LV12568B - Morfolīni un tiomorfolīni kā tahikinīna receptora atvasinājumi - Google Patents

Description

SUMMARī OF THE INVENTION [0001] This invention is concemed vvith novel compounds represented by structural formula I:

vvherein R¹, R², R³, R⁴, R⁵, and X are hereinafter defined.

[0002] The invention is also concerned vzith pharmaceutical formulations comprising these novel compounds as active ingredients and the use of the novel compounds and their formulations in the treatment of certain disorders. [0003] The compounds of this invention are tachykinin receptor antagonists and are useful in the treatment of inflammatory diseases. pain or migraine and asthma.

[0004] Also, some of these compounds are calcium channel btockers and are useful in the treatment of cardiovascular disorders such as angīna, hypertension or ischemia.

BACKGROUND OF THE INVENTION [0005] Analgesia has historically been achieved in the Central nervous system by opiates and analogs vvhich are addictive, and peripheraily by cyclooxygenase inhibitors that have gastric side effects. Substance P antagonists may inducē analgesia both centrally and peripherally. In addition, substance P antagonists are inhibitory of neurogenic inflammation.

[0006] The neuropeptide receptors for substance P (neurokinin-1; NK-1) are wideiy distributed throughout the mammalian nervous system (especialiy brain and spinai ganglia), the circulatory system and peripheral tissues (especialiy the duodenum and jejunum) and are involved in regulating a number of diverse biological processes. This includes sensory perception of olfaction, vision, audition and pain, movement control, gastric motility, vasodilation, salivation, and micturition (B. Pemovv, Pharmacol. Rev., 1983, 35, 85-141). The NK1 and NK2 receptor subtypes are implicated in synaptic transmission (Laneuville et al.. Life Sci.. 42:1295-1305 (1988)).

[0007] The receptor for substance P is a member of the superfamily of G protein-coupled receptors. This superfamily is an extremely diverse group of receptors in terms of activating ligands and biological functions. In addition to the tachykinin receptors, this receptor superfamily includes the opsins, the adrenergic receptors, the muscarinic receptors, the dopamine receptors, the serotonin receptors, a thyroid-stimulating hormone receptor, a luteinizing hormone-choriogonadotropic hormone receptor, the product of the oncogene ras, the yeast mating factor receptors, a Dictvostelium cAMP receptor, and receptors for other hormones and neurotransmitters (see A.D. Hershey, et aļ., J. Biol. Chem., 1991,226, 4366-4373).

[0008] Substance P (also called ‘SP herein) is a naturally occurring undecapeptide belonging to the tachykinin family ot peptides, the latter being so-named because of their prompt contractile action on extravascular smooth muscle tissue. The tachykinins are distinguished by a conserved carboxyl-terminal sequence Phe-X-Giy-leu-Net-NH₂. In addition to SP the knovvn mammalian tachykinins include neurokinin A and neurokinin B. The current nonmenclature designates the receptors for SP, neurokinin A and neurokinin B as NK-1, NK-2, and NK-3, respectively.

[0009] More specifjcally, substance P is a pharmacologically-active neuropeptide that is produced in mammals and possesses a characteristic amino acid sequence that is illustrated belovv:

Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Giy-Leu-Met-NH₂ fChang et al.. Nature New Biol. 232,86 (1971); D.F. Veber et aļ., U.S. Patent No, 4,680.283).

[0010] Neurokinin A possesses the follovving amino acid sequence: His-Lys-Thr-Asp-Ser-Phe-Val-Gly-Leu-Met-NH₂.

[0011] Neurokinin B possesses the follovving amino acid sequence: Asp-Met-His-Asp-Phe-Phe-Val-Gly-Leu-Met-NH₂.

[0012] Substance P acts as a vasodilator, a depressant, stimulates salivation and producēs increased capillary per2 meability. It is also capable of producing both analgesia and hyperalgesia in animals, depending on dose and pair responsiveness of the animal (see R.C.A. Frederickson et aļ., Science, 199, 1359 (1978); P. Oehme etal., Science. 208, 305 (1980)) and plays a role in sensory transmission and pain perception (T.M. Jessell, Advan. Biochem· Psvchopharmacol. 28,189 (1981)). For example, substance P is believed inter alia to be invoived in the neurotransmissior of pain sensations [Otsuka et al, Role of Substance P as a Sensory Transmitter in Spinal Cord and Sympathefcc 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 (Dec. 1987) 8 506-510], In particular. substance P has been shovvn to be invoived in the transmission of pain in migraine (see B.E.B. Sandberg etal., Journa of Medicīnai Chemistrv, 25,1009 (1982)), and in arthritis (Levine et al. Science, (1984) 226 547-549). These peptides have also been implicated in gastrointestinal (Gl) disorders and diseases of the Gl tract, such as inflammatory bowa disease, ulcerative colitis and Crohn's disease, etc. (see Mantyh et aļ., Neuroscience, 25 (3), 617-37 (1988) and D Regoli in Trends in Cluster Headache’ Ed. F. Sicuteri et aļ., Elsevier Scientific Publishers, Amsterdam, 1987, pp. 85-95).

[0013] It is also hypothesized that there is a neurogenic mechanism for arthritis in vvhich substance P may play 2 role (Kidd et aļ., Ά Neurogenic Mechanism for Symmetric Arthritis* in The Lancet, 11 November 1989 and Gronblac et aļ., Neuropeptides in Synovium of Patients vvith Rheumatoid Arthritis and Osteoarthritis in J, Rheumatol. (1985) 15(12) 1807-10). Therefore, substance P is believed to be invoived in the inflammatory response in diseases such as rheumatoid arthritis and osteoarthritis (O'Byrne et aļ., in Arthritis and Rheumatism (1990) 33 1023-8). Other disease areas vvhere tachykinin antagonists are believed to be useful are allergic conditions (Hamelet et aļ., Can. J. Pharmacc·. Physiol. (1988) 66 1361-7), immunoregulation (Lotz et al., Science (1988) 241 1218-21, Kimball etal., J. Immunoi. (1988) 141 (10) 3564-9 and A. Perianin, et al.. Biochem. Biophvs. Res. Commun. 161, 520 (1989)) vasodilation, brorchospasm, reflex or neuronal control of the viscera (Mantyh et aļ., PNAS (1988) 85 3235-9) and, possibly by arrestinc or slowing p-amyloid-mediated neurodegenerative changes (Yankner et aļ., Science, (1990) 250, 279-82) in senils dementia of the Alzheimer type, Alzheimer's disease and Downs Syndrome. Substance P may also play a role r demyelinating diseases such as multiple sclerosis and amyotrophic lateral sclerosis [J. Luber-Narod et. al., poster presented at C.I.N.P. XVIIIth Congress, 28th June-2nd July, 1992J.

Antagonists selective for the neurokinin-1 (NK-1) and/or the neurokinin-2 (NK-2) receptor may be useful in the treatmen: of asthmatic disease (Frossard et al., Life Sci., 49,1941 -1953 (1991); Advenier, etal., Biochem. Biophvs. Res. Comm.. 184(3), 1418-1424(1992)).

[0014] Substance P antagonists may be useful in mediating neurogenic mucus secretion in mammalian airways anc hence provide treatment and symptomatic relief in diseases characterized by mucus secretion, in particular, cystie fibrosis [S. Ramnarine, et al., abstract to be presented at 1993 ALA/ATS InVI Conference, 16-19 May, 1993, to be published in Am. Rev. of Respiratory Dis., May 1993, in press], [0015] In the recent past, some attempts have been made to provide peptide-like substances that are antagonists for substance P and other tachykinin peptides in order to more effectively treat the various disorders and diseases listed above. See for example European patent applications (EPO Publication Nos. 0,347,802, 0,401,177 anc 0,412,452) vvhich disclose various peptides as neurokinin A antagonists. Similarly, EPO Publication No. 0,336,230 discloses heptapeptides vvhich are substance P antagonists useful in the treatment of asthma. Merck U.S. Patent No 4,680,283 also discloses peptidal analogs of substance P.

[0016] Certain inhibitors of tachykinins have been described in U.S. Patent No. 4,501,733, by replacing residues in substance P sequence by Trp residues.

[0017] A further class of tachykinin receptor antagonists, comprising a monomeric or dimeric hexa- or heptapeptide unit in linear or cyclic form, is described in GB-A-2216529.

[0018] The peptide-like nature of such substances make them too labile from a metabolic point of view to serve as practical therapeutic aģents in the treatment of disease. The non-peptidic antagonists of the present invention, on the other hand, do not possess this dravvback, as they are expected to be more stable from a metabolic point of vievv than the previously-discussed aģents.

[0019] It is knovvn in the art that baclofen (p-(aminoethyl)-4-chlorobenzenepropanoic acid) in the Central nervous system effectively blocks the excitatory activity of substance P, but because in many areas the excitatory responses to other compounds such as acetyicholine and glutamate are inhibited as vvell, baclofen is not considered a specific substance P antagonist. Pfizer WIPO patent applications (PCT Publication Nos. WO 90/05525, WO 90/05729, WO 91/18899. WO 92/12151 and WO 92/12152) and publications (Science, 251,435-437 (1991); Science, 251,437-439 (1991); J. Med. Chem,, 35, 2591-2600 (1992)) disclose 2-arylmethyl-3-substituted amino-quinuclidine derivatives vvhich are disclosed as being useful as substance P antagonists for treating gastrointestinal disorders, central nervous system disorders, inflammatory diseases and pain or migraine. A Glaxo European patent application (EPO Publication No. 0,360 390) discloses various spirolactam-substituted amino acids and peptides vvhich are antagonists or agonists of substance P. A Pfizer WIP0 patent application (PCT Publication No. WO 92/06079) discloses fused-ring analogs of nitrogen-containing nonaromatic heterocycles as useful for the treatment of diseases mediated by an excess of substance P. A Pfizer WIPO patent application (PCT Publication No. WO 92/15585 discloses 1 -azabicyclo{3.2.2]nonan3- amine derivatives as substance P antagonists. A Sanofi publication (Life Sci., 50. PL101-PL106 (1992)) discloses a

4- phenyl piperidine derivative as an antagonist of the neurokinin Α (NK2) receptor.

[0020] Hovvson et al. (Biorg. & Med. Chem. Lett.. 2 (6), 559-564 (1992)) disclose certain 3-amino and 3-oxy quinuclidine compounds and their binding to substance P receptors. EPO Publication 0,499,313 discloses certain 3-oxy and 3-thio azabicyclic compounds as tachykinin antagonists. U.S, Patent No. 3,506,673 discloses certain 3-hydroxy quinuclidine compounds as Central nervous system stimulants. A Pfizer EPO Patent application (EPO Publication 0,436,334) discloses certain 3-aminopiperidine compounds as substance P antagonists. U.S. Patent No. 5,064,838 discloses certain 1,4-disubstituted piperidinyl compounds as analgesics. PCT Publication No. WO 92/12128 discloses certain piperidine and pyrroiidine compounds as analgesics. Peyronel, et al. (Biorg & Med. Chem. Lett., 2 (1), 37-40 (1992)) disclose a fused ring pyrrolidine compound as a substance P antagonist. EPO Publication No. 0,360,390 discloses certain spirolactam derivatives as substance P antagonists. U.S. Patent No. 4,804,661 discloses certain piperazine compounds as analgesics. U.S. Patent No. 4,943,578 discloses certain piperazine compounds useful in the treatment of pain. PCT Publication No. WO 92/01679 discloses certain 1,4-disubstituted piperazines useful in the treatment of mental disorders in which a dopaminergic deficit is implicated.

DETAILED DESCRIPTION OF THE INVENTION [0021] The novel compounds of this invention are represented by structural formula I:

or a pharmaceutically acceptable salt thereof, vvherein:

R^{1 * * *} is selected from the group consisting of:

(1) hydrogen;

(2) C_v6 aikyl, unsubstituted or substituted vvith one or more of the substituents selected from:

(a) hydroxy, (b) οχο, (c) Cļ.5 alkoxy, (d) phenyl-C,.₃ alkoxy, (e) phenyl, (f) -CN, (g) halo, (h) -NR⁹R¹⁰, vvherein R⁹ and R¹⁰ are independently selected from:

(i) hydrogen, (ii) C,^ alkyl, (iii) hydroxy-Cļ^ alkyl, and (iv) phenyl, (i) -NR⁹COR¹⁰, wherein R⁹ and R¹⁰ are as defined above, (j) -NR⁹CO₂R¹⁰, vvherein R⁹ and R¹⁰ are as defined above, (k) -CONR⁹R¹⁰, wherein R⁹ and R¹⁰ are as defined above, (l) -COR⁹, vvherein R⁹ is as defined above, (m) -CO₂R⁹, wherein R⁹ is as defined above;

(n) heterocycle, vvherein the heterocycle is selected from the group consisting of:

(A)	benzimidazolyl,
(B)	benzofuranyl,
(C)	benzothiophenyl,
(D)	benzoxazolyl,
(E)	furanyl,
(Π	imidazolyl,
(G)	indolyl,
(H)	isooxazolyl,
(I)	isothiazolyl,
(J)	oxadiazolyl,
(K)	oxazolyl,
(L)	pyrazinyl,
(M)	pyrazolyl,
(N)	pyridyl,
(O)	pyrimidyl,
(P)	pyrrolyl,
(Q)	quinolyl,
(R)	tetrazolyl,
(S)	thiadiazolyl,
(T)	thiazolyl,
(U)	thienyl,
(V)	triazolyl,
(W)	azetidinyl,
(X)	1,4-dioxanyl,
(Y)	hexahydroazepinyl,
(Z)	oxanyl,
(AA)	piperazinyl,
(AB)	piperidinyl,
(AC)	pyrrolidinyl,
(AD)	tetrahydrofuranyl, and
(AE)	tetrahydrothienyl,

and vvherein the heterocycle is unsubstituted or substituted vvith one or more substituents) selected from:

