HRP950222A2

HRP950222A2 - Substituted morpholine derivatives and their use as therapeutic agents

Info

Publication number: HRP950222A2
Authority: HR
Inventors: Raymond Baker; Andrew Pate Owens; Martin Richard Teall; Timothy Harrison; Eileen Mary Seward; Angus Murray Macleod; Christoper John Swain
Original assignee: Merck Sharp & Dohme
Priority date: 1994-04-12
Filing date: 1995-04-11
Publication date: 1997-08-31
Also published as: FI951762A0; FI951762A

Description

Ovaj spoj odnosi se na klasu aromatskih spojeva koji su korisni kao antagonisti tahikinina. Specifično, spojevi ovog izuma sadrže amino-supstituirani azo-heterociklični dio. This compound belongs to a class of aromatic compounds useful as tachykinin antagonists. Specifically, the compounds of this invention contain an amino-substituted azo-heterocyclic moiety.

Tahikinini su grupa prirodnih peptida koji se pojavljuju u prirodi, a široko su distribuirani u svim tkivima sisavaca, kako u središnjem nervnom sustavu, tako i u perifernom nervnom i cirkulatornom sustavu. Tachykinins are a group of natural peptides that occur in nature and are widely distributed in all mammalian tissues, both in the central nervous system and in the peripheral nervous and circulatory systems.

Tahikinini se razlikuju prema sačuvanoj karboksil-terminalnoj sekvenci: Tachykinins differ according to the conserved carboxyl-terminal sequence:

Phe-X-Gly-Leu-Met-NH2. Phe-X-Gly-Leu-Met-NH2.

Do sada, tri su poznata tahikinina sisavaca navedena kao supstanca P, neurokinin A (NKA, supstanca K, neuromedin L) i neurokonin B (NKB, neuromedin K) (za pregled vidi J.E. Maggio, Peptides (1985) 6 (suppl.3), 237-242). Postojeća nomenklatura označava tri receptora tahikinina koji posreduju u biološkom djelovanju supstanci P, NKA i NKB kao NK1, NK2 i NK3 receptori, pojedinačno. To date, the three known mammalian tachykinins are listed as substance P, neurokinin A (NKA, substance K, neuromedin L) and neurokonin B (NKB, neuromedin K) (for review, see J.E. Maggio, Peptides (1985) 6 (suppl.3) , 237-242). The existing nomenclature designates the three tachykinin receptors that mediate the biological action of substances P, NKA and NKB as NK1, NK2 and NK3 receptors, individually.

Dokazi za korisno djelovanje antagonista receptora tahikinina kod bolova, glavobolje, naročito migrene, Alzheimerove bolesti, multiple skleroze, simptoma smanjenja terapije morfinom, kardiovaskularnih promjena, edema, kao što su edemi izazvani termalnim ozlijedama, kroničnih upalnih bolesti kao što su reumatoidni artritis, astma/brohijalna hiperreaktivnost i ostale bolesti dišnih organa uključiv alergijski rinitis, upalnih bolesti crijeva uključiv ulcerozni kolitis i Crohnovu bolest, oštećenja oka i upalnih oboljenja oka, proliferativne vitreoretinopatije, sindroma iritabilnog crijeva i poremećaja funkcije mokraćnog mjehura uključiv cistitis i hiper refleksiju detruzera mokraćnog mjehura, prikazani su u "Tachykinin Receptors and Tachykinin Receptor Antagonists", C.A. Maggi, R. Patacchini, P. Rovero i A. Giachetti, J. Auton. Pharmacol. (1993) 13, 23-93. Evidence for the beneficial effect of tachykinin receptor antagonists in pain, headache, especially migraine, Alzheimer's disease, multiple sclerosis, symptoms of withdrawal from morphine therapy, cardiovascular changes, edema, such as edema caused by thermal injuries, chronic inflammatory diseases such as rheumatoid arthritis, asthma/ brochial hyperreactivity and other respiratory diseases including allergic rhinitis, inflammatory bowel diseases including ulcerative colitis and Crohn's disease, eye damage and inflammatory eye diseases, proliferative vitreoretinopathy, irritable bowel syndrome and bladder function disorders including cystitis and bladder detrusor hyperreflexia are presented in "Tachykinin Receptors and Tachykinin Receptor Antagonists", C.A. Maggi, R. Patacchini, P. Rovero and A. Giachetti, J. Auton. Pharmacol. (1993) 13, 23-93.

Na primjer, vjeruje se da je supstanca P inter alia uključena kod neurotransmisije osjećaja boli (Otsuka et al, "Role of Substance P as a Sensory Transmitter in Spinal Cord and Sympathetic Ganglia" u 1982. Substance P in the Nervouse System, Ciba Foundation Svmposium 91, 13-34 (izdavač Pitman) i Otsuka i Yanagisawa, "Does substance P Act as a Pain Transmitter?" TIPS (1987) 8, 506-510) naročito u prijenosu boli kod migrene (B.E.B. Sandberg et al, J.Med Chem, (1982) 25, 1009) i kod artritisa (Levine et al Science (1984) 226, 547-549). Tahikinini su također implicirani kod gastrointestinalnih (Gl) poremećaja i oboljenja Gl trakta kao što su upalna bolest crijeva (Mantyh et al Neuroscience (1988) 25 (3), 817-37 i D. Regoli u "Trends in Cluster Headache" Ed. Sicuteri et al Elsevier Scientific Publishers, Amsterdam (1987) str. 85)) i kod povraćanja (F.D. Tattersall et al, Eur.J. Pharmacol., (1993) 250, R5-R6). Također se pretpostavlja da postoji neurogenski mehanizam kod artritisa gdje supstanca P može imati ulogu (Kidd et al "A Neurogenic Mechanism for Symmetrical Arthritis" u The Lancet, 11 November 1989 i Groenblad et al, "Neuropeptides in Synovium of Patients with Rheumatoid Arthritis and Osteoarthritis" u J.Reumathol, (1988) 15 (12), 1807-10). Prema tome, vjeruje se da je supstanca P uključena pri upalnim reakcijama kod oboljenja kao što su reumatski artritis i osteoartritis i fibrozitis (O'Byrne er. al, Arthritis and Rheumatism (1990) 33, 1023-8). Ostala područja bolesti kod kojih se vjeruje da su antagonisti tahikinina korisni su alergijska oboljenja (Hamelet et al, Can.J.Pharmacol.Phisiol. (1988) 66, 1361-7), imunoregulacija (Lotz et al, Science (1988) 241, 1218-21 i Kimball et al, J. Immunol. (1988) 141(10), 3564-9) vazodilatacija, bronhospazam, refleksna ili živčana kontrola organa (Mantyh et al, PNAS (1988) 85, 3235-9) i, vjerojatno kod zaustavljanja ili usporavanja β-amiloid-posredovanih neuro-degenerativnih promjena (Yankner et al, Science (1990) 250, 279-82) kod senilne demencije Alzheimer tipa, Alzheimerove bolesti i Down sindroma. For example, substance P inter alia is believed to be involved in the neurotransmission of pain sensation (Otsuka et al, "Role of Substance P as a Sensory Transmitter in Spinal Cord and Sympathetic Ganglia" in 1982 Substance P in the Nervous System, Ciba Foundation Symposium 91, 13-34 (published by Pitman) and Otsuka and Yanagisawa, "Does substance P Act as a Pain Transmitter?" TIPS (1987) 8, 506-510) particularly in migraine pain transmission (B.E.B. Sandberg et al, J.Med Chem, (1982) 25, 1009) and in arthritis (Levine et al Science (1984) 226, 547-549). Tachykinins have also been implicated in gastrointestinal (Gl) disorders and diseases of the Gl tract such as inflammatory bowel disease (Mantyh et al Neuroscience (1988) 25 (3), 817-37 and D. Regoli in "Trends in Cluster Headache" Ed. Sicuteri et al Elsevier Scientific Publishers, Amsterdam (1987) p. 85)) and in emesis (F.D. Tattersall et al, Eur.J. Pharmacol., (1993) 250, R5-R6). It is also hypothesized that there is a neurogenic mechanism in arthritis where substance P may play a role (Kidd et al "A Neurogenic Mechanism for Symmetrical Arthritis" in The Lancet, 11 November 1989 and Groenblad et al, "Neuropeptides in Synovium of Patients with Rheumatoid Arthritis and Osteoarthritis " in J. Rheumathol, (1988) 15 (12), 1807-10). Accordingly, substance P is believed to be involved in inflammatory reactions in diseases such as rheumatoid arthritis and osteoarthritis and fibrositis (O'Byrne et al, Arthritis and Rheumatism (1990) 33, 1023-8). Other disease areas in which tachykinin antagonists are believed to be useful are allergic diseases (Hamelet et al, Can.J.Pharmacol.Phisiol. (1988) 66, 1361-7), immunoregulation (Lotz et al, Science (1988) 241, 1218-21 and Kimball et al, J. Immunol. (1988) 141(10), 3564-9) vasodilation, bronchospasm, reflex or nervous organ control (Mantyh et al, PNAS (1988) 85, 3235-9) and, possibly in arresting or retarding β-amyloid-mediated neurodegenerative changes (Yankner et al, Science (1990) 250, 279-82) in senile dementia of the Alzheimer type, Alzheimer's disease and Down syndrome.

Antagonisti tahikinina mogu također biti korisni kod liječenja karcinoma malih stanica, naročito karcinoma malih stanica pluća (SCLC) (Langdon etal, Cancer Research (1992) 52, 4554-7). Tachykinin antagonists may also be useful in the treatment of small cell carcinoma, particularly small cell lung carcinoma (SCLC) (Langdon et al, Cancer Research (1992) 52, 4554-7).

Substanca P može također sudjelovati kod demijelinizirajućih oboljenja kao što je multipla skleroza i amiotrofna lateralna skleroza (J.Luber-Narod et al, poster C.I.N.P. XVIIIth Congres, 28.lipanj -2.srpanj 1992.), i kod poremećaja funkcije mokraćnog mjehura kao što je hiper refleksija detruzora mokraćnog mjehura (Lancet, 16th May 1992, 1239). Substance P may also participate in demyelinating diseases such as multiple sclerosis and amyotrophic lateral sclerosis (J.Luber-Narod et al, poster C.I.N.P. XVIIIth Congres, June 28 - July 2, 1992), and in bladder function disorders such as is bladder detrusor hyperreflexia (Lancet, 16th May 1992, 1239).

Nadalje, sugerirano je da tahikinini imaju korisno djelovanje kod slijedećih poremećaja: depresija, distimični poremećaji, kronično opstruktivno oboljenje dišnih puteva, bolesti preosjetljivosti kao na otrovni bršljan, vazoplastička oboljenja kao što su angina i Reynaudova bolest, fibrozirajuća i kolagenska oboljenja kao što su skleroderma i eozinofilična fascioliaza, refleksna simpatička distrofija kao što je rame/ruka sindrom, ovisnički poremećaji kao što je alkoholizam, somatski poremećaji povezani sa stresom, neuropatija, neuralgija, poremećaji povezani s imunosupresijom ili imunopovećanjem, kao što je sistemni lupus eritematodes (Europska specifikacija patenta br. 0436334), oftalmička oboljenja kao što su konjunktivitis, vernalni konjunktivitis i sl. i akutne bolesti kao što su kontaktni dermatitis, atipični dermatitis, urticaria i ostali ekcematiodni dermatitisi (Europska specifikacija patenta br.0394989). Furthermore, tachykinins have been suggested to have beneficial effects in the following disorders: depression, dysthymic disorders, chronic obstructive airway disease, hypersensitivity diseases such as poison ivy, vasoplastic diseases such as angina and Reynaud's disease, fibrosing and collagen diseases such as scleroderma and eosinophilic fascioliasis, reflex sympathetic dystrophy such as shoulder/arm syndrome, addictive disorders such as alcoholism, somatic stress-related disorders, neuropathy, neuralgia, disorders associated with immunosuppression or immunoenhancement, such as systemic lupus erythematosus (European patent specification no. 0436334), ophthalmic diseases such as conjunctivitis, vernal conjunctivitis, etc. and acute diseases such as contact dermatitis, atypical dermatitis, urticaria and other eczematoid dermatitis (European patent specification no. 0394989).

Europska specifikacija patenta br. 0577394 (objavljeno 5.siječnja 1994.) objavljuje morfolin i tiomorfolin antagoniste receptora tahikinina opće formule European patent specification no. 0577394 (published January 5, 1994) discloses morpholine and thiomorpholine tachykinin receptor antagonists of the general formula

[image] [image]

unutar koje je R1a široka lepeza supstituenata; within which R1a is a wide variety of substituents;

R2a i R3a su inter alia vodik; R 2a and R 3a are inter alia hydrogen;

R4a je inter alia R4a is inter alia

[image] [image]

R5a je inter alia opcijski supstituirani fenil; R 5a is inter alia optionally substituted phenyl;

R6a, R7a i R8a su različiti supstituenti; R6a, R7a and R8a are different substituents;

Xa je O, S, SO ili SO2 ; Xa is O, S, SO or SO2;

Ya je inter alia O; i Ya is inter alia O; and

Za je vodik ili C1-4 alkil. Z is hydrogen or C1-4 alkyl.

Mi smo sada pronašlli slijedeću klasu ne-peptida koji su snažni antagonisti tahikinina, naročito supstance P. We have now found the next class of non-peptides that are potent tachykinin antagonists, especially substance P.

Poželjno je da se sastojci mogu davati oralno i injektiranjem. Sada su otkriveni spojevi koji djeluju kao snažni ne-peptidni antagonisti tahikinina i koji se, zbog svojeg svojstva dobre topivosti u vodi, naročito lako formuliraju za davanje i oralnim putem i putem injekcija, npr. u vodenom mediju. It is preferable that the ingredients can be given orally and by injection. Compounds have now been discovered that act as potent non-peptide antagonists of tachykinin and which, due to their property of good solubility in water, are particularly easy to formulate for administration both orally and by injection, e.g. in an aqueous medium.

Čak što više, spojevi prikazani u danom izumu imaju naročito dobar profil aktivnosti zbog snažnog antagonističkog djelovanja na NK1 receptor i zbog svojeg dugotrajnog djelovanja. Spojevi ovdje danog izuma, a naročito njihove farmaceutski prihvatljive kisele adicijske soli, također su pogodni za široku lepezu farmaceutskih pripravaka zbog svojstva njihove stabilnosti. Even more, the compounds presented in the given invention have a particularly good activity profile due to their strong antagonistic effect on the NK1 receptor and due to their long-term action. The compounds of the present invention, and in particular their pharmaceutically acceptable acid addition salts, are also suitable for a wide variety of pharmaceutical preparations due to their stability properties.

Ovdje dani izum daje spoj formule (I): The present invention provides a compound of formula (I):

[image] [image]

(I) (AND)

unutar koje within which

R1 je vodik, halogen, C1-6 alkil, C1-6 alkoksi, CF3, NO2, CN, SRa, SORa, SO2Ra, CO2Ra, CONRaRb, C2-6 alkenil, C2-6 alkinil ili C1-4 alkil supstituiran sa C1-4 alkoksi, gdje Ra i Rb svaki posebno prikazuju vodik ili C1-4 alkil; R1 is hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy, CF3, NO2, CN, SRa, SORa, SO2Ra, CO2Ra, CONRaRb, C2-6 alkenyl, C2-6 alkynyl or C1-4 alkyl substituted with C1- 4 alkoxy, wherein R a and R b each independently represent hydrogen or C 1-4 alkyl;

R2 je vodik, halogen, C1-6 alkil, C1-6 alkoksi supstituiran sa C1-4 alkoksi ili CF3; R 2 is hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy substituted with C 1-4 alkoxy or CF 3 ;

R3 je vodik, halogen ili CF3; R 3 is hydrogen, halogen or CF 3 ;

R4 je vodik, halogen,C1-6 alkil, C1-6 alkoksi, CF3, NO2, CN, SRa, SORa, SO2Ra, CO2Ra, CONRaRb, C2-6 alkenil, C2-6 alkinil ili C1-4 alkil supstituiran sa C1-4 alkoksi, gdje Ra i Rb svaki posebno prikazuju vodik ili C1-4 alkil; R4 is hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy, CF3, NO2, CN, SRa, SORa, SO2Ra, CO2Ra, CONRaRb, C2-6 alkenyl, C2-6 alkynyl or C1-4 alkyl substituted with C1- 4 alkoxy, wherein R a and R b each independently represent hydrogen or C 1-4 alkyl;

R5 je vodik, halogen, C1-6 alkil, C1-6 alkoksi supstituiran sa C1-4 alkosi ili CF3: R5 is hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy substituted with C1-4 lkoxy or CF3:

R6 je peteročlani ili šesteročlani heterociklični prsten koji sadrži 2 ili 3 dušikova atoma opcijski supstituirana sa =O, =S ili C1-4 alkilnom grupom, i opcijski supstituirana sa grupom formule ZNR7R8 gdje Z je C1-6 alkilen ili C3-6 cikloalkilen; R6 is a five-membered or six-membered heterocyclic ring containing 2 or 3 nitrogen atoms optionally substituted with =O, =S or a C1-4 alkyl group, and optionally substituted with a group of the formula ZNR7R8 where Z is C1-6 alkylene or C3-6 cycloalkylene;

R7 je vodik, C1-4 alkil, C3-7 cikloalkil ili C3-7 cikloalkil C1-4 alkil, ili C2-4 alkil supstituiran sa C1-4 alkoksi ili hidroksil; R 7 is hydrogen, C 1-4 alkyl, C 3-7 cycloalkyl or C 3-7 cycloalkyl C 1-4 alkyl, or C 2-4 alkyl substituted with C 1-4 alkoxy or hydroxyl;

R8 je vodik, C1-4 alkil, C3-7 cilkloalkil ili C3-7 cikloalkil C1-4 alkil, ili C2-4 alkil supstituiran sa jednim ili dva supstituenta odabrana od C1-4 alkoksi, hidroksil ili 4, 5 ili 6-članog heteroalifatskog prstena koji sadrži jedan ili dva heteroatoma odabrana od N, O i S; R8 is hydrogen, C1-4 alkyl, C3-7 cycloalkyl or C3-7 cycloalkyl C1-4 alkyl, or C2-4 alkyl substituted with one or two substituents selected from C1-4 alkoxy, hydroxyl or 4, 5 or 6-membered a heteroaliphatic ring containing one or two heteroatoms selected from N, O and S;

ili R7, R8 i dušikov atom na koji su vezani tvore heteroalifatski prsten od 4 do 7 atoma prstena, opcijski supstituirana s jednom od dvije grupe odabrane od hidroksi ili C1-4 alkila opcijski supstituirana sa C1-4 alkoksi ili hidroksil grupom, i opcijski imaju dvostruku vezu, čiji prsten može opcijski sadržavati kisik ili sumpor atom prstena, grupu S(O) ili S(O)2 ili drugi dušikov atom koji će biti dio NH ili NRC ostatka gdje RC je C1-4 alkil opcijski supstituiran sa hidroksi ili C1-4 alkoksi; or R7, R8 and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms, optionally substituted with one of two groups selected from hydroxy or C1-4 alkyl optionally substituted with a C1-4 alkoxy or hydroxyl group, and optionally having double bond, the ring of which may optionally contain an oxygen or sulfur atom of the ring, a group S(O) or S(O)2 or another nitrogen atom that will be part of the NH or NRC residue where RC is C1-4 alkyl optionally substituted with hydroxy or C1 -4 alkoxy;

ili R7, R8 i dušikov atom na koji su vezani tvore nearomatski azabiciklični prstenasti sustav od 6 do 12 atoma prstena; or R7, R8 and the nitrogen atom to which they are attached form a non-aromatic azabicyclic ring system of 6 to 12 ring atoms;

ili Z, R7 i dušikov atom na koji su vezani tvore heteroalifatski prsten od 4 do 7 atoma prstena koji mogu opcijski sadržavati kisikov atom prstena; or Z, R7 and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms which may optionally contain a ring oxygen atom;

R9a i R9b su svaki neovisno vodik ili C1-4 alkil, ili R9a i R9b su povezani tako, da zajedno sa ugljikovim atomima na koje su povezani tvore C5-7 prsten: R9a and R9b are each independently hydrogen or C1-4 alkyl, or R9a and R9b are connected so that together with the carbon atoms to which they are connected they form a C5-7 ring:

X je alkilenski lanac od 1 do 4 ugljikova atoma opcijski supstituirana sa okso; i X is an alkylene chain of 1 to 4 carbon atoms optionally substituted with oxo; and

Y je C1-4 alkil grupa opcijski supstituirana sa hidroksilnom grupom; Y is a C1-4 alkyl group optionally substituted with a hydroxyl group;

s uvjetom kada Y je C1-4 alkil, R6 je supstituiran najmanje s grupom formule ZNR7R8 kako je gore definirano; with the proviso that when Y is C1-4 alkyl, R6 is substituted with at least a group of the formula ZNR7R8 as defined above;

ili njegova farmaceutski prihvatljiva sol ili prodrug. or a pharmaceutically acceptable salt or prodrug thereof.

Neki naročito odgovarajući spojevi ovdje danog izuma uključuju one u kojima R1 je vodik, C1-4 alkil, C1-4 alkoksi, halo ili CF3. Some particularly suitable compounds of the invention herein include those wherein R 1 is hydrogen, C 1-4 alkyl, C 1-4 alkoxy, halo or CF 3 .

Odgovarajući R2 je vodik, C1-4 alkil, C1-4 alkoksi, halo ili CF3. A suitable R 2 is hydrogen, C 1-4 alkyl, C 1-4 alkoxy, halo or CF 3 .

Odgovarajući R3 je vodik, flour, klor ili CF3. Suitable R 3 is hydrogen, fluorine, chlorine or CF 3 .

Povoljan R1 je flour, klor ili CF3. A preferred R1 is fluorine, chlorine or CF3.

Povoljan R2 je vodik, fluor, klor ili CF3. A preferred R 2 is hydrogen, fluorine, chlorine or CF 3 .

Povoljan R3 je vodik, fluor, klor ili CF3. A preferred R 3 is hydrogen, fluorine, chlorine or CF 3 .

Poželjno R1 i R2 su na trećoj i petoj poziciji fenilnog prstena. Preferably R1 and R2 are in the third and fifth positions of the phenyl ring.

Poželjnije R1 je 3-fluoro ili 3-CF3. More preferably R1 is 3-fluoro or 3-CF3.

Poželjnije R2 je 5-flouro ili 5-CF3. More preferably, R 2 is 5-fluoro or 5-CF 3 .

Poželjnije R3 je vodik. More preferably, R 3 is hydrogen.

Najpoželjnije R1 je 3-F ili 3-CF3, R2 je 5-CF3 i R3 je vodik. Most preferably R1 is 3-F or 3-CF3, R2 is 5-CF3 and R3 is hydrogen.

Odgovarajući R4 je vodik. The corresponding R 4 is hydrogen.

Odgovarajući R5 je vodik, fluor, klor ili CF3. A suitable R 5 is hydrogen, fluorine, chlorine or CF 3 .

Poželjno R4 je vodik i R5 je vodik ili 4-fluoro. Preferably R4 is hydrogen and R5 is hydrogen or 4-fluoro.

Odgovarajući R9a i R9b su svaki neovisno vodik ili metil. The respective R9a and R9b are each independently hydrogen or methyl.

Poželjno R9a je vodik. Poželjno R9b je vodik. Najpoželjnije su R9a i R9b oba vodici. Preferably R 9a is hydrogen. Preferably R 9b is hydrogen. Most preferably, R9a and R9b are both hydrogen.

Iz prethodnog bit će razumljivo da je naročito pogodna podgrupa spojeva ovog izuma podgrupa formule (Ia) ili njezina farmaceutski prihvatljiva sol ili prodrug. It will be understood from the above that a particularly suitable subgroup of the compounds of this invention is the subgroup of formula (Ia) or its pharmaceutically acceptable salt or prodrug.

[image] [image]

Gdje Where

A1 je fluor ili CF3; A1 is fluorine or CF3;

A2 je fluor ili CF3; A 2 is fluorine or CF 3 ;

A3 je flour ili vodik; A3 is fluorine or hydrogen;

i X, Y i R6 su defini rani kao u formuli (I). and X, Y and R 6 are defined as in formula (I).

Prema drugom ili daljnjem aspektu danog izuma, preferirana klasa spoja formule (I) ili (Ia) je ona u kojoj Y prikazuje C1-4 alkil grupu supstituiranu sa hidroksi grupom; ili njezina farmaceutski prihvatljiva sol ili prodrug. According to another or further aspect of the present invention, a preferred class of compounds of formula (I) or (Ia) is that in which Y represents a C 1-4 alkyl group substituted with a hydroxy group; or a pharmaceutically acceptable salt or prodrug thereof.

Prema daljnjem ili drukčijem aspektu danog izuma, iduća preferirana klasa spoja formule (I) ili (Ia) je ona u kojoj Y prikazuje C1-4 alkil grupu, s uvjetom da je R6 supstituiran najmanje s grupom formule ZNR7R8 kako je gore definirana; ili njezina farmaceutski prihvatljiva sol ili prodrug. According to a further or different aspect of the present invention, the next preferred class of compounds of formula (I) or (Ia) is that in which Y represents a C1-4 alkyl group, provided that R6 is substituted at least with a group of the formula ZNR7R8 as defined above; or a pharmaceutically acceptable salt or prodrug thereof.

Prema slijedećem aspektu danog izuma, slijedeća preferirana klasa spojeva formule (I) ili (Ia) je ona u kojoj According to a further aspect of the present invention, a further preferred class of compounds of formula (I) or (Ia) is that in which

Y prikazuje C1-4 alkil grupu; i Y represents a C1-4 alkyl group; and

R6 je peteročlani ili šesteročlani heterociklični prsten koji sadrži 2 ili 3 dušikova atoma opcijski supstituirana sa =O ili =S i supstituirana sa grupom formule ZNR7R8 gdje R6 is a five-membered or six-membered heterocyclic ring containing 2 or 3 nitrogen atoms optionally substituted with =O or =S and substituted with a group of the formula ZNR7R8 where

Z je C1-6 alkilen ili C3-6 cikloalkilen; Z is C1-6 alkylene or C3-6 cycloalkylene;

ili R7, R8 i dušikov atom na koji su vezani tvore heteroalifatski prsten od 4 do 7 atoma prstena, opcijski supstituirana s hidroksi grupom, i opijski imaju dvostruku vezu, čiji prsten može opcijski sadržavati kisik ili sumpor atom prstena, grupu S(O) ili S(O)2 ili drugi dušikov atom koji će biti dio NH ili NRC ostatka gdje RC je C1-4 alkil opcijski supstituiran sa hidroksi ili C1-4 alkoksi; or R7, R8 and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms, optionally substituted with a hydroxy group, and optionally having a double bond, whose ring may optionally contain an oxygen or sulfur atom of the ring, the group S(O) or S(O)2 or another nitrogen atom which will be part of the NH or NRC residue where RC is C1-4 alkyl optionally substituted with hydroxy or C1-4 alkoxy;

ili Z, R7 i dušikov atom na koji su vezani tvore heteroaromatski prsten od 4 do 7 atoma prstena koji mogu opijski sadržavati jedan kisikov atom prstena; or Z, R7 and the nitrogen atom to which they are attached form a heteroaromatic ring of 4 to 7 ring atoms which may optionally contain one ring oxygen atom;

ili njezina farmaceutski prihvatljiva sol ili prodrug. or a pharmaceutically acceptable salt or prodrug thereof.

Prema još jedom aspektu danog izuma, preferirana klasa spojeva formule (I) ili (Ia) je ona u kojoj According to another aspect of the present invention, a preferred class of compounds of formula (I) or (Ia) is that in which

Y prikazuje C1-4 alkil grupu; i Y represents a C1-4 alkyl group; and

R7 je vodik, C1-4 alkil, ili C2-4 alkil supstituiran sa C1-4 alkoksi ili hidroksil; R 7 is hydrogen, C 1-4 alkyl, or C 2-4 alkyl substituted with C 1-4 alkoxy or hydroxyl;

R8 je vodik, C1-4 alkil ili C2-4 alkil supstituiran sa C1-4 alkoksi, hidroksil ili 5- ili 6-članim heteroalifatskim prstenom koji sadrži jedan ili dva heteroatoma odabrana od N, O i S; R 8 is hydrogen, C 1-4 alkyl or C 2-4 alkyl substituted with C 1-4 alkoxy, hydroxyl or a 5- or 6-membered heteroaliphatic ring containing one or two heteroatoms selected from N, O and S;

ili R7, R8 i dušikov atom na koji su vezani tvore heteroalifatski prsten od 4 do 7 atoma prstena, opcijski supstituirana s hidroksi grupom, čiji prsten može opcijski sadržavati kisik ili sumpor atom prstena, grupu S(O) ili S(O)2 ili drugi dušikov atom koji će biti dio NH ili NRC ostatka gdje RC je C1-4 alkil opcijski supstituiran sa hidroksi ili C1-4 alkoksi; or R7, R8 and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms, optionally substituted with a hydroxy group, whose ring may optionally contain an oxygen or sulfur atom of the ring, a group S(O) or S(O)2 or the second nitrogen atom which will be part of the NH or NRC residue where RC is C1-4 alkyl optionally substituted with hydroxy or C1-4 alkoxy;

Prema daljnjem aspektu ovdje danog izuma, slijedeća preferirana klasa spoja formue (I) ili (Ia) je ona u kojoj According to a further aspect of the invention provided herein, a further preferred class of compounds of formula (I) or (Ia) is that in which

Y prikazuje C1-4 alkil grupu supstituiranu sa hidroksil grupom; i Y represents a C 1-4 alkyl group substituted with a hydroxyl group; and

R6 je peteročlani ili šesteročlani heterociklični prsten koji sadrži 2 ili 3 dušikova atoma opcijski supstituirana sa =O ili =S i opcijski supstituirana sa grupom formule ZNR7R8 gdje R6 is a five- or six-membered heterocyclic ring containing 2 or 3 nitrogen atoms optionally substituted with =O or =S and optionally substituted with a group of the formula ZNR7R8 where

R8 je vodik, C1-4 alkil ili C2-4 alkil supstituiran sa C1-4 alkoksi, ili hidroksil; R 8 is hydrogen, C 1-4 alkyl or C 2-4 alkyl substituted with C 1-4 alkoxy, or hydroxyl;

ili R7, R8 i dušikov atom na koji su vezani tvore heteroalifatski prsten od 4 do 7 atoma prstena, koji može opcijski sadržavati kisik atom prstena ili drugi dušikov atom koji će biti dio NH ili NRCostatka gdje RC je C1-4 alkil opcijski supstituiran sa hidroksi ili C1-4 alkoksi; or R7, R8 and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms, which may optionally contain an oxygen atom of the ring or another nitrogen atom that will be part of an NH or NR residue where RC is C1-4 alkyl optionally substituted with hydroxy or C1-4 alkoxy;

Prema slijedećem aspektu danog izuma, slijedeća preferirana klasa spoja formule (I) ili (Ia) je ona u kojoj je According to a further aspect of the present invention, a further preferred class of compounds of formula (I) or (Ia) is that in which

R6 je peteročlani ili šesteročlani heterociklični prsten koji sadrži 2 ili 3 dušikova atoma opcijski supstituirana sa =O ili =S i opcijski supstituiran sa grupom formule ZNR7R8 gdje R6 is a five- or six-membered heterocyclic ring containing 2 or 3 nitrogen atoms optionally substituted with =O or =S and optionally substituted with a group of the formula ZNR7R8 where

Z je C1-6 alkilen ili C3-6 cikloalkil; Z is C1-6 alkylene or C3-6 cycloalkyl;

ili R7, R8 i dušikov atom na koji su vezani tvore heteroalifatski prsten od 4 do 7 atoma prstena, koji može opcijski sadržavati kisik atom prstena ili drugi dušikov atom koji će biti dio NH ili NRC ostatka gdje RC je C1-4 alkil opcijski supstituiran sa hidroksi ili C1-4 alkoksi; or R7, R8 and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms, which may optionally contain a ring oxygen atom or another nitrogen atom which will be part of the NH or NRC residue where RC is C1-4 alkyl optionally substituted with hydroxy or C1-4 alkoxy;

Preferirana grupa Y za spojeve formula (I) ili (Ia) je CH2OH grupa. The preferred group Y for the compounds of formulas (I) or (Ia) is the CH2OH group.

Slijedeća preferirana grupa Y za spojeve formula (I) ili (Ia) je CH3grupa. The next preferred Y group for compounds of formulas (I) or (Ia) is the CH3 group.

Naročito prikladne vrijednosti za X spojeve formula (I) ili (Ia) uključuju CH2, CH(CH3) i CH2CH2 među kojima se preferira grupa CH2. Particularly suitable values for X compounds of formula (I) or (Ia) include CH 2 , CH(CH 3 ) and CH 2 CH 2 among which the CH 2 group is preferred.

Povoljno R6 je 5-člani prsten. Advantageously, R6 is a 5-membered ring.

Posebice, R6 može, imajući na umu uvjet u definiciji formule (I), prikazivati heterociklični prsten odabran od: In particular, R 6 may, bearing in mind the condition in the definition of formula (I), represent a heterocyclic ring selected from:

[image] [image]

Posebno preferirani heterociklični prsteni prikazani sa R6 odabrani su od: Particularly preferred heterocyclic rings shown with R6 are selected from:

[image] [image]

Naročito posebno, R6 može prikazivati heterociklični prsten odabran od: In particular, R 6 may represent a heterocyclic ring selected from:

[image] [image]

Naročito preferirani heterociklični prsten prikazan sa R6 je: A particularly preferred heterocyclic ring represented by R6 is:

[image] [image]

Jedna preferirna grupa spojeva ovog izuma je formule (lb) i njezine farmaceutski prihvatljive soli i prodrugovi. One preferred group of compounds of the present invention is formula (Ib) and its pharmaceutically acceptable salts and prodrugs.

[image] [image]

gdje su A1, A2 i A3 definirani u odnosu na formulu (Ia) i gdje su Z, R7 i R8 definirani kao u formuli (I). where A1, A2 and A3 are defined in relation to formula (Ia) and where Z, R7 and R8 are defined as in formula (I).

Daljnja preferirana grupa spojeva danog izuma je formule (Ic) i njezine farmaceutski prihvatljive soli i prodrugovi: A further preferred group of compounds of the present invention is of formula (Ic) and its pharmaceutically acceptable salts and prodrugs:

[image] [image]

gdje su A1, A2 i A3 definirani u odnosu na formulu (Ia) i Q1 je CH ili N ili C-ZNR7R8 gdje su Z, R7 i R8 definirani u odnosu na formulu (I). where A 1 , A 2 and A 3 are defined in relation to formula (Ia) and Q 1 is CH or N or C-ZNR 7 R 8 where Z, R 7 and R 8 are defined in relation to formula (I).

Slijedeća preferirana grupa spojeva ovdje danog izuma je formule (Id) i njezine farmaceutski prihvatljive soli i prodrugovi: The next preferred group of compounds of the present invention is of formula (Id) and its pharmaceutically acceptable salts and prodrugs:

[image] [image]

(Id) (ID)

gdje su A1, A2 i A3 definirani u odnosu na formulu (Ia), Q2 je CH ili N i Z, R7 i R8 su definirani kao u formuli (I). where A1, A2 and A3 are defined in relation to formula (Ia), Q2 is CH or N and Z, R7 and R8 are defined as in formula (I).

Obzirom na spojeve formula (I), (Ia), (lb), (Ic) i (Id), Z može biti ravna, razgranata ili ciklička grupa. Povoljno Z sadrži 1 do 4 ugljikova atoma, a naročito povoljno 1 do 2 ugljkova atoma. Posebno favorizirana grupa Z je CH2. With respect to compounds of formulas (I), (Ia), (lb), (Ic) and (Id), Z may be a straight, branched or cyclic group. Advantageously, Z contains 1 to 4 carbon atoms, and particularly advantageously 1 to 2 carbon atoms. A particularly favored group Z is CH2.

U odnosu na spojeve formula (I), (Ia), (Ib), (Ic) i (Id), R7 može povoljno biti C1-4 alkil grupa ili C2-4 alkil grupa supstituirana sa hidroksil ili C1-2 alkoksi grupom, R8 može povoljno biti C1-4 alkil grupa ili C1-4 alkil grupa supstituirana sa hidroksil ili C1-2 alkoksi grupom, ili R7 i R8 mogu biti povezani tako da, zajedno sa atomom dušika na koji su vezani, tvore azetidinil, pirolidinil, piperidil, morfolino, tiomorfolino, piperazino ili piperazino grupu supstituiranu na atomu dušika sa C1-4 alkil grupom ili C2-4 alkil grupu supstituiranu sa hidroksi ili C1-2 alkoksi grupom. In relation to the compounds of formulas (I), (Ia), (Ib), (Ic) and (Id), R7 can advantageously be a C1-4 alkyl group or a C2-4 alkyl group substituted with a hydroxyl or C1-2 alkoxy group, R8 can advantageously be a C1-4 alkyl group or a C1-4 alkyl group substituted with a hydroxyl or C1-2 alkoxy group, or R7 and R8 can be linked so that, together with the nitrogen atom to which they are attached, they form azetidinyl, pyrrolidinyl, piperidyl , morpholino, thiomorpholino, piperazino or piperazino group substituted on the nitrogen atom with a C1-4 alkyl group or C2-4 alkyl group substituted with a hydroxy or C1-2 alkoxy group.

Tamo gdje grupa NR7R8 prikazuje heteroalifatski prsten sa 4 do 7 atoma prstena i navedeni prsten sadrži dvostruku vezu, naročito preferirana grupa je 3-pirolin. Where the group NR 7 R 8 shows a heteroaliphatic ring with 4 to 7 ring atoms and said ring contains a double bond, a particularly preferred group is 3-pyrroline.

Tamo gdje grupa NR7R8 prikazuje ne-aromatski azabiciklični prstenasti sustav, takav sustav može sadržavati između 6 i 12, poželjno između 7 i 10 atoma prstena. Odgovarajući prstenovi uključuju: Where the group NR 7 R 8 shows a non-aromatic azabicyclic ring system, such system may contain between 6 and 12, preferably between 7 and 10 ring atoms. Suitable rings include:

5-azabiciklo[2.1.1)heksil, 5-azabiciklo[2.2.1]heptil, 5-azabicyclo[2.1.1)hexyl, 5-azabicyclo[2.2.1]heptyl,

6-azabiciklo[3.2.1]oktil, 6-azabicyclo[3.2.1]octyl,

2-azabiciklo[2.2.2]oktil, 6-azabiciklo[3.2.2]nonil, 6-azabiciklo[3.3.1]nonil, 2-azabicyclo[2.2.2]octyl, 6-azabicyclo[3.2.2]nonyl, 6-azabicyclo[3.3.1]nonyl,

6-azabiciklo[3.2.2]decil, 7-azabiciklo[4.3.1]decil, 6-azabicyclo[3.2.2]decyl, 7-azabicyclo[4.3.1]decyl,

7-azabiciklo[4.4.1]undecil i 8-azabiciklo[5.4.1]dodecil, naročito 7-azabicyclo[4.4.1]undecyl and 8-azabicyclo[5.4.1]dodecyl, especially

5-azabiciklo[2.2.1]heptil i 6-azabiciklo[3.2.1]oktil. 5-azabicyclo[2.2.1]heptyl and 6-azabicyclo[3.2.1]octyl.

Tamo gdje R8 prikazije C2-4 alkil grupu supstituiranu sa 5- i 6-članim heteroalifatskim prstenom koji sadrži jedan ili dva heteroatoma odabrana od N, O i S, odgovarajući prstenovi uključuju pirolidinski, piperidinski, piperazinski, morfolinski ili tiomorfoiinski. Naročito preferirani su heteroalifatski prstenovi s dušikom, naročito pirolidinski i morfolinski prstenovi. Where R 8 represents a C 2-4 alkyl group substituted with a 5- and 6-membered heteroaliphatic ring containing one or two heteroatoms selected from N, O and S, suitable rings include pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine. Particularly preferred are heteroaliphatic rings with nitrogen, especially pyrrolidine and morpholine rings.

Naročito odgovarajući ostaci ZNR7R8 uključuju one kod kojih Z je CH2 ili CH2CH2 i NR7R8 je amino, metilamino, dimetilamino, dietilamino, azetidinil, pirolidin i morfolin. Particularly suitable ZNR7R8 residues include those where Z is CH2 or CH2CH2 and NR7R8 is amino, methylamino, dimethylamino, diethylamino, azetidinyl, pyrrolidine and morpholine.

Daljnji preferirani dijelovi prikazani sa ZNR7R8 su oni kod kojih Z je CH2 ili CH2CH2, R7 prikazuje vodik, C1-4 alkil ili C3-6 cikloalkil i R8 je C22-4 alkil supstituiran sa jednim ili dva supstituenta odabrana između hidroksi, C1-2 alkoksi, azetidinila, pirolidina, piperidina, morfolina ili tiomorfolina. Further preferred moieties shown by ZNR7R8 are those wherein Z is CH2 or CH2CH2, R7 represents hydrogen, C1-4 alkyl or C3-6 cycloalkyl and R8 is C22-4 alkyl substituted with one or two substituents selected from hydroxy, C1-2 alkoxy , azetidinyl, pyrrolidine, piperidine, morpholine or thiomorpholine.

Naročito, Z je poželjno CH2 i NHR7R8 je poželjno dimetilamino, azetidinil ili pirolidin, naročito dimetilamino. In particular, Z is preferably CH 2 and NHR 7 R 8 is preferably dimethylamino, azetidinyl or pyrrolidine, especially dimethylamino.

S obzirom na spojeve formula (Ia), (Ib), (Ic) i (Id), A1 je poželjno fluor ili CF3; A2 je poželjno CF3; i A3 je požejno fluor. With respect to compounds of formulas (Ia), (Ib), (Ic) and (Id), A1 is preferably fluorine or CF3; A2 is preferably CF3; and A3 is preferably fluorine.

Kako je ovdje navedeno, pojam "alkil" ili "alkoksi" kao grupa ili dio grupe znači da je grupa ravna ili razgranata. Primjeri odgovarajćih grupa uključuju metil, etil, n-propil, i-propil, n-butil, s-butil i t-butil. Primjeri oddgovarajućih alkoksi grupa uključuju metoksi, etoksi, n-propoksi, i-propoksi, n-butoksi, s-butoksi i t-butoksi. As stated herein, the term "alkyl" or "alkoxy" as a group or part of a group means that the group is straight or branched. Examples of suitable groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl and t-butyl. Examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy and t-butoxy.

Cikloakline grupe ovdje navedene mogu prikazivati, na primjer, ciklopropil, ciklobutil, ciklopentil ili cikloheksil. Odgovarajuća cikloalkilna grupa može biti, na primjer, ciklopropilmetil. Cycloalkyl groups recited herein may represent, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. A suitable cycloalkyl group may be, for example, cyclopropylmethyl.

Kako je ovdje navedeno, pojmovi "alkenil" i "alkinil" kao grupa ili dio grupe znači da je grupa ravna ili razgranata. Primjeri odgovarajućih alkenil grupa uključuju vinil i anil. Odgovarajuća alkinil grupa je propargil. As stated herein, the terms "alkenyl" and "alkynyl" as a group or part of a group mean that the group is straight or branched. Examples of suitable alkenyl groups include vinyl and anyl. The corresponding alkynyl group is propargyl.

Kako je ovdje upotrijebljen, pojam halogen znači fluor, klor, brom i jod. Najpovoljniji halogeni su fluor i klor, od čega se fluor preferira. As used herein, the term halogen means fluorine, chlorine, bromine and iodine. The most preferred halogens are fluorine and chlorine, of which fluorine is preferred.

Specifični spojevi u opsegu ovog izuma uključuju: Specific compounds within the scope of this invention include:

2-(R)-(1-(R)-(3,5-bis(trifluormetil)fenil)etoksi)-4-(2,3-dihidro-5-(N,N-dimetilamino)metil-2-okso-1,3-imidazol-4-il)metil-3-(S)-(4-fluorofenil) morfolin; 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(2,3-dihydro-5-(N,N-dimethylamino)methyl-2-oxo -1,3-imidazol-4-yl)methyl-3-(S)-(4-fluorophenyl)morpholine;

4-(2,3-dihidro-5-(N,N-dimetilamino)metil-2-okso-1,3-imidazol-4-il)metil-3-(S)-(4-fluorofenil)-2-(R)-(1-(R)-(3-fluoro-5-(trifluorometil)fenil)etoksi) morfolin; 4-(2,3-dihydro-5-(N,N-dimethylamino)methyl-2-oxo-1,3-imidazol-4-yl)methyl-3-(S)-(4-fluorophenyl)-2- (R)-(1-(R)-(3-fluoro-5-(trifluoromethyl)phenyl)ethoxy)morpholine;

3-(S)-(4-fluorofenil)-2-(R)-(1-(R)-(3-fluoro-5-(trifluorometil)fenil)etoksi)-4-(2,3-dihidro-2-oksi-5-pirolidinometil-1,3-imidazol-4-il)metilmorfolin; 3-(S)-(4-fluorophenyl)-2-(R)-(1-(R)-(3-fluoro-5-(trifluoromethyl)phenyl)ethoxy)-4-(2,3-dihydro-2 -oxy-5-pyrrolidinomethyl-1,3-imidazol-4-yl)methylmorpholine;

2-(R)-(1-(R)-(3,5-bis(trifluorometil)fenil)etoksi)-3-(S)-(4-fluorfenil)-4-(2)3-dihidro-2-okso-5-pirolidinometil-1,3-imidazol-4-il)metilmorfolin; 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(2)3-dihydro-2- oxo-5-pyrrolidinomethyl-1,3-imidazol-4-yl)methylmorpholine;

2-(R)-(1-(R)-(3,5-bis(triflourometil)fenil)etoksi)-3-(S)-(4-fluorofenil)-4-(2,3-dihidro-5-(4-hidroksipiperidino)metil-2-okso-1,3-imidazol-4-il)metilmorfolin; 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(2,3-dihydro-5- (4-hydroxypiperidino)methyl-2-oxo-1,3-imidazol-4-yl)methylmorpholine;

3-(S)-(4-fluorofenil)-2-(R)-(1-(R)-(3-fluoro-5-(trifluorometil)fenil)etoksi-4-(2,3-dihidro-5-morfolinometil-2-okso-1,3-imidazol-4-il)metilmorfolin; 3-(S)-(4-fluorophenyl)-2-(R)-(1-(R)-(3-fluoro-5-(trifluoromethyl)phenyl)ethoxy-4-(2,3-dihydro-5- morpholinomethyl-2-oxo-1,3-imidazol-4-yl)methylmorpholine;

2-(R)-(1-(R)-(3,5-bis(triflourometil)fenil)etoksi)-3-(S)-(4-fluorofenil)-4-(2,3-dihidro-5-morfolinometil-2-okso-1,3-imidazol-4-il)metilmorfolin; 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(2,3-dihydro-5- morpholinomethyl-2-oxo-1,3-imidazol-4-yl)methylmorpholine;

4-(5-azetidinilmetil-2,3-dihidro-2-okso-1,3-imidazol-4-il)metil-2-(R)-(1-(R)-(3,5-bis(trifluorometil)fenil)etoksi)-3-(4-fluorofenil)morfolin; 4-(5-azetidinylmethyl-2,3-dihydro-2-oxo-1,3-imidazol-4-yl)methyl-2-(R)-(1-(R)-(3,5-bis(trifluoromethyl )phenyl)ethoxy)-3-(4-fluorophenyl)morpholine;

2-(R)-(1-(R)-(3,5-bis(trifluorometil)fenil)etoksi)-3-(S)-(4-fluorofenil)-4-(2,3-dihidro-5-(N-metilpiperazinil)metil-2-okso-1,3-imidazol-4-il)metilmorfolin; 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(2,3-dihydro-5- (N-methylpiperazinyl)methyl-2-oxo-1,3-imidazol-4-yl)methylmorpholine;

2-(R)-(1-(R)-(3,5-bis(trifluormetil)fenil)etoksi)-3-(S)-(4-fluorofenil)-4-(2,3-dihidro-5-(N-(2-morfolinoetil)aminometil)-2-okso-1,3-imidazol-4-il)metilmorfolin; 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(2,3-dihydro-5- (N-(2-morpholinoethyl)aminomethyl)-2-oxo-1,3-imidazol-4-yl)methylmorpholine;

2-(R)-(l-(R)-(3,5-bis(trifluormetil)fenil)etoksi)-3-(S)-(4-fluorofenil)-4-(2,3-dihidro-2-okso-5-(N-(2-pirolidinoetil) aminometil)-1,3-imidazol-4-il)metilmorfolin; 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(2,3-dihydro-2- oxo-5-(N-(2-pyrrolidinoethyl)aminomethyl)-1,3-imidazol-4-yl)methylmorpholine;

2-(R)-(1-(R)-(3,5-bis(trifluormetil)fenil)etoksi)-4-(5-(dimetilamino)metil-1,2,3-triazol-4-il)metil-3-(S)-(4-fluorofenil)morfolin; 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(dimethylamino)methyl-1,2,3-triazol-4-yl)methyl -3-(S)-(4-Fluorophenyl)morpholine;

2-(R)-(1-(R)-(3,5-bis(trifluormetil)fenil)etoksi)-3-(S)-(4-fluorofenil)-4-(N-CN'-metilaminoetiO-l24-triazol-3-il)metilmorfolin; 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(N-CN'-methylaminoethyl)-124 -triazol-3-yl)methylmorpholine;

i njihove farmaceutski prihvatljive soli i prodrug-ove. and their pharmaceutically acceptable salts and prodrugs.

Daljnji preferirani spojevi unutar opsega ovdje danog izuma uključuju: Further preferred compounds within the scope of the invention herein include:

2-(R)-(1-(R)-(3,5-bis(trifluormetil)fenil)etoksi)-3-(S)-(4-fluorofenil)-4-(5-(N-metilaminometil)-1,2,3-triazol-4-il)metilmorfolin; 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(5-(N-methylaminomethyl)- 1,2,3-triazol-4-yl)methylmorpholine;

4-(5-aminometil)-1l2,3-triazol-4-il)metil-2-(R)-(1-(R)-(3,5-bis(trifluorometil)fenil)etoksi)-3-(S)-(4-fluorofenil)morfolin; 4-(5-aminomethyl)-1l2,3-triazol-4-yl)methyl-2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-( S)-(4-fluorophenyl)morpholine;

2-(R)-(1-(R)-(3,5-bis(trifluormetil)fenil)etoksi)-3-(S)-(4-fluorofenil)-4-(5-pirolidinometil)-1,2,3-triazol-4-il)metilmorfolin; 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(5-pyrrolidinomethyl)-1,2 ,3-triazol-4-yl)methylmorpholine;

4-(5-(azetidinilmetil)-1,2,3-triazol-4-il)metil-3-(S)-(4-fluorofenil)-2-(R)-(1-(R)-(3-fluoro-5-(trifluormetil)fenil)etoksi)morfolin; 4-(5-(azetidinylmethyl)-1,2,3-triazol-4-yl)methyl-3-(S)-(4-fluorophenyl)-2-(R)-(1-(R)-(3 -fluoro-5-(trifluoromethyl)phenyl)ethoxy)morpholine;

3-(S)-(4-fluorofenil)-2-(R)-(1-(R)-(3-fluoro-5-(trifluorometil)fenil)etoksi)-4-(5-(pirolidinometil)-1,2,3-triazol-4-il)metilmorfolin; 3-(S)-(4-fluorophenyl)-2-(R)-(1-(R)-(3-fluoro-5-(trifluoromethyl)phenyl)ethoxy)-4-(5-(pyrrolidinomethyl)-1 ,2,3-triazol-4-yl)methylmorpholine;

3-(S)-(4-fluorofenil)-2-(R)-(1-(R)-(3-fluoro-5-(trifluorometil)fenil)etoksi)-4-(5-(morfolinometil)-1,2,3-triazol-4-il)metilmorfolin; 3-(S)-(4-fluorophenyl)-2-(R)-(1-(R)-(3-fluoro-5-(trifluoromethyl)phenyl)ethoxy)-4-(5-(morpholinomethyl)-1 ,2,3-triazol-4-yl)methylmorpholine;

4-(5-(N,N-dimetilaminometil)-1,2,3-triazol-4-il)metil-3-(S)-(4-fluorofenil)-2-(R)-(1-(R)-(3-(trifluormetil)fenil)etoksi)morfolin; 4-(5-(N,N-dimethylaminomethyl)-1,2,3-triazol-4-yl)methyl-3-(S)-(4-fluorophenyl)-2-(R)-(1-(R) )-(3-(trifluoromethyl)phenyl)ethoxy)morpholine;

2-(R)-(1-(R)-(3,5-bis(trifluormetil)fenil)etoksi)-3-(S)-(4-fluorofenil)-4-(S-CN'-metilpiperazinometil)-1,2,3-triazol-4-il)metilmorfolin; 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(S-CN'-methylpiperazinomethyl)- 1,2,3-triazol-4-yl)methylmorpholine;

2-(R)-(1-(R)-(3,5-bis(trifluormetil)fenil)etoksi)-3-(S)-(4-(1-(2-pirolidinoetil)-1,2,3-triazol-4-il)metilmorfolin; 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-(1-(2-pyrrolidinoethyl)-1,2,3 -triazol-4-yl)methylmorpholine;

2-(R)-(1-(R)-(3,5-bis(trifluormetil)fenil)etoksi)-3-(S)-fenil-(4-(2-(2-pirolidinoetil)-1,2,3-triazol-4-il)metilmorfolin; 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-phenyl-(4-(2-(2-pyrrolidinoethyl)-1,2 ,3-triazol-4-yl)methylmorpholine;

2-(R)-(1-(R)-(3,5-bis(trifluormetil)fenil)etoksi)-3-(S)-(4-fluorfenil)-4-2(5-morfolinometil)-1,2,3-triazol-4-il)metilmorfolin; 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-2(5-morpholinomethyl)-1, 2,3-triazol-4-yl)methylmorpholine;

4-(5-azetidinilmetil)-1,2,3-triazol-4-il)metil-2-(R)-(1-(R)-(3,5-bis(trifluorometil)fenil)etoksi)-3-(S)-4-fluorofenil)morfolin; 4-(5-azetidinylmethyl)-1,2,3-triazol-4-yl)methyl-2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3 -(S)-4-fluorophenyl)morpholine;

2-(R)-(1-(R)-(3,5-bis(trifluormetil)fenil)etoksi)-3-(S)-(4-fluorfenil)-4-(5-(pirolinometil)-1,2,3-triazol-4-il)metilmorfolin; 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(5-(pyrrolinomethyl)-1, 2,3-triazol-4-yl)methylmorpholine;

2-(R)-(1-(R)-(3,5-bis(trifluormetil)fenil)etoksi)-4-(5-(bis(metoksietil)aminometil)-1,2,3-triazol-4-il)metil-3-(S)-(4-fluorofenil)morfolin; 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(bis(methoxyethyl)aminomethyl)-1,2,3-triazol-4- yl)methyl-3-(S)-(4-fluorophenyl)morpholine;

2-(R)-(1-(R)-(3,5-bis(trifluormetil)fenil)etoksi)-4-(2-kloro-5-morfolinometil-1,3-imidazol-4-il)metil-3-(S)-(4-fluorofenil)morfolin; 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(2-chloro-5-morpholinomethyl-1,3-imidazol-4-yl)methyl- 3-(S)-(4-Fluorophenyl)morpholine;

2-(R)-(1-(R)-(3,5-bis(trifluormeti!)fenil)etoksi)-4-(5-(N,N-dimetilaminometil)-1,3-imidazol-4-il)metil-3-(S)-(4-fluorofenil)morfolin; 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl!)phenyl)ethoxy)-4-(5-(N,N-dimethylaminomethyl)-1,3-imidazol-4-yl )methyl-3-(S)-(4-fluorophenyl)morpholine;

2-(R)-(1-(R)-(3,5-bis(trifluormetil)fenil)etoksi)-4-(5-(N,N-dimetilaminometil)-1,2,4-triazol-3-il)metil-3-(S)-(4-fluorofenil)morfolin; 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(N,N-dimethylaminomethyl)-1,2,4-triazol-3- yl)methyl-3-(S)-(4-fluorophenyl)morpholine;

2-(R)-(1-(R)-(3,5-bis(trifluormetil)fenil)etoksi)-4-(5-(N-(2,2-dimetoksietil)-N-metilaminometil)-1,2,3-triazol-4-il)metil-3-(S)-fenilmorfolin; 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(N-(2,2-dimethoxyethyl)-N-methylaminomethyl)-1, 2,3-triazol-4-yl)methyl-3-(S)-phenylmorpholine;

2-(R)-(1-(R)-(3,5-bis(trifluormetil)fenil)etoksi)-4-(5-(2-metoksietil)aminometil-1,2,3-triazol-4-il)metil-3-(S)-fenilmorfolin; 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(2-methoxyethyl)aminomethyl-1,2,3-triazol-4-yl )methyl-3-(S)-phenylmorpholine;

2-(R)-(1-(R)-(3,5-bis(trifluormetil)fenil)etoksi)-4-(5-(N-(2-metoksietil)-N-metil)aminometil)-1,2,3-triazol-4-il)metil-3-(S)-fenilmorfolin; 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(N-(2-methoxyethyl)-N-methyl)aminomethyl)-1, 2,3-triazol-4-yl)methyl-3-(S)-phenylmorpholine;

2-(R)-(1-(R)-(3,5-bis(trifluormetil)fenil)etoksi)-4-(5-(N-izopropil-N-(2-metoksietil)aminometil)-1,2,3-triazol-4-il)metil-3-(S)-fenilmorfolin; 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(N-isopropyl-N-(2-methoxyethyl)aminomethyl)-1,2 ,3-triazol-4-yl)methyl-3-(S)-phenylmorpholine;

2-(R)-(1-(R)-(3,5-bis(trifluormetil)fenil)etoksi)-4-(5-(N-ciklopropil-N-(2-metoksietil)aminometil)-1,2,3-triazol-4-il)metil-3-(S)-fenilmorfolin; 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(N-cyclopropyl-N-(2-methoxyethyl)aminomethyl)-1,2 ,3-triazol-4-yl)methyl-3-(S)-phenylmorpholine;

2-(R)-(1-(R)-(3,5-bis(trifIuormetil)fenil)etoksi)-4-(5-N,N-dibutilaminometil)-1,2,3-triazol-4-il)metil-3-(S)-fenilmorfolin; 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-N,N-dibutylaminomethyl)-1,2,3-triazol-4-yl )methyl-3-(S)-phenylmorpholine;

2-(R)-(1-(R)-(3,5-bis(trifluormetil)fenil)etoksi)-4-(5-N,N-diizopropilaminometil)-1,2,3-triazol-4-il)metil-3-(S)-fenilmorfolin; 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-N,N-diisopropylaminomethyl)-1,2,3-triazol-4-yl )methyl-3-(S)-phenylmorpholine;

i njihove farmaceutski prihvatjive soli i prodrug-ove. and their pharmaceutically acceptable salts and prodrugs.

