HRP940940A2 - Chemical compounds - Google Patents

Description

Ovaj izum se odnosi na supstituirane derivate karbazola, na postupke njihovog dobivanja, na farmaceutske pripravke koji ih sadrže kao i na njihovu uporabu u medicini za smanjenje nivoa estrogena i/ili androgena. Aktivnost 17,20-liaze je odgovorna za konverziju 17α-hidroksiprogesterona do androstenediona i 17α-hidroksipregnenolona do dehidroepiandrosterona. Ova aktivnost je kritična za biosintezu androgena, te inhibicija 17,20-liaze pomoću ketakonazola (poznatog antimikotičkog sredstva) pokazuje smanjenje nivoa testosterona kod životinja (English, H. F. i sur., Cancer Res. 47, 38-42 (1986) i ljudi (Pont, A. i sur., Arch. Intern. Med. 142, 2137-2140 (1982). This invention relates to substituted carbazole derivatives, to their production processes, to pharmaceutical preparations containing them, as well as to their use in medicine to reduce estrogen and/or androgen levels. 17,20-lyase activity is responsible for the conversion of 17α-hydroxyprogesterone to androstenedione and 17α-hydroxypregnenolone to dehydroepiandrosterone. This activity is critical for androgen biosynthesis, and inhibition of 17,20-lyase by ketaconazole (a known antimycotic agent) has been shown to decrease testosterone levels in animals (English, H.F. et al., Cancer Res. 47, 38-42 (1986)) and humans ( Pont, A. et al., Arch. Intern. Med. 142, 2137-2140 (1982).

U liječenju karcinoma prostate su korištene velike doze ketakonazola (Trachtenberg, J., J. Urol. 61-63 (1984) i Pont, A. i sur., Arch. Intern. Med. 145, 1429-1431 (1985)). Naravno, doze ketakonazola koje izazivaju inhibiciju produkcije testosterona su znatno toksičnije od antimikotičnih doza, a za selektivnije 17,20-liaza inhibitore se očekuje da imaju znatno bolji terapeutski indeks. Large doses of ketaconazole have been used in the treatment of prostate cancer (Trachtenberg, J., J. Urol. 61-63 (1984) and Pont, A. et al., Arch. Intern. Med. 145, 1429-1431 (1985)). Of course, doses of ketaconazole that cause inhibition of testosterone production are significantly more toxic than antimycotic doses, and more selective 17,20-lyase inhibitors are expected to have a significantly better therapeutic index.

Inhibicija 17,20-liaze, kao pristup inhibiciji biosinteza testosterona, ima prednost također i u tome da blokira adrenalno kao i testikularno dobivene androgene (English, H. F. i sur., Cancer Res. 46, 38-42 (1986)), te je za očekivati da će biti znatno učinkovitija u liječenju karcinoma prostate od LHRH agonista. Inhibition of 17,20-lyase, as an approach to inhibiting testosterone biosynthesis, also has the advantage of blocking adrenal as well as testicular derived androgens (English, H.F. et al., Cancer Res. 46, 38-42 (1986)), and is expect that it will be significantly more effective in the treatment of prostate cancer than LHRH agonists.

Tako prikazani izum osigurava spojeve opće formule (I) The invention thus presented provides compounds of the general formula (I)

[image] [image]

gdje R1 i R4 svaki zasebno predstavljaju vodikov atom ili C1-6alkil grupu; svaki od R2, koji mogu biti jednaki ili različiti, predstavlja grupu koja povlači elektrone; where R 1 and R 4 each separately represent a hydrogen atom or a C 1-6 alkyl group; each of R 2 , which may be the same or different, represents an electron withdrawing group;

svaki od R3, koji mogu biti jednaki ili različiti, predstavlja grupu koja povlači elektrone; each of R 3 , which may be the same or different, represents an electron withdrawing group;

R5 je grupa formule R5 is a group of formula

[image] [image]

R6 je atom halogena, C1-6 alkil grupa ili C1-6alkoksi grupa; R 6 is a halogen atom, a C 1-6 alkyl group or a C 1-6 alkoxy group;

m je nula ili broj između 1 i 4; m is zero or a number between 1 and 4;

n je nula ili broj između 1 i 3; te n is zero or a number between 1 and 3; you

p je nula, 1 ili 2 p is zero, 1 or 2

kao i njihove farmaceutski prihvatljive soli i solvate. as well as their pharmaceutically acceptable salts and solvates.

Svaki od R2 supstituenada može zauzeti bilo koji slobodan položaj izabran između položaja 5, 6, 7 ili 8. Each of the R 2 substituents can occupy any free position selected from positions 5, 6, 7 or 8.

Svaki od supstituenada može zauzeti bilo koji slobodan položaj izabran između položaja 1, 2, 3 ili 4, povoljniji su položaji 1, 3 ili 4. Each of the substituents can occupy any free position chosen from positions 1, 2, 3 or 4, positions 1, 3 or 4 being more favorable.

Grupa -CHR4R5 može zauzeti bilo koji od položaja 1, 2, 3 ili 4, na primjer položaje 1, 2 ili 3. Povoljno je kada je grupa -CHR4R5 na položaju 2. The -CHR4R5 group can occupy any of positions 1, 2, 3 or 4, for example positions 1, 2 or 3. It is preferred that the -CHR4R5 group is at position 2.

Tako, iz jednog aspekta izum osigurava spojeve formule (Ia) Thus, in one aspect the invention provides compounds of formula (Ia)

[image] [image]

gdje su R1, R2, R3, R4, R5, m i n isti kao i ranije definirani. where R1, R2, R3, R4, R5, m and n are the same as previously defined.

Supstituend R6 može biti povezan na bilo koji ugljikov atom u piridil prstenu, ali je povoljno kada je povezan na položajima 3, 4 ili 5. Substituent R 6 can be attached to any carbon atom in the pyridyl ring, but is preferably attached at positions 3, 4 or 5.

Stručnjaci iz struke će znati da će numeriranje prstenastog sistema pojedinačnih spojeva unutar dosega ovog izuma i formula (I), varirati ovisno o prirodi, broju i položaju supstituenda. Zbog jednostavnosti, numeriranje prstena atoma prihvaćeno ovdje prikazano je u formuli (I), osim u slučajevima kada su dana imena pojedinačnih spojeva. Those skilled in the art will recognize that the numbering of the ring system of the individual compounds within the scope of this invention and formula (I) will vary depending on the nature, number and position of the substituents. For simplicity, the ring numbering of atoms adopted herein is shown in formula (I), except where names of individual compounds are given.

Razumljivo je da spojevi formule (I) mogu sadržavati kiralni centar. Podrazumijeva se da formula (I) obuhvaća sve enantiomere i dijastereoizomere spojeva prema izumu kao i njihove smjese uključujući i racemate. It is understood that compounds of formula (I) may contain a chiral center. It is understood that formula (I) includes all enantiomers and diastereoisomers of the compounds according to the invention as well as their mixtures including racemates.

Grupe koje povlače elektrone su dobro poznate stručnjacima iz struke i može se upotrijebiti bilo koja grupa. Takve grupe uključuju atome halogena, poput atoma fluora, klora i broma, nitril grupe, nitro grupe, trifluorometil grupa, aldehido grupa, keto grupa i grupa karboksilne kiseline i estera, te je povoljno kada se izaberu između atoma fluora, atoma klora i nitril grupa. Posebno preferirani kao spojevi formule (I) su oni spojevi u kojima svaki od R2 i R3 predstavlja atom fluora. Electron withdrawing groups are well known to those skilled in the art and any group may be used. Such groups include halogen atoms, such as fluorine, chlorine and bromine atoms, nitrile groups, nitro groups, trifluoromethyl groups, aldehyde groups, keto groups and carboxylic acid and ester groups, and are preferably selected from fluorine atoms, chlorine atoms and nitrile groups . Particularly preferred as compounds of formula (I) are those compounds in which each of R2 and R3 represents a fluorine atom.

Povoljno je kada R2 predstavlja atom fluora, a m je broj između 1 i 4. It is advantageous when R 2 represents a fluorine atom and m is a number between 1 and 4.

Kada je m 1, povoljno je da je R2 na položaju 5 ili 7, posebno je povoljan položaj 7. When m is 1, it is advantageous for R2 to be at position 5 or 7, position 7 being particularly favorable.

C1-6alkil i C1-6alkoksi grupe mogu sadržavati alkil grupe ravnih ili razgranatih lanaca, npr. Metil, etil, n-propil, iso-propil, n-butil, t-butil, pentil ili heksil grupe, povoljne su C1-4 alkil grupe. Tako na primjer, svaki od R1 i R4 može biti atom vodila ili metil, etil, propil ili butil grupa. C1-6 alkyl and C1-6 alkoxy groups may contain straight or branched chain alkyl groups, e.g. methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, pentyl or hexyl groups, C1-4 alkyl are preferred groups. Thus, for example, each of R1 and R4 can be a lead atom or a methyl, ethyl, propyl or butyl group.

Povoljno je kada je svaki od R1 i R4 atom vodika ili metil grupa. It is advantageous when each of R1 and R4 is a hydrogen atom or a methyl group.

U preferiranoj grupi spojeva formule (I) R5 je piridin-3-il ili piridin-4-il grupa. In a preferred group of compounds of formula (I), R5 is a pyridin-3-yl or pyridin-4-yl group.

Povoljno je kada R6 predstavlja atom fluora, metil ili metoksi grupu. It is advantageous when R6 represents a fluorine atom, a methyl or a methoxy group.

U preferiranoj grupi spojeva formule (I), svaki od R1 i R4 predstavlja atom vodika ili metil grupu, R2 i R3 su atomi fluora, R6 je atom fluora, metil grupa ili metoksi grupa, m je broj između 1 i 4, ne je 0 ili broj između 1 i 3, te p je 0, 1 ili 2. In a preferred group of compounds of formula (I), each of R1 and R4 represents a hydrogen atom or a methyl group, R2 and R3 are fluorine atoms, R6 is a fluorine atom, a methyl group or a methoxy group, m is a number between 1 and 4, not 0 or a number between 1 and 3, and p is 0, 1, or 2.

U posebnoj preferiranoj grupi spojeva formule (I), svaki od R1 i R4 predstavlja atom vodila, R2 i R3 su atomi fluora, R6 je atom fluora ili metil ili metoski grupa, te svaki zasebno m, n i p, predstavlja nulu, 1 ili 2. In a particularly preferred group of compounds of formula (I), each of R1 and R4 represents a lead atom, R2 and R3 are fluorine atoms, R6 is a fluorine atom or a methyl or methoxy group, and each separately m, n and p represents zero, 1 or 2.

Speceifični spojevi prema izumu uključuju: Specific compounds according to the invention include:

2-Fluoro-7[1,2,4]triazol-1-ilmetil-9H-karbazol 2-Fluoro-7[1,2,4]triazol-1-ylmethyl-9H-carbazole

2-Fluoro-7-piridin-3-ilmetil-9H-karbazol 2-Fluoro-7-pyridin-3-ylmethyl-9H-carbazole

2-Fluoro-7-piridin-4-ilmetil-9H-karbazol 2-Fluoro-7-pyridin-4-ylmethyl-9H-carbazole

2-Fluoro-7-(3-fluoropiridin-4-ilmetil)-9H-karbazol 2-Fluoro-7-(3-fluoropyridin-4-ylmethyl)-9H-carbazole

2-Fluoro-7-(3-metilpiridin-4-ilmetil)-9H-karbazol 2-Fluoro-7-(3-methylpyridin-4-ylmethyl)-9H-carbazole

2-Fluoro-7-(3-metoksipiridin-4-ilmetil)-9H-karbazol 2-Fluoro-7-(3-methoxypyridin-4-ylmethyl)-9H-carbazole

1,7-Difluoro-2-[1,2,4]triazol-1-ilmetil-9H-karbazol 1,7-Difluoro-2-[1,2,4]triazol-1-ylmethyl-9H-carbazole

2,4-Difluoro-7-[1,2,4]triazol-1-ilmetil-9H-karbazol 2,4-Difluoro-7-[1,2,4]triazol-1-ylmethyl-9H-carbazole

1,4,7-Trifluoro-2-[1,2,4]triazol-1-ilmetil-9H-karbazol 1,4,7-Trifluoro-2-[1,2,4]triazol-1-ylmethyl-9H-carbazole

kao i njihove farmaceutski prihvatljive soli i solvate. as well as their pharmaceutically acceptable salts and solvates.

Prikladne farmacetski prihvatljive soli spojeva formule (I) uključuju kiselinske soli dobivene pomoću anorganskih ili organskih kiselina, poput hidroklorida, hidrobromida, sulfata, fosfata, citrata, tartarata, maleata, fumarata, sukcinata, ptoluensulfonata i metanesulfonata. Stručnjaci iz struke će zznati izabrati ostale prikladne soli. Posebno su preferirane hidrokloridne, sulfatne i fosfatne soli. Soli koje nisu farmaceutski prihvatljive mogu biti korisne u pripremi spojeva formule (I) i one čine idući dio izuma. Suitable pharmaceutically acceptable salts of the compounds of formula (I) include acid salts obtained using inorganic or organic acids, such as hydrochlorides, hydrobromides, sulfates, phosphates, citrates, tartrates, maleates, fumarates, succinates, ptoluenesulfonates and methanesulfonates. Experts in the field will know how to choose other suitable salts. Hydrochloride, sulfate and phosphate salts are particularly preferred. Salts which are not pharmaceutically acceptable may be useful in the preparation of compounds of formula (I) and they form a further part of the invention.

Spojevi prema izumu mogu biti izoliranu zajedno sa molekulama otapala kristalizacijom ili evaporacijom odgovarajućeg otapala. Takvi solvati spojeva formule (I) su uključeni u doseg prikazanog izuma. The compounds according to the invention can be isolated together with the solvent molecules by crystallization or evaporation of the appropriate solvent. Such solvates of compounds of formula (I) are included within the scope of the present invention.

Bilješke koje se nalaze u daljnjem tekstu i koje se odnose na spojeve prema izumu uključuju spojeve formule (I) kao i njihove farmaceutski prihvatljive soli i solvate. The notes which are found in the following text and which refer to the compounds according to the invention include the compounds of formula (I) as well as their pharmaceutically acceptable salts and solvates.

Spojevi prema izumu su snažni i selektivni inhibitori enima steroidalne 17,20-liaze, koji je ključni enzim uključen u konverziju C21-steroida (npr. pregnenolona) u androgene (npr. testosteron) i estrogene (npr. estradiol). 17,20-liaza-inhibicijska aktivnost spojev formule (I) je pokazana in vitro pomoću njihove sposobnosti da inhibiraju konverziju 17-α-hidroksipregnenolona u dehidroepiandrosteron pomoću humane testikularne 17,20-liaze i 17-α-hidroksiprogesteron u androstenedion pomoću testikularne 17,20-liaze štakora. Ova ispitivanja su vođena prema postupku baziranom na onom Ayub i Level, J. Steroid Biochem, 1987,28,521. The compounds according to the invention are potent and selective inhibitors of the steroid 17,20-lyase enzyme, which is a key enzyme involved in the conversion of C21-steroids (eg pregnenolone) to androgens (eg testosterone) and estrogens (eg estradiol). 17,20-lyase-inhibitory activity of the compounds of formula (I) has been demonstrated in vitro by their ability to inhibit the conversion of 17-α-hydroxypregnenolone to dehydroepiandrosterone by human testicular 17,20-lyase and 17-α-hydroxyprogesterone to androstenedione by testicular 17,20-lyase. Rat 20-lyase. These tests were conducted according to a procedure based on that of Ayub and Level, J. Steroid Biochem, 1987,28,521.

U in vivo testovima spojevi prema izumu su testiranu na njihovu sposobnost da suprimiraju podizanje nivoa testosterona producirano kod štakora nakon stimulacije sa humanim horionskim gonadotropinom (hCG). In in vivo tests, the compounds according to the invention were tested for their ability to suppress the increase in testosterone levels produced in rats after stimulation with human chorionic gonadotropin (hCG).

Inhibitori 17,20-liaze reduciraju nivoe androgena i estrogena u cirkulaciji i lokalno. Spojevi prema izumu se tako mogu koristiti u liječenju androgen- i estrogen-ovisnih poremećaja poput malignih i benignih bolesti prsiju, endometrija, ovarija, prostate i pankreasa. Ove bolesti uključuju karcinom prostate, prsiju i endometrija, hipertrofiju i hiperplaziju prostate, fibrocistično oboljenje prsiju, endometriozu i policistično oboljenje ovarija. Spojevi formule (I) su također korisni u liječenju Cushing-ovog sindroma, ginekomastije, preranog puberteta, ženskog hirsutizma, premenstrualnog sindroma, muške ćelavosti i akni. Spojevi prema izumu će biti posebno korisni u liječenju karcinoma prostate. 17,20-lyase inhibitors reduce circulating and local androgen and estrogen levels. The compounds according to the invention can thus be used in the treatment of androgen- and estrogen-dependent disorders such as malignant and benign diseases of the breast, endometrium, ovaries, prostate and pancreas. These diseases include prostate, breast and endometrial cancer, prostatic hypertrophy and hyperplasia, fibrocystic breast disease, endometriosis and polycystic ovarian disease. The compounds of formula (I) are also useful in the treatment of Cushing's syndrome, gynecomastia, precocious puberty, female hirsutism, premenstrual syndrome, male pattern baldness and acne. The compounds of the invention will be particularly useful in the treatment of prostate cancer.

Izum tako nadalje osigurava spojeve formule (I) i njihove farmaceutski prihvatljive soli i solvate za upotrebu kao aktivnih farmaceutskih sredstava posebno u liječenju stanja koja podliježu etiologiji povezanoj sa povišenim nivoima androgena i/ili estrogena kod životinja (posebno kod ljudi). The invention thus further provides compounds of formula (I) and their pharmaceutically acceptable salts and solvates for use as active pharmaceutical agents in particular in the treatment of conditions subject to an etiology associated with elevated levels of androgens and/or estrogens in animals (especially in humans).