(i) alkyl, unsubstituted or substituted vvith halo, -CF₃, -OCH₃, or phenyl, (ii) Ο,,θ alkoxy, (iii) 0X0, (iv) hydroxy, (v) thioxo, (vi) -SR⁹, vvherein R⁹ is as defined above, (vii) halo, (viii) cyano, (ix) phenyl, (x) trifluoromethyl, (xi) -(CH₂)_m-NR⁹R¹⁰, vvherein m is 0, 1 or 2, and R⁹ and R¹⁰ are as defined above, (xii) -NR⁹COR¹⁰, vvherein R⁹ and R¹⁰ are as defined above, (xiii) -CONR⁹R¹⁰, vvherein R⁹ and R¹⁰ are as defined above, (xiv) -CO₂R⁹, vvherein R⁹ is as defined above, and (xv) -(CH₂)_m-OR⁹, vvherein m and R⁹ are as defined above;

(3) C₂.₆ alkenyl, unsubstituted or substituted vvith one or more of the substituent(s) selected from:

(a) hydroxy, (b) οχο, (c) Ο_ν6 alkoxy, (d) phenyl-C,.₃ alkoxy, (e) phenyl, (0 -CN, (g) halo, (h) -CONR’R¹⁰ vvherein R⁹ and R¹⁰ are as defined above, (i) -COR⁹ vvherein R⁹ is as defined above,

0) -CO₂R⁹, vvherein R⁹ is as defined above, (k) heterocycle, vvherein the heterocycle is as defined above;

(4) C_2< alkynyl;

(5) phenyl, unsubstituted or substituted vvith one or more of the substituent(s) selected from;

(a) hydroxy, (b) Ο,^βΙΚοχγ, (c) C₁₄alkyl, (d) C₂.₅ alkenyl, (e) halo, (0-CN, (9)-NO₂, (h) -CF₃, (i) -(CH₂)_m-NR⁹R¹⁰, vvherein m, R⁹ and R¹⁰ are as defined above, (j) -NR⁹COR¹⁰, vvherein R⁹ and R¹⁰ are as defined above, (k) -NR⁹CO₂R¹⁰, wherein R⁹ and R¹⁰ are as defined above, (l) - CONR⁹R¹⁰, vvherein R⁹ and R¹⁰ are as defined above, (m) -CO₂NR⁹R¹⁰, vvherein R⁹ and R¹⁰ are as defined above, (n) -COR⁹, vvherein R⁹ is as defined above;

(o) -CO2R⁹, vvherein R⁹ is as defined above;

R² and R³ are independently selected from the group consisting of:

(1) hydrogen, (2) Cļ^ alkyl, unsubstituted or substituted with one or more of the substituents selected from:

(a) hydroxy, (b) οχο, (c) C,^ alkoxy, (d) phenyl-C_v3 alkoxy, (e) phenyl, (0-CN, (9) halo, (h) -NR’R¹⁰, vvherein R⁹ and R¹⁰ are as defined above, (i) -NR’COR¹⁰, vvherein R⁹ and R¹⁰ are as defined above, (j) -NR⁹CO₂R¹⁰, wherein R⁹ and R¹⁰ are as defined above, (k) -CONR’R¹⁰, vvherein R⁹ and R¹⁰ are as defined above, (l) -COR⁹, vvherein R⁹ is as defined above, and (m) -CO₂R⁹, vvherein R⁹ is as defined above;

(3) C₂.₆ alkenyl, unsubstituted or substituted vvith one or more of the substituent(s) selected from;

(a) hydroxy, (b) οχο, (c) alkoxy, (d) phenyl-C₁.₃ alkoxy, (e) phenyl, (f) -CN, (g) halo, (h) -CONR⁹R¹⁰ vvherein R⁹ and R¹⁰ are as defined above, (i) -COR⁹ vvherein R⁹ is as defined above, (j) -CO₂R⁹, vvherein R⁹ is as defined above;

(4) C₂^ alkynyl;

(5) phenyl, unsubstituted or substituted vvith one or more of the substituent(s) selected from;

(a) hydroxy, (b) C_v6 alkoxy, (c) alkyl, (d) C₂._s alkenyl, (e) halo, (f) -CN, (9)-NO₂, (h) -CF₃.

(i) -(CH2)mNR⁹R¹⁰. vvherein m, R⁹ and R¹⁰ are as defined above, (j) -NR⁹COR¹⁰, vvherein R⁹ and R¹⁰ are as defined above, (k) -NR⁹CO₂R¹⁰, vvherein R⁹ and R¹⁰ are as defined above, (l) -CONR⁹R¹⁰, vvherein R⁹ and R¹⁰ are as defined above, (m) -CO₂NR⁹R¹⁰, vvherein R⁹ and R¹⁰ are as defined above, (n) -COR⁹, vvherein R⁹ is as defined above;

(o) -CO₂R⁹, vvherein R⁹ is as defined above;

and the groups R¹ and R² may be joined together to form a heterocyclic ring selected from the group consisting of:

(a) pyrrolidinyl, (b) piperidinyl, (c) pyrrolyl, (d) pyridinyl, (e) imidazolyl, (f) oxazolyl, and (g) thiazolyl, and vvherein the heterocyclic ring is unsubstituted or substituted vvith one or more substituent(s) selected from;

(i) C^alkyl, (ii) οχο, (iii) Ο,^βΙΙωχγ, (iv) -NR⁹R¹⁰, vvherein R⁹ and R¹⁰ are as defined above, (v) halo, and (vi) trifluoromethyl;

and the groups R² and R³ may be joined together to form a carbocyclic ring selected from the group consisting of:

(a) cyclopentyl, (b) cyclohexyl, (c) phenyl, and vvherein the carbocyclic ring is unsubstituted or substituted vvith one or more substituents selected from;

(i) C_Malkyl, (ii) C₁_₆alkoxy, (iii) -NR⁹R¹⁰, vvherein R⁹ and R¹⁰ are as defined above, (iv) halo, and (v) trifluoromethyl;

and the groups R² and R³ may be joined together to form a heterocyclic ring selected from the group consisting of:

(a) pyrrolidinyl, (b) piperidinyl, (c) pyrrolyl, (d) pyridinyl, (β) imidazolyl, (f) furanyl, (g) oxazolyl, (h) thienyl, and (i) thiazolyl, and vvherein the heterocyclic ring is unsubstituted or substituted vvith one or more substituent(s) selected from:

(i) C₁^alkyl, (ii) oxo, (iii) Ο,^Ηςοχγ.

(iv) -NR⁹R¹⁰, vvherein R⁹ and R¹⁰ are as defined above, (v) halo, and (vi) trifluoromethyl;

Xis-O-;

R⁴ is selected from the group consisting of;

(2) alkyl, vvherein the alkyl is unsubstituted or substituted with one or more of the substituents selected from:

(a) hydroxy, (b) oxo, ' (c) alkoxy, (d) phenyl-C_V3 alkoxy, (e) phenyl, (f) -CN, (g) halo, ^: (h) -NR⁹R¹⁰, wherein R⁹ and R¹⁰ are as defined above, (i) -NR⁹COR¹⁰, wherein R⁹ and R¹⁰ are as defined above, (j) -Nf^COgR¹⁰, vvherein R⁹ and R¹⁰ are as defined above, (k) -CONR⁹R¹⁰ wherein R⁹ and R¹⁰ are as defined above, (l) -COR⁹, wherein R⁹ is as defined above, and (m) -CO₂R⁹, wherein R⁹ is as defined above;

(3)- Y-C₂^ alkenyl, vvherein the alkenyl is unsubstituted or substituted vvith one or more of the substituentfs selected from;

(a) hydroxy, (b) oxo, (c) C,^ alkoxy, (d) phenyl-C₁.₃ alkoxy, (e) phenyl, (f) -CN, (g) halo, (h) -CONR⁹R¹⁰ vvherein R⁹ and R¹⁰ are as defined above, (i) -COR⁹ vvherein R⁹ is as defined above, (j) -CO₂R⁹, vvherein R⁹ is as defined above;

(4) -O(CO)-phenyl, vvherein the phenyl is unsubstituted or substituted with one or more of R⁶, R⁷ and R⁸;

rs j_S phenyl, unsubstituted or substituted vvith one or more of R R¹² and R¹³;

R®, R⁷ and R⁸ are independently selected from the group consisting of:

(1) hydrogen;

(2) Cļ^ alkyl, unsubstituted or substituted vvith one or more of the substituents selected from:

(a) hydroxy, (b) oxo, (c) C^ alkoxy, (d) phenyl-C_v3 alkoxy, (e) phenyl, (f) -CN, (g) halo, (h) -NR⁹R¹⁰, wherein R⁹ and R¹⁰ are as defined above, (i) -NR⁹COR¹⁰, wherein R⁹ and R¹⁰ are as defined above, (j) -NR⁹CO₂R¹⁰, wherein R⁹ and R¹⁰ are as defined above, (k) -CONR⁹R¹⁰, vvherein R⁹ and R¹⁰ are as defined above, (l) -COR⁹, wherein R⁹ is as defined above, and (m) -CO₂R⁹, vvherein R⁹ is as defined above;

(3) C₂^ alkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:

(a) hydroxy, (b) oxo, (c) C,^ alkoxy, (d) phenyl-C₁.₃ alkoxy, (e) phenyl, (f) -CN.

(g) halo, (h) -CONR⁹R¹⁰ vvherein R⁹ and R¹⁰ are as defined above, (i) -COR⁹ vvherein R⁹ is as defined above, (j) -CO₂R⁹, vvherein R⁹ is as defined above;

(4) C₂.₆ alkynyl;

(5) phenyl, unsubstituted or substituted vvith one or more of the substituent(s) selected from:

(a) hydroxy, (b) C_ve alkoxy, (c) C.,__ealkyl, (d) C₂._s alkenyl, (e) halo, (f) -CN, (g) -no₂, (h) -CF₃, (i) -(CH₂)_m-NR⁹R¹⁰, vvherein m, R⁹ and R¹⁰ are as defined above, (j) -NR⁹COR¹⁰, vvherein R⁹ and R¹⁰ are as defined above, (k) -NR⁹CO₂R¹⁰, vvherein R⁹ and R¹⁰ are as defined above, (l) -CONR⁹R¹⁰, vvherein R⁹ and R¹⁰ are as defined above, (m) -CO₂NR⁹R^1ū, vvherein R⁹ and R¹⁰ are as defined above, (n) -COR⁹, wherein R⁹ is as defined above;

(o) -CO₂R⁹, vvherein R⁹ is as defined above;

(6) halo, (7) -CN, (Θ) -CF₃, (9) -N0₂, (10) -SR¹⁴, vvherein R¹⁴ is hydrogen or Cļ.₆alkyl, (11) -SOR¹⁴, wherein R¹⁴ is as defined above, (12) -SO₂R¹⁴, vvherein R¹⁴ is as defined above, (13) NR⁹COR¹⁰, wherein R⁹ and R¹⁰ are as defined above, (14) CONR⁹COR¹⁰, vvherein R⁹ and R¹⁰ are as defined above, (15) NR⁹R¹⁰, wherein R⁹ and R¹⁰ are as defined above, (16) NR⁹CO₂R¹⁰, vvherein R⁹ and R¹⁰ are as defined above, (17) hydroxy, (18) C,^alkoxy, (19) COR⁹, wherein R⁹ is as defined above, (20) CO^⁹, vvherein R⁹ is as defined above;

R¹¹, R¹² and R¹³ are independently selected from the definitions of R®, R⁷ and R⁸;

Y is selected from the group consisting of;

(1) a single bond, (2) -O-, (3) -S-, (4) -CO-, (5) -CH_r, (6) -CHR¹⁵-, and (7) -CR¹⁵R^ie-, vvherein R^1S and R¹⁶ are independently selected from the group consisting of:

(a) 0_νθ alkyl, unsubstituted or substituted vvith one or more of the substituents selected from:

(i) hydroxy, (ii) οχο, (iii) C,^ alkoxy, (iv) phenyl-C,.₃ alkoxy, (v) phenyi, (vi) -CN, (vii) halo, (viii) -NR⁹R¹⁰, vvherein R⁹ and R¹⁰ are as defined above, (ix) -NR⁹COR¹⁰, vvherein R⁹ and R¹⁰ are as defined above, (x) -NR⁹CO₂R¹⁰, wherein R⁹ and R¹⁰ are as defined above, (xi) -CONR⁹R¹⁰, vvherein R⁹ and R¹⁰ are as defined above, (xii) -COR⁹, wherein R⁹ is as defined above, and (xiii) -CO₂R⁹, wherein R⁹ is as defined above;

(b) phenyi, unsubstituted or substituted vvith one or more of the substituent(s) selected from:

(i) hydroxy, (ii) Ci-6 alkoxy, (iii) C₁₄ alkyl, (iv) C₂,₅ alkenyl, (v) halo, (vi) -CN, (vii) -NO₂, (viii) -CF₃, (ix) -(CH₂)_m-NR⁹R¹⁰, vvherein m, R⁹ and R¹⁰ are as defined above, (x) -NR⁹COR¹⁰, vvherein R⁹ and R¹⁰ are as defined above, (xi) -NR⁹CO₂R¹⁰, vvherein R⁹ and R¹⁰ are as defined above, (xii) -CONR⁹R¹⁰, vvherein R⁹ and R¹⁰ are as defined above, (xiii) -CO₂NR⁹R¹⁰, vvherein R⁹ and R¹⁰ are as defined above, (xiv) -COR⁹, vvherein R⁹ is as defined above, and (xv) -CO₂R⁹, wherein R⁹ is as defined above;

Z is selected from:

(1) hydrogen, (2) C₁₄ alkyl, and (3) hydroxy, vvith the proviso that if Y is -Ο-, Z is other than hydroxy, or if Y is -CHR¹⁵-, then Z and R^1S may be joined together to form a double bond.