I slijedeći preferirani spojevi unutar ospega ovdje danog izuma uključuju: And the following preferred compounds within the scope of the invention herein include:

2-(R)-(1-(S)-(3,5-bis(trifluormetil)fenil)-2-hidroksietoksi)-3-(S)-(4-fluorofenil)-4-(2,3-dihidro-3-okso-1,2,4-triazol-5-il)metilmorfolin; 2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)-4-(2,3-dihydro -3-oxo-1,2,4-triazol-5-yl)methylmorpholine;

2-(R)-(1-(S)-(3,5-bis(trifluormetil)fenil)-2-hidroksietoksi)-3-(S)-(4-fluorofenil)-4-(1,2,4-triazol-3-il)metilmorfolin; 2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)-4-(1,2,4 -triazol-3-yl)methylmorpholine;

4-(2,3-dihidro-3-okso-1,2,4-triazol-5-il)metil-3-(S)-(4-fluorofenil)-2-(R)-(1-(S)-(3-fluoro-5-(trifluorometil)fenil)-2-hidroksietoksi)morfolin; 4-(2,3-dihydro-3-oxo-1,2,4-triazol-5-yl)methyl-3-(S)-(4-fluorophenyl)-2-(R)-(1-(S) )-(3-fluoro-5-(trifluoromethyl)phenyl)-2-hydroxyethoxy)morpholine;

4-(2,3-dihidro-2-okso-1,3-imidazol-4-il)metil-2-(R)-(1-(S)-(3,5-bis(tritluorometil)fenil)-2-hidroksietoksi)-3-(S)-(4-fIuorofenil)morfolin; 4-(2,3-dihydro-2-oxo-1,3-imidazol-4-yl)methyl-2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)- 2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)morpholine;

4-(2,3-dihidro-2-okso-5-pirolidinometil-1,3-imidazol-4-il)metil-2-(R)-(1-(S)-(3,5-bis(tritluorometil)fenil)-2-hidroksietoksi)-3-(S)-(4-flourofenil)morfolin; 4-(2,3-dihydro-2-oxo-5-pyrrolidinomethyl-1,3-imidazol-4-yl)methyl-2-(R)-(1-(S)-(3,5-bis(trifluoromethyl )phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)morpholine;

4-(2,3-dihidro-3-okso-1,2,4-triazol-5-il)-3-(S)-fenil-2-(R)-(1-(S)-3-(trifluorometil)fenil)-2-hidroksietoksi)morfolin; 4-(2,3-dihydro-3-oxo-1,2,4-triazol-5-yl)-3-(S)-phenyl-2-(R)-(1-(S)-3-( trifluoromethyl)phenyl)-2-hydroxyethoxy)morpholine;

4-(2,3-dihidro-3-okso-1,2,4-triazol-5-il)metil-2-(R)-(1-(SH3-fluoro-5-(trifluorometil)fenil)-2-hidroksietoksi)-3-(S)-fenilmorfolin; 4-(2,3-dihydro-3-oxo-1,2,4-triazol-5-yl)methyl-2-(R)-(1-(SH3-fluoro-5-(trifluoromethyl)phenyl)-2 -hydroxyethoxy)-3-(S)-phenylmorpholine;

2-(R)-(1-(S)-(3,5-bis(trifluormetil)fenil)-2-hidroksietoksi)-4-(2,3-dihidro-3-okso-1,2,4-triazol-5-il)-3-(S)-fenilmetilmetilmorfolin; 2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-4-(2,3-dihydro-3-oxo-1,2,4-triazole -5-yl)-3-(S)-phenylmethylmethylmorpholine;

3-(S)-fenil-4-(1,2,4-triazol-3-il)-2-(R)-(1-(S)-3-(trifluormetil)fenil)-2-hidroksietoksi)morfolin; 3-(S)-phenyl-4-(1,2,4-triazol-3-yl)-2-(R)-(1-(S)-3-(trifluoromethyl)phenyl)-2-hydroxyethoxy)morpholine ;

Daljnji preferirani spojevi unutar opsega ovdje danog izuma opisani su u Primjerima ovdje opisanim. Further preferred compounds within the scope of the invention herein are described in the Examples described herein.

U daljnjem aspektu ovdje danog izuma, spojevi formule (I) poželjno će biti pripravljeni u obliku farmaceutski prihvatljive soli, naročito kisele adicijske soli. In a further aspect of the invention given here, the compounds of formula (I) will preferably be prepared in the form of a pharmaceutically acceptable salt, especially an acid addition salt.

Za medicinsku uporabu, soli spojeva formule (I) bit će netoksične farmaceutski prihvatljive soli. Ostale soli mogu, međutim, bit korisne kod pripravljanja spojeva prema danom izumu ili njihovih netoksičnih farmaceutski prihvatljivih soli. Odgovarajuće farmaceutski prihvatljive soli spojeva ovog izuma uključuju adicijske soli koje mogu, na primjer, biti stvorene miješanjem otopine spoja prema danom izumu s otopinom farmaceutski prihvatljive kiseline kao što su klorovodična kiselina, fumarna kiselina, p-toluensulfonska kiselina, jabučna kiselina, sukcinska kiselina, octena kiselina, limunska kiselina, vinska kiselina, ugljična kiselina, fosforna kiselina ili sumporna kiselina. Soli aminskih grupa mogu također sadržavati kvarterne amonijeve soli u kojima amino dušikov atom nosi odgovarajuću organsku grupu kao što je alkil, alkenil, alkinil ili aralkil grupa. Nadalje, tamo gdje spojevi prema danom izumu nose kiselinski ostatak, njihove odgovarajuće farmaceutski prihvatljive soli uključuju metalne soli kao što su soli alkalijskih metala, npr. natrijeve ili kalijeve soli; i soli zemnoalkalijskih metala, npr. kalcijeve ili magnezijeve soli. For medical use, the salts of the compounds of formula (I) will be non-toxic pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds of the present invention or their non-toxic pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of the present invention include addition salts which may, for example, be formed by mixing a solution of a compound of the present invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, fumaric acid, p-toluenesulfonic acid, malic acid, succinic acid, acetic acid acid, citric acid, tartaric acid, carbonic acid, phosphoric acid or sulfuric acid. Salts of amine groups may also contain quaternary ammonium salts in which the amino nitrogen atom carries a suitable organic group such as an alkyl, alkenyl, alkynyl or aralkyl group. Furthermore, where the compounds of the present invention carry an acid residue, their respective pharmaceutically acceptable salts include metal salts such as alkali metal salts, eg sodium or potassium salts; and salts of alkaline earth metals, eg calcium or magnesium salts.

Ovdje dani izum uključuje u svom opsegu prodrug-ove spojeva gore navedene formule (I). Općenito, takvi prodrug-ovi bit će funkcionalni derivati spojeva formule (I) koji se brzo konvertiraju in vivo u traženi spoj formule (I). Standardni postupci za odabir i pripremanje odgovarajućeg derivata prodrug-a opisani su npr. u "Design of Prodrugs", izdanje H. Bundgaard, Elsevier, 1985. The invention given here includes in its scope prodrugs of compounds of the above-mentioned formula (I). In general, such prodrugs will be functional derivatives of compounds of formula (I) that are rapidly converted in vivo to the desired compound of formula (I). Standard procedures for the selection and preparation of a suitable prodrug derivative are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.

Prodrug može biti farmakološki inaktivan derivat biološki aktivne supstance ("matični lijek" ili "matična molekula") koja zahtjeva transformaciju unutar tijela, da bi se oslobodila aktivna tvar, a to ima bolja svojsta prenošenja od molekule "matičnog lijeka". Transformacija in vivo može biti, npr. rezultat nekih metaboličkih procesa, kao što je kemijska ili enzimatska hidroliza karboksilnog, fosfornog ili sulfatnog estera, ili redukcija ili oksidacija osjetljive funkcionalnosti. A prodrug can be a pharmacologically inactive derivative of a biologically active substance ("parent drug" or "parent molecule") that requires transformation inside the body in order to release the active substance, which has better transmission properties than the "parent drug" molecule. Transformation in vivo can be, for example, the result of some metabolic processes, such as chemical or enzymatic hydrolysis of a carboxylic, phosphoric or sulfate ester, or reduction or oxidation of a sensitive functionality.

Zbog toga, na primjer, neki preferirani prodrug-ovi ne moraju biti antagonisti tahikinina, naročito supstance P, sa bilo kakvom značajnom aktivnosti (ili nikakvom). Takvi spojevi, međutim, još uvijek imaju prednost prilikom tretiranja različitih ovdje opisanih stanja, posebice tamo gdje se preferira injekcioni oblik primjene. Therefore, for example, some preferred prodrugs need not be tachykinin antagonists, especially substance P, with any significant activity (or none). Such compounds, however, still have an advantage when treating the various conditions described herein, particularly where an injectable form of administration is preferred.

Prednost progrug-a može biti u njegovim fizikalnim karakteristikama, kao što je poboljšana vodotopivost za parenteralnu primjenu u usporedbi s "matičnim lijekom", ili može povećati absorpciju iz probavnog trakta, ili može povećati stabilnost lijeka za čuvanje na duže vrijeme. Idealno, prodrug će povećati ukupnu efikasnost "matičnog lijeka", npr. reduciranjem toksičnosti i neželjenih efekata lijeka kontrolom njegove absorpcije, nivoa u krvi, metabolizma, distribucije i stanične apsorpcije. The advantage of progrug may be in its physical characteristics, such as improved water solubility for parenteral administration compared to the "parent drug", or it may increase absorption from the digestive tract, or it may increase the stability of the drug for long-term storage. Ideally, the prodrug will increase the overall efficacy of the "parent drug", eg by reducing the toxicity and side effects of the drug by controlling its absorption, blood levels, metabolism, distribution and cellular uptake.

Naročito preferirana klasa prodrug-ova spojeva ovdje danog izuma je ona u kojoj je hidroksilna skupina grupa Y u formuli (I) (kada Y je C1-4 alkil supstituiran sa hidroksi) derivirana. A particularly preferred class of prodrugs of the compounds of the invention herein is that in which the hydroxyl group of group Y in formula (I) (where Y is C 1-4 alkyl substituted with hydroxy) is derivatized.

Bit će shvaćeno da daljnja klasa prodrug-ova spojeva prema danom izumu je ona unutar koje je heterociklička grupa prikazana sa R6 u formuli (I) derivirana, ili alternativno, kada su obje, hidroksilna skupina grupe Y (kada Y je C1-4 alkil supstituiran sa hidroksilom) i heterociklična grupa prikazana sa R6 u formuli (I) derivirane. It will be understood that a further class of prodrugs of the compounds of the present invention are those within which the heterocyclic group represented by R6 in formula (I) is a derivative of, or alternatively, when both are, a hydroxyl group of Y (when Y is C1-4 alkyl substituted with hydroxyl) and the heterocyclic group represented by R 6 in the formula (I) derivative.

Odgovarajući prodrug derivati uključuju: Suitable prodrug derivatives include:

(a) -(CHR10)n-PO(OH)O-.M+; (a) -(CHR10)n-PO(OH)O-.M+;

(b) -(CHR10)n-PO(O-)2.2M+; (b) -(CHR10)n-PO(O-)2.2M+;

(c) -(CHR10)n-PO(O)2.D2+; (c) -(CHR10)n-PO(O)2.D2+;

(d) -(CHR10)n-SO3-.M+; (d) -(CHR10)n-SO3-.M+;

(e) -COCH2CH2C02- M+; (e) -COCH2CH2CO2- M+;

(f) -COH; (f) -COH;

(g) -CO(CH2)nN(R10)2; i (g) -CO(CH2)nN(R10)2; and

(h) -(CH(R10)O)n-COR11, (h) -(CH(R10)O)n-COR11,

unutar kojih within which

n je nula ili 1; n is zero or 1;

M+ je farmaceutski prihvatljiv jednovalentni "counter" ion M+ is a pharmaceutically acceptable monovalent "counter" ion

D2+ je farmaceutski prihvatljiv dvovalentni "counter" ion; D2+ is a pharmaceutically acceptable divalent "counter" ion;

R10 je vodik ili C1-3 alkil; i R 10 is hydrogen or C 1-3 alkyl; and

R11 je grupa odabrana od -O(CH2)2NH3+.M-; R11 is a group selected from -O(CH2)2NH3+.M-;

-O(CH2)2NH2(R12)+.M-; -OCH2CO2-.M+ ; -O(CH2)2NH2(R12)+.M-; -OCH2CO2-.M+ ;

-OCH(CO2-.M+)CH2CO2-M+ ; -OCH2CH(NH3+)CO2-; -OCH(CO2-.M+)CH2CO2-M+ ; -OCH2CH(NH3+)CO2-;

-OC(CO2-.M+)(CH2CO2-.M+)2; i -OC(CO2-.M+)(CH2CO2-.M+)2; and

[image] [image]

unutar čega M- je farmaceutski prihvatljiv jednovalentni ion, R12 je vodik, C1-4 alkil ili C2-4 alkil supstituiran sa hidroksil ili C1-4 alkoksi grupom. wherein M- is a pharmaceutically acceptable monovalent ion, R 12 is hydrogen, C 1-4 alkyl or C 2-4 alkyl substituted with a hydroxyl or C 1-4 alkoxy group.

Naročito preferirani prodrug derivati su: Particularly preferred prodrug derivatives are:

(a) -(CHR10)n-PO(OH)O-.M+ ; (a) -(CHR10)n-PO(OH)O-.M+;

(b) -(CHR10)nPO(O-)2.2M+ ; (b) -(CHR10)nPO(O-)2.2M+;

(c) -(CHR10)n-PO(O)2.D2+; (c) -(CHR10)n-PO(O)2.D2+;

posebice kada je n nula. especially when n is zero.

Izrazi "matična molekula", "matični spoj" ili "matični lijek" odnose se na biološki aktivne tvari koje se oslobađaju enzimatskom akcijom metabolitčkih ili katabolitičkih procesa, ili kemijskim procesima koji slijede primjenu prodrug-a. Matični spoj može također biti ishodišni materijal za pripremu njegovog odgovarajućeg prodrug-a. The terms "parent molecule", "parent compound" or "parent drug" refer to biologically active substances that are released by the enzymatic action of metabolic or catabolic processes, or by chemical processes that follow the application of the prodrug. The parent compound can also be the starting material for the preparation of its corresponding prodrug.

Dok su svi uobičajeni načini primjene korisni kod gore navedenih prodrug-ova, preferirani način primjene je oralni i intravenozni. Nakon gastrointestinalne absorpcije ili intravenozne primjene, prodrug se hidrolizira ili drugačije cijepa in vivo na odgovarajuće matične spojeve formule (I), ili njezine farmaceutski prihvatljive soli. Kako matični spojevi mogu biti ispod optimuma vodotopivosti, gore navedeni prodrug-ovi imaju bitnu prednost zbog naravi svoje relatvno povećane vodotopivosti. While all common routes of administration are useful for the above prodrugs, the preferred routes of administration are oral and intravenous. After gastrointestinal absorption or intravenous administration, the prodrug is hydrolyzed or otherwise cleaved in vivo to the corresponding parent compounds of formula (I), or pharmaceutically acceptable salts thereof. As the parent compounds may be below optimum water solubility, the above-mentioned prodrugs have a significant advantage due to the nature of their relatively increased water solubility.

Primjeri negativnih jednovalentnih iona ovdje definiranih kao "M" uključuju acetat, adipat, benzoat, benzensulfonat, bisulfat, butirat, kamforat, kamforosulfonat, citrat, etansulfonat, fumarat, hemisulfat, 2-hidroksietilsulfonat, heptanoat, heksanoat, hidroklorid, hidrobromid, hidrojodid, laktat, malat, maleat, metansulfonat, 2-naftalensulfonat, oksalat, pamoat, persulfat, pikrat, pivalat, propionat, saiicilat, stearat, sukcinat, sulfat, tartarat, tozilat (p-toluensulfonat) i undekanoat. Examples of negative monovalent ions defined herein as "M" include acetate, adipate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, citrate, ethanesulfonate, fumarate, hemisulfate, 2-hydroxyethylsulfonate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, lactate. , malate, maleate, methanesulfonate, 2-naphthalenesulfonate, oxalate, pamoate, persulfate, picrate, pivalate, propionate, saicylate, stearate, succinate, sulfate, tartarate, tosylate (p-toluenesulfonate) and undecanoate.

Bazične soli (koje su farmaceutski prihvatljivi jednovalentni kationi definirani ovdje kao "M+" ili farmaceutski prihvatljivi dvovalentni kationi definirani ovdje kao "D2+") uključuju amonijeve soli, soli alkalijskih metala kao što su natrijeve, litijeve i kalijeve soli, soli zemnoalkalijskih metala, kao što su aluminijeve, kalcijeve i magnezijeve soli, soli s organskim bazama kao što su dicikloheksaminske soli, N-metil-D-glukamin, i soli s aminokiselinama kao što su arginin, lizin, ornitin i td. Ako je M+ jednovalentni kation, shvatljivo je ukoliko je prisutna 2M+ definicija, da svaki od M+ može biti isti ili različit. Dodatno, jednako je shvatljivo ukoliko je prisutna 2M+ definicija, da umjesto toga može biti prisutan dvovalentni kation D2+. Također, bazične grupe koje sadrže dušik mogu biti kvaternizirane s agensima: niži alkil halidi, kao što su metil, etil, propil i butil kloridi, bromidi i jodidi; dialkil sulfati kao dimetil, dietil i dibutil; diamil sulfati; halidi dugih lanaca kao decil, lauril, miristil i stearil kloridi, bromidi i jodidi; aralkil halidi kao benzil bromid i drugi. Netoksične fiziološki prihvatljive soli su preferirane, iako su i druge soli korisne, kao kod izoliranja ili pročišćavanja proizvoda. Base salts (which are pharmaceutically acceptable monovalent cations defined herein as "M+" or pharmaceutically acceptable divalent cations defined herein as "D2+") include ammonium salts, alkali metal salts such as sodium, lithium and potassium salts, alkaline earth metal salts such as are aluminum, calcium and magnesium salts, salts with organic bases such as dicyclohexamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, ornithine, etc. If M+ is a monovalent cation, it is understandable if the 2M+ definition is present, that each of the M+ can be the same or different. Additionally, it is equally understandable if the 2M+ definition is present, that the divalent cation D2+ may be present instead. Also, nitrogen-containing basic groups can be quaternized with agents: lower alkyl halides, such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dialkyl sulfates such as dimethyl, diethyl and dibutyl; diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; aralkyl halides such as benzyl bromide and others. Non-toxic physiologically acceptable salts are preferred, although other salts are also useful, such as in product isolation or purification.

Soli mogu biti stvorene standarnim načinima, kao što je reakcija slobodnog bazičnog oblika proizvoda s jednim ili više ekvivalenata odgovarajuće kiseline u otapalu ili mediju u kojem je sol netopiva, ili u otapalu kao što je voda koja se odstranjuje in vacuo ili liofilizacijom ili izmjenom aniona postojeće soli za drugi anion na odgovarajućoj ionsko-izmjenjivačkoj smoli. Salts can be formed by standard means, such as reaction of the free base form of the product with one or more equivalents of the appropriate acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water that is removed in vacuo or by lyophilization or anion exchange of the existing salt for the second anion on a suitable ion-exchange resin.

Posebno preferirana pod-klasa prodrug-ova spojeva ovdje danog izuma je ona definirana formulom (Ie) i njezine farmaceutski prihvatljive soli: A particularly preferred sub-class of prodrugs of the compounds of the invention herein is that defined by formula (Ie) and its pharmaceutically acceptable salts:

[image] [image]

unutar koje R1, R2, R3, R4, R5, R6, R9a, R9b i X su definirani u odnosu na formulu (I) a zaokruženi P je PO(OH)O-.M+, PO(O-)2.2M+ ili PO(O)2.D2+. wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 9a , R 9b and X are as defined in relation to formula (I) and the encircled P is PO(OH)O-.M+, PO(O-)2.2M+ or PO (O)2.D2+.

Slijedeća preferirana pod-klasa prodrug-ova spojeva prema danom izumu je ona definirana formulom (If) i njezine farmaceutski prihvatljive soli; The next preferred sub-class of prodrug compounds according to the present invention is that defined by formula (If) and its pharmaceutically acceptable salts;

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unutar koje A1, A2 i A3 su definirani u odnosu na formulu (la), X i R6 su definirani u odnosu na formulu (I), a zaokruženi P je PO(OH)O-.M+ , PO(O-)2.2M+ ili PO(O)2.D2+. wherein A1, A2 and A3 are defined in relation to formula (Ia), X and R6 are defined in relation to formula (I) and circled P is PO(OH)O-.M+ , PO(O-)2.2M+ or PO(O)2.D2+.

Posebno preferirana pod-grupa prodrug-ova spojeva prema danom izumu je ona definirana formulom (Ig) i njezine farmaceutski prihvatljive soli: A particularly preferred sub-group of prodrug compounds according to the present invention is that defined by formula (Ig) and its pharmaceutically acceptable salts:

[image] [image]

unutar koje A1, A2 i A3 su definirani u odnosu na formulu (Ia), Q1 je definiran u odnosu na formulu (Ic), a zaokruženi P je PO(OH)O-.M+, PO(O-)2.2M+ ili PO(O)2.D2+. wherein A1, A2 and A3 are defined with reference to formula (Ia), Q1 is defined with reference to formula (Ic) and the encircled P is PO(OH)O-.M+, PO(O-)2.2M+ or PO (O)2.D2+.

Daljnja preferirana pod-grupa prodrug-ova spojeva prema danom izumu je ona definirana formulom (Ih) i njezine farmaceutski prihvatljive soli: A further preferred sub-group of prodrug compounds according to the present invention is that defined by formula (Ih) and its pharmaceutically acceptable salts:

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unutar koje A1, A2 i A3 su definirani u odnosu na formulu (Ia), Q1 i Q2 su definirani u odnosu na formulu (Ic) i (Id), pojedinačno, a zaokruženi P je PO(OH)O-.M+ , PO(O-)2.2M+ ili PO(O)2.D2+. wherein A1, A2 and A3 are defined with respect to formula (Ia), Q1 and Q2 are defined with respect to formula (Ic) and (Id), individually, and the encircled P is PO(OH)O-.M+ , PO (O-)2.2M+ or PO(O)2.D2+.

Specifični derivati prodrug-a unutar opsega ovog izuma uključuju: Specific prodrug derivatives within the scope of this invention include:

2-(R)-(1-(S)-(3,5-bis(trifluorometil)fenil)-2-fosforiloksietoksi)-3-(S)-(4-fluorofenil)-4-(2,3-dihidro-3-okso-1,2,4-triazol-5-il)metilmorfolin; 2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-phosphoryloxyethoxy)-3-(S)-(4-fluorophenyl)-4-(2,3-dihydro -3-oxo-1,2,4-triazol-5-yl)methylmorpholine;

2-(R)-(1-(S)-(3,5-bis(trifluorometil)fenil)-2-fosforiloksietoksi)-3-(S)-(4-fluorofenil)-4-(1,2,4-triazol-3-il)metilmorfolin; 2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-phosphoryloxyethoxy)-3-(S)-(4-fluorophenyl)-4-(1,2,4 -triazol-3-yl)methylmorpholine;

4-(2,3-dihidro-3-okso-1,2,4-triazol-5-il)metil-2-(R)-(1-(S)-3-fluoro-5-(trifluorometil)fenil)-2-fosforiloksietoksi)-3-(S)-fenilmorfolin; 4-(2,3-dihydro-3-oxo-1,2,4-triazol-5-yl)methyl-2-(R)-(1-(S)-3-fluoro-5-(trifluoromethyl)phenyl )-2-phosphoryloxyethoxy)-3-(S)-phenylmorpholine;

2-(R)-(1-(S)-(3,5-bis(trifluorometil)fenil)-2-fosforiloksietoksi)-4-(2,3-dihidro-3-okso-1,2,4-triazol-5-il)metil-3-(S)-fenilmorfolin; 2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-phosphoryloxyethoxy)-4-(2,3-dihydro-3-oxo-1,2,4-triazole -5-yl)methyl-3-(S)-phenylmorpholine;

Obzirom na spojeve formula (If), (Ig) i (Ih), A1 je poželjno fluor ili CF3; A2 je poželjno CF3 ; i A3 je poželjno fluor. Ovdje dani izum uključuje u svom opsegu otopine spojeva formule (I) i njihove soli, na primjer, hidrate. Spojevi prema danom izumu imaju najmanje tri asimeirična centra, i mogu prema tome postojati i kao enantiomeri i kao diastereoizomeri. Podrazumijeva se da su svi takvi izomeri i njihove smjese uključeni u opseg ovdje danog izuma. With regard to compounds of formulas (If), (Ig) and (Ih), A1 is preferably fluorine or CF3; A2 is preferably CF3; and A3 is preferably fluorine. The present invention includes within its scope solutions of compounds of formula (I) and their salts, for example, hydrates. The compounds according to the present invention have at least three asymmetric centers, and can therefore exist as both enantiomers and diastereomers. It is understood that all such isomers and mixtures thereof are included within the scope of the invention herein.

Preferirani spojevi formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) i (Ih) imat će 2- i 3- supstituent cis i preferirana stereokemja na 2-položaju je ona gdje je spoj iz Primjera 1 (tj. 2-(R)-), preferirana stereokemija na 3-položaju je ona gdje je spoj iz Primjera 1 (tj. 3-(S)), a preferirana stereokemija ugljika na kojem je grupa Y ili (R) kada je Y C1-4 alkil (npr. metil) ili (S) kada je Y C1-4 alkil supstituiran sa hidroksi (npr. CH2OH). Tako na primjer prikazan formulom (Ii) Preferred compounds of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) and (Ih) will have 2- and 3- substituents cis and preferred stereochemistry at the 2-position is that where the compound of Example 1 is (i.e., 2-(R)-), the preferred stereochemistry at the 3-position is that where the compound of Example 1 is (i.e., 3-(S)), and the preferred stereochemistry carbon on which the group is Y or (R) when Y is C1-4 alkyl (eg methyl) or (S) when Y is C1-4 alkyl substituted with hydroxy (eg CH2OH). For example, shown by formula (Ii)

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Ovdje dani izum dalje daje farmaceutske pripravke koji sadrže jedan ili više sastojaka formule (I) zajedno s farmaceutski prihvatljivim nosačem. The invention provided herein further provides pharmaceutical compositions comprising one or more ingredients of formula (I) together with a pharmaceutically acceptable carrier.

Poželjno pripravci prema danom izumu su u jediničnoj dozi u obliku tableta, pilula, kapsula, praška, granula, otopina ili suspenzija, ili supozitorija, za oralnu, parenteralnu ili rektalnu primjenu, ili primjenu inhalacijom ili insuflacijom. Preferably, the preparations according to the invention are in unit dose form of tablets, pills, capsules, powder, granules, solutions or suspensions, or suppositories, for oral, parenteral or rectal administration, or administration by inhalation or insufflation.

Za dobivanje čvrstih pripravaka kao što su tablete, glavna aktivna tvar miješa se sa farmaceutskim nosačem, npr. standardnim tabletirajućim agensima kao što su kukuruzni škrob, laktoza, saharoza, sorbitol, talk, stearinska kiselina, magnezijev stearat, dikalcijev fosfat ili smola, i ostalim farmaceutskim razrijeđivačima, npr. vodom, da bi se dobio čvrsti preformulirani pripravak koji sadrži homogenu mješavinu sastojka ovog izuma, ili njegove ne-toksične farmaceutski prihvatljive soli. Kada se ovi preformulirani pripravci navode kao homogeni, znači da je aktivna tvar potpuno dispergirana u čitavom pripravku tako da se pripravak može odmah razdijeliti u jednako djelotvorne jedinične doze za primjenu, kao što su tablete, pilule ili kapsule. Ovakav čvrsti preformulirani pripravak tada se dijeli u jedinične doze za primjenu gore već opisane, koji sadrže od 0.1 do oko 500 mg aktivne tvari prema ovom izumu. Tablete ili pilule novog sastava mogu biti prevučene ili drugačije sastavljene da osiguraju prednost produženog djelovanja primjenjenom obliku. Na primjer, tableta ili pilula može sadržavati unutarnju ili vanjsku dozirajuću komponentu, gdje je potonja u obliku omotača iznad prve. Dvije komponente mogu biti odvojene s enteričnim slojem koji služi da bi se onemogućila dezintegracija u želucu i omogućuje unutarnjoj komponenti da prijeđe nepromijenjena u duodenum ili da bude usporena pri oslobađanju. Mnogo tvari može se upotrijebiti za takve enterične omotače ili prevlake, takve tvari uključuju brojne polimerne kiseline i smjese polimernih kiselina s takvim tvarima kao što su šelak, cetilni alkohol i celulozni acetat. To obtain solid preparations such as tablets, the main active substance is mixed with a pharmaceutical carrier, for example, standard tableting agents such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or resin, and others with pharmaceutical diluents, eg water, to obtain a solid reformulated composition containing a homogeneous mixture of an ingredient of the present invention, or a non-toxic pharmaceutically acceptable salt thereof. When these reformulated preparations are stated as homogeneous, it means that the active substance is completely dispersed throughout the preparation so that the preparation can be immediately divided into equally effective unit doses for administration, such as tablets, pills or capsules. Such a solid reformulated preparation is then divided into unit doses for use as described above, containing from 0.1 to about 500 mg of the active substance according to the present invention. Tablets or pills of the new composition may be coated or otherwise formulated to provide the benefit of prolonged action to the form administered. For example, a tablet or pill may contain an internal or external dosage component, where the latter is in the form of a coating over the former. The two components may be separated by an enteric layer that serves to prevent disintegration in the stomach and allows the inner component to pass unchanged into the duodenum or to be delayed in release. Many substances can be used for such enteric coats or coatings, such substances include numerous polymeric acids and mixtures of polymeric acids with such substances as shellac, cetyl alcohol and cellulose acetate.

Tekući oblici u koje novi pripravci ovdje danog izuma mogu biti inkorporirani za oralnu primjenu ili injektiranje uključuju vodene otopine, odgovarajući aromatizirane sirupe, vodene ili uljne suspenzije i aromatizirane emulzije s jestivim uljima kao što su ulje sjemenki pamuka, sezamovo ulje, kokosovo ili kikiriki ulje, kao i eliksire i slična farmaceutska sredstva. Odgovarajuća dispergirajuća ili suspendirajuća sredstva za vodene suspenzije uključuju sintetske i prirodne smole kao što su tragakant, akacija, alginat, dekstran, natrijeva karboksimetilceluloza, metilceluloza, polivinilpirolidon ili želatina. Liquid forms into which the novel compositions of the present invention may be incorporated for oral administration or injection include aqueous solutions, suitable flavored syrups, aqueous or oily suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut or peanut oil, as well as elixirs and similar pharmaceuticals. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural resins such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin.

Preferirani pripravci za injekcionu primjenu uključuju one koji sadrže spoj formule (I), kao aktivnu tvar, zajedno s površinski aktivnom tvari (sredstvo za vlaženje ili "surfaktant") ili u obliku emulzije (kao voda-u-ulju ili ulje-u-vodi emulzija). Preferred compositions for injectable use include those containing a compound of formula (I) as the active ingredient together with a surface-active agent (wetting agent or "surfactant") or in emulsion form (as water-in-oil or oil-in-water emulsion).

Odgovarajući površinski aktivni agensi uključuju anionske agense kao što su natrijev bis-(2-etilheksil)sulfosukcinat, kationske agense kao što su alkiltrimetilamonij bromidi, (npr. cetiltrimetilamonij bromid (cetrimid)), i naročito ne-ionske agense, kao što su polioksietilensorbitani (npr. Tween™ 20, 40, 60, 80 ili 85) i ostali sorbitani (npr. Span™ 20, 40, 60, 80 ili 85). Pripravci s površinski aktivnom tvari odgovarajući će sadržavati između 0.05 i 5% površinski aktivne tvari, i poželjno između 0.1 i 2.5%. Bit će uvaženo da drugi sastojci mogu biti dodani, na primjer manitol ili ostala farmaceutski prihvatljiva sredstva, ukoliko je potrebno. Suitable surfactants include anionic agents such as sodium bis-(2-ethylhexyl) sulfosuccinate, cationic agents such as alkyltrimethylammonium bromides, (eg cetyltrimethylammonium bromide (cetrimide)), and especially non-ionic agents, such as polyoxyethylene sorbitans ( eg Tween™ 20, 40, 60, 80 or 85) and other sorbitans (eg Span™ 20, 40, 60, 80 or 85). Surfactant compositions will suitably contain between 0.05 and 5% surfactant, and preferably between 0.1 and 2.5%. It will be appreciated that other ingredients may be added, for example mannitol or other pharmaceutically acceptable agents, if necessary.

Odgovarajuće emulzije mogu biti pripremljene koristeći komercijalno raspoložive masne emulzije, kao što su Intralipid , Liposyn™, Infonutrol™, Lipofundin™ i Lipiphisan™. Aktivna tvar može biti ili otopljena u pred-izmiješanom sastavu emulzije ili alternativno može biti otopljena u ulju (npr. sojino ulje, šafranikino ulje, ulje sjemenki pamuka, sezamovo ulje, kukuruzno ulje ili bademovo ulje) i emulzija stvorena nakon miješanja s fosfolipidom (npr. fosfolipidi jajeta, soje ili sojin lecitin) i vodom. Bit će uvaženo da se drugi sastojci mogu dodati, na primjer glicerol ili glukoza, da bi se prilagodila toničnost emulzije. Odgovarajuće emulzije će tipično sadržavati do 20% ulja, na primjer, između 5 i 20%. Masne emulzije će poželjno sadržavati masne kapljice između 0.1 i 1.0 μm naročito 0.1 i 0.5 μm, i imati pH u rasponu od 5.5 do 8.0. Suitable emulsions can be prepared using commercially available fat emulsions, such as Intralipid, Liposyn™, Infonutrol™, Lipofundin™ and Lipiphisan™. The active substance can be either dissolved in the pre-mixed emulsion composition or alternatively it can be dissolved in an oil (e.g. soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil or almond oil) and an emulsion created after mixing with a phospholipid (e.g. phospholipids of egg, soy or soy lecithin) and water. It will be appreciated that other ingredients may be added, for example glycerol or glucose, to adjust the tonicity of the emulsion. Suitable emulsions will typically contain up to 20% oil, for example between 5 and 20%. Fat emulsions will preferably contain fat droplets between 0.1 and 1.0 μm, especially 0.1 and 0.5 μm, and have a pH in the range of 5.5 to 8.0.

Naročito preferirani pripravci emulzija su oni pripravljeni miješanjem spoja formule (I) s Intralipid™ ili njegovim komponentama (sojino ulje, fosfolipidi jajeta, glicerol i voda). Particularly preferred emulsion preparations are those prepared by mixing the compound of formula (I) with Intralipid™ or its components (soybean oil, egg phospholipids, glycerol and water).

Pripravci za inhalaciju ili insuflaciju uključuju otopine i suspenzije u farmaceutski prihvatljivom, vodenom ili organskom otapalu, ili njihovim smjesama, i praške. Tekući ili čvrsti pripravci mogu sadržavati odgovarajuće farmaceutski prihvatljive ekscipijente kao što su gore navedeni. Poželjno, pripravci se primjenjuju oralnim ili nazalnim respiratornim putem za lokalno ili sistemsko djelovanje. Pripravci u poželjno sterilnim farmaceutski prihvatljivim otapalima mogu biti nebulizirane korištenjem inertnih plinova. Nebulizirane otopine mogu biti udisane direktno iz uređaja za nebulizaciju ili se uređaj za nebulizaciju može priključiti na facijalnu masku, zastor ili uređaj za disanje s izmjeničnim pozitivnim tlakom. Preparations for inhalation or insufflation include solutions and suspensions in a pharmaceutically acceptable aqueous or organic solvent, or mixtures thereof, and powders. Liquid or solid preparations may contain suitable pharmaceutically acceptable excipients as listed above. Preferably, the compositions are administered by the oral or nasal respiratory route for local or systemic action. Preparations in preferably sterile pharmaceutically acceptable solvents can be nebulized using inert gases. Nebulized solutions may be inhaled directly from the nebulizer or the nebulizer may be attached to a face mask, drape, or alternating positive pressure breathing apparatus.

Otopine, suspenzije ili praškasti pripravci mogu se primjenjivati, poželjno oralno ili nazalno, iz uređaja koji daju pripravak na odgovarajući način. Solutions, suspensions or powder preparations can be administered, preferably orally or nasally, from devices that deliver the preparation in an appropriate manner.

Ovdje dani izum dalje daje postupak za dobivanje farmeceutskog sastojka koji sadrži spoj formule (I) zajedno s farmaceutski prihvatljivim nosačem ili ekscipijentom. The invention provided herein further provides a process for the preparation of a pharmaceutical composition comprising a compound of formula (I) together with a pharmaceutically acceptable carrier or excipient.

Spojevi formule (I) od značenja su kod liječenja različitih kliničkih stanja koja su karakterizirana prisustvom viška tahikininske, naročito supstance P, aktivnosti. To može uključivati poremećaje centralnog nervnog sustava, kao što su anksioznost, depresija, psihoza i šizofrenija; epilepsija, neurodegenerativne poremećaje kao što su demencija, uključujući senilnu demenciju Alzheimer tipa, Alzheimerovu bolest i Dow sindrom; demijelinizirajuća oboljenja kao što su MS i ALS i ostala neuropatološka oboljenja kao što su periferna neuropatija, npr. dijabetička neuropatija ili neuropatija inducirana kemoterapijom, i postherpesne i ostale neuralgije; karcinomi malih stanica kao što je karcinom malih stanica pluća, respiratorna oboljenja, naročito ona povezana s suvišnom sekrecijom mukusa kao što su kronična opstruktivna oboljenja dišnih puteva, bronhopneumonija, kronični bronhitis, cistična fibroza i astma, i bronhospazam; upalna oboljenja kao što su upala crijeva, psorijaza, fibrozitis, osteoartritis, reumatoidni artritis, pruritis i sunčane opekotine; alergije kao što su ekcemi i rinitis; bolesti preosjetljivosti kao na otrovni bršljan; oboljenja oka kao što su konjunktivitis, vernalni konjunktivitis i sl; stanja oka povezana s proliferacijom stanica kao što je proliferativna vitreoretinopatija; kutana oboljenja kao što su kontaktni dermatitis, površinski dermatitis, urtikarija i ostali ekcemski dermatitisi; ovisnički poremećaji kao što je alkoholizam; somatski poremećaji povezani sa stresom; refleksna simpatička distrofija kao što je rame/ruka sindrom; distimički poremećaji; negativne imunološke reakcije kao što je odbacivanje transplantiranog tkiva i poremećaji povezani s imunosupresiom ili imuno-povećanjem, kao što je sistemni lupus eritematodes; gastrointestinalni (Gl) poremećaji i bolesti Gl trakta kao što su poremećaji povezani s neruogenskom kontrolom organa, ulcerativni kolitis, Crohnova bolest, sindrom iritabilnog crijeva i povraćanje , uključujući akutno, odgođeno ili anticipatorno povraćanje kao što je povraćanje inducirano kemoterapijom, radijacijom, toksinima, virusnim ili bakterijskim infekcijama, trudnoćom, vestibularnim poremećajima, kretanjem, kirurškim zahvatima, migrenom i variranjem intrakranialnog tlaka, naročito, npr. povraćanje inducirano lijekovima ili zračenjem ili postoperativne mučnine i povraćanje; poremećaji funkcije mokraćnog mjehura kao što je cistitis, hiper refleksija detruzira mokraćnog mjehura i inkontinencija; fibrozirajuća i kolagenska oboljenja kao što su sklerodermija i eozinofilična fascioliaza; poremećaji toka krvi uzrokovani vazodilatacijom i vazospastična oboljenja kao što je angina, migrena i Reynaudova bolest; i boli ili osjeti boli, npr. primjenljivi ili povezani s bilo kojim gornjim stanjem, naročito kod prijenosa boli kod migrene. The compounds of formula (I) are of importance in the treatment of various clinical conditions characterized by the presence of excess tachykinin, especially substance P, activity. These may include central nervous system disorders, such as anxiety, depression, psychosis and schizophrenia; epilepsy, neurodegenerative disorders such as dementia, including senile dementia of the Alzheimer type, Alzheimer's disease and Dow syndrome; demyelinating diseases such as MS and ALS and other neuropathological diseases such as peripheral neuropathy, eg diabetic neuropathy or chemotherapy-induced neuropathy, and postherpetic and other neuralgias; small cell cancers such as small cell lung cancer, respiratory diseases, especially those associated with excess mucus secretion such as chronic obstructive airway diseases, bronchopneumonia, chronic bronchitis, cystic fibrosis and asthma, and bronchospasm; inflammatory diseases such as inflammatory bowel disease, psoriasis, fibrositis, osteoarthritis, rheumatoid arthritis, pruritis and sunburn; allergies such as eczema and rhinitis; hypersensitivity diseases such as poison ivy; eye diseases such as conjunctivitis, vernal conjunctivitis, etc.; eye conditions associated with cell proliferation such as proliferative vitreoretinopathy; skin diseases such as contact dermatitis, superficial dermatitis, urticaria and other eczematous dermatitis; addictive disorders such as alcoholism; somatic disorders related to stress; reflex sympathetic dystrophy such as shoulder/arm syndrome; dysthymic disorders; negative immune reactions such as rejection of transplanted tissue and disorders associated with immunosuppression or immunoenhancement, such as systemic lupus erythematosus; gastrointestinal (Gl) disorders and diseases of the Gl tract such as disorders associated with neurogenic organ control, ulcerative colitis, Crohn's disease, irritable bowel syndrome and vomiting, including acute, delayed or anticipatory vomiting such as vomiting induced by chemotherapy, radiation, toxins, viral or bacterial infections, pregnancy, vestibular disorders, movement, surgical procedures, migraine and varying intracranial pressure, especially, eg drug- or radiation-induced vomiting or postoperative nausea and vomiting; bladder function disorders such as cystitis, bladder detrusor hyperreflexia and incontinence; fibrosing and collagen diseases such as scleroderma and eosinophilic fascioliasis; blood flow disorders caused by vasodilation and vasospastic diseases such as angina, migraine and Reynaud's disease; and pain or pain sensations, eg, applicable to or associated with any of the above conditions, particularly in migraine pain transfer.

Spojevi formule (I) također su od značenja kod liječenja kombinacija gornjih stanja, naročito kod liječenja kombiniranih post-operativnih boli i post-operativne mučnine i povraćanja. The compounds of formula (I) are also of value in the treatment of combinations of the above conditions, particularly in the treatment of combined post-operative pain and post-operative nausea and vomiting.

Spojevi formule (I) naročito su korisni kod liječenja povraćanja, uključujući akutno, odgođeno ili anticipatorno povraćanje kao što je povraćanje inducirano kemoterapijom, radijacijom, toksinima, trudnoćom, vestibularnim poremećajima, kretanjem, kirurškim zahvatima, migrenom i variranjem intrakranialnog tlaka. Najizrazitije, spojevi formule (I) od koristi su kod liječenja povraćanja induciranog s antineopiastičkim (citotoksičnim) agensima, uključujući one rutinski korištene kod kemoterapije raka. The compounds of formula (I) are particularly useful in the treatment of emesis, including acute, delayed or anticipatory emesis such as emesis induced by chemotherapy, radiation, toxins, pregnancy, vestibular disorders, movement, surgery, migraine and fluctuating intracranial pressure. Most notably, the compounds of formula (I) are useful in the treatment of emesis induced with antineoplastic (cytotoxic) agents, including those routinely used in cancer chemotherapy.

Primjeri takvih kemoterapeutskih agensa uključuju alkilirajuće agense, npr. nitrogen mustard, etileneiminske spojeve, alkil sulfonate i ostale spojeve s alkilirajućim djelovanjem kao što su nitrosoure, cisplatin i dakarbazin; antimetabolitici, npr. folna kiselina, purinski ili pirimidinski antagonisti; inhibitori mitoze, npr. vinka alkaloidi i derivati podofilotoxina; i citotoksični antibiotici. Examples of such chemotherapeutic agents include alkylating agents, eg, nitrogen mustard, ethyleneimine compounds, alkyl sulfonates, and other alkylating compounds such as nitrosoures, cisplatin, and dacarbazine; antimetabolites, eg folic acid, purine or pyrimidine antagonists; mitosis inhibitors, eg vinca alkaloids and podophyllotoxin derivatives; and cytotoxic antibiotics.

Posebni primjeri kemoterapeutskih agensa opisani su kod D.J. Stewart u Nausea and Vomiting: Recent Research and Clinical Advances, Eds. J. Kucharczy et al, CRC Press Inc., Boca Raton, Florida, USA (1991) str. 177-203, posebice str. 188. Uobičajeno korišteni kemoterapijski agensi uključuju cisplatin, dakarbazin (DTIC), daktinomicin, mekloretamin (nitrogen mustard), streptozocin, ciklofosfamid, karmustin (BCNU), lomustin (CCNU), doksorubicin (adriamicin), daunorubicin, prokarbazin, mitomicin, citarabin, etoposid, metotreksat, 5-florouracil, vinblastin, vinkristin, bleomicin i klorambucil [R.J. Gralla et al u Cancer Treatment Reports (1984) 68 (1), 163-172]. Specific examples of chemotherapeutic agents are described in D.J. Stewart in Nausea and Vomiting: Recent Research and Clinical Advances, Eds. J. Kucharczy et al, CRC Press Inc., Boca Raton, Florida, USA (1991) p. 177-203, especially p. 188. Commonly used chemotherapy agents include cisplatin, dacarbazine (DTIC), dactinomycin, mechlorethamine (nitrogen mustard), streptozocin, cyclophosphamide, carmustine (BCNU), lomustine (CCNU), doxorubicin (adriamycin), daunorubicin, procarbazine, mitomycin, cytarabine, etoposide. , methotrexate, 5-fluorouracil, vinblastine, vincristine, bleomycin and chlorambucil [R.J. Gralla et al in Cancer Treatment Reports (1984) 68 (1), 163-172].

Spojevi formule (I) također su od koristi kod tretmana povraćanja induciranog radijacijom uključujući radio-terapiju kao kod tretmana raka, ili radijacijske bolesti; i u tretmanu post-operativne mučnine i povraćanja. Compounds of formula (I) are also useful in the treatment of emesis induced by radiation including radiotherapy such as in the treatment of cancer, or radiation sickness; and in the treatment of post-operative nausea and vomiting.

Bit će shvaćeno da spojevi formule (I) mogu biti prisutni zajedno s drugim terapeutskim agensom kao kombinirani pripravak za simultanu, separatnu ili sekvencijalnu primjenu za olakšanje povraćanja. Tako kombinirani pripravci mogu biti, npr. u obliku dvostrukog pakovanja. It will be understood that the compounds of formula (I) may be present together with another therapeutic agent as a combination composition for simultaneous, separate or sequential administration to relieve emesis. Such combined preparations can be, for example, in the form of a double package.

Daljnji aspekt ovdje danog izuma uključuje spojeve formule (I) u kombinaciji sa 5-HT3 antagonistom, kao što su ondasetron, granisetron ili tropisteron, ili ostalim lijekovima protiv povraćanja, npr. dopaminskin antagonistom kao što je metoklopramid. Dodatno, spoj formule (I) može se davati u kombinaciji s antiinflamatornim kortikosteroidom kao što je deksametazon. Dalje, spoj formule (I) može se davati u kombinaciji s kemoterapijskim agensom kao što je alkilirajuće sredstvo, antimetabolit, inhibitor mitoze ili cititoksični antibiotik, kao što je gore opisano. Općenito, sada raspoloživi oblici za primjenu poznatih terapeutskih sredstava za uporabu u takvim kombinacijama će biti odgovarajući. A further aspect of the invention provided herein includes compounds of formula (I) in combination with a 5-HT3 antagonist, such as ondasetron, granisetron or tropisterone, or other antiemetic drugs, eg a dopamine antagonist such as metoclopramide. Additionally, the compound of formula (I) can be administered in combination with an anti-inflammatory corticosteroid such as dexamethasone. Furthermore, a compound of formula (I) can be administered in combination with a chemotherapeutic agent such as an alkylating agent, antimetabolite, a mitotic inhibitor or a cytotoxic antibiotic, as described above. In general, currently available forms of administration of known therapeutic agents for use in such combinations will be appropriate.

Kod ispitivanja u ferret-modelu cisplatin-induciranog povraćanja opisanog od F. D. Tattersall et al, u Eur. J. Pharmacol., (1993) 250, R5-R6, ustanovljeno je da spojevi prema danom izumu izazivaju mučninu i povraćanje inducirano cisplatinom. In a ferret model study of cisplatin-induced emesis described by F. D. Tattersall et al, in Eur. J. Pharmacol., (1993) 250, R5-R6, compounds of the present invention were found to induce cisplatin-induced nausea and vomiting.

Spojevi formule (I) također su posebno korisni kod liječenja boli ili stanja i/ili upala i poremećaja povezanih s time, kao što su, npr. neuropatija kao što je dijabetička ili kemoterapijom inducirana neuropatija, postherpesne i ostale neuralgije, astma, osteoartritis, reumatski artritis i naročito migrene. Compounds of formula (I) are also particularly useful in the treatment of pain or conditions and/or inflammation and disorders associated therewith, such as, for example, neuropathy such as diabetic or chemotherapy-induced neuropathy, postherpetic and other neuralgias, asthma, osteoarthritis, rheumatic arthritis and especially migraines.

Ovdje dani izum dalje osigurava spoj formule (I) za upotrebu u terapiji. The invention provided herein further provides a compound of formula (I) for use in therapy.

Prema daljnjem ili alternativnom aspektu, ovdje dani izum osigurava spoj formule (I) za upotrebu u proizvodnji lijeka za tretiranje fizioliških poremećaja povezanih sa suviškom tahikinina, posebice supstance P. According to a further or alternative aspect, the present invention provides a compound of formula (I) for use in the manufacture of a medicament for the treatment of physiological disorders associated with an excess of tachykinin, in particular substance P.

Ovdje dani izum također osigurava postupak za tretman ili prevenciju fizioloških poremećaja povezanih sa suviškom tahikinina, naročito supsance P, gdje postupak uključuje davanje pacijentu kojem je potrebno za reduciranje tahikinina količinu spoja formule (I) ili pripravka koji sadrži spoj formule (I). The present invention also provides a method for the treatment or prevention of physiological disorders associated with an excess of tachykinin, especially substance P, where the method includes administering to a patient who needs to reduce tachykinin an amount of a compound of formula (I) or a preparation containing a compound of formula (I).

Za tretman nekih stanja može biti poželjno primijeniti spoj prema danom izumu zajedno s drugim farmaceutski aktivnim agensom. Na primjer, za tretman respiratornih oboljenja kao što je astma, spoj formule (I) može se koristiti zajedno s bronhodilatatorom, kao što je antagonist β2-adrenergičkog receptora ili antagonist tahikinina koji djeluju kao NK-2 receptori. Spoj formule (I) i bronhodilatator mogu se davati pacijentu simultano, jedan iza drugoga ili u kombinaciji. For the treatment of some conditions, it may be desirable to administer a compound of the present invention together with another pharmaceutically active agent. For example, for the treatment of respiratory diseases such as asthma, a compound of formula (I) can be used together with a bronchodilator, such as a β2-adrenergic receptor antagonist or a tachykinin antagonist that act as NK-2 receptors. The compound of formula (I) and the bronchodilator can be administered to the patient simultaneously, one behind the other or in combination.

Ovdje dani izum prema tome osigurava postupak za tretman respiratornih bolesti, kao što je astma, gdje postupak uključuje davanje pacijentu kojem je potrebno djelotvorne količine spoja formule (I) i djelotvorne količine bronhodilatatora. Accordingly, the invention provided herein provides a method for the treatment of respiratory diseases, such as asthma, wherein the method comprises administering to a patient in need thereof an effective amount of a compound of formula (I) and an effective amount of a bronchodilator.

Ovdje dani izum također osigurava pripravak koji sadrži spoj formule (I), bronhodilatator i farmaceutski prihvatljiv nosač. The invention provided herein also provides a composition comprising a compound of formula (I), a bronchodilator and a pharmaceutically acceptable carrier.

Izvrsni farmakološki profil spojeva ovdje danog izuma pruža mogućnost njihovog korištenja u terapiji u niskim dozama i na taj način minimizira rizik neželjenih nuspojava. The excellent pharmacological profile of the compounds of the present invention provides the possibility of using them in therapy in low doses and thus minimizes the risk of unwanted side effects.

Kod tretmana stanja povezanih suviškom tejhikinina, odgovarajući nivo doze je oko 0.001 do 50 mg/kg na dan, naročito oko 0.01 do oko 25 mg/kg, kao što je od oko 0.05 do oko 10 mg/kg na dan. In the treatment of conditions associated with excess teichyquine, a suitable dosage level is about 0.001 to about 50 mg/kg per day, particularly about 0.01 to about 25 mg/kg, such as from about 0.05 to about 10 mg/kg per day.

Na primjer, kod tretmana stanja koja imaju neurotransmisiju osjećaja boli, odgovarajući nivo doze je oko 0.001 do 25 mg/kg dnevno, poželjno oko 0.005 do 10 mg/kg na dan, a naročito oko 0.005 do 5 mg/kg na dan. Spojevi mogu biti davani prema režimu od 1 do 4 puta na dan, poželjno jednom ili dva puta dnevno. For example, in the treatment of conditions involving pain neurotransmission, a suitable dosage level is about 0.001 to 25 mg/kg per day, preferably about 0.005 to 10 mg/kg per day, and especially about 0.005 to 5 mg/kg per day. The compounds can be administered according to a regimen of 1 to 4 times a day, preferably once or twice a day.

Kod tretmana povraćanja koristeći injekcionu formulaciju, odgovarajući nivo doze je oko 0.001 do 10 mg/kg na dan, poželjno oko 0.005 do 5 mg/kg na dan, a naročito 0.01 do 2 mg/kg na dan. Spojevi mogu biti davani prema režimu od 1 do 4 puta na dan, poželjno jednom ili dva puta dnevno. In the treatment of emesis using an injectable formulation, a suitable dosage level is about 0.001 to 10 mg/kg per day, preferably about 0.005 to 5 mg/kg per day, and particularly 0.01 to 2 mg/kg per day. The compounds can be administered according to a regimen of 1 to 4 times a day, preferably once or twice a day.

Bit će uvaženo da će količina spoja formule (I) potrebna za uporabu u bilo kojem tretmanu ovisiti o pojedinom odabranom spoju ili spojevima, o putu primjene, vrsti stanja koje se tretira, dobi i stanju paicijenta, i na kraju, ovisit će i o mišljenju liječnika kojem je povjerena briga. It will be appreciated that the amount of a compound of formula (I) required for use in any treatment will depend on the particular compound or compounds selected, the route of administration, the type of condition being treated, the age and condition of the patient, and ultimately, the judgment of the physician. to whom care is entrusted.

