FR2607810A1 - NOVEL AZOLIC DERIVATIVES, THEIR PREPARATION AND THEIR USE AS MEDICAMENTS - Google Patents

Abstract

AZOLIC DERIVATIVES INHIBITORS OF AROMATASE OF FORMULA I (CF DRAWING IN BOPI) IN WHICH R AND R ARE THE SAME OR DIFFERENT AND EACH REPRESENTS A REMAINING UNSUBSTITUTED ARYL OR HETEROARYL, MONO- OR POLYSUBSTITUTE, R ALKKYL, ALKYL, R REPRESENT ONE , NON-SUBSTITUTED, MONO- OR POLYSUBSTITUTED HETEROARYL, A REMAINING CYCLOALKYL, ARYL OR HETEROARYLE CONDENSED WITH A BENZENIC CYCLE OR AN ALCOXY AND X GROUP REPRESENTS CH OR N, AND, IN CASE OR R REPRESENTS A METHYL AND R AND R AND ALL BOTH REPRESENT ONE PHENYL REMAINDER, AT LEAST ONE OF THESE PHENYL REMNANTS SHOULD BE SUBSTITUTED.

Description

The invention relates to novel azole derivatives,

  their preparation, pharmaceutical preparations

as well as their use.

  The invention relates in particular to azole derivatives of formula I!

R1-.CH. $ H [C0_R3 I

R2

  wherein R1 and R2 are the same or different and

  each has an unsubstituted, mono- or polysubstituted aryl or heteroaryl radical, R represents an unsubstituted, mono- or polysubstituted alkyl, cycloalkyl, aryl, heteroaryl radical, a radical

  cycloalkyl, aryl or heteroaryl condensed with a benign cycle

  zene or an alkoxy group and X represents CH or N, in other cases, if R3 represents a methyl and R1 and R2 both represent a phenyl residue, at least one of these phenyl residues will have to

  be substituted, as well as their acid addition salts.

  In the formula above, Ri, R2 and R3 as

  In particular, aryl radicals represent a phenyl

  as heteroaryl residues, preferably 5 or 6-membered, and as hetero atoms one or more

  sulfur or nitrogen. The non-condensed heteroaryl radicals

  for example, the thienyl or pyridine residue, the condensed heteroaryl residue represents, for example, the remainder

indolyl-2 or indolyl-3.

  As substituents for R1 and R2, it is especially

  halogen atoms, for example F or Cl. A mono-

  substitution is preferable, especially in

  Substituents for the radical R 3 as the aryl or heteroaryl radical are for example a halogen, the nitro group, the cyano group, a lower alkyl group, alkenyl

  lower, lower alkinyl, lower alkylthio, alkyl-

  lower sulfinyl, lower alkylsulfonyl or lower alkoxy

  optionally mono- or polysubstituted by halogen or phenyl or phenyl or optionally phenoxy

  substituted. As substituents, halo atoms are preferred.

gene, for example F or C1 and CN.

  R 3 as a cycloalkyl residue, possibly

  benzene is preferably 5 to 7 carbon atoms.

  C and is preferably unsubstituted.

  R3 as alkyl radical preferably has 1 to 4 C atoms and may be substituted, for example by CN, alkoxy, benzyloxy or by alkoxy- (mono, di or tri) ethyleneoxy. R3 as the alkoxy group preferably has 1 to 4 C atoms.

  In the case where the R3 radicals are substituted, a mono-

substitution is preferable.

  The lower alkyl groups present as substitutes

  substances contained in the substituents possess advantageously

  1 to 4 carbon atoms, the alkenyl and alkali groups

  lower nyls have up to 4 carbon atoms.

  In formula I above, the following meanings

  symbols, alone or in combination, are preferred: R 1 and R 2 are P-F- or in particular P-Cl-phenyl X is CH R 3 has the aforementioned preferred meanings

  and is especially D-F-, P-C1- or p-CN-phenyl.

  According to the invention, the compounds of formula I are acylated according to methods known per se, compounds of formula I2 il -I

R! -C C2S2

  wherein X, R 1 and R 2 have the meaning hereinabove

  sus, with a carboxylic acid R3COOH or a reactive derivative thereof. The process according to the invention can be carried out for example by reaction of a compound of formula II with a halogenated

  appropriate acid genide in an inert solvent in the

  reaction conditions, for example in an organic or inorganic base which acts at the same time as an acid scavenger,

  pyridine, possibly with the addition of an accelerating

  acylation factor, such as 4-dimethylaminopyridine. For

  acylation, it is also possible to react a compound of

  mule II with an active ester of R3COOH acid. For example, the reaction can be carried out at room temperature with a pyridyl-2-thiol ester in an inert solvent in

  reaction conditions, e.g. in a dialkyl

  carboxamide such as dimethylformamide. In addition, the compounds of formula II can be reacted with R 3 COOH.

  presence of N-hydroxybenzotriazole and dicyclohexylcarbonyl

  diimide. The final product can be isolated from the reaction mixture

  according to methods known per se and possibly be purified. The starting materials of formula II are in part new and can be obtained for example according to the following reaction scheme: R -CO-CH 3 + Ni 2 OH.HCl-R 1-C-CH 3 + 2 R 2 MgHal NOH R 1 R

R2 R / Y1 <SI

  The remaining starting materials as well as the acylating agents are known or can be prepared according to

  known methods or as described in the examples.

