described in any one of Examples 1 to 5 and
15. A pharmaceutical composition substantially as hereinbefore described in Example 8.
16. A compound having the formula (IV) reported in claim 6.
Publiabed 1990 at The Patent OMce, State House. 80,7 t High Holburn. London WC1R 4TP Further copies maybe obtamed fmzn The Pstant Offtes. Sales Branch. St Mary Cray. Orpington. Xsn't 131.0.5 3RD. Printed by Multiplox techniques itil. St Mary Cray. K#nt. Com 1.87 1
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8821136A GB2222588B (en) | 1988-09-09 | 1988-09-09 | Cycloalkyl-substituted 4-aminophenyl derivatives and process for their preparation |
| IT8921601A IT1232309B (en) | 1988-09-09 | 1989-09-04 | CYCLOALKYL-SUBSTITUTED 4-AMINOPHENYL DERIVATIVES AND PROCESS FOR THEIR PREPARATION |
| JP1231335A JPH02121953A (en) | 1988-09-09 | 1989-09-06 | Cycloalkyl-substituted 4- aminophenyl derivative and its production |
| DE3929660A DE3929660A1 (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 |
|---|---|---|---|
| GB8821136A GB2222588B (en) | 1988-09-09 | 1988-09-09 | Cycloalkyl-substituted 4-aminophenyl derivatives and process for their preparation |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| GB8821136D0 GB8821136D0 (en) | 1988-10-12 |
| GB2222588A true GB2222588A (en) | 1990-03-14 |
| GB2222588B GB2222588B (en) | 1991-03-06 |
Family
ID=10643295
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB8821136A Expired - Fee Related GB2222588B (en) | 1988-09-09 | 1988-09-09 | Cycloalkyl-substituted 4-aminophenyl derivatives and process for their preparation |
Country Status (4)
| Country | Link |
|---|---|
| JP (1) | JPH02121953A (en) |
| DE (1) | DE3929660A1 (en) |
| GB (1) | GB2222588B (en) |
| IT (1) | IT1232309B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MX2007007133A (en) * | 2004-12-15 | 2007-08-08 | Dompe Pha R Ma Spa Res & Mfg | 2-arylpropionic acid derivatives and pharmaceutical compositions containing them. |
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 GB8821136A patent/GB2222588B/en not_active Expired - Fee Related
-
1989
- 1989-09-04 IT IT8921601A patent/IT1232309B/en active
- 1989-09-06 JP JP1231335A patent/JPH02121953A/en active Pending
- 1989-09-06 DE DE3929660A patent/DE3929660A1/en not_active Withdrawn
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 |
Also Published As
| Publication number | Publication date |
|---|---|
| IT1232309B (en) | 1992-01-28 |
| IT8921601A0 (en) | 1989-09-04 |
| JPH02121953A (en) | 1990-05-09 |
| DE3929660A1 (en) | 1990-03-15 |
| GB2222588B (en) | 1991-03-06 |
| GB8821136D0 (en) | 1988-10-12 |
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Legal Events
| Date | Code | Title | Description |
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| PCNP | Patent ceased through non-payment of renewal fee |
Effective date: 19920909 |