Prema općenitom postupku (A), spojevi prema danom izumu mogu biti pripravljeni iz spojeva formule (II) According to the general procedure (A), compounds according to the given invention can be prepared from compounds of formula (II)

[image] [image]

u kojoj R1, R2, R3, R4, R5 i Y su definirani kao u formuli (I) u reakciji sa spojem formule (III): in which R1, R2, R3, R4, R5 and Y are defined as in formula (I) in reaction with a compound of formula (III):

X1-X-R6A (III) X1-X-R6A (III)

gdje je X definiran kao u formuli (I), R6a je grupa formule R6 kao što je definirano u formuli (Ia) ili njezin prekursor i X1 je otpuštajuća grupa kao što je bromidna ili kloridna; i, ako je R6a prekursor grupa, njenom konverzijom u grupu R6 (u kojem procesu bilo koja reaktivna grupa može biti zaštićena i nakon toga odstranjena ukoliko se želi). wherein X is defined as in formula (I), R6a is a group of formula R6 as defined in formula (Ia) or a precursor thereof and X1 is a leaving group such as bromide or chloride; and, if R6a is a precursor group, by its conversion to the R6 group (in which process any reactive group can be protected and subsequently removed if desired).

Ova reakcija može se izvesti na standardni način, na primjer u organskom otapalu kao što je dimetilformamid u prisustvu akceptora kiselina kao što je kalijev karbonat. This reaction can be carried out in a standard manner, for example in an organic solvent such as dimethylformamide in the presence of an acid acceptor such as potassium carbonate.

Prema drugom postupku (B), spojevi formule (I) gdje R prikazuje 1,2,3-triazol-4-il supstituiran sa CH2NR7R8, i X je -CH2-, mogu biti pripravljeni reakcijom sa spojem formule (IV) According to the second process (B), compounds of formula (I) where R represents 1,2,3-triazol-4-yl substituted with CH2NR7R8, and X is -CH2-, can be prepared by reaction with a compound of formula (IV)

[image] [image]

s azidom, npr. natrijev azid u odgovarajućem otapalu kao što je dimetilsulfoksid na temperaturi od između 40°C i 100°C, praćeno redukcijom karbonil grupe kraj -NR7R8 koristeći odgovarajuće reducirajuće sredstvo kao što je litij amonij hidrid na temperaturi između -10°C i sobne temperature, odgovarajuće na sobnoj temperaturi. with an azide, eg sodium azide in a suitable solvent such as dimethylsulfoxide at a temperature between 40°C and 100°C, followed by reduction of the carbonyl group at the end of -NR7R8 using a suitable reducing agent such as lithium ammonium hydride at a temperature between -10°C and room temperature, corresponding to room temperature.

Alternativno, prema postupku (C), spojevi formule (I) gdje R6 prikazuje 1,2,3-triazol-4-il supstituiran sa CH2NR7R8, i X je -CH2-, mogu biti pripravljeni reakcijom spoja formule (V) Alternatively, according to process (C), compounds of formula (I) where R 6 represents 1,2,3-triazol-4-yl substituted with CH 2 NR 7 R 8 , and X is -CH 2 -, can be prepared by reacting the compound of formula (V)

[image] [image]

s aminom formule NHR7R8, u odgovarajućem otapalu kao što je eter, npr. dioksan, na povišenoj temperaturi, na primjer između 50°C i 100°C, u zatvorenoj cijevi, ili sličnom. Ova reakcija temelji se na onoj opisanoj u Chemische berichte (1989) 122, s.1963. with an amine of the formula NHR7R8, in a suitable solvent such as an ether, eg dioxane, at an elevated temperature, for example between 50°C and 100°C, in a closed tube, or the like. This reaction is based on that described in Chemische berichte (1989) 122, s.1963.

Prema slijedećem postupku, (D), spojevi formule (I) gdje R6 prikazuje supstituirani ili nesupstituirani 1,3,5-triazin mogu biti pripravljeni reakcijom intermedijara formule (VI): According to the following procedure, (D), compounds of formula (I) where R 6 shows substituted or unsubstituted 1,3,5-triazine can be prepared by reaction of intermediates of formula (VI):

[image] [image]

sa supstituiranim ili nesupstituiranim 1,3,5-triazinom. with substituted or unsubstituted 1,3,5-triazine.

Reakcija se povoljno odvija u odgovarajućem organskom otapalu, kao što je acetonitril, pri povišenoj temperaturi, kao što je 80-90°C, poželjno oko 82°C. The reaction is conveniently carried out in a suitable organic solvent, such as acetonitrile, at an elevated temperature, such as 80-90°C, preferably around 82°C.

Prema daljnjem postupku, (E), spojevi formule (I) gdje R6 prikazuje supstituirani ili nesupstituirani 1,2,4-triazin, mogu biti pripravljeni rakcijom intermedijara formule (VII) s dikarbonil spojem formule (VIII): According to the further process, (E), the compounds of formula (I) where R 6 shows substituted or unsubstituted 1,2,4-triazine, can be prepared by the reaction of the intermediate of formula (VII) with the dicarbonyl compound of formula (VIII):

[image] [image]

gdje R35 prikazuje H ili odgovarajući supstituent kao stoje ZNR7R8 wherein R 35 represents H or a corresponding substituent such as ZNR 7 R 8

Reakcija se povoljno odvija u odgovarajućem organskom otapalu kao što je eter, npr. tetrahidrofuran, poželjno na sobnoj temperaturi. The reaction is preferably carried out in a suitable organic solvent such as an ether, eg tetrahydrofuran, preferably at room temperature.

Prema daljnjem procesu (F), spojevi formule (I) gdje R6 prikazuje supstituiranu 1,2,4-triazolil grupu, mogu biti pripravljeni reakcijom intermedijara formule (II) sa spojem formule (IX) According to the further process (F), the compounds of formula (I) where R6 shows a substituted 1,2,4-triazolyl group, can be prepared by reacting the intermediate of formula (II) with the compound of formula (IX)

[image] [image]

gdje je X definiran kao u formuli (I), Hal je atom halogena, na prirrjer brom, klor ili jod, a R18 je H, CONH2 ili OCH3 (koji se u uvjetima reakcije konvertita u okso supstituent), u prisustvu baze, praćeno gdje je potrebno konverzijom u spoj formule (I), na primjer redukcijom CONH2 grupe u CH2NH2. where X is defined as in formula (I), Hal is a halogen atom, for example bromine, chlorine or iodine, and R18 is H, CONH2 or OCH3 (which under the reaction conditions is converted into an oxo substituent), in the presence of a base, followed by where is required by conversion to the compound of formula (I), for example by reduction of the CONH2 group to CH2NH2.

Odgovarajuće baze za upotrebu u reakciji uključuju karbonate alkalijskih metala kao što je, npr. kalijev karbonat. Reakcija se povoljno odvija u bezvodnom organskom otapalu, kao što je, npr. bezvodni dimetilformamid, poželjno na povišenoj temperaturi, kao što je oko 140°C. Suitable bases for use in the reaction include alkali metal carbonates such as, for example, potassium carbonate. The reaction is advantageously carried out in an anhydrous organic solvent, such as, for example, anhydrous dimethylformamide, preferably at an elevated temperature, such as about 140°C.

Odgovarajući reducirajući agens za grupu CONH2 je litij aluminij hidrid, korišten između -10°C i sobne temperature. Prema slijedećem postupku (G), spojevi formule (I) gdje R6 prikazuje tioksotriazolil, može biti pripravljeni iz intermedijara formule (X) A suitable reducing agent for the CONH2 group is lithium aluminum hydride, used between -10°C and room temperature. According to the following process (G), compounds of formula (I) where R6 shows thioxotriazolyl, can be prepared from intermediates of formula (X)

[image] [image]

reakcijom sa spojem formule HNCS, u prisustvu baze. by reaction with a compound of the formula HNCS, in the presence of a base.

Odgovarajuće baze za upotrebu u reakciji uključuju organske baze kao što su, na primjer, 1,8-diazabiciklo[5.4.0]undec-7-en (DBU). Reakcija se povoljno odvija u odgovarajućem organskom otapalu, kao što je alkohol, npr. butanol. Suitable bases for use in the reaction include organic bases such as, for example, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The reaction is conveniently carried out in a suitable organic solvent, such as an alcohol, eg butanol.

Daljnji primjeri odgovarajućih postupaka naći će se u priloženim Primjerima. Further examples of appropriate procedures will be found in the attached Examples.

Spojevi formule (I) mogu biti pripravljeni iz drugih spojeva formule (I) korištenjem odgovarajućih interkonverzijskih postupaka. Na primjer, Compounds of formula (I) can be prepared from other compounds of formula (I) using appropriate interconversion procedures. For example,

spojevi formule (I) gdje X prikazuje C1-4 alkil može biti pripravljen iz spojeva formule (I) gdje X prikazuje C1-4 alkil supstituiran redukcijom sa okso, na primjer, korištenjem bor ili litij aluminij hidrida. Odgovarajući interkonverzijski postupci bit će već poznati vještima u praksi. compounds of formula (I) wherein X represents C 1-4 alkyl may be prepared from compounds of formula (I) wherein X represents C 1-4 alkyl substituted by reduction with oxo, for example, using boron or lithium aluminum hydride. Appropriate interconversion procedures will already be known to those skilled in the art.

Intermedijari formule (IV) mogu biti pripravljeni iz intermedijara formule (II) reakcijom sa acetilenskim spojem formule HC≡C-CH2-Hal u prisustvu baze kao što je kalijev karbonat u odgovarajućem otapalu kao što je dimetilformamid, povoljno na sobnoj temperaturi, praćeno reakcijom dobivenog acetilenskog intermedijara s amidom formule Hal-CO-NR7R8 u prisustvu odgovarajućeg katalizatora uključujući bis(trifenilfosfin)paladij(II)klorid, bakar(I)jodid i trifenilfosfin u odgovarajućem otapalu kao što je trietilamin, poželjno uz refluks. Intermediates of formula (IV) can be prepared from intermediates of formula (II) by reaction with an acetylenic compound of the formula HC≡C-CH2-Hal in the presence of a base such as potassium carbonate in a suitable solvent such as dimethylformamide, preferably at room temperature, followed by reaction of the resulting of an acetylene intermediate with an amide of the formula Hal-CO-NR7R8 in the presence of a suitable catalyst including bis(triphenylphosphine)palladium(II) chloride, copper(I) iodide and triphenylphosphine in a suitable solvent such as triethylamine, preferably under reflux.

Intermedijari formule (V) mogu biti pripravljeni iz spoja formule Intermediates of formula (V) can be prepared from compounds of formula

[image] [image]

gdje je Hal atom halogena, na primjer, klor, bor ili jod, naročito klor, u reakciji s azidom, na primjer, natrijev azid u odgovarajućem otapalu kao što je dimetilsulfoksid, na ili ispod sobne temperature. wherein Hal is a halogen atom, for example, chlorine, boron or iodine, especially chlorine, in reaction with an azide, for example, sodium azide in a suitable solvent such as dimethylsulfoxide, at or below room temperature.

Spojevi formule (XI) mogu biti priravljeni dodavanjem kapanjem intarmedijara formule (II) u dihaloacetilen formule Hal-CH2-C≡C-CH2-Hal gdje je svaki Hal neovisno klor, brom ili jod, naročito klor. Reakcija se povoljno odvija u odgovarajućem otapalu kao što je dimetilformamid u prisustvu baze kao što je kalijev karbonat. Compounds of formula (XI) can be prepared by dropwise addition of intermediates of formula (II) to dihaloacetylene of the formula Hal-CH2-C≡C-CH2-Hal where each Hal is independently chlorine, bromine or iodine, especially chlorine. The reaction is conveniently carried out in a suitable solvent such as dimethylformamide in the presence of a base such as potassium carbonate.

Intermedijari formule (VI) mogu biti pripravljeni iz intermedijara formule (II) reakcijom sa spojem formule Hal-X-C(NH)NH2, gdje su Hal i X kao što je prije definirano. Intermediates of formula (VI) can be prepared from intermediates of formula (II) by reaction with a compound of the formula Hal-X-C(NH)NH2, where Hal and X are as previously defined.

Intermedijari formule (VII) mogu biti pripravljeni iz intermedijara formule (II) reakcijom sa spojem formule Hal-X-C(NH)NHNH-Boc, gdje su Hal i X kao što je prije definirano, a Boc prikazuje t-butoksikarbonil, praćeno s odstranjivanjem zaštite u kiselim uvjetima. Intermediates of formula (VII) can be prepared from intermediates of formula (II) by reaction with a compound of the formula Hal-X-C(NH)NHNH-Boc, where Hal and X are as previously defined and Boc represents t-butoxycarbonyl, followed by deprotection in acidic conditions.

Spojevi formule (VIII) mogu se komercijalno nabaviti ili mogu biti pripravljeni iz komercijalno raspoloživih spojeva prema poznatim postupcima. Compounds of formula (VIII) can be obtained commercially or can be prepared from commercially available compounds according to known procedures.

Spojevi formule (IX) mogu biti pripravljeni kao što je opisano u J.Med. Chem., (1984) 27, 849. Compounds of formula (IX) may be prepared as described in J. Med. Chem., (1984) 27, 849.

Intermedijari formule (X) mogu biti pripravljeni iz odgovarajućih estera tretiranjem s hidrazinom. Reakcija se povoljno odvija u odgovarajućem organskom otapalu, kao što je alkohol, na primjer, etanol, na povišenoj temperaturi. Intermediates of formula (X) can be prepared from the corresponding esters by treatment with hydrazine. The reaction is conveniently carried out in a suitable organic solvent, such as an alcohol, for example ethanol, at an elevated temperature.

Za spojeve gdje je R6 heterociklični prsten supstituiran sa ZN7R8 grupom gdje Z je CH2, neki odabrani spojevi formule (I) mogu biti pripravljeni iz odgovarajućeg spoja s atomom vodika na mjestu ZNR7R8. Tako, na primjer spoj formule (I) gdje R6 je imidazolinon grupa koja nosi CH2NR7R8 dio može biti pripravljena iz odgovarajućeg spoja koji nema CH2NR7R8 dio, reakciom sa formaldehidom i aminom NHR7R8 pod standardnim Mannich reakcionim uvjetima, na primjer u metanolu uz zagrijavanje. Ukoliko se želi, prije stvoreni reagens kao R7R8N+=CH2.I- može biti upotrijebljen kao tercijarni amin kao što je trietilamin korišten kao receptor kiselne. For compounds where R 6 is a heterocyclic ring substituted with a ZN 7 R 8 group where Z is CH 2 , some selected compounds of formula (I) may be prepared from the corresponding compound with a hydrogen atom at the ZNR 7 R 8 position. Thus, for example, a compound of formula (I) where R6 is an imidazolinone group bearing a CH2NR7R8 moiety can be prepared from the corresponding compound lacking a CH2NR7R8 moiety by reaction with formaldehyde and the amine NHR7R8 under standard Mannich reaction conditions, for example in methanol with heating. If desired, a previously created reagent such as R7R8N+=CH2.I- can be used as a tertiary amine such as triethylamine used as an acid receptor.

Alternativno, spoj formule (I) gdje R6 prikazuje imidazolinon grupu bez CH2NR7R8 može reagirati sa paraformaldehidom i aminom, na primjer sekundarnim aminom kao što je pirolidin, da bi se dobio spoj u kojem je imidazolinonski prsten supstituiran sa CH2NR7R8 gdje R7, R8 i dušikov atom na koji su vezani tvore heteroalifatski prsten sa 4 do 7 atoma prstena koji opcijski mogu sadržavati jedan kisikov atom prstena ili drugi atom dušika koji će biti dio NH ili NRC ostatka, gdje je R6 kao što je ranije definirano. Alternatively, a compound of formula (I) wherein R 6 represents an imidazolinone group without CH 2 NR 7 R 8 can be reacted with paraformaldehyde and an amine, for example a secondary amine such as pyrrolidine, to give a compound wherein the imidazolinone ring is substituted with CH 2 NR 7 R 8 wherein R 7 , R 8 and a nitrogen atom to which they are attached form a heteroaliphatic ring with 4 to 7 ring atoms which may optionally contain one ring oxygen atom or another nitrogen atom to be part of an NH or NRC residue, where R 6 is as previously defined.

Ova reakcija može se odvijati na standardni način, na primjer, u odgovarajućem otapalu kao što je alkohol, npr. metanol uz povišenou temperaturu do točke vrelišta otapala. This reaction can be carried out in a standard manner, for example, in a suitable solvent such as an alcohol, eg methanol at an elevated temperature up to the boiling point of the solvent.

Idući alternativni postupak za pripravljanje nekih spojeva formule (I) uključuje reakciju intermedijara formule (II) kao što je gore definirano, s jednim od spojeva formule (XII): A further alternative procedure for the preparation of some compounds of formula (I) involves the reaction of an intermediate of formula (II) as defined above, with one of the compounds of formula (XII):

[image] [image]

u kojoj svaki LG, koji može biti isti ili različit, je otpuštajuća grupa, kao što je alkil- ili arilsulfoniloksi grupa (npr. mezilat ili tozilat) ili, naročito, atom halogena (npr. brom, klor ili jod) i X i Z su definirani kao u formuli (I), praćeno reakcijom dobivenog spoja s aminom NHR7R8 da se kompletira ZNR7R8 skupina. wherein each LG, which may be the same or different, is a leaving group, such as an alkyl- or arylsulfonyloxy group (eg mesylate or tosylate) or, in particular, a halogen atom (eg bromine, chlorine or iodine) and X and Z are defined as in formula (I), followed by reaction of the resulting compound with the amine NHR7R8 to complete the ZNR7R8 group.

Ova reakcija se uobičajeno odvija u organskom otapalu kao što je dimetilformamid u prisustvu akceptora kiselina kao što je kalijev karbonat. This reaction is usually carried out in an organic solvent such as dimethylformamide in the presence of an acid acceptor such as potassium carbonate.

Bit će uvaženo da, kada je potrebno, reaktivne grupe mogu biti zaštićene, tako na primjer, NH grupe imidazolinona formule (XIIa) mogu biti zaštićene s bilo kojom amino zaštitnom grupom kao što je acetil grupa. It will be appreciated that, when necessary, reactive groups may be protected, so for example, the NH groups of imidazolinones of formula (XIIa) may be protected with any amino protecting group such as an acetyl group.

Preferirani fosfat prodrug-ovi spojeva prema danom izumu mogu biti pripravljeni postupnim načinom iz spoja formule (I) gdje Y je, na primjer, -CH2OH-. Preferred phosphate prodrugs of the compounds according to the present invention can be prepared stepwise from the compound of formula (I) where Y is, for example, -CH2OH-.

Tako, hidroksi spoj se najprije tretira s dibenziloksidietilamino-fosfinom u odgovarajućem otapalu kao što je tetrahidrofuran, poželjno u prisustvu kiselog katalizatora kao što je tetrazol. Dobiveni spoj (Y=CH2OP(OCH2Ph)2) se tada oksidira koristeći npr. 4-metilmorfolin-N-oksid da bi se dobio dibenzil-zaštićeni fosfat. Odstranjivanje zaštite katalitičkom hidrogenacijom ili transfer hidrogenacijom (paladij katalizator na ugljiku i amonij format), u odgovarajućem otapalu kao što je metanol uz refluks, daje željeni fosfat prodrug koji se može standardnim metodama konvertirati u bilo koju željenu sol. Thus, the hydroxy compound is first treated with dibenzyloxydiethylaminophosphine in a suitable solvent such as tetrahydrofuran, preferably in the presence of an acidic catalyst such as tetrazole. The resulting compound (Y=CH2OP(OCH2Ph)2) is then oxidized using eg 4-methylmorpholine-N-oxide to give the dibenzyl-protected phosphate. Deprotection by catalytic hydrogenation or transfer hydrogenation (palladium on carbon catalyst and ammonium formate), in a suitable solvent such as methanol at reflux, gives the desired phosphate prodrug which can be converted to any desired salt by standard methods.

U alternativnoj metodi u dva stupnja, hidroksi spoj formule (I) može reagirati s odgovarajućom bazom kao što je natrijev hidrid u tetrahidrofuranu, i tetrabenzilpirofosfat dodan da bi se dobio dibenzil-zaštićeni fosfat kojemu se može odstraniti zaštita kako je gore opisano. In an alternative two-step method, the hydroxy compound of formula (I) can be reacted with an appropriate base such as sodium hydride in tetrahydrofuran, and tetrabenzylpyrophosphate added to give a dibenzyl-protected phosphate which can be deprotected as described above.

Spojevi formule (II) mogu biti pripravljeni kao što je prikazano u slijedećoj shemi gdje Ar1 prikazuje R1, R2, R3 supstituiranu fenilnu grupu; Ar2 prikazuje R4, R5 supstituiranu fenilnu grupu i Ph prikazuje fenil: Compounds of formula (II) may be prepared as shown in the following scheme where Ar 1 represents a R 1 , R 2 , R 3 substituted phenyl group; Ar2 represents R4, R5 a substituted phenyl group and Ph represents phenyl:

[image] [image]

L-Selektrid je litij tri-sec-butilborhidrid. L-Selectride is lithium tri-sec-butylborohydride.

Slijedeće reference opisuju postupke koje može primijeniti vješti stručnjak za ranije gore navedene kemijske sinteze nakon što stručnjak prouči ovdje objavljeno: The following references describe procedures that may be employed by the skilled artisan for the foregoing chemical syntheses after the skilled artisan has reviewed the disclosures herein:

(I) D. A. Evans et ai, J. Am. Chem. Soc, (1990) 112, 4011. (I) D. A. Evans et al., J. Am. Chem. Soc, (1990) 112, 4011.

(II) I. Yanagisawa et ai, J. Med. Chem., (1984) 27, 849. (II) I. Yanagisawa et al., J. Med. Chem., (1984) 27, 849.

(III) R. Duchinsky et al., J. Am, Chem. Soc, (1948) 70, 657. (III) R. Duchinsky et al., J. Am, Chem. Soc, (1948) 70, 657.

(IV) F. N. Tebbe et al., J. Am. Chem. Soc, (1978) 100, 3611. (IV) F. N. Tebbe et al., J. Am. Chem. Soc, (1978) 100, 3611.

(V) N. A. Petasis et al., J. Am. Chem. Soc, (1990) 112, 6532. (V) N.A. Petasis et al., J. Am. Chem. Soc, (1990) 112, 6532.

(VI) K. Takao et al., J. Org. Chem., (1987) 52, 4412. (VI) K. Takao et al., J. Org. Chem., (1987) 52, 4412.

Ovdje izloženim Primjerima dobivaju se prvenstveno preferirani izomeri. Neželjeni izomeri također se dobivaju u manjem dijelu. Ukoliko se želi, oni mog biti izolirani i iskorišteni za dobivanje različitih stereoizomera na standardni način, na primjer kromatografijom koristeći odgovarajću kolonu. Međutim, vješti stručnjak će shvatiti da iako su Primjeri optimizirani za proizvodnju preferiranih izomera, varijacije kod otapala, reagensa, kromatografije itd. mogu biti iskorišteni za dobivanje ostalih izomera. Preferred isomers are primarily obtained by the Examples set forth herein. Unwanted isomers are also obtained in a smaller proportion. If desired, they can be isolated and used to obtain different stereoisomers in a standard way, for example by chromatography using a suitable column. However, the skilled artisan will appreciate that although the Examples are optimized for the production of preferred isomers, variations in solvents, reagents, chromatography, etc. may be used to obtain other isomers.

Bit će shvaćeno da spojevi formule (I) gdje R6 sadrži =O ili =S supstituent mogu postojati u tautomernim oblicima. Svi takvi tautomerni oblici i njihove smjese uključeni su ovim izumom. Najpovoljnije =O ili =S supstituent R6 je =O supstitent. It will be understood that compounds of formula (I) wherein R 6 contains an =O or =S substituent may exist in tautomeric forms. All such tautomeric forms and mixtures thereof are included in the present invention. Most preferably the =O or =S substituent of R6 is the =O substituent.

Kada nisu komercijalno dobavljivi, intermedijari gornje formule (III) mogu biti pripravljeni postupcima opisanim u priloženim Primjerima ili alternativnim postupcima koji će biti poznati stručnjacima iz prakse. When not commercially available, intermediates of formula (III) above may be prepared by the procedures described in the attached Examples or by alternative procedures that will be known to those skilled in the art.

Tijekom bilo koje od gornjih sekvenci sinteze može biti potrebno i/ili poželjno zaštititi osjetljive ili reaktivne grupe bilo koje od navedenih molekula. To se može postići standardnim sredstvima za zaštitu grupa, kao što su ona opisana u Protective Groups in Organic Chemistn/, ed. J.F.VV. McOmie, Plenum Press, 1973; i T.W. Greene i P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. Zaštitne grupe mogu se odstraniti u odgovarajućem stadiju koristeći protupke poznate iz rada. During any of the above synthesis sequences, it may be necessary and/or desirable to protect sensitive or reactive groups of any of the above molecules. This can be achieved by standard protecting group means, such as those described in Protective Groups in Organic Chemistn/, ed. J.F.VV. McOmie, Plenum Press, 1973; and T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. Protective groups can be removed at an appropriate stage using reagents known in the art.

Spojevi iz primjera ovdje danog izuma ispitani su prema postupcima navedenim na stranicama 36 do 39 Međunarodne specifikacije patenata br. WO 93/01165. Spojevi ili, u slučaju prodrug-ova, parent-spojevi, bili su aktivni sa IC50 na NK1 receptom sa manje od 10nM prema navedenoj ispitoj metodi. The compounds from the examples of the invention given here were tested according to the procedures listed on pages 36 to 39 of the International Patent Specification no. WO 93/01165. Compounds or, in the case of prodrugs, parent compounds, were active with an IC50 at NK1 prescription of less than 10nM according to the specified test method.

Opis 1 Description 1

(S)-(4-fluorofenil)glicin (S)-(4-Fluorophenyl)glycine

Put kiralne sinteze: Path of chiral synthesis:

Stupanj A: 3-(4-fluorofenil)acetil-4-(S)-benzil-2-oksazolidinon Grade A: 3-(4-fluorophenyl)acetyl-4-(S)-benzyl-2-oxazolidinone

Sterilzirana, 1l 3-vrata bočica, sa pregradom, dušičnim inletom, termometrom i magnetskim štapićem za miješanje prelije se dušikom, napuni otopinom 5.09g (33.0mmol) 4-fluorofeniloctene kiseline u 100 ml bezvodnog etera. Otopina se ohladi na -10°C i tretira s 5.60ml (40.0mmol) trietilamina praćeno s 4.30ml (35.0mmol) trimetilacetil klorida. Odmah se stvara bijeli talog. Dobivena otopina se miješa na -10°C kroz 40 minuta i zatim ohladi na -78°C. A sterilized, 1l 3-door bottle, with a septum, a nitrogen inlet, a thermometer and a magnetic stirring rod is filled with nitrogen, filled with a solution of 5.09g (33.0mmol) of 4-fluorophenylacetic acid in 100 ml of anhydrous ether. The solution is cooled to -10°C and treated with 5.60 ml (40.0 mmol) of triethylamine followed by 4.30 ml (35.0 mmol) of trimethylacetyl chloride. A white precipitate forms immediately. The resulting solution is stirred at -10°C for 40 minutes and then cooled to -78°C.

Sterilizirana, 250 ml bočica s okruglim dnom, pregradom i magnetskim štapićem za miješanje ispere se dušikom i napuni otopinom 5.31 g (30.0mmol) 4-(S)-benzil-2-oksazolidinon u 40ml bezvodnog THF. Otopina se miješa u suhoj kupki led/aceton kroz 10 minuta, zatim se polagano dodaje 18.8ml 1.6M n-butillitij otopina u heksanu. Nakon 10 minuta dodaje se litizirani oksazolidinon kroz kanilu, u gornju otopinu u 3-vratu bočicu. Rashladna kupka se odstrani iz gornje smjese i dozvoli se porast temperature do 0°C. Reakcija se gasi sa 100ml otopine zasićenog vodenog amonijevog klorida, prebaci u 1l bocu, i eter i THF se odstrane in vacuo. Koncentrirana smjesa se razdijeli između 300ml metilen klorida i 50ml vode i slojevi se razdvoje. Organski sloj se ispere sa 100ml 2N vodene otopine klorovodične kiseline, 300ml otopine zasićenog vodenog natrijevog bikarbonata, osuši preko magnezij sulfata i koncentrira in vacuo. Fleš kromatografijom na 400g silikagela koristeći 3:2 v/v haksan/eter kao eluent dobiva se 8.95g ulja koje se polako skrutnjava stajanjem. Rekristalizacijom iz 10:1 heksan/etera dobiva se 7.89g (83%) naslovnog spoja kao bijele krute tvari: t.t. 64-66°C. MS (FAB): m/z 314 (M++H, 100%), 177 (M-ArCH2CO+H, 85%), 1H NMR (400MHz, CDCI3)δ 2.76 (1H, dd, J=13.2, 9.2), 3.26 (dd, J=13.2, 3.2), 4.16-4.34 (4H, m), 4.65 (1H, m), 7.02-7.33 (9H, m). Anal. računano za C18H16FNO3; C, 69.00; H, 5.15; N, 4.47; F, 6.06; Nađeno: C, 68.86; H, 5.14; N, 4.48; F, 6.08. A sterilized, 250 ml vial with a round bottom, a septum and a magnetic stir bar is purged with nitrogen and filled with a solution of 5.31 g (30.0 mmol) 4-(S)-benzyl-2-oxazolidinone in 40 ml anhydrous THF. The solution is stirred in a dry ice/acetone bath for 10 minutes, then 18.8ml of 1.6M n-butyllithium solution in hexane is slowly added. After 10 minutes, lithiated oxazolidinone is added through the cannula to the above solution in the 3-necked bottle. The cooling bath is removed from the above mixture and the temperature is allowed to rise to 0°C. The reaction is quenched with 100ml of saturated aqueous ammonium chloride solution, transferred to a 1L flask, and the ether and THF are removed in vacuo. The concentrated mixture is partitioned between 300ml of methylene chloride and 50ml of water and the layers are separated. The organic layer is washed with 100 ml of 2N aqueous hydrochloric acid solution, 300 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate and concentrated in vacuo. Flash chromatography on 400g of silica gel using 3:2 v/v hexane/ether as eluent gives 8.95g of oil which slowly solidifies on standing. Recrystallization from 10:1 hexane/ether gave 7.89 g (83%) of the title compound as a white solid: m.p. 64-66°C. MS (FAB): m/z 314 (M++H, 100%), 177 (M-ArCH2CO+H, 85%), 1H NMR (400MHz, CDCl3)δ 2.76 (1H, dd, J=13.2, 9.2 ), 3.26 (dd, J=13.2, 3.2), 4.16-4.34 (4H, m), 4.65 (1H, m), 7.02-7.33 (9H, m). Anal. calculated for C18H16FNO3; C, 69.00; H, 5.15; N, 4.47; F, 6.06; Found: C, 68.86; H, 5.14; N, 4.48; F, 6.08.

Stupanj B: 3-(S)-azido-(4-fluorofenil)acetil-4-(S)-benzil-2-oksazolidinon Grade B: 3-(S)-azido-(4-fluorophenyl)acetyl-4-(S)-benzyl-2-oxazolidinone

Sterilzirana, 1l 3-vrata bočica, sa pregradom, dušičnim inletom, termometrom i magnetskim štapićem za miješanje prelije se dušikom, napuni otopinom 58.0ml 1M kalij bis(trimetilsilil) amida u toluenu i 85ml THF i rashladi na -78°C. Sterilizirana, 250 ml bočica s okruglim dnom, sa pregradom i magnetskim štapićem za miješanje, ispere se dušikom i napuni otopinom 7.20g (23.0mmol) 3-(4-fluorofenil)acetil-4-(S)-benzil-2-oksazolidinona (iz Stupnja A) u 40ml THF. Otopina acil oksazolidinona miješa se u rashladnoj kupki led/aceton kroz 10 minuta, zatim prebaci kanilom u otopinu kalijevog bis(trimeltilsilil)amida tako da se interna temperatura smjese održava ispod -70°C. Acil oksazolidinonska bočica se ispere sa 15ml THF i sve zajedno se doda kanilom u reakcionu smjesu, i dobivena smjesa se miješa na -78°C kroz 30 minuta. Sterilizirana, 250 ml bočica s okruglim dnom, sa pregradom i magnetskim štapićem za miješanje ispere se dušikom i napuni otopinom 10.89g (35.0mmol) 2,4,6-triizopropilfenilsulfonil azida u 40ml THF. Azidna otopina se miješa u kupki led/aceton kroz 10 minuta, zatim prebaci kanilom u reakcionu smjesu na takav način da se unutarnja temperatura reakcije održava ispod -70°C. Nakon 2 minute, reakcija se ugasi sa 6.0ml glacijalne octene kiseline, rashladna kupka se odstrani i smjesa se miješa na sobnoj temperaturi 18 sati. Ugašena reakciona smjesa se razdijeli između 300ml etil acetata i 300 ml 50% zasićene vodene otopine natrijevog bikarbonata. Organski sloj se odvoji, osuši na magnezij sulfatu i koncentrira in vacuo. Fleš kromatografijom na 500g silikagelu koristeći 2:1 v/v, zatim 1:1 v/v heksani/metilenklorid kao eluent dobiva se 5.45g (67%) naslovnog spoja kao ulje. IR Spektar (čisti, cm-1); 2104, 1781, 1702. 1H NMR (400MHz, CDCI3)δ 2.86 (1H, dd, J=13.2, 9.6), 3.40 (1H, dd, J=13.2, 3.2), 4.09-4.19 (2H, m), 4.62-4.68 (1H, m), 6.14 (1H, s), 7.07-7.47 (9H, m). Analaliza: Računano za C18H15FN4O3; C 61.01; H, 4.27; N, 15.81; F, 5.36; Nađeno: C, 60.99; H, 4.19; N, 15.80; F, 5.34. A sterilized, 1l 3-door bottle, with a septum, nitrogen inlet, thermometer and magnetic stirring rod, is filled with nitrogen, filled with a solution of 58.0ml of 1M potassium bis(trimethylsilyl)amide in toluene and 85ml of THF and cooled to -78°C. A sterilized, 250 ml, round-bottomed vial with a septum and a magnetic stirring rod is flushed with nitrogen and filled with a solution of 7.20 g (23.0 mmol) of 3-(4-fluorophenyl)acetyl-4-(S)-benzyl-2-oxazolidinone ( from Step A) in 40ml THF. The acyl oxazolidinone solution is mixed in an ice/acetone cooling bath for 10 minutes, then transferred with a cannula into the potassium bis(trimethylsilyl)amide solution so that the internal temperature of the mixture is maintained below -70°C. The acyl oxazolidinone vial is washed with 15 ml of THF and everything is added together with a cannula to the reaction mixture, and the resulting mixture is stirred at -78°C for 30 minutes. A sterilized, 250 ml, round-bottomed vial with a septum and a magnetic stirring rod is flushed with nitrogen and filled with a solution of 10.89 g (35.0 mmol) of 2,4,6-triisopropylphenylsulfonyl azide in 40 ml of THF. The azide solution is mixed in an ice/acetone bath for 10 minutes, then transferred with a cannula into the reaction mixture in such a way that the internal temperature of the reaction is maintained below -70°C. After 2 minutes, the reaction is quenched with 6.0 ml of glacial acetic acid, the cooling bath is removed and the mixture is stirred at room temperature for 18 hours. The quenched reaction mixture was partitioned between 300 ml of ethyl acetate and 300 ml of a 50% saturated aqueous solution of sodium bicarbonate. The organic layer is separated, dried over magnesium sulfate and concentrated in vacuo. Flash chromatography on 500g silica gel using 2:1 v/v, then 1:1 v/v hexanes/methylene chloride as eluent afforded 5.45g (67%) of the title compound as an oil. IR Spectrum (pure, cm-1); 2104, 1781, 1702. 1H NMR (400MHz, CDCl3)δ 2.86 (1H, dd, J=13.2, 9.6), 3.40 (1H, dd, J=13.2, 3.2), 4.09-4.19 (2H, m), 4.62 -4.68 (1H, m), 6.14 (1H, s), 7.07-7.47 (9H, m). Analysis: Calculated for C18H15FN4O3; C 61.01; H, 4.27; N, 15.81; F, 5.36; Found: C, 60.99; H, 4.19; N, 15.80; F, 5.34.

Stupanj C: (S)-Azido-(4-fluorofenil) octena kiselina Step C: (S)-Azido-(4-fluorophenyl)acetic acid

Otopina 5.40g (15.2mmol) 3-((S)-azido-(4-fluorofenil))acetil-4-(S)-benzil-2-oksazolidinona (iz Stupnja B) u 200ml 3:1 v/v THF/voda miješa se u ledenoj kupki 10 minuta. 1.28g (30.4mmol) litij hidroksid monohidrata dodaje se u jednoj porciji i dobivena smjesa se hladno miješa 30 minuta. Reakciona smjesa se razdijeli između 100ml metilen klorida i 100ml 25%-tne zasićene vodene otopine natrijevog bikarbonata, i slojevi se razdvoje. Vodeni sloj se ispere s 2 x 100ml metilen klorida i zakiseli do pH 2 sa 2N vodenom otopinom klorovodične kiseline. Dobivena smjesa se ekstrahira sa 2 x 100ml etil acetata; ekstrakti se pomiješaju, isperu sa 50ml zasićene vodene otopine natrij klorida, osuše iznad magnezij sulfata i koncentriraju in vacuo da bi se dobilo 2.30g (77%) naslovnog spoja kao ulje koje se koristi u slijedećem stupnju bez daljnjeg pročišćavanja. IR Spektar (čisti, cm-1): 2111, 1724. 1H NMR (400MHz, CDCI3)δ 5.06 (1H, s), 7.08-7.45 (4H, m), 8.75 (1H, br s). A solution of 5.40g (15.2mmol) of 3-((S)-azido-(4-fluorophenyl))acetyl-4-(S)-benzyl-2-oxazolidinone (from Step B) in 200ml of 3:1 v/v THF/ water is mixed in an ice bath for 10 minutes. 1.28g (30.4mmol) of lithium hydroxide monohydrate was added in one portion and the resulting mixture was stirred cold for 30 minutes. The reaction mixture was partitioned between 100 ml of methylene chloride and 100 ml of 25% saturated aqueous sodium bicarbonate, and the layers were separated. The aqueous layer is washed with 2 x 100 ml of methylene chloride and acidified to pH 2 with a 2N aqueous solution of hydrochloric acid. The obtained mixture is extracted with 2 x 100 ml of ethyl acetate; the extracts are combined, washed with 50ml saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo to give 2.30g (77%) of the title compound as an oil which is used in the next step without further purification. IR Spectrum (neat, cm-1): 2111, 1724. 1H NMR (400MHz, CDCl3)δ 5.06 (1H, s), 7.08-7.45 (4H, m), 8.75 (1H, br s).

Stupanj D: (S)-(23-Fluorofenil)glicin Step D: (S)-(23-Fluorophenyl)glycine

Smjesa 2.30g (11.8mmol) (S)-azido-(4-fluorofenil) octene kiseline (iz Stupnja C), 250mg 10%-tnog paladija na ugljičnom katalizatoru i 160ml 3:1 v/v voda/octena kiselina miješa se u atmosferi vodika 18 sati. Reakciona smjesa se filtrira kroz Celit, i posuda i filter kolač se dobro isperu sa ~1l 3:1 v/v voda/octena kiselina. Filtrat se koncentrira in vacuo do oko 50ml volumena. Dodaje se 300ml toluena i smjesa koncentrira da bi se dobila krutina. Kruta tvar se suspendira u 1:1 v/v metanol/eter, filtrira i osuši da bi se dobilo 1.99g (100%) naslovnog spoja. 1H NMR (400MHz, D2O+NaOD)δ 3.97 (1H, s), 6.77 (2H, app t, J=8.8), 7.01 (2H, appt, J=5.6). A mixture of 2.30g (11.8mmol) (S)-azido-(4-fluorophenyl)acetic acid (from Grade C), 250mg of 10% palladium on carbon catalyst and 160ml of 3:1 v/v water/acetic acid is mixed in hydrogen atmosphere for 18 hours. The reaction mixture is filtered through Celite, and the vessel and filter cake are washed well with ~1l of 3:1 v/v water/acetic acid. The filtrate is concentrated in vacuo to a volume of about 50 ml. 300ml of toluene is added and the mixture is concentrated to obtain a solid. The solid was suspended in 1:1 v/v methanol/ether, filtered and dried to give 1.99g (100%) of the title compound. 1H NMR (400MHz, D2O+NaOD)δ 3.97 (1H, s), 6.77 (2H, appt, J=8.8), 7.01 (2H, appt, J=5.6).

Put rezolucije: Resolution path:

Stupanj A': (4-fluorofenil)acetil klorid Step A': (4-fluorophenyl)acetyl chloride

Otopina 150g (0.974mol) 4-(fluorofenil)octene kiseline i 1ml N,N-dimetilformamida u 500ml toluena na 40°C tretira se sa 20ml tionil klorida i zagrijava do 40°C. Dodatnih 61.2ml tionil klorida se doda kapanjem tijekom 1.5 sati. Nakon dodavanja, otopina se zagrije na 50°C kroz 1 sat, otapalo se odstrani in vacuo i dobiveno ulje se destilira pod smanjenim tlakom (1.5mmHg) da bi se dobilo 150.4g (89.5%) naslovnog spoja, t.v.=68-70°C. A solution of 150g (0.974mol) of 4-(fluorophenyl)acetic acid and 1ml of N,N-dimethylformamide in 500ml of toluene at 40°C is treated with 20ml of thionyl chloride and heated to 40°C. An additional 61.2 ml of thionyl chloride is added dropwise over 1.5 hours. After the addition, the solution is heated to 50°C for 1 hour, the solvent is removed in vacuo and the resulting oil is distilled under reduced pressure (1.5mmHg) to obtain 150.4g (89.5%) of the title compound, m.p.=68-70° C.

Stupanj B': Metil 2-bromo-3-(4-fluorofenil)acetat Step B': Methyl 2-bromo-3-(4-fluorophenyl)acetate

Smjesa 150.4g (0.872mol) 4-(fluorofenil)acetil klorida (iz Stupnja A') i 174.5g (1.09mol) broma ozračuje se kod 40-50°C kvarcnom lampom kroz 5 sati . Reakciona smjesa se dodaje kapanjem u 400ml metanola i otopina se miješa 16 sati. Otapalo se odstrani in vacuo i dobiveno ulje se destilira pod smanjenim tlakom (1.5mmHg) da bi se dobilo 198.5g (92%) naslovnog spoja, t.v. =106-110°C. A mixture of 150.4g (0.872mol) 4-(fluorophenyl)acetyl chloride (from Stage A') and 174.5g (1.09mol) bromine is irradiated at 40-50°C with a quartz lamp for 5 hours. The reaction mixture was added dropwise to 400 ml of methanol and the solution was stirred for 16 hours. The solvent was removed in vacuo and the resulting oil was distilled under reduced pressure (1.5 mmHg) to give 198.5 g (92%) of the title compound, b.p. =106-110°C.

Stupanj C: Metil (+) (4-fluorofenil)glicin Step C: Methyl (+) (4-fluorophenyl)glycine

Otopina 24.7g (0.1 mol) metil 2-bromo-2-(4-fluorofenil)acetata (iz Stupnja B') i 2.28g (0.01 mol) benzil trietilamonij klorida u 25ml metanola tretira se sa 6.8g (0.105mol) natrijevog azida i dobivena smjesa se miješa 20 sati na sobnoj temperaturi. Reakciona smjesa se filtrira; filtrat se razrijedi sa 50ml metanola i hidrogenizira u prisustvu 0.5g 10% Pd/C kod 50 psi kroz 1 sat. Otopina se filtrira i otapalo odstrani in vacuo. Dobiveni ostatak se razdijeli između 10%-tne otopine natrijevog karbonata i etil acetata. Organska faza se ispere vodom, zasićena vodena otopina natrijevog klorida suši se iznad magnezijevog sulfata i kkoncentrira in vacuo da bi se dobilo 9.8g naslovnog spoja kao ulje. A solution of 24.7g (0.1 mol) of methyl 2-bromo-2-(4-fluorophenyl)acetate (from Step B') and 2.28g (0.01 mol) of benzyl triethylammonium chloride in 25ml of methanol is treated with 6.8g (0.105mol) of sodium azide. and the resulting mixture is stirred for 20 hours at room temperature. The reaction mixture is filtered; the filtrate is diluted with 50 ml of methanol and hydrogenated in the presence of 0.5 g of 10% Pd/C at 50 psi for 1 hour. The solution is filtered and the solvent is removed in vacuo. The resulting residue is partitioned between a 10% solution of sodium carbonate and ethyl acetate. The organic phase was washed with water, saturated aqueous sodium chloride was dried over magnesium sulfate and concentrated in vacuo to give 9.8g of the title compound as an oil.

Stupanj D': Metil (S)-(4-fluorofenil)glicinat Step D': Methyl (S)-(4-Fluorophenyl)glycinate

Otopna 58.4g metil (+) 4-(fluorofenil)glicinata (iz Stupnja C) u 110ml 7:1 v/v etanol/voda miješa se s otopinom 28.6g (0.0799mol) O,O'-(+)dibenzoilvinske kiseline ((+)-DBT) (28.6g, 0.0799mol) u 110ml 7:1 v/v etanol:voda i dobivena otopina se ostavi stajati na sobnoj temperaturi. Etil acetat (220ml) se dodaje po završenoj kristalizaciji i dobivena smjesa se ohladi do -20°C i filtrira da bi se dobilo 32.4g metil (S)-(4-fluorofenil)glicinata, (+)-DBT sol (ee=93.2%). Matične tekućine se koncentriraju in vacuo i slobodne baze se oslobode razdjeljivanjem između etil acetata i vodene otopine natrijevog karbonata. Otopina slobodnih baza tako dobivenih, u 110ml 7:1 v/v etanol/voda, miješa se s otopinom 28.6g (0.0799mol) O,O'-(-)-dibenzoilvinske kiselina ((-)-DBT) (28.6g, 0.0799) u 110ml 7:1 v/v etanol:voda i dobivena otopina se ostavi stajati na sobnoj temperaturi. Etil acetat (220ml) se doda nakon završene kristalizacije i dobivena smjesa se ohladi na -20°C i filtrira da bi se dobilo 47.0g metil (R)-(4-fluorofenil)glicinata, (-)-DBT sol (ee=75.8%). Recikliranjem matičnih tekućina i dodatkom (+)-DBT dobiva se sekundarni prinos od 7.4g (S)-(4-fluorofenil)glicinata, (+)-DTB sol (96.4%). Dva prinosa (S)-amino estera (39.8g) se izmiješaju u 200ml 7:1 v/v etanol/voda i ohlade na sobnu temperaturu. Adicijom etil acetata, hlađenjem i filtracijom dobiva se 31.7g (S)-(4-fluorofenil)glicinat, (+)-DBT sol (ee>98%). Višak enantiomera se određuje kiralnom HPCL (Crownpak CR(+) 5% MeOH u aq HCIO4 pH2 1.5ml/min 40°C 200nm). Dissolving 58.4g of methyl (+) 4-(fluorophenyl)glycinate (from Step C) in 110ml of 7:1 v/v ethanol/water is mixed with a solution of 28.6g (0.0799mol) of O,O'-(+)dibenzoyltartaric acid ( (+)-DBT) (28.6g, 0.0799mol) in 110ml of 7:1 v/v ethanol:water and the resulting solution was allowed to stand at room temperature. Ethyl acetate (220ml) was added after the crystallization was complete and the resulting mixture was cooled to -20°C and filtered to give 32.4g of methyl (S)-(4-fluorophenyl)glycinate, (+)-DBT salt (ee=93.2 %). The mother liquors were concentrated in vacuo and the free bases were liberated by partitioning between ethyl acetate and aqueous sodium carbonate. A solution of the free bases thus obtained, in 110ml of 7:1 v/v ethanol/water, is mixed with a solution of 28.6g (0.0799mol) O,O'-(-)-dibenzoyltaric acid ((-)-DBT) (28.6g, 0.0799) in 110 ml of 7:1 v/v ethanol:water and the resulting solution is left to stand at room temperature. Ethyl acetate (220ml) was added after crystallization was complete and the resulting mixture was cooled to -20°C and filtered to give 47.0g of methyl (R)-(4-fluorophenyl)glycinate, (-)-DBT salt (ee=75.8 %). By recycling the mother liquors and adding (+)-DBT, a secondary yield of 7.4g (S)-(4-fluorophenyl)glycinate, (+)-DTB salt (96.4%) is obtained. Two yields of (S)-amino ester (39.8g) were mixed in 200ml of 7:1 v/v ethanol/water and cooled to room temperature. Addition of ethyl acetate, cooling and filtration yield 31.7g of (S)-(4-fluorophenyl)glycinate, (+)-DBT salt (ee>98%). The enantiomer excess is determined by chiral HPCL (Crownpak CR(+) 5% MeOH in aq HCIO4 pH2 1.5ml/min 40°C 200nm).

Smjesa 17.5g (S)-(4-fluorofenil)glicinata, (+)-DBT sol i 32ml 5.5N HCI (32ml) zagrijava se uz refluks 1.5 sat. Reakciona smjesa se koncentrira in vacuo i ostatak se otopi u 40ml vode. Vodena otopina se ispere (3 x 30ml etil acetata) i slojevi se razdvoje. pH vodenog sloja prilagodi se na 7 korištenjem amonij hidroksida i istaložena kruta tvar se filtrira da bi se dobilo 7.4g naslovnog spoja (ee=98.8%). A mixture of 17.5g of (S)-(4-fluorophenyl)glycinate, (+)-DBT salt and 32ml of 5.5N HCI (32ml) is heated under reflux for 1.5 hours. The reaction mixture is concentrated in vacuo and the residue is dissolved in 40 ml of water. The aqueous solution was washed (3 x 30 ml ethyl acetate) and the layers were separated. The pH of the aqueous layer was adjusted to 7 using ammonium hydroxide and the precipitated solid was filtered to give 7.4g of the title compound (ee=98.8%).

Opis 2 Description 2

4-benzil-3-(S)-(4-fluorofenil)-2-morfolinon 4-benzyl-3-(S)-(4-fluorophenyl)-2-morpholinone

Stupanj A: N-benzil-(S)-(4-fluorofenil)glicin Step A: N-benzyl-(S)-(4-fluorophenyl)glycine

Otopina 1.87g (11.05mmol) (S)-(4-fluorofenil)-glicina (iz Opisa 1) i 1.12ml (11.1mmol) benzaldehida u 11.1ml 1N vodene otopine natrijevog hidroksida i 11ml metanola na 0°C tretira se sa 165mg (4.4mmol) natrij borhidrida. Rashladna kupka se odstrani i dobivena smjesa miješa na sobnoj temperaturi 30 minuta. Druga porcija benzaldehida (1.12ml (11.1mmol)) i natrij borhidrida (165mg (4.4)) dodaje se u reakcionu smjesu i miješanje se nastavlja još 1.5 sati. Reakciona smjesa se razdijeli između 100ml etera i 50ml vode i slojevi se razdvoje. Vodeni sloj se separira i filtrira da bi se odstranila mala količina netopive tvari. Filtrat se zakiseli do pH 5 sa 2N vodene otopine klorovodične kiseline i istaložena kruta tvar se filtrira, dobro ispere vodom, zatim eterom, i osuši da bi se dobilo 1.95g naslovnog spoja. 1H NMR (400MHz, D2O + NaOD) δ 3.33 (2H, AB q, J=8.4), 3.85 (1H, s), 6.79-7.16 (4H, m). A solution of 1.87g (11.05mmol) (S)-(4-fluorophenyl)-glycine (from Description 1) and 1.12ml (11.1mmol) benzaldehyde in 11.1ml 1N aqueous sodium hydroxide solution and 11ml methanol at 0°C is treated with 165mg (4.4 mmol) of sodium borohydride. The cooling bath is removed and the resulting mixture is stirred at room temperature for 30 minutes. A second portion of benzaldehyde (1.12ml (11.1mmol)) and sodium borohydride (165mg (4.4)) was added to the reaction mixture and stirring was continued for another 1.5 hours. The reaction mixture is partitioned between 100 ml of ether and 50 ml of water and the layers are separated. The aqueous layer is separated and filtered to remove a small amount of insoluble material. The filtrate was acidified to pH 5 with 2N aqueous hydrochloric acid and the precipitated solid was filtered, washed well with water, then ether, and dried to give 1.95g of the title compound. 1H NMR (400MHz, D2O + NaOD) δ 3.33 (2H, AB q, J=8.4), 3.85 (1H, s), 6.79-7.16 (4H, m).

Stupanj B: 4-benzil-3-(S)-(4-fluorofenil)-2-morfolinon Step B: 4-benzyl-3-(S)-(4-fluorophenyl)-2-morpholinone

Smjesa 1.95g (7.5mmol) N-benzil (S)-(4-fluorofenil)glicina, 3.09ml (22.5mmol) N,N-diizopropiletilamina, 6.50ml (75.0mmol) 1,2-dibromoetana i 40ml N,N-dimetilformamida miješa se na 100°C 20 sati (tijekom zagrijavanja otapaju se sve krute tvari). Reakciona smjesa se ohladi i koncentrira in vacuo. Dobiveni ostatak se razdijeli između 250ml etera i 100ml 0.5 otopine kalij hidrogen sulfata i slojevi se razdvoje. Organska faza se ispere sa 100ml zasićene vodene otopine natrij bikarbonata, 3 x 150ml vode, osuši nad magnezil sulfatom, i koncentrira in vacuo. Fleš kromatografija na 125g silikagela koristeći 3:1 v/v heksani/eter kao eluent daje 1.58g (74%) naslovnog spoja kao ulje. 1H NMR (400MHz, CDCI3)δ 2.65 (1H, dt, J=3.2, 12.8), 3.00 (1H, dt, J=12.8, 2.8), 3.16 (1H, d, J=13.6), 3.76 (1H, d, J=13.6), 4.24 (1H, s), 4.37 (1H, dt, J=13.2, 3.2), 4.54 (1H, dt, J=2.8, 13.2), 7.07-7.56 (9H, m). A mixture of 1.95g (7.5mmol) N-benzyl (S)-(4-fluorophenyl)glycine, 3.09ml (22.5mmol) N,N-diisopropylethylamine, 6.50ml (75.0mmol) 1,2-dibromoethane and 40ml N,N- of dimethylformamide is mixed at 100°C for 20 hours (during heating, all solids dissolve). The reaction mixture was cooled and concentrated in vacuo. The obtained residue is divided between 250 ml of ether and 100 ml of 0.5 potassium hydrogen sulfate solution and the layers are separated. The organic phase is washed with 100 ml of saturated aqueous sodium bicarbonate solution, 3 x 150 ml of water, dried over magnesium sulfate, and concentrated in vacuo. Flash chromatography on 125g silica gel using 3:1 v/v hexanes/ether as eluent afforded 1.58g (74%) of the title compound as an oil. 1H NMR (400MHz, CDCl3)δ 2.65 (1H, dt, J=3.2, 12.8), 3.00 (1H, dt, J=12.8, 2.8), 3.16 (1H, d, J=13.6), 3.76 (1H, d , J=13.6), 4.24 (1H, s), 4.37 (1H, dt, J=13.2, 3.2), 4.54 (1H, dt, J=2.8, 13.2), 7.07-7.56 (9H, m).