  In the examples that follow, all the indications

  are in degrees Celsius and are not correct.

rigées.

  Example 1 2,2-bis (4-chlorophenyl) -2- (1H-imidazol-1-yl) -1

(4-chlorobenzoyl-amino) ethane

  0.34 ml of 4-chlorobenzoyl chloride are added

  dropwise, with ice-cooling, to 670 mg of 2,2-bis- (4-chlorophenyl) -2- (1H-imidazol-1-yl) -1-aminoethane in 4 ml of dry pyridine. The mixture is stirred for 4 hours at room temperature. It is poured onto a cold saturated sodium hydrogencarbonate solution and extracted with ethyl acetate. The combined organic phases are washed with: a solution of saturated sodium hydrogen carbonate and a solution of sodium chloride,

  dried over magnesium sulphate and concentrated by evaporation

  tion. The residue crystallizes by digestion with ethyl acetate and diethyl ether. Colorless crystals,

pt.F: 241-244.

  2,2-bis- (4-chlorophenyl) -2- (1H-imidazol-1-yl) -

  1-aminoethane used as starting material may be

  prepared as follows: (a) 2,2-bis (4-chlorophenyl) aziridine

  A Grignard solution from 8.45 g of

  gnesium and 36 ml of bromobenzene in 200 ml of absolute ether

  300 ml of dry toluene are added to the solution and the ether is distilled off until an internal temperature of 107 is reached. 28.8 g of p-chloroacetophenone oxime in ml of dried toluene are now added dropwise to the boiling solution, the mixture is heated to reflux.

  for 1 1/2 hours and then added, with cooling

  with ice, 300 ml of a 20% ammonium chloride solution. After the phase separation, the aqueous phase is extracted with ether. The combined organic phases are washed with a saturated sodium chloride solution, dried over magnesium sulphate and concentrated by evaporation. The oily residue is gel chromatographed

  of silica (0.040 to 0.063 mm) with petroleum ether 60-

    and a diethyl ether / petroleum ether mixture (3/2).

  The oil thus obtained is characterized by the NMR spectrum.

  1H-NMR (CDCl3): 2.36 (2H, s, broad, -CH2); 7.20-7.55 (8H, m,

3 2 '

  aromat.). b) 2,2-Bis- (4-chlorophenyl) -2- (1H-imidazol-1-yl) -1-aminoethane 3.96 g of 2,2-bis (4-chlorophenyl) aziridine are heated for 20 minutes. 95 hours (melt) with 5.1 g of imidazole. It is taken up with ethyl acetate / water and extracted

  several times the aqueous phase with ethyl acetate.

  The organic phases are washed with a solution of 0.25% tartaric acid and with a saturated solution of sodium chloride, dried over magnesium sulphate and concentrated by

  evaporation. The residue which also contains, beside the

  of the desired title, the 1,1-bis- (4-chlorophenyl) -2- (1H-imidazol-1-yl) -1-aminoethane isomer is separated on a gel of

  silica (0.040-0.063 mm) with the dichloromethane / methyl mixture

  thanol / petroleum ether (20/1/5). A yellow oil is obtained

viscous brown.

  1H-NMR (CDCl3): 1.40 (2H, broad, -NH2); 2.90 (2H, s, -CH 2, 6.9-7.5, 6H, m, aromat, imidazole); 7.68 (1H, imidazole) As described in Example 1, the following compounds of formula I can also be obtained from the corresponding starting materials:

lexe X R [R 3PFe-

_, _

Plex__ R_ l R3 PF @ C

2 C H 6H5 6H5 - -C 193-197

3 N - C.Cl -c -162

4 CH - "- -" H 178-18.

CH - "- -C (CH) 3 131-136A

  6 CH - "- -" - - / - / - / -Ci 220.2240

\\ $ '' \ /, '

  Exe, X R 1 R 2 R 3 Amine CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 amorphine Racmat) H He CH 14g2325