[0022] The compounds of the present invention have asymmetric centers and this invention includes ali of the optical isomers and mixtures thereof.

[0023] ln addition compounds vvith carbon-carbon double bonds may occur in Z- and E- forms with ali isomeric forms of the compounds being included in the present invention.

[0024] When any variable (e.g., alkyl, aryl, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, etc.) occurs more than one time in any variable or in Formula I, its definition on each ocurrence is independent of its definition at every other occurrence. [0025] As used herein, the term *alkyl* includes those alkyl groups of a designated number of carbon atoms of either a straight, branched, or cyclic configuration. Examples of alky|· include methyl, ethyl, propyl, isopropyl, butyl, iso- secand tert-butyl, pentyl, hexyl, heptyl, 3-ethylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbomyl, and the Iike. *Alkoxy* represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge, such as methoxy, ethoxy, propoxy, butoxy and pentoxy. Alkenyl‘ is intended to include hydrocarbon chains of a specified number of carbon atoms of either a straight- or branched- configuration and at least one unsaturation, vvhich may occur at any point along the chain, such as ethenyl, propenyl, butenyl, pentenyl, dimethylpentyl, and the Iike, and includes E and Z forms, vvhere applicable. ‘Halogen* or ‘halo*, as used herein, means fluora, chlora, bromo and iodo. [0026] The term *aryl* means phenyl or naphthyl either unsubstituted or substituted vvith one, tvvo or three substituents selected from the group consisting of halo, C_w-alkyl, C₁^-alkoxy, NO₂, CF₃, Cļ^-alkylthio, OH, -N(R®)₂, -CO₂R®, C₁₄perfluoroalkyl, C3^-perfluorocycloalkyl, and tetrazol-5-yl.

[0027] The term ’heteroaryl‘ means an unsubstituted, monosubstituted or disubstituted five or six membered aromatic heterocycle comprising from 1 to 3 heteroatoms selected from the group consisting of Ο, N and S and vvherein the substituents are members selected from the group consisting of -OH, -SH, -C^-alk/f, -CM-^alk°xy. -CF₃, halo, -NO₂, -CO₂R⁹,-N(R⁹R¹⁰) and a fused benzo group;

[0028] As will be understood by those skilled in the art, pharmaceutically acceptable salts include, but are not limited to salts vvith inorganic acids such as hydrochloride, sulfate, phosphate, diphosphate, hydrobromide, and nitrate or salts vvith an organic acid such as malate, maleate, fumarate, tartrate, succinate, citrate, acetate, iactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethylsulfonate, pamoate, salicylate and stearate. Similarly pharmaceutically acceptable cations include, but are not limited to sodium, potassium, calcium, aluminum, lithium and ammonium.

[0029] ln the compounds of formula I it is preferred that:

R¹ is selected from the group consisting of:

(1) C_v6 alkyl, substituted vvith one or more of the substituents selected from:

(a) heterocycle, vvherein the heterocycle is selected from the group consisting of:

(A) benzimidazolyl, (B) imidazolyl, (C) isooxazolyl, (D) isothiazolyl, (E) oxadiazoiyl, (F) pyrazinyl, (G) pyrazolyl, (H) pyridy I, (I) pyrrolyl, (J) tetrazolyl, (K) thiadiazolyi, (L) triazolyl, and (M) piperidinyl, and vvherein the heterocycle is unsubstituted or substituted vvith one or more substituent(s) selected from:

(i) C_V5 alkyl, unsubstituted or substituted vvith halo, -CF₃, -OCH₃, or phenyf, (ii) Cļ_₆ alkoxy, (iii) οχο, (iv) thioxo, (v) cyano, (vi) -SCH₃, (vii) phenyl, (viii) hydroxy, (be) trifluoromethyl, (x) -(CH₂)_m-NR⁹R¹⁰, vvherein m is 0,1 or 2, and vvherein RP and R¹⁰ are independently selectec from:

(I) hydrogen, (II) alkyl.

(III) hydroxy-C₁_₆ alkyl, and (IV) phenyl, (xi) -NR⁹COR¹⁰, vvherein R⁹ and R¹⁰ are as defined above, and (xii) -CONR⁹R¹⁰, wherein R⁹ and R¹⁰ are as defined above;

R² and R³ are independently selected from the group consisting of:

(1) hydrogen, (2) C_Malkyl, (3) C₂₄ alkenyl, and (4) phenyl;

X is -O-; R*is:

(D

R⁵ is phenyl, unsubstituted or substituted vvith halo;

R⁶, R⁷ and R⁸ are independently selected from the group consisting of:

(1) hydrogen, (2) C^alkyl, (3) halo, and (4) -CF₃;

Y is -O-; and

Z is hydrogen or C_1M alkyl.

[0030] An embodiment of the novel compounds of this invention is that vvherein X is 0, R⁴ is -YCHZ-phenyl, and is phenyl of structural formula:

,6

R

1 or a pharmaceutically acceptable salt thereof, vvherein R¹, R², R³, R⁶, R⁷, R®, R¹¹, R¹² R¹³, Y and Z are as defined above.

[0031] In the compounds of the present invention a preferred embodiment is that in vvhich R¹ is selected from the follovving group of substituents:

[0032]

Specfc compounds « m. scope d me presen, nvenuon Muds:

1) (+/-)-2-(3,5-bis(trifluoromethyl)benzyloxy)-3-phenyl-morpholine;

2) (2R,S)-(3,5-bis(trifluoromethyl)benzyloxy)-(3R)-phenyl-(6R)-m0thyl-morpholine;

3) (2R,S)-(3₁5-bis(trifluoromethyl)benzytoxy)-(3S)-phenyl-(6R)-methyl-morpholine;

4) (+/-)-2-(3,5-bis(trifluoromethyl)benzyloxy)-3-phenyl-4-methylcarboxamido-morpholin0;

5) (+/-)-2-(3,5-bis(trifluorornethyl)benzyloxy)-3-pheriyl-4-rnethoxy-cart}onylmethyl-morpholine;

6) 2-(2-(3,5-bis(trrfluoromethyl)phenyl)ethenyl)-3-phenyl-5-oxo-morpholine;

7) 3-phenyI-2-(2-(3,5-bis(trifluoromethyl)phenyl)ethyl)-morpholine;

8) 2-{R)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-6-(S)-methyl-morpholine;

9) 2-(R)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-6-(S)-methyl-morpholine;

10) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-6-(S)-methyl-morpholine;

11) 2-(S)-(3,5-bis(trifluoromethy))benzyloxy)-3-(S)-phenyl-6-(S)-methyl-morpholine;

12) 2-(R)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-5-(R)-methyl-morpholine;

13) 2-(R)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-5-(R)-methyl-morpholine;

14) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-5-(R)-methyl-morpholine;

15) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-5-(R)-fnethyl-morpholine;

16) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenylmorpholine;

17) 4-(3-(1,2,4-triazolo)methyl)-2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-morpholine;

18) 4-(3-(5-oxo-1 H.4H-1,2,4-triazolo)methyl)-2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-morphc

19) 2-(R)-(3,5-bis(trifluoromethyl)benzytoxy)-3-(R)-phenyl-6-(R)-methyl-morpholine;

20) 2-(S)-(3,5-bis(triRuoromethyl)benzyloxy)-3-(R)-phenyl-6-(R)-methyl-morpholine;

21) 2-(R)-(3,5-bis(trifluoromethyl)benzytoxy)-3-(S)-phenyl-6-(R)-methyl-morpholīne;

22) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-6-(R)-fnethyl-morpholine;

23) 2-(R)-(3,5-bis(trifluoromethyl)-benzyloxy)-3-(S)-phenyl-5-(S)-methyl-morpholine,'

24) 2-{S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-5-(S)-methyl-morpholine;

25) 2-(R)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-5-(S)-methyl-morpholine;

26) 2-(R)-(3,5-bis(trifluoromethyl)benzytoxy)-3-(S)-phenyl-5-(R)-phenyl-morpholine;

27) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-5-(R)-phenyl-morpholine;

28) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-5-(S)-phenyl-morpholine;

29) 2-(R)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-5-(S)-phenyl-morpholine;

30) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-6-(R)-methyl-3-(S)-phenyl-4-(3-(1,2₁4-triazolo)methyl)morpholine;

31) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-6-(R)-methyl-4-(3-(5-oxo-1 H.4H-1,2,4-triazolo)methyl)-3-(S)-phenyl-morpholine;

32) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-morpholine;

33) 4-(3-(1,2,4-triazolo)methyl)-2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-morpholine;

34) 4-(3-(5-oxo-1H_l4H-1,2_l4-triazolo)m0thyl)-2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-morpholine;

35) 4-(2-(imidazolo)methyl)-2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-morpholine;

36) 4-{4-(imidazolo)methyl)-2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-morpholine;

37) 4-(aminocarbonylmethyl)-2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-morpholine;

38) 4-(2-(imidazolo)methyl)-2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-morpholine;

39) 4-(4-(imidazolo)methyl)-2-(S)-(3,5-bis(trifluoronnethyl)benzyloxy)-3-(S)-phenyl-morpholine;

40) 4-(2-(imidazolo)methyl)-2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-6-(R)-methyl-morpholine;

41) 4-(4-(imidazolo)methyl)-2-(S)-(3,5-bis(trīfluoromethyl)benzyloxy)-3-(S)-phenyl-6(R)-methyl-morpholine;

42) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-4-((6-hydroxy)hexyl)-3-(R)-phenyl-morpholine;

43) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-4-(5-(methylaminocarbonyl)pentyl)-3-(R)-phenyl-morpholine;

44) 4-(3-(1,2,4-triazolo)methyl)-2-(3,5-dimethylbenzyloxy)-3-phenyl-morpholine;

45) 4-(3-(5-oxo-1 H,4H-1,2,4-triazolo)methyl)-2-(3,5-dimethyl)benzyloxy)-3-phenyl-morpholine;

46) 4-(3-(1,2,4-triazolo)methyl)-2-(3,5-di(tert-butyl)-benzyloxy)-3-phenyl-morpholine;

47) 4-(3-(5-oxo-1 H.4H-1,2,4-triazolo)methyl)-2-(3,5-di(tert-butyl)benzyloxy)-3-phenyl-morphoiine;

48) 4-(3-(1,2,4-triazolo)methyl)-2-(3-(tert-butyl)-5-methylbenzyloxy)-3-phenyl-morpholine;

49) 4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)-2-(3-(tert-butyl)-5-methylbenzyloxy)-3-phenyl-morpholine;

50) 4-(3-(1,2,4-triazolo)methyl)-2-(3-(trifluoromethyl)-5-methylbenzyloxy)-3-phenyl-morpholine;

51) 4-(3-(5-oxo-1 Η, 4H-1,2,4-triazolo)methyl)-2-(3-(trifluoromethyl)-5-methylbenzyloxy)-3-phenyl-morpholine;

52) 4-(3-(1,2,4-triazolo)methyl)-2-(3-(tert-butyl)-5-(trifIuoromethyl)benzyloxy)-3-phenyl-morpholine;

53) 4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)-2-(3-(tert-butyl)-5-(trifluoromethyl)benzyloxy)-3-phenyl-morpholine;

54) 4-(2-(imidazolo)methyl)-2-(3,5-dimethylbenzyloxy)-3-phenyl-morpholine;

55) 4-(4-(imidazolo)methyl)-2-(3,5-dimethylbenzyloxy)-3-phenyl-morpholine;

56) 4-(2-(imidazolo)methyl)-2-(3,5-di(tert-butyl)-benzyloxy)-3-phenyl-morpholine;

57) 4-(4-(imidazolo)methyl)-2-(3,5-di(tert-butyl)-benzyloxy)-3-phenyl-morphoiine;

58) 4-(2-(imidazolo)methyl)-2-(3-(tert-butyl)-5-methylbenzyloxy)-3-phenyl-morpholine;

59) 4-(4-(imidazolo)methyl)-2-(3-(tert-butyl)-5-methylbenzytoxy)-3-phenyl-morpholine;

60) 4-(2-(imidazolo)methyl)-2-(3-(trifluoromethyl)-5-methylbenzyloxy)-3-phenyl-morpholine;

61) 4-(4-(imidazolo)mathyl)-2-(3-{trifluoromethyl)-5-methylbenzyloxy)-3-phenyl-morphorme;

62) 4-(2-(imidazolo)rnethyl)-2-(3-(tert-biityl)-5-(trifluoromethyl)benzyloxy)-3-phenyl-rnorphoIine;

62) 4-(4-(imidazolo)rnethyl)-2-(3-(tert-butyl)-5-(trifluoromethyl)benzyloxy)-3-phenyl-morpholine;

63) 2-{S)-(3,5-dichlorobenzytoxy)-3-(S)-phenyl-morpholine;

64) 2-(S)-(3,5-dichlorobenzyloxy)-4-(3-(5-oxo-1,2,4-triazolo)methyl)-3-(S}-phenylmorpholine;

65) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-4-(methoxycarbonylmethyl)-3-(S)-phenylmorpholine;

66) 2-(S)-(3,5-bis(trifluoromethyl)b0nzyloxy)-4-(carboxyrnethyl)-3-(S)-phenylrnorpholine;

67) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-4-((2-aminoethyl)aminocarbonylmethyl)-3-(S)-phenylmorpholine;

66) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-4-((3-aminopropyl)amino carbonylrnethyl)-3-(S)-phenylmorpholine;

69) 4-benzyl-5-(S),6-(R)-dimethyl-3-(S)-phenylmorpholinone and 4-benzyl-5-(R),6-(S)-dimethyl-3-(S)-phenyi morpholinone;

70) 2-{R)-(3,5-bis(trifluoromethyl)benzyloxy)-[5-(S), 6-(R) or 5-{R),6-(S)-dimethyl]-3-(S)-phenylmorpholinone;

71) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-{5-(R), 6-(S) or 5-(S),6-(R)-dimethyl]-3-(S)-phenylmorpholinone;

72) 2-{R)-(3,5-bis(trifluoromethyl)benzyloxy)-4-(3-(1,2,4-triazolo)methyl)-[5-(S),6-(R) or 5-(R), 6-(S)-dimethyl]-i (S)-phenylmorpholinone;

73) 2-(R)-(3,5-bis(trifluoromethyl)benzyloxy)-4-(3-(5-oxo-1,2,4-triazolo) methyl)-[5-(S),6-(R) or 5-(R),6-(S)-dim thyl]-3-(S)-phenylmorpholinone; «

74) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-4-(3-(1,2,4-triazolo)methyl)-[5-(R),6-(S) or 5-(S),6-(R)-dimethyl]-, (S)-phenytmorpholinone;

75) 2-(S)-(3,5-bis(trffluoromethyl)benzyloxy)-4-(3-(5-oxo-1,2,4-triazolo)methyl)-[5-(R)_l6-(S) or 5-(S),6-(R)-dirr thyl]-3-(S)-phenylmorpholinone;

76) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-4-(2-(1-(4-benzyl)piperidino)ethyl)-3-(S)-phenylmorpholine;

77) 3-{S)-(4-fluorophenyl)-4-benzyl-2-morpholinone;

78) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-(4-fluorophenyl)-4-benzylmorpholine;

79) 2-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(S)-(4-fluorophenyl) morpholine;

80) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methylr pholine;

81) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-4-((3-pyridyl)methyl carbonyl)-3-(R)-phenylmorpholine;

82) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-4-(methoxycarbonylpentyl)-3-(R)-phenylmorpholine;

83) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-4-(carboxypentyl)-3-(R)-phenylmorpholine;

84) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-4-(methylaminocarbonylpentyl)-6-oxo-hexyl)-3-(R)-phenylmorpholine;

and pharmaceutically acceptable salts thereof.

TACHYKININ ANTAGONISM ASSAY [0033] The compounds of this invention are useful for antagonizing tachykinins, in particular substance P and neurokinin A in the treatment of gastroin-testinal disorders, central nervous system disorders, inflammatory diseases, pain or migraine and asthma in a mammai in need of such treatment. This activity can be demonstrated by the follovving assay.

A. Receptor Expression in COS [0034] To express the cloned human neurokinin-1 receptor (NKIR) transiently in COS, the cDNA for the human NKIR vvas cloned into the expression vector pCDM9 vvhich was derived from pCDMS (INVITROGEN) by inserting the ampicillin resistance gene (nucleotide 1973 to 2964 from BLUESCRIPT SK+) into the Sac II site. Transfection of 20 ug of the plasmid DNA into 10 miliion COS celis was achieved by electroporation in 800 ul of transfection buffer (135 mM NaCl, 1.2 mM CaCIj,, 1.2 mM MgCI* 2.4 mM K₂HPO₄, 0.6 mM KH₂PO₄,10 mM glucose, 10 mM HEPES pH 7.4) at 260 V and 950 uF using the IBIGENEZAPPER (IBI, Nevv Haven, CT). The celis vvere incubated in 10% fetal calf serum, 2 mM glutamine, 100U/ml penicillin-streptomycin, and 90% DMEM media (GIBCO, Grand Island, NY) in 5% CO₂ at 37“C for three days before the binding assay.

B. Stable Expression in CHO [0035] To establish a stable celi line expressing the cloned human NKIR, the cDNA was subcloned into the vector pRcCMV (INVITROGEN). Transfection of 20 ug of the plasmid DNA into CHO celis vvas achieved by electroporation in 800 ul of transfection buffer suplemented with 0.625 mg/ml Herring sperm DNA at 300 V and 950 uF using the IBI GENEZAPPER (IBI). The transfected celis vvere incubated in CHO media [10 % fetal calf serum, 100 U/rnl pennicilinstreptomycin, 2 mM glutamine, 1/500 hypoxanthine-thymidine (ATCC), 90% IMDM media (JRH BIOSCIENCES, Lenexa, KS), 0.7 mg/ml G418 (GIBCO)] in 5% CO₂ at 37*C until colonies vvere visible. Each colony vvas separated and propagated. The celi clone vvith the highest number of human NKIR was selected for subsequent applications such as drug screening.

C. Assav Protocol using COS or CHO [0036] The binding assay of human NKIR expressed in either COS or CHO celis is based on the use of ^12SI -substance P (i2S|-SP, from DU PONT, Boston, MA) as a radioactively labeled ligand vvhich competes vvith unlabeled substance P or any other ligand for binding to the human NKIR. Monolayer celi cultures of COS or CHO vvere dissociated by the non-enzymatic solution (SPECIALTY MEDIA, Lavallette, NJ) and resuspended in appropriate volume of the binding buffer (50 mM Tris pH 7.5,5 mM MnCI2, 150 mM NaCl, 0.04 mg/ml bacitracin, 0.004 mg/ml leupeptin, 0.2 mg/ml BSA, 0.01 mM phosphoramidon) such that 200 ul of the celi suspension vvould give risēto about 10,000 cpm of specific ^12SISP binding (approximately 50,000 to 200,000 celis). In the binding assay, 200 ul of celis vvere added to a tube containing 20 ul of 1.5 to 2.5 nM of ^12SI-SP and 20 ul of unlabeled substance P or any other tēst compound. The tubes vvere incubated at 4°C or at room temperature for 1 hour vvith gentle shaking. The bound radioactivity vvas separated from unbound radioactivity by GF/C filter (BRANDEL, Gaithersburg, MD) vvhich vvas pre-wetted vvith 0.1 % polyethylenimine. The filter vzas vvashed vvith 3 ml of vvash buffer (50 mM Tris pH 7.5, 5 mM MnCI2, 150 mM NaCl) three times and its radioactivity vvas determined by gamma counter.

[0037] The activation of phospholipase C by NKIR may also be measured in CHO celis expressing the human NKIR by determining the accumulation of inositol monophosphate vvhich is a degradation product of IP₃. CHO celis are seeded in 12-well plate at 250,000 celis per vvell. After incubating in CHO media for 4 days, celis are loaded vvith 0.025 uCi/ml of ³H-myoinositol by overnight incubation. The extracellular radioactivity is removed by vvashing with phosphate buffered saline. LiCI is added to the vvell at final concentration of 0.1 mM vzith or vvithout the tēst compound, and incubation is continued at 37“C for 15 min. Substance P is added to the vvell at final concentration of 0.3 nM to activate the human NKIR. After 30 min of incubation at 37’C, the media is removed and 0.1 N HCl is added. Each vvell is sonicated at 4’C and extracted vvith CHCI^methanol (1:1). The aqueous phase is applied to a 1 ml Dowex AG 1X8 ion exchange column. The column is vzashed vzith 0.1 N formic acid follovzed by 0.025 M ammonium formate-0.1 N formic acid. The inositol monophosphate is eluted vzith 0.2 M ammonium formate-0.1 N formic acid and quantitated by beta counter.

[0038] The compounds of the present invention are useful in the prevention and treatment of a vvide variety of clinical conditions which are characterized by the presence of an excess of tachykinin, in particular substance P, actrvity [0039] These conditions may include disorders of the Central nervous system such as anxiety, depression, psychosis and schizophrenia; epilepsy; neurodegenerative disorders such as AIDS related dementia, senilo dementia of the Alzheimer type, Alzheimer's disease and Down*s syndrome;

demyelinating diseases such as multiple sclerosis and amyotrophic lateral sclerosis (ALS; Lou Gehrig's disease) and other neuropathological disorders such as peripheral neuropathy, for example AIDS related neuropathy, diabetic neuropathy, chemotherapy-induced neuropathy, and postherpetic and other neuralgias; small celi carcinomas such as small celi lung cancer; respiratory diseases such as chronic obstructive airways disease, bronchopneumonia, bronchospasm and asthma; diseases characterized by neurogenic mucus secretion, such as cystic fibrosis; inflammatory diseases such as inflammatory bowel disease, psoriasis, fibrositis, osteoarthritis and rheumatoid arthritis; allergies such as eczema and rhinitis; hypersensitivity disorders such as poison ivy; ophthalmic diseases such as conjunctivitis, vemal conjunctivitis, and the like; cutaneous diseases such as contact dermatitis, atropic dermatitis, urticaria, and other eczematoid dermatitis; addiction disorders such as alcholism; stress related somatic disorders; reflex sympathetic dystrophy such as shoulder/hand syndrome; dysthymic disorders; adverse immunological reactions such as rejection of transplanted tissues and disorders related to immune enhancement or suppression, such as systemic lupus erythematosis; gastrointestinal (Gl) disorders and diseases of the Gl tract such as disorders associated with the neuronal control of viscera such as ulcerative colitis, Crohn's disease and incontinence; emesis, including acute, delayed and anticipatory emesis, for example, induced by chemotherapy, radiation, toxins, pregnancy, vestibular disorder, motion, surgery, migraine and variations in intercranial pressure; disorders of bladder function such as bladder detrusor hyperreflexia; fibrosing and coilagen diseases such as scleroderma and eosinophilic fascioliasis; disorders of blood flovv caused by vasodiiation and vasospastic diseases such as angina, migraine and Reynaud*s disease; and pain or nociception, for example, that attributable to or associated vvith any of the foregoing conditions especially the transmission of pain in migraine. Hence, these compounds may be readily adapted to therapeutic use for the treatment of phvsiological disorders associated with an excessive stimulation of tachykinin receptors, especially neurokinin-1, and as neurokinin-1 antagonists the control and/or treatment of any of the aforesaid clinical conditions in mammals, including humāns.

[0040] For example, the compounds of the present invention may suitably be used in the treatment of disorders of the Central nervous system such as anxiety, psychosis and schizophrenia;

neurodegenerative disorders such as senile dementia of the Alzheimer type, Alzheimer's disease and Dovvn's sindroms; respiratory diseases, particularfy those associated vvith excess mucus secretion, such as chronic obstructive airways disease, bioncho-pneumonia, chronic bronehitis, cystic fibrosis and asthma, and bronehospasm; inflammatqry diseases such as inflammatory bovvel disease, osteoarthritis and rheumatoid arthritis; adverse immunological reactions such as rejection of transplanted tissues; gastro-intestinal (Gl) disorders and diseases of the Gl tract such as disorders associated vvith the neuronal control of viscera such as ulcerative colitis, Crohn's disease and incontinence; disorders of blood flow caused by vasodiiation; and pain or nociception, for exampie, that attributable to or associated vvith any of the foregoing conditions or the transmission of pain in migraine.

[0041] As calcium channel blocking aģents some of the compounds of the present invention are useful in the prevention of treatment of clinical conditions vvhich benefit from inhibition of the transfer of calcium ions aeross the plasma membrane of celis. These include diseases and disorders of the heart and vascular system such as angina pectoris, myocardial infarction, cardiac arrhythmia, cardiac hypertrophy, cardiac vasospasm, hypertension, cerebrovascular spasm and other ischemic disease. Furthermore, these compounds may be capable of k>wering elevated intraocular pressure vvhen administered topically to the hypertensive eye in solution in a suitable ophthalmic vehicle. Also, these compounds may be useful in the reversai of muitidrug resistance in tumor celis by enhancing the eificacy of chemotherapeutic aģents. In addition, these compounds may have activity in blocking calcium channels in insect brain membranes and so may be useful as insecticides.

[0042] The compounds of the present invention are particularly useful in the treatment ot pain or nociception and/or inflammation and disorders associated therewith such as, for example:

neuropathy, such as diabetic or peripheral neuropathy and chemotherapy-induced neruopathy; postherpetic and other neuralgias; asthma; osteoarthritis; rheumatoid arthritis; and especially migraine. The compounds of the present invention are also particuiarly useful in the treatment of diseases characterized by neurogenic mucus secretion, especially cystic fibrosis.

[0043] in the treatment of the clinical conditions noted above, the compounds of this invention may be utilized in compositions such as tablets, capsules or elixirs for oral administration, suppositories for rectal administration, sterile Solutions or suspensions for parenteral or intramuscular administration, and the like.

[0044] The pharmaceutical compositions of this invention can be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liguid form, vvhich contains one or more of the compounds of the present invention, as an active ingredient, in admixture vvith an organic or inorganic carrier or excipient suitable for external, enteraf or parenteral applications. The active ingredient may be compounded, for example, vvith the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, Solutions, emulsions, suspensions, and any other form suitable for use. The carriers vvhich can be used are water, glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, taic, com starch, keratin, colloidal silica, potato starch, urea and other carriers suitable for use in manufacturing preparations, in solid, semisolid, or liquid form, and in addition auxiliary, stabilizing, thickening and coloring aģents and perfumes may be used. The active object compound is included in the pharmaceutical composition in an amount sufficient to producē the desired effect upon the process or condition of the disease.

[0045] For preparing solid compositions such as tablets, the principal active ingredient is mixed vvith a pharmaceutical carrier, e.g. conventional tableting ingredients such as com starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. vvater, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a non-toxic pharmaceuticailv acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdtvided into equally effective unit dosage forms such as tablets, pilis and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention. The tablets or pilis of the novel composition can be coated or othervvise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pili can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer vvhich serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materiāls can be used for such enteric layers or coatings, such materiāls including a number of pofymeric acids and mixtures of polymeric acids with such materiāls as shellac, cetyl alcohol and cellulose acetate.