Opis 3 Description 3

4-benzil-2-(R)-(3,5-bis(trifluormetil)benzoiloksi)-3-(S)-(4-fluorofenil) morfolin 4-benzyl-2-(R)-(3,5-bis(trifluoromethyl)benzoyloxy)-3-(S)-(4-fluorophenyl)morpholine

Otopina 2.67g (10.0mmol) 4-benzil-3-(S)-(4-fluorofenil)-2-morfolinona (Opis 2) u 40ml bezvodnog THF ohladi se na -78°C. Hladna otopina se tretira s 12.5ml 1.0M otopine L-Selectrida(R) u THF, održavajući unutarnju temperaturu reakcije ispod -70°C. Dobivena otopina se hladno miješa 45 minuta i reakcija se dopuni s 3.60ml (20.0mmol) 3,5-bis(trifluorometil)benzoil klorida. Dobivena žuta smjesa se hladno miješa 30 minuta i reakcija se gasi sa 50ml zasićene vodene otopine natrijevog bikarbonata. Ugašena smjesa se razdijeli između 300ml etera i 50ml vode i slojevi se razdvoje. Organska faza se osuši iznad magnezij sulfata. Vodena faza se ekstrahira sa 300ml etera; ekstrakt se osuši i pomiješa s dobivenom organskom fazom. Pomiješane tvari se osuše in vacuo. Fleš kromatografija na 150g silikagela koristeći 37:3 v/v heksani/eter kao eluent daje 4.06g (80%) naslovnog spoja kao krutu tvar. 1H NMR (200MHz, CDCI3)δ 2.50 (1H, dt, J=3.4, 12.0), 2.97 (1H, app d, J=12.0), 2.99 (1H, d, J=13.6), 3.72-3.79 (1H, m), 3.82 (1H, d, J=2.6), 4.00 (1H, d, J=13.6), 4.20 (dt, J=2.4, 11.6), 6.22 (1H, d, J=2.6), 7.22-7.37 (7H, m), 7.57 (2H, app d, J=6.8), 8.07 (1H, s), 8.47 (2H, s). MS (FAB) m/z 528 (M+H, 25%), 270 (100%). Analiza: Računano za C26H20F7NO3: C, 59.21; H, 3.82; N, 2.66; F, 25.21. Nađeno: C, 59.06; H, 4.05; N, 2.50; F, 25.18. A solution of 2.67 g (10.0 mmol) of 4-benzyl-3-(S)-(4-fluorophenyl)-2-morpholino (Description 2) in 40 ml of anhydrous THF was cooled to -78°C. The cold solution is treated with 12.5ml of a 1.0M solution of L-Selectride(R) in THF, maintaining the internal temperature of the reaction below -70°C. The resulting solution was stirred cold for 45 minutes and the reaction was supplemented with 3.60 ml (20.0 mmol) of 3,5-bis(trifluoromethyl)benzoyl chloride. The resulting yellow mixture is stirred cold for 30 minutes and the reaction is quenched with 50 ml of saturated aqueous sodium bicarbonate solution. The quenched mixture is divided between 300 ml of ether and 50 ml of water and the layers are separated. The organic phase is dried over magnesium sulfate. The aqueous phase is extracted with 300 ml of ether; the extract is dried and mixed with the obtained organic phase. The mixed substances are dried in vacuo. Flash chromatography on 150g silica gel using 37:3 v/v hexanes/ether as eluent afforded 4.06g (80%) of the title compound as a solid. 1H NMR (200MHz, CDCl3)δ 2.50 (1H, dt, J=3.4, 12.0), 2.97 (1H, app d, J=12.0), 2.99 (1H, d, J=13.6), 3.72-3.79 (1H, m), 3.82 (1H, d, J=2.6), 4.00 (1H, d, J=13.6), 4.20 (dt, J=2.4, 11.6), 6.22 (1H, d, J=2.6), 7.22-7.37 (7H, m), 7.57 (2H, app d, J=6.8), 8.07 (1H, s), 8.47 (2H, s). MS (FAB) m/z 528 (M+H, 25%), 270 (100%). Analysis: Calcd for C26H20F7NO3: C, 59.21; H, 3.82; N, 2.66; F, 25.21. Found: C, 59.06; H, 4.05; N, 2.50; F, 25.18.

Opis 4 Description 4

4-benzil-2-(R)-(1-(3,5-bis(trifluormetil)fenil)eteniloksi)-3-(S)-(4-fluorofenil)morfolin 4-benzyl-2-(R)-(1-(3,5-bis(trifluoromethyl)phenyl)ethenyloxy)-3-(S)-(4-fluorophenyl)morpholine

Stupanj A: Dimetil titanocen Grade A: Dimethyl titanocene

Otopina 2.49g (l0.0mmol) titanocen diklorida u 50ml eteru u mraku na 0°C tretira se sa 17.5ml 1.4M otopine metillitija u eteru održavajući unutarnju temperaturu reakcije ispod 5°C. Dobivena žuto/narančasta smjesa se miješa na sobnoj temperaturi 30 minuta i reakcija gasi polaganim dodavanjem 25g leda. Ugašena reakciona smjesa razrijedi se sa 50ml etera i 25ml vode i faze se odvoje. Organski sloj se osuši na magnezij sulfatu i koncentrira in vacuo da bi se dobilo 2.03g (98%) naslovnog spoja kao kruta tvar osjetljiva na svjetlo. Dimetil titanocen može se čuvati kao otopina u toluenu na 0°C najmanje 2 tjedna bez vidljive kemijske degradacije. 1H NMR (200MHz, CDCI3) δ-0.15 (6H, s), 6.06 (10H, s). A solution of 2.49g (10.0mmol) of titanocene dichloride in 50ml of ether in the dark at 0°C is treated with 17.5ml of a 1.4M methyllithium solution in ether keeping the internal temperature of the reaction below 5°C. The resulting yellow/orange mixture is stirred at room temperature for 30 minutes and the reaction is quenched by slowly adding 25g of ice. The quenched reaction mixture is diluted with 50 ml of ether and 25 ml of water and the phases are separated. The organic layer was dried over magnesium sulfate and concentrated in vacuo to give 2.03g (98%) of the title compound as a light-sensitive solid. Dimethyl titanocene can be stored as a solution in toluene at 0°C for at least 2 weeks without visible chemical degradation. 1H NMR (200MHz, CDCl3) δ-0.15 (6H, s), 6.06 (10H, s).

Stupanj B: 4-benzil-2-(R)-(1-(3,5-bis(trifluormetil)feni)eteniloksi)-3-(S)-(4-fluorofenil)morfolin Grade B: 4-benzyl-2-(R)-(1-(3,5-bis(trifluoromethyl)phenyl)ethenyloxy)-3-(S)-(4-fluorophenyl)morpholine

Otopina spoja iz Opisa 3 (2.50g, 4.9mmol) i 2.50g (12.0mmol) dimetil titanocena (iz Stupnja A) u 35ml 1:1 v/v THF/toluenu miješa se u uljnoj kupki na 80°C 16 sati. Reakciona smjesa se ohladi i koncentrira in vacuo. Fleš kromatografija na 150g silikagelu koristeći 3:1 v/v heksani/metilen klorid kao eluent daje 1.71g (69%) naslovnog spoja kao krutu tvar. Analitički uzorak dobiven je rekristalizacijom iz izopropanola: 1H NMR (400MHz, CDCI3) δ-2.42 (1H, dt, J=3.6, 12.0), 2.90 (1H, app d, J=12.0), 2.91 (1H, d, J=13.6), 3.62-3.66 (1H, m), 3.72 (1H, d, J=2.6), 3.94 (1H, d, J=13.6), 4.09 (1H, dt, J=2.4, 12.0), 4.75 (1H, d, J=3.2), 4.82 (1H, d, J=3.2), 5,32 (1H, d, J=2.6), 7.09 (2H, t, J=8.8), 7.24-7.33 (5H, m), 7.58-7.62 (2H, m), 7.80 (1H, s), 7.90 (2H, s); MS (FAB) 526 (M+H, 75%), 270 (100%). Analiza: Računano za C22H22F7NO2: C, 61.72; H, 4.22; N, 2.67; F, 25.31. Nađeno: C, 61.79; H, 4.10; N, 2.65; F, 25.27%. A solution of the compound from Description 3 (2.50g, 4.9mmol) and 2.50g (12.0mmol) of dimethyl titanocene (from Step A) in 35ml of 1:1 v/v THF/toluene was stirred in an oil bath at 80°C for 16 hours. The reaction mixture was cooled and concentrated in vacuo. Flash chromatography on 150g silica gel using 3:1 v/v hexanes/methylene chloride as eluent afforded 1.71g (69%) of the title compound as a solid. The analytical sample was obtained by recrystallization from isopropanol: 1H NMR (400MHz, CDCl3) δ-2.42 (1H, dt, J=3.6, 12.0), 2.90 (1H, app d, J=12.0), 2.91 (1H, d, J= 13.6), 3.62-3.66 (1H, m), 3.72 (1H, d, J=2.6), 3.94 (1H, d, J=13.6), 4.09 (1H, dt, J=2.4, 12.0), 4.75 (1H , d, J=3.2), 4.82 (1H, d, J=3.2), 5.32 (1H, d, J=2.6), 7.09 (2H, t, J=8.8), 7.24-7.33 (5H, m ), 7.58-7.62 (2H, m), 7.80 (1H, s), 7.90 (2H, s); MS (FAB) 526 (M+H, 75%), 270 (100%). Analysis: Calcd for C22H22F7NO2: C, 61.72; H, 4.22; N, 2.67; F, 25.31. Found: C, 61.79; H, 4.10; N, 2.65; F, 25.27%.

Opis 5 Description 5

2-(R)-(1-(R)-(3,5-bisarifluormetil)fenil)etoksi)-3-(S)-(4-fluorofenil) morfolin 2-(R)-(1-(R)-(3,5-bisarifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)morpholine

Spoj iz Opisa 4 (4.0g) otopi se u etil acetatu (50ml) i izopropanolu (16ml). U tu otopinu doda se paladij na ugljenu (1.5g) i smjesa se hidrogenizira kod 40 psi 36 sati. Katalizator se odstrani filtracijom kroz Celit i otapala se odstrane in vacuo. Ostatak se pročisti fleš kromatografijom na siliciju koristeći 100%-tni etil acetat, zatim 1-10%-tni metanol u etil acetatu. To daje izomer A 500mg (15%) i izomer B 2.6g (80%) kao bistra ulja - izomer B stajanjem kristalizira. Za naslovni spoj: 1H NMR (400MHz, CDCI3) δ-1.16 (3H, d, J=6.8MHz), 1.80 (1H, br s), 3.13 (1H, dd, J=3.2, 12.4Hz), 3.23 (1H, dt, J=3.6, 12.4Hz), 3.63 (1H, dd, J=2.4, 11.2Hz), 4.01 (1H, d, J=2.4Hz), 4.13 (1H, dt, J=3.2, 12.0Hz), 4.42 (1H, d, J=2.4Hz), 4.19 (1H, q, J=6.8Hz), 7.04-7.09 (2H, m), 7.27-7.40 (4H, m), 7.73 (1H, s); MS (FAB) 438 (M+H, 75%), 180 (100%). The compound from Description 4 (4.0g) was dissolved in ethyl acetate (50ml) and isopropanol (16ml). Palladium on charcoal (1.5g) is added to this solution and the mixture is hydrogenated at 40 psi for 36 hours. The catalyst was removed by filtration through Celite and the solvents were removed in vacuo. The residue was purified by flash chromatography on silica using 100% ethyl acetate, then 1-10% methanol in ethyl acetate. This gives isomer A 500mg (15%) and isomer B 2.6g (80%) as clear oils - isomer B crystallizes on standing. For the title compound: 1H NMR (400MHz, CDCl3) δ-1.16 (3H, d, J=6.8MHz), 1.80 (1H, br s), 3.13 (1H, dd, J=3.2, 12.4Hz), 3.23 (1H , dt, J=3.6, 12.4Hz), 3.63 (1H, dd, J=2.4, 11.2Hz), 4.01 (1H, d, J=2.4Hz), 4.13 (1H, dt, J=3.2, 12.0Hz) , 4.42 (1H, d, J=2.4Hz), 4.19 (1H, q, J=6.8Hz), 7.04-7.09 (2H, m), 7.27-7.40 (4H, m), 7.73 (1H, s); MS (FAB) 438 (M+H, 75%), 180 (100%).

Stvaranje HCI soli. Otopini slobodne baze (0.77g) u dietil eteru (10ml) doda se 1M-HCI u metanolu (1.75ml). Otopina se evaporira do suhog i dodavanjm dietil etera stvaraju se kristali. Otopina se filtrira i ostatak se ispere s dietil eterom da bi se dobio naslovni spoj klorovodične soli t.t.248-250°C. Nađeno: C, 50.46; H, 3.85; N, 3.01; Cl, 7.31. Formation of HCI salt. To a solution of the free base (0.77g) in diethyl ether (10ml) was added 1M-HCl in methanol (1.75ml). The solution is evaporated to dryness and crystals are formed by adding diethyl ether. The solution was filtered and the residue washed with diethyl ether to give the title compound as the hydrochloride salt, m.p. 248-250°C. Found: C, 50.46; H, 3.85; N, 3.01; Cl, 7.31.

C20H18F7NO2.HCI zahtijeva: C, 50.70; H, 4.04; N, 2.96; Cl, 7.48%. C20H18F7NO2.HCl requires: C, 50.70; H, 4.04; N, 2.96; Cl, 7.48%.

Opis 6 Description 6

4-benzil-3-(S)-(4-fluorofenin-2-(R)-(3-fluoro-5-trifluormetil)benzoiloksi morfolin 4-benzyl-3-(S)-(4-fluorophenin-2-(R)-(3-fluoro-5-trifluoromethyl)benzoyloxy morpholine

Naslovni spoj je pripravljen reakcijom spoja iz Opisa 2 sa 3-fluoro-5-(trifluormetil)benzoil kloridom prema postupku opisanom u Opisu 3. 1H NMR (360MHz, CDCI3) δ 2.50 (1H, dt, J=3.3, 12.0), 2.96 (1H, d, J=12.0), 2.98 (1H, d, J=13.6), 3.75 (1H, dd, J=1.7, 11.5), 3.80 (1H, d, J=2.5), 3.92 (1H, d, J=13.6), 4.19 (1H, dt, J=2.1, 12.0), 6.20 (1H, d, J=2.5), 6.99 (2H, t, J=8.7), 7.2-7.37 (5H, m), 7.51-7.55 (3H, m), 7.89 (1H, d, J=8.4), 8.09 (1H, s). MS (Cl+) m/z 478 (M++1, 100%). Analiza: Računano za C25H20F5NO3:C, 62.88; H, 4.23; N, 2.93. Nađeno: C, 62.59; H, 4.03; N, 3.07%. The title compound was prepared by reacting the compound from Description 2 with 3-fluoro-5-(trifluoromethyl)benzoyl chloride according to the procedure described in Description 3. 1H NMR (360MHz, CDCl3) δ 2.50 (1H, dt, J=3.3, 12.0), 2.96 (1H, d, J=12.0), 2.98 (1H, d, J=13.6), 3.75 (1H, dd, J=1.7, 11.5), 3.80 (1H, d, J=2.5), 3.92 (1H, d , J=13.6), 4.19 (1H, dt, J=2.1, 12.0), 6.20 (1H, d, J=2.5), 6.99 (2H, t, J=8.7), 7.2-7.37 (5H, m), 7.51-7.55 (3H, m), 7.89 (1H, d, J=8.4), 8.09 (1H, s). MS (Cl+) m/z 478 (M++1, 100%). Analysis: Calculated for C25H20F5NO3:C, 62.88; H, 4.23; N, 2.93. Found: C, 62.59; H, 4.03; N, 3.07%.

Opis 7 Description 7

4-benzil-3-(S)-(4-fluorofenil)-2-(,R)-(1-(3-fluoro-5-trifluormetil) fenil)eteniloksi)morfolin 4-benzyl-3-(S)-(4-fluorophenyl)-2-(,R)-(1-(3-fluoro-5-trifluoromethyl)phenyl)ethenyloxy)morpholine

Naslovni spoj pripravljen je u 85% prinosa spoja iz Opisa 6 prema postupku opisanom u Opisu 4. 1H NMR (360MHz, CDCI3) δ 2.42 (1H, dt, J=3.6, 12.0), 2.90 (1H, d, J=12.0), 2.91 (1H, d, J=13.6), 3.60-3.62 (1H, m), 3.72 (1H, d, J=2.6), 3.92 (1H, d, J=13.6), 4.09 (1H, dt, J=2.4, 12.0), The title compound was prepared in 85% yield of the compound from Description 6 according to the procedure described in Description 4. 1H NMR (360MHz, CDCl3) δ 2.42 (1H, dt, J=3.6, 12.0), 2.90 (1H, d, J=12.0) , 2.91 (1H, d, J=13.6), 3.60-3.62 (1H, m), 3.72 (1H, d, J=2.6), 3.92 (1H, d, J=13.6), 4.09 (1H, dt, J =2.4, 12.0),

4.67 (1H, d, J=2.9), 4.76 (1H, d, J=2.9), 5.28 (1H, d, J=2.6), 7.07 (2H, t, J=8.7), 7.2-7.37 (7H, m), 7.53 (1H, s), 7.57-7.61 (2H, m). MS (Cl+) 476 (M+1, 100%). 4.67 (1H, d, J=2.9), 4.76 (1H, d, J=2.9), 5.28 (1H, d, J=2.6), 7.07 (2H, t, J=8.7), 7.2-7.37 (7H, m), 7.53 (1H, s), 7.57-7.61 (2H, m). MS (Cl+) 476 (M+1, 100%).

Opis 8 Description 8

3-(S)-(4-fluorofenil)-2-(R)-(1-(R)-(3-f1uoro-5-(trif1uormetil)fenil) etoks)morfolin 3-(S)-(4-fluorophenyl)-2-(R)-(1-(R)-(3-fluoro-5-(trifluoromethyl)phenyl)ethox)morpholine

Spoj iz Opisa 7 hidrogenizira se prema postupku navedenom u Opisu 5. Time se dobiva smjesa 2 epimerna proizvoda izomer A i izomer B (glavni proizvod) kao bistra ulja. Za naslovni spoj: 1H NMR (360MHz, CDCI3) δ 1.42 (3H, d, J=6.6Hz), 1.91 (1H, s), 3.11 (1H, dd, J=3.2, 12.4Hz), 3.22 (1H, dt, J=3.6, 12.4Hz), 3.58-3.62 (1H, m), 4.01 (1H, d, J=2.3Hz), 4.11 (1H, dt, J=3.2, 12.0Hz), 4.41 (1H, d, J=2.3Hz), 4.80 (1H, q, J=6.6Hz), 6.41 (1H, d, J=9.2Hz), 6.86 (1H, s), 7.02 (2H, t, J=8.7Hz), 7.08 (2H, d, J=9.2Hz), 7.21-7.26 (2H, m). MS (Cl+) m/z 387 (M+1, 100%). Analiza: Računano za: C19H18F5NO2: C, 58.91; H, 4.69; N, 3.62. Nađeno: C, 58.88; H, 4.81; N, 3.76%. The compound from Description 7 is hydrogenated according to the procedure specified in Description 5. This gives a mixture of 2 epimeric products, isomer A and isomer B (main product) as clear oils. For the title compound: 1H NMR (360MHz, CDCl3) δ 1.42 (3H, d, J=6.6Hz), 1.91 (1H, s), 3.11 (1H, dd, J=3.2, 12.4Hz), 3.22 (1H, dt , J=3.6, 12.4Hz), 3.58-3.62 (1H, m), 4.01 (1H, d, J=2.3Hz), 4.11 (1H, dt, J=3.2, 12.0Hz), 4.41 (1H, d, J=2.3Hz), 4.80 (1H, q, J=6.6Hz), 6.41 (1H, d, J=9.2Hz), 6.86 (1H, s), 7.02 (2H, t, J=8.7Hz), 7.08 (2H, d, J=9.2Hz), 7.21-7.26 (2H, m). MS (Cl+) m/z 387 (M+1, 100%). Analysis: Calcd for: C19H18F5NO2: C, 58.91; H, 4.69; N, 3.62. Found: C, 58.88; H, 4.81; N, 3.76%.

Opis 9 Description 9

2-(R)-(1-(R)-(3,5-bis(trifluormetil)fenil)etoksi)-3-(S)-(4-fluorofenin-4-(2,3-dihidro-2-okso-1,3-imidazol-4-il)metilmorfolin 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenin-4-(2,3-dihydro-2-oxo) -1,3-imidazol-4-yl)methylmorpholine

Smjesa spoja iz Opisa 5 (1g), N,N-diacetil-4-bromometil-2-imidazolinon (0.62g) (pripravljena prema postupku Dolan i Dushinsky JACS 1948, 70, 657) i kalijevog karbonata (0.63g) u 10ml dimetilformamida miješa se na sobnoj temperaturi 15 minuta. Reakciona smjesa se razrijedi etil acetatom (100ml) i ispere vodom i slanom otopinom. Etil acetatna faza se osuši (MgSO4) i evaporira in vacuo. Dobiveno ulje se otopi u etanolu (10ml), doda se 33% etanolni metilamin (1ml) i smjesa se miješa na sobnoj temperaturi 10 minuta. Smjesa se koncentrira in vacuo da bi se dobila kruta tvar. Rekristalizacijom iz etil acetata/metanola dobiva se naslovni spoj (0.63g), t.t. 192-194°C. 1H NMR (360MHz, DMSO-d6) δ 1.35 (3H, d, J=6.5HZ), 2.25 (1H, dt, J=8.7Hz), 2.60 (1H, d, J=13.8Hz), 2.89 (1H, d, J=11.6Hz), 3.28-3.36 (2H, m), 3.62 (1H, d, J=10.2Hz), 4.1 (1H, t, J=10.0), 4.31 (1H, d, J=2.7Hz), 4.92 (1H, q, J=6.5Hz), 5.97 (1H, s), 7.06 (2H, t, J=8.8Hz), 7.36 (2H, s), 7.65-7.85 (2H, m), 7.84 (1H, s), 9.58 (1H, s), 9.8(1H,s). A mixture of the compound from Description 5 (1g), N,N-diacetyl-4-bromomethyl-2-imidazolinone (0.62g) (prepared according to the procedure of Dolan and Dushinsky JACS 1948, 70, 657) and potassium carbonate (0.63g) in 10ml of dimethylformamide it is mixed at room temperature for 15 minutes. The reaction mixture was diluted with ethyl acetate (100 ml) and washed with water and brine. The ethyl acetate phase was dried (MgSO4) and evaporated in vacuo. The obtained oil is dissolved in ethanol (10ml), 33% ethanolic methylamine (1ml) is added and the mixture is stirred at room temperature for 10 minutes. The mixture is concentrated in vacuo to give a solid. Recrystallization from ethyl acetate/methanol gave the title compound (0.63g), m.p. 192-194°C. 1H NMR (360MHz, DMSO-d6) δ 1.35 (3H, d, J=6.5Hz), 2.25 (1H, dt, J=8.7Hz), 2.60 (1H, d, J=13.8Hz), 2.89 (1H, d, J=11.6Hz), 3.28-3.36 (2H, m), 3.62 (1H, d, J=10.2Hz), 4.1 (1H, t, J=10.0), 4.31 (1H, d, J=2.7Hz ), 4.92 (1H, q, J=6.5Hz), 5.97 (1H, s), 7.06 (2H, t, J=8.8Hz), 7.36 (2H, s), 7.65-7.85 (2H, m), 7.84 (1H, s), 9.58 (1H, s), 9.8(1H, s).

Opis 10 Description 10

3-(S)-(4-fluorofenil)-2-(R)-(1-(R)-(3-fluoro-5-(trifluormetil)fenil)etoksi)-4-(2.3-dihidro-2-okso-1,3-imidazol-4-il)metilmorfolin 3-(S)-(4-fluorophenyl)-2-(R)-(1-(R)-(3-fluoro-5-(trifluoromethyl)phenyl)ethoxy)-4-(2,3-dihydro-2-oxo -1,3-imidazol-4-yl)methylmorpholine

Naslovni spoj dobiven je iz spoja iz Opisa 8 rabeći postupak analogan onom iz Opisa 9. t.t.209-210°C. [α]D=+92.8 (c=1.0, metanol). 1H NMR (360MHz, DMSO-d6) δ 1.31 (3H, d, J=6.5Hz), 2.24 (1H, dt, J=3.0, 11.9Hz), 2.6 (1H, d, J=13.9Hz), 3.61 (1H, d, J=11.2Hz), 4.1 (1H, t, J=11.0Hz), 4.29 (1H, d, J=2.3Hz), 4.8 (1H, q, J=6.5Hz), 6.00 (1H, s), 6.55 (1H, d, J=9.3Hz), 6.94 (1H, s), 7.11 (2H, t, J=8.7Hz), 7.39 (1H, d, J=8.4Hz), 7.51 (2H, s), 9.59 (1H, s), 9.84 (1H, s). The title compound was obtained from the compound of Description 8 using a procedure analogous to that of Description 9. m.p. 209-210°C. [α]D=+92.8 (c=1.0, methanol). 1H NMR (360MHz, DMSO-d6) δ 1.31 (3H, d, J=6.5Hz), 2.24 (1H, dt, J=3.0, 11.9Hz), 2.6 (1H, d, J=13.9Hz), 3.61 ( 1H, d, J=11.2Hz), 4.1 (1H, t, J=11.0Hz), 4.29 (1H, d, J=2.3Hz), 4.8 (1H, q, J=6.5Hz), 6.00 (1H, s), 6.55 (1H, d, J=9.3Hz), 6.94 (1H, s), 7.11 (2H, t, J=8.7Hz), 7.39 (1H, d, J=8.4Hz), 7.51 (2H, s), 9.59 (1H, s), 9.84 (1H, s).

Opis 11 Description 11

2-(R)-(1-(R)-(3,5-bis(trifluorometil)fenil)etoksi)-3-(S)-(4-fluorofenil)-4-(1,2,4-triazol-3-il)metilmorfolin 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(1,2,4-triazol- 3-yl)methylmorpholine

Otopina spoja iz Opisa 5 (3.77g) i kalij karbonata (3.59g) u bezvodnom dimetilformamidu (7ml) miješa se na sobnoj temperaturi 10 minuta. U reakcionu smjesu se doda N-formil-2-kloroacetamidrazon (pripremljen prema I. Yanagisawa, J. Med. Chem. (1984), 27, 849) i reakciona smjesa se zagrijava na 60°C 1 sat. Zatim se temperatura povisi na 140°C kroz 2 sata. Smjesa se ohladi i razdijeli između etil acetata i vode i organske faze se isperu vodom, slanom otopinom, osuše (MgSO4) i evaporiraju da bi se dobilo smeđe ulje. Ostatak se pročisti kromatografijom na siliciju rabeći 1-5% metanol u diklormetanu. To je dalo proizvod kao bijelu pjenu (2.99g). 1H NMR (360MHz, DMSO) δ 8.25 (1H, s), 7.85 (1H, s), 7.50 (2H, t), 7.37 (2H, s), 7.11 (2H, t, J=9.0Hz), 4.93 (1H, q, J=6.6Hz), 4.32 (1H, d, J=2.8Hz), 4.09 (1H, dt, J=11.5HZ), 3.63 (1H, d, J=14.1Hz), 3.59 (1H, d, J=3.0Hz), 3.17 (1H, d, J=14.0Hz), 2.49 (1H, dt, J=15.7Hz), 1.36 (3H, d, J=6.6Hz). MS (Cl+) m/z 519. Analiza: Računano za C23H19F7N4O2: C, 53.29; H, 4.08; N, 10.81. Nađeno: C, 52.92; H, 3.94; N, 10.33. A solution of the compound from Description 5 (3.77g) and potassium carbonate (3.59g) in anhydrous dimethylformamide (7ml) was stirred at room temperature for 10 minutes. N-formyl-2-chloroacetamidrazone (prepared according to I. Yanagisawa, J. Med. Chem. (1984), 27, 849) was added to the reaction mixture and the reaction mixture was heated at 60°C for 1 hour. Then the temperature is raised to 140°C for 2 hours. The mixture was cooled and partitioned between ethyl acetate and water and the organic phases were washed with water, brine, dried (MgSO 4 ) and evaporated to give a brown oil. The residue was purified by chromatography on silica using 1-5% methanol in dichloromethane. This gave the product as a white foam (2.99g). 1H NMR (360MHz, DMSO) δ 8.25 (1H, s), 7.85 (1H, s), 7.50 (2H, t), 7.37 (2H, s), 7.11 (2H, t, J=9.0Hz), 4.93 ( 1H, q, J=6.6Hz), 4.32 (1H, d, J=2.8Hz), 4.09 (1H, dt, J=11.5Hz), 3.63 (1H, d, J=14.1Hz), 3.59 (1H, d, J=3.0Hz), 3.17 (1H, d, J=14.0Hz), 2.49 (1H, dt, J=15.7Hz), 1.36 (3H, d, J=6.6Hz). MS (Cl+) m/z 519. Analysis: Calcd for C23H19F7N4O2: C, 53.29; H, 4.08; N, 10.81. Found: C, 52.92; H, 3.94; N, 10.33.

Opis 12 Description 12

4-benzil-3-(SH4-f1uorofenil)-2-(RH3-(trifluormetil) benzoiloksi)morfolin 4-benzyl-3-(SH4-fluorophenyl)-2-(RH3-(trifluoromethyl)benzoyloxy)morpholine

Naslovni spoj je pripravljen reakcijom spoja iz Opisa 2 sa 3-(trifluormetil)benzoil kloridom prema postupku opisanom u Opisu 3. 1H NMR (360MHz, CDCI3) δ 2.48 (1H, dt, J=12.0, 3.5), 2.94 (1H, d, J=13.6), 3.73 (1H, app.d., J=11.4), 3.78 (1H, d, J=2.7), 3.91 (1H, d, J=13.6), 4.21 (1H, dt, J=11.7, 2.4), 6.20 (1H, d, J=2.8), 6.97 (2H, t, J=8.7), 7.25-7.37 (5H, m), 7.53 (2H, m), 7.61 (1H, t, J=7.8), 7.84 (1H, d, J=8.0), 8.21 (1H, d, J=7.8), 8.30 (1H, s). MS (Cl+) m/z460 (M+1, 100%). The title compound was prepared by reacting the compound from Description 2 with 3-(trifluoromethyl)benzoyl chloride according to the procedure described in Description 3. 1H NMR (360MHz, CDCl3) δ 2.48 (1H, dt, J=12.0, 3.5), 2.94 (1H, d , J=13.6), 3.73 (1H, app.d., J=11.4), 3.78 (1H, d, J=2.7), 3.91 (1H, d, J=13.6), 4.21 (1H, dt, J= 11.7, 2.4), 6.20 (1H, d, J=2.8), 6.97 (2H, t, J=8.7), 7.25-7.37 (5H, m), 7.53 (2H, m), 7.61 (1H, t, J =7.8), 7.84 (1H, d, J=8.0), 8.21 (1H, d, J=7.8), 8.30 (1H, s). MS (Cl+) m/z460 (M+1, 100%).

Opis 13 Description 13

4-benzil-3-(S)-(4-fluorofenil)-2-(R)-(1-3-(trifluormetil)fenil)eteniloksi)-morfolin 4-benzyl-3-(S)-(4-fluorophenyl)-2-(R)-(1-3-(trifluoromethyl)phenyl)ethenyloxy)-morpholine

Naslovni spoj pripremljen je iz spoja Opisa 12 prema postupku opisanom u Opisu 4. 1H NMR (360MHz, CDCI3) δ 2.40 (1H, dt, J=11.9, 3.6Hz), 2.87 (1H, app.d, J=11.8Hz), 2.89 (1H, d, J=13.5Hz), 3.62 (1H, app.d, J=11.5Hz), 3.70 (1H, d, J=2.7Hz), 3.91 (1H, d, J=13.5Hz), 4.12 (1H, dt, J=11.7, 2.4Hz), 4.62 (1H, d, J=2.7Hz), 4.74 (1H, d, J=2.7Hz), 5.30 (1H, d, J=2.7Hz), 7.07 (2H, t, J=8.7Hz), 7.21-7.32 (5H, m), 7.40 (1H, t, J=7.8Hz), 7.53-7.63 (4H, m), 7.74 (1H, s). MS (Cl+) m/z 458 (M+1, 100%). The title compound was prepared from the compound of Description 12 according to the procedure described in Description 4. 1H NMR (360MHz, CDCl3) δ 2.40 (1H, dt, J=11.9, 3.6Hz), 2.87 (1H, app.d, J=11.8Hz) , 2.89 (1H, d, J=13.5Hz), 3.62 (1H, app.d, J=11.5Hz), 3.70 (1H, d, J=2.7Hz), 3.91 (1H, d, J=13.5Hz) , 4.12 (1H, dt, J=11.7, 2.4Hz), 4.62 (1H, d, J=2.7Hz), 4.74 (1H, d, J=2.7Hz), 5.30 (1H, d, J=2.7Hz) , 7.07 (2H, t, J=8.7Hz), 7.21-7.32 (5H, m), 7.40 (1H, t, J=7.8Hz), 7.53-7.63 (4H, m), 7.74 (1H, s). MS (Cl+) m/z 458 (M+1, 100%).

Opis 14 Description 14

3-(S)-(4-fluorofenil)-2-(R)-(1-(R)-(3-(trifluormetil)fenil)etoksi)-morfolin 3-(S)-(4-fluorophenyl)-2-(R)-(1-(R)-(3-(trifluoromethyl)phenyl)ethoxy)-morpholine

Spoj iz opisa 13 hidrogenizira se prema postupku opisanom u Opisu 5. Time se dobiva smjesa 2 epimerna proizvoda izomera A i izomera B u otprilike sličnoj količini kao žuta ulja. Naslovni spoj (izomer B): 1H NMR (360MHz, CDCI3) δ 1.43 (3H, d, J=6.6), 3.11 (1H, dd, J=12.6, 2.9), 3.22 (1H, dt, J=12.4, 3.7), 3.60 (1H, dd, J=11.1, 2.8), 3.99 (1H, d, J=2.2), 4.13 (1H, dt, J=11.6, 3.2), 4.42 (1H, d, J=2.2), 4.81 (1H, q, J=6.6), 6.84 (1H, d, J=7.8), 6.96-7.03 (3H, m), 7.16-7.27 (3H, m), 7.38 (1H, d, J=7.5). MS (Cl+) m/z 370 (M+1, 100%). Analiza: Računano za: C19H19F4NO2: C, 61.77; H, 5.20; N, 3.79. Nađeno: C, 61.60; H, 5.16; N, 3.95%. The compound from description 13 is hydrogenated according to the procedure described in description 5. This gives a mixture of 2 epimeric products of isomer A and isomer B in approximately the same amount as the yellow oil. Title compound (isomer B): 1H NMR (360MHz, CDCl3) δ 1.43 (3H, d, J=6.6), 3.11 (1H, dd, J=12.6, 2.9), 3.22 (1H, dt, J=12.4, 3.7 ), 3.60 (1H, dd, J=11.1, 2.8), 3.99 (1H, d, J=2.2), 4.13 (1H, dt, J=11.6, 3.2), 4.42 (1H, d, J=2.2), 4.81 (1H, q, J=6.6), 6.84 (1H, d, J=7.8), 6.96-7.03 (3H, m), 7.16-7.27 (3H, m), 7.38 (1H, d, J=7.5) . MS (Cl+) m/z 370 (M+1, 100%). Analysis: Calcd for: C19H19F4NO2: C, 61.77; H, 5.20; N, 3.79. Found: C, 61.60; H, 5.16; N, 3.95%.

Opis 15 Description 15

4-benzil-3-(S)-fenil-2-morfolinon 4-benzyl-3-(S)-phenyl-2-morpholinone

Stupanj A: N-benzil-(S)-fenilglicin Grade A: N-benzyl-(S)-phenylglycine

Otopina 1.5g (10.0mmol) (S)-fenilglicina u 5ml 2N vodene otopine natrijevog hidroksida tretira se sa 1.0ml (10.0mmol) benzaldehida i miješa na sobnoj temperaturi 20 minuta. Otopina se razrijedi sa 5ml metanola, ohladi na 0°C, i pažljivo tretira sa 200mg (5.3mmol) natrij borhidrida. Rashladna kupka se odstrani i reakciona smjesa miješa na sobnoj temperaturi 1.5 sat. Reakcija se razrijedi sa 20ml vode i ekstrahira sa 2 x 25ml metilen klorida. Vodeni sloj se zakiseli sa koncentriranom klorovodičnom kiselinom do pH 6, a istaložena krutina se filtrira, ispere sa 50ml vode, 50ml 1:1 v/v metanol/etil eterom i 50ml etera, i osuši da bi se dobilo 1.83g (76%) proizvoda, t.t. 230-232°C. Analiza: Računano za: C15H15NO2: C, 74.66; H, 6.27; N, 5.81. Nađeno: C, 74.17; H. 6.19; N, 5.86. A solution of 1.5 g (10.0 mmol) of (S)-phenylglycine in 5 ml of 2N aqueous sodium hydroxide solution is treated with 1.0 ml (10.0 mmol) of benzaldehyde and stirred at room temperature for 20 minutes. The solution is diluted with 5 ml of methanol, cooled to 0°C, and carefully treated with 200 mg (5.3 mmol) of sodium borohydride. The cooling bath is removed and the reaction mixture is stirred at room temperature for 1.5 hours. The reaction is diluted with 20 ml of water and extracted with 2 x 25 ml of methylene chloride. The aqueous layer was acidified with concentrated hydrochloric acid to pH 6, and the precipitated solid was filtered, washed with 50ml water, 50ml 1:1 v/v methanol/ethyl ether and 50ml ether, and dried to give 1.83g (76%) product, m.p. 230-232°C. Analysis: Calcd for: C15H15NO2: C, 74.66; H, 6.27; N, 5.81. Found: C, 74.17; H. 6.19; N, 5.86.

Stupanj B: 4-benzil-3-(S)-fenil-2-morfolinon Step B: 4-benzyl-3-(S)-phenyl-2-morpholinone

Smjesa 4.00g (16.6mmol) N-benzil-(S)-fenilglicina (iz Stupnja A) 5.00g (36.0mmol) kalij karbonata, 10.0ml 1,2-dibromoetana i 25ml N,N-dimetilformamida miješa se na 100°C 20 sati. Smjesa se ohladi i razdijeli između 200ml etil etera i 100ml vode. Slojevi se razdvoje i organska faza se ispere sa 3 x 50ml vode, osuši nad magnezij sulfatom i koncentrira in vacuo. Ostatak se pročisti fleš kromatografijom na 125g slikagela elucijom sa 9:1 v/v, zatim 4:1 heksani/etil eter da bi se dobilo 2.41 g (54%) proizvoda kao krute tvari, t.t. 98-100°C. 1H NMR (250MHz, CDCI3) δ 2.54-2.68 (1H, m), 2.96 (1H, dt, J=12.8, 2.8), 3.14 (1H, d, J=13.3), 3.75 (1H, d, J=13.3), 4.23 (1H, s), 4.29-4.37 (1H, m), 4.53 (dt, J=3.2, 11.0), 7.20-7.56 (10H, m). MS (FAB): m/z 268 (M+H; 100%). Analiza: Računano za C17H17NO2: C, 76.38; H, 6.41; N, 5.24. Nađeno: C, 76.06; H, 6.40; N, 5.78. A mixture of 4.00g (16.6mmol) N-benzyl-(S)-phenylglycine (from Stage A), 5.00g (36.0mmol) potassium carbonate, 10.0ml 1,2-dibromoethane and 25ml N,N-dimethylformamide is mixed at 100°C. 20 hours. The mixture is cooled and partitioned between 200 ml of ethyl ether and 100 ml of water. The layers are separated and the organic phase is washed with 3 x 50 ml of water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on 125g slica gel eluting with 9:1 v/v, then 4:1 hexanes/ethyl ether to give 2.41 g (54%) of product as a solid, m.p. 98-100°C. 1H NMR (250MHz, CDCl3) δ 2.54-2.68 (1H, m), 2.96 (1H, dt, J=12.8, 2.8), 3.14 (1H, d, J=13.3), 3.75 (1H, d, J=13.3) ), 4.23 (1H, s), 4.29-4.37 (1H, m), 4.53 (dt, J=3.2, 11.0), 7.20-7.56 (10H, m). MS (FAB): m/z 268 (M+H; 100%). Analysis: Calcd for C17H17NO2: C, 76.38; H, 6.41; N, 5.24. Found: C, 76.06; H, 6.40; N, 5.78.

Opis 16 Description 16

4-benzil-2-(R)-(3,5-bis(trifluormetil)benzioiloksi)-3-(S)-fenilmorfolin 4-benzyl-2-(R)-(3,5-bis(trifluoromethyl)benzoyloxy)-3-(S)-phenylmorpholine

Otopina 2.67g (10.0mmol) spoja iz Opisa 15 u 14 ml bezvodnog THF ohladi se na -78°C. Hladna otopina se tretira sa 12.5ml 1.0L L-Selectrida(R) u THF, održavajući unutarnju temperatruru reakcije ispod -70°C. Dobivena otopina se hladno miješa 45 minuta i reakcija se dopuni sa 3.60ml (20.0mmol) 3,5-bis(trifluormetil)benzoil klorida. Dobivena žuta smjesa se hladno miješa 30 minuta i reakcija se gasi sa 50ml zasićene vodene otopine natrij bikarbonata. Ugašena smjesa se razdijeli između 300ml etera i 50 ml vode i slojevi se razdvoje. Organska faza se osuši iznad magnezij sulfata. Vodena faza se ekstrahira sa 300ml etera; ekstrakt se osuši i pomiješa sa dobivenim organskim slojem. Pomiješane organske tvari se koncentriraju in vacuo. Fleš kromatografijom na 150g silikagela rabeći 37:7 v/v heksani/eter kao eluent dobiva se 4.06g (80%) naslovnog spoja kao krute tvari. 1H NMR (200MHz ppm, CDCI3) δ 2.50 (1H, dt, J=3.4, 12.0), 2.97 (1H, app d, J=12.0), 2.99 (1H, d, J=13.6), 3.72-3.79 (1H, m), 3.82 (1H, d, J=2.6), 4.00 (1H, d, J=13.6), 4.20 (dt, J=2.4, 11.6), 6.22 (1H, d, J=2.6), 7.22-7.37 (7H, m), 7.57 (2H, app d, J=6.8), 8.07 (1H, s), 8.47 (2H, s). Analiza: Računano za C26H26F6NO3: C, 61.29; H, 4.16; N, 2.75; F, 22.38. Nađeno: C, 61.18; H, 4.14; N, 2.70; F, 22.13. A solution of 2.67 g (10.0 mmol) of the compound from Description 15 in 14 ml of anhydrous THF was cooled to -78°C. The cold solution is treated with 12.5ml of 1.0L L-Selectrid(R) in THF, maintaining the internal reaction temperature below -70°C. The resulting solution was stirred cold for 45 minutes and the reaction was supplemented with 3.60 ml (20.0 mmol) of 3,5-bis(trifluoromethyl)benzoyl chloride. The resulting yellow mixture is stirred cold for 30 minutes and the reaction is quenched with 50 ml of saturated aqueous sodium bicarbonate solution. The quenched mixture is divided between 300 ml of ether and 50 ml of water and the layers are separated. The organic phase is dried over magnesium sulfate. The aqueous phase is extracted with 300 ml of ether; the extract is dried and mixed with the obtained organic layer. The mixed organics are concentrated in vacuo. Flash chromatography on 150g of silica gel using 37:7 v/v hexanes/ether as eluent afforded 4.06g (80%) of the title compound as a solid. 1H NMR (200MHz ppm, CDCl3) δ 2.50 (1H, dt, J=3.4, 12.0), 2.97 (1H, app d, J=12.0), 2.99 (1H, d, J=13.6), 3.72-3.79 (1H , m), 3.82 (1H, d, J=2.6), 4.00 (1H, d, J=13.6), 4.20 (dt, J=2.4, 11.6), 6.22 (1H, d, J=2.6), 7.22- 7.37 (7H, m), 7.57 (2H, app d, J=6.8), 8.07 (1H, s), 8.47 (2H, s). Analysis: Calcd for C26H26F6NO3: C, 61.29; H, 4.16; N, 2.75; F, 22.38. Found: C, 61.18; H, 4.14; N, 2.70; F, 22.13.

Opis 17 Description 17

4-benzil-2-(R)-(1-(3,5-bis(trifluormetil)fenil)eteniloksi)-3-(S)-fenilmorfolin 4-benzyl-2-(R)-(1-(3,5-bis(trifluoromethyl)phenyl)ethenyloxy)-3-(S)-phenylmorpholine

Otopina 2.50g (4.9mmol) spoja iz Opisa 16 i 2.50g (12.0mmol) dimetil titanocena (Opis 4a), u 35ml 1:1 v/v THF/toluen miješa se u uljnoj kupki na 80°C 16 sati. Reakciona smjesa se ohladi i koncentrira in vacuo. Fleš kromatografijom na 150g silikagela rabeći 3:1 v/v haksani/metilen klorid kao eluent dobiva se 1.71g (69%) naslovnog spoja kao kruta tvar. 1H NMR (400MHz, CDCI3) δ 2.42 (1H, dt, J=3.6, 12.0), 2.89 (app d, J=11.6), 2.92 (1H, d, J=13.6), 3.61-3.66 (1H, m), 3.37 (1H, d, J=2.8), 4.00 (1H, d, J=13.6), 4.09 (1H, dt, J=2.4, 11.6), 4.75 (1H, d, J=2.8), 4.79 (1H, d, J=2.8), 5.36 (1H, d, J=2.4), 7.23-7.41 (7H, m), 7.63 (1H, app d, J=7.2), 7.79 (1H, s), 7.91 (2H, s). MS (FAB) m/z 508 (M+1, 25%). Analiza: Računano za: C27H23F6NO2: C, 63.90; H, 4.57; N, 2.76; F, 22.46. Nađeno: C, 63.71; H, 4.53; N, 2.68; F, 22.66. A solution of 2.50 g (4.9 mmol) of the compound from Description 16 and 2.50 g (12.0 mmol) of dimethyl titanocene (Description 4a) in 35 ml of 1:1 v/v THF/toluene was mixed in an oil bath at 80°C for 16 hours. The reaction mixture was cooled and concentrated in vacuo. Flash chromatography on 150g of silica gel using 3:1 v/v hexanes/methylene chloride as eluent gave 1.71g (69%) of the title compound as a solid. 1H NMR (400MHz, CDCl3) δ 2.42 (1H, dt, J=3.6, 12.0), 2.89 (app d, J=11.6), 2.92 (1H, d, J=13.6), 3.61-3.66 (1H, m) , 3.37 (1H, d, J=2.8), 4.00 (1H, d, J=13.6), 4.09 (1H, dt, J=2.4, 11.6), 4.75 (1H, d, J=2.8), 4.79 (1H , d, J=2.8), 5.36 (1H, d, J=2.4), 7.23-7.41 (7H, m), 7.63 (1H, app d, J=7.2), 7.79 (1H, s), 7.91 (2H , with). MS (FAB) m/z 508 (M+1, 25%). Analysis: Calcd for: C27H23F6NO2: C, 63.90; H, 4.57; N, 2.76; F, 22.46. Found: C, 63.71; H, 4.53; N, 2.68; F, 22.66.

Opis 18 Description 18

2-(R)-(1-(S)-(3,5-bis(trifluorometil)fenil)etoksi)-3-(S)-fenilmorfolin 2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-phenylmorpholine

Smjesa spoja iz Opisa 17 (1.5g) i 10% paladij na ugljiku katalizatora (750mg) u smjesi izopropanol/etil acetata (25ml, 3.2 v/v) miješa se pod atmosferom vodika 48 sati. Katalizator se odstrani flitracijom kroz Celit i reakciona posuda i filter tkanina se isperu sa etil acetatom (500ml). Filtrat se koncentrira in vacuo, fleš kromatografijom dobivaju se epimer A (106mg) i epimer B (899mg) kao prozirna ulja. Naslovni spoj, epimer B ima slijedeću analizu: A mixture of the compound from Description 17 (1.5g) and 10% palladium on carbon catalyst (750mg) in a mixture of isopropanol/ethyl acetate (25ml, 3.2 v/v) was stirred under a hydrogen atmosphere for 48 hours. The catalyst was removed by filtration through Celite and the reaction vessel and filter cloth were washed with ethyl acetate (500ml). The filtrate is concentrated in vacuo, flash chromatography gives epimer A (106 mg) and epimer B (899 mg) as transparent oils. The title compound, epimer B has the following analysis:

1H NMR (CDCI3 , 400MHz) δ l.46 (3H, d, J=6.8Hz), 1.92 (1H, brs), 3.13 (1H, dd, J=3.0, 12.6Hz), 3.24 (1H, dt, J=3.6, 12.6Hz), 3.62 (1H, dd, J=3.6, 11.2Hz), 4.04 (1H, d, J=2.4Hz), 4.14 (1H, dt, J=3.0, 11.2Hz), 4.48 (1H, d, J=2.4Hz), 4.90 (1H, q, J=6.8Hz), 7.21-7.32 (7H, m), 7.64 (1H, s). MS (Cl+) m/z 420 (M++1, 20%), 178 (100%). Analiza: Računano za C20H19F6NO2: C, 57.28; H, 4.57; N, 3.34; F, 27.18. Nađeno: C, 57,41; H, 4.61; N, 3.29; F, 27.23. 1H NMR (CDCl3 , 400MHz) δ 1.46 (3H, d, J=6.8Hz), 1.92 (1H, brs), 3.13 (1H, dd, J=3.0, 12.6Hz), 3.24 (1H, dt, J =3.6, 12.6Hz), 3.62 (1H, dd, J=3.6, 11.2Hz), 4.04 (1H, d, J=2.4Hz), 4.14 (1H, dt, J=3.0, 11.2Hz), 4.48 (1H , d, J=2.4Hz), 4.90 (1H, q, J=6.8Hz), 7.21-7.32 (7H, m), 7.64 (1H, s). MS (Cl+) m/z 420 (M++1, 20%), 178 (100%). Analysis: Calcd for C20H19F6NO2: C, 57.28; H, 4.57; N, 3.34; F, 27.18. Found: C, 57.41; H, 4.61; N, 3.29; F, 27.23.

Opis 19 Description 19

2-(R)-1-(R)-(3,5-bis(trifluorometil)fenil)etoksi)-3-(S)-fenil-4-(1,2,4-triazol-3-il)metilmorfolin 2-(R)-1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-phenyl-4-(1,2,4-triazol-3-yl)methylmorpholine

Ovaj spoj pripravljen je iz spoja iz Opisa 18 slijedeći postupak naveden u Opisu 11. MS (Cl+) m/z 501 (M++1, 100%). This compound was prepared from the compound of Description 18 following the procedure of Description 11. MS (Cl+) m/z 501 (M++1, 100%).

Opis 280 Description 280

4-benzil-2-(R)-1-(S)-(3.5-bis(trifluorometil)fenil)-2-hidroksietoksi)-3-(S)-(4-fluorofenil)morfolin 4-benzyl-2-(R)-1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)morpholine

Spoj iz Opisa 4 (12.8g) otopi se u tetrahidrofuranu (50ml) i smjesa se ohladi na ledu. Bor (49ml od 1.0M u tetrahidrofuranu) doda se kapanjem i reakciona sjesa se miješa na sobnoj temperaturi 3 sata. Otopina se ohladi u ledu i kapanjem se oprezno dodaju natrij hidroksid (120ml, 1M) i vodikov peroksid (36ml, 30 tež%). Dobivena smjesa se miješa 1 sat, zatim razriijedi s vodom (200ml) i ekstrahira etil acetatom (3 x 50ml). Organski ekstrakti se isperu natrijevim sulfitom i zatim slanom otopinom. Organska faza se osuši (MgSO4) i evaporira da bi se dobilo bisto ulje. TLC (50:50 etil acetat/heksan) pokazuje dva glavna produkta koja se separiraju fleš kromatografijom na silikagelu koristeći postupno eluiranje sa 1-30% etil acetatom u heksanu. Minorni spoj se eluira prvi (2.3g), a glavni posljednji (8g). Glavni proizvod se izolira kao bijela pjena. 1H NMR (360MHz, DMSO-d6) δ 2.23-2.29 (1H, m), 2.73 (1H, d), 2.80 (1H, d, J=13.0Hz), 3.48 (1H, d, J=3.5Hz), 3.45-3.52 (2H, m), 3.56-3.65 (2H, m), 4.00-4.06 (1H, m), 4.37 (1H, d, J=3.0Hz), 4.81 (1H, t, J=6.0Hz), 4.92 (1H, t, J=5.5Hz), 7.14 (2H, t, J=9.0Hz), 7.23-7.33 (5H, m), 7.35 (2H, s, ArH), 7.57 (2H, t, ArH), 7.85 (1H, s, ArH). MS (Cl+) m/z 544 (M++1, 100%). The compound from Description 4 (12.8g) was dissolved in tetrahydrofuran (50ml) and the mixture was cooled on ice. Boron (49ml of 1.0M in tetrahydrofuran) was added dropwise and the reaction mixture was stirred at room temperature for 3 hours. The solution is cooled in ice and sodium hydroxide (120ml, 1M) and hydrogen peroxide (36ml, 30% by weight) are cautiously added dropwise. The resulting mixture is stirred for 1 hour, then diluted with water (200ml) and extracted with ethyl acetate (3 x 50ml). The organic extracts are washed with sodium sulfite and then with saline. The organic phase was dried (MgSO4) and evaporated to give a clear oil. TLC (50:50 ethyl acetate/hexane) shows two major products which are separated by flash chromatography on silica gel using stepwise elution with 1-30% ethyl acetate in hexane. The minor compound is eluted first (2.3g), and the major compound is eluted last (8g). The main product is isolated as a white foam. 1H NMR (360MHz, DMSO-d6) δ 2.23-2.29 (1H, m), 2.73 (1H, d), 2.80 (1H, d, J=13.0Hz), 3.48 (1H, d, J=3.5Hz), 3.45-3.52 (2H, m), 3.56-3.65 (2H, m), 4.00-4.06 (1H, m), 4.37 (1H, d, J=3.0Hz), 4.81 (1H, t, J=6.0Hz) , 4.92 (1H, t, J=5.5Hz), 7.14 (2H, t, J=9.0Hz), 7.23-7.33 (5H, m), 7.35 (2H, s, ArH), 7.57 (2H, t, ArH ), 7.85 (1H, s, ArH). MS (Cl+) m/z 544 (M++1, 100%).

Opis 21 Description 21

2-(R)-(1-(S)-3.5-bis(trifluorometil)fenil)-2-hidroksietoksi)-3-(S)-(4-fluorofenil)morfolin 2-(R)-(1-(S)-3.5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)morpholine

Spoj iz Opisa 20 (8g) otopi se u etil acetatu (100ml) i u otopinu se dodaju izopropanol (50ml) i paladij na ugljenu (1.5g). Takva otopina se hidrogenizira kod 40 psi preko noći. Katalizator se odstrani filtracijom i otapala se odstrane in vacuo. Ostatak se pročisti fleš kromatografijom na siliciju koristeći 1-10% metanol u diklorometanu kao eluent. Time se dobiva proizvod kao bijeli prah (5.7g, 90%). 1H NMR (360MHz, CDCI3) δ 2.68-2.73 (1H, m), 3.03-3.15 (1H, m), 3.43-3.65 (3H, m), 3.95 (1H, d, J=3.0Hz), 4.12-4.22 (1H, m), 4.40 (1H, d, J=3.0Hz), 4.89 (1H, t, J=7.0Hz), 6.99 (t, J=9.0Hz, ArH), 7.15 (2H, s, ArH), 7.26-7.31 (1H, m, ArH), 7.62 (1H, s, ArH). MS (Cl+) m/z 454 (M++1, 100%). The compound from Description 20 (8g) is dissolved in ethyl acetate (100ml) and isopropanol (50ml) and palladium on charcoal (1.5g) are added to the solution. Such a solution is hydrogenated at 40 psi overnight. The catalyst was removed by filtration and the solvent was removed in vacuo. The residue was purified by flash chromatography on silica using 1-10% methanol in dichloromethane as eluent. This gives the product as a white powder (5.7g, 90%). 1H NMR (360MHz, CDCl3) δ 2.68-2.73 (1H, m), 3.03-3.15 (1H, m), 3.43-3.65 (3H, m), 3.95 (1H, d, J=3.0Hz), 4.12-4.22 (1H, m), 4.40 (1H, d, J=3.0Hz), 4.89 (1H, t, J=7.0Hz), 6.99 (t, J=9.0Hz, ArH), 7.15 (2H, s, ArH) , 7.26-7.31 (1H, m, ArH), 7.62 (1H, s, ArH). MS (Cl+) m/z 454 (M++1, 100%).

Opis 22 Description 22

3-(S)-(4-fluorofenil)-2-(R)-(1-(S)-(3-fluoro-5-(trifluormetil)fenil-2-hidroksietoksi)morfolin 3-(S)-(4-fluorophenyl)-2-(R)-(1-(S)-(3-fluoro-5-(trifluoromethyl)phenyl-2-hydroxyethoxy)morpholine

Stupanj A: 4-benzil-3-(S)-4-fluorofeniu-2-(R)-(1-(S)-(3-fluoro-5-(trifluorometil)fenil)-2-hidroksietoksi)morfolin Grade A: 4-benzyl-3-(S)-4-fluorophenyl-2-(R)-(1-(S)-(3-fluoro-5-(trifluoromethyl)phenyl)-2-hydroxyethoxy)morpholine

Spoj iz Opisa 7 (0.8g) otopi se u tetrahidrofuranu (5ml) na sobnoj temperaturi, i doda se bor (5ml, 1.0M u tetrahidrofuranu). Otopina se miješa pod dušikom 30 minuta, dok sav polazni materijal ne reagira. Vodikov peroksid (5ml, 29% aq.) i natrijev hidroksid (10ml, 4N) dodaju se kapanjem u ohlađenu (0°C) otopinu uz mnogo pjenušanja. Dobivena smjesa se ekstrahira s etil acetatom, organske faze se isperu sa natrij bisulfitom i slanom otopinom, osuše (MgSO4) i evaporiraju da bi se dobilo bezbojno ulje (1g). Ovaj materijal nije daljne pročišćavan, nego je reagirao kako je opisano u slijedećem stupnju. The compound from Description 7 (0.8g) was dissolved in tetrahydrofuran (5ml) at room temperature, and boron (5ml, 1.0M in tetrahydrofuran) was added. The solution is stirred under nitrogen for 30 minutes, until all the starting material reacts. Hydrogen peroxide (5ml, 29% aq.) and sodium hydroxide (10ml, 4N) were added dropwise to the cooled (0°C) solution with much bubbling. The resulting mixture was extracted with ethyl acetate, the organic phases were washed with sodium bisulfite and brine, dried (MgSO4) and evaporated to give a colorless oil (1g). This material was not further purified, but reacted as described in the next step.