U posebnom aspektu prikazanog izuma, osiguran je spoj formule (I) ili njegova farmaceutski prihvatljiva sol ili solvat za upotrebu u liječenju karcinoma prostate. In a particular aspect of the present invention, there is provided a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in the treatment of prostate cancer.

U idućem alternativnom aspektu izuma, osiguran je postupak snižavanja nivoa androgena i/ili estrogena kod sisavaca, uključujući i ljude, koji obuhvaća primjenu učinkovite količine spoja formule (I) ili njegove farmaceutski prihvatljive soli ili solvata. In a further alternative aspect of the invention, there is provided a method of lowering androgen and/or estrogen levels in mammals, including humans, which comprises the administration of an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

U idućem ili alternativnom aspektu izuma, osigurana je upotreba spoja formule (I) ili njegove farmaceutski prihvatljive soli ili solvata, u proizvodnji lijeka za smanjenje nivoa androgena i/ili estrogena. In a further or alternative aspect of the invention, the use of the compound of formula (I) or its pharmaceutically acceptable salt or solvate, in the production of a drug for reducing the level of androgens and/or estrogens, is ensured.

Stručnjaci iz struke će razumijeti da se bilješke u svezi tretiranja odnose na profilaksu isto tako kao i na liječenje utvrđenih simptoma. Those skilled in the art will understand that the notes regarding treatment apply to prophylaxis as well as treatment of established symptoms.

Premda je moguće da se za liječenje spoj prema izumu može primijeniti pacijentu kao čista kemikalija, preferira se da on bude aktivni sastojak u farmaceutskoj formulaciji. Although it is possible for a compound of the invention to be administered to a patient as a pure chemical for treatment, it is preferred that it be the active ingredient in a pharmaceutical formulation.

U skladu s time, izum osigurava farmaceutsku formulaciju koja sadrži spoj formule (I) ili njegovu farmaceutski prihvatljivu sol ili solvat, zajedno sa jednom ili više farmaceutski prihvatljivih podloga ili punila, te je povoljno sa ostalim terapeutskim i/ili profilaktičkim sastojcima. Podloge moraju biti "prihvatljive" u smislu da su kompatibilne sa ostalim sastojcima i da nisu štetne za pacijenta. Accordingly, the invention provides a pharmaceutical formulation containing a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, together with one or more pharmaceutically acceptable bases or fillers, and preferably with other therapeutic and/or prophylactic ingredients. The bases must be "acceptable" in the sense that they are compatible with the other ingredients and that they are not harmful to the patient.

Farmaceutske formulacije uključuju one prikladne za oralnu, rektalnu, nazalnu, topikalnu, implatacijsku ili parenteralnu primjenu (uključujući intramuskularnu, subkutanu i intravenoznu) ili oblike prikladne za primjenu inhalacijom ili insuflacijom. Formulacije mogu biti, gdje je to odgovarajuće, pripremljene u pojedinačnim dozirnim jedinicama i mogu se pripremiti bilo kojim postupkom poznatim u farmaciji. Svi postupci uključuju korak miješanja aktivnog sastojka sa tekućim ili fino podijeljenim krutim podlogama, ili sa jednim i drugim, te ako je to neophodno, oblikovanje produkta u željeni oblik. Pharmaceutical formulations include those suitable for oral, rectal, nasal, topical, implantation or parenteral administration (including intramuscular, subcutaneous and intravenous) or forms suitable for administration by inhalation or insufflation. The formulations may, where appropriate, be prepared in individual dosage units and may be prepared by any method known in the art of pharmacy. All procedures include the step of mixing the active ingredient with liquid or finely divided solid bases, or with both, and if necessary, molding the product into the desired shape.

Za oralnu primjenu, farmaceutski pripravci mogu biti u obliku, na primjer, tableta ili kapsula pripremljenih na uobičajen način pomoću farmaceutski prihvatljivih pomoćnih sredstava poput vezivnih sredstava (npr. kukuruznog škroba, polivinilpirolidona ili hidroksipropil metilceluloze); punila (npr. laktoze, mikrokristalinične celuloze ili kalcij fosfata); lubrikanata (npr. magnezij stearata, talka ili silicija); dezintegratora (npr. krumpirovog škroba ili natrijevog škrobnog glikolata); ili sredstava za vlaženje (npr. natrij lauril sulfata). Tablete mogu biti prevučene postupcima dobro poznatim u struci. For oral administration, the pharmaceutical preparations may be in the form of, for example, tablets or capsules prepared in a conventional manner using pharmaceutically acceptable excipients such as binders (eg corn starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (eg lactose, microcrystalline cellulose or calcium phosphate); lubricants (eg magnesium stearate, talc or silicon); disintegrators (eg potato starch or sodium starch glycolate); or wetting agents (eg sodium lauryl sulfate). The tablets may be coated by methods well known in the art.

Tekući pripravci za oralnu primjenu mogu biti u obliku npr. otopina, sirupa ili suspenzija, ili mogu biti u obliku suhog produkta za miješanje sa vodom ili ostalim prikladnim vehikulima prije upotrebe. Takvi tekući pripravci mogu biti pripremljeni uobičajenim načinom uz farmaceutski prihvatljive dodatke kao što su sredstva zu suspenziranje (npr. sorbitol sirup, metil celuloza ili hidrirana jestiva ulja); sredstva za emulgiranje (npr. lecitin ili akcija); ne-vodeni vehikulumi (npr. bademovo ulje, uljni esteri ili etil alkohol); te konzervansi (npr. metil ili propil-p-hidroksibenzoati ili sorbinska kiselina). Liquid preparations for oral administration can be in the form of, for example, solutions, syrups or suspensions, or they can be in the form of a dry product for mixing with water or other suitable vehicles before use. Such liquid preparations can be prepared in the usual way with pharmaceutically acceptable additives such as suspending agents (eg sorbitol syrup, methyl cellulose or hydrogenated edible oils); emulsifying agents (eg lecithin or action); non-aqueous vehicles (eg almond oil, oil esters or ethyl alcohol); and preservatives (eg methyl or propyl-p-hydroxybenzoates or sorbic acid).

Za topikalnu primjenu u ustima, farmaceutski pripravci mogu biti u obliku bukalnih ili sublingvalnih tableta, kapi ili pastila pripremljenih na uobičajen For topical use in the mouth, pharmaceutical preparations can be in the form of buccal or sublingual tablets, drops or pastilles prepared in the usual way.

način. way.

Za topikalnu primjenu na epidermis, spojevi prema izumu mogu biti formulirani kao kreme, gelovi, masti ili losioni, ili kao transdermalni flasteri. Takvi spojevi mogu, na primjer, biti formulirani pomoću vodenih ili uljnih podloga uz dodatak prikladnih sredstava za zgušnjavanje, geliranje, emulziranje, stabiliziranje, dispergiranje, suspenziranje i/ili bojenje. For topical application to the epidermis, the compounds of the invention may be formulated as creams, gels, ointments or lotions, or as transdermal patches. Such compounds may, for example, be formulated using aqueous or oily bases with the addition of suitable thickening, gelling, emulsifying, stabilizing, dispersing, suspending and/or coloring agents.

Spojevi prema izumu mogu također biti formulirani kao depo preparati. Tako dugo djelujuće formulacije mogu biti primjenjene implatacijom (npr. subkutano ili intramuskularno) ili pomoću intramuskularnih injekcija. Tako, npr. spojevi mogu biti formulirani pomoću prikladnih polimernih ili hidrofobnih materijala (npr. kao emulzije u prihvatljivom ulju) ili pomoću smola za ionsku izmjenu, ili mogu biti u obliku slabo topivih derivata, npr. u obliku slabo topivih soli. The compounds according to the invention can also be formulated as depot preparations. Such long-acting formulations can be administered by implantation (eg, subcutaneously or intramuscularly) or by intramuscular injections. Thus, for example, the compounds can be formulated using suitable polymeric or hydrophobic materials (eg as emulsions in an acceptable oil) or using ion exchange resins, or they can be in the form of poorly soluble derivatives, eg in the form of poorly soluble salts.

Spojevi prema ovom izumu mogu biti formulirani za parenteralnu primjenu pomoću injekcija, konvencionalnih intravenoznih, intramuskularnih ili subkutanih injekcija, na primjer bolus injekcija, ili pomoću kontinuirane infuzije. Formulacije za injekcije mogu biti u jediničnom dozirnom obliku npr. u ampulama ili u multidozirnim spremnicima uz dodatak konzervansa. Pripravci mogu biti u obliku suspenzija, otopina ili emulzija u uljnim ili vodenim podlogama, te mogu sadržavati sredstva za formuliranje poput sredstava za suspenziranje, stabiliziranje i/ili disperziranje. Alternativno, aktivni sastojak može biti u obliku praha za pripremu uz dodatak prikladnog vehikuluma, npr. sterilne apirogene vode, neposredno prije upotrebe. The compounds of the present invention may be formulated for parenteral administration by injection, conventional intravenous, intramuscular or subcutaneous injection, for example bolus injection, or by continuous infusion. Formulations for injections can be in unit dosage form, for example in ampoules or in multi-dose containers with the addition of preservatives. The preparations may be in the form of suspensions, solutions or emulsions in oil or water bases, and may contain formulation agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form for preparation with the addition of a suitable vehicle, eg sterile pyrogen-free water, immediately prior to use.

Spojevi prema izumu mogu biti formulirani i kao rektalni pripravci kao što su supozitorija ili rektalne masti, te sadrže npr. uobičajene podloge za supozitorija poput kakao maslaca ili ostalih glicerida. The compounds according to the invention can also be formulated as rectal preparations such as suppositories or rectal ointments, and contain, for example, common bases for suppositories such as cocoa butter or other glycerides.

Za intranazalnu primjenu, spojevi prema izumu mogu biti npr. u obliku tekućeg raspršivača, praha ili kapi. For intranasal administration, the compounds according to the invention can be, for example, in the form of a liquid spray, powder or drops.

Za primjenu inhaliranjem, spojevi prema izumu se uobičajeno oslobađaju u obliku aerosol raspršivača iz pakiranja pod povećanim tlakom ili iz nebulizatora, uz upotrebu prikladnog propelenta, npr. diklorodifluorometana, triklorotrifluorometana, diklorotetrafluoroetana, 1,1,1,2-tetrafluoroetana, ugljičnog dioksida ili ostalih prikladnih plinova. U slučaju aerosola pod povećanim tlakom, dozirna jedinica može biti određena time da ventil oslobađa određenu količinu. Kapsule ili patrone, npr. želatinozne za upotrebu u ihalatorima ili insuflatorima mogu biti formulirane tako da sadrže praškastu smjesu spoja prema izumu i prikladnu praškastu podlogu poput laktoze ili škroba. For administration by inhalation, the compounds of the invention are usually released in the form of an aerosol spray from a pressurized package or from a nebulizer, using a suitable propellant, e.g. dichlorodifluoromethane, trichlorotrifluoromethane, dichlorotetrafluoroethane, 1,1,1,2-tetrafluoroethane, carbon dioxide or others suitable gases. In the case of aerosols under increased pressure, the dosage unit can be determined by the valve releasing a certain amount. Capsules or cartridges, eg gelatinous for use in inhalers or insufflators, may be formulated to contain a powder mixture of a compound of the invention and a suitable powder base such as lactose or starch.

Bilo koji ranije opisani praškasti pripravak može biti na uobičajen način povezan sa oblicima za kontrolirano otpuštanje. Any of the previously described powder compositions may be associated with controlled release forms in a conventional manner.

Povoljno je kada su farmaceutski pripravci prema izumu prikladni za oralnu, raktalnu ili topikalnu primjenu. It is advantageous when the pharmaceutical preparations according to the invention are suitable for oral, rectal or topical administration.

Uobičajene jedinične formulacije sadrže aktivni sastojak u količini od 0.1 do 200 mg. Common unit formulations contain the active ingredient in the amount of 0.1 to 200 mg.

Razumljivo je da će količina spoja formule (I) potrebna za upotrebu u liječenju, varirati ne samo ovisno o pojedinačnom spoju već također ovisno i o putu primjene, prirodi stanja kojeg treba liječiti kao i o dobi, težini i stanju pacijenta te će ju odrediti liječnik, odnosno veterinar. Općenito, naravno, prikladna doza će biti u rasponu od oko 1 do oko 500 mg po danu, povoljnije je u rasponu od 20 do 200 mg po danu, a najpovoljnije je u rasponu 50 do 120 mg po danu. It is understandable that the amount of the compound of formula (I) required for use in treatment will vary not only depending on the individual compound but also depending on the route of administration, the nature of the condition to be treated as well as the age, weight and condition of the patient and will be determined by the doctor, or veterinarian. In general, of course, a suitable dosage will be in the range of about 1 to about 500 mg per day, more preferably in the range of 20 to 200 mg per day, and most preferably in the range of 50 to 120 mg per day.

Prikladna dnevna doza za upotrebu u profilaksi će općenito biti u rasponu od 0.1 do 50 mg. A suitable daily dose for use in prophylaxis will generally be in the range of 0.1 to 50 mg.

Željena doza može biti u obliku jedinične doze ili u podijeljenim dozama koje se primjenjuju u određenim intervalima, na primjer kao dvije, tri, četiri ili više sub-doza po danu. Spoj se uobičajeno primjenjuje kao jedinični dozirni oblik. The desired dose may be in the form of a unit dose or in divided doses administered at certain intervals, for example as two, three, four or more sub-doses per day. The compound is usually administered as a unit dosage form.

Spojevi prema prikazanom izumu se također mogu kombinirati sa ostalim terapeutskim sredstvima, na primjer, sa ostalim sredstvima za snižavanje nivoa androgena i/ili estrogena. Posebno se može istaknuti da se spojevi prema izumu mogu koristiti zajedno sa dobro poznatim antikancerogenim sredstvima. The compounds according to the present invention can also be combined with other therapeutic agents, for example, with other agents for lowering androgen and/or estrogen levels. In particular, it can be emphasized that the compounds according to the invention can be used together with well-known anticancer agents.

Izum tako osigurava, sa idućeg aspekta, kombinaciju koja sadrži spoj formule (I) koja je ranije definirana zajedno sa drugim terapeutski aktivnim sredstvima, posebno sa antikancerogenim sredstvima. The invention thus provides, from a further aspect, a combination containing the compound of formula (I) previously defined together with other therapeutically active agents, especially with anticancer agents.

Ranije navedena kombinacija se može nalaziti u obliku farmaceutskog pripravka i tako farmaceutski pripravci koji sadrže ranije navedene kombinacije uz farmaceutski prihvatljive podloge, čine idući aspekt izuma. The previously mentioned combination can be in the form of a pharmaceutical preparation, and thus pharmaceutical preparations containing the previously mentioned combinations with pharmaceutically acceptable bases constitute the next aspect of the invention.

Kada se spojevi formule (I) koriste u kombinaciji sa drugim terapeutskim sredstvom, spojevi se mogu primjeniti bilo neposredno jedan iza drugoga ili istovremeno ranije opisanim putevima. When the compounds of formula (I) are used in combination with another therapeutic agent, the compounds can be administered either immediately after each other or simultaneously by the previously described routes.

Prikladna terapeutska sredstva za upotrebe u kombinacijama koje su ranije navedene uključuju, na primjer ciproteron acetat, flutamid i anandron. Suitable therapeutic agents for use in the combinations listed above include, for example, cyproterone acetate, flutamide and anandrone.

Kada se spojevi formule (I) koriste u kombinacijama sa drugim terapeutskim sredstvom učinkovitim u snižavanju nivoa androgena i/ili estrogena u sisavaca, uključujući i ljude, doze pojedinačnih spojeva će varirati od onih kada se spojevi upotrebljavaju sami. Tako, kada se spojevi formule (I) koriste sa drugim terapeutskim sredstvom, doza svakog spoja može biti jednaka ili različita od one koja se koristi kada se spoj upotrebljava sam. Odgovarajuće doze će odrediti stručnjaci. When the compounds of formula (I) are used in combination with another therapeutic agent effective in lowering androgen and/or estrogen levels in mammals, including humans, the doses of the individual compounds will vary from those when the compounds are used alone. Thus, when compounds of formula (I) are used with another therapeutic agent, the dose of each compound may be the same or different than that used when the compound is used alone. Appropriate doses will be determined by experts.

Spojevi prema izumu se mogu pripremiti bilo kojim postupkom poznatim u struci za pripremu spojeva analogne strukture. U slijedećim opisima R1, R2, R3, R4, R5, R6, m, n i p su jednaki kao i ranije definirani za formulu (I), osim kada je to drugačije naznačeno. The compounds of the invention can be prepared by any method known in the art for the preparation of compounds of analogous structure. In the following descriptions, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , m, n and p are the same as previously defined for formula (I), unless otherwise indicated.

U općem postupku (A), spoj opće formule (I) u kojoj je R1 vodikov atom, može se pripremiti iz intermedijera formule (II) In the general procedure (A), the compound of the general formula (I) in which R1 is a hydrogen atom, can be prepared from the intermediate of the formula (II)

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ciklizacijom. Reakcija se uobičajeno provodi u prisutnosti prikladnog otapala, poput ugljikovodičnih otapala, na primjer dodekana, ili u prisutnosti halogeniranih otapala poput diklorobenzena, povoljno je pri povišenoj temperaturi, na primjer 100 do 300°C, povoljnije je pri 150 do 220°C. Opći postupak (A) je posebno koristan za pripremu spojeva formule (I) u kojima je R5 triazol grupa. cyclization. The reaction is usually carried out in the presence of a suitable solvent, such as hydrocarbon solvents, for example dodecane, or in the presence of halogenated solvents such as dichlorobenzene, preferably at an elevated temperature, for example 100 to 300°C, more preferably at 150 to 220°C. The general procedure (A) is particularly useful for the preparation of compounds of formula (I) in which R5 is a triazole group.