[0046] The Ikjuid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solution, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oiis such as cottonseed oil, sesame oil, coconut oil or peanut oil, as vvell as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending aģents for aqueous suspensions include synthetic and natūrai gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin.

[0047] Compositions for inhalation or insufflation include Solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as set out above. Preferably the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably sterile pharmaceutically acceptable solvents may be nebulized by use of. inert gases. Nebulized Solutions may be breathed directly from the nebuiizing device or the nebuiizing device may be attached to a face mask, tent or intermittent positive pressure breathing machine. Solution, suspension or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.

[0048] For the treatment of the clinical conditions and diseases noted above, the compounds of this invention may be administered orally, topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrastemal injection or infusion techniques. [0049] For the treatment of certain conditions it may be desirable to empk>y a compound of the present invention in conjunction with another pharmacologically active aģent. For example, for the treatment of respiratory diseases such as asthma, a compound of the present invention may be used in conjunction vvith a bronchodilator, such as a β₂· adrenergic receptor agonist or tachykinin antagonist vvhich acts at NK-2 receptors. The compound of the present invention and the bronchodilator may be administered to a patient simultaneously, sequentially or in combination. [0050] The compounds of this invention may be administered to patients (animals and human) in need of such treatment in dosages that vvill provide optimal pharmaceutical efficacy. The dose vvill vary from patient to patient depending upon the nature and severity of disease, the patients vveight, special diets then being follovved by a patient, concurrent medication, and other factors which those skilled in the art wiil recognize.

[0051] ln the treatment ot a condition associated with an excess of tachykinins, an appropriate dosage Ievel vvill generally be about 0.001 to 50 mg per kg patient body vveight per day vvhich can be administered in single or multiple doses. Preferably, the dosage Ievel vvill be about 0.01 to about 25 mg/kg per day; more preferably about 0.05 to about 10 mg/kg per day. For example, in the treatment of conditions involving the neruotransmission of pain sensations, a suitable dosage Ievel is about 0.001 to 25 mg/kg per day, preferably about 0.005 to 10 mg/kg per day, and especiaffy about 0.005 to 5 mg/kg per day. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or tvvice per day.

[0052] Several methods for preparing the compounds of this invention are illustrated in the follovving Schemes and

Examples vvherein R¹, R², R³, R⁴, R⁵, R®, R⁷, R®, R®, R¹⁰, R¹¹, R¹² and R¹³ are as defined above.

ABBREVIATIONS USED IN SCHEMES AND EXAMPLES [0053]

Table 1

Reaģents:
Et3N	triethylamine
Ph3P	triphenylphosphine
TFA	trifluoroacetic acid
NaOEt	sodium ethoxide
DCC	N,N'-dicyciohexylcarbodiimide
DCU	N,N'-dicyclohexylurea
CDI	I, l'-carbonyldiimidazole
MCPBA	m-chloroperbenzoic acid
DBU	1,8-diazabicyclo[5.4.0]undec-7-ene
Cbz-CI	benzyl chloroformate
iPr2NEt or DIEA	N, N-diisopropylethylamine
NHS	N-hydroxysuccinimide
DIBAL	diisobutylaluminum hydride
	dimethyl sulfate
HOBt	1-hydroxybenzotriazole hydrate
EDAC	1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
Solvents:
DMF	dimethylformamide
THF	tetrahydrofuran
MeOH	methanol
EtOH	ethanol
AmOH	n-amyl alcohol
AcOH	acetic acid
MeCN	acetonitrile
DMSO	dimethyisulfoxide
Others:
Ph	phenyl
Ar	aryl
Me	methyl
Et	ethyl
iPr	isopropyl
Am	n-amyl
Cbz	carbobenzyioxy (benzyloxycarbonyl)
BOC	tert-butoxycarbonyl
PTC	phase transfer catalyst
cat.	cataiytic
FAB-MS	fast atom bombardment mass spectrometry
rt	room temperature

SCgEME X

III

R¹-X

K₂CO₃, iPrOH, Δ

SCHEME 1 (cont'di

IV

H* toluene Δ

BOC

VI

SCgEBE.2 ,1 3

VII

1) NaBH*

VIII

2) TFA

SCHEME 2 (cont'd)

OH

XI

SCHEME 4

HO-R⁴

H*

HO

R^J u

R² R⁵

OK‘), r’-χ

K₂CO₃, iPrOH, Δ

SC.HEHE 3 ) PhCHO, OH ~

2) NaBFĻ, MeOH/H₂O

BrCHR²CHR³Br K₂CO₃, DMF

100°C

DIBALH or L-Selectride -78°C

SCHEME 5 (cont'dī

SCHEME 5 (cont'dJ

DIEA

DMF or CH₃CN Δ or

R¹CHO, NaBH₃CN THF, MeOH

SCHEME.fr.

Chfe,

1) CCF₃SQ₂)₂Q, CC1₄

2) filter under N₂

3) concentrate, dissolve in toluene

pr-FTpļft 6 (cont'dī

SCggņS fr (cont’d)

DIEA

DMF ΟΓ CH₃CN Δ or

R¹CHO, NaBH₃CN THF, hfeOH

SCHEME 7

) pivaloyl chloride, R₃N, ether, 0°C ²) O’Li*

.....THF, -78°C to 0°C

Ph

1) KHMDS, THF, -78°C

2) Ar' SO₂N₃, THF, -78°C

3) HOAc

1) LiOH, THF/vater

2) H₂, Pd/C, HOAc/vater

[0054] The compounds of the present invention in vvhich X = Υ = O may be prepared by the general route outlined in Scheme 1. Thus, the appropriately substituted a-bromo-phenylacetaldehyde, dimethyl acetal I (prepared using the method of Jacobs in Journal of the American Chemical Societv, 1953, 75, 5500) may be converted to the dibenzy' acetal II by stirring I and a slight excess of a benzyl alcohol in the presence of an acid catalyst vvith concommitan removal of methanol. Alkylation of a substituted amino alcohol by benzyl bromide II may give N-alkyl amino alcohol III use of a chiral amino alcohol vvould result in the formation of diastereomers and these can be separated at this (or at a later) stage using Standard chromatographic methods. N-Alkylation or N-acylation of III can give the dialkyl- or acyl/ alkyl-amino alcohol IV in which the group R¹ may serve as a protecting group or be used as or laborated into a substituent in the final target compound. Cyclization to give substituted morpholine V may be realized by warming a solution of IV and an acid catalyst. Diastereomers of V that may be formed may be separated using Standard chromatographic methods. If R¹ is a protecting group, it may be removed using knovvn procedures (Greene, T.W., Wuts, P.G.M. Protective Groups in Organic Synthesis, 2nd ed., John Wiley & Sons, Inc., New York, 1991). If the preparation of l-V results in the formation of enantiomers, these may be resolved by alkylating or acylating V (R¹ = H) with a chiral auxiliary, separating the diastereomers thus formed using knovvn chromatographic methods, and removing the chiral auxiliary to give the enantiomers of V.

Altematively, the diastereomers of V may be separated via fractional crystallization from a suitable solvent of the diastereomeric salts formed by V and a chiral organic acid.

[0055] The compounds of the present invention in vvhich X = O and Y = CHg may be prepared by the general route outlined in Scheme 2. Thus, the N-methoxy-N-methyl amide of a protected phenyl glycine Vl (prepared from the carboxylic acid via the mixed anhydride according to the procedure of Rapoport in Journal of Organic Chemistrv, 1985, 50, 3972) may be used to acylate the lithium enolate of methyl diethylphosphonate to give the ketophosphonate VII. The sodium salt of VII may be condensed with an appropriately substituted benzaldehyde to give the ο,β-unsaturated ketone VIII. Reduction of the ketone and removal of the t-butylcarbamate protecting group may give amino alcohol IX; diastereomers that may form may be separated at this (or at a later) stage using Standard chromatographic techniques. VVilliamson etherification of IX using a substituted chloroacetate, follovved by vvarming, may result in the formation of morpholinone X Reduction of the double bond and amide carbonyl may be accomplished in a straightforvvard manner to give the substituted morpholine XI. If the preparation of VI-ΧΙ results in the formation of enantiomers, these may be resolved by alkylating or acylating XI (R¹ = H) vvith a chiral auxiliary, separating the diastereomers thus formed using knovvn chromatographic methods, and removing the chiral auxiliary to give the enantiomers of XI. Altematively, the diastereomers of XI may be separated via fractional crystallization from a suitable solvent of the diastereomeric salts formed by XI and a chiral organic acid. If it is desired that R¹ is other than H, the morpholine nitrogen of XI may be further functionalized using Standard methods for the alkyiation or acylation of secondary amines. If it is desired that R² is other than H, morpholinone X may be elaborated into the carbinolcarbamate (R¹ = RO₂C, R² = OH), an intermediate that could be alkylated and would allovv for variation in R².

[0056] The compounds of the present invention in vvhich X = Y = 0 may also be prepared by the general route outlined in Scheme 4. Thus, the appropriately substituted a-bromo-acetaldehyde, dimethyl acetal (prepared using the method of Jacobs in Journal of the American Chemical Societv. 1953,75,5500) may be converted to theacetal by stirring and a slight excess of the appropriate alcohol in the presence of an acid catalyst vvith concommitant removal of methanol. Alkylation of a substituted amino alcohol by a bromide may give the N-alkyl amino alcohol; use of a chiral amino alcohol vvould result in the formation of diastereomers and these can be separated at this (or at a later) stage using Standard chromatographic methods. N-Alkylation or N-acylation may give the dialkyl- or acyl/alkyl-amino alcohol in vvhich the group R¹ may serve as a protecting group or be used as or elaborated into a substituent in the final target compound. Cyclization to give substituted morpholine may be realized by vvarming a solution with an acid catalyst. Diastereomers that may be formed may be separated using Standard chromatographic methods. If R¹ is a protecting group, it may be removed using knovvn procedures (Greene, T.W., Wuts, P.G.M. Protective Groups in Organic Synthesis, 2nd ed., John Wiley & Sons, Inc., New York, 1991). If the preparation of such compounds results in the formation of enantiomers, these may be resolved by alkylating or acylating the final product (R¹ = H) vvith a chiral auxiliary, separating the diastereomers thus formed using knovvn chromatographic methods, and removing the chiral auxiliary to give the desired enantiomers.

Altematively, the diastereomers may be separated via fractional crystallization from a suitable solvent of the diastereomeric salts formed by the compound of a chiral organic acid.

[0057] One method of synthesizing enantiomerically pure substituted morpholines is iliustrated in Scheme 5. Protection of enantiomerically pure phenylglycine as the N-benzyl derivative follovved by double alkylation vvith a 1,2-dibromoethane derivative leads to the morpholinone. Reduction vvith an active hydride reaģent such as diisobutyl aluminum hydride, lithium aluminum hydride, lithium tri(sec-butyl)-borohydride (L-Selectride®) or other reducing aģents leads predominantly to the 2,3-trans morpholine derivatives. Alkylation of the alcohol, removal of the protecting group on nitrogen (for example, vvith a palladium hydrogenation catalyst or vvith 1 -chloroethyl chloroformate (Olofson in J. Org. Chem., 1984, 2081 and 2795), and alkylation of the nitrogen producēs the 2,3-trans compounds.

[0058] One method of producing enantiomerically pure 2,3-cis morpholines is iliustrated in Scheme 6. ln the first step, formation of the trifluoromethanesulfonate ester of the appropiate benzyl alcohol (especially benzyl alcohols vvhich are substituted vvith electron-vv'rthdravving groups such as -NO₂, -F, -Cl, -Br, -COR, -CF₃, etc) is carried out in the presence of an unreactive base, in an inert solvent. Other leaving groups such as iodide, mesylate, tosylate, pnitrophenylsulfonate and the like may also be employed. Appropriate bases include 2,6-di-t-butylpyridine, 2,6-di-t-butyI35

4-methylpyridine, diisopropylethylamine, potassium carbonate, sodium carbonate, and the like. Suitable solvents include toluene, hexanes, benzene, carbon tetrachloride, dichloromethane, chloroform, dichloroethane, and the like and mbaures thereof. The filtered solution ot the triflate is then added to a solution of the intermediate formed vvhen the morpholinone is contacted vvith an active hydride reaģent such as diisobutyl aluminum hydride, lithium aluminum hydride, or lithium tri(sec-butyf)-borohydride (L-Selectride®) at low temperature, preferably from -78’C to -20’C. After several hours at lovv temperature, workup and purification provides predominantly 2,3-cis substituted products, vvhich can be carried on to final compounds as shown in Scheme 6.

[0059] Enantiomerically pure phenylglycines substituted on the phenyl ring may be prepared by the procedure shovzn in Scheme 7 (D.A Evans, et al, J, Am. Chem. Soc.. 1990,112, 4011}.

[0060] Methods for preparing the nitrogen alkyfating aģents R’CH^ used in Scheme 5 and Scheme 6 are based on knovzn literature methods (for R¹ = 3-(1,2,4-triazolyl) or 5-(1,2,4-triazol-3-one)-yl and X = Cl, see Yanagisawa, I.;

Hirata, Υ; Ishii, Y. Journal of Medicīnai Chemistrv. 1984, 27, 849; for R¹ = 4-{{2H)-imidazol-2-one)-yl or 5-(4-ethoxycarbonyi-(2H)-imidazol-2-one)-yl and X = Br, see Ducschinsky, R., Dolan, L.A Journal of the American Chemical Societv. 1948,70,657).