Stupanj B: 3-(S)-(4-fluorofenil)-2-(R)-(1-(S)-(3-fluoro-5-trifluormetil) fenil)-2-hidroksietoksi)morfolin Grade B: 3-(S)-(4-fluorophenyl)-2-(R)-(1-(S)-(3-fluoro-5-trifluoromethyl)phenyl)-2-hydroxyethoxy)morpholine

Gornji spoj (a) (1g) otopljen je u etil acetatu/2-propanolu (20ml, 3:1) i tretiran sa Pd na ugljiku (100mg). Smjesa se hidrogenizira na 60 psi 12 sati. Katalizator se odstrani filtracijom i otapalo se odstrani in vacuo. Ostatak se pročisti kromatografijom srednjeg tlaka na siliciju (Lobar) koristeći 5% metanol u diklormetanu kao eluent. Proizvod se rekristalizira iz etera. 1H NMR (360MHz, DMSO-d6) δ 2.77-3.04 (3H, m), 3.36-3.51 (2H, m), 3.93 (1H, br s), 4.05-4.13 (1H, m), 4.36 (1H, d, J=2.0Hz), 4.72 (1H, t, J=5.0Hz), 4.98 (1H, t, J=7.0Hz), 6.66 (1H, d, J=9.2Hz), 6.89 (1H, s), 7.10 (2H, t, J=9.0Hz), 7.33-7.37 (2H, m), 7.41 (1H, d, J=9.0Hz); MS (Cl+) m/z 404 (M++1, 100). The above compound (a) (1g) was dissolved in ethyl acetate/2-propanol (20ml, 3:1) and treated with Pd on carbon (100mg). The mixture is hydrogenated at 60 psi for 12 hours. The catalyst was removed by filtration and the solvent was removed in vacuo. The residue was purified by medium pressure chromatography on silica (Lobar) using 5% methanol in dichloromethane as eluent. The product is recrystallized from ether. 1H NMR (360MHz, DMSO-d6) δ 2.77-3.04 (3H, m), 3.36-3.51 (2H, m), 3.93 (1H, br s), 4.05-4.13 (1H, m), 4.36 (1H, d , J=2.0Hz), 4.72 (1H, t, J=5.0Hz), 4.98 (1H, t, J=7.0Hz), 6.66 (1H, d, J=9.2Hz), 6.89 (1H, s), 7.10 (2H, t, J=9.0Hz), 7.33-7.37 (2H, m), 7.41 (1H, d, J=9.0Hz); MS (Cl+) m/z 404 (M++1, 100).

Opis 23 Description 23

N-karbometoksi-2-kloroacetamidrazon (CICH2C(=NH)NHNHCOOCH3) N-carbomethoxy-2-chloroacetamidrazone (CICH2C(=NH)NHNHCOOCH3)

Natrijev metoksid (20ml, 1M) dodan je otopini kloroacetonitrila (54.1g) u bezvodnom metanolu (100ml) na 0°C. Smjesa se miješa na sobnoj temperaturi 30 minuta i zatim neutralizira s octenom kiselinom (1.2ml). Metil hidrazinkarboksilat (64.5g, predestiliran in vacuo) otopljen je u toplom dimetilformamidu (35ml) i metanol (300ml) je dodan reakcionoj smjesi na 0°C. Smjesa se miješa 30 minuta i formirana kristalna kruta tvar se odstrani flitracijom i ispere etil acetatom da bi se dobio naslovni spoj: t.t. 138-140°C. Sodium methoxide (20ml, 1M) was added to a solution of chloroacetonitrile (54.1g) in anhydrous methanol (100ml) at 0°C. The mixture is stirred at room temperature for 30 minutes and then neutralized with acetic acid (1.2ml). Methyl hydrazinecarboxylate (64.5g, predistilled in vacuo) was dissolved in warm dimethylformamide (35ml) and methanol (300ml) was added to the reaction mixture at 0°C. The mixture was stirred for 30 minutes and the crystalline solid formed was removed by filtration and washed with ethyl acetate to give the title compound: m.p. 138-140°C.

Opis 294 Description 294

2-(R)-(1-(S)-(3,5-bis(trifluormetil)fenin-2-hidroksietoksi)-3-(S)-fenilmorfolin 2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyne-2-hydroxyethoxy)-3-(S)-phenylmorpholine

Stupanj A: 4-benzil-2-(R)-(1-(S)-(3.5-bis(trifluormetil)fenil)-2-hidroksietoksi)-3-(S)-fenilmorfolin Grade A: 4-benzyl-2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-phenylmorpholine

Spoj iz Opisa 17 reagira s diboranom i nakon toga s bazičnim vodikovim peroksidom prema postupku navedenom u Opisu 20. Ovaj intermedijar nije pročišćavan i sirov je reagirao u slijedećem stupnju. The compound of Description 17 is reacted with diborane and then with basic hydrogen peroxide according to the procedure outlined in Description 20. This intermediate was not purified and reacted crudely in the next step.

Stupanj B: 2-(R)-(1-(S)-(3,5-bis(trifluormetil)fenil)-2-hidroksietoksi-3-(S)-fenilmorfolin Grade B: 2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy-3-(S)-phenylmorpholine

Gornjem spoju (a) odstrani se zaštita hidrogenolizom navedenom u Opisu 21 da bi se dobio naslovni spoj kao bijela kruta tvar: 1H NMR (360MHz, CDCI3) δ 2.85 (1H, app d, J=11.0Hz), 3.15 (1H, dt, J=12.0, 3.5Hz), 3.58 (1H, dd, J=11.0, 3.0Hz), 3.63-3.71 (2H, m), 4.02 (1H, d, J=3.0Hz), 4.25 (dt, J=12.0, 3.0Hz), 4.53 (1H, d, J=3.0Hz), 4.93 (1H, t, J=5.0Hz), 7.22 (2H, s), 7.35 (5H, br s), 7.67 (1H, s). MS (Cl+) m/z 436 (M+1, 100%). The above compound (a) was deprotected by hydrogenolysis as described in Description 21 to give the title compound as a white solid: 1H NMR (360MHz, CDCl3) δ 2.85 (1H, app d, J=11.0Hz), 3.15 (1H, dt , J=12.0, 3.5Hz), 3.58 (1H, dd, J=11.0, 3.0Hz), 3.63-3.71 (2H, m), 4.02 (1H, d, J=3.0Hz), 4.25 (dt, J= 12.0, 3.0Hz), 4.53 (1H, d, J=3.0Hz), 4.93 (1H, t, J=5.0Hz), 7.22 (2H, s), 7.35 (5H, br s), 7.67 (1H, s ). MS (Cl+) m/z 436 (M+1, 100%).

Opis 25 Description 25

4-benzil-2-(R)-(3-fluoro-5-(trifluorometil)benzoiloksi)-3-(S) fenilmorfolin 4-benzyl-2-(R)-(3-fluoro-5-(trifluoromethyl)benzoyloxy)-3-(S) phenylmorpholine

Spoj iz Opisa 15 reagira sa L-Selectridom, praćeno sa 3-fluoro-5-(trifluormetil)benzoil kloridom prema postupku navedenom u Opisu 3, da bi se dobio naslovni spoj kao bisto ulje. 1H NMR (250MHz, CDCI3) δ 2.47 (1H, dt, J=8.5, 2.5Hz), 2.93-2.97 (2H, m), 3.72-3.76 (1H, m), 3.79 (1H, d, J=3.0Hz), 3.97 (1H, d, J=9.5Hz), 4.17 (1H, dt, J=8.5, 2.5Hz), 6.22 (1H, d, J=3.0Hz), 7.19-7.35 (8H, m), 7.45-7.56 (3H, m), 7.88 (1H, br d), 8.09 (1H, s). MS (Cl+) m/z 460 (M+1, 100%). The compound of Description 15 is reacted with L-Selectride, followed by 3-fluoro-5-(trifluoromethyl)benzoyl chloride according to the procedure of Description 3, to give the title compound as a clear oil. 1H NMR (250MHz, CDCl3) δ 2.47 (1H, dt, J=8.5, 2.5Hz), 2.93-2.97 (2H, m), 3.72-3.76 (1H, m), 3.79 (1H, d, J=3.0Hz ), 3.97 (1H, d, J=9.5Hz), 4.17 (1H, dt, J=8.5, 2.5Hz), 6.22 (1H, d, J=3.0Hz), 7.19-7.35 (8H, m), 7.45 -7.56 (3H, m), 7.88 (1H, no d), 8.09 (1H, s). MS (Cl+) m/z 460 (M+1, 100%).

Opis 26 Description 26

4-benzil-2-(R)-(3-fluoro-5-(trifluormetil)fenil)eteniloksi)-3-(S)-fenilmorfolin 4-benzyl-2-(R)-(3-fluoro-5-(trifluoromethyl)phenyl)ethenyloxy)-3-(S)-phenylmorpholine

Spoj iz Opisa 25 reagira s dimetil titanocenom prema postupku navedenom u Opisu 4. Time se dobiva naslovni spoj kao bisto ulje (66%). 1H NMR (250MHz, CDCI3) δ 2.29-2.39 (1H, m), 2.79-2.86 (2H, m), 3.53-3.64 (2H, m), 3.92 (1H, d, J=13.5Hz), 4.00-4.09 (1H, m), 4.61 (1H, d, J=3.0Hz), 4.66 (1H, d, J=3.0Hz), 5.25 (1H, d, J=3.0Hz), 7.14-7.35 (10H, m), 7.47 (1H, s), 7.56 (2H, brd). MS (Cl+) m/z 458 (M+1, 100%). The compound from Description 25 is reacted with dimethyl titanocene according to the procedure specified in Description 4. This gives the title compound as a clear oil (66%). 1H NMR (250MHz, CDCl3) δ 2.29-2.39 (1H, m), 2.79-2.86 (2H, m), 3.53-3.64 (2H, m), 3.92 (1H, d, J=13.5Hz), 4.00-4.09 (1H, m), 4.61 (1H, d, J=3.0Hz), 4.66 (1H, d, J=3.0Hz), 5.25 (1H, d, J=3.0Hz), 7.14-7.35 (10H, m) , 7.47 (1H, s), 7.56 (2H, brd). MS (Cl+) m/z 458 (M+1, 100%).

Opis 27 Description 27

2-(R)-(1-(S)-(3-fluoro-5-(trifluorometil)fenil)-2-hidroksietoksi-3-(S)-fenilmorfolin 2-(R)-(1-(S)-(3-fluoro-5-(trifluoromethyl)phenyl)-2-hydroxyethoxy-3-(S)-phenylmorpholine

Stupanj A: 4-benzil-2-(R)-( 1 -(S)-3-fluoro-5-(trifluorometil)fenil)-2-hidroksietoksi)-3-(S)-fenilmorfolin Grade A: 4-benzyl-2-(R)-( 1 -(S)-3-fluoro-5-(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-phenylmorpholine

Spoj iz Opisa 26 reagira s di-borom praćeno tretmanom s bazičnim vodikovim peroksidom prema postupku navedenom u Opisu 20 da bi se dobilo bistro ulje. MS (Cl+) m/z 476 (M+1, 100%). The compound of Description 26 is reacted with di-boron followed by treatment with basic hydrogen peroxide according to the procedure of Description 20 to give a clear oil. MS (Cl+) m/z 476 (M+1, 100%).

Stupanj B: 2-(R)-(1-(S)-(3-fluoro-5-(trifluorometil)fenil)-2-hidroksietoksi-3-(S)-fenilmorfolin Grade B: 2-(R)-(1-(S)-(3-fluoro-5-(trifluoromethyl)phenyl)-2-hydroxyethoxy-3-(S)-phenylmorpholine

Gornjem spoju (a) odstrani se zaštita prema postupku navedenom u Opisu 21. Time se dobiva naslovni spoj kao bijela kruta tvar. Analiza: Računano za: C19H19F4NO3: C, 59.22; H, 4.97; N, 3.63. Nađeno: C, 59.18, H, 5.12; N, 3.62%. MS (Cl+) m/z 386 (M+1, 100%). The above compound (a) is deprotected according to the procedure specified in Description 21. This gives the title compound as a white solid. Analysis: Calcd for: C19H19F4NO3: C, 59.22; H, 4.97; N, 3.63. Found: C, 59.18, H, 5.12; N, 3.62%. MS (Cl+) m/z 386 (M+1, 100%).

Opis 28 Description 28

4-benzil-3-(S)-fenil-2-(R)-(3-(trifluormetil)benzoiloksi)morfolin 4-benzyl-3-(S)-phenyl-2-(R)-(3-(trifluoromethyl)benzoyloxy)morpholine

Pripravlja se iz spoja iz Opisa 15 prema postupku navedenom u Opisu 3. 1H NMR (250MHz, CDCI3) δ 2,47 (1H, dt), 2.89-2.99 (2H, m), 3.69-3.82 (2H, m), 3.98 (1H, d), 4.23 (1H, dt), 6.22 (1H, d), 7.22-7.40 (8H, m), 7.54-7.66 (3H, m), 7.83 (1H, d), 8.22 (1H, d), 8.31 (1H, s). It is prepared from the compound from Description 15 according to the procedure specified in Description 3. 1H NMR (250MHz, CDCl3) δ 2.47 (1H, dt), 2.89-2.99 (2H, m), 3.69-3.82 (2H, m), 3.98 (1H, d), 4.23 (1H, dt), 6.22 (1H, d), 7.22-7.40 (8H, m), 7.54-7.66 (3H, m), 7.83 (1H, d), 8.22 (1H, d ), 8.31 (1H, s).

Opis 29 Description 29

4-benzil-3-(S)-fenil-2-(R)-(1-(3-trifluormetil)fenil)eteniloksi) morfolin 4-benzyl-3-(S)-phenyl-2-(R)-(1-(3-trifluoromethyl)phenyl)ethenyloxy)morpholine

Pripravlja se iz spoja iz Opisa 28 prema postupku navedenom u Opisu 4. 1H NMR (250MHz, CDCI3) δ 2.41 (1H, dt), 2.84-2.96 (2H, m), 3.58-3.66 (1H, m), 3.72 (1H, d) 3.99 (1H, d), 4.13 (1H, dt), 4.63 (1H, d), 4.72 (1H, d), 5.34 (1H, d), 7.21-7.43 (9H, m), 7.50-7.68 (4H, m), 7.75 (1H, s). It is prepared from the compound from Description 28 according to the procedure specified in Description 4. 1H NMR (250MHz, CDCl3) δ 2.41 (1H, dt), 2.84-2.96 (2H, m), 3.58-3.66 (1H, m), 3.72 (1H , d) 3.99 (1H, d), 4.13 (1H, dt), 4.63 (1H, d), 4.72 (1H, d), 5.34 (1H, d), 7.21-7.43 (9H, m), 7.50-7.68 (4H, m), 7.75 (1H, s).

Opis 30 Description 30

3-(S)-fenil-2-(R)-(1-(S)-(3-trifluormetil)fenil)-2-hidroksietoksi) morfolin 3-(S)-phenyl-2-(R)-(1-(S)-(3-trifluoromethyl)phenyl)-2-hydroxyethoxy)morpholine

Stupanj A: 4-benzil-3-(S)-fenil-2-(R)-(1-(S)-(3-(trifluorometil) fenil)-2-hidroksietoksi)morfolin Grade A: 4-benzyl-3-(S)-phenyl-2-(R)-(1-(S)-(3-(trifluoromethyl)phenyl)-2-hydroxyethoxy)morpholine

Priprema se iz spoja iz Opisa 29 prema postupku navedenom u Opisu 20. It is prepared from the compound from Description 29 according to the procedure specified in Description 20.

Stupanj B: 3-(S)-fenil-2-(R)-(1-(S)-(3-trifluormetil)fenil)-2-hidroksietoksi) morfolin Grade B: 3-(S)-phenyl-2-(R)-(1-(S)-(3-trifluoromethyl)phenyl)-2-hydroxyethoxy)morpholine

Naslovni spoj se dobiva bez pročišćavanja prema postupku navedenom u Opisu 21. 1H NMR (250MHz, CDCI3) δ 2.81 -2.90 (1H, br d), 3.16 (1H, dt), 3.54-3.68 (3H, m), 4.02 (1H, d), 4.28 (1H, dt), 4.53 (1H, d), 4.85-4.92 (1H, m), 6.85 (1H, d), 6.99 (1H, s), 7.15-7.24 (1H, m), 7.34-7.45 (6H, m). The title compound is obtained without purification according to the procedure described in Description 21. 1H NMR (250MHz, CDCl3) δ 2.81 -2.90 (1H, br d), 3.16 (1H, dt), 3.54-3.68 (3H, m), 4.02 (1H , d), 4.28 (1H, dt), 4.53 (1H, d), 4.85-4.92 (1H, m), 6.85 (1H, d), 6.99 (1H, s), 7.15-7.24 (1H, m), 7.34-7.45 (6H, m).

Primjer 1 Example 1

2-(RV(1-(RH3,5-bis(trifluorometil)fenil)etoksi)-4-(2.3-dihidro-5-(N,N-dimetilaminometil)-2-okso-1,3-imidazol-4-il)metil-3-(S)-4-fluorofenil)morfolin 2-(RV(1-(RH3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(2,3-dihydro-5-(N,N-dimethylaminomethyl)-2-oxo-1,3-imidazole-4- yl)methyl-3-(S)-4-fluorophenyl)morpholine

Spoj iz Opisa 9 (0.35g) tretira se sa N.N-dimetilmetilenamonij jodidom (0.48g) i trietilaminom (111 μl) u tetrahidrofuranu (10ml), i smjesa se zagrije uz refluks kroz 4 sata. Otapalo se odstrani in vacuo i ostatak se pročisti kromatografijom na siliciju koristeći 1-10% metanol u diklormetanu kao eluent da bi se dobio nalsovni spoj (0.2g). 1H NMR (250MHz, CDCI3) δ 9.72 (1H, s), 9.68 (1H, s), 7.86 (1H, s), 7.50-7.60 (2H, m), 7.36 (2H, s), 7.07 (2H, t, J=8.8Hz), 4.96-4.89 (1H, q, J=6.5Hz), 4.31 (1H, d, J=2.7Hz), 4.08 (1H, t, J=10.1Hz), 3.62 (1H, d, J=10.1Hz), 3.34 (2H, s), 3.24 (1H, d, J=13.6Hz), 3.00 (1H, d, J=13.4Hz), 2.85 (1H, d, J=11.1Hz), 2.62 (1H, d, J=13.6Hz), 2.25 (1H, t, J=11Hz), 2.01 (6H, s) i 1.35 (3H, d, J=6.5Hz). MS (Cl+) m/z 591 (M+1). The compound of Description 9 (0.35g) was treated with N,N-dimethylmethyleneammonium iodide (0.48g) and triethylamine (111 μl) in tetrahydrofuran (10ml), and the mixture was heated at reflux for 4 hours. The solvent was removed in vacuo and the residue was purified by chromatography on silica using 1-10% methanol in dichloromethane as eluent to give the title compound (0.2g). 1H NMR (250MHz, CDCl3) δ 9.72 (1H, s), 9.68 (1H, s), 7.86 (1H, s), 7.50-7.60 (2H, m), 7.36 (2H, s), 7.07 (2H, t , J=8.8Hz), 4.96-4.89 (1H, q, J=6.5Hz), 4.31 (1H, d, J=2.7Hz), 4.08 (1H, t, J=10.1Hz), 3.62 (1H, d , J=10.1Hz), 3.34 (2H, s), 3.24 (1H, d, J=13.6Hz), 3.00 (1H, d, J=13.4Hz), 2.85 (1H, d, J=11.1Hz), 2.62 (1H, d, J=13.6Hz), 2.25 (1H, t, J=11Hz), 2.01 (6H, s) and 1.35 (3H, d, J=6.5Hz). MS (Cl+) m/z 591 (M+1).

Primjer 2 Example 2

4-(2,3-dihidro-5-(N,N-dimetilaminometil)-2-okso-1,3-imidazol-4-il)metil-3-(S)-(4-fluorofenil)-2-(R)-(1-(R)-(3-fluoro-5-trifluorometil)fenil)etoksi)morfolin 4-(2,3-dihydro-5-(N,N-dimethylaminomethyl)-2-oxo-1,3-imidazol-4-yl)methyl-3-(S)-(4-fluorophenyl)-2-( R)-(1-(R)-(3-fluoro-5-trifluoromethyl)phenyl)ethoxy)morpholine

Pripravlja se iz spoja iz Opisa 10 prema postupku analognom onom u Primjeru 1. 1H NMR (250MHz, CDCI3) δ 51.38 (3H, d, J=6.2Hz), 2.22 (6H, s), 2.78 (1H, d, J=14Hz), 2.92 (1H, d, J=11.2Hz), 3.14 (2H, app q, J=14Hz), 3.34 (1H, d, J=2.8Hz), 3.46 (1H, d, J=11.2Hz), 3.60 (1H, d, J=10Hz), 4.22 (2H, m), 4.26 (1H, d, J=2.8Hz), 4.47 (1H, q, J=6.2Hz), 6.32 (1H, d, J=8.4Hz), 6.72 (1H, s), 7.06 (3H, t, J=8.4Hz), 7.36 (2H, br s), 8.70 (1H, br s), 9.20 (1H, br s). It is prepared from the compound from Description 10 according to a procedure analogous to that in Example 1. 1H NMR (250MHz, CDCl3) δ 51.38 (3H, d, J=6.2Hz), 2.22 (6H, s), 2.78 (1H, d, J= 14Hz), 2.92 (1H, d, J=11.2Hz), 3.14 (2H, app q, J=14Hz), 3.34 (1H, d, J=2.8Hz), 3.46 (1H, d, J=11.2Hz) , 3.60 (1H, d, J=10Hz), 4.22 (2H, m), 4.26 (1H, d, J=2.8Hz), 4.47 (1H, q, J=6.2Hz), 6.32 (1H, d, J =8.4Hz), 6.72 (1H, s), 7.06 (3H, t, J=8.4Hz), 7.36 (2H, no s), 8.70 (1H, no s), 9.20 (1H, no s).

Primjer 3 Example 3

3-(S)-(4-fluorofenin-2-(R)-(1-(R)-(3-fluoro-5-trifluorometil) fenil)etoksi)- 4-(2,3-dihidro-2-okso-5-pirolidinometil-1,3-imidazol-4-il)metilmorfolin 3-(S)-(4-fluorophenin-2-(R)-(1-(R)-(3-fluoro-5-trifluoromethyl)phenyl)ethoxy)- 4-(2,3-dihydro-2-oxo -5-pyrrolidinomethyl-1,3-imidazol-4-yl)methylmorpholine

Smjesa spoja iz Opisa 10 (0.1g), paraformaldehida (0.012g) i pirolidina (0.04ml) u metanolu (2ml) grije se na 90°C 1 sat. Dodatni alikvot paraformaldehida (12mg) se doda u smjesu i nastavi se grijati daljnjih 30 minuta. Smjesa se ohladi i otapalo se odstrani in vacuo. Ostatak se pročisti kromatografijom na siliciju koristeći 0.5% vodenog amonijaka i 5% metanola u diklormetanu. Proizvod se dobiva u obliku pjene. Proizvod se daje pročišćava kao klorovodična sol: t.t. 157-9°C. 1H NMR (250MHz, (slobodne baze) CDCI3) δ 1.40 (3H, t, J=6.2Hz), 1.72 (4H, br s), 2.41 (4H, br s), 2.76 (1H, d, J=12.9Hz), 2.92 (1H, d, J=11.2Hz), 3.14-3.50 (5H, m), 3.62 (1H, d, J=11.2Hz), 4.16 (1H, d, J=12.9Hz), 4.26 (1H, d, J=2.8Hz), 4.71 (1H, q, J=6.Hz), 6.30 (1H, d, J=8.4Hz), 6.75 (1H, s), 7.06 (3H, t, J=8.4Hz), 7.34 (2H, br s), 8.86 (1H, br s), 9.14 (1H, br s). MS (Cl+) m/z 567 (M++H). A mixture of the compound from Description 10 (0.1g), paraformaldehyde (0.012g) and pyrrolidine (0.04ml) in methanol (2ml) is heated at 90°C for 1 hour. An additional aliquot of paraformaldehyde (12 mg) is added to the mixture and heating is continued for another 30 minutes. The mixture was cooled and the solvent was removed in vacuo. The residue was purified by chromatography on silica using 0.5% aqueous ammonia and 5% methanol in dichloromethane. The product is obtained in the form of foam. The product is purified as the hydrochloride salt: m.p. 157-9°C. 1H NMR (250MHz, (free base) CDCl3) δ 1.40 (3H, t, J=6.2Hz), 1.72 (4H, br s), 2.41 (4H, br s), 2.76 (1H, d, J=12.9Hz ), 2.92 (1H, d, J=11.2Hz), 3.14-3.50 (5H, m), 3.62 (1H, d, J=11.2Hz), 4.16 (1H, d, J=12.9Hz), 4.26 (1H , d, J=2.8Hz), 4.71 (1H, q, J=6.Hz), 6.30 (1H, d, J=8.4Hz), 6.75 (1H, s), 7.06 (3H, t, J=8.4 Hz), 7.34 (2H, br s), 8.86 (1H, br s), 9.14 (1H, br s). MS (Cl+) m/z 567 (M++H).

Primjer 4 Example 4

2-(R)-(1-(R)-(3.5-bis(trifluorometil)fenil)etoksi)-3-(S)-(4-fluorofenil)-4-(2,3-dihidro-2-okso-5-pirolidinometil-1,3-imidazol-4-il)metilmorfolin 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(2,3-dihydro-2-oxo- 5-Pyrrolidinomethyl-1,3-imidazol-4-yl)methylmorpholine

Otopina spoja iz Opisa 5 (1.5g) u bezvodnom dimetilformamidu (15ml) kapanjem se dodaje kroz 5 minuta u miješanu otopinu 4,5-bis(bromoetil)-1,3-diacetil-2-imidazolinona (1.8g) (dobiveno postupkom prema Dolan i Dushinsky JACS (1948) 70, 657) u dimetilformamidu (10ml) sa kalijevim karbonatom (1.4g) s ledenim hlađenjem. Reakciona smjesa se miješa 10 minuta i u jednoj porciji se dodaje pirolidin (1.1g) i miješanje se nastavi 20 minuta. Reakciona smjesa se razrijedi vodom (250ml) i ekstrahira etil acetatom (3 x 50ml). Pomiješani organski ekstrakti se isperu vodom (2 x 50ml) i slanom otopinom (1 x 50ml), te zatim osuše (K2CO3) i koncentriraju in vacuo. Dobiveni ostatak se pročisti kromataografijom na siliciju koristeći postupnu eluciju diklormetanom (100%) do diklormetan/metanol/vodeni amonijak smjese (85:15:0.5) da bi se dobio naslovni spoj kao pjena. 1H NMR (360MHz, DMSO-d6) δ 9.63 (2H, br s), 7.84 (1H, s), 7.53 (2H, br t), 7.36 (2H, s), 7.06 (2H, t, J=8.7Hz), 4.94-4.90 (1H, q, J=6.5Hz), 4.31 (1H, d, J=2.68Hz), 4.07 (1H, t, J=11.4Hz), 3.61 (1H, d, J=11.20Hz), 3.34 (1H, J=2.7Hz), 3.27 (1H, d, J=13.7Hz), 3.17 (1H, d, J=13.4Hz), 3.00 (1H, d, J=13.4Hz), 2.86 (1H, d, J=11.6), 2.62 (1H, d, J=13.6Hz), 2.40-2.22 (5H, m), 1.64-1.58 (2H, m), 1.35 (3H, d, J=6.5Hz). MS (Cl+) m/z 615 (M++H). A solution of the compound from Description 5 (1.5g) in anhydrous dimethylformamide (15ml) was added dropwise over 5 minutes to a mixed solution of 4,5-bis(bromoethyl)-1,3-diacetyl-2-imidazolinone (1.8g) (obtained by the procedure according to Dolan and Dushinsky JACS (1948) 70, 657) in dimethylformamide (10ml) with potassium carbonate (1.4g) under ice-cooling. The reaction mixture is stirred for 10 minutes and pyrrolidine (1.1g) is added in one portion and the stirring is continued for 20 minutes. The reaction mixture was diluted with water (250 ml) and extracted with ethyl acetate (3 x 50 ml). The mixed organic extracts are washed with water (2 x 50ml) and saline (1 x 50ml), then dried (K2CO3) and concentrated in vacuo. The resulting residue was purified by chromatography on silica using stepwise elution with dichloromethane (100%) to dichloromethane/methanol/aqueous ammonia (85:15:0.5) to give the title compound as a foam. 1H NMR (360MHz, DMSO-d6) δ 9.63 (2H, br s), 7.84 (1H, s), 7.53 (2H, br t), 7.36 (2H, s), 7.06 (2H, t, J=8.7Hz ), 4.94-4.90 (1H, q, J=6.5Hz), 4.31 (1H, d, J=2.68Hz), 4.07 (1H, t, J=11.4Hz), 3.61 (1H, d, J=11.20Hz ), 3.34 (1H, J=2.7Hz), 3.27 (1H, d, J=13.7Hz), 3.17 (1H, d, J=13.4Hz), 3.00 (1H, d, J=13.4Hz), 2.86 ( 1H, d, J=11.6), 2.62 (1H, d, J=13.6Hz), 2.40-2.22 (5H, m), 1.64-1.58 (2H, m), 1.35 (3H, d, J=6.5Hz) . MS (Cl+) m/z 615 (M++H).

Primjeri 5 do 11 u Tabeli 1 pripremljeni su na jednak način opisan u Primjeru 4, iz odgovarajućeg morfolina, 4,5-bis(bromometil)-1,3-diacetil-2-imidazolinona i odgovarajućeg amina. Examples 5 to 11 in Table 1 were prepared in the same manner as described in Example 4, from the corresponding morpholine, 4,5-bis(bromomethyl)-1,3-diacetyl-2-imidazolinone and the corresponding amine.

Primjer 12 Example 12

2-(R)-(1-(R)-3.5-bis(trifluorometil)fenil)etoksi-4-(5-dimetilaminometil)-1,2,3-triazol-4-il)metil-3-(S)-4-fluorofenil)morfolin 2-(R)-(1-(R)-3.5-bis(trifluoromethyl)phenyl)ethoxy-4-(5-dimethylaminomethyl)-1,2,3-triazol-4-yl)methyl-3-(S) -4-fluorophenyl)morpholine

Postupak A Procedure A

a) 2-(R)-(1-(R)-3,5-bis(trif1uorometil)fenil)etoksi-3-(S)-(4-fluorofenil)-4-propargilmorfolin a) 2-(R)-(1-(R)-3,5-bis(trifluoromethyl)phenyl)ethoxy-3-(S)-(4-fluorophenyl)-4-propargylmorpholine

Propargil bromid (1.9ml) dodaje se u miješanu smjesu spoja iz Opisa 5 (5g) i kalij karbonata (4.76g) u suhom dimetilformamidu pri 23°C. Nakon 15 minuta reakciona smjesa se razrijedi vodom (250ml) i ekstrahira etil acetatom (3 x 100ml). Pomiješane organske faze se isperu slanom otopinom (1x 100ml), zatim osuše (K2CO3) i koncentriraju do ulja. To se pročišćava kromatografijom na siliciju koristeći etil acetat u heksanu (1:9 zatim 1:4) kao eluent da bi se dobio naslovni spoj kao ulje. 1H NMR (259MHz, CDCI3) δ.1.50 (3H, d, J=6.6Hz), 2.21 (1H, s), 2.84 (1H, d, J=11.1Hz), 2.97 (1H, td, J=3.2, 11.7Hz), 3.26 (2H, d, J=1.8Hz), 3.62 (1H, d, J=2.2Hz), 3.71 (1H, dd, J=2.3, 11.1Hz), 4.33 (2H, m), 4.89 (1H, q, J=6.6Hz), 7.03 (2H, t, J=8.6Hz), 7.18 (2H, s), 7.38 (2H, br s), 7.63 (1H, s). MS (Cl+) m/z 476 (MH, 100%). Propargyl bromide (1.9ml) is added to a stirred mixture of the compound from Description 5 (5g) and potassium carbonate (4.76g) in dry dimethylformamide at 23°C. After 15 minutes, the reaction mixture is diluted with water (250 ml) and extracted with ethyl acetate (3 x 100 ml). The mixed organic phases are washed with brine (1x 100ml), then dried (K2CO3) and concentrated to an oil. This was purified by chromatography on silica using ethyl acetate in hexane (1:9 then 1:4) as eluent to give the title compound as an oil. 1H NMR (259MHz, CDCl3) δ.1.50 (3H, d, J=6.6Hz), 2.21 (1H, s), 2.84 (1H, d, J=11.1Hz), 2.97 (1H, td, J=3.2, 11.7Hz), 3.26 (2H, d, J=1.8Hz), 3.62 (1H, d, J=2.2Hz), 3.71 (1H, dd, J=2.3, 11.1Hz), 4.33 (2H, m), 4.89 (1H, q, J=6.6Hz), 7.03 (2H, t, J=8.6Hz), 7.18 (2H, s), 7.38 (2H, br s), 7.63 (1H, s). MS (Cl+) m/z 476 (MH, 100%).

b) 2-(R)-(1-(R)-(3.5-bis(trifluorometil)fenil)etoksi)-4-(4-dimetilamino-4-okso-but-2-inil)-3-(S)-(4-fluorofenil)morfolin b) 2-(R)-(1-(R)-(3.5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-dimethylamino-4-oxo-but-2-ynyl)-3-(S) -(4-fluorophenyl)morpholine

Smjesa N,N-dimetilkarbamoil klorida (0.195ml), bakrenog jodida (2mg), bis(trifenilfosfin)paladij (II) klorida (2mg), trifenilfosfina (3mg) i spoja gore opisanog (a) (1g) u trietilaminu (4ml) grije se na 90°C 5 sati u atmosferi inertnog plina. Smjesa se ohladi na 23°C, dodaje se metanol (1ml) i otapalo se odstrani in vacuo. Dobiveni ostatak se razdijeli između vode i etil acetata i slojevi se razdvoje. Vodena faza se ekstrahira s etil acetatom (2 x 20ml). Pomiješane organske faze se isperu vodom, slanom otopinom, osuše (MgSO4) i koncentriraju do ulja. Dobiveni ostatak se pročisti kromatografijom na siliciju koristeći etil acetat u heksanu (1:1), zatim etil acetat kao eluent da bi se dobio naslovni spoj kao ulje. 1H NMR (250MHz, CDCI3) δ 1.49 (3H, d, J=6.6Hz), 2.84-3.06 (2H, m), 3.00 (3H, s), 3.17 (3H, s), 3.44 (2H, s), 3.64 (1H, br s), 3.73 (1H, dd, J=2.0, 11.1Hz), 4.33 (2H, m), 4.88 (1H, q, J=6.6Hz), 7.03 (2H, t, J=8.7Hz), 7.17 (2H, s), 7.38 (2H, br s), 7.63 (1H, s). MS (Cl+) m/z 547 (MH, 100%). A mixture of N,N-dimethylcarbamoyl chloride (0.195ml), copper iodide (2mg), bis(triphenylphosphine)palladium (II) chloride (2mg), triphenylphosphine (3mg) and the compound described above (a) (1g) in triethylamine (4ml) it is heated to 90°C for 5 hours in an inert gas atmosphere. The mixture was cooled to 23°C, methanol (1ml) was added and the solvent was removed in vacuo. The resulting residue is partitioned between water and ethyl acetate and the layers are separated. The aqueous phase is extracted with ethyl acetate (2 x 20ml). The mixed organic phases are washed with water, brine, dried (MgSO4) and concentrated to an oil. The resulting residue was purified by chromatography on silica using ethyl acetate in hexane (1:1), then ethyl acetate as eluent to afford the title compound as an oil. 1H NMR (250MHz, CDCl3) δ 1.49 (3H, d, J=6.6Hz), 2.84-3.06 (2H, m), 3.00 (3H, s), 3.17 (3H, s), 3.44 (2H, s), 3.64 (1H, br s), 3.73 (1H, dd, J=2.0, 11.1Hz), 4.33 (2H, m), 4.88 (1H, q, J=6.6Hz), 7.03 (2H, t, J=8.7 Hz), 7.17 (2H, s), 7.38 (2H, br s), 7.63 (1H, s). MS (Cl+) m/z 547 (MH, 100%).

c) 2-(R)-(1-(R)-(3,5-bis(trifluormetil)fenil)etoksi)-4-(5-N.N-dimetilkarboksamido-1,2,3-triazol-4-il)metil-3-(S)-(4-fluorofenil)morfolin c) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-N,N-dimethylcarboxamido-1,2,3-triazol-4-yl) methyl-3-(S)-(4-fluorophenyl)morpholine

Smjesa spoja (b) gore opisanog (1.1 g) i natrij azida (0.65g) u dimetilsulfoksidu (7.5ml) grije se na 70°C 17 sati. Smjesa se ohladi na 23°C i suvišak dimetilsulfoksida se odstrani destilacijom in vacuo. Dobiveni ostatak se razdijeli između slane otopine i etil acetata. Slojevi se razdvoje i organski sloj se ispere slanom otopinom (2 x 20ml) zatim osuši (MgSO4) i koncentrira do ulja. To se pročisti kromatografijom na siliciju koristeći etil acetat u heksanu (1:2 zatim 1:1) zatim etil acetat kao eluent da bi se dobio naslovni spoj kao blijedožuta pjena. 1H NMR (360MHz, CDCI3) δ 1.47 (3H, d, J=6.6Hz), 2.64 (1H, m), 2.90 (1H, d, J=11.6Hz), 3.09 (3H, s), 3.34 (3H, s), 3.65 (3H, m), 3.92 (1H, d, J=15.5Hz), 4.27 (1H, td, J=2.1, 9.5Hz), 4.35 (1H, d, J=2.6Hz), 4.89 (1H, q, J=6.6Hz), 7.01 (2H, t, J=8.7Hz), 7.16 (2H, s), 7.39 (2H, br s), 7.64 (1H, s). m/z 590 (MH, 100%). A mixture of compound (b) described above (1.1 g) and sodium azide (0.65 g) in dimethylsulfoxide (7.5 ml) is heated at 70°C for 17 hours. The mixture was cooled to 23°C and excess dimethylsulfoxide was removed by distillation in vacuo. The resulting residue was partitioned between brine and ethyl acetate. The layers were separated and the organic layer was washed with brine (2 x 20ml) then dried (MgSO4) and concentrated to an oil. This was purified by chromatography on silica using ethyl acetate in hexane (1:2 then 1:1) then ethyl acetate as eluent to give the title compound as a pale yellow foam. 1H NMR (360MHz, CDCl3) δ 1.47 (3H, d, J=6.6Hz), 2.64 (1H, m), 2.90 (1H, d, J=11.6Hz), 3.09 (3H, s), 3.34 (3H, s), 3.65 (3H, m), 3.92 (1H, d, J=15.5Hz), 4.27 (1H, td, J=2.1, 9.5Hz), 4.35 (1H, d, J=2.6Hz), 4.89 ( 1H, q, J=6.6Hz), 7.01 (2H, t, J=8.7Hz), 7.16 (2H, s), 7.39 (2H, br s), 7.64 (1H, s). m/z 590 (MH, 100%).

d) 2-(RV(1-(R)-3,5-bis(trifluormetl)feninetoksi)-4-(5-dimetilarninometil)-1,2,3-triazol-4-il)metil-3-(S)-4-fluorofenil) morfolin d) 2-(RV(1-(R)-3,5-bis(trifluoromethyl)phenylethoxy)-4-(5-dimethylaminomethyl)-1,2,3-triazol-4-yl)methyl-3-(S )-4-fluorophenyl)morpholine

Litij aluminij hidrid (0.47ml, 1M u tetrahidrofuranu) kapanjem se dodaje u otopinu spoja (c) gore opisanog (0.11g) u bezvodnom tetrahidrofuranu (1ml) u atmosferi inertnog plina na 23°C. Nakon 30 minuta dodaje se natrijev hidroksid (10 kapi, 1M) praćen vodom (5 kapi). Zatim se dodaje etil acetat (50ml) i dobivena smjesa se filtrira kroz Hyflo tkaninu. Filtrat se koncentrira in vacuo i dobiveni ostatak se pročisti kromatografijom na siliciju koristeći etil acetat u metanolu (9:1 zatim 4:1) kao eluent, da bi se dobio naslovni spoj kao pjena. 1H NMR (360MHz, CDCI3) δ 1.44 (3H, d, J=6.6Hz), 2.25 (6H, s), 2.57 (1H, td, J=3.4, 8.55Hz), 2.90 (1H, d, J=11.7Hz), 3.25 (1H, d, J=14.0Hz), 3.43 (1H, d, J=13.6), 3.45 (1H, d, J=2.2Hz), 3.53 (1H, d, J=13.6Hz), 3.61 (1H, d, J=11.2Hz), 3.78 (1H, d, J=14.0Hz), 4.22 (1H, t, J=9.3Hz), 4.32 (1H, d, J=2.2Hz), 4.86 (1H, q, J=6.6Hz), 7.06 (2H, t, J=8.7Hz), 7.16 (2H, s), 7.48 (2H, br s), 7.63 (1H, s). m/z 576 (MH). Lithium aluminum hydride (0.47ml, 1M in tetrahydrofuran) was added dropwise to a solution of compound (c) described above (0.11g) in anhydrous tetrahydrofuran (1ml) in an inert gas atmosphere at 23°C. After 30 minutes sodium hydroxide (10 drops, 1M) is added followed by water (5 drops). Ethyl acetate (50ml) is then added and the resulting mixture is filtered through a Hyflo cloth. The filtrate was concentrated in vacuo and the resulting residue was purified by silica chromatography using ethyl acetate in methanol (9:1 then 4:1) as eluent to afford the title compound as a foam. 1H NMR (360MHz, CDCl3) δ 1.44 (3H, d, J=6.6Hz), 2.25 (6H, s), 2.57 (1H, td, J=3.4, 8.55Hz), 2.90 (1H, d, J=11.7 Hz), 3.25 (1H, d, J=14.0Hz), 3.43 (1H, d, J=13.6), 3.45 (1H, d, J=2.2Hz), 3.53 (1H, d, J=13.6Hz), 3.61 (1H, d, J=11.2Hz), 3.78 (1H, d, J=14.0Hz), 4.22 (1H, t, J=9.3Hz), 4.32 (1H, d, J=2.2Hz), 4.86 ( 1H, q, J=6.6Hz), 7.06 (2H, t, J=8.7Hz), 7.16 (2H, s), 7.48 (2H, br s), 7.63 (1H, s). m/z 576 (MH).

Postupak B Procedure B

2-(R)-1-(R)-(3.5-bis(trifluormetil)fenil)etoksi)-3-(S)-(4-fluorofenin-4-(4-klorobut-2-inil)morfolin 2-(R)-1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenin-4-(4-chlorobut-2-ynyl)morpholine

a) Otopina proizvoda iz Opisa 5 (slobodne baze, 5g) u N,N-dimetilformamidu (20ml) polako se dodaje zagrijanoj (50°C) otopini 1,4-diklorobut-2-ina (2.2ml) i kalij karbonata (4.8g) u N,N-dimetilformamidu (20ml). Otopina se zagrijava daljnih 5 sati na 50°C i zatim se otapalo odstrani in vacuo. U ostatak se dodaje voda (400ml) i proizvod se ekstrahira u etil acetatu (3 x 150ml). Pomiješane organske faze se isperu vodom, zasićenom slanom otopinom i osuše (MgSO4). Otapalo se odstrani in vacuo i ostatak se kromatografira na silikagelu (elucija sa 10% etil acetata u petrolej eteru t.v. 60-80°C) da bi se dobio naslovni spoj. 1H NMR (250MHz, CDCI3) δ 1.41 (3H, d, J=6.6Hz), 2.80 (1H, app t, J=10.8Hz), 2.87 (1H, td, J=3.5Hz, 11.7Hz), 3.22 (2H, t, J=1.9Hz), 3.52 (1H, d, J=2.8Hz), 3.68 (1H, d, J=1.4Hz, 11.1Hz), 4.00 (2H, t, J=1.9Hz), 4.22-4,32 (2H, m), 4.81 (1H, q, J=6.6Hz), 6.96 (2H, t, J=8.7Hz), 7.10 (2H, s), 7.31 (2H, br s), 7.56 (1H, s). m/z (Cl+) 524 (M+H, 100%). a) A solution of the product from Description 5 (free bases, 5g) in N,N-dimethylformamide (20ml) is slowly added to a heated (50°C) solution of 1,4-dichlorobut-2-ine (2.2ml) and potassium carbonate (4.8 g) in N,N-dimethylformamide (20ml). The solution is heated for a further 5 hours at 50°C and then the solvent is removed in vacuo. Water (400ml) was added to the residue and the product was extracted into ethyl acetate (3 x 150ml). The mixed organic phases are washed with water, saturated brine and dried (MgSO4). The solvent was removed in vacuo and the residue was chromatographed on silica gel (elution with 10% ethyl acetate in petroleum ether, r.p. 60-80°C) to give the title compound. 1H NMR (250MHz, CDCl3) δ 1.41 (3H, d, J=6.6Hz), 2.80 (1H, app t, J=10.8Hz), 2.87 (1H, td, J=3.5Hz, 11.7Hz), 3.22 ( 2H, t, J=1.9Hz), 3.52 (1H, d, J=2.8Hz), 3.68 (1H, d, J=1.4Hz, 11.1Hz), 4.00 (2H, t, J=1.9Hz), 4.22 -4.32 (2H, m), 4.81 (1H, q, J=6.6Hz), 6.96 (2H, t, J=8.7Hz), 7.10 (2H, s), 7.31 (2H, br s), 7.56 (1H, s). m/z (Cl+) 524 (M+H, 100%).

b) N-(4-azidobut-2-inil)-2-(R)-(1-(R)-(3,5-bis(trifluorometil) fenil)etoksi)-3-(S)-(4-fluorofenil)morfolin b) N-(4-azidobut-2-ynyl)-2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4- fluorophenyl)morpholine

Otopini 2-(R)-(1-(R)-(3,5-bis(trifluorometil)fenil)etoksi)-3-(S)-(4-fluorofenil)-4-(4-klorobut-2-inil)morfolina (4g) u dimetil sulfoksidu (17ml) dodaje se natrijev azid (0.562g). Otopina se miješa 20 sati i vodeni amonijev klorid i etil acetat se dodaju. Organska faza se ispere vodom (2 puta), zasićenom slanom otopinom i osuši (MgSO4). Otapalo se odstrani in vacuo i ostatak kromatografira na silikagelu (elucija sa 20% etil acetata u petrolej eteru t.v. 60-80°C) da bi se dobio naslovni spoj. 1H NMR (360MHz, CDCI3) δ 1.48 (3H, s, J=6.6Hz), 2.87 (1H, app t, J=10.2Hz), 2.98 (1H, td, J=3.6, 11.7Hz), 3.35 (2H, t, J=1.9Hz), 3.61 (1H, d, J=2.8Hz), 3.72 (1H, dq, J=1.4Hz, 10.0Hz), 3.92 (2H, t, J=1.9Hz), 4.30-4.40 (2H, m), 4.89 (1H, q, J=6.6Hz), 7.03 (2H, t, J=8.7Hz), 7.17 (2H, s), 7.72 (2H, br s), 7.63 (1H, s). Solutions of 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(4-chlorobut-2-ynyl) )morpholine (4g) in dimethyl sulfoxide (17ml), sodium azide (0.562g) is added. The solution was stirred for 20 hours and aqueous ammonium chloride and ethyl acetate were added. The organic phase is washed with water (2 times), saturated brine and dried (MgSO4). The solvent was removed in vacuo and the residue chromatographed on silica gel (elution with 20% ethyl acetate in petroleum ether, r.p. 60-80°C) to give the title compound. 1H NMR (360MHz, CDCl3) δ 1.48 (3H, s, J=6.6Hz), 2.87 (1H, app t, J=10.2Hz), 2.98 (1H, td, J=3.6, 11.7Hz), 3.35 (2H , t, J=1.9Hz), 3.61 (1H, d, J=2.8Hz), 3.72 (1H, dq, J=1.4Hz, 10.0Hz), 3.92 (2H, t, J=1.9Hz), 4.30- 4.40 (2H, m), 4.89 (1H, q, J=6.6Hz), 7.03 (2H, t, J=8.7Hz), 7.17 (2H, s), 7.72 (2H, br s), 7.63 (1H, with).

c) 2-(R)-(1-(R)-3,5-bis(trifluormetil)fenil)etoksi)-4-(5-(dimetilaminometil)-1,2,3-triazol-4-inmetil-3-(S)-(4-fluorofenil) morfolin c) 2-(R)-(1-(R)-3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(dimethylaminomethyl)-1,2,3-triazol-4-ynmethyl-3 -(S)-(4-Fluorophenyl)morpholine

Dimetilamin (oko 10ml) kondenzira se na -80 C u tlačnoj cijevi i tome se doda otopina N-(4-azidobut-2-inil)-2-(R)-(1-(R)-(3,5-bis(trifluormetil)fenil)etoksi)-3-(S)-(4-fluorofenil)morfolina (3.2g) u dioksanu (15ml). Cijev se zatvori i otopina grije na 90°C 16 sati. Otopina se evaporira do suhog i dobiveni ostatak se kromatografira na silikagelu (elucija sa 5% metanola u diklormetanu sa 0.25% amonijaka (SG. 0.88)) i frakcije sa željenim proizvodom evaporiraju se in vacuo da bi se dobio naslovni spoj. Otopini ovog ostatka u dietil eteru doda se 1M-HCI u metanolu. Otopina se evaporira do suhog i ponovo otopi u dietil eteru da bi se dobili kristali klorovodične soli naslovnog spoja t.t. 194-198°C, [α]22D +65.0° (c=0.5, H2O). Ustanovljeno je da su kristali stabilni najmanje pet dana na 40°C; pri 40°C/75% relativne vlažnosti; na 80°C, i 2000LUX-a. Dimethylamine (about 10 ml) is condensed at -80 C in a pressure tube and a solution of N-(4-azidobut-2-ynyl)-2-(R)-(1-(R)-(3,5-bis) is added to it (trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)morpholine (3.2g) in dioxane (15ml). The tube is closed and the solution is heated at 90°C for 16 hours. The solution was evaporated to dryness and the resulting residue was chromatographed on silica gel (elution with 5% methanol in dichloromethane with 0.25% ammonia (SG. 0.88)) and fractions with the desired product were evaporated in vacuo to give the title compound. To a solution of this residue in diethyl ether was added 1M-HCl in methanol. The solution was evaporated to dryness and redissolved in diethyl ether to give crystals of the hydrochloride salt of the title compound, m.p. 194-198°C, [α]22D +65.0° (c=0.5, H2O). The crystals were found to be stable for at least five days at 40°C; at 40°C/75% relative humidity; at 80°C, and 2000 LUX.

Primjer 13 Example 13

2-(R)-(1-(R)-(3.5-bis(trifluorometil)fenil)etoksi)-3-(S)-(4-fluorofenil)-4-(N-(2-metilaminoetil)-1,2,4-triazol-3-il)metilmorfolin: 2-(R)-(1-(R)-(3.5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(N-(2-methylaminoethyl)-1, 2,4-triazol-3-yl)methylmorpholine:

Regioizomer B Regioisomer B

a) 2-(R)-(1-(R)-(3,5-bis(trifluorometil)fenil)etoksi)-4-(N-karbometoksimetil-1,2,4-triazol-3-il)metil-3-(S)-(4-fluorofenil) morfolin a) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(N-carbomethoxymethyl-1,2,4-triazol-3-yl)methyl- 3-(S)-(4-Fluorophenyl)morpholine

Spoj iz Opisa 11 (2.94g), kalijev karbonat (2.03g) i metil bromoacetat (0.74ml) zagrijavaju se 45 minuta u dimetilformamidu. Reakcija se razdijeli između etil acetata i vode, ispere (slana otopina), osuši (MgSO4) i pročisti na siliciju koristeći petrol-etil acetat smjesu. Dva proizvoda, izomer A i izomer B dobiveni su kao bijela pjena. The compound from Description 11 (2.94g), potassium carbonate (2.03g) and methyl bromoacetate (0.74ml) were heated for 45 minutes in dimethylformamide. The reaction was partitioned between ethyl acetate and water, washed (brine), dried (MgSO4) and purified on silica using petrol-ethyl acetate. Two products, isomer A and isomer B, were obtained as a white foam.

Izomer A: 1H NMR (360MHz, DMSO) δ 7.89 (1H, s), 7.84 (1H, s), 7.48 (3H, s), 7.33-7.30 (3H, m, J=10.1), 5.26 (1H, d, J=17.8), 5.07 (1H, d, J=17.8), 4.96 (1H, q, J=6.5), 4.39 (1H, d, J=2.8), 4.04 (1H, br t, J=10.1Hz), 3.72 (3H, s), 3.58 (2H, d, J=14.0), 3.51 (1H, d, J=2.8), 3.20 (1H, d, J=14.0), 2.55 (1H, d, J=11.5), 2.37 (1H, br t, J=3.5), 1.40 (3H, d, J=6.6). Isomer A: 1H NMR (360MHz, DMSO) δ 7.89 (1H, s), 7.84 (1H, s), 7.48 (3H, s), 7.33-7.30 (3H, m, J=10.1), 5.26 (1H, d , J=17.8), 5.07 (1H, d, J=17.8), 4.96 (1H, q, J=6.5), 4.39 (1H, d, J=2.8), 4.04 (1H, br t, J=10.1Hz ), 3.72 (3H, s), 3.58 (2H, d, J=14.0), 3.51 (1H, d, J=2.8), 3.20 (1H, d, J=14.0), 2.55 (1H, d, J= 11.5), 2.37 (1H, br t, J=3.5), 1.40 (3H, d, J=6.6).