Intermedijeri formule (II) se mogu pripremiti iz odgovarajućih amina formule (III) Intermediates of formula (II) can be prepared from corresponding amines of formula (III)

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tretiranjem sa natrij nitritom u prisutnosti mineralne kiseline, npr. sumporne kiseline, nakon čega slijedi tretiranje sa natrij azidom. Reakcija se uobičajeno provodi u vodenoj otopini. by treatment with sodium nitrite in the presence of a mineral acid, eg sulfuric acid, followed by treatment with sodium azide. The reaction is usually carried out in an aqueous solution.

Spojevi formule (III) se mogu pripremiti iz odgovarajućih nitro spojeva formule (IV) Compounds of formula (III) can be prepared from corresponding nitro compounds of formula (IV)

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redukcijom uz upotrebu vodika ili donatora vodika, npr. amonij formata u prisutnosti katalizatora, poput katalizatora od plemenith metala, npr. platine, platina oksida ili rodija, koji se mogu nalaziti na drvenom ugljenu. Redukcija se može provesti u otapalu poput alkohola, npr. metanola ili etanola ( koji mogu biti vodeni), octene kiseline, vodene octene kiseline, etera npr. dioksana.estera npr. etil acetata ili amida npr. dimetilformamida, te se uobičajeno provodi pri temperaturi od -10 do +50°C, povoljnije je pri 20 do 30°C. by reduction using hydrogen or a hydrogen donor, eg ammonium formate in the presence of a catalyst, such as a noble metal catalyst, eg platinum, platinum oxide or rhodium, which may be on charcoal. The reduction can be carried out in a solvent such as alcohol, eg methanol or ethanol (which can be aqueous), acetic acid, aqueous acetic acid, ether eg dioxane, ester eg ethyl acetate or amide eg dimethylformamide, and is usually carried out at temperature from -10 to +50°C, it is more favorable at 20 to 30°C.

Spojevi opće formule (IV) se mogu pripremiti iz spojeva formule (V) Compounds of general formula (IV) can be prepared from compounds of formula (V)

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tretiranjem sa spojem formule HR5 ili njegovom natrijevom soli. Reakcija se uobičajeno provodi u prikladnom otapalu, npr. dimetilformamidu. treatment with the compound of formula HR5 or its sodium salt. The reaction is usually carried out in a suitable solvent, eg dimethylformamide.

Intermedijeri formule (V) se mogu pripremiti iz spojeva formule (VI) Intermediates of formula (V) can be prepared from compounds of formula (VI)

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bromiranjem slobodnih radikala, na primjer upotrebom N-bromsukcinimida u prisutnosti inicijatora, kakav je peroksid i/ili ultraljubičasto svjetlo. Reakcija se uobičajeno provodi u ne-polarnom otapalu, kakvo je na primjer halogenirano otapalo, npr. kloroform ili tetraklorometan, pri temperaturi od 20 do 80°C. by free radical bromination, for example using N-bromosuccinimide in the presence of an initiator such as peroxide and/or ultraviolet light. The reaction is usually carried out in a non-polar solvent, such as a halogenated solvent, for example chloroform or tetrachloromethane, at a temperature of 20 to 80°C.

Spojevi formule (VI) se mogu pripremiti iz spojeva formule (VII) Compounds of formula (VI) can be prepared from compounds of formula (VII)

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(u kojoj L predstavlja lako zamjenjivu grupu ili atom) reakcijom sa spojem formule (VIII) (in which L represents an easily replaceable group or atom) by reaction with a compound of formula (VIII)

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u prisutnosti prikladnog paladij(O) katalizatora poput tetrakis(trifenilfosfin)paladij(O) i lužine, na primjer natrij karbonata, u prikladnom vodenom otapalu poput alkohola, npr. etanola, aromatskih ugljikovodika, npr. benzena, ili etera npr. dimetoksietana, ili u vodenoj smjesi otapala. Prikladni atomi ili grupe predstavljene sa L uključuju halogene atome, npr. atome broma ili joda, ili malene grupe. in the presence of a suitable palladium(O) catalyst such as tetrakis(triphenylphosphine)palladium(O) and a base, for example sodium carbonate, in a suitable aqueous solvent such as an alcohol, for example ethanol, an aromatic hydrocarbon, for example benzene, or an ether, for example dimethoxyethane, or in an aqueous solvent mixture. Suitable atoms or groups represented by L include halogen atoms, eg bromine or iodine atoms, or small groups.

U idućem, općem postupku (B), spoj formule (I) se može pripremiti iz spoja formule (IX) In the next, general process (B), the compound of formula (I) can be prepared from the compound of formula (IX)

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deoksidacijom. Reakcija deoksidacije se provodi upotrebom prikladnog reducirajućeg sredstva poput vodika u prisutnosti katalizatora, poput katalizatora od plemenitih metala, npr. platine, platina oksida ili rodija, koji mogu biti npr. na drvenom ugljenu. Reakcija se uobičajeno provodi u otapalu poput alkohola, npr. metanola ili etanola, koji mogu biti vodeni, te u prisutnosti kiseline, npr klorovodične kiseline, povoljno je pri povišenoj temperaturi, npr. pri temperaturi refluksa otapala ili pri povišenom tlaku. deoxidation. The deoxidation reaction is carried out using a suitable reducing agent such as hydrogen in the presence of a catalyst, such as a noble metal catalyst, eg platinum, platinum oxide or rhodium, which may be eg on charcoal. The reaction is usually carried out in a solvent such as an alcohol, eg methanol or ethanol, which can be aqueous, and in the presence of an acid, eg hydrochloric acid, preferably at an elevated temperature, eg at the reflux temperature of the solvent or at elevated pressure.

Općenito, postupak (B) je posebno koristan za pripremu spojeva formule (I) u kojoj je R5 piridil grupa. In general, process (B) is particularly useful for the preparation of compounds of formula (I) wherein R 5 is a pyridyl group.

Intermedijeri formule (IX) se mogu pripremiti iz spojeva formule (X) Intermediates of formula (IX) can be prepared from compounds of formula (X)

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reakcijom sa spojem formule (XI) by reaction with a compound of formula (XI)

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u prisutnosti prikladne lužine, poput alkillitija, npr. n-butillitija. in the presence of a suitable base, such as alkyllithium, eg n-butyllithium.

Reakcija se uobičajeno provodi u prisutnosti prikladnog otapala poput etera, npr. dietil etera, dimetoksietana ili tetrahidrofurana, ili u smjesi otapala, povoljno je pri niskoj temperaturi, npr. -90 do -50°C, povoljnije je na oko 70°C. The reaction is usually carried out in the presence of a suitable solvent such as an ether, eg diethyl ether, dimethoxyethane or tetrahydrofuran, or in a mixture of solvents, preferably at a low temperature, eg -90 to -50°C, more preferably at about 70°C.

Spojevi formule (X) se mogu pripremiti iz spojeva formule (XII) Compounds of formula (X) can be prepared from compounds of formula (XII)

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oksidacijom. Prikladna oksidirajuća sredstva će znati izabrati stručnjak iz struke, a ta sredstva uključuju piridin klorokromat, kalij dikromat u sumpornoj kiselini i barij manganatu. Reakcija se uobičajeno vodi u prisutnosti otapala, npr. halogeniranih otapala poput dikorometana. by oxidation. Suitable oxidizing agents will be known to one skilled in the art, and these agents include pyridine chlorochromate, potassium dichromate in sulfuric acid, and barium manganate. The reaction is usually carried out in the presence of a solvent, eg halogenated solvents such as dichloromethane.

Spojevi formule (XII) se mogu pripremiti iz spojeva formule (XIII) Compounds of formula (XII) can be prepared from compounds of formula (XIII)

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ciklizacijom. Reakcija se uobičajeno provodi u prisutnosti prikladnog otapala, poput ugljikovodikovih otapala, npr poput dodekana ili u prisutnosti halogeniranog otapala, npr. diklorometan, povoljno je pri povišenoj temperaturi, npr. 100 do 300°C, povoljnije je pri 150 do 220°C. cyclization. The reaction is usually carried out in the presence of a suitable solvent, such as hydrocarbon solvents, such as dodecane, or in the presence of a halogenated solvent, such as dichloromethane, preferably at an elevated temperature, such as 100 to 300°C, preferably at 150 to 220°C.

Spojevi formule (XIII) se mogu pripremiti iz spojeva formule (XIV) Compounds of formula (XIII) can be prepared from compounds of formula (XIV)

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tretiranjem sa natrij nitritom u prisutnosti mineralne kiseline, npr. sumporne kiseline, nakon čega slijedi natrij azid. Reakcija se uobičajeno provodi u vodenoj otopini. by treatment with sodium nitrite in the presence of a mineral acid, eg sulfuric acid, followed by sodium azide. The reaction is usually carried out in an aqueous solution.

Spojevi formule (XIV) se mogu dobiti iz spojeva formule (XV) Compounds of formula (XIV) can be obtained from compounds of formula (XV)

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(u kojoj G predstavlja hidroksi zaštitnu grupu) redukcijom uz upotrebu vodika ili donatora vodika, npr. amonij formata u prisutnosti katalizatora, poput katalizatora od plemenitih metala, npr platine, platina oksida ili rodija, koji se mogu nalaziti na drvenom ugljenu te se kasnije ukloni zaštitna grupa G. Redukcija se uobičajeno provodi u otapalu poput alkohola, npr. u metanolu ili u etanolu, koji mogu biti vodeni, te je povoljno kada se radi u prisutnosti kiseline, npr. klorovodične kiseline. Prikladne hidroksi grupe su opisane kasnije u tekstu. (in which G represents a hydroxy protecting group) by reduction using hydrogen or a hydrogen donor, eg ammonium formate in the presence of a catalyst, such as a noble metal catalyst, eg platinum, platinum oxide or rhodium, which may be present on charcoal and later removed protecting group G. The reduction is usually carried out in a solvent such as an alcohol, for example in methanol or in ethanol, which can be aqueous, and it is advantageous when it is carried out in the presence of an acid, for example hydrochloric acid. Suitable hydroxy groups are described later in the text.

Spojevi formule (XV) se mogu pripremiti iz spojeva formule (XVI) Compounds of formula (XV) can be prepared from compounds of formula (XVI)

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(u kojoj L predstavlja lako zamjenjiv atom ili grupu) reakcijom sa spojem formule (XVII) (in which L represents an easily replaceable atom or group) by reaction with the compound of formula (XVII)

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u prisutnosti prikladnog paladij(O) katalizatora kakav je tetrakis(trifenilfosfin)paladij(O) i u prisutnosti lužine, npr. natrij karbonata, u prikladnom vodenom otapalu poput alkohola, npr. etanola, aromatskog ugljikovodika, npr. benzena, ili etera, npr. dimetoksietana, ili u vodenoj smjesi otapala, povoljno pri povišenoj temperaturi. Prikladni atomi ili grupe predstavljene sa L uključuju atom halogena, npr. atom broma ili joda, ili malu grupu. in the presence of a suitable palladium(O) catalyst such as tetrakis(triphenylphosphine)palladium(O) and in the presence of a base, eg sodium carbonate, in a suitable aqueous solvent such as an alcohol, eg ethanol, an aromatic hydrocarbon, eg benzene, or an ether, eg dimethoxyethane, or in an aqueous solvent mixture, preferably at an elevated temperature. Suitable atoms or groups represented by L include a halogen atom, eg a bromine or iodine atom, or a small group.

Alternativni putevi sinteze za intermedijere formule (X) će biti jasni stručnjacima iz struke. Alternative synthetic routes for intermediates of formula (X) will be apparent to those skilled in the art.

U idućem općem postupku (C) spoj formule (I) prema izumu može se prevesti u neki drugi spoj prema izumu In the following general procedure (C), the compound of formula (I) according to the invention can be converted into another compound according to the invention

upotrebom uobičajenih postupaka. using usual procedures.

Prema jednom obliku općeg postupka (C), spoj formule (I) u kojoj R1 predstavlja atom vodika, se može alkilirati upotrebom uobičajene tehnike. Reakcija se može provesti upotrebom prikladnog alkilirajućeg sredstva poput alkil halida, alkil tosilata ili dialkilsulfata. Reakcija se uobičajeno može provesti u inertnom organskom otapalu poput amida, npr. dimetilformamida, ili etera, npr. tetrahidrofurana, povoljno je u prisutnosti lužine. Prikladne lužine uključuju, na primjer, hidride alkalijskih metala, npr. natrijev hidrid, karbonate alkalijskih metala, npr. natrijev karbonat, ili alkokside alkalijskih metala, npr. natrijev ili kalijev metoksid, etoksid ili t-butoksid. Reakcija alkiliranja se uobičajeno provodi pri temperaturi 25 do 100°C. According to one form of the general process (C), the compound of formula (I) in which R1 represents a hydrogen atom, can be alkylated using a conventional technique. The reaction can be carried out using a suitable alkylating agent such as an alkyl halide, alkyl tosylate or dialkyl sulfate. The reaction can usually be carried out in an inert organic solvent such as an amide, eg dimethylformamide, or an ether, eg tetrahydrofuran, preferably in the presence of an alkali. Suitable bases include, for example, alkali metal hydrides, eg sodium hydride, alkali metal carbonates, eg sodium carbonate, or alkali metal alkoxides, eg sodium or potassium methoxide, ethoxide or t-butoxide. The alkylation reaction is usually carried out at a temperature of 25 to 100°C.

Prema idućem općem postupku (D), spoj formule (I) prema izumu, ili njegova sol se mogu pripremiti podvrgavanjem zaštićenog derivata formule (I) ili njegove soli, reakciji da bi se uklonila zaštitna grupa ili grupe. Tako, u ranijem koraku tokom pripreme spoja formule (I) ili njegove soli, može biti neophodno i/ili poželjno da se zaštiti jedna ili više osjetljivih grupa u molekuli da bi se spriječile nepoželjne nuz reakcije. Takova zaštita se može provesti na uobičajen način, na primjer kako je to opisano u "Protective Groups in Organic Chemistry" Ed.J.F.W.McOmie (Plenum Press 1973) ili u "Protective Groups in Organic Synthesis" od TW Greene (John Wiley and Sons 1981). According to the following general procedure (D), a compound of formula (I) according to the invention, or a salt thereof, can be prepared by subjecting a protected derivative of formula (I) or a salt thereof, to a reaction to remove the protecting group or groups. Thus, in an earlier step during the preparation of a compound of formula (I) or a salt thereof, it may be necessary and/or desirable to protect one or more sensitive groups in the molecule to prevent undesirable side reactions. Such protection can be carried out in a conventional manner, for example as described in "Protective Groups in Organic Chemistry" by Ed.J.F.W.McOmie (Plenum Press 1973) or in "Protective Groups in Organic Synthesis" by TW Greene (John Wiley and Sons 1981 ).

U spojevima formule (I) u kojima R1 predstavlja vodik, grupa NR1 može biti zaštićena na primjer sa uobičajenom amino zaštitnom grupom. Takove grupe mogu uklučivati na primjer aralkil grupe, poput benzil, difenilmetil ili trifenilmetil grupa; te acil grupe poput tosil, N-benziloksikarbonil ili t-butoksikarbonil. In compounds of formula (I) in which R1 represents hydrogen, the group NR1 can be protected, for example, with a conventional amino protecting group. Such groups may include, for example, aralkyl groups, such as benzyl, diphenylmethyl or triphenylmethyl groups; and acyl groups such as tosyl, N-benzyloxycarbonyl or t-butoxycarbonyl.

Uklanjanje bilo koje prikazane zaštitne grupe se može postići uobičajenim postupcima. Tako se, aralkil grupe poput benzil grupe, mogu odcijepiti hidrogenolizom u prisutnosti katalizatora (npr. paladij na drvenom ugljenu); acil grupa poput t-butoksikarbonil grupe se može ukloniti cijepanjem sa, na primjer, klorovodikom u dioksanu ili sa natrijevim metoksidom u metanolu. Removal of any protecting group shown can be accomplished by conventional procedures. Thus, aralkyl groups such as benzyl groups can be cleaved by hydrogenolysis in the presence of a catalyst (eg palladium on charcoal); an acyl group such as a t-butoxycarbonyl group can be removed by cleavage with, for example, hydrogen chloride in dioxane or sodium methoxide in methanol.

Razumljivo je da će u nekim slučajevima ranije opisanih općih postupaka (A) do (C), biti neophodno ili poželjno da se zaštiti bilo koja osjetljiva grupa na upravo opisan način. Tako, reakcijski korak koji obuhvaća deprotekciju zaštićenog derivata opće formule (I) ili njegove soli se može provesti neposredno nakon bilo kojeg od opisanih postupaka (A) do (C). It is understood that in some cases of the previously described general procedures (A) to (C), it will be necessary or desirable to protect any vulnerable group in the manner just described. Thus, the reaction step comprising the deprotection of the protected derivative of the general formula (I) or its salt can be carried out directly after any of the described processes (A) to (C).