12 CH - "- GN 233-235

  13 CH - "- -" - CH2 (O-CH2-CHZ) OCH3 Oil

14 CH "- CH2-CN 219-220

"CHt 218-221

16 CH - "- 229.'232

l7 lC - CH

17 CH - "- -" - CH 181-183

  The compounds of formula I and the salts of

  of pharmaceutically acceptable acids of these compounds

  present, in animal experimentation, interesting

  pharmacodynamic properties. They can therefore be used

  as medicines. The compounds of formula I according to the invention and their salts have in particular an aromatase inhibiting action. This inhibition of aromatase can be demonstrated, for example, in the following tests: 1. In vitro aromatase inhibition Human placenta microsomes serve as an enzyme source. For the preparation of these microsomes, whole human placentas are, immediately after delivery, brought cooled to the laboratory, rid of excess sana Dar a

  rinsing with sazch r-su [, 25 ", ds cs in rr-

  and then homogenized under refrigeration (1 g of

  + 1.5 g of KCl / tris buffer, pH 7.4; Ultraturrax 3 x 10 sec / 0 C). After sedimentation of partially broken cells, nuclei and mitochondria at 200, 7000 and 11000 g for 10 minutes each time, recovery of the fraction

  microsomal is carried out by centrifugation of the postmito-

  chondrial at 105,000 g / 60 min. The pellet once washed is then suspended in KCl / tris isotonic buffer until

  a concentration of Cyt P-450 of 0.5 μM.

  The determination of the aromatase activity is carried out

  according to a modified known method (Thompson E.A., Siiteri P.K.

  1974, J. Biol. Chem. 249, 5364-5372) by using lfp, 2e,

  3H-androstenedione as substrate, in the presence of a

  NADPH generator. The compounds to be examined are added to

  concentrations of 0.01 and 1 PM. After 30 minutes of incubation

  at 37 ° C, the reaction is terminated by mixing with a fat

  excess of chloroform and separates the aqueous and organic phases.

  The radioactivity of the aqueous phase is attributed to 3H20 which

  is formed during the aromatization of e (, 2 / 3H-andros-

  tedenedione to estrone and serves as a measure of enzyme activity

  matic. Compounds that inhibit aromatase significantly

  ficative under these test conditions are then evaluated in a wider range of concentration for the purpose of determining

  IC50 values (IE = inhibition concentration).

  For the compound of Example 1, it was found

  in this test an IC50 of 4.2 nM (for the substance of com-

  parison, aminoglutethimide, the IC50 is 700 nM).

  2. Inhibition of ovulation Female rats with a regular cycle receive the substance to be tested at around 16 hours the day before.

  ovulation and around 11 o'clock on the day of ovulation

  tion. Ovulation is determined by counting the eggs in the vaginal smear. ID50 (ID = inhibition dose

  oral for the compound of Example 1 is 0.15 mg / kg.

  For the substances of comparison, amide-dimethyl and 4-hydroxyandrostenedicine, the sweeteners are,

  in this test, values above 10 g / kg.

  3. Influence on ovarian aromatase and on in vivo E production Adult female rats are pretreated during

  12 days with 25 IU / day PMSG (pregnant mare serum gonado-

  trophin) subcutaneously and on the 13th day the test substance is administered orally at a concentration of 0.032 to 10 mg / kg. Spleens are sacrificed 8, 24 and 48 hours later, after which blood and ovaries are removed. Microsomes are prepared from an ovary of each animal and their aromatase activity is determined as described above. Estradiol is extracted from the second ovary and quantified quantitatively by RIA; the same is true of estradiol

from the blood.

  In this test, the ID50 of the compound of Example 1 for the inhibition of aromatase in the ovary was

  below 0.032 mg / kg after 24 hours (for aminoglycoside

tethimide> 5.6 mg).

  4. Subchronic effects in vivo The test substance is administered for 7 days,

  once a day to young 23-day-old female rats.

  From the 4th to the 7th day, testosterone propionate is

  additionally injected subcutaneously. On the 8th day, the animals are sacrificed, the blood is collected and the uteri

  are removed, cleaned and weighed. Tester administrations

  sterone causes a marked increase in the weights of

  rus, related to the conversion of testosterone to estradiol

  under the effect of aromatase. As a result, the inhibition of

  Pertrophy of the uterus with a test substance is a

  sure about the inhibition of estrogen production

  by aromatase during the seven-day treatment.

  In this test, the ID50 for the compound of Example 1

amounted to 0.4 mg / kg / day p.o.

  5. Chronic Effects Estrogen-dependent breast tumors are caused in rats by a single oral administration

  7,12-dimethylbenz [a] anthracene (DMBA). Once the

  On average, they reach a size of about 1500 mm, the treatment with the test substance is started and

continue until 6 weeks.