Izomer B: 1H NMR (360MHz, DMSO) δ 8.43 (1H, s), 7.82 (1H, s), 7.44 (2H, d, J=1.4), 7.37 (2H, s), 7.31-7.25 (3H, m, J=3.2), 5.16 (2H, s), 4.91 (1H, q, J=6.5), 4.35 (1H, d, J=2.8), 4.08 (1H, brt, J=10.1), 3.69 (3H, s), 3.60 (1H, d, J=8.8), 3.55 (1H, d, J=2.7), 3.30 (1H, d, J=8.7), 3.08 (1H, d, J=13.7), 2.95 (1H, d, J=11.5), 2.47 (1H, br t, J=3.4), 1.35 (3H, d, J=6.5). MS (Cl+) m/z 573 (M+1). Isomer B: 1H NMR (360MHz, DMSO) δ 8.43 (1H, s), 7.82 (1H, s), 7.44 (2H, d, J=1.4), 7.37 (2H, s), 7.31-7.25 (3H, m , J=3.2), 5.16 (2H, s), 4.91 (1H, q, J=6.5), 4.35 (1H, d, J=2.8), 4.08 (1H, brt, J=10.1), 3.69 (3H, s), 3.60 (1H, d, J=8.8), 3.55 (1H, d, J=2.7), 3.30 (1H, d, J=8.7), 3.08 (1H, d, J=13.7), 2.95 (1H , d, J=11.5), 2.47 (1H, br t, J=3.4), 1.35 (3H, d, J=6.5). MS (Cl+) m/z 573 (M+1).

b) 2-(R)-(1-(R)-(3,5-bis(trifluormetil)fenil)etoksi)-3-(S)-(4-fluorofenil)-4-(N-(N'-metilkarboksamido)metil-1,2,4-triazol-3-il)metilmorfolin b) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(N-(N'- methylcarboxamido)methyl-1,2,4-triazol-3-yl)methylmorpholine

Monometilaminski plin se rasprši kroz otopinu (a) gornjeg spoja (375mg izomera b) u metanolu (25ml) kroz 10 minuta i zatim zatvori na 16 sati. Reakciona smjesa se evaporira, ponovno otopi u etil acetatu i koncentrira in vacuo do bijele krute tvari (374mg). 1H NMR (250MHz, CDCI3) δ 8.09 (1H, s), 7.61 (1H, s), 7.45 (2H, br s), 7.33 (2H, s), 7.31 (1H, br s), 7.13 (2H, br s), 4.85 (1H, q, J=6.5Hz), 4.76 (2H, s), 4.37 (1H, br s), 4.36 (1H, br s), 3.85 (1H, d), 3.66 (1H, br s), 3.63 (1H, br s), 3.49 (1H, d), 3.03 (1H, br s), 2.82 (3H, d), 2.80 (1H, br s), 1.46 (3H, d). MS (Cl+) 573 (M++1). Monomethylamine gas was sparged through a solution of (a) of the above compound (375mg of isomer b) in methanol (25ml) for 10 minutes and then closed for 16 hours. The reaction mixture was evaporated, redissolved in ethyl acetate and concentrated in vacuo to a white solid (374mg). 1H NMR (250MHz, CDCl3) δ 8.09 (1H, s), 7.61 (1H, s), 7.45 (2H, br s), 7.33 (2H, s), 7.31 (1H, br s), 7.13 (2H, br s), 4.85 (1H, q, J=6.5Hz), 4.76 (2H, s), 4.37 (1H, br s), 4.36 (1H, br s), 3.85 (1H, d), 3.66 (1H, br s), 3.63 (1H, no s), 3.49 (1H, d), 3.03 (1H, no s), 2.82 (3H, d), 2.80 (1H, no s), 1.46 (3H, d). MS (Cl+) 573 (M++1).

c) 2-(R)-(1-(R)-3.5-bis(trifluorometil)fenil)etoksi)-3-(S)-(4-fluorofenin-4-(N-(2-metilaminoetil)-1.2,4-triazol-3-il) metilmorfolin c) 2-(R)-(1-(R)-3.5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenin-4-(N-(2-methylaminoethyl)-1.2, 4-triazol-3-yl) methylmorpholine

Ohlađena otopina gornjeg (b) spoja (302mg) u tetrahidrofuranu (5ml) i bor-tetrahidrofuran kompleksu (1.59ml, 1M) miješa se 60 minuta prije zagrijavanja (60°C) daljnjih 60 minuta. Reakcija se evaporira i ponovno otopi u CH3OH sa K2CO3 prije zagrijavanja do refluksa 30 minuta. Reakcija se ulije u etil acetat, ispere (voda x 2, slana otopina), osuši (MgSO4). Pročišćavanjem na siliciju koristeći CH3OH-diklormetan smjesu dobiva se naslovni spoj kao bezbojno ulje (54mg). 1H NMR (250MHz, CDCI3) δ 7.97 (1H, s), 7.53 (1H, s), 7.39 (2H, br s), 7.29-7.23 (3H, m, J=2.6), 7.06 (2H, s), 4.77 (1H, q, J=6.6), 4.29 (1H, d, J=2.9), 4.25 (1H, brt, J=2.6), 4.13 (2H, t, J=5.7), 3.76 (1H, d, J=14.2), 3.57 (1H, t, J=3.5), 3.53 (1H, d, J=2.8), 3.31 (1H, d, J=14.1), 2.95 (1H, t, J=9.3), 2.92 (2H, t, J=5.9), 2.56 (1H, br t, J=3.5), 2.36 (3H, s), 2.16 (1H, br s), 1.37 (3H, d, J=6.6). MS (Cl+) m/z 558 (M++1). A cooled solution of the above (b) compound (302mg) in tetrahydrofuran (5ml) and boron-tetrahydrofuran complex (1.59ml, 1M) was stirred for 60 minutes before heating (60°C) for a further 60 minutes. The reaction was evaporated and redissolved in CH 3 OH with K 2 CO 3 before heating to reflux for 30 min. The reaction was poured into ethyl acetate, washed (water x 2, brine), dried (MgSO4). Purification on silica using a CH3OH-dichloromethane mixture gave the title compound as a colorless oil (54mg). 1H NMR (250MHz, CDCl3) δ 7.97 (1H, s), 7.53 (1H, s), 7.39 (2H, br s), 7.29-7.23 (3H, m, J=2.6), 7.06 (2H, s), 4.77 (1H, q, J=6.6), 4.29 (1H, d, J=2.9), 4.25 (1H, brt, J=2.6), 4.13 (2H, t, J=5.7), 3.76 (1H, d, J=14.2), 3.57 (1H, t, J=3.5), 3.53 (1H, d, J=2.8), 3.31 (1H, d, J=14.1), 2.95 (1H, t, J=9.3), 2.92 (2H, t, J=5.9), 2.56 (1H, br t, J=3.5), 2.36 (3H, s), 2.16 (1H, br s), 1.37 (3H, d, J=6.6). MS (Cl+) m/z 558 (M++1).

Primjeri 14 do 21 u Tabeli 2 pripravljeni su na jednak način opisan u Primjeru 12, Postupak B, s odgovarajućim N-(4-azidobut-2-inil)morfolinom i odgovarajućim aminom. Examples 14 to 21 in Table 2 were prepared in the same manner as described in Example 12, Process B, with the appropriate N-(4-azidobut-2-ynyl)morpholine and the appropriate amine.

Primjer 22 Example 22

2-(R)-(1-(R-(3,5-bis(trifluorometil)fenil)etoksi)-3-(S)-fenil-4-(1-(2-pirolidinoetil)-1,2,4-triazol-3-il)metilmorfolin 2-(R)-(1-(R-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-phenyl-4-(1-(2-pyrrolidinoethyl)-1,2,4 -triazol-3-yl)methylmorpholine

a) 2-(R)-(1-(R-(3,5-bis(trifluorometil)fenil)etoksi)-4-(1-(2-okso-2-pirolidinoetin-1,2,4-triazol-3-inmetil-3-(S)-fenilmorfolin a) 2-(R)-(1-(R-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(1-(2-oxo-2-pyrrolidinoethyne-1,2,4-triazol- 3-inmethyl-3-(S)-phenylmorpholine

Otopina spoja iz Opisa 19 (2.86g), kalij karbonata 82.37g) i I-bromoacetilpirolidina (1.21g) zagrijava se na 60°C u dimetilformamidu (15ml). Smjesa se ohladi i razdijeli između vode i etil acetata. Organska faza se ispere vodom, slanom otopinom i osuši (MgSO4). Otapalo se odstrani in vacuo i ostatak se pročisti na siliciju koristeći 1.5% metanol i dikormetanu kao eluent. Time se dobivaju 2 proizvoda, izomer A i izomer B. A solution of the compound from Description 19 (2.86g), potassium carbonate 82.37g) and I-bromoacetylpyrrolidine (1.21g) is heated to 60°C in dimethylformamide (15ml). The mixture was cooled and partitioned between water and ethyl acetate. The organic phase is washed with water, brine and dried (MgSO4). The solvent was removed in vacuo and the residue was purified on silica using 1.5% methanol and dichloromethane as eluent. This gives 2 products, isomer A and isomer B.

Izomer A (alkilacija na položaju 2 1,2,4-triazola): 1H NMR (250MHz, CDCL3) δ 7.83 (1H, s), 7.61 (1H, s), 7.39-7.30 (5H, m), 7.16 (2H, s), 5.00 (1H, d, J=16.4Hz), 4.88 (1H, q, J=6.6Hz), 4.67 (1H, d, J=16.4Hz), 4.35 (1H, d, J=2.8Hz), 4.20 (1H, brt, J=11.6Hz), 3.77 (1H, d, J=14.4Hz), 3.62 (1H, dd, J=11.3Hz), 3.51-3.44 (4H, m), 3.39 (1H, s), 3.33 (1H, d, J=14.4Hz), 2.90 (1H, d, J=11.4Hz), 2.74 (1H, br t, J=11.8Hz), 2.12-2.02 (2H, m), 1.97-1.86 (2H, m), 1.45 (3H, d, J=6.6Hz). Isomer A (alkylation at position 2 of 1,2,4-triazole): 1H NMR (250MHz, CDCL3) δ 7.83 (1H, s), 7.61 (1H, s), 7.39-7.30 (5H, m), 7.16 (2H , s), 5.00 (1H, d, J=16.4Hz), 4.88 (1H, q, J=6.6Hz), 4.67 (1H, d, J=16.4Hz), 4.35 (1H, d, J=2.8Hz ), 4.20 (1H, brt, J=11.6Hz), 3.77 (1H, d, J=14.4Hz), 3.62 (1H, dd, J=11.3Hz), 3.51-3.44 (4H, m), 3.39 (1H , s), 3.33 (1H, d, J=14.4Hz), 2.90 (1H, d, J=11.4Hz), 2.74 (1H, br t, J=11.8Hz), 2.12-2.02 (2H, m), 1.97-1.86 (2H, m), 1.45 (3H, d, J=6.6Hz).

Izomer B (alkilacija na položaju 1 1,2,4-triazola): 1H NMR (250MHz, CDCI3) δ 5 8.19 (1H, s), 7.60 (1H, s), 7.47 (2H, br s), 7.36-7.27 (3H, m), 7.14 (2H, s), 4.89 (2H, s), 4.85 (1H, q, J=6.6Hz), 4.36 (1H, d, J=2.8Hz), 4.31 (1H, br t, J=11.4Hz), 3.86 (1H, d, J=14.0Hz), 3.60 (1H, dd, J=11.3Hz), 3.59 (1H, d, J=2.7Hz), 3.53-3.48 (4H, m), 3.35 (1H, d, J=14.1Hz), 3.03 (1H, d, J=11.8Hz), 2.60 (1H, br t, J=11.9Hz), 2.08-2.00 (2H, m), 1.94-1.84 (2H, m), 1.44 (3H, d, J=6.6Hz). Isomer B (alkylation at position 1 of 1,2,4-triazole): 1H NMR (250MHz, CDCl3) δ 5 8.19 (1H, s), 7.60 (1H, s), 7.47 (2H, br s), 7.36-7.27 (3H, m), 7.14 (2H, s), 4.89 (2H, s), 4.85 (1H, q, J=6.6Hz), 4.36 (1H, d, J=2.8Hz), 4.31 (1H, no t , J=11.4Hz), 3.86 (1H, d, J=14.0Hz), 3.60 (1H, dd, J=11.3Hz), 3.59 (1H, d, J=2.7Hz), 3.53-3.48 (4H, m ), 3.35 (1H, d, J=14.1Hz), 3.03 (1H, d, J=11.8Hz), 2.60 (1H, br t, J=11.9Hz), 2.08-2.00 (2H, m), 1.94- 1.84 (2H, m), 1.44 (3H, d, J=6.6Hz).

b) 2-(R)-(1-(R-(3,5-bis(trifluorometil)fenil)etoksi)-3-(S)-fenil-4-(1-(2-pirolidinoetil)-1,2,4-triazol-3-il)metilmorfolin b) 2-(R)-(1-(R-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-phenyl-4-(1-(2-pyrrolidinoethyl)-1,2 ,4-triazol-3-yl)methylmorpholine

Litij aluminij hidrid (1.0M otopina u tetrahidrofuranu, 1.9ml) dodaje se otopini gore opisanog (a) spoja (izomer B) u terahidrofuranu (5ml) na 0°C. Smjesa se zagrije do sobne temperature i miješa 1 sat. Smjesa se ugasi (natrijev hidroksid i voda) i filtrira kroz celit da bi se odstranile anorganske tvari. Filtrat se evaporira i pročišćava na siliciju koristeći 10% metanol u diklormetanu kao eluent. Time se dobiva proizvod kao žuto ulje. 1H NMR (250MHz, CDCI3) δ 8.08 (1H, s), 7.60 (1H, s), 7.49 (2H, br s), 7.37-7.31 (3H, m), 7.13 (2H, s), 4.85 (1H, q, J=6.6Hz), 4.36 (1H, d, J=2.8Hz), 4.33-4.24 (1H, m), 4.22 (2H, t, J=6.5Hz), 3.86 (1H, dd, J=14.1Hz), 3.63 (1H, d, J=9.2Hz), 3.60 (1H, d, J=2.9Hz), 3.38 (1H, dd, J=14.0Hz), 3.00 ( 1H, d, J=11.7Hz), 2.89 (2H, t, J=6.6Hz), 2.59 (1H, br t, J=11.9Hz), 2.59-2.49 (4H, m), 1.79 (4H, m), 1.43 (3H, d, J=6.5Hz). Lithium aluminum hydride (1.0M solution in tetrahydrofuran, 1.9ml) was added to a solution of compound (a) described above (isomer B) in terahydrofuran (5ml) at 0°C. The mixture is warmed to room temperature and stirred for 1 hour. The mixture is quenched (sodium hydroxide and water) and filtered through celite to remove inorganics. The filtrate is evaporated and purified on silica using 10% methanol in dichloromethane as eluent. This gives the product as a yellow oil. 1H NMR (250MHz, CDCl3) δ 8.08 (1H, s), 7.60 (1H, s), 7.49 (2H, br s), 7.37-7.31 (3H, m), 7.13 (2H, s), 4.85 (1H, q, J=6.6Hz), 4.36 (1H, d, J=2.8Hz), 4.33-4.24 (1H, m), 4.22 (2H, t, J=6.5Hz), 3.86 (1H, dd, J=14.1 Hz), 3.63 (1H, d, J=9.2Hz), 3.60 (1H, d, J=2.9Hz), 3.38 (1H, dd, J=14.0Hz), 3.00 (1H, d, J=11.7Hz) , 2.89 (2H, t, J=6.6Hz), 2.59 (1H, br t, J=11.9Hz), 2.59-2.49 (4H, m), 1.79 (4H, m), 1.43 (3H, d, J= 6.5Hz).

Primjer 23 Example 23

2-(R)-n-(R)-(3.5-bisftrifluorometil)fenil)etoksi)-3-(S)-fenil-4-(2-(2-pirolidinoetil)-1,2,4-triazol-3-il)metilmorfolin 2-(R)-n-(R)-(3,5-bisfluoromethyl)phenyl)ethoxy)-3-(S)-phenyl-4-(2-(2-pyrrolidinoethyl)-1,2,4-triazol-3 -yl)methylmorpholine

Spoj opisan u Primjeru 22a (izomer A) reagira prema postupku opisanom u Primjeru 22b, da bi se dobio naslovni spoj kao žuto ulje. 1H NMR (250MHz, CDCI3) δ 7.80 (1H, s, CH), 7.61 (1H, s, ArH), 7.53-7.48 (2H, m, PhH), 7.38-7.34 (3H, m), 7.17 (2H, s), 4.88 (1H, q, J=6.5Hz), 4.36 (1H, d, J=2.9Hz), 4.34-4.20 (1H, m), 4.23-4.07 (3H, m), 3.83 (1H, d, J=14.0Hz), 3.66 (1H, m), 3.42 (1H, d, J=2.8Hz), 3.27 (1H, d, J=14.1Hz), 2.88-2.73 (1H, m), 2.88-2.73 (2H, m), 2.88-2.73 (1H, m), 2.50 (3H, brs), 1.73 (4H, brs), 1.4 (4H, d, J=6.6Hz). The compound described in Example 22a (isomer A) is reacted according to the procedure described in Example 22b to give the title compound as a yellow oil. 1H NMR (250MHz, CDCl3) δ 7.80 (1H, s, CH), 7.61 (1H, s, ArH), 7.53-7.48 (2H, m, PhH), 7.38-7.34 (3H, m), 7.17 (2H, s), 4.88 (1H, q, J=6.5Hz), 4.36 (1H, d, J=2.9Hz), 4.34-4.20 (1H, m), 4.23-4.07 (3H, m), 3.83 (1H, d , J=14.0Hz), 3.66 (1H, m), 3.42 (1H, d, J=2.8Hz), 3.27 (1H, d, J=14.1Hz), 2.88-2.73 (1H, m), 2.88-2.73 (2H, m), 2.88-2.73 (1H, m), 2.50 (3H, brs), 1.73 (4H, brs), 1.4 (4H, d, J=6.6Hz).

Primjer 24 Example 24

2-(R)-(1-(R)-(3,5-bis(trifluorometinfenil)etoksi)-3-(S)-(4-fluorofenil)-4-(5-morfolinometil-1,2,3-triazol-4-il) metilmorfolin 2-(R)-(1-(R)-(3,5-bis(trifluoromethinephenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(5-morpholinomethyl-1,2,3- triazol-4-yl) methylmorpholine

Ovaj spoj pripravljen je postupkom opisanim u Primjeru 12 (Postupak A) i pročišćen kromatografijom na siliciju koristeći etil acetat, petrolej eter (60-80°C) i metanol (3:10:0, zatim 1:0:0 praćeno sa 9:0:1) kao eluent da bi se dobio naslovni spoj kao bijela pjena. 1H NMR (360MHz, CDCI3) δ 1.44 (3H, d, J=6.6Hz), 2.43 (4H, m), 2.57 (1H, dd, J=11.9, 3.4Hz), 2.90 (1H, d, J=11.6Hz), 3.27 (1H, d, J=14.1Hz), 3.46-3.67 (8H, m), 3.82 (1H, d, J=14.1Hz), 4.23 (1H, m), 4.32 (1H, d, J=2.8Hz), 4.87 (1H, m), 7.06 (2H, t, J=8.7Hz), 7.16 (2H, s), 7.48 (2H, br s), 7.64 (1H, s). MS (ES+) m/z 618 (MH+, 54%). This compound was prepared by the procedure described in Example 12 (Procedure A) and purified by chromatography on silica using ethyl acetate, petroleum ether (60-80°C) and methanol (3:10:0, then 1:0:0 followed by 9: 0:1) as eluent to give the title compound as a white foam. 1H NMR (360MHz, CDCl3) δ 1.44 (3H, d, J=6.6Hz), 2.43 (4H, m), 2.57 (1H, dd, J=11.9, 3.4Hz), 2.90 (1H, d, J=11.6 Hz), 3.27 (1H, d, J=14.1Hz), 3.46-3.67 (8H, m), 3.82 (1H, d, J=14.1Hz), 4.23 (1H, m), 4.32 (1H, d, J =2.8Hz), 4.87 (1H, m), 7.06 (2H, t, J=8.7Hz), 7.16 (2H, s), 7.48 (2H, br s), 7.64 (1H, s). MS (ES+) m/z 618 (MH+, 54%).

Primjeri 25 do 27 u Tabeli 2 pripravljeni su na jednak način opisan u Primjeru 12, Postupak B, s odgovarajućim N-(4-azidobut-2-inil)morfolinom i odgovarajućim aminom. Examples 25 to 27 in Table 2 were prepared in the same manner as described in Example 12, Process B, with the appropriate N-(4-azidobut-2-ynyl)morpholine and the appropriate amine.

Primjer 28 Example 28

2-(R)-(1-(R)-(3,5-bis(trifluorometil)fenil)etoksi)-4-(2-kloro-5-morfolinometil-1,3-imidazol-4-il)-3-(S)-4-fluorofenil) morfolin 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(2-chloro-5-morpholinomethyl-1,3-imidazol-4-yl)-3 -(S)-4-fluorophenyl)morpholine

Proizvod iz Primjera 7 (0.2g) i fosforni oksiklorid (0.5ml) zagrijavaju se uz refluks 20 sati. Smjesa se ohladi i razdijeli između diklormetana i vodene otopine kalij karbonata. Organski sloj se ispere (H2O), osuši (MgSO4) i evaporira in vacuo. Proizvod se pročisti kromatografijom na siliciju koristeći 100% etil acetat praćeno sa 5% metanol:95% etil acetata da bi se dobio naslovni spoj kao ulje. MS (ES+) m/z 651 (MH+, 100%). The product from Example 7 (0.2g) and phosphorus oxychloride (0.5ml) are heated under reflux for 20 hours. The mixture was cooled and partitioned between dichloromethane and aqueous potassium carbonate. The organic layer is washed (H2O), dried (MgSO4) and evaporated in vacuo. The product was purified by chromatography on silica using 100% ethyl acetate followed by 5% methanol:95% ethyl acetate to afford the title compound as an oil. MS (ES+) m/z 651 (MH+, 100%).

Primjer 29 Example 29

2-(R)-(1-(R)-3,5-bis(trifluorometil)fenil)etoksi)-4-(5-(N,N-dimetilaminometil)imidazol-4-il)metil-3-(S)-4-fluorofenil) morfolin 2-(R)-(1-(R)-3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(N,N-dimethylaminomethyl)imidazol-4-yl)methyl-3-(S )-4-fluorophenyl)morpholine

4,5-bis(klorometil)imidazol hidroklord (British Patent Specification No. GB-2,068,362-A) reagira sa spojem iz Opisa 5 prema postupku navedenom u Primjeru 4, da bi se dobio naslovni spoj kao bijela kruta tvar. 1H NMR (250MHz, CDCI3) δ 1.44 (3H, d, J=6Hz), 2.19 (3H, s), 2.46-2.62 (1H, m), 2.92-3.07 (2H, m), 3.25-3.44 (3H, m), 3.56-3.70 (2H, m), 4.16-4.33 (2H, m), 4.85 (1H, q, J=6Hz), 7.01-7.17 (4H, m), 7.38-7.67 (4H, m). MS (ES) m/z 575 (M+1+, 100%). 4,5-bis(chloromethyl)imidazole hydrochloride (British Patent Specification No. GB-2,068,362-A) is reacted with the compound of Description 5 according to the procedure outlined in Example 4 to give the title compound as a white solid. 1H NMR (250MHz, CDCl3) δ 1.44 (3H, d, J=6Hz), 2.19 (3H, s), 2.46-2.62 (1H, m), 2.92-3.07 (2H, m), 3.25-3.44 (3H, m), 3.56-3.70 (2H, m), 4.16-4.33 (2H, m), 4.85 (1H, q, J=6Hz), 7.01-7.17 (4H, m), 7.38-7.67 (4H, m). MS (ES) m/z 575 (M+1+, 100%).

Primjer 30 Example 30

2-(R)-(1-(R)-(3.5-bis(trifluorometil)fenil)etoksi)-4-(5-(N,N-dimetilaminometil)-1,2,4-triazol-3-il)metil-3-(S)-(4-fluorofenil)morfolin 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(N,N-dimethylaminomethyl)-1,2,4-triazol-3-yl) methyl-3-(S)-(4-fluorophenyl)morpholine

3,5-bis(klorometil)triazol (J. Het. Chem. (1986) 23, 361-368) reagira sa spojem iz Opisa 5 prema postupku navedenom u Primjeru 4 da bi se dobio naslovni spoj kao kruta tvar. 1H NMR (250MHz, CDCI3) δ 1.27 (3H, d, J=6.6Hz), 2.15 (6H, s, CH3), 2.43 (1H, dt, J=11.7, 3.2Hz), 2.79-2.83 (1H, m), 3.16 (1H, d, J=14.5Hz), 3.38 (1H, d, J=2.8Hz), 3.43-3.48 (1H, m), 3.48 (2H, s, CH2), 3.36 (1H, d, J=14.5Hz), 4.12 (1H, dt, J=11.7, 3.2Hz), 4.15 (1H, d, J=2.8Hz), 4.69 (1H, q, J=6.6Hz), 6.85 (2H, t, J=8.75Hz), 6.97 (2H, s), 7.27 (2H, br t), 7.45 (1H, s). MS (ES) m/z 576 (M++1, 100%). 3,5-bis(chloromethyl)triazole (J. Het. Chem. (1986) 23, 361-368) is reacted with the compound of Description 5 according to the procedure of Example 4 to give the title compound as a solid. 1H NMR (250MHz, CDCl3) δ 1.27 (3H, d, J=6.6Hz), 2.15 (6H, s, CH3), 2.43 (1H, dt, J=11.7, 3.2Hz), 2.79-2.83 (1H, m ), 3.16 (1H, d, J=14.5Hz), 3.38 (1H, d, J=2.8Hz), 3.43-3.48 (1H, m), 3.48 (2H, s, CH2), 3.36 (1H, d, J=14.5Hz), 4.12 (1H, dt, J=11.7, 3.2Hz), 4.15 (1H, d, J=2.8Hz), 4.69 (1H, q, J=6.6Hz), 6.85 (2H, t, J=8.75Hz), 6.97 (2H, s), 7.27 (2H, br t), 7.45 (1H, s). MS (ES) m/z 576 (M++1, 100%).

Primjeri 31 do 37 iz Tabele 2 pripravljeni su na jednak način opisan u Primjeru 12, Postupak B, s odgovarajućim N-(4-azidobut-2-inil)morfolinom i odgovarajućim aminom. Examples 31 to 37 of Table 2 were prepared in the same manner as described in Example 12, Process B, with the appropriate N-(4-azidobut-2-ynyl)morpholine and the appropriate amine.

Primjeri 38 do 41 iz Tabele 1 pripravljeni su na jednak način opisan u Primjeru 4, iz odgovarajućeg morfolina, 4,5-bis(bromoetil)-1,3-diacetil-2-imidazolinona i odgovarajućeg amina. Examples 38 to 41 of Table 1 were prepared in the same manner as described in Example 4, from the corresponding morpholine, 4,5-bis(bromoethyl)-1,3-diacetyl-2-imidazolinone and the corresponding amine.

Primjer 42 Example 42

2-(R)-(1-(R)-bis(trifluormetil)fenil)etoksi)-3-(S)-(4-fluorofenil)-4-(2,3-dihidro-2-okso-5-tiomorfolinometil-1,3-imidazol-4-il)metilmorfolin S-oksid 2-(R)-(1-(R)-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(2,3-dihydro-2-oxo-5-thiomorpholinomethyl) -1,3-imidazol-4-yl)methylmorpholine S-oxide

Spoj iz Primjera 38 (67mg; 1eq) otopi se u CF3CO2H (0.3ml) pod N2, zatim ohladi do 0°C i doda se otopina CF3CO3H (2M u CF3CO2H; 57 µ, 1.1 eq). Nakon miješanja na 0°C 1 sat, otapalo se odstrani in vacuo i dobiveni ostatak otopi u EtOAc i ispere sa zasićenom vodenom otopinom NaHCO3, osuši (K2CO3) i koncentrira do žute pjene. To se pročišćava kolonskom kromatografijom koristeći MeOH/CH2Cl2/NH3 (3:97:0.25) kao eluent da bi se dobio naslovni spoj kao bijela kruta tvar. 1H NMR (250MHz, CDCI3) δ 9.48 (1H, s), 8.66 (1H, s), 7.64 (1H, s), 7.40 (2H, m), 7.14 (2H, s), 7.06 (2H, t, J=8.6Hz), 4.87 (1H, q, J=6.5Hz), 4.30 (1H, d, J=2.70Hz), 4.23 (1H, t, J=10.0Hz), 3.65 (1H, d, J=9.6Hz), 3.45 (1H, m), 3.75 (1H, m), 3.36 (1H, d, J=2.7Hz), 3.30 (1H, d, J=14Hz), 3.20 (1H, d, J=14Hz), 3.05-2.60 (9H, m), 2.36 (1H, m), 1.46 (3H, d, J=6.5Hz). The compound from Example 38 (67mg; 1eq) was dissolved in CF3CO2H (0.3ml) under N2, then cooled to 0°C and a solution of CF3CO3H (2M in CF3CO2H; 57 µ, 1.1 eq) was added. After stirring at 0°C for 1 hour, the solvent was removed in vacuo and the resulting residue was dissolved in EtOAc and washed with saturated aqueous NaHCO3, dried (K2CO3) and concentrated to a yellow foam. This was purified by column chromatography using MeOH/CH2Cl2/NH3 (3:97:0.25) as eluent to afford the title compound as a white solid. 1H NMR (250MHz, CDCl3) δ 9.48 (1H, s), 8.66 (1H, s), 7.64 (1H, s), 7.40 (2H, m), 7.14 (2H, s), 7.06 (2H, t, J =8.6Hz), 4.87 (1H, q, J=6.5Hz), 4.30 (1H, d, J=2.70Hz), 4.23 (1H, t, J=10.0Hz), 3.65 (1H, d, J=9.6 Hz), 3.45 (1H, m), 3.75 (1H, m), 3.36 (1H, d, J=2.7Hz), 3.30 (1H, d, J=14Hz), 3.20 (1H, d, J=14Hz) , 3.05-2.60 (9H, m), 2.36 (1H, m), 1.46 (3H, d, J=6.5Hz).

Primjeri 43 do 62 iz Tabele 2 pripravljeni su na jednak način opisan u Primjeru 12, Postupak B, s odgovarajućim N-(4-azidobut-2-inil)morfolinom i odgovarajućim aminom. Examples 43 to 62 of Table 2 were prepared in the same manner as described in Example 12, Process B, with the appropriate N-(4-azidobut-2-ynyl)morpholine and the appropriate amine.

Primjer 63 Example 63

2-(R)-(1-(R)-(3.5-bisarifluorometil)fenil)etoksi)-4-(1-(2-(N,N-diizopropilamino)etil)-1,2,4-triazol-3-il)metil-3-(S)-fenilmorfolin 2-(R)-(1-(R)-(3.5-bisarifluoromethyl)phenyl)ethoxy)-4-(1-(2-(N,N-diisopropylamino)ethyl)-1,2,4-triazole-3 -yl)methyl-3-(S)-phenylmorpholine

a) 2-(R)-(1-(R)-(3,5-bis(trifluorometil)feninetoksi)-4-(1-(2-hidroksietil)-1,214-triazol-3-il)metil-3-(S)-fenilmorfolin a) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenylethoxy)-4-(1-(2-hydroxyethyl)-1,214-triazol-3-yl)methyl-3- (S)-phenylmorpholine

Spoj iz Opisa 19 (3.90g, 7.8mM) zagrijava se (60°C) u dimetilformamidu (20ml) sa 2-bromoetanolom (1.66, 23.4 mM) i kalij karbonatom (3.23g, 23.4mM) 2 sata. Reakcija se ulije u etil acetat i ispere vodom i slanom otopinom, osuši (MgSO4) i evaporira. Dva izomera se pročiste i separiraju na siliciju elucijom sa smjesom metanol-diklormetana (3.06g). MS (ES+) m/z 545. The compound from Description 19 (3.90g, 7.8mM) is heated (60°C) in dimethylformamide (20ml) with 2-bromoethanol (1.66, 23.4mM) and potassium carbonate (3.23g, 23.4mM) for 2 hours. The reaction was poured into ethyl acetate and washed with water and brine, dried (MgSO4) and evaporated. The two isomers are purified and separated on silica by elution with a methanol-dichloromethane mixture (3.06g). MS (ES+) m/z 545.

b) 2-(R)-(1-(R)-(3,5-bis(trifluorometil)fenil)etoksi)-3-(S)-fenil-4-(1-(2-toziloksietin-1,2,4-triazol-3-il)metilmorfolin b) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-phenyl-4-(1-(2-tosyloxyethene-1,2 ,4-triazol-3-yl)methylmorpholine

Alkohol iz gornjeg (a) stupnja (1.81g, 3.22mM) otopi se u diklormetanu (20ml), tozil klorid (1.84g, 9.66mM) i trietilamin (1.34ml, 9.66mM) se dodaju i reakcija miješa na sobnoj temperaturi 18 sati. Otapalo se odstrani i dobiveni ostatak ponovno otopi u etil acetatu i ispere s vodom i slanom otopinom, osuši (MgSO4) i evaporira. Proizvod se pročišćava na siliciju elucijom sa smjesom metanol-diklormetan (1.87g). The alcohol from step (a) above (1.81g, 3.22mM) is dissolved in dichloromethane (20ml), tosyl chloride (1.84g, 9.66mM) and triethylamine (1.34ml, 9.66mM) are added and the reaction is stirred at room temperature for 18 hours. . The solvent was removed and the resulting residue was redissolved in ethyl acetate and washed with water and brine, dried (MgSO4) and evaporated. The product is purified on silica by elution with a methanol-dichloromethane mixture (1.87g).

c) 2-(R)-(1-(R)-(3.5-bis(trifluorometil)fenil)etoksi)-(1-(2-(N,N-diizopropilamino)etil)-1.2,4-triazol-3-il)metil-3-(S)-fenilmorfolin c) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-(1-(2-(N,N-diisopropylamino)ethyl)-1,2,4-triazol-3 -yl)methyl-3-(S)-phenylmorpholine

Tozilat (b) iz gornjeg stupnja (0.29g, 0.41 mM) otopi se u dimetilformamidu (5ml), dipropilamin (0.18ml, 1.24mM) i trietilamin (0.18, 1.24mM) se dodaju u reakciju i reakcija se zagrijava u zatvorenoj cijevi 18 sati. Ovaj ostatak se otopi u etil acetatu, ispere vodom i slanom otopinom, osuši (MgSO4) i evaporira. Pročišćavanjem na siliciju elucijom sa smjesom metanol-diklormetan dobiva se naslovni spoj (0.095g). 1H NMR (360MHz, d6-DMSO) δ 8.31 (1H, s), 7.82 (1H, s), 7.46-7.42 (2H, m), 7.36 (2H, s), 7.32-7.22 (3H, m), 4.89-4.92 (1H, q, J=6.5Hz), 4.34 (1H, d, J=2.8Hz), 4.18-4.04 (3H, m), 3.60-3.56 (3H, m), 3.09 (1H, d, J=13.6Hz), 3.94 (1H, d, J=11.5Hz), 2.71 (2H, t, J=5.8Hz), 2.44-2.40 (1H, m), 2.30 (4H, t, J=7.0Hz), 1.34 (3H, d, J=6.5Hz), 1.32-1.20 (4H, m) i 0.73 (6H, t, J=7.4Hz). M/S+ 628. The tosylate (b) from the above step (0.29g, 0.41mM) was dissolved in dimethylformamide (5ml), dipropylamine (0.18ml, 1.24mM) and triethylamine (0.18, 1.24mM) were added to the reaction and the reaction was heated in a closed tube for 18 hours. This residue was dissolved in ethyl acetate, washed with water and brine, dried (MgSO4) and evaporated. Purification on silica by elution with a methanol-dichloromethane mixture gives the title compound (0.095g). 1H NMR (360MHz, d6-DMSO) δ 8.31 (1H, s), 7.82 (1H, s), 7.46-7.42 (2H, m), 7.36 (2H, s), 7.32-7.22 (3H, m), 4.89 -4.92 (1H, q, J=6.5Hz), 4.34 (1H, d, J=2.8Hz), 4.18-4.04 (3H, m), 3.60-3.56 (3H, m), 3.09 (1H, d, J =13.6Hz), 3.94 (1H, d, J=11.5Hz), 2.71 (2H, t, J=5.8Hz), 2.44-2.40 (1H, m), 2.30 (4H, t, J=7.0Hz), 1.34 (3H, d, J=6.5Hz), 1.32-1.20 (4H, m) and 0.73 (6H, t, J=7.4Hz). M/S+ 628.

Primjeri 64 do 74 u Tabeli 3 pripravljeni su na jednak način opisan u Primjeru 63 iz odgovarajućeg 1,2,4-triazol-3-il-metilmorfolina i odgovarajućeg amina. Examples 64 to 74 in Table 3 were prepared in the same manner as described in Example 63 from the corresponding 1,2,4-triazol-3-yl-methylmorpholine and the corresponding amine.

Primjer 75 Example 75

2-(R)-(l-(R)-3,5-bis(trifluormetil)fenil)etoksi)-4-(5-(N,N-dimetilaminometil)-1,2,4-triazol-3-il)metil-3-(S)-4-fluorofenil)morfolin 2-(R)-(1-(R)-3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(N,N-dimethylaminomethyl)-1,2,4-triazol-3-yl )methyl-3-(S)-4-fluorophenyl)morpholine

a) 2-(R)-(1-(R)-(3,5-bis(trifluorometil)fenil)etoksn-3-(S)-(4-fluorofenil)-4-(1-tetrahidro-2-piranil)5-(N.N-dimetilaminometil)-1H-1,2,4-triazol-3-il)metilmorfolin a) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxn-3-(S)-(4-fluorophenyl)-4-(1-tetrahydro-2-pyranyl) )5-(N,N-dimethylaminomethyl)-1H-1,2,4-triazol-3-yl)methylmorpholine

Spoj iz Opisa 5 (1g, 2.28mM) otopi se u izopropanolu (20ml), dodaju se 3,5-bis(klorometil)-1-(tetrahidro-2-piranil)-1H-1,2,4-triazol (1.14g, 4.57mM) (pripremljeno prema postupku Bradshaw, J. Het. Chem. (1986), 23, 361) i kalijev karbonat (0.95g, 6.84mM) i reakcija zagrijava do 60°C 18 sati. Zatim se doda dimetilamin (3 eq) i reagensi prebace u cijev, zatvore i zagrijavaju daljnjih 18 sati. Nakon toga se otapala odstrane i ostatak se pročišćava na siliciju elucijom sa smjesom metanol diklormetan-amonijak da bi se dobio naslovni spoj (0.62g). The compound from Description 5 (1g, 2.28mM) was dissolved in isopropanol (20ml), 3,5-bis(chloromethyl)-1-(tetrahydro-2-pyranyl)-1H-1,2,4-triazole (1.14 g, 4.57mM) (prepared according to the method of Bradshaw, J. Het. Chem. (1986), 23, 361) and potassium carbonate (0.95g, 6.84mM) and the reaction heated to 60°C for 18 hours. Dimethylamine (3 eq) is then added and the reagents are transferred to a tube, sealed and heated for a further 18 hours. After that, the solvents were removed and the residue was purified on silica by elution with a mixture of methanol dichloromethane-ammonia to give the title compound (0.62g).

b) 2-(R)-(1-(R)-3,5-bis(trifluormetil)fenil)etoksi)-4-(5-(N,N-dimetilaminometil)-1,2,4-triazol-3-il)metil-3-(S)-(4-fluorofenil)morfolin b) 2-(R)-(1-(R)-3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(N,N-dimethylaminomethyl)-1,2,4-triazol-3 -yl)methyl-3-(S)-(4-fluorophenyl)morpholine

Zaštićeni amin iz gornjeg stupnja (a) (0.62g, 0.94mM) otopi se u metanolu (15ml), tretira sa HCI u metanolu (1N, 25ml) i miješa na sobnoj temperaturi 1 sat. Otapalo se odstrani i ostatak pročišćava na siliciju elucijom sa smjesom metanol-diklormetan amonijak da bi se dobio naslovni spoj (0.48g). 1H NMR (250MHz, CDCI3) δ 7.45 (1H, s), 7.30-7.22 (2H, m), 6.97 (2H, s), 6.85 (2H, t, J=8.7Hz), 4.72-4.66 (1H, q, J=6.5Hz), 4.15 (1H, d, J=2.8Hz), 4.15-4.07 (1H, m), 3.63 (1H, d, J=14.4Hz), 3.48 (4H, s), 3.44-3.41 (1H, m), 3.38 (1H, d J=2.8Hz), 3.16 (1H, d, J=14.5Hz), 2.81 (1H, d, J=11.1Hz), 2.50-2.39 (1H, m), 2.15 (6H, s) i 1.27 (3H, d, J=6.6Hz). M/S ES+ 576. The protected amine from step (a) above (0.62g, 0.94mM) was dissolved in methanol (15ml), treated with HCl in methanol (1N, 25ml) and stirred at room temperature for 1 hour. The solvent was removed and the residue was purified on silica by eluting with a mixture of methanol-dichloromethane ammonia to give the title compound (0.48g). 1H NMR (250MHz, CDCl3) δ 7.45 (1H, s), 7.30-7.22 (2H, m), 6.97 (2H, s), 6.85 (2H, t, J=8.7Hz), 4.72-4.66 (1H, q , J=6.5Hz), 4.15 (1H, d, J=2.8Hz), 4.15-4.07 (1H, m), 3.63 (1H, d, J=14.4Hz), 3.48 (4H, s), 3.44-3.41 (1H, m), 3.38 (1H, d J=2.8Hz), 3.16 (1H, d, J=14.5Hz), 2.81 (1H, d, J=11.1Hz), 2.50-2.39 (1H, m), 2.15 (6H, s) and 1.27 (3H, d, J=6.6Hz). M/S ES+ 576.

Primjer 76 Example 76

4-(5-(N,N-dimetilaminometil)-1,2,3-triazol-4-il)metil-3-(S)-4-fluorofenil)-2-(R)-(1-(R)-3-metiltio-5-(trifluormetil)fenil) etoksi)morfolin 4-(5-(N,N-dimethylaminomethyl)-1,2,3-triazol-4-yl)methyl-3-(S)-4-fluorophenyl)-2-(R)-(1-(R) -3-methylthio-5-(trifluoromethyl)phenyl)ethoxy)morpholine

Spoj iz Primjera 57 (270mg, 0.51 mmol) zagrijava se do 120°C sa natrijevim tiometoksidom (178mg, 2.55mmol) u bezvodnom DMF (10ml) između 2 i 5 sati. Ohlađena otopina se razrijedi vodom (150ml), ekstrahira etil acetatom (4 x 40ml), osuši (MgSO4) i koncentrira in vacuo do sirovog ulja (372mg) koje se pročišćava fleš silikagel kromatografijom u 5-10% metanol/diklormetanu da bi se dobio naslovni spoj kao viskozna smola/staklo (170mg, 60%), 1H NMR (360MHz, CDCL3), δ 1.31 (3H, d, J=6.6Hz), 2.17 (6H, s), 2.28 (3H, s), 2.47 (1H, dt, J=12.1, 3.4Hz), 2.82 (1H, d, J=11.6Hz), 3.14 (1H, d, J=13.9Hz), 3.35 (2H, m), 3.46 (1H, d, J=13.5Hz), 3.52 (1H, dd, J=11.2, 1.9Hz), 3.70 (1H, d, J=13.9Hz), 4.14 (1H, dt, J=11.6Hz), 4.26 (1H, d, J=2.7Hz), 4.66 (1H, q, J=6.5Hz), 6.64 (2H, s), 6.99 (2H, t, J=8.6Hz), 7.11 (1H, s), 7.41 (2H, brs), 10.0-10.8 (1H, vbr s); MS (ES+) m/z 554 (M+1, 100%). The compound from Example 57 (270mg, 0.51mmol) was heated to 120°C with sodium thiomethoxide (178mg, 2.55mmol) in anhydrous DMF (10ml) between 2 and 5 hours. The cooled solution was diluted with water (150ml), extracted with ethyl acetate (4 x 40ml), dried (MgSO4) and concentrated in vacuo to a crude oil (372mg) which was purified by flash silica gel chromatography in 5-10% methanol/dichloromethane to give title compound as viscous resin/glass (170mg, 60%), 1H NMR (360MHz, CDCL3), δ 1.31 (3H, d, J=6.6Hz), 2.17 (6H, s), 2.28 (3H, s), 2.47 (1H, dt, J=12.1, 3.4Hz), 2.82 (1H, d, J=11.6Hz), 3.14 (1H, d, J=13.9Hz), 3.35 (2H, m), 3.46 (1H, d, J=13.5Hz), 3.52 (1H, dd, J=11.2, 1.9Hz), 3.70 (1H, d, J=13.9Hz), 4.14 (1H, dt, J=11.6Hz), 4.26 (1H, d, J=2.7Hz), 4.66 (1H, q, J=6.5Hz), 6.64 (2H, s), 6.99 (2H, t, J=8.6Hz), 7.11 (1H, s), 7.41 (2H, brs) , 10.0-10.8 (1H, vbr s); MS (ES+) m/z 554 (M+1, 100%).

Primjer 77 Example 77

3-(S)-(4-fluorofenil)-2-(R)-(1-(R)-(3-metiltio-5-(trifluormetil)fenil)etoksi)-4-(5-pirolidinometil-1,2,3-triazol-4-il)metilmorfolin 3-(S)-(4-fluorophenyl)-2-(R)-(1-(R)-(3-methylthio-5-(trifluoromethyl)phenyl)ethoxy)-4-(5-pyrrolidinomethyl-1,2 ,3-triazol-4-yl)methylmorpholine

Naslovni spoj dobiven je iz spoja iz Primjera 18 prema postupku iz Primjera 76, kao pjena (620mg, 81%). 1H NMR (360MHz, CDCI3) δ 1.40 (3H, d, J=6.6Hz), 1.79 (4H, br s), 2.36 (3H, s), 2.5-2.6 (5H, m), 2.87 (1H, d, J=11.7Hz), 3.23 (1H, d, J=13.9Hz), 3.43 (1H, d, J=2.8Hz),3.57-3.64 (2H, m), 3.71 (1H, d, J=13.7Hz), 3.78 (1H, d, J=14.0Hz), 4.21 (1H, m), 4.33 (1H, d, J=2.8Hz), 4.74 (1H, q, J=6.5Hz), 6.71 (2H, s), 7.06 (2H, t, J=8.7Hz), 7.19 (1H, s), 7.47 (2H, br s); MS (ES+) m/z 580 (M+1, 100%). The title compound was obtained from the compound of Example 18 according to the procedure of Example 76, as a foam (620mg, 81%). 1H NMR (360MHz, CDCl3) δ 1.40 (3H, d, J=6.6Hz), 1.79 (4H, br s), 2.36 (3H, s), 2.5-2.6 (5H, m), 2.87 (1H, d, J=11.7Hz), 3.23 (1H, d, J=13.9Hz), 3.43 (1H, d, J=2.8Hz), 3.57-3.64 (2H, m), 3.71 (1H, d, J=13.7Hz) , 3.78 (1H, d, J=14.0Hz), 4.21 (1H, m), 4.33 (1H, d, J=2.8Hz), 4.74 (1H, q, J=6.5Hz), 6.71 (2H, s) , 7.06 (2H, t, J=8.7Hz), 7.19 (1H, s), 7.47 (2H, no s); MS (ES+) m/z 580 (M+1, 100%).

Primjer 78 Example 78

3-(S)-(4-fluorofenil)-2-(R)-(1-(R)-(3-metiltio-5-(trifluormetil)fenil)etoksi)-4-(5-morfolinometil-1,2,3-triazol-4-il)metilmorfolin 3-(S)-(4-fluorophenyl)-2-(R)-(1-(R)-(3-methylthio-5-(trifluoromethyl)phenyl)ethoxy)-4-(5-morpholinomethyl-1,2 ,3-triazol-4-yl)methylmorpholine

Naslovni spoj dobiven je iz spoja iz Primjera 19 prema postupku iz Primjera 76 kao pjena (126mg, 66%). 1H NMR (360MHz, CDCI3) δ 1.40 (3H, s, J=6.6Hz), 2.37 (3H, s), 2.32-2.49 (4H, m), 2.54 (1H, dt, J=11.9, 3.4Hz), 2.90 (1H, d, J=11.7Hz), 3.25 (1H, d, J=13.9Hz), 3.48 (1H, d, J=13.5Hz), 3.57-3.68 (7H, m), 3.82 (1H, d, J=14.1Hz), 4.23 (1H, m), 4.35 (1H, d, J=2.8Hz), 4.75 (1H, q, J=6.5Hz), 6.71 (2H, s), 7.06 (2H, t, J=8.7Hz), 7.19 (1H, s), 7.49 (2H, br s); MS (ES+) m/z 596 (M+1, 55%), 203 (100%). The title compound was obtained from the compound of Example 19 according to the procedure of Example 76 as a foam (126mg, 66%). 1H NMR (360MHz, CDCl3) δ 1.40 (3H, s, J=6.6Hz), 2.37 (3H, s), 2.32-2.49 (4H, m), 2.54 (1H, dt, J=11.9, 3.4Hz), 2.90 (1H, d, J=11.7Hz), 3.25 (1H, d, J=13.9Hz), 3.48 (1H, d, J=13.5Hz), 3.57-3.68 (7H, m), 3.82 (1H, d , J=14.1Hz), 4.23 (1H, m), 4.35 (1H, d, J=2.8Hz), 4.75 (1H, q, J=6.5Hz), 6.71 (2H, s), 7.06 (2H, t , J=8.7Hz), 7.19 (1H, s), 7.49 (2H, no s); MS (ES+) m/z 596 (M+1, 55%), 203 (100%).

Primjer 79 Example 79

4-(5-(N,N-dimetilaminometil)-1,2.3-triazol-4-il)metil-2-(R)-(1-(R)-(3-metiltio-5-(trifluormetil)fenil)etoksi)-3-(S)-fenilmorfolin 4-(5-(N,N-dimethylaminomethyl)-1,2.3-triazol-4-yl)methyl-2-(R)-(1-(R)-(3-methylthio-5-(trifluoromethyl)phenyl) ethoxy)-3-(S)-phenylmorpholine

Naslovni spoj pripremljen je iz triazola iz Primjera 102 prema postupku iz Primjera 76, kao pjena (116mg, 36%). 1H NMR (250MHz, CDCI3) δ 1.39 (3H, d, J=6.5Hz), 2.24 (6H, s), 2.32 (3H, s), 2.59 (1H, dt, J=11.8, 3.3Hz), 3.25 (1H, d, J=13.6Hz), 3.62 (1H, dd, J=11.2, 1.8Hz), 3.81 (1H, d, J=13.9Hz), 4.23 (1H, m), 4.39 (1H, d, J=2.6Hz), 4.75 (1H, q, J=6.5Hz), 6.71 (2H, s), 7.17 (1H, s), 7.34-7.41 (3H, m), 7.49 (2H, br s); MS (ES+) m/z 536 (M+1, 100%). The title compound was prepared from the triazole of Example 102 according to the procedure of Example 76, as a foam (116mg, 36%). 1H NMR (250MHz, CDCl3) δ 1.39 (3H, d, J=6.5Hz), 2.24 (6H, s), 2.32 (3H, s), 2.59 (1H, dt, J=11.8, 3.3Hz), 3.25 ( 1H, d, J=13.6Hz), 3.62 (1H, dd, J=11.2, 1.8Hz), 3.81 (1H, d, J=13.9Hz), 4.23 (1H, m), 4.39 (1H, d, J =2.6Hz), 4.75 (1H, q, J=6.5Hz), 6.71 (2H, s), 7.17 (1H, s), 7.34-7.41 (3H, m), 7.49 (2H, br s); MS (ES+) m/z 536 (M+1, 100%).

Primjer 80 Example 80

4-(5-(N,N-dimetilaminometil)-1.2,3-triazol-4-il)metil-3-(S)-(4-fluorofenil)-2-(R)-(1-(R)-(3-terc-butiltio-5-(trifluormetil)fenil)etoksi)morfolin 4-(5-(N,N-dimethylaminomethyl)-1,2,3-triazol-4-yl)methyl-3-(S)-(4-fluorophenyl)-2-(R)-(1-(R)- (3-tert-butylthio-5-(trifluoromethyl)phenyl)ethoxy)morpholine

Naslovni spoj pripremljen je iz spoja iz Primjera 57 prema postupku iz Primjera 76, kao pjena (117mg, 68%). 1H NMR (360MHz, CDCI3) δ 1.19 (9H, s), 1.42 (3H, d, J=6.6Hz), 2.23 (6H, s), 2.57 (1H, dt, J=12.0, 3.5Hz), 2.92 (1H, d, J=11.6Hz), 3.24 (1H, d, J=13.9Hz), 3.39-3.44 (2H, m), 3.51 (1H, d, J=14.8Hz), 3.62 (1H, m), 3.80 (1H, d, J=13.9Hz), 4.23 (1H, m), 4.41 (1H, d, J=2.7Hz), 4.77 (1H, q, J=6.5Hz), 6.89 (1H, s), 7.14 (1H, s), 7.31-7.35 (3H, m), 7.46 (2H, br s), 7.51 (1H, s); MS (ES+) m/z 578 (M+1, 100%). The title compound was prepared from the compound of Example 57 according to the procedure of Example 76, as a foam (117mg, 68%). 1H NMR (360MHz, CDCl3) δ 1.19 (9H, s), 1.42 (3H, d, J=6.6Hz), 2.23 (6H, s), 2.57 (1H, dt, J=12.0, 3.5Hz), 2.92 ( 1H, d, J=11.6Hz), 3.24 (1H, d, J=13.9Hz), 3.39-3.44 (2H, m), 3.51 (1H, d, J=14.8Hz), 3.62 (1H, m), 3.80 (1H, d, J=13.9Hz), 4.23 (1H, m), 4.41 (1H, d, J=2.7Hz), 4.77 (1H, q, J=6.5Hz), 6.89 (1H, s), 7.14 (1H, s), 7.31-7.35 (3H, m), 7.46 (2H, br s), 7.51 (1H, s); MS (ES+) m/z 578 (M+1, 100%).

Primjer 81 Example 81

4-(5-(N,N-dimetilaminometil)-1,2,3-triazol-4-il)metil-3-(S)-(4-fluorofenil)-2-(R)-(1-(R)-(3-metilsulfinil-5-(trifluormetil)fenil)etoksi)morfolin 4-(5-(N,N-dimethylaminomethyl)-1,2,3-triazol-4-yl)methyl-3-(S)-(4-fluorophenyl)-2-(R)-(1-(R) )-(3-methylsulfinyl-5-(trifluoromethyl)phenyl)ethoxy)morpholine

Tioeter iz Primjera 76 (115mg, 0.28mmol) otopi se u trifluoroctenoj kiselini (800 ohladi na 0°C i tretira s 2.0M otopinom trifluorperoctene kiseline u trifluoroctenoj kiselini (153ml, 0.308mmol), uz miješanje 30 minuta. Reakciona smjesa se ulije u 0.5M otopinu natrijevog bikarbonata (50ml), ekstrahira s diklormetanom (3 x 15ml), osuši (MgSO4) i koncentrira in vacuo. Dobivena sirova kruta tvar (200mg) se pročisti fleš silikagel kromatografijom u 8% metanolu: diklormetanu da bi se dobio naslovni spoj kao nepodijeljni stereoizomeri u obliku bijele pjene (81mg, 51%). 1H NMR (360MHz, CDCI3) δ l.44 i 1.46 (3H ukupno, 2 x d, J=6.6Hz), 2.24 (6H, s), 2.56 (1H, m), 2.59 i 2.62 (3H ukupno 2 x s), 2.88 (1H, d, J=11.9Hz), 3.23 i 3.26 (1H ukupno, 2 x d, J=13.9Hz), 3.42-3.55 (3H, m), 3.62 (1H, br d, J=11.3Hz), 3.75 i 3.79 (1H ukupno, 2 x d, J=14.4Hz), 4.22 (1H, m), 4.32 i 4.35 (1H ukupno, 2 x d, J=2.7Hz), 4.89 (1H, m), 6.85 (1/2H, s), 7.04-7.13 (3H, m), 7.24 (1/2H, s), 7.50 (2H, br s), 7.73 i 7.75 (1H ukupno, 2 x s); MS (ES+) m/z 570 (M+1, 100%). The thioether from Example 76 (115mg, 0.28mmol) is dissolved in trifluoroacetic acid (800, cooled to 0°C and treated with a 2.0M solution of trifluoroperacetic acid in trifluoroacetic acid (153ml, 0.308mmol), with stirring for 30 minutes. The reaction mixture is poured into 0.5M sodium bicarbonate solution (50ml), extracted with dichloromethane (3 x 15ml), dried (MgSO4) and concentrated in vacuo The resulting crude solid (200mg) was purified by flash silica gel chromatography in 8% methanol:dichloromethane to give the title compound as inseparable stereoisomers as a white foam (81mg, 51%). 1H NMR (360MHz, CDCl3) δ 1.44 and 1.46 (3H total, 2 x d, J=6.6Hz), 2.24 (6H, s), 2.56 ( 1H, m), 2.59 and 2.62 (3H total 2 x s), 2.88 (1H, d, J=11.9Hz), 3.23 and 3.26 (1H total, 2 x d, J=13.9Hz), 3.42-3.55 (3H, m ), 3.62 (1H, no d, J=11.3Hz), 3.75 and 3.79 (1H total, 2 x d, J=14.4Hz), 4.22 (1H, m), 4.32 and 4.35 (1H total, 2 x d, J= 2.7Hz), 4.89 (1H, m), 6.85 (1/2H, s), 7.04-7.13 (3H, m), 7.24 (1/2H, s), 7.50 (2H, no s), 7.73 and 7.75 ( 1 H total, 2 x s); MS (ES+) m/z 570 (M+1, 100%).

Primjer 82 Example 82

3-(S)-(4-fluorofenil)-2-(R)-(1-(R)-(3-metilsulfinil-5-(trifluormetil)fenil)etoksi)-4-(5-pirolidinometil-1,2,3-triazol-4-il)metilmorfolin 3-(S)-(4-fluorophenyl)-2-(R)-(1-(R)-(3-methylsulfinyl-5-(trifluoromethyl)phenyl)ethoxy)-4-(5-pyrrolidinomethyl-1,2 ,3-triazol-4-yl)methylmorpholine

Naslovni spoj kao nepodijeljena smjesa stereoizomera pripremljen je iz Primjera 77 prema postupku iz Primjera 81 kao pjena (90mg, 63%). 1H NMR (360MHz, CDCI3) δ 1.44 i 1.46 (3H ukupno, 2 x d, J=6.6), 1.86 (4H, brs), 2.50-2.60 (1H, m), 2.59 i 2.62 (3H ukupno, 2 x s), 2.70-2.90 (5H, m), 3.24 i 3.26 (1H, 2 x d, J=14.0), 3.46 (1H, d, J<2), 3.62 (1H, br d, J=11.2), 3.71-3.86 (3H, m), 4.20 (1H, m), 4.32 i 4.35 (1H ukupno, 2 x d, J=2.7), 4.89 (1H, m), 6.89 (1/2H, s), 7.03-7.13 (3H, m), 7.25 (1/2H, s), 7.49 (2H, br s), 7.73 i 7.75 (1H ukupno, 2 x s); MS (ES+) m/z 596 (M+1, 100%). The title compound as an undivided mixture of stereoisomers was prepared from Example 77 according to the procedure of Example 81 as a foam (90mg, 63%). 1H NMR (360MHz, CDCl3) δ 1.44 and 1.46 (3H total, 2 x d, J=6.6), 1.86 (4H, brs), 2.50-2.60 (1H, m), 2.59 and 2.62 (3H total, 2 x s), 2.70-2.90 (5H, m), 3.24 and 3.26 (1H, 2 x d, J=14.0), 3.46 (1H, d, J<2), 3.62 (1H, br d, J=11.2), 3.71-3.86 ( 3H, m), 4.20 (1H, m), 4.32 and 4.35 (1H total, 2 x d, J=2.7), 4.89 (1H, m), 6.89 (1/2H, s), 7.03-7.13 (3H, m ), 7.25 (1/2H, s), 7.49 (2H, no s), 7.73 and 7.75 (1H total, 2 x s); MS (ES+) m/z 596 (M+1, 100%).