[0061] The object compounds of Formula I obtained according to the reactions as explained above may be isolated and purified in a conventional manner, for example, extraction, precipitation, fractional crystaliization, recrystallization, chromatography, and the like.

[0062] The compounds of the present invention are capable of forming salts vzith various inorganic and organic acids and bases and such salts are also vzithin the scope of this invention. Examples of such acid addition salts include acetate, adipate, benzoate, benzenesutfonate, bisutfate, butyrate, citrate, camphorate, camphorsulfonate, ethanesulfonate, fumarate, hemisulfate, heptanoate, hexanoate, hydrochlorlde, hydrobromide, hydroiodide, methanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, oxalate, pamoate, persulfate, picrate, pivalate, propionate, succinate, tartrate, tosylate, and undecanoate. Base salts Include ammonium salts, alkali meta) salts such as sodium, lithium and potassium salts, alkaline earth mētai salts such as calcium and magnesium salts, salts vzith organic bases such as dicyclohexytamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine and so forth. Also, the basie nitrogen-eontaining groups may be quatemized vzith such aģents as; lovzer alkyl haiides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl,dibutyl; diamyl sulfates; long chain haiides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; aralkyl haiides like benzyl bromide and others. The non-toxic physiologically acceptable salts are preferred, although other ? salts are also useful, such as in isolating or purifying the product.

[0063] The salts may be formed by conventional means, such as by reacting the free base form of the product vzith one or more equivalents of the appropriate acid in a solvent or medium in vvhich the salt is insoluble, or in asolvent such as vzater vzhich is removed in vacuo or by freeze drying or by exchanging the anions of an existing salt for another « anion on a suitable ion exchange resin.

[0064] Although the reaction schemes described herein are reasonably general, it vrill be understood by those skilled # in the art of organic synthesis that one or more functional groups present in a given compound of formula I may render <

the molecule incompatible vzith a particular synthetic sequence. 3.

[0065] In such a case an alternative route, an altered order of steps, or a strategy of protection and deprotection may be empioyed. In ali cases the particular reaction conditions, including reaģents, solvent, temperature, and time, should be chosen so that they are consistent with the nature of the functionality present in the molecule.

[0066] The follovzing examples are given for the purpose of illustrating the present invention and shall not be construed as being limitations on the scope or spirit of the instant invention.

EXAMPLE 1 (+/-)-g-Bromo-phenvtacetaldehyde, 3,5-bisftrifluoromethvDbenzvlacetal [0067] A solution of 2.50 g (10.2 mmol) of a-bromo-phenylacetaldehyde, dimethyl acetal, 8.00 g (32.8 mmol) of 3,5-bis(trifluoromethyl)benzyl aicohol and 0.50 g (2.6 mmol) of p-toluenesulfonic acid monohydrate in 10 mL of toluene vzas stirred under vacuum (35 mmHg) at rt for 3 days. The reaction mixture was partitioned betvzeen 100 mL of ether and 50 mL of saturated aqueous sodium bicarbonate solution and the layers vzere separated. The organic layer vzas vzashed vzith 25 mL ot saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. Flash chromatography on 200 g of silica gel using 9:1 v/v hexane/methylene chloride as the eluant afforded 5.41 g (81%) of the title compound as a solid, mp 79-82’C: ’H NMR 4.47 and 4.62 (AB q, 2 H, J = 12.5), 4.78-4.93 (2 H), 5.09 and 5.21 (AB q, 2 H, J = 7.7), 7.31-7.44 (m, 7 H), 7.70 (app s, 1 H), 7.82 (app s, 1 H), 7.84 (app s 2 H);

IR (thin film) 1363,1278, 1174, 1130, 704, 682.

Anal. Calcd for C₂₆H₁₇BrF₁₂O₂: C, 46.76; H, 2.23;

Br, 11.64; F, 33.70. Found: C, 46.65; H, 2.56; Br, 11.94; F, 34.06.

ΕΧΑΜΡΙΕ2 (+/-)-N-(2-Hydroxvethvl)-phenylqlvcinal, 3,5-bis-(trifluoromethyl)benzvlacetal [0068] A solution of 1.50 g (2.2 mmol) of (+Z-)-a-bromo-phenylacetaldehyde, 3,5-bis(trifluoromethyl)-benzyl acetal (Example 1), 100 mg (0.67 mmol) of sodium iodide and 3 mL of ethanolamine in 6 mL of isopropanol vvas heated at reflux for 20 h. The solution vvas cooled and concentrated to -25% the original volume in vacuo. The concentrated solution vvas partitioned betvveen 50 mL of ether and 20 mL of 2Ņ aqueous sodium hydroxide solution and the layers vvere separated. The organic layer vvas washed with 20 mL of saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. Flash chromatography on 50 g of siiica gel using 65:35 v/v ether/hexane as the eluant afforded 1.16 g (83%) of the title compound as an oil: ¹H NMR 2.66 (br s, 2 H), 2.61 and 2.68 (ddAB q, 2 H, J_AB = 12.4, J_{2 61} = 6.8, 6.2, X> ₆₈ = 6.2, 6.2), 3.57 and 3.66 (ddAB q, 2 H, J_AB = 10.8, J₃₅₇ = 6.2,6.2), J₃ = 6.8, 6.2), 4.02 (d, 1 H, j = 7.0), 4.37 and 4.64 (AB q, 2 H. J = 12.5), 4.80 and 4.87 (AB q, 2 H, J = 12.8), 4.87 (d,’ 1 H, J = 7.0), 7.31-7.40 (7 H). 7.73 (app s, 1 H), 7.81 (app s, 3 H);

IR (neat) 3342, 1456, 1373, 1278, 1173, 1128, 704, 682;

FAB-MS 650(M+1)+.

Anal. Calcd for C₂₈H₂₃F₁₂NO₃: C, 51.78; H, 3.57; N, 2.16; F, 35.11. Found: C, 51.80; H. 3.67; N, 2.10; F, 35.41.

ΕΧΑΜΡΙΕ 3 (+/-)-N-(2-Hydroxvethyl)-N-(prop-2-enyl)-phenylqlycinal, 3,5-bisftrifluoromethyl)benzyl acetal [0069] A mixture of 1.45 g (2.2 mmol) of (+/-)-N-(2-hydroxyethyl)-phenylglycinal, 3,5-bis-(trifluoromethyl)benzyl acetal (Example 2), 1.0 g (7.2 mmol) of potassium carbonate, 3.0 mL (35.0 mmol) of allyl bromide and 15 mL of ethanol was stirred at 60 ’C for 20 h. The mixture vvas cooled, partitioned betvveen 100 mL of ether and 25 mL of vvater and the layers vvere separated. The organic layer vvas dried over magnesium sulfate. The aqueous layer vvas extracted vvith 100 mL of ether; the ether extract vvas dried and combined vvith the original organic layer. The combined organic layers vvere concentrated in vacuo. Flash chromatography on 50 g of siiica gel using 4:1 v/v hexane/ether as the eluant afforded 1.36 g (88%) of the title compound as an oil; ¹H NMR 2.40 (dt, 1 H, J = 13.2, 2.8), 2.93-3.08 (3 H), 3.30 (ddt, 1 H, J = 12.0, 2.8, 1.6), 3.54 (br m, 2 H), 3.65 (dt, 1 H, J = 10.0, 2.8), 4.23 (d. 1 H, J = 8.4), 4.52 and 4.58 (AB q, 2 H, J = 12.4), 4.85 and 4.95 (AB q , 2 H, J = 12.4), 5.25 (d, 1 H, J = 9.6), 5.28 (d. 1 H, J = 16.4), 5.39 (d, 1 H, J = 8.4), 5.81 (m, 1 H), 7.24-7.40 (7 H), 7.68 (s 1 H), 7.83 (s, 1 H), 7.86 (s, 2 H);

IR (neat) 3457, 1362, 1278, 1174, 1132, 1056, 759, 705, 682; FAB-MS 690(M+1)⁺.

Anal. Calcd for C₃₁H₂₇F₁₂NO₃; C, 53.99; H, 3.95; N, 2.03; F, 33.07. Found: C, 54.11; H, 4.08; N, 1.78; F, 32.75.

EXAMPLE 4 (+/-)-2-(3,5-Bis(trifluoromethyl)benzvloxv)-3-phenvlmorpholine [0070] Step Α: A solution of 850 mg (1.2 mmol) of (+/-)-N-(2-hydroxyethyl)-N-(prop-2-enyl)-phenyl-glycinal, 3,5-bis (trifluoromethyl)benzyl acetal (Example 3) and 700 mg (3.7 mmol) ot p-toluenesulfonic acid monohydrate in 15 mLof toluene was heated at reflux for 1.5 h. The reaction mixture vvas cooled and partitioned betvveen 100 mL of ether and 25 mL of saturated aqueous sodium bicarbonate solution. The layers vvere separated; the organic layer was vvashed vvith 25 mL of saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. Flash chromatography on 30 g of siiica gel using 50:1 v/v hexane/ether as the eluant afforded 426 mg (78%) ol the Nallyl morpholines vvhich were used in the next step vvithout further purification.

Step Β: A 50 mL 2-necked flask, equipped vvith a stopper and a short path distiilation apparatus, vvas charged with a solution of the N-allyl morpholines (Example 4, Step A) (540 mg, 1.2 mmol)) and 80 mg (0.09 mmol) tris(triphenylphosphine)rhodium chloride (VVilkinson's catalyst) in 25 mL of 4:1 v/v acetonitrile/vvater. The reaction mixture vvas heated to boiling and solvent vvas allovved to distill from the reaction mixture. The volume of the reaction mixture vvas maintained betvveen 10 and 20 mL by adding solvent through the stoppered inlet. After 1 h and 4 h, the reaction vvas treated vvith additionai 80 mg portions of the Wilkinson‘s catalyst. After 6 h, the reaction mixture cooled and partitioned between 75 mL of ether and 50 mL of vvater. The layers were separated and the organic layer was dried over magnesium sulfate. The aqueous layer vvas extracted with 75 mL of ether, the extract was dried and combined vvith the original organic layer. The combined organic layers were concentrated in vacuo. Flash chromatography on 35 g of siiica gel using 1: 1 v/v ether/hexane as the eluant afforded 200 mg of trans-isomer and 130 mg of a mixture of cis- and trans-isomers (68% total). Chromatography of the mixture on 8 g of siiica gel using 4:1 v/v hexane/ether as the eluant afforded 64 mg of cis-V and 57 mg of a mixture of the cis- and trans-isomers of the title compound.

Fortrans-V: ¹H NMR 2.03 (brs, 1 H), 2.94 (ddd, 1 H, J = 11.0, 2.5, 2.5), 3.08 (dt, 1 H, J = 11.0, 3.2), 3.71 (d, 1 H, J = 7.0), 3.83 (dt, 1 H, J = 11.2, 2.8), 4.05 (ddd, 1 H, J = 11.2, 3.2, 3.2), 4.43 (d, 1 H, J = 7.0), 4.53 and 4.88 (AB q, 2 H, J = 13.3), 7.26-7.45 (7 H), 7.70 (s, 1 H);

IR (neat) 3333, 2859, 1456, 1374, 1278,1173, 1131, 1082, 757, 702, 682;

FAB-MS 406(M+1)+.

Anal. Calcd for C₁₉H₁₇F₆NO₂: C, 56.30; H, 4.23; N, 3.46; F, 28.12. Found: C, 56.39; H, 4.28; N, 3.36; F, 28.32.

Forcis-V: Ή NMR2.10 (brs, 1 H), 3.13 (dd, 1 H. J = 12.4, 3.0), 3.26 (dt, 1 H, J = 12.4, 3.6), 3.65 (dd, 1 H, J = 11.6, 3.6), 4.07 (dt. I H, J = 11.6, 3.0), 4.14 (d, 1 H, J = 2.4), 4.52 and 4.82 (AB q, 2 H, J = 13.6), 4.76 (d. 1 H, J = 2.4), 7.30-7.42 (6 H), 7.70 (s, 1 H),

FAB-MS 406(M+1)*.

ΕΧΑΜΡΙΕ 5 (+/-)-2-(3,5-Bis(trifluoromethvl)benzyloxv)-3-phenvl-4-methvlcarbox-amido morpholine [0071] A solution of 105 mg (0.26 mmol) of the trans-isomer of (+/-)-2-(3,5-bis(trifIuoromethyi)-benzyloxy)-3-phenylmorpholine (Example 4) and 0.09 mL (0.50 mmol) of N,N-diisopropylethylamine in 3 mL of acetonitrile was treated vvith 90 mg (0.50 mmol) of iodoacetamide and the resulting solution viras stirred at rt for 16 h. The solution vvas concentrated in vacuo and the residue was partitioned betvveen 20 mL of ethyl acetate and 10 mL of 0.5 Ņ aqueous potassium hydrogen sulfate solution. The layers were separated; the organic layer vvas vvashed vvith 10 mL of 5% aqueous sodium thiosulfate solution, 10 mL of saturated aqueous sodium bicarbonate solution, 10 mL of saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo.

Flash chromatography on 5 g of silica gel using 2:1 v/v ethyi acetate/hexane as the eluant afforded 99 mg (82%) of the trans-isomer of the title compound as an oil: ’H NMR 2.56 (dt, 1 H, J = 3.2, 11.6), 2.67 and 3.16 (AB q, 2 H, J = 16.4), 2.96 (dt, 1 H, J = 12.0, 1.6), 3.30 (d, 1 H, J = 7.0), 3.86 (dt, 1 H, J = 3.2,12.0), 4.08 (ddt, 1 H, J = 11.6, 3.2,1.6), 4.48 and 4.84 (ABq, 2 H, J = 13.2), 4.49 (d, 1 H, J = 7.0), 5.98 (brs, 1 H), 6.83 (brs, 1 H), 7.33 (app s, 7 H), 7.70 (s, 1 H); IR (neat) 3445, 2838, 1682, 1278, 1173, 1132, 760, 704, 682; FAB-MS 463 (M+1)*.