Tamo gdje je poželjno da se spoj prema izumu izolira kao sol, na primjer kao kiselinska sol, to se može postići tretiranjem slobodne baze opće formule (I) sa odgovarajućom kiselinom, povoljno je sa ekvivalentim iznosom. Solvati spojeva prema izumu se mogu pripremiti kristalizacijom iz ili evaporacijom odgovarajućeg otapala iz otopine spoja formule (I). Separacija enantiomera formule (I) se može provesti na uobičajen način, na primjer re-otapanjem racemičnih smjesa npr. upotrebom kiralne HPLC tehnike ili pomoću stereospecifične sinteze iz izomerično čistih polaznih materijala ili intermedijera, na primjer kako je to opisano u Stereochemistry of Carbon Compounds od E. L. Eliel (McGraw Hill, 1962) i u Tables of Resolving Agents od S.H.Wilen. Where it is desirable to isolate a compound of the invention as a salt, for example as an acid salt, this can be achieved by treating the free base of general formula (I) with an appropriate acid, preferably an equivalent amount. Solvates of the compounds according to the invention can be prepared by crystallization from or evaporation of a suitable solvent from a solution of the compound of formula (I). Separation of the enantiomers of formula (I) can be carried out in a conventional way, for example by re-dissolving racemic mixtures, for example using a chiral HPLC technique or by stereospecific synthesis from isomerically pure starting materials or intermediates, for example as described in Stereochemistry of Carbon Compounds by E. L. Eliel (McGraw Hill, 1962) and in Tables of Resolving Agents by S. H. Wilen.

Tako, prema idućem aspektu izuma, slijedeće reakcije se mogu, ako je to neophodno i/ili poželjno provesti bilo kojim odgovarajućim redoslijedom neposredno nakon bilo kojeg od postupaka (A) do (C): Thus, according to a further aspect of the invention, the following reactions can, if necessary and/or desirable, be carried out in any suitable order immediately after any of the processes (A) to (C):

(i) uklanjanje bilo koje zaštitne grupe; (i) removal of any protecting group;

(ii) konverzija spoja formule (I) ili njegove soli ili solvata u njegovu farmaceutski prihvatljivu sol ili solvat (na primjer, hidrat); (ii) converting a compound of formula (I) or a salt or solvate thereof into a pharmaceutically acceptable salt or solvate thereof (for example, a hydrate);

(iii) odijeljivanje racemične smjese u pojedinačne enantiomere formule (I). (iii) separation of the racemic mixture into individual enantiomers of formula (I).

Osim što se mogu koristiti kao posljednji glavni korak u pripremi, ranije navedeni opći postupci za pripremu spojeva prema izumu, mogu se koristiti i za uvođenje željenih grupa u bilo kojem intermedijernom stadiju u toku pripreme željenog spoja. Zbog toga, treba biti razumljivo da u takvom višestepenom postupku, redoslijed reakcija treba izabrati tako da reakcijski uvjeti ne utječu na grupe prisutne u molekuli, koje se žele zadržati u konačnom produktu. In addition to being used as the last major step in the preparation, the previously mentioned general procedures for the preparation of the compounds according to the invention can also be used to introduce the desired groups at any intermediate stage during the preparation of the desired compound. Therefore, it should be understood that in such a multi-step procedure, the order of the reactions should be chosen so that the reaction conditions do not affect the groups present in the molecule, which want to be retained in the final product.

Kao što je to ranije navedeno, spojevi prema izumu su korisni 17,20-liaza inhibitori. 17,20-iaza inhibicija se može prikazati slijedećim testovima: As noted earlier, the compounds of the invention are useful 17,20-lyase inhibitors. 17,20-Iase inhibition can be demonstrated by the following tests:

Aktivnost in vitro Activity in vitro

Biološka aktivnost in vitro je određena mjerenjem inhibicije 17,20-liaza aktivnosti u mikrosomalnom preparatu dobivenom iz humanih testisa. Raspon koncentracija svakog spoja je inkubiran sa mikrosomalnim preparatom i 17-α-hidroksi (21-14C) pregnenolonom kao supstratom tokom 60 minuta na 37°C. Ispita se radioaktivni produkt i inhibicija se odredi usporedbom sa neinhibiranim kontrolnim uzorcima. Biological activity in vitro was determined by measuring the inhibition of 17,20-lyase activity in a microsomal preparation obtained from human testes. A range of concentrations of each compound was incubated with the microsomal preparation and 17-α-hydroxy (21-14C) pregnenolone as a substrate for 60 minutes at 37°C. The radioactive product is tested and inhibition is determined by comparison with non-inhibited control samples.

Aktivnost in vivo Activity in vivo

Biološka aktivnost in vivo je određena na modelu biosinteze testosterona kod štakora. Spojevi su primjenjeni p.o. u dozi 3mg/kg. Jedan sat kasnije štakorima je dano s.c. humani korionski gonadotropin (hCG) da bi se stimulirala sinteza testosterona te je dva sata nakon primjene hCG uzeta krv i mjerene su koncentracije testosterona u serumu. Inhibicijska aktivnost je određena usporedbom sa vrijednostima dobivenim za štakore koji su primili isključivo vehikulum. Biological activity in vivo was determined on the model of testosterone biosynthesis in rats. Compounds were administered p.o. in a dose of 3 mg/kg. One hour later, rats were given s.c. human chorionic gonadotropin (hCG) to stimulate testosterone synthesis, and two hours after hCG administration blood was taken and serum testosterone concentrations were measured. Inhibitory activity was determined by comparison with values obtained for rats that received vehicle alone.

Rezultati isitivanja in vivo i in vitro za spojeve iz slijedećih primjera su prikazani u Tabeli 1. Rezultati za poznati 17,20-liaza inhibitor ketokonazol su uključeni radi usporedbe. The results of the in vivo and in vitro assays for the compounds of the following examples are shown in Table 1. The results for the known 17,20-lyase inhibitor ketoconazole are included for comparison.

Tabela 1 Table 1

[image] *Doza ketokonazola je bila 30 mg/kg. [image] *The dose of ketoconazole was 30 mg/kg.

Proučavanja akutne toksičnosti ukazuju da je pojedinačna doza od 3mg/kg p.o. spoja iz Primjera 2 dobro podnošljiva za štakore i nije primjećena prekomjerna toksičnost. Acute toxicity studies indicate that a single dose of 3mg/kg p.o. of the compound of Example 2 was well tolerated in rats and no excessive toxicity was observed.

Izum je nadalje prikazan slijedećim ne-limitirajućim primjerima. Sve temperature su prikazane u °C. Kromatografija se provodila na silika gelu. Sušenje podrazumijeva sušenje iznad anhidridnog magnezij sulfata. DMSO označava dimetilformamid. THF označava tetrahidrofuran. DME označava dimetoksietan. IPE označava isopropil eter. The invention is further illustrated by the following non-limiting examples. All temperatures are shown in °C. Chromatography was performed on silica gel. Drying means drying over anhydrous magnesium sulfate. DMSO stands for dimethylformamide. THF stands for tetrahydrofuran. DME stands for dimethoxyethane. IPE stands for isopropyl ether.

Intermedijer 1 Intermediary 1

4-(t-Butildimetilsililoksimetil)fenilboronijeva kiselina 4-(t-Butyldimethylsilyloxymethyl)phenylboronic acid

(i)4-(t-Butildimetilsililoksimetil)-bromobenzen (i) 4-(t-Butyldimethylsilyloxymethyl)-bromobenzene

Otopina t-butildimetilsilil klorida (21.1g) u DMF-u (25 ml) se tretira kapajući sa otopinom 4-bromo-benzil alkoholom (25g) i imidazolom (18.2g) u DMF-u (100ml). Rezultirajuća otopina se ostavi stajati na sobnoj temperaturi tokom 72 sata. Reakcijska smjesa se doda u etil acetat (2000ml) i organski sloj se ispere sa 2N HCl (2x250 ml), vodom (4x250 ml), rasolom (250 ml), suši se i evaporira da bi se dobilo žuto ulje. Kromatografija na silika gelu (1 kg) uz eluaciju sa cikloheksan/etil acetatom (10:1v/v) daje produkt kao svjetlo žuto ulje. A solution of t-butyldimethylsilyl chloride (21.1g) in DMF (25ml) was treated dropwise with a solution of 4-bromo-benzyl alcohol (25g) and imidazole (18.2g) in DMF (100ml). The resulting solution is left to stand at room temperature for 72 hours. The reaction mixture was added to ethyl acetate (2000ml) and the organic layer was washed with 2N HCl (2x250ml), water (4x250ml), brine (250ml), dried and evaporated to give a yellow oil. Chromatography on silica gel (1 kg) eluting with cyclohexane/ethyl acetate (10:1 v/v) gives the product as a light yellow oil.

(ii) 4(t-Butildimetilsililoksimetil)fenilboronijeva kiselina (ii) 4(t-Butyldimethylsilyloxymethyl)phenylboronic acid

Otopina (i) (32,37g) u suhom tetrahidrofuranu (250ml) se ohladi na -70°C pod N2. Kapajući se dodaje n-butillitij (70 ml 1.6M otopine u heksanu) tokom 15 minuta zadržavajući temperaturu ispod -65°C. Rezultirajuća žuta otopina se miješa tokom dva sata na temperaturi ispod -70°C, zatim se kapajući doda triisopropil borat (75ml), zadržavajući temperaturu ispod -65°C. Nakon završenog dodavanja, dozvoli se reakciji da se ugrije na sobnu temperaturu, te se zatim prekine reakcija dodavanjem vode (550ml) i zatim etera (250ml). A solution of (i) (32.37g) in dry tetrahydrofuran (250ml) was cooled to -70°C under N2. n-butyllithium (70 ml of a 1.6M solution in hexane) is added dropwise over 15 minutes, keeping the temperature below -65°C. The resulting yellow solution is stirred for two hours at a temperature below -70°C, then triisopropyl borate (75ml) is added dropwise, keeping the temperature below -65°C. After the addition was complete, the reaction was allowed to warm to room temperature, and the reaction was then quenched by the addition of water (550ml) and then ether (250ml).

Organski sloj se odijeli i zatim se vodena faza ekstrahira sa eterom (2x500 ml). Spojeni organski slojevi se isperu sa rasolom (200 ml), suše i evaporiraju da bi se dobio produkt kao svjetlo žuta kristalna krutina. The organic layer is separated and then the aqueous phase is extracted with ether (2x500 ml). The combined organic layers were washed with brine (200 ml), dried and evaporated to give the product as a light yellow crystalline solid.

Da bi se izbjegle nedoumice, u spojevima iz Primjera 1 do 7 i u Primjeru 9, R2 je na položaju 7 u formuli (I), u Primjeru 8 R2 je u položajima 5 i 7, u Primjeru 7 R3 je u položaju 1 i u Primjeru 9 R3 je u položajima 1 i 4 u formuli (I). Imena pojedinih spojeva su u skladu sa IUPAC nomenklaturom. For the avoidance of doubt, in the compounds of Examples 1 to 7 and in Example 9, R 2 is in position 7 of formula (I), in Example 8 R 2 is in positions 5 and 7, in Example 7 R 3 is in position 1 and in Example 9 R 3 is in positions 1 and 4 in formula (I). The names of individual compounds are in accordance with the IUPAC nomenclature.

Primjer 1 Example 1

2-Fluoro-7-[1,2,4]triazol-1-ilmetil-9H-karbazol 2-Fluoro-7-[1,2,4]triazol-1-ylmethyl-9H-carbazole

1(i)4-Fluoro-4'-metil-2-nitro-bifenil 1(i)4-Fluoro-4'-methyl-2-nitro-biphenyl

Otopina 2-bromo-5-fluoronitrobenzena (15g) u benzenu (60ml) se brzo miješa pod N2, te se tretira sa tetrakisfenilfosfin paladijem(O) (1.13g), vodenim 2M natrijevim karbonatom (35.7ml) i otopinom p-tolilboronijeve kiseline (10.2g) u 95%-tnom etanolu (25ml). Smjesa se zagrijava na 95°C i brzo miješa pod N2 tokom 16 sati. Reakcijska smjesa se ekstrahira sa etil acetatom (400ml) i zatim još sa (2x100ml). Spojeni ekstrakti se isperu sa vodom (100ml), rasolom (100ml), suše se (MgSO4) i evaporiraju da bi se dobilo smeđe ulje. Kromatografija na silika gelu (500g) uz eluaciju sa cikloheksan/etil acetatom (25:1v/v) daje naslovni spoj. A solution of 2-bromo-5-fluoronitrobenzene (15g) in benzene (60ml) is stirred rapidly under N2, and treated with tetrakisphenylphosphine palladium(O) (1.13g), aqueous 2M sodium carbonate (35.7ml) and p-tolylboronic acid solution (10.2g) in 95% ethanol (25ml). The mixture is heated to 95°C and stirred rapidly under N2 for 16 hours. The reaction mixture is extracted with ethyl acetate (400ml) and then with (2x100ml). The combined extracts were washed with water (100ml), brine (100ml), dried (MgSO4) and evaporated to give a brown oil. Chromatography on silica gel (500g) eluting with cyclohexane/ethyl acetate (25:1v/v) gives the title compound.

1 (ii)4'-Bromometil-4-fluoro-2-nitro-bifenil 1 (ii) 4'-Bromomethyl-4-fluoro-2-nitro-biphenyl

Otopina 1(i) (2.04g) u ugljik tetrakloridu (40ml) se tretira sa tragovima benzoil peroksida i N-bromosukcinimidom (1.81 g). Smjesa se refluksira tokom jednog sata preko 150 W žarulje i zatim se précipitât sukcinimida ukloni filtriranjem i ispere sa CCl4 (2x5ml). Filtrat i tekućina od ispiranja se evaporiraju da bi se dobio naslovni produkt kao žuto ulje. A solution of 1(i) (2.04g) in carbon tetrachloride (40ml) was treated with traces of benzoyl peroxide and N-bromosuccinimide (1.81g). The mixture is refluxed for one hour over a 150 W lamp and then the succinimide precipitate is removed by filtration and washed with CCl4 (2x5ml). The filtrate and washings were evaporated to give the title product as a yellow oil.

1 (iii) 1-(4'-Fluoro-2'-nitro-bifenil-4-ilmetil)-1H-[1,2,4]triazol 1 (iii) 1-(4'-Fluoro-2'-nitro-biphenyl-4-ylmethyl)-1H-[1,2,4]triazole

Otopina 1,2,4-triazola (0,613g) u DMF-u (5ml) se tretira sa natrij hidridom (0,266g 80%-tne disperzije u ulju). 5 minuta nakon što prestane razvijanje svih plinova, smjesa se tretira sa otopinom 1(ii) (3,1g) u DMF-u (3ml). Rezultirajuća blijedo smeđa otopina se miješa pri sobnoj temperaturi tokom 20 sati. Smjesa se doda etil acetatu (500ml) i organska faza se ispere vodom (4x50ml) i zatim se ekstrahira sa 2N HCl (6x80ml), te se zatim ispere rasolom (100ml), suši (MgSO4) i evaporira. Ostatak se pročisti kromatografijom na silika gelu (150g) uz eluaciju sa CHCI3 dajući svjetlo žutu krutinu. Eluacija sa CHCl3/MeOH (19:1) daje naslovni spoj kao žutu gumu. A solution of 1,2,4-triazole (0.613g) in DMF (5ml) is treated with sodium hydride (0.266g of 80% dispersion in oil). 5 minutes after the evolution of all gases has ceased, the mixture is treated with a solution of 1(ii) (3.1g) in DMF (3ml). The resulting pale brown solution was stirred at room temperature for 20 hours. The mixture was added to ethyl acetate (500ml) and the organic phase was washed with water (4x50ml) and then extracted with 2N HCl (6x80ml), then washed with brine (100ml), dried (MgSO4) and evaporated. The residue was purified by chromatography on silica gel (150 g) eluting with CHCl 3 to give a light yellow solid. Elution with CHCl3/MeOH (19:1) gave the title compound as a yellow gum.

1 (iv) 4-Fluoro-4'-[1,2,4]triazol-1-ilmetil-bifenil-2-ilamin 1 (iv) 4-Fluoro-4'-[1,2,4]triazol-1-ylmethyl-biphenyl-2-ylamine

Otopina 1(iii) (1,20g) u octenoj kiselini (5ml) se tretira sa 10%-tnim Pd/C katalizatorom (400mg) i miješa se pod H2 tokom tri sata. Katalizator se ukloni filtriranjem kroz Kieselguhr pločicu, te se zatim ispere sa octenom kiselinom (2x5ml), zatim se filtrat i otopina od filtriranja evaporiraju dajući žutu gumu. Ona se otopi u diklorometanu (100ml) i pažljivo ispere zasićenom vodenom NaHCO3 (100ml), te se zatim organski sloj suši (MgSO4) i evaporira dajući naslovni spoj kao smeđkastu kristaliničnu krutinu. A solution of 1(iii) (1.20g) in acetic acid (5ml) was treated with 10% Pd/C catalyst (400mg) and stirred under H2 for three hours. The catalyst is removed by filtering through a Kieselguhr plate, and then washed with acetic acid (2x5ml), then the filtrate and the solution from the filtration are evaporated to give a yellow gum. It was dissolved in dichloromethane (100ml) and carefully washed with saturated aqueous NaHCO3 (100ml), then the organic layer was dried (MgSO4) and evaporated to give the title compound as a brownish crystalline solid.

1(iv) 1-(2'Azido-4'-fluoro-bifenil-4-ilmetil)-1H-[1,2,4]triazol 1(iv) 1-(2'Azido-4'-fluoro-biphenyl-4-ylmethyl)-1H-[1,2,4]triazole

Otopina 1(iv) (970mg) u vodi (9ml) i koncentriranoj sumpornoj kiselini (0,75ml) se ohladi u ledenoj kupki. Otopina natrij nitrita (261 mg) u vodi (3ml) se dodaje kapajući. Rezultirajuća žuta otopina se miješa u ledenoj kupki tokom 30 minuta. Kapajući se dodaje otopina natrij azida (243mg) u vodi (6ml). Primjeti se brzo razvijanje plina N2. Nakon 30 minuta smjesa se neutralizira sa zasićenom vodenom NaHCO3, zatim se ekstrahira sa diklorometanom (4x50ml). Spojeni ekstrakti se suše (MgSO4) i evaporiraju dajući naslovni spoj kao svjetlo smeđu kristaliničnu krutinu. A solution of 1(iv) (970mg) in water (9ml) and concentrated sulfuric acid (0.75ml) was cooled in an ice bath. A solution of sodium nitrite (261 mg) in water (3 ml) is added dropwise. The resulting yellow solution was stirred in an ice bath for 30 minutes. A solution of sodium azide (243mg) in water (6ml) is added dropwise. Notice the rapid evolution of N2 gas. After 30 minutes, the mixture is neutralized with saturated aqueous NaHCO3, then extracted with dichloromethane (4x50ml). The combined extracts were dried (MgSO4) and evaporated to give the title compound as a light brown crystalline solid.

