NZ222765A

NZ222765A - Azole derivatives and pharmaceutical compositions

Info

Publication number: NZ222765A
Application number: NZ222765A
Authority: NZ
Inventors: Helmut Egger; Rudolf Walchli
Original assignee: Sandoz Ltd
Priority date: 1986-12-03
Filing date: 1987-12-01
Publication date: 1990-11-27
Also published as: PT86255A; DK631287A; AU605522B2; IT1211944B; GB8727978D0; PL151588B1; IL84665A0; PL269180A1; HUT45506A; MY103004A; IL84665A; ES2010235A6; AU8196287A; BE1001235A4; FR2607810B1; HU198694B; CH677925A5; ATA316887A; GB2199579B; FR2607810A1

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £22765 nc srjmm Priority Oata(s): . Complete Specification Fifed: Claae: .SvC£7f.k )s. pz>7?IQZl^/qZ; .Q?7l P^hz} Osipzp^/^?-;. Ay.K$.l/HX.yS. Publication Date: ?7.'P.Y.J??P P.O. Journal, No: , ....IlSS-. 2 2 7 6 5 No.: Date: NEW ZEALAND PATENTS ACT, 1953 COMPLETE SPECIFICATION AZOLE DERIVATIVES +/ We, SANDOZ LTD., 35 Lichtstrasse, CH-4002 Basle, Switzerland; a Swiss Body Corporate, hereby declare the invention for which I- / we pray that a patent may be granted to me/us, and the method by which it is to be performed, to be particularly described in and by the following statement: - - 1 - (followed by page la) Jfe '■$■ % iii 1 >S<) 9 •"> -1<\ - 27 65 r> Case 900-9474 AZOLE DERIVATIVES The invention concerns novel azole derivatives, their preparation, pharmaceutical preparations containing them and their use. More particularly the invention concerns azole derivatives of formula I n—JH I n R,~C-CH_-NH-C0-R, 1 ' 2 3 : i " i O Q wherein Rj and R2 are the same or different and each represent unsub-stituted or mono- or poly-substituted aryl or heteroaryl, R^ represents unsubstituted or mono- or poly-substituted alkyl, cycloalkyl, aryl, or heteroaryl; or cycloalkyl, aryl or heteroaryl condensed with a benzene ring; or alkoxy, and X represents CH or N, whereby when R^ represents methyl and R^ and R2 represent phenyl at least one of said phenyls must be substituted. In the above formula R^, R2 and R^ stand as aryl, particularly for phenyl or naphthyl, especially phenyl, as heteroaryl they preferably contain 5 or 6 ring atoms and as heteroatoms one or more sulphur or nitrogen atoms. Non-condensed heteroaryl is e.g. thienyl or pyridyl. Examples of condensed radicals are indolyl (e.g. indol-2-yl or indol-3-yl). Suitable substituents on R^ and R2 are in particular halogen atoms such as chlorine, bromine, iodine or fluorine, especially fluorine or chlorine. Mono-substitution is preferred, especially in p-position when Rj and R2 are phenyl. Substituents on aryl or heteroaryl groups as R^ are e.g. halogen, nitro or cyano; or lower alkyl, lower alkenyl, lower alkynyl, lower 222765 - 2 - alkylthio, lower alkylsulphinyl, lower alkyl sulphonyl or lower alkoxy each optionally substituted by halogen or phenyl; or optionally substituted phenyl or phenoxy. Particular examples of such substituents are ^alkyl, especially methyl, halogen or phenyl. Preferred substituents on R^ are halogen atoms e.g. fluorine or chlorine or cyano. R^ as cycloalkyl condensed with benzene has preferably 5 to 7 carbon atoms and is unsubstituted e.g.indanyl especially indan-2-yl. R^ as alkyl preferably has 1 to A carbon atoms and can be substituted by cyano, alkoxy, benyzloxy or polyether (e.g. alkoxy-(mono-, di- or tri-ethylenoxy). R^ as alkoxy preferably has 1 to 4 carbon atoms. Lower alkyl moieties appearing as substituents or contained in substituents preferably have 1 to 4 carbon atoms. Lower alkenyl or alkynyl moieties preferably have 2 to 4 carbon atoms. The following meanings for the symbols in formula I are preferred either alone or in combination: R^ and R£ are each p-F- especially p-Cl-phenyl. X is CH. R^ has the above-mentioned preferred meanings and is especially p-F-, p-Cl or p-CN-phenyl. A. particular group of compounds of formula I has R^, R2 and X as defined above and as unsubstituted or mono- or poly-substituted alkyl, aryl or heteroaryl. The compounds of formula I may be present in free form or in the form of acid addition salts. The compounds of formula I in free form or in acid addition salt form can be obtained according to the invention by acylating a compound of formula II -w| % s I ■i t ' '5.. v, • , 7--^./->W*.- . . ;222765 ;O ;o o ;wherein Rj, R2 and X have the above meanings and recovering the compound thus obtained in free form or in the form of an acid addition salt. ;Acylation is preferably carried out using a carboxylic acid R^COOH or a reactive derivative thereof in conventional manner. ;The process according to the invention can be carried out for example by reacting a compound of formula II with a corresponding acid halide in a solvent which is inert under the reaction conditions, e.g. in an organic or inorganic base, which simultaneously functions as an acid binding agent, such as pyridine, optionally adding an acylation accelerator such as 4-dimethylaminopyridine. For acylation, a compound of formula II can also be reacted with an active ester e.g. of the acid R^COOH. The reaction may be effected for example with a pyridyl-2-thiolester in a solvent which is inert under the reaction conditions, e.g. in a di-lower alkyl-carboxylic acid amide such as dimethylformamide, at room temperature. Furthermore the compound of formula II can be reacted with R^COOH in the presence of N-hydroxy-benzotriazole and dicyclohexylcarbodiimide. ;The end product can be isolated from the reaction mixture by known methods, and purified if required. ;The starting products of formula II are partly new and may be obtained for example in accordance with the following reaction scheme: ;r1-co-ch3 + nh2oh.hci ;R-.-C-CH- + 2 R0MgHal ;11, 3 2 ;NOH ;7 ;>0 ;n h ;II ;The remaining starting products, as well as the acylation agents, are known or may be produced analogously to known methods, or resp. analogously to the methods described in the examples. ;In the following examples, which illustrate the invention more fully but in no way limit its scope, all temperatures are* given in degrees celsius and are uncorrected. ''EW ZEALAND ^patent OFFICE £8 OCT1990 "" RECEIVED 4 22 2 7 6 5 - 4 - 900-9474 Example 1; 2,2-Bis-(4-chlorophenyl)-2-(lH-imidazol-l-yl)-l-(4-chlorobenzoylaaino)ethane 0.34 ml of 4-chlorobenzoyl chloride are added dropwise whilst cooling with ice to 670 mg of 2,2-bis-(4-chlorophenyl)-2-(1H-imidazol-l-yl)-l-aminoethane in 4 ml of dry pyridine. The mixture is stirred for 4 hours at room temperature. It is poured onto cold, saturated sodium hydrogen carbonate solution and extracted with ethyl acetate. The combined organic phases are washed with saturated sodium hydrogen carbonate solution and sodium chloride solution, dried over magnesium sulphate and concentrated by evaporation. The residue crystallises upon digestion with ethyl acetate and diethylether. Colourless crystals, m.p.: 241-244°. The 2,2-bis-(4-chlorophenyl)-2-(lH-imidazol-l-yl)-l-aminoethane used as starting material can be obtained as follows. a) 2,2-Bis-(4-chlorophenyl)aziridine A Grignard solution consisting of 8.45 g of magnesium and 36 ml of bromobenzene in 200 ml of absolute ether is mixed with 300 ml of dry toluene and the ether is distilled off until reaching an internal temperature of 107°. Then 28.8 g of p-chloro acetophenoneoxime in 100 ml of dry toluene are added dropwise to the boiling solution, the mixture is refluxed for 1% hours, and then mixed whilst cooling with ice with 300 ml of 20% ammonium chloride solution. After phase separation, the aqueous phase is extracted with ether. The combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulphate and concentrated by evaporation. The oily residue is chromatographed over silica gel (0.040 to 0.063 mm) with petroleum ether 60-80° and diethylether/petroleum ether (3/2). The brown oil thus obtained is characterised by the NHR spectrum. 