Anal. Calcd for CgļHajFeNOa: C, 54.54; H, 4.36; N, 6.06; F, 24.65. Found: C, 54.54; H, 4.52; N, 5.61; F, 24.45.

[0072] A similar experiment vvas carried out on 40 mg (0.99 mmol) of the cis-isomer of (+/-)-2-(3,5-bis-(trifluocomethyl)-benzyloxy)-3-phenyl-morpho!ine (Example 4) using 0.035 mL (0.2 mmol) of N,N-diisopropylethylamine and 37 mg (0.2 mmol) of iodoacetamide in the reaction. Work-up and flash chromatography afforded 30 mg (65%) of the cisisomer of the title compound as an oil: ¹H NMR 2.54 and 3.04 (AB q , 2 H, J = 16.8), 2.63 (dt, 1 H, J = 3.6,12.0), 3.04 (d, 1 H, J = 11.6), 3.65 (d, 1 H, J = 2.8), 3.71 (ddt, 1 H, J = 11.6, 3.2, 1.2), 4.21 (dt, 1 H, J = 11.6, 2.4), 4.44 and 4.89 (AB q , 2 H, J = 13.6), 4.71 (d, 1 H, J = 2.8), 5.86 (br s, 1 H), 7.15 (br s, 1 H), 7.27-7.45 (7 H), 7.73 (s, 1 H); FAB-MS 463(M+1)⁺.

EXAMPLE 6 (+/-)-2-(3,5-Bis(trifluoromethvl)benzvloxv)-3-phenvl-4-(methoxycarbonvlmethvl)morpholine [0073] A solution of 150 mg (0.37 mmol) of the trans-isomer of (+/-)-2-(3,5-bis(trifIuoromethyi)benzyloxy)-3-phenyl morpholine (Example 4) (R¹ = H) and 0.1Θ mL (1.00 mmol) of N,N-diisopropylethytamine in 2 mL of acetonitrile vvas treated with 0.095 mL (1.00 mmol) of methyl bromoacetate and the resulting solution vvas stirred at rt for 20 h. The solution was concentrated in vacuo and the residue was partitioned between 20 mL of ethyl acetate and 5 mL of 0.5 Ņ aqueous potassium hydrogen sulfate solution. The layers vvere separated; the organic layer vvas vvashed vvith 10 mL of saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. Flash chromatography on 10 g of silica gel using 4:1 v/v hexanes/ether as the eluant afforded 164 mg (93%) of the transisomer of the title compound as an oil:

¹H NMR 2.79 (dt, 1 H, J = 3.2,11.2), 2.93 (dt, 1 H, J = 11.2, 1.6), 3.52 (d, 1 H, J = 7.2), 3.63 (s, 3 H), 3.92 (dt, 1 H, J = 2.8, 11.6), 4.04 (ddd, 1 H, J = 11.6, 3.2, 1.6), 4.45 and 4.84 (AB q, 2 H, J = 13.2), 4.46 (d, 1 H. J = 7.2), 7.31 - 7.38 (m, 6 H), 7.68 (s, 1 H);

IR (neat) 2861, 1744, 1455,1375, 1346,1278, 1170, 887, 759, 704, 682; FAB-MS 478(M+1)⁺.

Anal. Calcd for C^Hgļ F₆NO₄: C, 55.35; H, 4.43; N, 2.93; F, 23.88. Found: C, 55.74; H, 4.50; N, 2.79; F, 24.01.

EXAMPLE 7

N-Methoxv-N-methvl-(N-t-butoxvcarbonvl)-phenylqivcinamide [0074] A solution of 20.0 g (79.7 mmol) of (N-t-butoxycarbonyl)phenylglycine in 150 mL of ethyl acetate at -10 ’C was treated vvith 8.8 mL (79.7 mmol) of 4-methylmorpholine. Isobutylchloroformate (10.3 mL, 79.7 mmol) vvas added dropvvise over 10 minūtes maintaining the temperature at -10 ’C; the resulting suspension vvas stirred cold for 15 min. The mixture was treated vvith 11.6 g (119.0 mmol) of N,O-Dimethylhydroxylamine · HCI. A second portion of 4-methylmorpholine (13.0 mL, 119.0 mmol) was added and the reaction was stirred at -10 ’C for 15 min and at 25 ’C for 2 h. The reaction mixture vvas partitioned betvveen 100 mL of ethyl acetate and 100 mL of 10% aqueous citric acid solution and the layers vvere separated. The organic layer vvas vvashed vvith 100 mL of saturated aqueous sodium bicarbonate solution, 100 mL of saturated aqueous ammonium chloride solution, dried over magnesium sulfate and concentrated in vacuo. Crystallization from hexanes at -20 ’C for 72 h afforded 8.0 g (34%) of the title compound as a solid: ’H NMR 1.40 (s, 9 H), 3.20 (s, 3 H), 3.40 (s, 3 H), 5.80 (m, 2 H), 7.40 (m, 5 H).

EXAMPLE 8

Diethyl (2-oxo-3-t-butoxycarbamido-3-phenyl)propvlphosphonate [0075] A solution of 7.45 mL (51.0 mmol) of diethyl methylphosphonate in tetrahydrofuran at -78 ’C vvas treated vvith 31.8 mL (51.0 mmol) of 1.6 M n-butyllithium in hexanes solution and the resulting mixture vvas stirred cold for 30 min. A solution of 4.0 g (14.0 mmol) of N-methoxy-N-methyl-(N-t-butoxycarbonyl)pheny|-g|ycinamide (Example 7) in 20 mL of tetrahydrofuran was added and the reaction vvas stirred at -78’C for 15 min and at 25'C for 15 min. The reaction was quenched with 150 mL of saturated aqueous ammonium chloride solution, diluted vvith 300 mL of ethyl acetate, and the layers vvere separated. The organic layer vvas dried over magnesium sulfate and concentrated in vacuo. Flash chromatography on silica gel using 7:3 v/v then 4:1 v/v ethyl acetate/hexanes as the eluant afforded 4.8 g (92%) of the title compound as an oil: ¹H NMR 1.20-1.42 (15 H), 2.84 (dd, 1 H), 3.20 (dd, 1 H), 4.00-4.20 (m, 4 H), 5.50 (d, 1 H), 5.94 (br s, 1 H), 7.32 (m, 5 H).

EXAMPLE 9

N-t-Butoxvcarbonyl-1-phenyl-2-oxo-4-(3,5-bis(trifluoromethvl)phenyl)-but-3-enamine [0076] A solution of 4.80 g (12.5 mmol) of diethyl (2-oxo-3-t-butoxycarbamido-3-phenyl)propylphosphonate (Example 8) in 20 mL of THF vvas added dropvvise to a suspension of 1.05 g (26.3 mmol, 60% dispersion in mineral oil) of sodium hydride in 30 mL of tetrahydrofuran at O’C. After 15 min, 2.06 mL (12.5 mmol) of 3,5-bis(trifluoromethyl)benzaldehyde vvas slowly added and the resulting mixture vvas stirrred cold for 15 min. The reaction vvas quenched vvith 50 mL of saturated aqueous ammonium chloride solution, diluted vvith 50 mL of ethyl acetate, and the layers vvere separated. The organic iayer vvas dried over magnesium sulfate and concentrated in vacuo. Flash chromatography on silica gel using 19:1 v/v, then 9:1 v/v ethyl acetate/petroleum ether as the eluant afforded 3.30 g (56%) of the title compound as a solid: ’H NMR 1.40 (s, 9 H), 5.38 (d, 1 H), 5.90 (d, 1 H), 6.80 (d, 1 H), 7.39 (m, 5 H), 7.70 (s, 1 H), 7.84 (s, 3 H).

EXAMPLE 10

-Phenvl-2-hvdroxv-4-(3,5-bis(trifluoromethvl)phenyl)but-3-enamine · HCI [0077] A solution of 1.00 g (2.1 mmol) of N-t-butoxycarbonyl-1 -phenyl-2-oxo-4-(3,5-bis(trifluoromethyl)phenyl)-but3-enamine (Example 8) in 30 mLof methanol at 0 ’C vvas treated vvith 241 mg (6.3 mmol) of sodium borohydride. After 30 min, the reaction vvas quenched with 50 mL of vvater and concentrated in vacuo to remove the methanol. The mixture vvas partitioned betvveen 100 mL of ethyl acetate and 50 mL of vvater and the layers vvere separated. The organic layer vvas dried over magnesium sulfate and concentrated in vacuo. Crystallization from ether/hexanes afforded 680 mg (58%) of the title compound as a 5:1 mixture of diastereomers (each protected as the t-butylcarbamate): ’H NMR (* indicates the resonances of the minor diastereomer) 1.40 (s, 9 H), 4.60 (dd, 1 H), 4.90 (br s, 1 H), 5.20 (br d, 1 H), 6.30 (dd, 1 H), 6.40 (dd. 1 H*), 6.70 (dd, 1 H), 6.80 (dd, 1 H*), 7.40 (m, 5 H), 7.80 (m, 3 H).

[0078] A solution of BOC-protected title compound in methanol (saturated vvith HCI) vvas allovved to stand for 72 h. The solution vvas concentrated in vacuo. Recrystallization of the resulting solid from ether/hexane afforded 500 mg (60%) of the title compound · HCI as a solid: ’H NMR 4.20 (br s, 1 H), 4.40 (d, 1 H), 6.20 (dd, 1 H), 6.60 (dd, 1 H), 7.30 (m 5 H), 7.80 (m, 3 H).

[0079] The title compound · HCl was dissolved in ethyl acetate and 1Ņ aqueous sodium hydroxide solution. The layers vvere separated; the organic layer vvas dried over magnesium sulfate and concentrated in vacuo to afford the title compound as the free base.

ΕΧΑΜΡΙ,Ε 11

2- (2-(3,5-Bis(trifluoromethy|)phenvl)ethenvl)-3-phenvl-5-oxo-morpholine [0080] A solution of 1.95 g (5.2 mmol) of 1 -pheny!-2-hydroxy-4-(3,5-bis(trifluoromethyl)phenyl)-but-3-enamine (Example 10) in 20 mL of toluene vvas added to a suspension of 250 mg (6.2 mmol, 60% dispersion in mineral oil) of sodium hydride in 30 mL of toluene and the resulting mixture was stirred at rt for 15 min. A solution of 0.60 mL (1.15 mol) of ethyl chloroacetate in 5 mL of toluene vvas slowly added and the resulting mixture vvas heated at reflux for 3 h. The reaction vvas cooled, quenched vvith 50 mL of saturated aqueous ammonium chloride solution, diluted with 50 mL of ethyl acetate and the layers vvere separated. The organic layer vvas dried over magnesium sulfate and concentrated in vacuo. Flash chromatography using ethyl acetate/hexanes (4:1 v/v, then 3:1 v/v, then 1:1 v/v) then ethyl acetate as the eluant afforded 300 mg of trans-title compound and B00 mg of cis-title compound (55% total), both as solids. For the cis-isomer 1H NMR 1.20-1.40 (m, 1 H), 1.50-1.62 (m. 1 H), 2.60-2.98 (m, 2 H), 3.86 (dt. 1 H), 4.24 (d, 1 H), 4.34 (dd, 1 H), 4.45 (d, 1 H), 6.40 (brs, 1 H), 7.24 (m, 2 H), 7.40 (m, 3 H), 7.50 (s, 2 H), 7.70 (s, 1 H).

EXAMPLE12

3- Phenyl-2-(2-(3,5-bis(trifluoromethvl)phenvl)ethvl)morpholine [0081] A solution of 95 mg (0.23 mmol) of 2-(2-(3,5-bis(trifluoromethyl)phenyl)ethenyl)-3-phenyl-5-oxo-morpholine (Example 11) in 10 mL of 1:1 v/v ethanol/ethyl acetate vvas treated with 10 mg of palladium hydroxide and the resulting mixture was stirred under an atmosphere of hydrogen for 2 h. The catalyst vvas filtered and the filtrate was concentrated in vacuo. The crude product was used directly vvithout further purification.

[0082] A solution of 65 mg of the crude morpholinone vvas dissolved in 10 mL of tetrahydrofuran was treated vvith 0.84 mL of 1 M borane-tetrahydrofuran complex solution in tetrahydrofuran and the resulting solution vvas heated at reflux for 16 h. The reaction was quenched by adding 10 mL of methanol and 70 mg of potassium carbonate and heating the resulting mixture at reflux for 3 h. Ali volatiles were removed in vacuo and the residue was partitioned between 20 mL of ethyl acetate and 10 mL of saturated ammonium chloride solution. The organic layer vvas separated, dried over sodium carbonate, and concentrated in vacuo. The residue was dissolved in saturated HCl in methanol and concentrated in vacuo. The residue was triturated vvith ether; the resulting solid was filtered and dried to afford.32 mg (46%) of the title compound · HCl, mp 114-116’C: ¹H NMR 1.42 (m, 1 H), 1.66-1.84 (m, 1 H), 2.70-2.94 (m, 2 H), 3.00 (m, 1 H), 3.30-3.46 (m, 1 H), 3.80-3.94 (m, 2 H), 4.10 (m, 1 H), 4.20 (d, 1 H), 7.40 (m, 3 H), 7.84 (m, 5 H); CI-MS 402 (M+1)⁺.