Primjer 83 Example 83

3-(S)-4-fluorofenil)-2-(R)-(1-(R)-(3-metilsulfinil-5-(trifluorometil)fenil)etoksi)-4-(5-morfolinometil-1,2,3-triazol-4-il)metilmorfolin 3-(S)-4-fluorophenyl)-2-(R)-(1-(R)-(3-methylsulfinyl-5-(trifluoromethyl)phenyl)ethoxy)-4-(5-morpholinomethyl-1,2, 3-triazol-4-yl)methylmorpholine

Naslovni spoj kao smjesa nepodijeljenih stereoizomera dobiven je iz Primjera 78 prema postupku iz Primjera 81 kao pjena (113, 92%). 1H NMR (360MHz, CDCI3) δ 1.3 i 1.41 (3H ukupno, 2 x d, J=6.6), 2.54 i 2.57 (3H ukupno, 2 x s), 2.54-2.65 (1H, m), 2.82-2.89 (1H, m), 3.05-3.25 (4H, vbr s), 3.35 (1H, m), 3.50 (1H, m), 3.61 (1H, m), 3.72 i 3.74 (1H, 2 x d, J=14.5), 3.85-4.22 (6H, m), 4.29 i 4.33 (1H, 2xd, J=2.5), 4.81 (1H, m), 6.99-7.09 (31/2H, m), 7.30 (1/2H, s), 7.42 (2H, br s), 7.64 i 7.66 (1H ukupno, 2 x s); MS (ES+) m/z 612 (M+1, 100%). The title compound as a mixture of unresolved stereoisomers was obtained from Example 78 according to the procedure of Example 81 as a foam (113, 92%). 1H NMR (360MHz, CDCl3) δ 1.3 and 1.41 (3H total, 2 x d, J=6.6), 2.54 and 2.57 (3H total, 2 x s), 2.54-2.65 (1H, m), 2.82-2.89 (1H, m ), 3.05-3.25 (4H, vbr s), 3.35 (1H, m), 3.50 (1H, m), 3.61 (1H, m), 3.72 and 3.74 (1H, 2 x d, J=14.5), 3.85-4.22 (6H, m), 4.29 and 4.33 (1H, 2xd, J=2.5), 4.81 (1H, m), 6.99-7.09 (31/2H, m), 7.30 (1/2H, s), 7.42 (2H, no s), 7.64 and 7.66 (1H total, 2 x s); MS (ES+) m/z 612 (M+1, 100%).

Primjer 84 Example 84

3-(S)-(4-fluorofenil)-2-(R)-(1-(R)-(3-metilsulfonil-5-(trifluorometil)fenil)etoksi)-4-(5-morfolinometil-1,2,3-triazol-4-il)metilmorfolin 3-(S)-(4-fluorophenyl)-2-(R)-(1-(R)-(3-methylsulfonyl-5-(trifluoromethyl)phenyl)ethoxy)-4-(5-morpholinomethyl-1,2 ,3-triazol-4-yl)methylmorpholine

Sulfoksid iz Primjera 83 (78mg, 0.128mmol) otopi se u trifluoroctenoj kiselini (500 l), ohladi na 0°C i tretira sa 2.0M otopinom trifluorperoctene kiseline u trifluoroctenoj kiselini (70ml, 0.140mmol) uz miješanje 21/2 sata. Daljnji ekvivalent trifluoperoctene kiseline (70ml, 0.140mmol) se doda nakon tog vremena i proizvod se pročisti nakon 3 sata prema postupku iz Primjera 81 da bi se dobio naslovni spoj kao pjena (27mg, 34%). 1H NMR (360MHz, CDCI3) δ 1.47 (3H, d, J=6.6Hz), 2.38-2.45 (4H, m), 2.57 (1H, dt, J=11.9, 3.5), 2.90 (1H, d, J=11.7Hz), 2.96 (3H, s), 3.26 (1H, d, J=14.0Hz), 3.46-3.51 (2H, m), 3.56-3.68 (6H, m), 3.79 (1H, d, J=14.1Hz), 4.22 (1H, m), 4.35 (1H, d, J=2.8Hz), 4.90 The sulfoxide from Example 83 (78mg, 0.128mmol) is dissolved in trifluoroacetic acid (500 l), cooled to 0°C and treated with a 2.0M solution of trifluoroperacetic acid in trifluoroacetic acid (70ml, 0.140mmol) with stirring for 21/2 hours. A further equivalent of trifluoperacetic acid (70ml, 0.140mmol) was added after this time and the product was purified after 3 hours according to the procedure of Example 81 to give the title compound as a foam (27mg, 34%). 1H NMR (360MHz, CDCl3) δ 1.47 (3H, d, J=6.6Hz), 2.38-2.45 (4H, m), 2.57 (1H, dt, J=11.9, 3.5), 2.90 (1H, d, J= 11.7Hz), 2.96 (3H, s), 3.26 (1H, d, J=14.0Hz), 3.46-3.51 (2H, m), 3.56-3.68 (6H, m), 3.79 (1H, d, J=14.1 Hz), 4.22 (1H, m), 4.35 (1H, d, J=2.8Hz), 4.90

(1H, q, J=6.8Hz), 7.07 (2H, t, J=8.6Hz), 7.17 (1H, s), 7.50 (2H, br d), 7.76 (1H, s), 7.97 (1H, s); MS (ES+) m/z 628 (M+1, 100%). (1H, q, J=6.8Hz), 7.07 (2H, t, J=8.6Hz), 7.17 (1H, s), 7.50 (2H, br d), 7.76 (1H, s), 7.97 (1H, s ); MS (ES+) m/z 628 (M+1, 100%).

Primjer 85 Example 85

2-(R)-(1-(R)-(3,5-bis(trifluormetil)fenil)etoksi)-3-(S)-(4-fluorofenil)-4-(,2-(5-((S)-(+)-2-metoksimetilpirolidinometil)-1,2,3-triazol-4-il)etinmorfolin 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(,2-(5-( S)-(+)-2-methoxymethylpyrrolidinomethyl)-1,2,3-triazol-4-yl)ethynemorpholine

Stupanj A: 2-(R)-(1-(R)-(3,5-bis(trifluorometil)fenil)etoksi)-4-(but-3-inil)-3-(S)-4-fluorofenil)morfolin Step A: 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(but-3-ynyl)-3-(S)-4-fluorophenyl) morpholine

Otopina iz Opisa 5 (1.24g; 1eq), 3-butin-1-ol-tozilat (1.43g; 2.5eq), K2CO3 (1.32g; 3.7eq) i Nal (kat) u bezvodnom DMF (7ml) zagrijava se na 100°C 12 sati. Nakon hlađenja na sobnu temperaturu reakciona smjesa se razdijeli između H2O i EtOAc. Slojevi se razdvoje i vodene faze ekstrahiraju sa EtOAc (2x). Pomiješane organske faze se osuše (MgSO4) i koncentriraju i dobiveni ostatak pročisti kromatografijom (heksani/EtOAc 9:1 → 4:1) da bi se dobio naslovni spoj kao bistro bezbojno ulje. MS m/z 490 (MH+). A solution of Description 5 (1.24g; 1eq), 3-butyn-1-ol-tosylate (1.43g; 2.5eq), K2CO3 (1.32g; 3.7eq) and Nal(kat) in anhydrous DMF (7ml) was heated at 100°C for 12 hours. After cooling to room temperature, the reaction mixture was partitioned between H2O and EtOAc. The layers were separated and the aqueous phases were extracted with EtOAc (2x). The combined organic phases were dried (MgSO4) and concentrated and the resulting residue was purified by chromatography (hexanes/EtOAc 9:1 → 4:1) to give the title compound as a clear colorless oil. MS m/z 490 (MH+).

Stupanj B: 2-(R)-(1-(R)-(3,5-bis(trifluormetil)fenil)etoksi)-3-(S)-(4-fluorofenil)-4-(4hidroksibut-3-inil)morfolin Step B: 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(4hydroxybut-3-ynyl) )morpholine

Acetilen iz Stupnja A (1.2g; 1.0eq) otopi se u bezvodnom THF (5ml), zatim ohladi na -78°C i doda se n-BuLi (2.5M u heksanu; 1ml, 1.05eq). Reakciona smjesa se miješa na -78°C 1 sat, zatim se HCHO plin uvodi kroz otopinu dok se ne zasiti. Reakciona smjesa se zagrije do sobne temperature i miješa 1 sat. Doradom (NH4Cl/EtOAc) praćenom pročišćavanjem na silikagelu (heksani/EtOAc 9:1 → 4:1 dobiva se naslovni spoj kao bistro, viskozno ulje. MS m/z 520 (MH+). Acetylene from Step A (1.2g; 1.0eq) was dissolved in anhydrous THF (5ml), then cooled to -78°C and n-BuLi (2.5M in hexane; 1ml, 1.05eq) was added. The reaction mixture is stirred at -78°C for 1 hour, then HCHO gas is introduced through the solution until it is saturated. The reaction mixture is warmed to room temperature and stirred for 1 hour. Dorado (NH4Cl/EtOAc) followed by purification on silica gel (hexanes/EtOAc 9:1 → 4:1) afforded the title compound as a clear, viscous oil. MS m/z 520 (MH+).

Stupanj C: 2-((R)-(1-(R)-(3,5-bis(trifluormetil)fenil)etoksi)-4-(4-klorobut-3-inil)-3-(S)-(4-fluorofenil)morfolin Step C: 2-((R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-chlorobut-3-ynyl)-3-(S)-( 4-fluorophenyl)morpholine

Alkohol iz Stupnja B (0.42g; 1eq) otopi se u bezvodnom THF (5ml) pod N2 i doda se trifosgen (84mg, 0.35eq) praćeno piridinom (128ml; 2.0eq). Reakciona smjesa se miješa na sobnoj temperaturi pola sata, zatim se razrijedi sa EtOAc i ispere sa H2O i slanom otopinom, osuši (MgSO4) i koncentrira o žutog ulja. To se pročisti kromatografijom (heksani/EtOAc 9:1 → 4:1) da bi se dobio naslovni spoj kao bistro, viskozno ulje. MS m/z 538, 540 (MH+). The alcohol from Stage B (0.42g; 1eq) was dissolved in anhydrous THF (5ml) under N2 and triphosgene (84mg, 0.35eq) was added followed by pyridine (128ml; 2.0eq). The reaction mixture was stirred at room temperature for half an hour, then diluted with EtOAc and washed with H2O and brine, dried (MgSO4) and concentrated to a yellow oil. This was purified by chromatography (hexanes/EtOAc 9:1 → 4:1) to give the title compound as a clear, viscous oil. MS m/z 538, 540 (MH+).

Stupanj D: N-(4-azidobut-3-inil)-2-(R)-(1-(R)-(3,5-bis(trifluormetil)fenil)etoksi)-3-(S)-4-fluorofenil)morfolin Step D: N-(4-azidobut-3-ynyl)-2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-4- fluorophenyl)morpholine

Klorid iz Stupnja C (0.23g; 1eq) i NaN3 (31mg; 1eq) u DMSO (0.8ml) se miješa na sobnoj temperaturi 14 sati. Dorada sa (NH4Cl/EtOAc) daje naslovni spoj kao ulje, koje se koristi bez daljnjeg pročišćavanja. The chloride from Step C (0.23g; 1eq) and NaN3 (31mg; 1eq) in DMSO (0.8ml) was stirred at room temperature for 14 hours. Workup with (NH4Cl/EtOAc) gave the title compound as an oil, which was used without further purification.

Stupanj E: 2-(R)-(1-(R)-(3.5-bis(trifluormetil)fenil)etoksi)-3-(S)-(4-fluorofenil)-4-(2-(5-((S)-(+)-2-metoksimetilpirolidinometil)-1,2,3-triazol-4-il)etil)morfolin Step E: 2-(R)-(1-(R)-(3.5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(2-(5-( S)-(+)-2-methoxymethylpyrrolidinomethyl)-1,2,3-triazol-4-yl)ethyl)morpholine

Otopina azida iz Stupnja D (0.205g; 1eq) i (S)-(+)-2-metoksimetil pirolidinometilpirolidina (114ml; 3eq) zagrijava se na 80°C pod N2, otapalo se odstrani in vacuo i dobiveni ostatak pročisti kromatografijom koristeći CH2Cl2/MeOH/NH3 (98:2:0.1 zatim 97:3:0.1) kao eluent da bi se dobio naslovni spoj kao bijela pjena. 1H NMR (250MHz, CDCI3) δ 7.62 (1H, s), 7.24 (2H, m), 7.14 (2H, s), 6.95 (2H, t, J=8.7Hz), 4.87 (1H, q, J=6.5Hz), 4.30 (2H, m), 3.95 (1H, d, J=14Hz), 3.70 (1H, dd, J=2, 11.3Hz), 3.53-3.34 (7H, m), 3.19 (1H, d, J=11.6Hz), 2.86-2.56 (6H, m), 2.29 (1H, m), 2.09 (1H, m), 1.88 (1H, m), 1.70 (3H, m), 1.45 (3H, d, J=6.5Hz). MS m/z=660. A solution of the azide from Step D (0.205g; 1eq) and (S)-(+)-2-methoxymethyl pyrrolidinomethylpyrrolidine (114ml; 3eq) was heated to 80°C under N2, the solvent was removed in vacuo and the resulting residue was purified by chromatography using CH2Cl2 /MeOH/NH3 (98:2:0.1 then 97:3:0.1) as eluent to give the title compound as a white foam. 1H NMR (250MHz, CDCl3) δ 7.62 (1H, s), 7.24 (2H, m), 7.14 (2H, s), 6.95 (2H, t, J=8.7Hz), 4.87 (1H, q, J=6.5 Hz), 4.30 (2H, m), 3.95 (1H, d, J=14Hz), 3.70 (1H, dd, J=2, 11.3Hz), 3.53-3.34 (7H, m), 3.19 (1H, d, J=11.6Hz), 2.86-2.56 (6H, m), 2.29 (1H, m), 2.09 (1H, m), 1.88 (1H, m), 1.70 (3H, m), 1.45 (3H, d, J =6.5Hz). MS m/z=660.

Primjer 86 Example 86

2-(R)-(1-(S)-(3,5-bis(trifluormetil)fenil)-2-hidroksietoksi)-4-(5-(N.N-dimetilaminometil)-1,2.3-triazol-4-il)metil-3-(S)-(4-fluorofenil)morfolin 2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-4-(5-(N,N-dimethylaminomethyl)-1,2.3-triazol-4-yl )methyl-3-(S)-(4-fluorophenyl)morpholine

Stupanj A: 2-(R)-n-(S)-(3,5-bis(trifluormetil)fenil)-2-terc-butildimetilsililoksietoksi)-3-(S)-(4-fluorofenil)morfolin Grade A: 2-(R)-n-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-tert-butyldimethylsilyloxyethoxy)-3-(S)-(4-fluorophenyl)morpholine

Proizvod iz Opisa 21 (2g) otopi se u bezvodnom diklormetanu (16ml), pod dušikom, i ohladi na 0°C. 2,6-lutidin (0.5ml) i terc-butildimetiltrifluorometan sulfonat (1.0ml) se potom dodaju i smjesa se miješa 15 minuta. Reakciona smjesa se ispere (H2O, slana otopina), osuši (MgSO4) i evaporira in vacuo. Pročišćavanjem na gravitacijskoj silicij koloni uz 20%-50% etilacetat/petrol kao eluent dobiva se naslovni spoj kao bezbojno ulje. The product from Description 21 (2g) was dissolved in anhydrous dichloromethane (16ml), under nitrogen, and cooled to 0°C. 2,6-lutidine (0.5ml) and tert-butyldimethyltrifluoromethanesulfonate (1.0ml) were then added and the mixture was stirred for 15 minutes. The reaction mixture was washed (H2O, brine), dried (MgSO4) and evaporated in vacuo. Purification on a gravity silica column with 20%-50% ethyl acetate/petrol as eluent afforded the title compound as a colorless oil.

1H NMR (250MHz, CDCI3) δ -0.04 (3H, s), 0.00 (3H, s), 0.87 (9H, s), 3.15-3.36 (2H, m), 3.64-3.70 (2H, m), 3.90-3.96 (1H, m), 4.10 (1H, d, J=2.2.Hz), 4.22-4.53 (1H, m), 4.53 (1H, d, J=2.2Hz), 4.91 (1H, t, J=5.9Hz), 7.04-7.14 (2H, m), 7.29-7.36 (4H, m), 7.74 (1H, br s). MS (ES+) m/z=567. 1H NMR (250MHz, CDCl3) δ -0.04 (3H, s), 0.00 (3H, s), 0.87 (9H, s), 3.15-3.36 (2H, m), 3.64-3.70 (2H, m), 3.90- 3.96 (1H, m), 4.10 (1H, d, J=2.2.Hz), 4.22-4.53 (1H, m), 4.53 (1H, d, J=2.2Hz), 4.91 (1H, t, J=5.9 Hz), 7.04-7.14 (2H, m), 7.29-7.36 (4H, m), 7.74 (1H, br s). MS (ES+) m/z=567.

Stupanj B: 2-(R)-(1-(S)-(3,5-bis(trifluormetil)fenil)-2-tero-butildimetilsililoksietoksi)-3-(S)-4-fluorofenil)-4-(4-klorobut-2-inil)morfolin Step B: 2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-ter-butyldimethylsilyloxyethoxy)-3-(S)-4-fluorophenyl)-4-(4 -chlorobut-2-ynyl)morpholine

Priprema se na analogni način nao Stupanj (a) iz Primjera 12, Postupak B, koristeći proizvod iz gornjeg Stupnja A, da bi se dobio naslovni spoj kao bistro ulje. 1H NMR (360MHz, CDCI3) δ 0.00 (3H, s), 0.04 (3H, s), 0.91 (9H, s), 2.95-3.09 (2H, m), 3.40 (2H, br s), 3.72-3.83 (3H, m), 4.01 (1H, dd, J=10.2, J=5.5Hz), 4.25 (2H, m), 4.50 (2H, m), 4.9 (1H, t, J=5.9Hz), 7.15 (2H, t, J=8.7Hz), 7.29 (2H, s), 7.52 (2H, br s), 7.76 (1H,s). It is prepared analogously to Step (a) of Example 12, Procedure B, using the product of Step A above, to give the title compound as a clear oil. 1H NMR (360MHz, CDCl3) δ 0.00 (3H, s), 0.04 (3H, s), 0.91 (9H, s), 2.95-3.09 (2H, m), 3.40 (2H, br s), 3.72-3.83 ( 3H, m), 4.01 (1H, dd, J=10.2, J=5.5Hz), 4.25 (2H, m), 4.50 (2H, m), 4.9 (1H, t, J=5.9Hz), 7.15 (2H , t, J=8.7Hz), 7.29 (2H, s), 7.52 (2H, no s), 7.76 (1H, s).

Stupanj C: 2-(R)-(1-(S)-(3.5-bis(trifluormetil)fenil)-2-terc-butildimetilsililoksietoksi)-4-(5-(N,N-dimetilaminometil)-1,2,3-triazol-4-il)metil-3-(S)-(4-fluorofenil)morfolin Step C: 2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-tert-butyldimethylsilyloxyethoxy)-4-(5-(N,N-dimethylaminomethyl)-1,2, 3-Triazol-4-yl)methyl-3-(S)-(4-fluorophenyl)morpholine

Priprema se na analogni način kao Stupanj (b) i (c) Primjera 12, Postupak B, koristeći proizvod gornjeg Stupnja B, da bi se dobio naslovni spoj. 1H NMR (250MHz, CDCI3) δ -0.02 (3H, s), 0.00 (3H, s), 0.88 (9H, s), 2.30 (6H, s), 2.60-2.70 (1H, m), 2.93-2.98 (1H, br d, J=11.6Hz), 3.30 (1H, d, J=13.8Hz), 3.48-3.63 (3H, m), 3.68-3.74 (2H, m), 3.84-3.97 (2H, m), 4.33-4.41 (1H, m), 4.46 (1H, d, J=2.8Hz), 4.90 (1H, t, J=5.6Hz), 7.16 (2H, t, J=8.7Hz), 7.25 (2H, br s), 7.59 (2H, vbr m), 7.74 (1H, br s). Prepared analogously to Steps (b) and (c) of Example 12, Procedure B, using the product of Step B above, to give the title compound. 1H NMR (250MHz, CDCl3) δ -0.02 (3H, s), 0.00 (3H, s), 0.88 (9H, s), 2.30 (6H, s), 2.60-2.70 (1H, m), 2.93-2.98 ( 1H, no d, J=11.6Hz), 3.30 (1H, d, J=13.8Hz), 3.48-3.63 (3H, m), 3.68-3.74 (2H, m), 3.84-3.97 (2H, m), 4.33-4.41 (1H, m), 4.46 (1H, d, J=2.8Hz), 4.90 (1H, t, J=5.6Hz), 7.16 (2H, t, J=8.7Hz), 7.25 (2H, no s), 7.59 (2H, vbr m), 7.74 (1H, br s).

Stupanj D: 2-(R)-(1-(S)-(3,5-bis(trifluormetil)fenil)-2-hidroksietoksi)-4-(5-(N,N-dimetilaminometil)-1,2,3-triazol-4-il)metil-3-(S)-(4-fluorofenil)morfolin Step D: 2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-4-(5-(N,N-dimethylaminomethyl)-1,2, 3-Triazol-4-yl)methyl-3-(S)-(4-fluorophenyl)morpholine

Proizvod iz gornjeg Stupnja C (0.2g) miješa se u bezvodnom tetrahidrofuranu (2ml) sa tetrabutilamonij fluoridom (1.0M) u tetrahidrofuranu (0.42ml) 30 minuta. Smjesa se razdijeli između otopine amonij klorida i etil acetata i organske faze se isperu (H2O, slana otopina), osuše (MgSO4) i evaporiraju in vacuo. Pročišćavanjem na gravitacijskoj silicij koloni sa 4-10% MeOH/0.1% NH4OH/diklormetan dobiva se naslovni spoj. 1H NMR (250MHz, CDCI3) δ 2.26 (6H, s), 2.51 (1H, m), 3.09 (2H, m), 3.35 (2H, m), 3.51-3.63 (4H, m), 3.78 (2H, d, J=13.8), 4.30-4.36 (2H, m), 4.88 (1H, m), 7.01-7.10 (4H, m), 7.50 (2H, vbrs), 7.59 (1H, brs). The product from Step C above (0.2g) was stirred in anhydrous tetrahydrofuran (2ml) with tetrabutylammonium fluoride (1.0M) in tetrahydrofuran (0.42ml) for 30 minutes. The mixture was partitioned between ammonium chloride and ethyl acetate solution and the organic phases were washed (H2O, brine), dried (MgSO4) and evaporated in vacuo. Purification on a gravity silica column with 4-10% MeOH/0.1% NH4OH/dichloromethane gives the title compound. 1H NMR (250MHz, CDCl3) δ 2.26 (6H, s), 2.51 (1H, m), 3.09 (2H, m), 3.35 (2H, m), 3.51-3.63 (4H, m), 3.78 (2H, d , J=13.8), 4.30-4.36 (2H, m), 4.88 (1H, m), 7.01-7.10 (4H, m), 7.50 (2H, vbrs), 7.59 (1H, brs).

PRIMJER 87 EXAMPLE 87

2-(R)-(1-(R)-(3,5-bis(trifluormetil)fenil)etoksi)-4-(5-N-etil-N-izopropilaminometil)-1-(ili 2 ili 3)metil-1,2,3-triazol-4-il) metil-3-(S)-fenilmorfolin 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-N-ethyl-N-isopropylaminomethyl)-1-(or 2 or 3)methyl -1,2,3-triazol-4-yl)methyl-3-(S)-phenylmorpholine

Proizvod iz Primjera 101 (2g) otopi se u N,N-dimetilformamidu (4ml) na sobnoj temperaturi pod dušikom. Doda se jodometan, praćeno sa natrijevim hidridom (60%) (14mg) i smjesa se miješa 16 sati. Reakciona smjesa se razdijeli između etilacetata i vode i organski sloj se ispere (H2O x 2, slana otopina), osuši (MgSO4) i evaporira in vacuo. Pročišćavanjem gravitacijskom silicij kromatografijom elucijom sa 100% etilacetatom praćeno sa 10% metanol/0.1% NH4OH/diklormetan dobiva se naslovni spoj. 1H NMR (250MHz, CDCI3) δ 0.85-1.02 (9H, m), 1.44 (3H, d, J=6.6Hz), 2.25-2.40 (2H, m), 2.57-2.68 (1H, m), 2.75-2.85 (1H, m), 2.96 (1H, br d, J=13.5Hz), 3.15 (1H, d, J=13.5), 3.38 (1H, d, J=2.7Hz), 3.44 (2H, s), 3.60-3.73 (2H, m), 4.07 (3H, s), 4.18 (1H, m),4.35 (1H, d, J=2.8Hz), 4.83 (1H, m), 7.15 (2H, br s), 7.33 (3H, m), 7.48 (2H, vbr s), 7.61 (1H, br s). MS (ES+) m/z=613 (MH+, 100%). The product from Example 101 (2g) was dissolved in N,N-dimethylformamide (4ml) at room temperature under nitrogen. Iodomethane was added, followed by sodium hydride (60%) (14mg) and the mixture was stirred for 16 hours. The reaction mixture was partitioned between ethyl acetate and water and the organic layer was washed (H 2 O x 2, brine), dried (MgSO 4 ) and evaporated in vacuo. Purification by gravity silica chromatography eluting with 100% ethyl acetate followed by 10% methanol/0.1% NH4OH/dichloromethane gives the title compound. 1H NMR (250MHz, CDCl3) δ 0.85-1.02 (9H, m), 1.44 (3H, d, J=6.6Hz), 2.25-2.40 (2H, m), 2.57-2.68 (1H, m), 2.75-2.85 (1H, m), 2.96 (1H, br d, J=13.5Hz), 3.15 (1H, d, J=13.5), 3.38 (1H, d, J=2.7Hz), 3.44 (2H, s), 3.60 -3.73 (2H, m), 4.07 (3H, s), 4.18 (1H, m), 4.35 (1H, d, J=2.8Hz), 4.83 (1H, m), 7.15 (2H, no s), 7.33 (3H, m), 7.48 (2H, vbr s), 7.61 (1H, br s). MS (ES+) m/z=613 (MH+, 100%).

Primjer 88 Example 88

2-(R)-1-(S)-(3,5-bis(trifluormetil)fenil)-2-hidroksietoksi)-3-(S)-(4-fluorofenil)-4-(2,3-dihidro-3-okso-1.2,4-triazol-5-il)metilmorfolin 2-(R)-1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)-4-(2,3-dihydro- 3-oxo-1,2,4-triazol-5-yl)methylmorpholine

Spoj iz Opisa 6 (0.5g), N-karbometoksi-2-kloroacetamidrazon (Opis 23) (182mg) i kalijev karbonat (0.3g) suspendiraju se u diemetilformamidu (3.6ml) i smjesa se zagrijava na 60°C 2 sata. Smjesa se ohladi i anorganske tvari se odstrane filtracijom kroz celit. Otapalo se odstrani in vacuo azeotropijom sa ksilenom. Dobiveni ostatak se pročisti na siliciju fleš kromatografijom koristeći 1-10% metanol u diklormetanu. Time se dobiva naslovni spoj kao bijeli prah (300mg). 1H NMR (360MHz, DMSO-d6) δ 2.38-2.41 (1H, m), 2.78 (1H, d, J=14.0Hz), 2.81-2.84 (1H, m), 3.36 (1H, d, J=14.0Hz), 3.45-3.48 (1H, m), 3.52 (1H, d, J=3.0Hz), 3.58-3.61 (2H, m), 4.81 (1H, t, J=6.0Hz), 4.88 (1H, br t), 7.09 (2H, t, J=9.0Hz), 7.33 (2H, s), 7.50 (2H, brt), 7.85 (1H, s), 11.26 (1H, s), 11.30 (1H, s). MS (Cl+) m/z 551 (M+1, 10%), 454 (M+-CH2triazolon, 20). The compound from Description 6 (0.5g), N-carbomethoxy-2-chloroacetamidrazone (Description 23) (182mg) and potassium carbonate (0.3g) are suspended in dimethylformamide (3.6ml) and the mixture is heated at 60°C for 2 hours. The mixture is cooled and the inorganic substances are removed by filtration through celite. The solvent was removed in vacuo by azeotropy with xylene. The resulting residue was purified on silica by flash chromatography using 1-10% methanol in dichloromethane. This gives the title compound as a white powder (300mg). 1H NMR (360MHz, DMSO-d6) δ 2.38-2.41 (1H, m), 2.78 (1H, d, J=14.0Hz), 2.81-2.84 (1H, m), 3.36 (1H, d, J=14.0Hz ), 3.45-3.48 (1H, m), 3.52 (1H, d, J=3.0Hz), 3.58-3.61 (2H, m), 4.81 (1H, t, J=6.0Hz), 4.88 (1H, br t ), 7.09 (2H, t, J=9.0Hz), 7.33 (2H, s), 7.50 (2H, brt), 7.85 (1H, s), 11.26 (1H, s), 11.30 (1H, s). MS (Cl+) m/z 551 (M+1, 10%), 454 (M+-CH2triazolone, 20).

Primjer 89 Example 89

2-(R)-(1-(S)-(3,5-bis(trifluormetinfenil)-2-hidroksietoksi)-3-(S)-(4-fluorofenil)-4-(1,2,4-triazol-3-il)metilmorfolin 2-(R)-(1-(S)-(3,5-bis(trifluoromethinephenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)-4-(1,2,4-triazole -3-yl)methylmorpholine

Spoj iz Opisa 6 (270mg), bezvodni kalijev karbonat (250mg) i N-formil-2-kloroacetamidhidrazon (92mg) (pripremljeno prema I. Yanagisawa, J. Med. Chem. (1984), 27, 849) zagrijavaju se na 60°C u bezvodnom dimetilformamidu 1 sat i zatim na 140°C 2 sata. Reakciona smjesa se ohladi i razrijedi vodom (100ml). Proizvod se ekstrahira u etil acetatu (3 x 50ml) i organski sloj se ispere slanom otopinom, osuši (MgSO4) i evaporira in vacuo. Dobiveni ostatak se pročisti kromatografijom na siliciju koristeći 7%-tni metanol u diklormetanu kao eluent. Time se dobiva naslovni spoj (200mg, 60%) kao bijela kruta tvar. 1H NMR (360MHz, DMSO-d6) δ 2.47 (1H, t, J=9.0Hz), 2.89 (1H, d, J=11.0Hz), 3.18 (1H, d, J=14.0Hz), 3.44-3.49 (1H, m), 3.55-3.61 (4H, m), 3.64 (1H, d, J=6Hz), 4.25 (1H, t, J=11.0Hz), 4.34 (1H, d, J=3.0Hz), 4.81 (1H, t, J=5.0Hz), 7.11 (2H, t, J=9.0Hz), 7.34 (2H, s), 7.52 (2H, m), 7.85 (1H, s), 8.19 (1H, brs). MS (Cl) m/z 535 (M+1, 10%). The compound of Description 6 (270mg), anhydrous potassium carbonate (250mg) and N-formyl-2-chloroacetamidehydrazone (92mg) (prepared according to I. Yanagisawa, J. Med. Chem. (1984), 27, 849) were heated at 60 °C in anhydrous dimethylformamide for 1 hour and then at 140°C for 2 hours. The reaction mixture is cooled and diluted with water (100 ml). The product was extracted into ethyl acetate (3 x 50ml) and the organic layer was washed with brine, dried (MgSO4) and evaporated in vacuo. The obtained residue was purified by chromatography on silica using 7% methanol in dichloromethane as eluent. This gives the title compound (200mg, 60%) as a white solid. 1H NMR (360MHz, DMSO-d6) δ 2.47 (1H, t, J=9.0Hz), 2.89 (1H, d, J=11.0Hz), 3.18 (1H, d, J=14.0Hz), 3.44-3.49 ( 1H, m), 3.55-3.61 (4H, m), 3.64 (1H, d, J=6Hz), 4.25 (1H, t, J=11.0Hz), 4.34 (1H, d, J=3.0Hz), 4.81 (1H, t, J=5.0Hz), 7.11 (2H, t, J=9.0Hz), 7.34 (2H, s), 7.52 (2H, m), 7.85 (1H, s), 8.19 (1H, brs) . MS (Cl) m/z 535 (M+1, 10%).

Primjer 90 Example 90

4-(2,3-dihidro-3-okso-1,2,4-triazol-5-il)metil-3-(S)-(4-fluorofenil)-2-(R)-(1-(S)-(3-flluoro-5-(trifluormetil)fenil)-2-hidroksietoksi)morfolin 4-(2,3-dihydro-3-oxo-1,2,4-triazol-5-yl)methyl-3-(S)-(4-fluorophenyl)-2-(R)-(1-(S) )-(3-fluoro-5-(trifluoromethyl)phenyl)-2-hydroxyethoxy)morpholine

Spoj iz Opisa 22 (350mg), N-karbometoksi-2-kloroacetamidrazon (150mg) (Opis 23) i kalijev karbonat (150mg) u dimetilformamidu zagrijavaju se na 60°C 3 sata dok se sav početni materijal ne utroši. Smjesa se zatim grije na 140°C 3 sata. Smjesa se ohladi i filtrira kroz celit da bi se odstranile anorganske tvari. Dobiveni ostatak se evaporira koristeći ksilen da bi se azeotopiralo zaostali dimetilformamid. Dobiveni ostatak se pročisti kromatografijom na siliciju koristeći 1-10% metanol u diklormetanu kao eluent. Time se dobiva nalsovni spoj kao pjena koja se rekristalizira iz etera. 1H NMR (360MHz, DMSO-d6) δ J2.34-2.46 (1H, m), 2.74-2.84 (2H, m), 3.34-3.43 (3H, m), 3.50-3.60 (2H, m), 4.21-4.31 (2H, m), 4.68 (1H, t, J=5.0Hz), 4.90 (1H, t, J=7.0Hz), 6.54 (1H, d, J=9.0Hz), 6.88 (1H, s), 7.14 (t, J=9.0Hz), 7.42 (1H, d, J=9.0Hz), 7.44 (2H, m). The compound of Description 22 (350mg), N-carbomethoxy-2-chloroacetamidrazone (150mg) (Description 23) and potassium carbonate (150mg) in dimethylformamide were heated at 60°C for 3 hours until all the starting material was consumed. The mixture is then heated at 140°C for 3 hours. The mixture is cooled and filtered through celite to remove inorganic matter. The resulting residue is evaporated using xylene to azeotopize the residual dimethylformamide. The resulting residue was purified by chromatography on silica using 1-10% methanol in dichloromethane as eluent. This gives the nal compound as a foam which is recrystallized from ether. 1H NMR (360MHz, DMSO-d6) δ J 2.34-2.46 (1H, m), 2.74-2.84 (2H, m), 3.34-3.43 (3H, m), 3.50-3.60 (2H, m), 4.21- 4.31 (2H, m), 4.68 (1H, t, J=5.0Hz), 4.90 (1H, t, J=7.0Hz), 6.54 (1H, d, J=9.0Hz), 6.88 (1H, s), 7.14 (t, J=9.0Hz), 7.42 (1H, d, J=9.0Hz), 7.44 (2H, m).

Primjer 91 Example 91

4-(2.3-dihidro-2-okso-1.3-imidazol-4-inmetil-2-(R)-(1-(S)-(3.5-bis(trifluormetinfenil)-2-hidroksietoksi)-3-(S)-(4-fluorofenil)morfolin 4-(2.3-dihydro-2-oxo-1.3-imidazol-4-ynmethyl-2-(R)-(1-(S)-(3.5-bis(trifluoromethinephenyl)-2-hydroxyethoxy)-3-(S) -(4-fluorophenyl)morpholine

Smjesa spoja iz Opisa 6 (2g), 4-bromometil-1,3-diacetil-2-imidazolona (1.38g) (pripremljeno prema postupku Dolan i Dushinsky, JACS (1948) 70, 657) i kalij karbonata (1.2g) u dimetilformamidu (14ml) miješa se na sobnoj temperaturi 30 minuta dok sav polazni morfolin ne reagira. Smjesa se razrijedi vodom (150ml) i ekstrahira s etil acetatom (3 x 50ml). Pomiješani ekstrakti se isperu slanom otopinom i organsko otapalo se evaporira in vacuo. Dobiveno ulje se otopi u etanolu (20ml) i doda se metilamin (2ml 8M otopine u etanolu). Otopina se miješa 1 sat i zatim se otapalo odstrani in vacuo. Dobiveno ulje se pročisti na siliciju koristeći 1-10% metanol u diklormetanu kao eluent. Time se dobiva proizvod (2g, 83%) kao bijela pjena. To se dalje tretira metanskim klorovodikom da bi se dobila bijela kruta tvar koja se rekristalizira iz vode. 1H NMR (360MHz, DMSO-d6) δ 2.22-2.34 (1H, m), 2.62 (1H, d, J=14.0Hz), 2.89 (1H, app d, J=11.0Hz), 3.26 (1H, d, J=14.0Hz), 3.38 (1H, d, J=3.0Hz), 3.43-3.50 (1H, m), 3.57-3.62 (2H, m), 4.19-4.28 (1H, m), 4.32 (1H, d, J=3.0Hz), 4.81 (1H, t, J=5.5Hz), 4.93 (1H, t, J=6.0Hz), 6.00 (1H, s), 7.09 (1H, t, J=9.0), 7.33 (2H, s), 7.54 (2H, br t), 7.86 (1H, s), 9.63 (1H, s), 9.83 (1H, s). MS (Cl) m/z 550 (M+1, 20%), 454 (80) 116 (100). A mixture of the compound of Description 6 (2g), 4-bromomethyl-1,3-diacetyl-2-imidazolone (1.38g) (prepared according to the procedure of Dolan and Dushinsky, JACS (1948) 70, 657) and potassium carbonate (1.2g) in dimethylformamide (14 ml) is stirred at room temperature for 30 minutes until all the starting morpholine reacts. The mixture is diluted with water (150ml) and extracted with ethyl acetate (3 x 50ml). The mixed extracts are washed with saline and the organic solvent is evaporated in vacuo. The obtained oil is dissolved in ethanol (20ml) and methylamine (2ml of 8M solution in ethanol) is added. The solution was stirred for 1 hour and then the solvent was removed in vacuo. The resulting oil was purified on silica using 1-10% methanol in dichloromethane as eluent. This gives the product (2g, 83%) as a white foam. This is further treated with methane hydrogen chloride to give a white solid which is recrystallized from water. 1H NMR (360MHz, DMSO-d6) δ 2.22-2.34 (1H, m), 2.62 (1H, d, J=14.0Hz), 2.89 (1H, app d, J=11.0Hz), 3.26 (1H, d, J=14.0Hz), 3.38 (1H, d, J=3.0Hz), 3.43-3.50 (1H, m), 3.57-3.62 (2H, m), 4.19-4.28 (1H, m), 4.32 (1H, d , J=3.0Hz), 4.81 (1H, t, J=5.5Hz), 4.93 (1H, t, J=6.0Hz), 6.00 (1H, s), 7.09 (1H, t, J=9.0), 7.33 (2H, s), 7.54 (2H, br t), 7.86 (1H, s), 9.63 (1H, s), 9.83 (1H, s). MS (Cl) m/z 550 (M+1, 20%), 454 (80) 116 (100).

Primjer 92 Example 92

4-(2,3-dihidro-2-okso-5-pirolidinometil-1,3-imidazol-4-il)metil-2-(R)-(1-(S)-(3,5-bis(trifluormetil)fenil)-2-hidroksietoksi)-3-(S)-(4-fluorofenil)morfolin 4-(2,3-dihydro-2-oxo-5-pyrrolidinomethyl-1,3-imidazol-4-yl)methyl-2-(R)-(1-(S)-(3,5-bis(trifluoromethyl )phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)morpholine

Smjesa spoja iz Opisa 6 (1.8g), 4,5-bis(bromometil)-1,3-diacetil-2-imidazolon (pripremljen prema postupku Dolan i Duschinsky, JACS (1948) 70, 657) (2.2g) i kalijev karbonat u dimetilformamidu (13ml) miješaju se na sobnoj temperaturi 10 minuta dok sav početni materijal ne reagira. U dobivenu smeđu smjesu kapanjem se doda pirolidin (1.65ml, višak) što rezultira egzotermičkom reakcijom. Otapalo se odstrani in vacuo i dobiveni ostatak se ekstrahira s etil acetatom (3 x 50ml) i ispere slanom otopinom. Organska faza se osuši (MgSO4) i otapalo odstrani in vacuo. Smeđi ostatak se pročisti silikagel kromatografijom srednjeg tlaka suprotne faze C18, koristeći 30% acetonitril u 0.1% vodene trifluoroctene kiseline kao eluent. Time se dobiva naslovni proizvod kao svjetlosmeđa kruta tvar (1g). 1H NMR (360MHz, DMSO-d6) δ 1.16 (4H, br s), 2.26-2.30 (5H, m), 2.66 (1H, d, J=14.0Hz), 2.83-2.87 (1H, br d), 3.02 (1H, d, J=13.5Hz), 3.15 (1H, d, J=13.5Hz), 3.23 (1H, d, J=14.0), 3.37 (1H, d, J=3.0Hz), 3.42-3.47 (1H, m), 3.57-3.60 (2H, m), 4.17-4.24 (1H, m), 4.32 (1H, d, J=3.0Hz), 4.79 (1H, t, J=5.5Hz), 4.89 (1H, t, J=5.5Hz), 7.08 (2H, t, J=9.0Hz), 7.32 (2H, s), 7.56 (2H, mc), 7.85 (1H, s), 9.61 (1H, s), 9.65 (1H, s). MS (Cl+) m/z 633 (M+1), 454 (50%). A mixture of the compound from Description 6 (1.8g), 4,5-bis(bromomethyl)-1,3-diacetyl-2-imidazolone (prepared according to the procedure of Dolan and Duschinsky, JACS (1948) 70, 657) (2.2g) and potassium carbonate in dimethylformamide (13ml) are stirred at room temperature for 10 minutes until all the starting material reacts. Pyrrolidine (1.65ml, excess) is added dropwise to the resulting brown mixture, which results in an exothermic reaction. The solvent was removed in vacuo and the resulting residue was extracted with ethyl acetate (3 x 50ml) and washed with brine. The organic phase was dried (MgSO4) and the solvent was removed in vacuo. The brown residue was purified by medium pressure reverse phase silica gel chromatography C18, using 30% acetonitrile in 0.1% aqueous trifluoroacetic acid as eluent. This gives the title product as a light brown solid (1g). 1H NMR (360MHz, DMSO-d6) δ 1.16 (4H, br s), 2.26-2.30 (5H, m), 2.66 (1H, d, J=14.0Hz), 2.83-2.87 (1H, br d), 3.02 (1H, d, J=13.5Hz), 3.15 (1H, d, J=13.5Hz), 3.23 (1H, d, J=14.0), 3.37 (1H, d, J=3.0Hz), 3.42-3.47 ( 1H, m), 3.57-3.60 (2H, m), 4.17-4.24 (1H, m), 4.32 (1H, d, J=3.0Hz), 4.79 (1H, t, J=5.5Hz), 4.89 (1H , t, J=5.5Hz), 7.08 (2H, t, J=9.0Hz), 7.32 (2H, s), 7.56 (2H, mc), 7.85 (1H, s), 9.61 (1H, s), 9.65 (1H, s). MS (Cl+) m/z 633 (M+1), 454 (50%).

Primjer 93 Example 93

2-(R)-(1-(S)-(3,5-bis(trifluormetil)fenil)-2-fosforiloetoksi)-3-(S)-4-fluorofenil)-4-(2,3-dihidro-3-okso-1.2,4-triazol-5-il)metilmorfolin 2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-phosphoryloethoxy)-3-(S)-4-fluorophenyl)-4-(2,3-dihydro- 3-oxo-1,2,4-triazol-5-yl)methylmorpholine

Spoj iz primjera 88 (200mg) u bezvodnom tetrahidrofuranu (1ml) tretira se sa dibenziloksidietilaminofosfinom (200mg) i tetrazolom (100mg). Reakcija se miješa 2 sata i zatim se tretira s daljnjih 100mg dibenziloksidietilaminofosfina, praćeno nakon 1 sata s tetrazolom (100mg). Reakcija se miješa daljnjih 1 sat prije dodavanje 4-metilmorfolin-N-oksida (1.0g) i zatim se miješa 16 sati. Reakcija se ulije u otopinu kalij karbonata i ekstrahira u etil acetatu. Organski sloj se osuši (MgSO4), filtrira, evaporira i pročisti kromatografijom na silikagelu koristeći metanol/diklormetan (4:96) kao eluent da bi se dobilo ulje. To se otopi u metanolu (2ml) i dodaju se amonijev fomat (100mg) i paladij hidroksid (20% na ugljiku). Reakciona smjesa se zagrijava do refluksa 1 sat i zatim filtrira, evaporira i liofilizira iz acetonitrila/vode da bi se dobila amonijeva sol naslovnog spoja (93mg). 1H NMR (360MHz, D6-DMSO) δ 11.29 (1H, s), 7.85 (1H, s), 7.53 (2H, s), 7.36 (2H, m), 7.06 (2H, t, J=7.2), 4.96 (1H, t, J=5.4Hz), 4.34 (1H, d, J=3.6Hz), 4.29 (1H, t, J=11.2Hz), 3.92-3.85 (1H, m), 3.68-3.63 (1H, m), 3.62.3.55 (1H, m), 3.49 (1H, d, J=3.6Hz), 3.38 (1H, d, J=14.4Hz), 2.82-2.79 (1H, m), 2.77 (1H, d, J=14.4Hz), 2.41-2.35 (1H, m); MS (ES+) 631 (M+H). The compound from example 88 (200mg) in anhydrous tetrahydrofuran (1ml) is treated with dibenzyloxydiethylaminophosphine (200mg) and tetrazole (100mg). The reaction was stirred for 2 hours and then treated with a further 100mg of dibenzyloxydiethylaminophosphine, followed after 1 hour with tetrazole (100mg). The reaction was stirred for a further 1 hour before the addition of 4-methylmorpholine-N-oxide (1.0g) and then stirred for 16 hours. The reaction is poured into potassium carbonate solution and extracted into ethyl acetate. The organic layer was dried (MgSO 4 ), filtered, evaporated and purified by chromatography on silica gel using methanol/dichloromethane (4:96) as eluent to give an oil. This is dissolved in methanol (2ml) and ammonium formate (100mg) and palladium hydroxide (20% on carbon) are added. The reaction mixture was heated to reflux for 1 hour and then filtered, evaporated and lyophilized from acetonitrile/water to give the ammonium salt of the title compound (93mg). 1H NMR (360MHz, D6-DMSO) δ 11.29 (1H, s), 7.85 (1H, s), 7.53 (2H, s), 7.36 (2H, m), 7.06 (2H, t, J=7.2), 4.96 (1H, t, J=5.4Hz), 4.34 (1H, d, J=3.6Hz), 4.29 (1H, t, J=11.2Hz), 3.92-3.85 (1H, m), 3.68-3.63 (1H, m), 3.62.3.55 (1H, m), 3.49 (1H, d, J=3.6Hz), 3.38 (1H, d, J=14.4Hz), 2.82-2.79 (1H, m), 2.77 (1H, d , J=14.4Hz), 2.41-2.35 (1H, m); MS (ES+) 631 (M+H).

Primjer 94 Example 94

2-(R)-(1-(S)-(3.5-bis(trifluormetil)fenil)2-fosforiloetoksi)-3-(S)-4-fluorofenil)-4-(1,2,4-triazol-3-il)metilmorfolin 2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)2-phosphoryloethoxy)-3-(S)-4-fluorophenyl)-4-(1,2,4-triazol-3 -yl)methylmorpholine

Amonijeva sol naslovnog spoja pripremljena je iz spoja iz Primjera 89 prema postupku iz Primjera 93. The ammonium salt of the title compound was prepared from the compound of Example 89 according to the procedure of Example 93.

1H NMR (250MHz, D6-DMSO + 0.1% TFA) δ 8.74 (1H, s), 7.95 (1H, s), 7.68 (2H, brs), 7.54 (2H, s), 7.30 (2H, t, J=8.7Hz), 5.16 (1H, dd, J=7Hz i 5Hz), 4.72 (1H, d, J=1Hz), 4.66 (1H, d, J=1Hz), 4.42 (1H, t, J=11Hz), 3.95-4.27 (3H, m), 3.72 (1H, d, J=11Hz) i 3.41-3.55 (1H, m). 1H NMR (250MHz, D6-DMSO + 0.1% TFA) δ 8.74 (1H, s), 7.95 (1H, s), 7.68 (2H, brs), 7.54 (2H, s), 7.30 (2H, t, J= 8.7Hz), 5.16 (1H, dd, J=7Hz and 5Hz), 4.72 (1H, d, J=1Hz), 4.66 (1H, d, J=1Hz), 4.42 (1H, t, J=11Hz), 3.95-4.27 (3H, m), 3.72 (1H, d, J=11Hz) and 3.41-3.55 (1H, m).

Primjer 95 Example 95

4-(2,3-dihidro-3-okso1,2,4-triazol-5-il)-3-(S)-fenil-2-(R)-(1-(S)-(3-(trifluormetil)fenil)-2-hidroksietoksi)morfolin 4-(2,3-dihydro-3-oxo1,2,4-triazol-5-yl)-3-(S)-phenyl-2-(R)-(1-(S)-(3-(trifluoromethyl) )phenyl)-2-hydroxyethoxy)morpholine

Pripravlja se iz spoja iz Opisa 30 prema postupku navedenom u Primjeru 88. MS (Cl+) m/z 465 ((M+1)+, 71%). It is prepared from the compound of Description 30 according to the procedure given in Example 88. MS (Cl+) m/z 465 ((M+1)+, 71%).

Primjer 96 Example 96

4-(2,3-dihidro-3-okso-1,2,4-triazol-5-il)metil-2-(R)-(1-(S)-(3-fluoro-5-(trifluormetil)fenil)-2-hidroksietoksi)-3-(S)-fenilmorfolin 4-(2,3-dihydro-3-oxo-1,2,4-triazol-5-yl)methyl-2-(R)-(1-(S)-(3-fluoro-5-(trifluoromethyl) phenyl)-2-hydroxyethoxy)-3-(S)-phenylmorpholine

Spoj iz Opisa 27 (600mg), N-karbometiksi-2-kloroacetamidrazon (271 mg) i kalij karbonat (258mg) reagiraju u dimetilformamidu prema postupku opisanom u Primjeru 88. Time se dobiva proizvod kao bijela kruta tvar koji se rekristalizira iz eter/heksana (220mg, 30%). 1H NMR (360MHz, DMSO-d6) δ 2.38 (1H, m), 2.78 (1H, d, J=14.0Hz), 2.84 (1H, s), 3.38-3.39 (2H, m), 3.45 (1H, d, J=14.0Hz), 3.50 (1H, d, J=3.0Hz), 3.56 (1H, d, J=11.0Hz), 4.26 (1H, t, J=11.0Hz), 4.34 (1H, d, J=3.0Hz), 4.68 (1H, t, J=6.0Hz), 4.85 (1H, t, J=6.0Hz), 6.40 (1H, d, J=9.0Hz), 6.96 (1H, s), 7.33 (3H, m), 7.36 (1H, d, J=9.0Hz), 7.49 (2H, m). MS (Cl+) m/z 483 (M+1, 20%). The compound from Description 27 (600mg), N-carbomethoxy-2-chloroacetamidrazone (271mg) and potassium carbonate (258mg) are reacted in dimethylformamide according to the procedure described in Example 88. This gives the product as a white solid which is recrystallized from ether/hexane. (220mg, 30%). 1H NMR (360MHz, DMSO-d6) δ 2.38 (1H, m), 2.78 (1H, d, J=14.0Hz), 2.84 (1H, s), 3.38-3.39 (2H, m), 3.45 (1H, d , J=14.0Hz), 3.50 (1H, d, J=3.0Hz), 3.56 (1H, d, J=11.0Hz), 4.26 (1H, t, J=11.0Hz), 4.34 (1H, d, J =3.0Hz), 4.68 (1H, t, J=6.0Hz), 4.85 (1H, t, J=6.0Hz), 6.40 (1H, d, J=9.0Hz), 6.96 (1H, s), 7.33 ( 3H, m), 7.36 (1H, d, J=9.0Hz), 7.49 (2H, m). MS (Cl+) m/z 483 (M+1, 20%).

Primjer 97 Example 97

4-(2,3-dihidro-3-okso-1,2,4-triazol-5-il)metil-2-(R)-(1-(S)-(3-fluoro-5-(trifluormetil)fenil)-2-fosforiloksietoksi)-3-(S)-fenilmorfolin 4-(2,3-dihydro-3-oxo-1,2,4-triazol-5-yl)methyl-2-(R)-(1-(S)-(3-fluoro-5-(trifluoromethyl) phenyl)-2-phosphoryloxyethoxy)-3-(S)-phenylmorpholine

Amonijeva sol naslovnog spoja pripremljena je iz spoja iz Primjera 96 prema postupku iz Primjera 93. 1H NMR (360MHz, DMSO-d6) δ 11.29 (1H, s), 7.49-7.29 (5H, m), 7.38 (1H, d, J=10.8Hz), 6.96 (1H, s), 6.45 (1H, d, J=10.8Hz), 4.84 (1H, d, J=7.2Hz), 4.34 (1H, d, J=3.6Hz), 4.28 (1H, t, J=10.8Hz), 3.80-3.76 (1H, m), 3.57 (1H, d, J=3.6Hz), 3.57-3.49 (2H, m), 3.47 (1H, d, J=14.4Hz), 2.83-2.76 (1H, m), 2.78 (1H, d,J=14.4Hz), 2.46-2.36 (1H, m). The ammonium salt of the title compound was prepared from the compound of Example 96 according to the procedure of Example 93. 1H NMR (360MHz, DMSO-d6) δ 11.29 (1H, s), 7.49-7.29 (5H, m), 7.38 (1H, d, J =10.8Hz), 6.96 (1H, s), 6.45 (1H, d, J=10.8Hz), 4.84 (1H, d, J=7.2Hz), 4.34 (1H, d, J=3.6Hz), 4.28 ( 1H, t, J=10.8Hz), 3.80-3.76 (1H, m), 3.57 (1H, d, J=3.6Hz), 3.57-3.49 (2H, m), 3.47 (1H, d, J=14.4Hz ), 2.83-2.76 (1H, m), 2.78 (1H, d, J=14.4Hz), 2.46-2.36 (1H, m).

Primjer 98 Example 98

2-(R)-(1-(S)-(3,5-bis(trifluormetil)fenil)2-hidroksietoksi)-4-(2,3-dihidro-3-okso-1,2,4-triazol-5-inmetil-3-(S)-fenilmorfolin 2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)2-hydroxyethoxy)-4-(2,3-dihydro-3-oxo-1,2,4-triazol- 5-inmethyl-3-(S)-phenylmorpholine

Spoj iz Opisa 17 reagira sa N-karbometoksi-2-kloroacetamidra-zonom (Opis 23) i kalij karbonatom prema postupku opisanom u Primjeru 88. Time se dobiva proizvod kao bijela kruta tvar. 1H NMR (360MHz, DMSO-d6) δ 2.42 (1H, dt, J=12.0, 3.5Hz), 2.76 (1H, d, J=14.0Hz), 2.83 (1H, d, J=12.0Hz), 3.39 (1H, d, J=14.0Hz), 3.44-3.47 (1H, m), 3.50 (1H, d, J=3.0Hz), 3.60 (2H, m), 4.22-4.28 (1H, m), 4.40 (1H, d, J=3.0Hz), 4.77-4.83 (2H, m), 7.25-7.34 (3H, m), 7.41 (2H, s), 7.48-7.50 (2H, m), 7.82 (1H, s), 11.20 (1H, s), 11.25 (1H, s), MS (Cl) m/z 533 (M+1, 30%) 434 (20), 117 (100). The compound from Description 17 reacts with N-carbomethoxy-2-chloroacetamidrazone (Description 23) and potassium carbonate according to the procedure described in Example 88. This gives the product as a white solid. 1H NMR (360MHz, DMSO-d6) δ 2.42 (1H, dt, J=12.0, 3.5Hz), 2.76 (1H, d, J=14.0Hz), 2.83 (1H, d, J=12.0Hz), 3.39 ( 1H, d, J=14.0Hz), 3.44-3.47 (1H, m), 3.50 (1H, d, J=3.0Hz), 3.60 (2H, m), 4.22-4.28 (1H, m), 4.40 (1H , d, J=3.0Hz), 4.77-4.83 (2H, m), 7.25-7.34 (3H, m), 7.41 (2H, s), 7.48-7.50 (2H, m), 7.82 (1H, s), 11.20 (1H, s), 11.25 (1H, s), MS (Cl) m/z 533 (M+1, 30%) 434 (20), 117 (100).