1H-NHR(CDC13): 2.36 (2H, s, broad, -CH2); 7.20-7.55 (8H,m,aromat). b) 2,2-bis-(4-chlorophenyl)-2-(lH-imidazol -1-yl)-1-aminoethane 3.96 g of 2,2-di-(4-chlorophenyl)aziridine are heated to 95° (melt) for 20 hours with 5.1 g of imidazole. The melt is taken up with ethyl acetate/water, and the 1^0 phase is extracted a few times with ethyl acetate. The organic phases are washed with 0.25% tartaric acid solution and saturated sodium chloride solution, dried over magnesium sulphate and concentrated by evaporation. The residue, which as well as the desired product, also contains the position isomer l,l-bis-(4-chlorophenyl)-2-(lH-imidazol-l-yl)-l-aminoethane, is separated over silica gel (0.040-0.063 mm) with dichloromethane/methanol/petroleum ether (20/1/5). A viscous, yellow-brown oil is obtained. 1H-NMR(CDC13): 1.40 (2H, broad, -NH2); 3.90 (2H, s, -CH2); 6.9-7.5 (6H, m, aromat, imidazole); 7.68 (1H, imidazole). The following starting materials may be obtained analogously: 2,2-bis-phenyl-2(lH-imidazol-l-yl)-l-aminoethane (for example 2). Obtained as a viscous yellowish oil; 2,2-bis-(4-chlorophenyl)-2-(1H-1,2,4-triazol-l-yl)-l-aminoethane (for Example 3). Obtained as a viscous yellow-brown oil; 1H-NMR (CDC13): 1.75 (2H, s, broad, -NH2); 3.93 (2H, s, -CH2; 6.9-7.5 (8H, m, aromat); 7.88 (1H, s, triazole); 8.10 (1H, s, triazole). The following compounds of formula I can be obtained analogously to Example 1 from appropriate starting material. -6- ! ? 2 7 6 5 900-9474 Ex. | X { ! CH N CH CH CH CH CH CH CH CH CH CH CH CH CH 17 I CH C6H5 O CI C6H5 .-CI ^ /y CI \v / -CH3 -C(CH3)3 ; C1 C0 1 I1 1 H ; oc2h5 I CH(CH3)-0-CH2 . i< 1 -^N J^V \2/~CN CH2(0-CH2-CH2)l30CH3 ch2-cn y, 2/-F ^\-Cl CH. i m.p. °C i i 193-197° 158-162° 178-182° 131-136° 220-224° 144-146° amorph. amorph. amorph.(racemate) 253-256° 233-235° ! i oil | i 219-220° 218-220° 229-232° 181-183° 22 2 7 6 5 900-9474 The compounds of formula I exhibit pharmacological activity and are, therefore indicated for use as pharmaceuticals. In particular the compounds show aromatase inhibiting activity in the following tests. 1. Aromatase inhibition in vitro Microsomes of human placenta are used as a source of enzyme. To prepare these microsomes whole human placenta is taken under cooling to the laboratory directly after delivery, the excess blood is removed by intensive rinsing with 0.25 M sucrose, then the placenta is cut into sections and immediately homogenised whilst cooling (1 g organ + 1.5 g KCl/tris buffer, pH 7.4; ultraturrax 3 x 10 s/0°C). After sedimentation of partly broken down cells, cell nuclei and mitochondria at 200, 7000 and 11000 g, for 10 minutes each, the microsome fraction is obtained by centrifugation of the postmito-chondrial supernatant at 105,000 g/60 mins. The pellet which is washed once is then suspended in isotonic KCl/tris buffer to a Cyt P-450 concentration of 0.5-1 uM. Determination of the aromatasis activity is made by a modified known method (Thompson E.A., Siiteri P.K. {1974], J. Biol. Chem. 249, 3 5364-5372), using IB, 2B H-androstenedione as the substrate in the prsence of a NADPH regenerating system. The test compounds are added in concentrations of 0.01 and 1 pM. After incubating for 30 minutes at 37°C, the reaction is ended by mixing with a large excess of chloroform, and the aqueous and organic phases are separated. The 3 radio-activity of the aqueous phase is attributed to H„0 which is 3 produced upon the aromatisation of IB, 2B H-androstenedione to oestrone, and is used as a measure of enzymatic activity. Compounds which significantly inhibit aromatasis under these test conditions are then tested in an extended range of concentrations to determine IC50 values. 