1 (v) 2-Fluoro-7-[1,2,4]triazol-1-ilmetil-9H-karbazol 1 (v) 2-Fluoro-7-[1,2,4]triazol-1-ylmethyl-9H-carbazole

Otopina 1(v) (200mg) u 1,2-diklorobenzenu (5ml) se zagrijava na 170°C tokom 4 sata. Reakcijska smjesa se razrijedi sa etil acetatom (200ml) i ekstrahira sa 2N HCl (3x60ml). Organski sloj se zatim ispere sa rasolom (50ml), suši (MgSO4) i evaporira dajući nepročišćen produkt uz diklorobenzen. A solution of 1(v) (200mg) in 1,2-dichlorobenzene (5ml) is heated at 170°C for 4 hours. The reaction mixture was diluted with ethyl acetate (200ml) and extracted with 2N HCl (3x60ml). The organic layer is then washed with brine (50ml), dried (MgSO4) and evaporated to give the crude product along with dichlorobenzene.

Nepročišćenom produktu se doda cikloheksan (100ml) i krutina se filtrira i suši dajući kristale naslovnog spoja. Cyclohexane (100ml) was added to the crude product and the solid was filtered and dried to give crystals of the title compound.

NMR δ (DMSO-d6) 5.57 s (2H9, 6,99 t (1H), 7,12 d (1H), 7,25 dd (1H), 7,38s (1H), 8,00 s (1H), 8,00 s (1H9, 8,05 d (1H), 8,10 dd (1H), 8,70 s (1H), 11,42 s (1H). NMR δ (DMSO-d6) 5.57 s (2H9, 6.99 t (1H), 7.12 d (1H), 7.25 dd (1H), 7.38s (1H), 8.00 s (1H) , 8.00 s (1H9, 8.05 d (1H), 8.10 dd (1H), 8.70 s (1H), 11.42 s (1H).

Primjer 2 Example 2

2-Fluoro-7-piridin-3-ilmetil-9H-karbazol 2-Fluoro-7-pyridin-3-ylmethyl-9H-carbazole

2(i) 4-t-Butildimetilsililoksimetil-4'-fluoro-2'-nitrodifenil 2(i) 4-t-Butyldimethylsilyloxymethyl-4'-fluoro-2'-nitrodiphenyl

Otopina 4-(t-butildimetilsililoksimetil)-fenilboronijeve kiseline (intermedijer 1) (25g) i 2-bromo-5-fluoro-nitrobenzena (15,5g) u suhom dimetoksietanu (120ml) se tretira sa tetrakistrifenilfosfin paladij(O) (1.1g) i 2M vodenim natrijevim karbonatom (40ml). Rezultirajuća smjesa se refluksira tokom 16 sati pod N2. Reakcijska smjesa se razrijedi sa etil acetatom (600ml) i ispere vodom (2x100ml), rasolom (100ml), suši se (MgSO4) i evaporira dajući smeđe ulje. Kromatografija na silika gelu (750g), eluacija uz cikloheksan->cikloheksan/etil acetat (15:1) daje naslovni spoj kao žuto ulje. A solution of 4-(t-butyldimethylsilyloxymethyl)-phenylboronic acid (intermediate 1) (25g) and 2-bromo-5-fluoro-nitrobenzene (15.5g) in dry dimethoxyethane (120ml) is treated with tetrakistriphenylphosphine palladium(O) (1.1g ) and 2M aqueous sodium carbonate (40ml). The resulting mixture was refluxed for 16 hours under N2. The reaction mixture was diluted with ethyl acetate (600ml) and washed with water (2x100ml), brine (100ml), dried (MgSO4) and evaporated to give a brown oil. Chromatography on silica gel (750g), eluting with cyclohexane->cyclohexane/ethyl acetate (15:1) gave the title compound as a yellow oil.

2(ii) 2-Amino-4'-t-butildimetilsililoksimetil-4-fluorodifenil 2(ii) 2-Amino-4'-t-butyldimethylsilyloxymethyl-4-fluorodiphenyl

Otopina 2(i) (21 g) u metanolu (300ml) se tretira sa 10% Pd/C katalizatorom (3,4g) i suhim amonijevim formatom (16,48g). Smjesa se miješa pod N2 pri sobnoj temperaturi tokom 24 sata. Katalizator se ukloni filtriranjem, ispere se sa metanolom (2x25ml), pod pokrivačem N2, te se zatim i filtrat i tekućine od isiranja evaporiraju dajući smeđkasti ostatak. On se otopi u vodi (200ml) i ekstrahira sa diklorometanom (3x200ml). Spojeni ekstrakti se suše (MgSO4) i evaporiraju dajući naslovni spoj kao smeđe ulje. A solution of 2(i) (21 g) in methanol (300 ml) was treated with 10% Pd/C catalyst (3.4 g) and dry ammonium formate (16.48 g). The mixture was stirred under N2 at room temperature for 24 hours. The catalyst is removed by filtration, washed with methanol (2x25ml), under a blanket of N2, and then both the filtrate and the separation liquids are evaporated to give a brownish residue. It is dissolved in water (200ml) and extracted with dichloromethane (3x200ml). The combined extracts were dried (MgSO4) and evaporated to give the title compound as a brown oil.

2(iii) (2'-Azido-4'-fluoro-bifenil-4-il)-metanol 2(iii) (2'-Azido-4'-fluoro-biphenyl-4-yl)-methanol

Otopina 2(ii) (18.408g) u dioksanu (200mi) i vodi (200ml) se tretira sa koncentriranom sumpornom kiselinom (11.47ml) i zatim se ohladi na 5°C. Kapajući se doda otopina natrijevog nitrita (4.00g) u vodi (15ml). Rezultirajuća narančasta otopina se miješa na 5°C tokom 30 minuta, a zatim se pažljivo dodaje otopina natrijevog azida (3.75g) u vodi (20ml) izbjegavajući pretjerano stvaranje plina N2. Kada se završi dodavanje, reakcija se miješa na 5°C tokom 30 minuta, a zatim se pažljivo tretira sa zasićenom vodenom otopinom NaHCO3 do neutralnog. Smjesa se ekstrahira sa diklorometanom (5x200ml) i ekstrakti se osuše (MgSO4) i evaporiraju dajući naslovni spoj kao smeđe ulje. A solution of 2(ii) (18.408g) in dioxane (200ml) and water (200ml) was treated with concentrated sulfuric acid (11.47ml) and then cooled to 5°C. A solution of sodium nitrite (4.00g) in water (15ml) is added dropwise. The resulting orange solution was stirred at 5°C for 30 minutes, then a solution of sodium azide (3.75g) in water (20ml) was carefully added avoiding excessive N2 gas formation. When the addition is complete, the reaction is stirred at 5°C for 30 minutes and then carefully treated with saturated aqueous NaHCO 3 until neutral. The mixture was extracted with dichloromethane (5x200ml) and the extracts were dried (MgSO4) and evaporated to give the title compound as a brown oil.

2(iv) (7-Fluoro-9H-karbazol-2-il)-metanol 2(iv) (7-Fluoro-9H-carbazol-2-yl)-methanol

Otopina 2(iii) (13.9g) u 1,2-diklorobenzenu (200ml) se refluksira pod N2 tokom 3 sata. Smjesi se dozvoli da se ohladi i zatim se doda cikloheksan (100ml). Kruti materijal se ukloni filtriranjem i ispere sa cikloheksanom (2x100ml), zatim se suši in vacuo dajući naslovni spoj kao svjetlo smeđu krutinu. A solution of 2(iii) (13.9g) in 1,2-dichlorobenzene (200ml) was refluxed under N2 for 3 hours. The mixture was allowed to cool and then cyclohexane (100ml) was added. The solid was removed by filtration and washed with cyclohexane (2x100ml), then dried in vacuo to give the title compound as a light brown solid.

2(v) 2-Fluoro-7-formil-karbazol-9-karboksilne kiseline tert-butil ester 2(v) 2-Fluoro-7-formyl-carbazole-9-carboxylic acid tert-butyl ester

Otopina 2(iv) (7.18g) u diklorometanu (1500ml) se tretira sa barij manganatom (54.5g) i miješa pod N2 tokom 5 sati. Krutina se ukloni filtriranjem i ispere sa diklorometanom (4x100ml). Filtrat i tekućine od ispiranja se evaporiraju dajući zeleno-smeđu krutinu. Ona se suspendira u diklorometanu (100ml) i tretira sa 4-dimetilaminopiridinom (3.78g) i di-tbutilkarbonatom (7.43g). Rezultirajuća smeđa otopina se ostavi stajati na sobnoj temperaturi tokom 30 minuta, zatim se razrijedi sa etil acetatom. Organska otopina se ispere sa 2N HCl (2x400ml), vodom (200ml), rasolom (2x200ml) i zatim se suši (MgSO4) i evporira dajući nečist produkt. On se pročisti kromatografijom na silika gelu (500g), uz eluaciju sa cikloheksan/etil acetatom (15:1 v/v) dajući naslovni spoj kao svjetlo krem krutinu. A solution of 2(iv) (7.18g) in dichloromethane (1500ml) was treated with barium manganate (54.5g) and stirred under N2 for 5 hours. The solid is removed by filtration and washed with dichloromethane (4x100ml). The filtrate and washings were evaporated to give a green-brown solid. It is suspended in dichloromethane (100ml) and treated with 4-dimethylaminopyridine (3.78g) and di-tbutylcarbonate (7.43g). The resulting brown solution is allowed to stand at room temperature for 30 minutes, then diluted with ethyl acetate. The organic solution was washed with 2N HCl (2x400ml), water (200ml), brine (2x200ml) and then dried (MgSO4) and evaporated to give impure product. It was purified by chromatography on silica gel (500g), eluting with cyclohexane/ethyl acetate (15:1 v/v) to give the title compound as a light cream solid.

2(vi)2-Fluoro-7-(hidroksi-piridin-3-il-metil)-karbazol-9-karboksilne kiseline tert-butil ester 2(vi)2-Fluoro-7-(hydroxy-pyridin-3-yl-methyl)-carbazole-9-carboxylic acid tert-butyl ester

Otopina 3-bromopiridina (0.306ml) u eteru (10ml) se ohladi na -45°C pod N2. Kapajući se dodaje otopina nbutillitija (2ml 1.6M otopina u heksanu). Rezultirajuća se smeđa suspenzija ugrije na 0°C, zatim se ponovno ohladi na - 45°C i stavi stajati tokom 15 minuta. Doda se otopina 2(v) (0.5g) u suhom THF (10ml). Smjesa se miješa na - 40°C tokom 1 sat, zatim se reakcija prekine sa otopinom amonijevog klorida (20ml). Smjesa se ekstrahira sa etil acetatom (3x30ml) i spojeni ekstrakti se isperu sa rasolom (200ml), suše (MgSO4) i evaporiraju dajući naslovni spoj kao žutu pjenu. A solution of 3-bromopyridine (0.306ml) in ether (10ml) was cooled to -45°C under N2. A solution of nbutyllithium (2ml of 1.6M solution in hexane) is added dropwise. The resulting brown suspension was heated to 0°C, then cooled again to -45°C and allowed to stand for 15 minutes. A solution of 2(v) (0.5g) in dry THF (10ml) was added. The mixture is stirred at - 40°C for 1 hour, then the reaction is stopped with ammonium chloride solution (20ml). The mixture was extracted with ethyl acetate (3x30ml) and the combined extracts were washed with brine (200ml), dried (MgSO4) and evaporated to give the title compound as a yellow foam.

2(vii)2-Fluoro-7-piridin-3-ilmetil-9H-karbazol 2(vii) 2-Fluoro-7-pyridin-3-ylmethyl-9H-carbazole

Otopina 2(vi) (670mg) u metanolu (20ml) se tretira pod N2 sa crnim paladij katalizatorom (300mg) i koncentriranom HCl (0.8ml). Smjesa se miješa pod H2 tokom 3 sata na 50°C, zatim se doda daljnjih 300mg katalizatora i reakcija se nastavi tokom 3 sata. Katalizator se ukloni filtriranjem i ispere sa metanolom (2x1 Omi), zatim se filtrat i tekućine od ispiranja evaporiraju dajući ljepljivu žutu pjenu. Kromatografija na silikagelu (100g) uz eluaciju sa CHCl3/IPE (50:1 → 20:1 v/v) daje naslovni spoj. A solution of 2(vi) (670mg) in methanol (20ml) was treated under N2 with black palladium catalyst (300mg) and concentrated HCl (0.8ml). The mixture was stirred under H2 for 3 hours at 50°C, then a further 300 mg of catalyst was added and the reaction continued for 3 hours. The catalyst is removed by filtration and washed with methanol (2 x 1 O), then the filtrate and washings are evaporated to give a sticky yellow foam. Chromatography on silica gel (100g) eluting with CHCl3/IPE (50:1 → 20:1 v/v) gives the title compound.

NMR δ (DMSO-d6) 4.12 s (2H), 6,97 t (1H), 7.08 d (1H), 7.22 d (1H), 7.32 m (1H), 7.68 d (1H), 8.05 m (2H), 8.41 d (1H), 8.58 s (1H), 11.31 (1H). NMR δ (DMSO-d6) 4.12 s (2H), 6.97 t (1H), 7.08 d (1H), 7.22 d (1H), 7.32 m (1H), 7.68 d (1H), 8.05 m (2H) , 8.41 d (1H), 8.58 s (1H), 11.31 (1H).

Primjer 3 Example 3

2-Fluoro-7-piridin-4-ilmetil-9H-karbazol 2-Fluoro-7-pyridin-4-ylmethyl-9H-carbazole

i) 2-Fluoro-7-(hidroksi-piridin-4-il-metil)-karbnazol-9-karboksilne kiseline tert-butil ester i) 2-Fluoro-7-(hydroxy-pyridin-4-yl-methyl)-carbnazole-9-carboxylic acid tert-butyl ester

Otopina 4-bromopiridina (253mg) u eteru (10ml) se ohladi na -75°C pod N2. Doda se otopina nbutillitija (1ml 1.6M otopine u heksanu). Nakon miješanja tokom 10 minuta na - 75°C doda se otopina 2(v) (0.5g) u suhom THF (5ml).Nakon miješanja reakcije na -70°C tokom 1 sata, iduća smjesa 4-bromopiridina (506mg) i 2ml nbutillitija (2ml 1.6M otopine) u eteru (.10 ml) se doda (ranije pomiješano na -70°C). Nakon idućeg sata na -70°C, doda se vodeni amohijev klorid (10ml). Smjesa se ekstrahira sa eterom (4x30 ml). Spojeni eterski ekstrakti se zatim ekstrahiraju sa 2N HCl (3x30ml). Ovi spojeni kiselinski ekstrakti se tretiraju sa 40%-tnim vodenim amonijevim hidroksidom do pH 11, zatim se ekstrahiraju sa diklorometanom (4x40ml), te se zatim spojeni ekstrakti suše (MgSO4) i evaporiraju dajući žutu krutinu. Preparativna t.l.c. daje naslovni spoj kao žutu krutinu. A solution of 4-bromopyridine (253mg) in ether (10ml) was cooled to -75°C under N2. A solution of nbutyllithium (1 ml of a 1.6M solution in hexane) is added. After stirring for 10 minutes at -75°C, a solution of 2(v) (0.5g) in dry THF (5ml) was added. After stirring the reaction at -70°C for 1 hour, the following mixture of 4-bromopyridine (506mg) and 2ml nbutyllithium (2ml of a 1.6M solution) in ether (.10ml) was added (previously mixed at -70°C). After the next hour at -70°C, aqueous ammonium chloride (10ml) is added. The mixture is extracted with ether (4x30 ml). The combined ether extracts are then extracted with 2N HCl (3x30ml). These combined acid extracts were treated with 40% aqueous ammonium hydroxide to pH 11, then extracted with dichloromethane (4x40ml), and then the combined extracts were dried (MgSO4) and evaporated to give a yellow solid. Preparative t.l.c. gives the title compound as a yellow solid.

ii)2-Fluoro-7-piridin-4-ilmetil-9H-carbazol ii) 2-Fluoro-7-pyridin-4-ylmethyl-9H-carbazole

Otopina 3(i) u metanolu (5ml) se tretira pod N2 sa crnim paladij katalizatorom (40mg) i koncentriranom HCl (0.2ml). Smjesa se miješa pod H2 tokom 1,5 sati na 50°C, zatim se doda iduće punjenje katalizatora (80mg) i zatim se reakcija miješa pod H2 na 50°C tokom 3 sata. Katalizator se ukloni filtriranjem, ispere se metanolom (2x5ml) i zatim se filtrati i otopine od ispiranja evaporiraju do gume. Ona se otapa u 4M HCI u dioksanu (5ml) tokom 30 minuta i zatim evaporira dajući žutu gumu. Ona se otopi u vodi (10ml), tretira sa 40%-tnim vodenim natrijevim hidroksidom do pH 11 i zatim se smjesa ekstrahira sa diklorometanom (4x20ml). Spojeni ekstrakti se suše (MgSO4) i evaporiraju dajući žutu krutinu. Preparativna t.l.c. daje naslovni spoj kao žutu krutinu. A solution of 3(i) in methanol (5ml) was treated under N2 with black palladium catalyst (40mg) and concentrated HCl (0.2ml). The mixture was stirred under H2 for 1.5 hours at 50°C, then the next charge of catalyst (80mg) was added and then the reaction was stirred under H2 at 50°C for 3 hours. The catalyst is removed by filtration, washed with methanol (2x5ml) and then the filtrates and washing solutions are evaporated to rubber. It was dissolved in 4M HCl in dioxane (5ml) over 30 minutes and then evaporated to give a yellow gum. It is dissolved in water (10ml), treated with 40% aqueous sodium hydroxide to pH 11 and then the mixture is extracted with dichloromethane (4x20ml). The combined extracts were dried (MgSO4) and evaporated to give a yellow solid. Preparative t.l.c. gives the title compound as a yellow solid.