Primjer 99 Example 99

2-(R)-(1-(S)-(3.5-bis(trifluormetil)fenil)2-fosforiloksietoksi)-4-(2.3-dihidro-3-okso-1,2,4-triazol-5-inmetil-3-(S)-fenilmorfolin 2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)2-phosphoryloxyethoxy)-4-(2,3-dihydro-3-oxo-1,2,4-triazol-5-ynmethyl- 3-(S)-phenylmorpholine

Amonijeva sol naslovnog spoja pripremljena je iz Primjera 98 prema postupku iz Primjera 93. 1H NMR (360MHz, d6-DMSO) δ 11.26 (1H, s), 7.83 (1H, s), 7.48-7.24 (7H, m), 4.95 (1H, t, J=5.4), 4.39 (1H, d, J=3.6), 4.29 (1H, t, J=11.2), 3.92-3.89 (1H, m), 3.60-3.64 (1H, m), 3.55-3.59 (1H, m), 3.48 (1H, d, J=3.6), 3.42 (1H, d, J=14.4), 2.84-2.79 (1H, m), 2.78 (1H, d, J=14.4), 2.42 (1H, m). The ammonium salt of the title compound was prepared from Example 98 according to the procedure of Example 93. 1H NMR (360MHz, d6-DMSO) δ 11.26 (1H, s), 7.83 (1H, s), 7.48-7.24 (7H, m), 4.95 ( 1H, t, J=5.4), 4.39 (1H, d, J=3.6), 4.29 (1H, t, J=11.2), 3.92-3.89 (1H, m), 3.60-3.64 (1H, m), 3.55 -3.59 (1H, m), 3.48 (1H, d, J=3.6), 3.42 (1H, d, J=14.4), 2.84-2.79 (1H, m), 2.78 (1H, d, J=14.4), 2.42 (1H, m).

HPCL na Zorbax Z-Ph (250 x 4.6mm i.d. 5 M) kolonsi elucijom sa 40% acetonitrilom u 25mM KH2PO4 sa 0.2% trietilaminom (pH 3.0), protok 1 ml/min, UV detektor 210nM. Vrijeme retencije 4.68 min. HPCL on Zorbax Z-Ph (250 x 4.6mm i.d. 5 M) column eluting with 40% acetonitrile in 25mM KH2PO4 with 0.2% triethylamine (pH 3.0), flow rate 1 ml/min, UV detector 210nM. Retention time 4.68 min.

Primjer 100 Example 100

3-(S)-fenil-4-(1,2,4-triazol-3-il)-2-(R)-(1(S)-3-(trifluormetin fenil)-2-hidroksietoksi)morfolin 3-(S)-phenyl-4-(1,2,4-triazol-3-yl)-2-(R)-(1(S)-3-(trifluoromethine phenyl)-2-hydroxyethoxy)morpholine

Pripravljeno kao klorovodična sol iz spoja iz Opisa 30 prema postupku opisanom u Primjeru 89. MS (ES+) m/z 449 ((M+1+ 100%). Prepared as the hydrochloride salt of the compound from Description 30 according to the procedure described in Example 89. MS (ES+) m/z 449 ((M+1+ 100%).

Primjeri 101 i 102 u Tabeli 2 pripremljeni su na način sličan onome opisanom u Primjeru 12, Postupak B, s odgovarajućim N-(4-azidobut-2-inil)morfolinom i odgovarajućim aminom. Examples 101 and 102 in Table 2 were prepared in a manner similar to that described in Example 12, Procedure B, with the appropriate N-(4-azidobut-2-ynyl)morpholine and the appropriate amine.

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Slijedeći primjeri prikazuju farmaceutske sastave prema ovdje danom izumu. The following examples illustrate the pharmaceutical compositions of the present invention.

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Spoj formule (I), celuloza, laktoza i dio kukuruznog škroba pomiješaju se i granuliraju sa 10%-tnom pastom kukuruznog škroba. Dobiveni granulat se prosije, osuši i pomiješa s ostatkom kukuruznog škroba i magnezijevog stearata. Dobiveni granulat se komprimira u tablete koje sadrže 1.0mg, 2.0mg, 25.0mg, 26.0mg, 50.0mg i 100mg aktivnog sastojka po tableti. The compound of formula (I), cellulose, lactose and part of corn starch are mixed and granulated with 10% corn starch paste. The obtained granulate is sieved, dried and mixed with the rest of corn starch and magnesium stearate. The resulting granulate is compressed into tablets containing 1.0mg, 2.0mg, 25.0mg, 26.0mg, 50.0mg and 100mg of active ingredient per tablet.

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Natrijev fosfat, monohidrat limunske kiseline i natrijev klorid otope se u dijelu vode. Spoj formule (I) otopi se ili suspendira u otopini i dopuni do potrebnog volumena. Sodium phosphate, citric acid monohydrate and sodium chloride are dissolved in part of the water. The compound of formula (I) is dissolved or suspended in a solution and made up to the required volume.

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Meki bijeli parafin se zagrijava dok se ne rastopi. Tekući parafin i emulgirajući vosak se dodaju i miješaju dok se ne otope. Doda se spoj formule (I) i miješanje nastavi do disperzije. Smjesa se hladi dok se ne skrutne. Soft white paraffin is heated until it melts. Liquid paraffin and emulsifying wax are added and mixed until dissolved. The compound of formula (I) is added and mixing is continued until dispersion. The mixture is cooled until it solidifies.

Primjer 106A - (Površinski aktivna tvar) Injekciona formulacija Example 106A - (Surfactant) Injectable formulation

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[u 5%-tnom vodenom manitolu (izotoničan)] [in 5% aqueous mannitol (isotonic)]

Spoj formule (I) direktno se otopi u otopini komercijalno raspoloživog Tween 80™ (polioksietilensorbitan monooleat) i 5%-tnom vodenom manitolu (izotoničan). The compound of formula (I) is directly dissolved in a solution of commercially available Tween 80™ (polyoxyethylenesorbitan monooleate) and 5% aqueous mannitol (isotonic).

Primjer 106B - (Emulzija) Injekciona formulacija Example 106B - (Emulsion) Injection formulation

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Spoj formule (I) direktno se otopi u komercijalno raspoloživom lntralipid™-u (10-20%) da bi se dobila emulzija. The compound of formula (I) is directly dissolved in commercially available Intralipid™ (10-20%) to obtain an emulsion.

Primjer 106C - Alternativna (emulzija) injektabilna formulacija Example 106C - Alternative (emulsion) injectable formulation

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Sav materijal je steriliziran i ne-pirogen. Spoj formule (I) otopi se u sojinom ulju. Emulzija se dobiva miješanjem ove otopine sa fosfolipidom jajeta, glicerolom i vodom. Emulzija se potom zatvori u sterilne ampule. All material is sterilized and non-pyrogenic. The compound of formula (I) is dissolved in soybean oil. The emulsion is obtained by mixing this solution with egg phospholipid, glycerol and water. The emulsion is then sealed in sterile ampoules.

Claims

1. Spoj formule (I): [image] (I) unutar kojeg R1 je vodik, halogen, C1-6 alkil, C1-6 alkoksi, CF3, NO2, CN, SRa, SORa, SO2Ra, CO2Ra, CONRaRb, C2-6 alkenil, C2-6 alkinil ili C1-4 alkil supstituiran sa C1-4 alkoksi, gdje Ra i Rb svaki posebno prikazuju vodik ili C1-4 alkil; R2 je vodik, halogen, C1-6 alkil, C1-6 alkoksi supstituiran sa C1-4 alkoksi ili CF3; R3je vodik, halogen ili CF3; R4 je vodik, halogen, C1-6 alkil, C1-6 alkoksi, CF3, NO2, CN, SRa, SORa, SO2Ra, CO2Ra, CONRaRb, C2-6 alkenil, C2-6 alkinil ili C1-4 alkil supstituiran sa C1-4 alkoksi, gdje Ra i Rb svaki posebno prikazuju vodik ili C1-4 alkil; R5 je vodik, halogen, C1-6 alkil, C1-6 alkoksi supstituiran sa C1-4 alkosi ili CF3; R6 je peteročlani ili šesteročlani heterociklični prsten koji sadrži 2 ili 3 dušikova atoma opcijski supstituirana sa =O, =S ili alkilnom grupom, i opcijski supstituirana sa grupom formule ZNR7R8 gdje Z je C1-6 alkilen ili C3-6 cikloalkilen; R7 je vodik, C1-4 alkil, C3-7 cikloalkil ili C3-7 cikloalkil C1-4 alkil, ili C2-4 alkil supstituiran sa C1-4 alkoksi ili hidroksil; R8 je vodik, C1-4 alkil, C3-7 cilkloalkil ili C3-7 cikloalkil C1-4 alkil, ili C2-4 alkil supstituiran sa jednim ili dva supstituenta odabrana od C1-4 alkoksi, hidroksil ili 4, 5 ili 6-članog heteroalifatskog prstena koji sadrži jedan ili dva heteroatoma odabrana od N, O i S; ili R7, R8 i dušikov atom na koji su vezani tvore heteroalifatski prsten od 4 do 7 atoma prstena, opcijski supstituirana s jednom od dvije grupe odabrane od vodika ili C1-4 alkila opcijski supstituirana sa C1-4 alkoksi ili hidroksil grupom, i opcijski imaju dvostruku vezu, čiji prsten može opcijski sadržavati kisik ili sumpor atom prstena, grupu S(O) ili S(O)2 ili drugi dušikov atom koji će biti dio NH ili NRC ostatka gdje RC je C1-4 alkil opcijski supstituiran sa hidroksi ili C1-4 alkoksi; ili R7, R8 i dušikov atom na koji su vezani tvore nearomatski azabiciklični prstenasti sustav od 6 do 12 atoma prstena; ili Z, R7 i dušikov atom na koji su vezani tvore heteroalifatski prsten od 4 do 7 atoma prstena koji mogu opcijski sadržavati kisikov atom prstena; R9a i R9b su svaki neovisno vodik ili C1-4 alkil, ili R9a i R9b su povezani tako, da zajedno sa ugljikovim atomima na koje su povezani tvore C5-7 prsten: X je alkilenski lanac od 1 do 4 ugljikova atoma opcijski supstituirana sa okso; i Y je C1-4 alkil grupa opcijski supstituirana sa hidroksilnom grupom; s uvjetom kada Y je C1-4 alkil, R6 je supstituiran najmanje s grupom formule ZNR7R8 kako je gore definirano; ili negova farmaceutski prihvatljiva sol ili prodrug.1. Compound of formula (I): [image] (AND) within which R1 is hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy, CF3, NO2, CN, SRa, SORa, SO2Ra, CO2Ra, CONRaRb, C2-6 alkenyl, C2-6 alkynyl or C1-4 alkyl substituted with C1- 4 alkoxy, wherein R a and R b each independently represent hydrogen or C 1-4 alkyl; R 2 is hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy substituted with C 1-4 alkoxy or CF 3 ; R 3 is hydrogen, halogen or CF 3 ; R4 is hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy, CF3, NO2, CN, SRa, SORa, SO2Ra, CO2Ra, CONRaRb, C2-6 alkenyl, C2-6 alkynyl or C1-4 alkyl substituted with C1- 4 alkoxy, wherein R a and R b each independently represent hydrogen or C 1-4 alkyl; R 5 is hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy substituted with C 1-4 lkoxy or CF 3 ; R6 is a five-membered or six-membered heterocyclic ring containing 2 or 3 nitrogen atoms optionally substituted with =O, =S or an alkyl group, and optionally substituted with a group of the formula ZNR7R8 where Z is C1-6 alkylene or C3-6 cycloalkylene; R 7 is hydrogen, C 1-4 alkyl, C 3-7 cycloalkyl or C 3-7 cycloalkyl C 1-4 alkyl, or C 2-4 alkyl substituted with C 1-4 alkoxy or hydroxyl; R8 is hydrogen, C1-4 alkyl, C3-7 cycloalkyl or C3-7 cycloalkyl C1-4 alkyl, or C2-4 alkyl substituted with one or two substituents selected from C1-4 alkoxy, hydroxyl or 4, 5 or 6-membered a heteroaliphatic ring containing one or two heteroatoms selected from N, O and S; or R7, R8 and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms, optionally substituted with one of two groups selected from hydrogen or C1-4 alkyl optionally substituted with a C1-4 alkoxy or hydroxyl group, and optionally having double bond, the ring of which may optionally contain an oxygen or sulfur atom of the ring, a group S(O) or S(O)2 or another nitrogen atom that will be part of the NH or NRC residue where RC is C1-4 alkyl optionally substituted with hydroxy or C1 -4 alkoxy; or R7, R8 and the nitrogen atom to which they are attached form a non-aromatic azabicyclic ring system of 6 to 12 ring atoms; or Z, R7 and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms which may optionally contain a ring oxygen atom; R9a and R9b are each independently hydrogen or C1-4 alkyl, or R9a and R9b are connected so that together with the carbon atoms to which they are connected they form a C5-7 ring: X is an alkylene chain of 1 to 4 carbon atoms optionally substituted with oxo; and Y is a C1-4 alkyl group optionally substituted with a hydroxyl group; with the proviso that when Y is C 1-4 alkyl, R 6 is substituted with at least a group of the formula ZNR 7 R 8 as defined above; or a pharmaceutically acceptable salt or prodrug thereof.

2. Spoj formule (I): [image] unutar kojeg R1 je vodik, halogen, C1-6 alkil, C1-6 alkoksi, CF3, NO2, CN, CO2Ra, CONRaRb, C2-6 alkenil, C2-6 alkinil ili C1-4 alkil supstituiran sa C1-4 alkoksi, gdje Ra i Rb svaki posebno prikazuju vodik ili C1-4 alkil; R2 je vodik, halogen, C1-6 alkil, C1-6 alkoksi supstituiran sa C1-4 alkoksi ili CF3; R3 je vodik, halogen ili CF3; R4 je vodik, halogen, C1-6 alkil, C1-6 alkoksi, CF3, NO2, CN, CO2Ra, CONRaRb, C2-6 alkenil, C2-6 alkinil ili C1-4 alkil supstituiran sa C1-4 alkoksi, gdje Ra i Rb svaki posebno prikazuju vodik ili C1-4 alkil; R5 je vodik, halogen, C1-6 alkil, C1-6 alkoksi supstituiran sa C1-4 alkosi ili CF3; R6 je peteročlani ili šesteročlani heterociklični prsten koji sadrži 2 ili 3 dušikova atoma opcijski supstituirana sa =O, =S, i opcijski supstituirana sa grupom formule ZNR7R8 gdje Z je C1-6 alkilen ili C3-6 cikloalkilen; R7 je vodik, C1-4 alkil, ili C2-4 alkil supstituiran sa C1-4 alkoksi ili hidroksil; R8 je vodik, C1-4 alkil, ili C2-4 alkil supstituiran sa C1-4 alkoksi, ili hidroksil; ili R7, R8 i dušikov atom na koji su vezani tvore heteroalifatski prsten od 4 do 7 atoma prstena, koji može opcijski sadržavati kisik ili sumpor atom prstena, ili drugi dušikov atom koji će biti dio NH ili NRC ostatka gdje RC C1-4 je alkil opcijski supstituiran sa hidroksi ili C1-4 alkoksi; ili Z, R7 i dušikov atom na koji su vezani tvore heteroalifatski prsten od 4 do 7 atoma prstena koji mogu opcijski sadržavati kisikov atom prstena; R9a i R9b su svaki neovisno vodik ili C1-4 alkil, ili R9a i R9b su povezani tako, da zajedno sa ugljikovim atomima na koje su povezani tvore C5-7 prsten: X je alkilenski lanac od 1 do 4 ugljikova atoma opcijski supstituirana sa okso, i Y je C1-4 alkil grupa opcijski supstituirana sa hidroksilnom grupom; ili njegova farmaceutski prihvatljiva sol ili prodrug.2. Compound of formula (I): [image] within which R1 is hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy, CF3, NO2, CN, CO2Ra, CONRaRb, C2-6 alkenyl, C2-6 alkynyl or C1-4 alkyl substituted with C1-4 alkoxy, where Ra and R b each independently represent hydrogen or C 1-4 alkyl; R 2 is hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy substituted with C 1-4 alkoxy or CF 3 ; R 3 is hydrogen, halogen or CF 3 ; R4 is hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy, CF3, NO2, CN, CO2Ra, CONRaRb, C2-6 alkenyl, C2-6 alkynyl or C1-4 alkyl substituted with C1-4 alkoxy, where Ra and R b each independently represent hydrogen or C 1-4 alkyl; R 5 is hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy substituted with C 1-4 lkoxy or CF 3 ; R6 is a five- or six-membered heterocyclic ring containing 2 or 3 nitrogen atoms optionally substituted with =O, =S, and optionally substituted with a group of the formula ZNR7R8 where Z is C1-6 alkylene or C3-6 cycloalkylene; R 7 is hydrogen, C 1-4 alkyl, or C 2-4 alkyl substituted with C 1-4 alkoxy or hydroxyl; R 8 is hydrogen, C 1-4 alkyl, or C 2-4 alkyl substituted with C 1-4 alkoxy, or hydroxyl; or R7, R8 and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms, which may optionally contain an oxygen or sulfur atom of the ring, or another nitrogen atom which will be part of the NH or NRC residue where RC is C1-4 alkyl optionally substituted with hydroxy or C 1-4 alkoxy; or Z, R7 and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms which may optionally contain a ring oxygen atom; R9a and R9b are each independently hydrogen or C1-4 alkyl, or R9a and R9b are connected so that together with the carbon atoms to which they are connected they form a C5-7 ring: X is an alkylene chain of 1 to 4 carbon atoms optionally substituted with oxo, and Y is a C1-4 alkyl group optionally substituted with a hydroxyl group; or a pharmaceutically acceptable salt or prodrug thereof.

3. Spoj formule (I): [image] unutar kojeg R1 je vodik, halogen, C1-6 alkil, C1-6 alkoksi, CF3, NO2, CN, CO2Ra, CONRaRb, C2-6 alkenil, C2-6 alkinil ili C1-4 alkil supstituiran sa C1-4 alkoksi, gdje Ra i Rb svaki posebno prikazuju vodik ili C1-4 alkil; R2 je vodik, halogen, C1-6 alkil, C1-6 alkoksi supstituiran sa C1-4 alkoksi ili CF3; R3 je vodik, halogen ili CF3; R4 je vodik, halogen, C1-6 alkil, C1-6 alkoksi, CF3, NO2, CN, CO2Ra, CONRaRb, C2-6 alkenil, C2-6 alkinil ili C1-4 alkil supstituiran sa C1-4 alkoksi, gdje Ra i Rb svaki posebno prikazuju vodik ili C1-4 alkil; R5 je vodik, halogen, C1-6 alkil, C1-6 alkoksi supstituiran sa C1-4 alkosi ili CF3: R6 je peteročlani ili šesteročlani heterociklični prsten koji sadrži 2 ili 3 dušikova atoma opcijski supstituirana sa =O ili =S i supstituirana sa grupom formule ZNR7R8 gdje Z je C1-6 alkilen ili C3-6 cikloalkilen; R7 je vodik, C1-4 alkil, C3-7 cikloalkil ili C3-7 cikloalkil C1-4 alkil, ili C2-4 alkil supstituiran sa C1-4 alkoksi ili hidroksil; R8 je vodik, C1-4 alkil, C3-7 cilkloalkil ili C3-7 cikloalkil C1-4 alkil, ili C2-4 alkil supstituiran sa jednim ili dva supstituenta odabrana od C1-4 alkoksi, hidroksil ili 4, 5 ili 6-članog heteroalifatskog prstena koji sadrži jedan ili dva heteroatoma odabrana od N, O i S; ili R7, R8 i dušikov atom na koji su vezani tvore heteroalifatski prsten od 4 do 7 atoma prstena, opcijski supstituirana s hidroksilnom grupom, i opcijski imaju dvostruku vezu, čiji prsten može opcijski sadržavati kisik ili sumpor atom prstena, grupu S(O) ili S(O)2 ili drugi dušikov atom koji će biti dio NH ili NRC ostatka gdje RC je C1-4 alkil opcijski supstituiran sa hidroksi ili C1-4 alkoksi; ili Z, R7 i dušikov atom na koji su vezani tvore heteroalifatski prsten od 4 do 7 atoma prstena koji mogu opcijski sadržavati kisikov atom prstena; R9a i R9b su svaki neovisno vodik ili C1-4 alkil, ili R9a i R9b su povezani tako, da zajedno sa ugljikovim atomima na koje su povezani tvore C5-7 prsten; X je alkilenski lanac od 1 do 4 ugljikova atoma opcijski supstituirana sa okso; i Y je C1-4 alkil grupa; ili njegova farmaceutski prihvatljiva sol ili prodrug.3. Compound of formula (I): [image] within which R1 is hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy, CF3, NO2, CN, CO2Ra, CONRaRb, C2-6 alkenyl, C2-6 alkynyl or C1-4 alkyl substituted with C1-4 alkoxy, where Ra and R b each independently represent hydrogen or C 1-4 alkyl; R 2 is hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy substituted with C 1-4 alkoxy or CF 3 ; R 3 is hydrogen, halogen or CF 3 ; R4 is hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy, CF3, NO2, CN, CO2Ra, CONRaRb, C2-6 alkenyl, C2-6 alkynyl or C1-4 alkyl substituted with C1-4 alkoxy, where Ra and R b each independently represent hydrogen or C 1-4 alkyl; R5 is hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy substituted with C1-4 lkoxy or CF3: R6 is a five-membered or six-membered heterocyclic ring containing 2 or 3 nitrogen atoms optionally substituted with =O or =S and substituted with a group of the formula ZNR7R8 where Z is C1-6 alkylene or C3-6 cycloalkylene; R 7 is hydrogen, C 1-4 alkyl, C 3-7 cycloalkyl or C 3-7 cycloalkyl C 1-4 alkyl, or C 2-4 alkyl substituted with C 1-4 alkoxy or hydroxyl; R8 is hydrogen, C1-4 alkyl, C3-7 cycloalkyl or C3-7 cycloalkyl C1-4 alkyl, or C2-4 alkyl substituted with one or two substituents selected from C1-4 alkoxy, hydroxyl or 4, 5 or 6-membered a heteroaliphatic ring containing one or two heteroatoms selected from N, O and S; or R7, R8 and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms, optionally substituted with a hydroxyl group, and optionally having a double bond, which ring may optionally contain an oxygen or sulfur atom of the ring, the group S(O) or S(O)2 or another nitrogen atom which will be part of the NH or NRC residue where RC is C1-4 alkyl optionally substituted with hydroxy or C1-4 alkoxy; or Z, R7 and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms which may optionally contain a ring oxygen atom; R9a and R9b are each independently hydrogen or C1-4 alkyl, or R9a and R9b are linked so that together with the carbon atoms to which they are linked they form a C5-7 ring; X is an alkylene chain of 1 to 4 carbon atoms optionally substituted with oxo; and Y is a C1-4 alkyl group; or a pharmaceutically acceptable salt or prodrug thereof.

4. Spoj kao što je zahtjevano u zahtjevu 3 unutar kojeg R6 je peteročlani ili šesteročlani heterociklični prsten koji sadrži 2 ili 3 dušikova atoma opcijski supstituirana sa =O ili =S i supstituirana sa grupom formule ZNR7R8 gdje Z je C1-6 alkilen ili C3-6 cikloalkilen; R7 je vodik, C1-4 alkil ili C2-4 alkil supstituiran sa C1-4 alkoksi ili hidroksil; R8 je vodik, C1-4 alkil ili C C2-4 alkil supstituiran sa jednim ili dva supstituenta odabrana od C1-4 alkoksi, hidroksil ili 5 ili 6-članog heteroalifatskog prstena koji sadrži jedan ili dva heteroatoma odabrana od N, O i S; ili R7, R8 i dušikov atom na koji su vezani tvore heteroalifatski prsten od 4 do 7 atoma prstena, opcijski supstituirana s hidroksilnom grupom, čiji prsten može opcijski sadržavati kisik ili sumpor atom prstena, grupu S(O) ili S(O)2 ili drugi dušikov atom koji će biti dio NH ili NRC ostatka gdje RC je C1-4 alkil opcijski supstituiran sa hidroksi ili C1-4 alkoksi; ili Z, R7 i dušikov atom na koji su vezani tvore heteroalifatski prsten od 4 do 7 atoma prstena koji mogu opcijski sadržavati kisikov atom prstena; ili njegova farmaceutski prihvatljiva sol ili prodrug.4. A compound as claimed in claim 3 wherein R6 is a five-membered or six-membered heterocyclic ring containing 2 or 3 nitrogen atoms optionally substituted with =O or =S and substituted with a group of the formula ZNR7R8 where Z is C1-6 alkylene or C3-6 cycloalkylene; R 7 is hydrogen, C 1-4 alkyl or C 2-4 alkyl substituted with C 1-4 alkoxy or hydroxyl; R 8 is hydrogen, C 1-4 alkyl or C 2-4 alkyl substituted with one or two substituents selected from C 1-4 alkoxy, hydroxyl or a 5- or 6-membered heteroaliphatic ring containing one or two heteroatoms selected from N, O and S; or R7, R8 and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms, optionally substituted with a hydroxyl group, whose ring can optionally contain an oxygen or sulfur atom of the ring, a group S(O) or S(O)2 or the second nitrogen atom which will be part of the NH or NRC residue where RC is C1-4 alkyl optionally substituted with hydroxy or C1-4 alkoxy; or Z, R7 and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms which may optionally contain a ring oxygen atom; or a pharmaceutically acceptable salt or prodrug thereof.

5. Spoj kao što je zahtjevano u bilo kojem zahtjevu od 1 do 4 formule (Ia): [image] unutar kojeg A1 fluor ili CF3; A2 e fluor ili CF3; A3 e fluor ili vodik; ili njegova farmaceutski prihvatiljiva sol ili prodrug.5. A compound as claimed in any one of claims 1 to 4 of formula (Ia): [image] within which A1 fluorine or CF3; A2 is fluorine or CF3; A3 is fluorine or hydrogen; or a pharmaceutically acceptable salt or prodrug thereof.

6. Spoj kao što je zahtijevano u bilo kojem zahtjevu od 1 do 5 unutar kojeg R6 prikazuje heterociklični prsten odabran od: [image] ili njegova farmaceutski prihvatljiva sol ili prodrug.6. A compound as claimed in any of claims 1 to 5 wherein R 6 represents a heterocyclic ring selected from: [image] or a pharmaceutically acceptable salt or prodrug thereof.

7. Spoj kao što je zahtjevano u bilo kojem od zahtjeva 1,3,4, ili 5 formule (Id): [image] unutar kojeg su A1, A2 i A3 definirani u zahtjevu 5, a Q2 je CH ili N; ili njegova farmaceutski prihvatljiva sol ili prodrug.7. A compound as claimed in any one of claims 1, 3, 4, or 5 of formula (Id): [image] wherein A1, A2 and A3 are as defined in claim 5 and Q2 is CH or N; or a pharmaceutically acceptable salt or prodrug thereof.

8. Spoj odabran od: 2-(R)-(1-(R)-(3,5-bis(trifluormetil)fenil)etoksi)-4-(2,3-dihidro-5-(N,N-dimetilamino)metil-2-okso-1,3-imidazol-4-il)metil-3(S)-(4-fluorofenil) morfolin; 4-(2,3-dihidro-5-(N,N-dimetilamino)metil-2-okso-1,3-imidazol-4-il)metil-3-(S)-(4-fluorofenil)-2-(R)-(1-(R)-(3-fluoro-5-(trifluorometil)fenil)etoksi)morfolin; 3-(S)-(4-fluorofenil)-2-(R)-(1-(R)-(3-fluoro-5-(trifluorometil)fenil)etoksi)-4-(2,3-dihidro-2-okso-5-pirolidinometil-1,3-imidazol-4-il)metilmorfolin; 2-(R)-(1-(R)-(3,5-bis(trifluorometil)fenil)etoksi)-3-(S)-(4-fluorfenil)-4-(2,3-dihidro-2-okso-5-pirolidinometil-1,3-imidazol-4-il)metilmorfolin; 2-(R)-(1-(R)-(3,5-bis(triflourometil)fenil)etoksi)-3-(S)-(4-fluorofenil)-4-(2,3-dihidro-5-(4-hidroksipiperidino)metil-2-okso-1,3-imidazol-4-il)metilmorfolin; 3-(S)-(4-fluorofenil)-2-(R)-(1-(R)-(3-fluoro-5-(trifluorometil)fenil)etoksi-4-(2,3-dihidro-5-morfolinometil-2-okso-1,3-imidazol-4-il)metilmorfolin; 2-(R)-(1-(R)-(3,5-bis(triflourmetil)fenil)etoksi)-3-(S)-(4-fluorofenil)-4-(2,3-dihidro-5-morfolinometil-2-okso-1,3-imidazol-4-il)metilmorfolin; 4-(5-azetidinilmetil-2,3-dihidro-2-okso-1,3-imidazol-4-il)metil-2-(R)-(1-(R)-(3,5-bis(trifluorometil)fenil)etoksi)-3-(4-fluorofenil)morfolin; 2-(R)-(1-(R)-(3,5-bis(trifluorometil)fenil)etoksi)-3-(S)-(4-fluorofenil)-4-(2,3-dihidro-5-(N-metilpiperazinil)metil-2-okso-1,3-imidazol-4-il)metilmorfolin; 2-(R)-(1-(R)-(3,5-bis(trifluormetil)fenil)etoksi)-3-(S)-(4-fluorofenil)-4-(2,3-dihidro-5-(N-(2-morfolinoetil)aminometil)-2-okso-1,3-imidazol-4-il)metilmorfolin; 2-(R)-(1-(R)-(3,5-bis(trifluormetii)fenil)etoksi)-3-(S)-(4-fluorofenil)-4-(2,3-dihidro-2-okso-5-(N-(2-pirolidinoetil) aminometil)-1,3-imidazol-4-il)metilmorfolin; 2-(R)-(1-(R)-(3,5-bis(trifluormetil)fenil)etoksi)-4-(5-(dimetilamino)meti!-1,2,3-triazol-4-il)metil-3-(S)-(4-fluorofenil) morfolin; 2-(R)-(1-(R)-(3,5-bis(trifluormetil)fenil)etoksi)-3-(S)-(4-fluorofenil)-4-(N-(N'-metilaminoetil)-1,2,4-triazol-3-il) metilmorfolin; 2-(R)-(1-(R)-(3,5-bis(trifluormetil)fenil)etoksi)-3-(S)-(4-fluorofenil)-4-(5-(N-metilaminometil)-1,2,3-triazol-4-il) metilmorfolin; 4-(5-aminometil)-1,2,3-triazol-4-il)metil-2-(R)-(1-(R)-3,5-bis(trifluorometil)fenil)etoksi)-3-(S)-(4-fluorofenil)morfolin; 2-(R)-(1-(R)-(3,5-bis(trifluormetil)fenil)etoksi)-3-(S)-(4-fluorofenil)-4-(5-pirolidinometil)-1,2,3-triazol-4-il) metilmorfolin; 4-(5-(azetidinilmetil)-1,2,3-triazol-4-il)metil-3-(S)-(4-fluorofenil)-2-(R)-(1-(R)-(3-fluoro-5-(trifluormetil)fenil)etoksi) morfolin; 3-(S)-(4-fluorofenil)-2-(R)-(1-(R)-(3-fiuoro-5-(trifluorometil)fenil)etoksi)-4-(5-(pirolidinometil)-1,2,3-triazol-4-il) metilrriorfolin; 3-(S)-(4-fluorofenil)-2-(R)-(1-(R)-(3-fluoro-5-(trifluorometil)fenil)etoksi)-4-(5-(morfolinometil)-1,2,3-triazol-4-il) metilmorfolin; 4-(5-(N,N-dimetilaminometil)-1,2,3-triazol-4-il)metil-3-(S)-(4-fluorofenil)-2-(R)-(1-(R)-(3-(trifluormetil)fenil)etoksi) morfolin; 2-(R)-(1-(R)-(3,5-bis(trifluormetil)fenil)etoksi)-3-(S)-(4-fluorofenil)-4-(5-N'-metilpiperazinometil)-1,2,3-triazol-4-il) metilmorfolin; 2-(R)-(1-(R)-(3,5-bis(trifluormetil)fenil)etoksi)-3-(S)-(4-(1-(2-pirolidinoetil)-1,2,3-triazol-4-il)metilmorfolin; 2-(R)-(1-(R)-(3,5-bis(trifluormetil)fenil)etoksi)-3-(S)-fenil-(4-(2-(2-pirolidinoetil)-1,2,3-triazol-4-il)metilmorfolin; 2-(R)-(1-(R)-(3,5-bis(trifluormetil)fenil)etoksi)-3-(S)-(4-fIuorfenil)-4-(5-morfolinometil)-1,2,3-triazol-4-il) metilmorfolin; 4-(5-azetinidilmetil)-1,2,3-triazol-4-il)metil-2-(R)-(1-(R)-(3,5-bis(trifluorometil)fenil)etoksi)-3-(S)-4-fluorofenil) morfolin; 2-(R)-(1-(R)-(3,5-bis(trifluormetil)fenil)etoksi)-3-(S)-(4-fluorfenil)-4-(5-(pirolinometil)-1,2,3-triazol-4-il)metilmorfolin; 2-(R)-(1-(R)-(3,5-bis(trifluormetil)fenil)etoksi)-4-(5-(bis(metoksietil)aminornetil)-1,2,3-triazol-4-il)metil-3-(S)-(4-fluorofenil)morfolin; 2-(R)-(1-(R)-(3,5-bis(trifluormetil)fenil)etoksi)-4-(2-kloro-5-morfolinometil-1,3-imidazol-4-il)metil-3-(S)-(4-fluorofenil)morfolin; 2-(R)-(1-(R)-(3,5-bis(trifluormetil)fenil)etoksi)-4-(5-(N,N-dimetilaminometil)-1,3-imidazol-4-il)metil-3-(S)-(4-fluorofenil)morfolin; 2-(R)-(1-(R)-(3,5-bis(trifluormetil)fenil)etoksi)-4-(5-(N,N-dimetilaminometil)-1,2,4-triazol-3-il)metil-3-(S)-(4-fluorofenil)morfolin; 2-(R)-(1-(R)-(3,5-bis(trifluormetil)fenil)etoksi)-4-(5-(N-(2,2-dimetoksietil)-N-metilaminometil)-1,2,3-triazol-4-il)metil-3-(S)-fenilmorfolin; 2-(R)-(1-(R)-(3,5-bis(trifluormetil)fenil)etoksi)-4-(5-(2-metoksietil)aminometil)-1,2,3-triazol-4-il)metil-3-(S)-fenilmorfolin; 2-(R)-(1-(R)-(3,5-bis(trifluormetil)fenil)etoksi)-4-(5-(N-(2-metoksietil)-N-metil)aminometil)-1,2,3-triazol-4-il)metil-3-(S)-fenilmorfolin; 2-(R)-(1-(R)-(3,5-bis(trifluormetil)fenil)etoksi)-4-(5-(N-izopropil-N-(2-metoksietil)aminometil)-1,2,34riazol-4-il)metil-3-(S)-fenilmorfolin; 2-(R)-(1-(R)-(3,5-bis(trifluormetil)fenil)etoksi)-4-(5-(N-ciklopropil-N-(2-metoksietil)aminometil)-1,2,3-triazol-4-il)metil-3-(S)-fenilmorfolin; 2-(R)-(1-(R)-(3,5-bis(trifluormetil)fenil)etoksi)-4-(5-N,N-dibutilaminometil)-1,2,3-triazol-4il)metil-3-(S)-fenilmorfolin; 2-(R)-(1-(R)-(3,5-bis(trifluormeti!)fenil)etoksi)-4-(5-N,N-diizopropilaminometil)-1,2,3-triazol-4-il)metil-3-(S)-fenilmorfolin; 2-(R)-(1-(S)-(3,5-bis(trifluormetil)fenil)-2-hidroksietoksi)-3-(S)-(4-fluorofenil)-4-(2,3-dihidro-3-okso-1,2,4-triazol-5-il)metilmorfolin; 2-(R)-(1-(S)-(3,5-bis(trifluormetil)fenil)-2-hidroksietoksi)-3-(S)-(4-fluorofenil)-4-(1,2,4-triazol-3-il)metilmorfolin; 4-(2,3-dihidro-3-okso-1,2,4-triazol-5-il)metil-3-(S)-(4-fluorofenil)-2-(R)-(1-(S)-(3-fluoro-5-(trifluorometil)fenil)-2-hidroksietoksi)morfolin; 4-(2,3-dihidro-2-okso-1,3-imidazol-4-il)metil-2-(R)-(1-(S)-(3,5-bis(trifluorornetil)fenil)-2-hidroksietoksi)-3-(S)-(4-fluorofenil)morfolin; 4-(2,3-dihidro-2-okso-5-pirolidinometil-1,3-imidazol-4-il)metil-2-(R)-(1-(S)-(3,5-bis(trifluorometil)fenil)-2-hidroksietoksi)-3-(S)-(4-flourofenil)morfolin; 4-(2,3-dihidro-3-okso-1,2,4-triazol-5-il)-3-(S)-fenil-2-(R)-(1-(S)-3-(trifluorometil)fenil)-2-hidroksietoksi)morfolin; 4-(2,3-dihidro-3-okso-1,2,4-triazol-5-il)metil-2-(R)-(1-(S)-(3-fluoro-5-(trifluorometil)fenil)-2-hidroksietoksi)-3-(S)-fenilmorfolin; 2-(R)-(1-(S)-(3,5-bis(trifluormetil)fenil)-2-hidroksietoksi)-4-(2,3-dihidro-3-okso-1,2,4-triazol-5-il)-3-(S)-fenilmetilmetilmorfolin; 3-(S)-fenil-4-(1,2,4-triazol-3-il)-2-(R)-(1-(S)-3-(trifluormetil)fenil)-2-hidroksietoksi)morfolin; ili njegova farmaceutski prihvatljiva sol ili prodrug.8. Compound selected from: 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(2,3-dihydro-5-(N,N-dimethylamino)methyl-2-oxo -1,3-imidazol-4-yl)methyl-3(S)-(4-fluorophenyl)morpholine; 4-(2,3-dihydro-5-(N,N-dimethylamino)methyl-2-oxo-1,3-imidazol-4-yl)methyl-3-(S)-(4-fluorophenyl)-2- (R)-(1-(R)-(3-fluoro-5-(trifluoromethyl)phenyl)ethoxy)morpholine; 3-(S)-(4-fluorophenyl)-2-(R)-(1-(R)-(3-fluoro-5-(trifluoromethyl)phenyl)ethoxy)-4-(2,3-dihydro-2 -oxo-5-pyrrolidinomethyl-1,3-imidazol-4-yl)methylmorpholine; 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(2,3-dihydro-2- oxo-5-pyrrolidinomethyl-1,3-imidazol-4-yl)methylmorpholine; 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(2,3-dihydro-5- (4-hydroxypiperidino)methyl-2-oxo-1,3-imidazol-4-yl)methylmorpholine; 3-(S)-(4-fluorophenyl)-2-(R)-(1-(R)-(3-fluoro-5-(trifluoromethyl)phenyl)ethoxy-4-(2,3-dihydro-5- morpholinomethyl-2-oxo-1,3-imidazol-4-yl)methylmorpholine; 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(2,3-dihydro-5- morpholinomethyl-2-oxo-1,3-imidazol-4-yl)methylmorpholine; 4-(5-azetidinylmethyl-2,3-dihydro-2-oxo-1,3-imidazol-4-yl)methyl-2-(R)-(1-(R)-(3,5-bis(trifluoromethyl )phenyl)ethoxy)-3-(4-fluorophenyl)morpholine; 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(2,3-dihydro-5- (N-methylpiperazinyl)methyl-2-oxo-1,3-imidazol-4-yl)methylmorpholine; 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(2,3-dihydro-5- (N-(2-morpholinoethyl)aminomethyl)-2-oxo-1,3-imidazol-4-yl)methylmorpholine; 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(2,3-dihydro-2- oxo-5-(N-(2-pyrrolidinoethyl)aminomethyl)-1,3-imidazol-4-yl)methylmorpholine; 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(dimethylamino)methyl-1,2,3-triazol-4-yl) methyl-3-(S)-(4-fluorophenyl)morpholine; 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(N-(N'-methylaminoethyl) -1,2,4-triazol-3-yl) methylmorpholine; 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(5-(N-methylaminomethyl)- 1,2,3-triazol-4-yl) methylmorpholine; 4-(5-aminomethyl)-1,2,3-triazol-4-yl)methyl-2-(R)-(1-(R)-3,5-bis(trifluoromethyl)phenyl)ethoxy)-3- (S)-(4-Fluorophenyl)morpholine; 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(5-pyrrolidinomethyl)-1,2 ,3-triazol-4-yl) methylmorpholine; 4-(5-(azetidinylmethyl)-1,2,3-triazol-4-yl)methyl-3-(S)-(4-fluorophenyl)-2-(R)-(1-(R)-(3 -fluoro-5-(trifluoromethyl)phenyl)ethoxy)morpholine; 3-(S)-(4-fluorophenyl)-2-(R)-(1-(R)-(3-fluoro-5-(trifluoromethyl)phenyl)ethoxy)-4-(5-(pyrrolidinomethyl)-1 ,2,3-triazol-4-yl)methyltriorpholine; 3-(S)-(4-fluorophenyl)-2-(R)-(1-(R)-(3-fluoro-5-(trifluoromethyl)phenyl)ethoxy)-4-(5-(morpholinomethyl)-1 ,2,3-triazol-4-yl) methylmorpholine; 4-(5-(N,N-dimethylaminomethyl)-1,2,3-triazol-4-yl)methyl-3-(S)-(4-fluorophenyl)-2-(R)-(1-(R) )-(3-(trifluoromethyl)phenyl)ethoxy)morpholine; 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(5-N'-methylpiperazinomethyl)- 1,2,3-triazol-4-yl) methylmorpholine; 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-(1-(2-pyrrolidinoethyl)-1,2,3 -triazol-4-yl)methylmorpholine; 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-phenyl-(4-(2-(2-pyrrolidinoethyl)-1,2 ,3-triazol-4-yl)methylmorpholine; 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(5-morpholinomethyl)-1,2 ,3-triazol-4-yl) methylmorpholine; 4-(5-Azetinidylmethyl)-1,2,3-triazol-4-yl)methyl-2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3 -(S)-4-fluorophenyl)morpholine; 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(5-(pyrrolinomethyl)-1, 2,3-triazol-4-yl)methylmorpholine; 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(bis(methoxyethyl)aminomethyl)-1,2,3-triazol-4- yl)methyl-3-(S)-(4-fluorophenyl)morpholine; 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(2-chloro-5-morpholinomethyl-1,3-imidazol-4-yl)methyl- 3-(S)-(4-Fluorophenyl)morpholine; 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(N,N-dimethylaminomethyl)-1,3-imidazol-4-yl) methyl-3-(S)-(4-fluorophenyl)morpholine; 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(N,N-dimethylaminomethyl)-1,2,4-triazol-3- yl)methyl-3-(S)-(4-fluorophenyl)morpholine; 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(N-(2,2-dimethoxyethyl)-N-methylaminomethyl)-1, 2,3-triazol-4-yl)methyl-3-(S)-phenylmorpholine; 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(2-methoxyethyl)aminomethyl)-1,2,3-triazol-4- yl)methyl-3-(S)-phenylmorpholine; 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(N-(2-methoxyethyl)-N-methyl)aminomethyl)-1, 2,3-triazol-4-yl)methyl-3-(S)-phenylmorpholine; 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(N-isopropyl-N-(2-methoxyethyl)aminomethyl)-1,2 ,34riazol-4-yl)methyl-3-(S)-phenylmorpholine; 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(N-cyclopropyl-N-(2-methoxyethyl)aminomethyl)-1,2 ,3-triazol-4-yl)methyl-3-(S)-phenylmorpholine; 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-N,N-dibutylaminomethyl)-1,2,3-triazol-4yl)methyl -3-(S)-phenylmorpholine; 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl!)phenyl)ethoxy)-4-(5-N,N-diisopropylaminomethyl)-1,2,3-triazole-4- yl)methyl-3-(S)-phenylmorpholine; 2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)-4-(2,3-dihydro -3-oxo-1,2,4-triazol-5-yl)methylmorpholine; 2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)-4-(1,2,4 -triazol-3-yl)methylmorpholine; 4-(2,3-dihydro-3-oxo-1,2,4-triazol-5-yl)methyl-3-(S)-(4-fluorophenyl)-2-(R)-(1-(S) )-(3-fluoro-5-(trifluoromethyl)phenyl)-2-hydroxyethoxy)morpholine; 4-(2,3-dihydro-2-oxo-1,3-imidazol-4-yl)methyl-2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)- 2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)morpholine; 4-(2,3-dihydro-2-oxo-5-pyrrolidinomethyl-1,3-imidazol-4-yl)methyl-2-(R)-(1-(S)-(3,5-bis(trifluoromethyl )phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)morpholine; 4-(2,3-dihydro-3-oxo-1,2,4-triazol-5-yl)-3-(S)-phenyl-2-(R)-(1-(S)-3-( trifluoromethyl)phenyl)-2-hydroxyethoxy)morpholine; 4-(2,3-dihydro-3-oxo-1,2,4-triazol-5-yl)methyl-2-(R)-(1-(S)-(3-fluoro-5-(trifluoromethyl) phenyl)-2-hydroxyethoxy)-3-(S)-phenylmorpholine; 2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-4-(2,3-dihydro-3-oxo-1,2,4-triazole -5-yl)-3-(S)-phenylmethylmethylmorpholine; 3-(S)-phenyl-4-(1,2,4-triazol-3-yl)-2-(R)-(1-(S)-3-(trifluoromethyl)phenyl)-2-hydroxyethoxy)morpholine ; or a pharmaceutically acceptable salt or prodrug thereof.

9. Spoj: 2-(R)-(1-(R)-(3,5-bis(trifluormetil)fenil)etoksi)-4-(5-(N,N-dimetilamino)metil-1,2,3-triazol-4-il)metil-3-(S)-(4-fluorofenil)morfolin; ili njegova farmaceutski prihvatljiva sol.9. Connection: 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(N,N-dimethylamino)methyl-1,2,3-triazole-4 -yl)methyl-3-(S)-(4-fluorophenyl)morpholine; or a pharmaceutically acceptable salt thereof.

10. Spoj kao što je zahtijevano u zahtjevu 2 formule (Ie): [image] unutar kojeg R1, R2, R3, R4, R5, R6, R9a, R9b i X su definirani u zahtjevu 1 i zaokruženi P je PO(OH)O-.M+, PO(O-)2.2M+, ili PO(O-)2D2+; unutar čega M+ je farmaceutski prihvatljiv jednovalentni counterion; i D2+ je, farmaceutski prihvatljiv dvovalentni counterion.10. A compound as claimed in claim 2 of formula (Ie): [image] wherein R1, R2, R3, R4, R5, R6, R9a, R9b and X are as defined in claim 1 and the encircled P is PO(OH)O-.M+, PO(O-)2.2M+, or PO(O- )2D2+; wherein M+ is a pharmaceutically acceptable monovalent counterion; and D 2+ is a pharmaceutically acceptable divalent counterion.

11. Spoj odabran od: 2-(R)-(1-(S)-(3,5-bis(trifluorometil)fenil)-2-fosforiloksietoksi)-3-(S)-(4-fluorofenil)-4-(2,3-dihidro-3-okso-l,2,4-triazol-5-il)metilmorfolin; 2-(R)-(1-(S)-(3,5-bis(trifluorometil)fenil)-2-fosforiloksietoksi)-3-(S)-(4-fluorofenil)-4-(1,2,4-triazol-3-il)metilmorfolin; 4-(2,3-dihidro-3-okso-1,2,4-triazol-5-il)metil-2-(R)-(1-(S)-3-fluoro-5-(trifluorometil)fenil)-2-fosforiloksietoksi)-3-(S)-fenilmorfolin; 2-(R)-(1-(S)-3,5-bis(trrfluorometil)fenil)-2-fosforiloksietoksi)-4-(2,3-dihidro-3-okso-l,2,4-triazol-5-il)metil-3-(S)-fenilmorfolin; ili njegova farmaceutski prihvatljiva sol.11. Compound selected from: 2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-phosphoryloxyethoxy)-3-(S)-(4-fluorophenyl)-4-(2,3-dihydro -3-oxo-1,2,4-triazol-5-yl)methylmorpholine; 2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-phosphoryloxyethoxy)-3-(S)-(4-fluorophenyl)-4-(1,2,4 -triazol-3-yl)methylmorpholine; 4-(2,3-dihydro-3-oxo-1,2,4-triazol-5-yl)methyl-2-(R)-(1-(S)-3-fluoro-5-(trifluoromethyl)phenyl )-2-phosphoryloxyethoxy)-3-(S)-phenylmorpholine; 2-(R)-(1-(S)-3,5-bis(trifluoromethyl)phenyl)-2-phosphoryloxyethoxy)-4-(2,3-dihydro-3-oxo-1,2,4-triazol- 5-yl)methyl-3-(S)-phenylmorpholine; or a pharmaceutically acceptable salt thereof.

12. Spoj kao što je zahtijevano u zahtjevu 1 formule (Ii): [image] unutar kojeg R1, R2, R3, R4, R5, R6, R9a, R9b, X i Y su definirani u zahtjevu 1; ili njegova farmaceutski prihvatljiva sol ili prodrug.12. A compound as claimed in claim 1 of formula (Ii): [image] within which R1, R2, R3, R4, R5, R6, R9a, R9b, X and Y are as defined in claim 1; or a pharmaceutically acceptable salt or prodrug thereof.

13. Spoj kao što je zahtijevano u bilo kojem prethodnom zahtijevu za uporabu u terapiji.13. A compound as claimed in any preceding claim for use in therapy.

14. Farmaceutski pripravak koji sadrži spoj koji je zahtijevan u bilo kojem zahtjevu od 1 do 12 zajedno s farmaceutski prihvatljivim nosačem ili ekscipijentom.14. A pharmaceutical composition comprising a compound as claimed in any of claims 1 to 12 together with a pharmaceutically acceptable carrier or excipient.

15. Postupak za tretiranje ili prevenciju fizioloških poremećaja povezanih sa suviškom tehikinina, gdje postupak uključuje davanje pacijentu kojem je to potrebno za reduciranje tahikinina količinu spoja prema Zahtjevu 1, ili njegove soli ili prodrug-a, ili pripravka koji sadrži spoj prema Zahtjevu 1, ili njegovu sol ili prodrug.15. A method for treating or preventing physiological disorders associated with excess tachykinin, where the method includes administering to a patient who needs it to reduce tachykinin an amount of the compound according to Claim 1, or its salt or prodrug, or a preparation containing the compound according to Claim 1, or its salt or prodrug.

16. Postupak prema zahtjevu 15 za tretiranje ili prevenciju boli ili upale.16. The method according to claim 15 for treating or preventing pain or inflammation.

17. Postupak prema zahtjevu 15 za tretiranje ili prevenciju migrene.17. The method according to claim 15 for the treatment or prevention of migraine.

18. Postupak prema zahtjevu 15 za tretiranje ili prevenciju povraćanja.18. The method according to claim 15 for treating or preventing vomiting.

19. Postupak za pripremanje spoja formule (I) kao što je zahtjevano u zahtjevu 1, koji uključuje: (A) reagiranje spoja formule (II): [image] unutar koje R1, R2, R3, R4, R5 i Y su definirani kao u formuli (I) u reakciji sa spojem formule (III): X1-X2-R6a (III). gdje je X definiran kao u zahtjevu 1, R6a je grupa formule R6 kao što je definirano u zahtjevu 1 ili njezin prekursor i X1 je otpuštajuća grupa kao što je brom ili klor; i, ukoliko je R6a prekursor grupa, njezina konverzija u R6 grupu; ili (B) gdje R6 prikazuje 1,2,3-triazol-4-il supstituiran sa CH2NR7R8 i X je -CH2-, u reakciji spoja formule (IV) [image] sa azidom, praćeno redukcijom karbonil grupe uz -NR7R8; ili (C) gdje R6 prikazuje 1,2,3-triazol-4-il supstituiran sa CH2NR7R8 i X je -CH2-, u reakciji spoja formule (V) [image] s aminom formule NHR7R8; ili (D) gdje R6 prikazuje supstituirani ili nesupstituirani 1,3,5-triazin, u reakciji spoja formule (VI): [image] sa supstituiranim ili nesupstituiranim 1,2,5-triazinom; ili (E) gdje R6 prikazuje supstituirani ili nesupstituirani 1,2,4-triazin, u reakciji spoja formule (VII) sa dikarbonilnim spojem formule (VIII): [image] gdje R35 prikazuje H ili odgovarajući supstituent kao što je ZNR7R8; ili (F) gdje R6 prikazuje supstituirani 1,2,4-triazolnu grupu, u reakciji spoja formule (II) sa spojem formule (IX) [image] gdje je X definiran kao u zahtjevu 1, Hal je atom halogena, i R18 je H, CONH2 ili OCH3 (koji se konvertira u okso supstituent u uvjetima reakcije), u prisustvu baze, praćeno gdje je potrebno konverzijom u spoj formule (I); ili (G) gdje R6 prikazuje tioksotriazolil, u reakciji spoja formule (X) [image] sa spojem formule HNCS, u prisustvu baze; ili (H) gdje je R6 supstituiran s grupom ZNR7R8, reagirajući sa spojem formule (XII): [image] gdje svaki LG, koji može biti jednak ili različit, je otpuštajuća grupa, i X i Z su definirani kao u zahtjevu 1, praćeno reakcijom dobivenog spoja s aminom NHR7R8 da bi se kompletirao ZNR7R8 dio; ili (J) interkonverzijom spoja formule (I) u drugi spoj formule (I); svaki proces praćen, gdje je potrebno, odstranjivanjem bilo koje prisutne zaštitne grupe; i kada je spoj formule (I) dobiven kao smjesa enantiomera ili diastereoizomera, opcijski razdvajanjem smjese da bi se dobio željeni enantiomer; i/ili, ukoliko je željeno, konverzijom dobivenog spoja formule (I) ili njegove soli, u farmaceutski prihvatljivu sol ili njegov prodrug.19. A process for preparing a compound of formula (I) as claimed in claim 1, comprising: (A) reacting the compound of formula (II): [image] wherein R1, R2, R3, R4, R5 and Y are defined as in formula (I) in reaction with a compound of formula (III): X1-X2-R6a (III). where X is defined as in claim 1, R 6a is a group of the formula R 6 as defined in claim 1 or a precursor thereof and X 1 is a leaving group such as bromine or chlorine; and, if R6a is a precursor group, its conversion to an R6 group; or (B) where R6 represents 1,2,3-triazol-4-yl substituted with CH2NR7R8 and X is -CH2-, in the reaction of the compound of formula (IV) [image] with azide, followed by reduction of the carbonyl group with -NR7R8; or (C) where R6 represents 1,2,3-triazol-4-yl substituted with CH2NR7R8 and X is -CH2-, in the reaction of the compound of formula (V) [image] with an amine of the formula NHR7R8; or (D) where R6 represents a substituted or unsubstituted 1,3,5-triazine, in the reaction of the compound of formula (VI): [image] with substituted or unsubstituted 1,2,5-triazine; or (E) where R6 represents a substituted or unsubstituted 1,2,4-triazine, in the reaction of a compound of formula (VII) with a dicarbonyl compound of formula (VIII): [image] wherein R 35 represents H or a corresponding substituent such as ZNR 7 R 8 ; or (F) where R6 represents a substituted 1,2,4-triazole group, in the reaction of the compound of formula (II) with the compound of formula (IX) [image] where X is defined as in claim 1, Hal is a halogen atom, and R 18 is H, CONH 2 or OCH 3 (which is converted to an oxo substituent under the reaction conditions), in the presence of a base, followed where necessary by conversion to a compound of formula (I); or (G) where R6 represents thioxotriazolyl, in the reaction of the compound of formula (X) [image] with a compound of the formula HNCS, in the presence of a base; or (H) where R6 is substituted with the group ZNR7R8, reacting with the compound of formula (XII): [image] wherein each LG, which may be the same or different, is a leaving group, and X and Z are defined as in claim 1, followed by reaction of the resulting compound with the amine NHR7R8 to complete the ZNR7R8 moiety; or (J) interconversion of a compound of formula (I) into another compound of formula (I); each process followed, where necessary, by removal of any protecting groups present; and when the compound of formula (I) is obtained as a mixture of enantiomers or diastereoisomers, optionally by separating the mixture to obtain the desired enantiomer; and/or, if desired, by converting the obtained compound of formula (I) or its salt into a pharmaceutically acceptable salt or its prodrug.