22 2 7 - 8 - 900-9474 2. Inhibition of ovulation Female rats with regular cycles received the test substance at 16.00 hrs on the day before ovulation and at 11.00 hrs on the day of ovulation. Ovulation is determined by the counting of ovula in a vaginal smear. 3. influence on ovarian aroaatase and E2 production invivo Adult female rats are pre-treated for 12 days with 25 IU/day s.c. of PHSG (pregnant mare serum gonadotrophin), on the 13th day the test substance is administered orally in a concentration of 0.032 to 10 mg/kg. The rats are then killed 8, 24 and 48 hours later and the blood and ovaries are removed. Microsomes are prepared from one respective ovary per animal, and the aromatasis activity is determined as described above. Oestradiol is extracted from the second ovary and is quantified by RIA; similarly the oestradiol from the blood. 4. Subchronic effects in vivo: The test substance is administered once daily for 7 days to youthful, 23 day old, female rats. On the 4th to the 7th day, testosterone propionate is additionally injected s.c. On the 8th day, the animals are killed, the blood collected and the uteri removed, cleaned and weighed. Administrations of testosterone bring about a considerable increase in weight of the uterus, caused by the change of testosterone by aromatasis into oestradiol. Thus, the inhibition of metrauxe (uterus hypertrophy) by a test substance is an exact measure of the inhibition of oestrogen production by aromatasis during the seven-day treatment. 5. Chronic effects Oestrogen dependent breast tumors are induced in rats by one-off oral administration of >y IZ-dimethylbenzlaJanthrazene (DMBA). Treatment with test substance is commenced when the tumors have reached an 3 average size of ca. 1500 m and continued for up to six weeks. ■ " ' ,'-•»- .■"iWi'-'vO- ' i a ' © 222765 /~N - 9 - The compounds of formula I show this activity at p.o. concentrations of from about 1 mg/kg to about 10 mg/kg once or twice daily. Aromatase plays an important role in the biosynthesis of oestrogens in mammals. The blocking of this enzyme by specific inhibitors can effect a drastic lowering of the normal steroid level. Such a non-invasive chemical reduction in the steroid level, in contrast to the surgical removal of hormone-producing organs (prostate, ovary, adrenal glands), appears to be a desirable alternative and suplement to the treatment of steroid-dependent tumors, e.g. of the prostate, polycystic ovarian syndrome, carcinoma of the mamma, ovaries, endometrium, as well as Cushing's syndrome. The compounds of formula I are therefore indicated for use as specific inhibitors of steroid synthesis, for the treatment of tumors such as listed above. An indicated suitable daily dosage is in the range from about 10 mg to about 100 mg of a compound of formula I conveniently administered, for example, in divided doses up to four times a day. The compounds of formula I may be administered by any conventional route, in particular enterally preferably orally, e.g., in the form of tablets or capsules, or parenterally e.g., in the form of injectable solutions or suspensions. </div>