  The compound of Example 1 clearly inhibits the growth

  tumor level at 1 mg and 10 mg / kg p.o. per day. The subs-

  comparison, aminoglutethimide, is ineffective

even at 100 mg / kg daily.

  Aromatase plays a predominant role in the bio-

  estrogen synthesis in mammals. The blocking of this enzyme by specific inhibitors can induce a strong lowering of the normal rate of steroids. Such a non-sterile chemical lowering of steroid levels occurs, in the face of the surgical removal of hormone producing organs.

  (prostate, ovaries, adrenal glands), as an alterna-

  desirable and a complement for the treatment of

  steroid-dependent diseases, eg prostate, polycystic ovary syndrome, breast carcinoma,

  ovaries, endometrium, as well as Cushing's disease.

  The compounds of formula I can therefore be used as appropriate specific inhibitors of steroid synthesis when treating many of the

evoked tumors.

  For the above applications, the dose to be employed

  of course depending on the substance used, the method of

  administration and the desired treatment. Satisfactory results

  These compounds are generally obtained with administration of the compounds of formula I at a dose of about 0.15 to 1.5 mg / kg.

body weight alive.

  For larger mammals, the appropriate daily dose is in the range of about 10 to about mg. This daily intake can be carried out in smaller unit doses> 2 to 4 times per day or in the delayed form. As a result, an appropriate unit dose contains

  applications envisaged, alongside diluents or exci-

  pharmaceutically acceptable pharmaceutically acceptable salts, about 2.5 to about mg of the compounds of formula I. The compounds of formula I may be administered as free base or pharmaceutically acceptable acid addition salts, enterally (e.g. orally, in the form of tablets or capsules) or parenterally (eg in the form of

  solutions or suspensions to be injected).

  The invention also relates to pharmaceutical preparations containing a compound of formula I or a

  its pharmaceutically acceptable acid addition salts.

  These preparations, for example a solution or a tablet, can be produced according to methods known from

  use of usual adjuvants and excipients.

  The invention further relates to the compounds of

  mule I or their pharmaceutically acid addition salts

  acceptable for use as medicinal products, including

  as an aromatase inhibitor.

he

Claims (10)

  1. Azole Derivatives of Formula I C R C-CH 2 -tH-CO-R 3 2 '3 R2   wherein R1 and R2 are the same or different and   each has an unsubstituted, mono- or polysubstituted aryl or heteroaryl radical, R3 represents an unsubstituted, mono- or polysubstituted alkyl, cycloalkyl, aryl, heteroaryl radical, a radical   cycloalkyl, aryl or heteroaryl condensed with a benign cycle   or X is CH or N, and in case R3 is methyl and R and R both represent 1 2   a phenyl residue, at least one of these phenyl residues will have to   be substituted, as well as their acid addition salts.   2. Azole derivatives of formula I according to claim   cation 1, in which formula R 1 and R 2 are identical   or different and each represents a phenyl radical which may   monosubstituted, R3 represents an alkyl group with 1 to 4 carbon atoms, optionally substituted by CN, a (C1-C4) alkoxy,   benzyloxy or (C1-C4) alkoxy- (mono-, di- or tri-) ethyl-   leneoxy, an alkoxy group with 1 to 4 carbon atoms, an optionally substituted phenyl group, a cycloalkyl group with 5 to 7 carbon atoms, optionally fused with a ring   benzene or a 5- or 6-membered heterocycle, possibly   is condensed with a benzene ring and contains as hetero atoms one or more sulfur or nitrogen atoms,   as well as their acid addition salts.   3. Azole derivatives according to claim 1 or 2, wherein R1 and R2 represent p-C1- or p-F-phenyl,   as well as their acid addition salts.   4. Azole derivatives according to one of the claims   1 to 3, wherein R 3 represents p-F-, p-Cl- or p-CN-phenyl,   as well as their acid addition salts.   5. The compound. 2,2-bis (4-chlorophenyl) -2- (lH-imidazolyl   zol-1-yl) -1- (4-chlorobenzoyl-amino) ethane, and its salts of acid addition.   6. Process for the preparation of the azole derivatives of formula I according to claim 1, characterized in that acyl compounds according to methods known per se are used. R2   in which X, R1 and R2 have the meaning indicated in claim 1, with a carboxylic acid R3COOH   o R3 has the meaning indicated in the claim   1 or with a reactive derivative thereof.   7. Compounds as defined in one of the claims   cations 1 to 5, for use as a medicine.   8. Compounds as defined in one of the   dications 1 to 5, intended for use as inhibitors of aromatase.   9. Use of the compounds according to one of the   1 to 5 for the preparation of aromatase inhibiting drugs.   10. Pharmaceutical preparations containing a compound   Formula 1, as defined in claim 1, or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable adjuvant or excipient for it.