NMR (DMS0d6) 4.12δ s (2H), 6,97δ t (1H), 7.06δ d (1H), 7.2-7.4δ m (4H), 8.0-8.1δ m (2H), 8.46δ d (1H), 11.33δ s (1H). NMR (DMS0d6) 4.12δ s (2H), 6.97δ t (1H), 7.06δ d (1H), 7.2-7.4δ m (4H), 8.0-8.1δ m (2H), 8.46δ d (1H) , 11.33δ s (1H).

Primjer 4 Example 4

2-Fluoro-7-(fluoropiridin-4-il-metil)-9H-karbazol 2-Fluoro-7-(fluoropyridin-4-yl-methyl)-9H-carbazole

i)2-Fluoro-7-(hidroksi-(3-fluoropiridin-4-il)-metil)-karbazol-9-karboksilne kiseline tert-butil ester i) 2-Fluoro-7-(hydroxy-(3-fluoropyridin-4-yl)-methyl)-carbazole-9-carboxylic acid tert-butyl ester

Otopina N,N,N',N'-tetrametilenediamina (0.48ml) u suhom THF-u (5ml) se ohladi na - 70°C pod N2. Doda se otopina nbutillitija (2ml 1.6M otopine u heksanu). Rezultirajuća otopina se miješa na - 20°C tokom jednog sata i zatim se ohladi na - 70°C. Doda se otopina 3-fluoropiridina (0.273ml) u suhom THF-u (3ml). Rezultirajuća suspenzija se miješa na - 40°C tokom jednog sata, zatim se tokm dvije minute doda otopina 2(v) (500mg) u suhom THF-u (10ml). Reakcija se miješa na - 70°C tokom jednog sata i zatim se ugasi sa vodenom otopinom amonijevog klorida (20ml). Smjesa se ekstrahira sa etil acetatom (3x30ml), te se zatim spojeni ekstrakti isperu vodom (4x1 Omi) i rasolom (10ml), zatim se suše (MgSO4) i evaporiraju dajući žutu krutinu. Kromatografija na silika gelu (100g) uz eluaciju sa smjesom kloroform/isopropanol (50:1 → 20:1 v/v) daje naslovni spoj kao bijelu krutinu. A solution of N,N,N',N'-tetramethylenediamine (0.48ml) in dry THF (5ml) was cooled to -70°C under N2. A solution of nbutyllithium (2 ml of a 1.6M solution in hexane) is added. The resulting solution was stirred at -20°C for one hour and then cooled to -70°C. A solution of 3-fluoropyridine (0.273ml) in dry THF (3ml) was added. The resulting suspension was stirred at -40°C for one hour, then a solution of 2(v) (500mg) in dry THF (10ml) was added over two minutes. The reaction was stirred at -70°C for one hour and then quenched with aqueous ammonium chloride (20ml). The mixture was extracted with ethyl acetate (3x30ml), and then the combined extracts were washed with water (4x10ml) and brine (10ml), then dried (MgSO4) and evaporated to give a yellow solid. Chromatography on silica gel (100g) eluting with a mixture of chloroform/isopropanol (50:1 → 20:1 v/v) gives the title compound as a white solid.

ii)2-Fluoro-7-(3-fluoropiridin-4-il-metil)-9H-karbazol ii) 2-Fluoro-7-(3-fluoropyridin-4-yl-methyl)-9H-carbazole

Otopina 4(i) u metanolu (10ml) se tretira sa crnim paladijevim katalizatorom (320mg) i koncentriranom HCl (0.4ml). Smjesa se miješa pod H2 tokom 6 sati na 50°C. Katalizator se ukloni filtriranjem i ispere sa metanolom (3x5ml). Filtrat i tekućine od ispiranja se evaporiraju dajući žutu krutinu. Ona se otopi u vodi (20ml) i tretira sa 40%-tnim vodenim natrijevim hidroksidom do pH 11. A solution of 4(i) in methanol (10ml) was treated with black palladium catalyst (320mg) and concentrated HCl (0.4ml). The mixture is stirred under H2 for 6 hours at 50°C. The catalyst is removed by filtration and washed with methanol (3x5ml). The filtrate and washings were evaporated to give a yellow solid. It is dissolved in water (20ml) and treated with 40% aqueous sodium hydroxide to pH 11.

Smjesa se ekstrahira sa diklorometanom (4x30ml), zatim se spojeni ekstrakti suše (MgSO4) i evaporiraju dajući krem krutinu. Kromatografija na silika gelu(50g), uz eluaciju sa smjesom kloroform/izopropanol (50:1 → 20:1 v/v) daje naslovni spoj kao bijelu krutinu. The mixture is extracted with dichloromethane (4x30ml), then the combined extracts are dried (MgSO4) and evaporated to give a cream solid. Chromatography on silica gel (50g), eluting with a mixture of chloroform/isopropanol (50:1 → 20:1 v/v) gives the title compound as a white solid.

NMR (DMSOd6). 4.19δ s (2H), 6.97δ t (1H), 7.07δ d (1H), 7.23δ d (1H), 7.40δ m (2H), 8.05δ m (2H), 8.35δ d (1H), 8.52δ s (1H), 11.32δ s (1H). NMR (DMSO 6 ). 4.19δ s (2H), 6.97δ t (1H), 7.07δ d (1H), 7.23δ d (1H), 7.40δ m (2H), 8.05δ m (2H), 8.35δ d (1H), 8.52 δ s (1H), 11.32 δ s (1H).

Primjer 5 Example 5

2-Fluoro-7-(3-metilpiridin-4-il-metil)-9H-karbazol 2-Fluoro-7-(3-methylpyridin-4-yl-methyl)-9H-carbazole

i)2-Fluoro-7-(hidroksi-(3-metilpiridin-4-il)-metiil)-9-karboksilne kiseline tert-butil ester i) 2-Fluoro-7-(hydroxy-(3-methylpyridin-4-yl)-methyl)-9-carboxylic acid tert-butyl ester

Otopina 4-bromo-3-metilpiridina (549mg) u eteru (10ml) se ohladi na - 70°C pod N2. Doda se otopina nbutillitija (3.2ml 1.6M otopina u heksanu). Rezultirajuća suspenzija se miješa na - 70°C tokom 30 minuta, zatim se doda otopina 2(v) (500mg) u suhom THF-u (10ml). Otopina se miješa na 70°C tokom jednog sata i zatim se prekine sa vodenim amonijevim kloridom (20ml). Smjesa se ekstrahira sa etil acetatom (3x30ml) i zatim se spojeni ekstrakti isperu rasolom (10ml), suše se (MgSO4) i evaporiraju dajući žutu gumu. Kromatografija na silika gelu (90g), uz eluaciju sa smjesom kloroform:izopropanol (50:1 20:1 v/v) daje naslovni spoj kao svjetlo žutu pjenu. A solution of 4-bromo-3-methylpyridine (549mg) in ether (10ml) was cooled to -70°C under N2. A solution of nbutyllithium (3.2ml of 1.6M solution in hexane) is added. The resulting suspension was stirred at -70°C for 30 minutes, then a solution of 2(v) (500mg) in dry THF (10ml) was added. The solution was stirred at 70°C for one hour and then quenched with aqueous ammonium chloride (20ml). The mixture was extracted with ethyl acetate (3x30ml) and then the combined extracts were washed with brine (10ml), dried (MgSO4) and evaporated to give a yellow gum. Chromatography on silica gel (90g), eluting with a mixture of chloroform:isopropanol (50:1 20:1 v/v) gives the title compound as a light yellow foam.

ii)2-Fluoro-7-(3-metilpiridin-4-il-metil)-9H-karbazol ii) 2-Fluoro-7-(3-methylpyridin-4-yl-methyl)-9H-carbazole

Otopina 5(i) (267mg) u metanolu (5ml) se tretira sa crnim paladijevim katalizatorom (100mg) i koncentriranom HCl (0.25ml). Smjesa se miješa pod H2 tokom 14 sati uz povremeno dodavanje novih količina katalizatora. Katalizator se ukloni filtriranjem i ispere se sa metanolom (3x2ml) i octenom kiselinom (2x1 ml). Filtrat i tekućine od ispiranja se evaporiraju dajući svjetlo žutu gumu. Ona se otopi u vodi i tretira sa 40%-tnom vodenom otopinom natrijevog hidroksida do pH 11. Smjesa se ekstrahira sa diklorometanom (4x15ml), zatim se spojeni ekstrakti suše (MgSO4) i evaporiraju dajući blijedo krem pjenu. Kromatografija na silika gelu (50g) uz eluaciju sa smjesom kloroform:izopropanol (50:1→20:1 v/v) daje naslovni spoj kao bijelu krutinu. A solution of 5(i) (267mg) in methanol (5ml) was treated with black palladium catalyst (100mg) and concentrated HCl (0.25ml). The mixture is stirred under H2 for 14 hours with occasional addition of new amounts of catalyst. The catalyst is removed by filtration and washed with methanol (3x2ml) and acetic acid (2x1ml). The filtrate and washings are evaporated to give a light yellow gum. It is dissolved in water and treated with 40% aqueous sodium hydroxide solution to pH 11. The mixture is extracted with dichloromethane (4x15ml), then the combined extracts are dried (MgSO4) and evaporated to give a pale cream foam. Chromatography on silica gel (50g) eluting with a mixture of chloroform:isopropanol (50:1→20:1 v/v) gives the title compound as a white solid.

NMR (DMSOd6). 2.25δ s (3H), 4.14δ s (2H), 6.97δ t (1H), 7.01δ d (1H), 7.135δ (1H), 7.23δ m (2H), 8.0-8.1δ m (2H), 8.33δ m (2H), 11.27δ s (1H). NMR (DMSO 6 ). 2.25δ s (3H), 4.14δ s (2H), 6.97δ t (1H), 7.01δ d (1H), 7.135δ (1H), 7.23δ m (2H), 8.0-8.1δ m (2H), 8.33δ m (2H), 11.27δ s (1H).

Primjer 6 Example 6

2-Fluoro-7-(3-metoksipiridin-4-il-metil)-9H-karbazol 2-Fluoro-7-(3-methoxypyridin-4-yl-methyl)-9H-carbazole

i)2-Fluoro-7-midroksi-(3-metoksipiridin-4-il-)-metil-karbazol-9-karboksilne kiseline tert-butil ester i) 2-Fluoro-7-midroxy-(3-methoxypyridin-4-yl-)-methyl-carbazole-9-carboxylic acid tert-butyl ester

Otopina 4-bromo-3-metoksipiridina (530mg) u eteru (10ml) se ohladi na 70°C pod N2. Doda se otopina nbutillitija (1.76ml 1.6M otopine u heksanu). Rezultirajuća suspenzija se miješa na - 70°C tokom 30 minuta, a zatim se doda otopina 2(v) (442mg) u suhom THF-u (10ml). Otopina se miješa na - 70°C tokom jednog sata i zatim se prekine sa vodenom otopinom amonijevog klorida (20ml). Smjesa se ekstrahira sa etil acetatom (3x50ml) i zatim se spojeni ekstrakti isperu vodom (30ml), rasolom (30ml), suše se (MgSO4) i evaporiraju dajući žutu krutinu. Kromatografija na silika gelu (90g) uz eluaciju sa smjesom kloroform.izopropanol (50:1 →20:1 v/v) daje naslovni spoj kao bijelu krutinu. A solution of 4-bromo-3-methoxypyridine (530mg) in ether (10ml) was cooled to 70°C under N2. A solution of nbutyllithium (1.76ml of a 1.6M solution in hexane) is added. The resulting suspension was stirred at -70°C for 30 minutes, then a solution of 2(v) (442mg) in dry THF (10ml) was added. The solution was stirred at -70°C for one hour and then quenched with aqueous ammonium chloride (20ml). The mixture was extracted with ethyl acetate (3x50ml) and then the combined extracts were washed with water (30ml), brine (30ml), dried (MgSO4) and evaporated to give a yellow solid. Chromatography on silica gel (90g) eluting with a mixture of chloroform and isopropanol (50:1 →20:1 v/v) gives the title compound as a white solid.

ii) 2-Fluoro-7-(3-metoksipiridin-4-il-metil)-9H-karbazol ii) 2-Fluoro-7-(3-methoxypyridin-4-yl-methyl)-9H-carbazole

Otopina 6(i) (200mg) u metanolu (5ml) se tretira pod N2 sa crnim paladijevim katalizatorom (100mg) i koncentriranom HCl (0.25ml). Smjesa se miješa pod H2 tokom 8 sati na 50°C. Katalizator se ukloni filtriranjem, ispere se metanolom i octenom kiselinom i zatim se filtrat i tekućine od ispiranja evaporiraju dajući biljelu krutinu. Ona se otopi u 4M HCl u dioksanu (15ml) i diklorometanu (50ml) te se miješa na sobnoj temperaturi tokom 6 sati i zatim se evaporira do gume. Ona se otopi u vodi (10ml), tretira se sa 40%-tnom vodenom otopinom natrijevog hidroksida do pH 11 i zatim se smjesa ekstrahira sa diklorometanom (4x20ml). Spojeni ekstrakti se suše (MgSO4) i evaporiraju dajući žutu krutinu. Kromatografija na silika gelu (50g) uz eluaciju sa smjesom kloroform:izopropanol (50:1 -» 20:1 v/v) daje naslovni spoj kao bijelu krutinu. A solution of 6(i) (200mg) in methanol (5ml) was treated under N2 with black palladium catalyst (100mg) and concentrated HCl (0.25ml). The mixture is stirred under H2 for 8 hours at 50°C. The catalyst was removed by filtration, washed with methanol and acetic acid, and then the filtrate and washings were evaporated to give a white solid. It is dissolved in 4M HCl in dioxane (15ml) and dichloromethane (50ml) and stirred at room temperature for 6 hours and then evaporated to a gum. It is dissolved in water (10ml), treated with 40% aqueous sodium hydroxide solution to pH 11 and then the mixture is extracted with dichloromethane (4x20ml). The combined extracts were dried (MgSO4) and evaporated to give a yellow solid. Chromatography on silica gel (50g) eluting with a mixture of chloroform:isopropanol (50:1 -» 20:1 v/v) gives the title compound as a white solid.

NMR(DMSOd6). 3.93δ s (3H), 4.07δ s (2H), 6.96δ t (1H), 7.04δ d (1H), 7.13δ d (1H), 7.21δ d (1H), 7.29δ s (1H), 7.95-8.15δ m (3H), 8.33δ s (1H), 11.28δ s (1H). NMR (DMSO 6 ). 3.93δ s (3H), 4.07δ s (2H), 6.96δ t (1H), 7.04δ d (1H), 7.13δ d (1H), 7.21δ d (1H), 7.29δ s (1H), 7.95 -8.15δ m (3H), 8.33δ s (1H), 11.28δ s (1H).

Primjeri 7 do 9 Examples 7 to 9

Slijedeći spojevi su pripremljeni postupcima koji su analogni onima opisanima u Primjerima 1 do 6: The following compounds were prepared by procedures analogous to those described in Examples 1 to 6:

7. 1.7-Difluoro-2-[1,2,4]triazol-1-ilmetil-9H-karbazol 7. 1,7-Difluoro-2-[1,2,4]triazol-1-ylmethyl-9H-carbazole

NMR δ (DMSO-d6) 5.63 s (2H), 7.10 m (2H), 7.26 dd (1H), 7.92 d (1H), 7,98 s (1H), 8.15 dd (1H), 8.69 s (1H), 11.90 s (1H). NMR δ (DMSO-d6) 5.63 s (2H), 7.10 m (2H), 7.26 dd (1H), 7.92 d (1H), 7.98 s (1H), 8.15 dd (1H), 8.69 s (1H) , 11.90 s (1H).

8. 2.4-Difluoro-7-[1,2,4]triazol-1-ilmetil-9H-karbazol 8. 2,4-Difluoro-7-[1,2,4]triazol-1-ylmethyl-9H-carbazole

NMR δ (DMS0-d6) 5.59 s (2H), 696 t (1H), 7.19 m (2H), 7.44 s (1H), 7.99 m (2H), 8.72 s (1H). NMR δ (DMS0-d6) 5.59 s (2H), 696 t (1H), 7.19 m (2H), 7.44 s (1H), 7.99 m (2H), 8.72 s (1H).

9. 1.4.7-Trifluoro-2-[1,2,4]triazol-1-ilmetil-9H-karbazol 9. 1.4.7-Trifluoro-2-[1,2,4]triazol-1-ylmethyl-9H-carbazole

NMR δ (DMS0-d6) 5.62 s (2H), 6.96 dd (1H), 7.11 t (1H), 7.31 dd (1H), 8.02 m (2H), 8.72 s (1H), 12.25 s (1H). NMR δ (DMS0-d6) 5.62 s (2H), 6.96 dd (1H), 7.11 t (1H), 7.31 dd (1H), 8.02 m (2H), 8.72 s (1H), 12.25 s (1H).