Claims

<div class="application article clearfix printTableText" id="claims"> 222765 -10 - The compounds of formula I may be administered in free base form or in pharmaceutically acceptable acid addition salt form. Such salts may be prepared in conventional manner and exhibit the same order of activity as the free bases. The present invention also provides pharmaceutical compositions comprising a compound of formula I in free base or pharmaceutically acceptable acid addition salt form in association with at least one pharmaceutical carrier or diluent. Such compositions may be manufactured in conventional manner. Unit dosage forms contain, for example, from about 2.5 mg to about 50 mg of a compound of formula I in free base or pharmaceutically acceptable acid addition salt form. The invention also concerns compounds of formula I in free form or in pharmaceutically acceptable acid addition salt form suitable for use as pharmaceuticals in particular as aromatase inhibitors and the use of compounds of formula I in free form or in pharmaceutically acceptable acid addition salt form for the manufacture of a medicament for aromatase inhibition. 222765 r> - 11 ,0 WHAT WE CLAIM IS:

1. Azole derivatives of formula I O y o R1-C-CH2-NH-CO-R3 ^2 wherein R^ and R2 are the same or different and each represent unsubstituted or mono- or poly-substituted aryl or heteroaryl, R^ represents unsubstituted or mono- or poly-substituted alkyl, cycloalkyl, aryl, or heteroaryl; or cycloalkyl, aryl or heteroaryl condensed with a benzene ring; or alkoxy, and X represents CH or N, whereby when R^ represents methyl and R^ and R2 represent phenyl at least one of said phenyls must be substituted, in free form or in acid addition salt form.

2. A compound according to Claim 1 wherein R^ and R2 are the same or different and each represent optionally mono-substituted phenyl, R3 represents Chalky! optionally substituted by cyano, Ci_4alkoxy, benzyloxy or Cj_4alkoxy-(mono-, di- or tri-) ethylenoxy; Ci_4alkoxy ; optionally substituted phenyl; C5_7cycloalkyl optionally condensed with a benzyl ring; or a heterocycle containing 5 or 6 ring atoms, having one or more sulphur or nitrogen atoms as heteroatoms and optionally condensed with a benzyl ring. NEW ZEALAND PATENT OFFIC. 11 & 8 OCT 1990 m RECEIVED i •^i i IS i I ■' O I - 12- O 222765

3. A compound according to Claim 1 or 2, wherein R^ and R2 each represent p—CI— or p-F-phenyl.

4. A compound according to anyone of Claims 1 to 3, wherein R^ represents p-Cl-, p-F- or p-CN-phenyl.

5. 2,2-Bis-(4-chlorophenyl)-2-(lH-imidazol-l-yl)-l-(4-chloro-benzoylamino)e thane.

6. A compound according to Claim 1, wherein R^ represents unsubstituted or mono- or poly-substituted alkyl, aryl or heteroaryl.

7. A process for preparing a compound according to Claim 1, which comprises acylating a compound of formula II fl N o II R1-C-CH2-NH2 2 wherein R^ R2 and X have the meanings given in Claim 1, and recovering the compound thus obtained in free form or in the form of an acid addition salt.

8. A compound of formula I as defined in Claim 1 in free form or in pharmaceutically acceptable acid addition salt form suitable for use as a pharmaceutical.

9. A compound of formula I as defined in Claim 1 in free form or in pharmaceutically acceptable acid addition salt form suitable for use as an aromatase inhibitor. 222765 - 13-

10. The use of a compound of formula I as defined in Claim 1 in free form or in pharmaceutically acceptable acid addition salt form for manufacturing a medicament for aromatase inhibition.

11. A pharmaceutical composition containing a compound of formula I as defined in Claim 1 in free form or in pharmaceutically acceptable acid addition salt form together with a pharmaceutically acceptable diluent or carrier. nATLX' "HUn DAY CF CfO / . J-rP £ i ■ : >i ^ SO M AC.;ir\"''i: A.^PLICAN i S </div>