Primjer 10 Example 10

i)4-Fluorofenil boronijeva kiselina i) 4-Fluorophenyl boronic acid

Otopina 1-bromo-4-fluorobenzena (318.2g) u THF-u (300ml) se ohladi na 52°C pod N2. Dodaje se nbutillitij (2.5M u heksanu, 800ml) preko kanile tokom 5 minuta, te se temperatura povisi na ~ - 44°C. Nakon što se dovrši dodavanje, reakciji se dozvoli da stoji na - 52°C tokom 15 minuta, zatim se doda tri-izopropil borat (1240ml) tokom 10 minuta. Prekine se sa hlađenjem i dozvoli se reakciji da se ugrije na - 15°C. Reakcija se prekine dodavanjem vode (2000ml). Smjesa se zatim podijeli između daljnje količine od 2000ml vode i etil acetata (2000ml). Želatinozni bijeli materijal koji preostaje u tikvici se isprazni. A solution of 1-bromo-4-fluorobenzene (318.2g) in THF (300ml) was cooled to 52°C under N2. Nbutyllithium (2.5M in hexane, 800ml) is added via cannula over 5 minutes, and the temperature is raised to ~ - 44°C. After the addition was complete, the reaction was allowed to stand at -52°C for 15 minutes, then tri-isopropyl borate (1240ml) was added over 10 minutes. Stop cooling and allow the reaction to warm to -15°C. The reaction is stopped by adding water (2000ml). The mixture is then partitioned between a further 2000ml of water and ethyl acetate (2000ml). The gelatinous white material remaining in the flask is emptied.

Vodena faza se zatim ekstrahira sa etil acetatom (2000ml), zatim se spojeni etil acetatni slojevi isperu rasolom (1500ml), suše (MgSO4) i evaporiraju dajući blijedo krem krutinu (228.12g). Krutina se kristalizira iz vode koja vrije (1100ml) dajući naslovni spoj (152.18g). The aqueous phase was then extracted with ethyl acetate (2000ml), then the combined ethyl acetate layers were washed with brine (1500ml), dried (MgSO4) and evaporated to give a pale cream solid (228.12g). The solid was crystallized from boiling water (1100ml) to give the title compound (152.18g).

ii)m-Nitro-p-bromobenzaldehid ii) m-Nitro-p-bromobenzaldehyde

Pomiješaju se koncentrirana sumporna kiselina (3125ml) i koncentrirana dušična kiselina (1250ml) (koncentrirana dušična kiselina se dodaje u 100 ml obrocima ) i istovremeno se hlade na 5°C, u ledeno/slanoj kupki. Zatim se u obrocima doda p-bromobenzaldehid (500g) zadržavajući temperaturu ispod 10°C. Nakon što se završi dodavanje, rezultirajuća smjesa se čuva na sobnoj temperaturi tokom približno 3 sata (dok se ne otopi p-bromobenzaldehid) te se zatim pažljivo prelije preko leda. Formirani precipitat se sakupi filtracijom i ispere se vodom sve dok pH tekućine od ispiranja nije oko 6, zatim se suši in vacuo na 40°C dajući naslovni spoj kao bijeli prašak (607.63g). Concentrated sulfuric acid (3125 ml) and concentrated nitric acid (1250 ml) are mixed (concentrated nitric acid is added in 100 ml portions) and simultaneously cooled to 5°C in an ice/salt bath. Then p-bromobenzaldehyde (500g) is added in portions, keeping the temperature below 10°C. After the addition is complete, the resulting mixture is kept at room temperature for approximately 3 hours (until the p-bromobenzaldehyde dissolves) and then carefully poured over ice. The formed precipitate is collected by filtration and washed with water until the pH of the washing liquid is about 6, then dried in vacuo at 40°C to give the title compound as a white powder (607.63g).

iii)4'-Fluoro-2-nitrobifenil-4-karbaldehid iii) 4'-Fluoro-2-nitrobiphenyl-4-carbaldehyde

Smjesa 10(i) (300g), 10ii) (448g), tetratristrifenil fosfin paladij (O) (15g) i vodenog 2M natrijevog karbonata (1.07L) u DME (3.2L) se refluksira pod N2 tokom 16 sati. Nakon hlađenja, reakcijska smjesa se ekstrahira sa etil acetatom (2x2000ml). Spojeni ekstrakti se isperu rasolom (100ml), suše (MgSO4) i evaporiraju. Prije nego li se završi evaporacija, produkt kristalizira. Kristali se uklone filtriranjem, isperu se sa IPE, zatim se suše da bi dali naslovni spoj (244.3g). A mixture of 10(i) (300g), 10ii) (448g), tetratritriphenyl phosphine palladium(O) (15g) and aqueous 2M sodium carbonate (1.07L) in DME (3.2L) was refluxed under N2 for 16 hours. After cooling, the reaction mixture is extracted with ethyl acetate (2x2000ml). The combined extracts are washed with brine (100ml), dried (MgSO4) and evaporated. Before the evaporation is complete, the product crystallizes. The crystals are removed by filtration, washed with IPE, then dried to give the title compound (244.3g).

Tekućine od ispiranja i osnovna tekućina se koncentriraju. Ostatak kristalizira i triturira se sa eterom, zatim se krutina ukloni filtriranjem i suši se da bi dala daljnju količinu naslovnog spoja. (120g). Wash liquids and base liquor are concentrated. The residue crystallizes and is triturated with ether, then the solid is removed by filtration and dried to give a further amount of the title compound. (120g).

iv)2-(4'-Fluoro-2-nitrobifenil-4-il)-[1,3]-dioksolan iv) 2-(4'-Fluoro-2-nitrobiphenyl-4-yl)-[1,3]-dioxolane

Otopina 10(iii) (357.4g) u izopropil acetatu (4000ml) se tretira sa monohidratom p-toluen sulfonske kiseline (27g) i etilen glikolom (750ml). Smjesa se refluksira sa Dean-Stark opremom tokom 2 sata. Nakon hlađenja, otopina se ispere vodom (2000ml), zasićenom vodenom NaHCO3 (2000ml), vodom (2x2000ml), rasolom (1000ml), te se zatim suši (MgSO4) i evaporira dajući naslovni spoi kao žućkasti sirup (520.96g). A solution of 10(iii) (357.4g) in isopropyl acetate (4000ml) is treated with p-toluene sulfonic acid monohydrate (27g) and ethylene glycol (750ml). The mixture is refluxed with Dean-Stark equipment for 2 hours. After cooling, the solution was washed with water (2000ml), saturated aqueous NaHCO3 (2000ml), water (2x2000ml), brine (1000ml), then dried (MgSO4) and evaporated to give the title compound as a yellowish syrup (520.96g).

Pronađeno je da je i toluen prikladno otapalo za ovu reakciju. Toluene was also found to be a suitable solvent for this reaction.

v)2-[1,3]-Dioksolan-2-il-7-fluoro-9H-karbazol v) 2-[1,3]-Dioxolan-2-yl-7-fluoro-9H-carbazole

Ksilen (1250ml) i trietilfosfit (1250ml) se mehanički miješaju pod N2 i zagrijavaju do refluksa (oko 142°C). Otopina 10(iv) (514.76g) u ksilenu (3750ml) se doda tokom 2 sata uz zadržavanje refluksa. Sa refluksom se nastavi tokom idućih 5 i pol sati i zatim se doda kapajući iduća količina trietilfosfita (500ml). Sa refluksom se nastavi tokom sat i pol i zatim se reakcija ostavi stajati da se ohladi na sobnu temperaturu preko noći. Nakon hlađenja u led/voda kupki tokom 30 minuta, kristali se uklone filtriranjem, isperu se sa ksilenom i cikloheksanom i zatim se suše in vacuo na 40°C da bi se dobio naslovni spoj (171.75q). Xylene (1250ml) and triethylphosphite (1250ml) are mechanically mixed under N2 and heated to reflux (about 142°C). A solution of 10(iv) (514.76g) in xylene (3750ml) was added over 2 hours while maintaining reflux. Reflux is continued for the next 5 and a half hours and then the next amount of triethylphosphite (500ml) is added dropwise. Reflux is continued for an hour and a half and then the reaction is left to cool to room temperature overnight. After cooling in an ice/water bath for 30 min, the crystals were removed by filtration, washed with xylene and cyclohexane and then dried in vacuo at 40°C to give the title compound (171.75q).

Iduća količina je dobivena iz cikloheksana od ispiranja i od osnovne tekućine. The next amount was obtained from cyclohexane from the wash and from the base liquor.

Pronađeno je da je i čisti trietilfosfin prikladno otapalo za ovu reakciju. Pure triethylphosphine was also found to be a suitable solvent for this reaction.

vi)7-Fluoro-9H-karbazol-2-karbaldehid vi) 7-Fluoro-9H-carbazole-2-carbaldehyde

Suspenzija 10(v) (209.626g) u acetonu (5000ml) se tretira sa 2N HCl (1250ml) i rezultirajuća žuta otopina soli se čuva tokom 30 minuta. Aceton se ukloni evaporacijom i vodeni sloj i krutina se ekstrahiraju sa etil acetatom (7000ml). Organska otopina se ispere vodom (1000ml) suši (MgSO4) i evaporira dajući naslovni spoj kao blijedu krutinu boje marelica/mango (171.59g). A suspension of 10(v) (209.626g) in acetone (5000ml) was treated with 2N HCl (1250ml) and the resulting yellow salt solution was kept for 30 minutes. The acetone was removed by evaporation and the aqueous layer and solid were extracted with ethyl acetate (7000ml). The organic solution was washed with water (1000ml), dried (MgSO4) and evaporated to give the title compound as a pale apricot/mango colored solid (171.59g).

vii) 2-Fluoro-7-formil-karbazol-9-karboksilne kiseline tert-butil ester vii) 2-Fluoro-7-formyl-carbazole-9-carboxylic acid tert-butyl ester

Suspenzija 10(vi) (168.25g) u etil acetatu (300ml) se miješa sa 4-dimetilaminopiridinom (96.41 g) na sobnoj temperaturi pod N2. Otopina dimetilkarbonata (172.2g) u etil acetatu (1000ml) se dodaje tokom 30 minuta.pri tome se slabo razvijaju mjehurići CO2 i zatim se doda iduća količina BOC (25g) da bi se završila reakcija. Iskristalizira bijela krutina. Nakon miješanja tokom oko 30 minuta, ukloni se filtriranjem, ispere se sa 2N HCl (2x500ml) i zatim vodom do neutralnog te se zatim suši in vacuo dajući naslovni spoj (187.44g). A suspension of 10(vi) (168.25g) in ethyl acetate (300ml) was mixed with 4-dimethylaminopyridine (96.41g) at room temperature under N2. A solution of dimethylcarbonate (172.2g) in ethyl acetate (1000ml) is added over 30 minutes. CO2 bubbles develop slightly and then the next amount of BOC (25g) is added to complete the reaction. A white solid crystallizes. After stirring for about 30 minutes, it is removed by filtration, washed with 2N HCl (2x500ml) and then with water until neutral and then dried in vacuo to give the title compound (187.44g).

Iduća količina je dobivena iz osnovne tekućine. The next amount was obtained from the base liquid.

viii)2-Fluoro-7-(hidroksi-piridin-3-ilmetil)-9H-karbazol viii) 2-Fluoro-7-(hydroxy-pyridin-3-ylmethyl)-9H-carbazole

Otopina 3-bromopiridina (16.6ml) u THF-u (500ml) se ohladi na - 70°C pod N2. Ova otopina se kapajući dodaje tokom 10 minuta u otopinu n-butillitija (220ml 1.6M otopine u heksanu) i zatim se ohladi na - 70°C. Nakon 10 minuta, kapajući tokom 20 minuta se doda otopina 10(vii) (27g) u THF-u (700ml) koja je ohlađena na - 70°C. Smjesa se miješa na - 70°C tokom 40 minuta, te se zatim reakcija prekine sa otopinom amonijevog klorida (300ml). Smjesa se ekstrahira sa etil acetatom (2x500ml) i spojeni organski slojevi se isperu rasolom (500ml),suše se (MgSO4) i evaporiraju dajući smjesu 2-fluoro-7-(hidroksi-piridin-3-ilmetil)-karbazol-9-karboksilne kiseline tert-butil estera i 2-fluoro-7-(hidroksi-piridin-3-ilmetil)-9H-karbazola kao ulje jantarne boje. A solution of 3-bromopyridine (16.6ml) in THF (500ml) was cooled to -70°C under N2. This solution is added dropwise over 10 minutes to a solution of n-butyllithium (220ml of 1.6M solution in hexane) and then cooled to -70°C. After 10 minutes, a solution of 10(vii) (27g) in THF (700ml) cooled to -70°C was added dropwise over 20 minutes. The mixture is stirred at -70°C for 40 minutes, and then the reaction is stopped with ammonium chloride solution (300ml). The mixture was extracted with ethyl acetate (2x500ml) and the combined organic layers were washed with brine (500ml), dried (MgSO4) and evaporated to give a mixture of 2-fluoro-7-(hydroxy-pyridin-3-ylmethyl)-carbazole-9-carboxylic acid tert-butyl ester and 2-fluoro-7-(hydroxy-pyridin-3-ylmethyl)-9H-carbazole as an amber oil.

To ulje se otopi u metanolu (500ml) i tretira se natrijevim metoksidom (37g 25%-tne otopine u metanolu). Nakon miješanja tokom 24 sata, reakcija se ukoncentrira na 50 ml, zatim se doda voda (250ml) i smjesa se ekstrahira sa etil acetatom (3x250ml). Spojeni organski slojevi se ekstrahiraju sa HCl (20%-tna vodena otopina, 3x250ml). Spojeni HCl slojevi se isperu sa etil acetatom (250ml). Vodeni sloj se zatim neutralizira do pH10 pomoću peleta NaOH, zatim se ekstrahira sa metilen kloridom (2x500ml). Spojeni metHen klorićni slojevi se isperu rasolom (500ml), suše (MgSO4) i evaporiraju do 100ml. Doda se toluen (250ml) i suspenzija se koncentrira do 150ml. Sakupljanjem rezultirajućeg precipitata za vrijeme sušenja, naslovni spoj je dobiven kao bijeli prah. This oil is dissolved in methanol (500ml) and treated with sodium methoxide (37g of a 25% solution in methanol). After stirring for 24 hours, the reaction is concentrated to 50 ml, then water (250 ml) is added and the mixture is extracted with ethyl acetate (3x250 ml). The combined organic layers are extracted with HCl (20% aqueous solution, 3x250ml). The combined HCl layers are washed with ethyl acetate (250ml). The aqueous layer is then neutralized to pH 10 using NaOH pellets, then extracted with methylene chloride (2x500ml). The combined methane chloride layers are washed with brine (500ml), dried (MgSO4) and evaporated to 100ml. Toluene (250ml) is added and the suspension is concentrated to 150ml. By collecting the resulting precipitate during drying, the title compound was obtained as a white powder.

ix)2-Fluoro-7-piridin-3-ilmetil-9H-karbazol ix) 2-Fluoro-7-pyridin-3-ylmethyl-9H-carbazole

Otopina 10(viii) u 50%-tnom metanol/THF-u (200ml) se tretira sa koncentriranom HCl (5ml) i paladijem na ugljenu kao katalizatorom (10% aktivnog katalizatora, 50% vodene vlage). Suspenzija se smjesti u Parr-ovu tikvicu za hidriranje i tretira se sa plinovitim vodikom pri 10 PSI na 25°C tokom 3 sata. Katalizator se ukloni filtriranjem, katalizator se ispere sa HCl (10%,100ml), vodom (100ml) i 10%-tnom NaOH (100ml). Filtrat se ukoncentrira do 200ml, zatim se neutralizira sa peletama NaOH do pH 9. Otopina se ekstrahira sa etil acetatom (2x250ml), te se spojeni organski slojevi isperu sa rasolom (250ml), suše se (Na2SO4) i koncentriraju dajući biljelu krutinu. Sirovi produkt se otopi u metanolu (400ml) i kapajući se tretira sa vodom (200ml). A solution of 10(viii) in 50% methanol/THF (200ml) is treated with concentrated HCl (5ml) and palladium on charcoal as catalyst (10% active catalyst, 50% water moisture). The suspension was placed in a Parr flask for hydration and treated with hydrogen gas at 10 PSI at 25°C for 3 hours. The catalyst is removed by filtration, the catalyst is washed with HCl (10%, 100ml), water (100ml) and 10% NaOH (100ml). The filtrate is concentrated to 200ml, then neutralized with NaOH pellets to pH 9. The solution is extracted with ethyl acetate (2x250ml), and the combined organic layers are washed with brine (250ml), dried (Na2SO4) and concentrated to give a white solid. The crude product is dissolved in methanol (400ml) and treated dropwise with water (200ml).

Rezultirajući precipitat se sakupi i suši dajući naslovni spoj kao bijelu, kristaliničnu krutinu. The resulting precipitate was collected and dried to give the title compound as a white, crystalline solid.

Točka taljenja: 196-197°C. Melting point: 196-197°C.

Maseni spektar (FAB+): 277 Mass spectrum (FAB+): 277

Analiza elemenata: Analysis of elements:

[image] [image]

Slijedeći primjeri ilustriraju farmaceutske pripravke prema izumu koji sadrže 2-fluoro-7-piridin-3-ilmetil-9H-karbazol kao aktivni sastojak. Ostali spojevi prema izumu mogu biti formulirani na sličan način. The following examples illustrate pharmaceutical compositions according to the invention containing 2-fluoro-7-pyridin-3-ylmethyl-9H-carbazole as an active ingredient. Other compounds according to the invention can be formulated in a similar way.

Tablete za oralnu primjenu Tablets for oral administration

a) Izravno komprimirane tablete a) Directly compressed tablets

[image] [image]

Svi sastojci osim magnezijevog stearata se miješaju sve dok nisu dobro promiješani. Magnezijev stearat se prosije i doda smjesi koja je potpuno promiješana. Rezultirajuća smjesa se komprimira na ranije određenu veličinu i težinu tableta. All ingredients except magnesium stearate are mixed until well mixed. The magnesium stearate is sieved and added to the mixture which is thoroughly mixed. The resulting mixture is compressed to a previously determined tablet size and weight.

b) Tablete dobivene vlažnim granuluranjem b) Tablets obtained by wet granulation

[image] [image]

Svi sastojci osim otopine polivinilpirolidona i magnezijevog stearata se miješaju u fluidiziranom ležištu. Otopina polivinilpirolidona se doda pomiješanim prascima uz stalno miješanje da se jednolično navlaže. Nakon sušenja, granule se samelju da bi se smanjila veličina čestica i povećala jednoličnost, te se pomiješaju sa magnezijevim stearatom. Granule se zatim komprimiraju na ranije određenu veličinu i težinu tableta. All ingredients except the solution of polyvinylpyrrolidone and magnesium stearate are mixed in a fluidized bed. The polyvinylpyrrolidone solution is added to the mixed powders with constant stirring to wet them uniformly. After drying, the granules are ground to reduce particle size and increase uniformity, and are mixed with magnesium stearate. The granules are then compressed to a previously determined tablet size and weight.

Tablete drugih jačina se mogu prirediti promjenom odnosa aktivnog sastojka i npr. laktoze ili promjenom komprimirane težine granula. Tablets of other strengths can be prepared by changing the ratio of the active ingredient and eg lactose or by changing the compressed weight of the granules.

Tablete se mogu prevući filmom sa odgovarajućim materijalima koji formiraju film, poput npr. hidroksipropil metilceluloze upotrebom uobičajene tehnike. Osim toga, tablete mogu biti prevučene šećernom ovojnicom ili enteričkom ovojnicom. Tablets can be film-coated with suitable film-forming materials, such as hydroxypropyl methylcellulose, using conventional techniques. In addition, the tablets can be coated with a sugar coating or an enteric coating.

Sirup za oralnu primjenu Syrup for oral use

[image] [image]

Natrijeva karboksimetilceluloza i magnezijev aluminijev silikat se hidriraju u otopini natrijevog lauril sulfata i vodi tokom 24 sata. Aktivni sastojak se suspenzira u vehikulumu uz pomoć miješalice. Konzervansi se otope u preostaloj količini vode uz zagrijavanje i nakon hlađenja na sobnu temperaturu, doda se otopina sorbitola. Otopina se doda u suspenziju, primjesa se korigens i namjesti se pH kako je to potrebno. Konačna suspenzija se miješa u homogenizatoru. Sodium carboxymethylcellulose and magnesium aluminum silicate are hydrated in a solution of sodium lauryl sulfate and water for 24 hours. The active ingredient is suspended in the vehicle with the help of a mixer. Preservatives are dissolved in the remaining amount of water with heating and after cooling to room temperature, sorbitol solution is added. The solution is added to the suspension, the corrigen is mixed in and the pH is adjusted as necessary. The final suspension is mixed in a homogenizer.

Meke želatinozne kapsule za oralnu primjenu Soft gelatin capsules for oral administration

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Glikoli se miješaju uz zagrijavanje do homogenosti. Doda se aktivni sastojak i puni se u odgovarajuću želatoniznu masu da bi se dobile meke želatinozne kapsule sa punjenjem odgovarajuće težine. Glycols are mixed with heating until homogeneous. The active ingredient is added and filled into the appropriate gelatinous mass to obtain soft gelatinous capsules with filling of the appropriate weight.

Čepići za rektalnu primjenu Suppositories for rectal use

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Aktivni sastojak se u obrocima doda u rastaljen Witepsol (aproksimativno na 36°C) te se pripremi smjesa upotrebom mješalice velike brzine i zatim se doda u preostalu količinu krute masti. Suspenzija se puni upotrebom prikladne aparature u kalupe za 1 ili 2 gramske čepiće i ostavi se skrutnuti. The active ingredient is added in portions to the melted Witepsol (at approximately 36°C) and the mixture is prepared using a high-speed mixer and then added to the remaining amount of solid fat. The suspension is filled using suitable equipment into molds for 1 or 2 gram suppositories and left to solidify.

Transdermalni pripravci Transdermal preparations

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Silikon fluid i aktivni sastojak se pomiješaju te se doda koloidni silicijev dioksid da bi se povećala viskoznost. Materijal se zatim dozira u polimerne folije koje se odmah iza toga zatvaraju, a sastoje se od slijedećeg:poliesetrski dio za oslobađanje, adheziv za kontakt sa kožom koji se sastoji od silikonskog ili akrilnog polimera, kontrolna membrana koja je poliolefin (npr. polietilen ili polivinil acetat) ili poliuretan, te impermeabilna membrana sa stražnje strane koja je načinjena od poliesterskog multi- laminata. Laminirana tabla se zatim dijeli u odgovarajuće flastere. Silicone fluid and active ingredient are mixed and colloidal silica is added to increase viscosity. The material is then dosed into polymer foils that are sealed immediately afterwards, and consist of the following: a polyester release part, an adhesive for contact with the skin consisting of a silicone or acrylic polymer, a control membrane that is a polyolefin (e.g. polyethylene or polyvinyl acetate) or polyurethane, and an impermeable membrane on the back, which is made of polyester multi-laminate. The laminated board is then divided into appropriate patches.

Formulacije za parenteralnu primjenu Formulations for parenteral administration

a)Intravenozne otopine a) Intravenous solutions

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Aktivni sastojak se otopi u vodi zajedno sa ostalim sastojcima i sterilno se filtrira (0.22µm filter). Otopina se puni u staklenu ambalažu koja se zatvara i zatali prije autoklaviranja. The active ingredient is dissolved in water together with other ingredients and sterile filtered (0.22 µm filter). The solution is filled in a glass container that is closed and sealed before autoclaving.

b)Liofiliziran produkt b) Lyophilized product

[image] [image]

Aktivni sastojak se otopi u vodi zajedno sa ostalim sastojcima i sterilno se filtrira (0.22 µm filter). Otopina se puni u staklenu ambalažu, zatvori se i liofilizira prije zataljivanja. Liofilizirani produkt se rekonstruira sa fiziološkom otopinom prije primjene pacijentima. The active ingredient is dissolved in water together with other ingredients and sterile filtered (0.22 µm filter). The solution is filled in a glass container, closed and lyophilized before sealing. The lyophilized product is reconstituted with saline solution before administration to patients.

Claims (22)

1. Spoj, naznačen time, da ima opću formulu (I) [image] gdje R1 i R4 svaki zasebno predstavljaju vodikov atom ili C1-6alkil grupu; svaki od R2, koji mogu biti jednaki ili različiti, predstavlja grupu koja povlači elektrone; svaki od R3, koji mogu biti jednaki ili različiti, predstavlja grupu koja povlači elektrone; R5 je grupa formule [image] R6 je atom halogena, C1-6 alkil grupa ili C1-6alkoksi grupa; m je nula ili broj između 1 i 4; n je nula ili broj između 1 i 3; te p je nula, 1 ili 2 kao i njihove farmaceutski prihvatljive soli i solvate.1. A compound characterized by having the general formula (I) [image] where R 1 and R 4 each separately represent a hydrogen atom or a C 1-6 alkyl group; each of R 2 , which may be the same or different, represents an electron withdrawing group; each of R 3 , which may be the same or different, represents an electron withdrawing group; R5 is a group of formula [image] R 6 is a halogen atom, a C 1-6 alkyl group or a C 1-6 alkoxy group; m is zero or a number between 1 and 4; n is zero or a number between 1 and 3; you p is zero, 1 or 2 as well as their pharmaceutically acceptable salts and solvates. 2. Spoj prema zahtjevu 1, naznačen time, da ima -CHR4R5 grupu na položaju 1, 2 ili 3.2. A compound according to claim 1, characterized in that it has a -CHR4R5 group at position 1, 2 or 3. 3. Spoj prema zahtjevu 1 ili 2, naznačen time, da ima -CHR4R5 grupu na položaju 2.3. A compound according to claim 1 or 2, characterized in that it has a -CHR4R5 group at position 2. 4. Spoj prema bilo kojem zahtjevu od 1 do 3, naznačen time, da R2 i R3, koji mogu biti jednaki ili različiti, predstavljaju atom halogena ili nitril, nitro, trifluorometil, aldehido, keto grupu, grupu karboksilne kiseline ili grupu estera karboksilne grupe.4. A compound according to any of claims 1 to 3, characterized in that R2 and R3, which may be the same or different, represent a halogen atom or a nitrile, nitro, trifluoromethyl, aldehyde, keto group, carboxylic acid group or carboxylic ester group . 5. Spoj prema bilo kojem zahtjevu od 1 do 4, naznačen time, da R2 i R3, koji mogu biti jednaki ili različiti, predstavljaju atom fluora, atom klora ili nitril grupu.5. A compound according to any of claims 1 to 4, characterized in that R2 and R3, which may be the same or different, represent a fluorine atom, a chlorine atom or a nitrile group. 6. Spoj prema bilo kojem zahtjevu od 1 do 5, naznačen time, da R2 predstavlja atom fluora te je m broj od 1 do 4.6. A compound according to any claim from 1 to 5, characterized in that R2 represents a fluorine atom and m is a number from 1 to 4. 7. Spoj prema bilo kojem zahtjevu od 1 do 6, naznačen time, da je m 1 te je R2 na položaju 5 ili 7, povoljno je na položaju 7.7. Compound according to any claim from 1 to 6, characterized in that m is 1 and R2 is in position 5 or 7, preferably in position 7. 8. Spoj prema bilo kojem zahtjevu od 1 do 7, naznačen time, da su R1 i R4, svaki zasebno, atom vodika ili metil grupa.8. A compound according to any one of claims 1 to 7, characterized in that R1 and R4 are, each separately, a hydrogen atom or a methyl group. 9. Spoj prema bilo kojem zahtjevu od 1 do 8, naznačen time, da je R5 piridin-3-il ili piridin-4-il grupa.9. A compound according to any one of claims 1 to 8, characterized in that R5 is a pyridin-3-yl or pyridin-4-yl group. 10. Spoj prema bilo kojem zahtjevu od 1 do 9, naznačen time, da R6 predstavlja atom fluora, metil grupu ili metoksi grupu.10. A compound according to any one of claims 1 to 9, characterized in that R6 represents a fluorine atom, a methyl group or a methoxy group. 11. Spoj prema bilo kojem zahtjevu od 1 do 10, naznačen time, da R1 i R4, svaki zasebno, predstavlja atom vodika ili metil grupu, R2 i R3 su atomi fluora, R6 je atom fluora, metil grupa ili metoksi grupa, m je broj od 1 do 4, n je nula ili broj od 1 do 3, p je nula, 1 ili 2.11. Compound according to any claim from 1 to 10, characterized in that R1 and R4, each separately, represent a hydrogen atom or a methyl group, R2 and R3 are fluorine atoms, R6 is a fluorine atom, a methyl group or a methoxy group, m is a number from 1 to 4, n is zero or a number from 1 to 3, p is zero, 1 or 2. 12. Spoj prema bilo kojem zahtjevu od 1 do 10, naznačen time, da R1 i R4, svaki zasebno, predstavlja atom vodika, R2 i R3 su atomi fluora, Re je atom fluora, metil grupa ili metoksi grupa, te su m, n i p svaki zasebno nula, 1 ili 2.12. A compound according to any of claims 1 to 10, characterized in that R1 and R4, each separately, represent a hydrogen atom, R2 and R3 are fluorine atoms, Re is a fluorine atom, a methyl group or a methoxy group, and m, n and p are each separately zero, 1 or 2. 13. Spoj, naznačen time, da je 2-Fluoro-7[1,2,4]triazol-1-ilmetil-9H-karbazol 2-Fluoro-7-piridin-3-ilmetil-9H-karbazol 2-Fluoro-7-piridin-4-ilmetil-9H-karbazol 2-Fluoro-7-(3-fluoropiridin-4-ilmetil)-9H-karbazol 2-Fluoro-7-(3-metilpiridin-4-ilmetil)-9H-karbazol 2-Fluoro-7-(3-metoksipiridin-4-ilmetil)-9H-karbazol 1,7-Difluoro-2-[1,2,4]triazol-1-ilmetil-9H-karbazol 2,4-Difluoro-7-[1,2,4]triazol-1-ilmetil-9H-karbazol 1,4,7-Trifluoro-2-[1,2,4]triazol-1-ilmetil-9H-karbazol kao i njihove farmaceutski prihvatljive soli i solvate.13. Compound, indicated by the fact that 2-Fluoro-7[1,2,4]triazol-1-ylmethyl-9H-carbazole 2-Fluoro-7-pyridin-3-ylmethyl-9H-carbazole 2-Fluoro-7-pyridin-4-ylmethyl-9H-carbazole 2-Fluoro-7-(3-fluoropyridin-4-ylmethyl)-9H-carbazole 2-Fluoro-7-(3-methylpyridin-4-ylmethyl)-9H-carbazole 2-Fluoro-7-(3-methoxypyridin-4-ylmethyl)-9H-carbazole 1,7-Difluoro-2-[1,2,4]triazol-1-ylmethyl-9H-carbazole 2,4-Difluoro-7-[1,2,4]triazol-1-ylmethyl-9H-carbazole 1,4,7-Trifluoro-2-[1,2,4]triazol-1-ylmethyl-9H-carbazole as well as their pharmaceutically acceptable salts and solvates. 14. Spoj, naznačen time, da je 2-fluoro-7-piridin-3-ilmetil-9H-karbazol kao i njegove farmaceutski prihvatljive soli i solvati.14. The compound, characterized in that it is 2-fluoro-7-pyridin-3-ylmethyl-9H-carbazole as well as its pharmaceutically acceptable salts and solvates. 15. Spoj formule (I) prema bilo kojem zahtjevu od 1 do 14, naznačen time, da služi za upotrebu kao aktivno terapeutsko sredstvo.15. The compound of formula (I) according to any claim from 1 to 14, characterized in that it is used as an active therapeutic agent. 16. Farmaceutski pripravak, naznačen time, da sadrži kao aktivni sastojak spoj formule (I) prema bilo kojem zahtjevu od 1 do 15 ili njegovu farmaceutski prihvatljivu sol ili solvat zajedno s jednom ili više farmaceutski prihvatljivom podlogom ili punilom.16. Pharmaceutical preparation, characterized in that it contains as an active ingredient the compound of formula (I) according to any claim from 1 to 15 or its pharmaceutically acceptable salt or solvate together with one or more pharmaceutically acceptable base or filler. 17. Farmaceutski pripravak prema zahtjevu 16, naznačen time, da služi za oralnu, rektalnu ili topikalnu primjenu.17. Pharmaceutical preparation according to claim 16, characterized in that it serves for oral, rectal or topical administration. 18. Farmaceutski pripravak prema zahtjevu 16 ili 17, naznačen time, da je formuliran u jedinični dozirni oblik koji sadrži 0.1 do 200mg aktivnog sastojka.18. Pharmaceutical preparation according to claim 16 or 17, characterized in that it is formulated in a unit dosage form containing 0.1 to 200 mg of the active ingredient. 19. Upotreba spoja prema bilo kojem zahtjevu od 1 do 15 ili njegove farmaceutski prihvatljive soli ili solvata, naznačena time, da služi za proizvodnju lijeka za liječenje stanja koja podliježu etiologiji povezanoj s podignutim nivoima androgena i/ili estrogena u sisavaca, uključujući i ljude.19. Use of a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of conditions subject to an etiology associated with elevated levels of androgens and/or estrogens in mammals, including humans. 20. Postupak za liječenje sisavaca, uključujući i ljude, naznačen time, da obuhvaća primjenu učinkovite količine spoja prema bilo kojem zahtjevu od 1do 15 ili njihove farmaceutski prihvatljive soli ili solvata za snižavanje nivoa androgena i/ili estrogena20. A method for the treatment of mammals, including humans, characterized by the fact that it comprises the administration of an effective amount of a compound according to any of claims 1 to 15 or a pharmaceutically acceptable salt or solvate thereof for lowering the level of androgens and/or estrogens 21. Postupak za liječenje karcinoma prostate, naznačen time, da obuhvaća primjenu učinkovite količine spoja prema bilo kojem zahtjevu od 1 do 15 ili njegove farmaceutski prihvatljive soli ili solvata.21. A method for the treatment of prostate cancer, characterized in that it comprises the use of an effective amount of a compound according to any of claims 1 to 15 or a pharmaceutically acceptable salt or solvate thereof. 22. Postupak za pripremu spoja prema bilo kojem zahtjevu od 1 do 15 ili njegove farmaceutski prihvatljive soli ili solvata, naznačen time, da obuhvaća (A) za pripremu spoja formule (I) u kojoj R1 predstavlja aton vodika, ciklizaciju spoja formule (II) [image] ili (B) deoksigenaciju spoja formule (IX) [image] ili njegovih zaštićenih derivata; ili (C) prevođenje spoja formule (I) u drugi spoj formule (I); te ako je neophodno i/ili poželjno podvrgavanje spoja koji rezultira iz koraka A, B ili C jednoj ili više daljnjih reakcija koje obuhvaćaju: (i)uklanjanje bilo koje zaštitne grupe; (ii) prevođenje spoja formule (I) ili njegove soli ili solvata u farmaceutski prihvatljivu sol ili solvat; (iii) odijeljivanje racemične smjese u pojedinačne enantiomere formule (I).22. Process for the preparation of a compound according to any claim from 1 to 15 or its pharmaceutically acceptable salt or solvate, characterized in that it comprises (A) for the preparation of the compound of formula (I) in which R1 represents a hydrogen atom, cyclization of the compound of formula (II) [image] or (B) deoxygenation of the compound of formula (IX) [image] or its protected derivatives; or (C) converting a compound of formula (I) into another compound of formula (I); and if it is necessary and/or desirable to subject the compound resulting from step A, B or C to one or more further reactions that include: (i) removal of any protecting group; (ii) converting the compound of formula (I) or its salt or solvate into a pharmaceutically acceptable salt or solvate; (iii) separation of the racemic mixture into individual enantiomers of formula (I).