EXAMPLE 13

N-Benzyl-(S)-phenylglycine [0083] A solution of 1.51 g (10.0 mmol) of ($)-phenylglycine in 5 mL of 2 Ņ aqueous sodium hydroxide solution vvas treated with 1.0 mL (10.0 mmol) of benzaldehyde and stirred at room temperature for 20 minūtes. The solution vvas diluted vvith 5 mL of methanol, cooled to 0’C, and carefully treated with 200 mg (5.3 mmol) of sodium borohydride. The cooling bath was removed and the reaction mixture was stirred at room temperature for 1.5 hours. The reaction was diluted vvith 20 mL of vvater and extracted vvith 2x25 mL of methylene chloride. The aqueous layer vvas acidified vvith concentrated hydrochloric acid to pH 6 and the solid that precipitated vvas filtered, vvashed vvith 50 mL of vvater, 50 mL of 1:1 v/v methanol/ethyl ether and 50 mL of ether, and dried to afford 1.83 g (76%) of product, mp 230-232’C

Analysis:
Calcd for CiSH15NO2 I C-74.66 Found j C-74.17	H-6.27 H-6.19	N-5.81 N-5.86

EXAMPLE 14

3-(S)-Phenyl-4-benzyl-2-morpholinone [0084] A mbcture of 4.00 g (16.6 mmol) of N-benzyl-(S)-phenylglycine (from Example 13), 5.00 g (36.0 mmol) of potassium carbonate, 10.0 mL of 1,2-dibromoethane and 25 mL of N,N-dimethylformamide vvas stirred at 100 “C for 20 hours. The mixture vvas cooled and partitioned between 200 mL of ethyl ether and 100 mL of water. The layers vvere separated and the organic layer vvas vvashed vvith 3x50 mL of water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on 125 g of siiica gel eluting with 9:1 v/v, then 4:1 v/v hexanes/ethyl ether to afford 2.41 g (54%) of the product as a solid, mp 98-100°C.

Mass Spectrum (FAB): m/Z 26Θ (M+H, 100%).

iH NMR (CDCI_3> 200 MHz, ppm): d 2.54-2.68 (m, 1H), 2.96 (dt, J= 12.8, 2.8, 1H), 3.14 (d. J= 13.3, 1H), 3.75 (d, J= 13.3, 1H), 4.23 (s, 1H), 4.29-4.37 (m, 1H), 4.53 (dt, J= 3.2, 11.0), 7.20-7.56 (m, 10H).

Analysis:
Calcd for C17H17NO2 j C-76.38 Found I C-76.06	H-6.41 H-6.40	N-5.24 N-5.78

EXAMPLE 15

2-(S)-(3,5-Bis(trifluoromethyl)benzvloxv)-3-(S)-phenylmorphoiine

Step A 3,5-Bis(trifluoromethvl)benzvl alcohol, trifluoromethanesulfonate ester [0085] A solution of 1.00g (4.1 mmole) of 3,5-bis(trifluoromethyl)benzyl alcohol and 1.05.g (5.12 mmole) of 2,6-di-tbutyl-4-methylpyridine in 45 mL of dry caibon tetrachloride under a nitrogen atmosphere vvas treated vvith 0.74 mL (4.38 mmole) of trifluoromethanesulfonic anhydride at room temperature. A vvhite precipitate formed shortly after the addition of the anhydride. After 90 min, the slurry vvas filtered under nitrogen vvith a Schlenk filter, and the filtrate vvas concentrated in vacuo. The residue, vvhich vvas a two-phase oil, vvas dissolved under nitrogen in 10 mL of dry toluene. The resulting clear solution vvas used immediately in Step B belovv.

Step B 4-Benzyl-2-(S)-(3,5-bis(trifluoromethyl)benzyloxv)-3-(S)-phenylmorpholine [0086] A solution of 0.500 g (1.87 mmole) of N-benzyl-3-(S)-phenylmorpholin-2-one (from Example 14) in 10 mL of dry THF vvas cooled to -75^eC under nitrogen and vvas treated dropvvise vvith 2.06 mL (2.06 mmole) of a 1M solution of lithium tri(sec-butyl)-borohydride (L^:Selectride®) in THF. After stirring the solution at -75’C for 30 min, a solution of 3,5-bis(trifluoromethyl)benzyl alcohol, trifluoromethanesulfonate ester in toluene vvas added by cannula so that the internai temperature vvas maintained belovv -60’C. The resulting solution vvas stirred at -75’C for 1 hrand then betvveen -38’C and -50’C for 2 hr. The solution vvas then poured into a mixture of 25 mL of ethyl acetate and 20 mL of saturated aqueous sodium bicarbonate, and the layers vvere separated. The aqueous phase vvas extracted vvith 2x30 mL of ethyI acetate, the combined organic layers vvere dried over sodium sulfate, the mbcture vvas filtered and the filtrate concentrated in vacuo. The residue was purified by flash chromatography on 130 g of silica eluting vvith 2 L of 100:5 hexanes: ethyl acetate to give 0.68 g (73%) of an oil, vvhich by ¹H NMR is a 20:1 mbcture of cis.trans morpholines.

’H NMR (CDCI₃, 400 MHz, ppm): δ major (cis) isomer: 2.37 (td, J= 12, 3.6, 1H), 2.86 (app t, J= 13, 2H), 3.57 (d, J= 2.6, 1H), 3.63 (dq, J= 11.3, 1,6, 1H), 3.89 (d, J= 13.3, 1H), 4.12 (td. J= 11.6, 2.4, 1H), 4.40 (d, J= 13.6, 1H), 4.69 (d, J= 2.9, 1H), 4.77 (d, J= 13.6), 7.2-7.4 (m, 8H), 7.43 (s, 2H), 7.55 (br d, 2H), 7.69 (s, 1H).

Step C 2-(S)-(3,5-Bis(trifluoromethyl)benzvloxv)-3-(S)-phenylmorpholine [0087] A mbcture of 0.68 g (1.37 mmole) of 4-benzyl-2-(S)-(3,5-bis(trifIuoromethyl)benzyloxy)-3-(S)-phenyl morpholine and 280 mg of 10% Pd/C in 36 mL of 97:3 ethanol:water vvas stirred under one atmosphere of hydrogen for 15 hr. The mixture vvas filtered through Celite, the filter cake was vvashed generously vvith ethanol, and the filtrated vvas concentrated in vacuo. The residue vvas purified by flash chromatography on 68 g of silica eluting vvith 1L of 33:67 hexanes: diethyl ether, then 1L of 25:75 hexanes: diethyl ether to give 0.443 g (80%) of an oil, which by ’H NMR vvas pure cis morpholine.

¹H NMR (CDCI₃, 400 MHz, ppm): δ 1.8 (br s, 1H), 3.10 (dd, J= 12.5, 2.9,1H), 3.24 (td, J= 12.2, 3.6,1H), 3.62 (dd, J= 11.3, 2.5, 1H), 4.04 (td, J= 11.7, 3, 1H), 4.11 (d, J= 2.4, 1H), 4.49 (d, J= 13.5, 1H), 4.74 (d, J= 2.5, 1H), 4.80 (d, J=

13.3, 1H), 7.25-7.40 (m, 5H), 7.40 (s, 2H), 7.68 (s, 1H).

Analysis:
Calcd for C19H17F6NO2 ļ C-56.30 Found j C-56.20	H-4.23 H-4.29	N-3.46 N-3.34	F-28.12 F-27.94

EXAMPLE 16

2(R)-(3,5-Bis(trifluoromethvBbenzyloxv)-3(R)-phenylmorpholine [0088] The title compound vvas prepared from (R)-phenylglycine employing the procedures of Examples 13,14 and 15.

EXAMPLE 17

4-(3-(1,2,4-Triazolo)methyl)-2-(S)-(3,5-bis(trifluoromathv0benzyloxy)-3-(S)-phenvlmorpholine

Step A N-Formyl-2-chloroacetamidrazone [0089] A solution of 5g (66.2 mmole) of chtoroacetonitrile in 30 mL of dry methanol was cooled to 0’C under nitrogen and was treated with 0.1g (1.8 mmole) of sodium methoxide. The mixture vvas allovved to warm to room temperature and was stirred for 30 min, and 0.106 mL (1.8 mmole) of acetic acid vvas added. To the resulting mixture vvas then added 3.9g (64.9 mmole) of formic hydrazide, and the material was stirred for 30 min. The reaction mixture vvas concentrated in vacuo to a solid, and vvas used as such in Step B belovv.

Step B 4-(3-(1,2,4-Triazoto)methvl)-2-(S)-(3,5-bis-(trifluoromethvl)benzvloxy)-3-(S)-phenvlmorpholine [0090] A solution of 0.295g (0.73 mmole) of 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl morpholine (ftpm Example 15) in 10 mL of dry DMF vvas treated with 0.302g (2.18 mmole) of anhydrous potassium carbonate and then 0.168g (1.24 mmole) of N-formyl-2-chtoroacetamidrazone (from Example 17, Step A) and the suspension vvas stirred at 60’C for 4 hr. The mixture vvas then heated to 120’C for 4.5 hr. After cooling, the reaction was diiuted with 80 mL of ethyI acetate and the organic layer was washed with 3x20 mL of water. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue vvas purified by flash chromatography on 67 g of siiica eluting vvith 1.5 L of 100:2 methylene chloride:methanol to give 0.22g of a yellow solid, which was recrystallized from hexanes/ methylene chloride to give 0.213g (60%) of a vvhite crystalline solid, mp 134-135’C.

Mass Spectrum (FAB): nVZ 487 (M+H, 100%), 259 (35%), 243 (65%), 227 (40%), 174 (25%).

’H NMR (CDCĻ 400 MHz, ppm): 52.67 (td, J= 11.9,3.4,1H), 2.90 (brd, J= 11.7,1H), 3.43 (d. J= 15.2,1H), 3.66 (app dd, J= 13,1.9, 2H), 3.88 (d, J= 15.1, 1H), 4.17 (td, J= 11.7, 2.3, 1H), 4.42 (d, J= 13.5, 1H), 4.69 (d, J= 2.6, 1H), 4.77 (d, J= 13.5,1H), 7.30-7.50 (m, 7H), 7.70 (s, 1H), 7.94 (s, 1H).

EXAMPLE18

4-(3-(5-Oxo-1H,4H-1,2,4-triazolo)methyl)-2-(S)-(3,5-bis(trifluoromethvl)benzyloxy)-3-(S)-phenvlmorpholine

Step A N-Methylcarboxv-2-chtoroacetamidrazone [0091] A solution of 5.0 g (66.2 mmol) of chtoroacetonitrile in 35 mL of dry methanol was cooled to 0’C and vvas treated vvith 0.105g (1.9 mmol) of sodium methoxide. The ice-bath vvas removed and the mixture vvas alovved to stir at room temperature for 30 minūtes. To the reaction was then added 0.110 mL (1.9 mmol) of acetic acid and then 5.8 g (64.9 mmol) of methyl hydrazinecarboxylate. After stirring 30 minūtes at room temperature, the suspension vvas concentrated in vacuo, and piaced on the high-vac line overnight, to give 10.5 g (98%) of a yellow povvder, which vvas emptoyed in Step C belovv.

’H NMR (CD₃OD, 400 MHz, ppm): 5 3.71 (s, 3H), 4.06 (s, 2H).

Step B4-(2-(N-Methylcaiboxy-acetamidrazono)-2-(S)-(3,5-bis(trifluoromethvl)benzyloxy)-3-(S)-phenylmorpholine [0092] A solution of 2.30 g (5.7 mmol) of 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenylmorpho line (frorr

Example 15), 1.13 g (6.8 mmol) of N-methylcarboxy-2-chtoroacteamidrazone (from Step A), and 1.50 mL (8.6 mmol)

N, N-diisopropylethylamine in 25 mL of acetonitrile vvas stirred at room temperature for 20 hours. The product, vvhich had preciptated, vvas filtered, vvashed vvith 5 mL of ice cold acetonitrile and dried to give 1.83 g of a vvhite solid. The Filtrate vvas concentrated in vacuo and the residue vvas partitioned betvveen 50 mL of methyiene chloride and 20 mL of vvater. The layers vvere separated and the organic layer vvas dried over magnesium sulfate. The aqueous layer vvas extracted vvith 50 mL of methylene chloride; the extract vvas dried, combined with the original organic layer, and the combined organics vvere concentrated in vacuo. The residue was purified by flash chromatography on 30 g of silica gel eiuting vvith 50:1:0.1 v/v/v methylene chioride/methanol/ammonium hydroxide to afford an additional 1.09 g of product (96% total).

Mass Spectrum (FAB): m/Z 535 (M+H, 100%), 462 (16%), 291 (30%), 226 (35%), 173 (25%).

¹H NMR (CDCI₃, 400 MHz, ppm): δ 2.53 (dt, J= 3.5, 12.2,1H), 2.59 (d, J= 14.6,1H), 2.94 (d, J= 11.8,1H), 3.37 (d, J= 14.6,1H). 3.58 (d, J= 2.8), 1H), 3.62-3.72 (m, 1H), 3.75 (s, 3H), 4.16 (dt, J= 2.2,11.8,1H). 4.44 (d, J= 13.2, IH), 4.70 (d, J= 2.8,1H), 4.79 (d, J= 13.2), 5.55 (br s, 2H), 7.30-7.46 (m, 7H), 7.72 (s, 1H).

Step C 2-fS)-(3,5-Bis(trifluoromethvl)benzvloxv)-4-f3-(5-oxo-1H,4H-1,2,4-triazolo)methvl)-3-(S)-phenylmorpholine [0093] A solution of 2.89 g (5.4 mmol) of 4-(2-(N-methylcarboxy-acetamidrazono)-2-(S)-(3,5-bis(trifluoromethyl) benzytoxy)-3-(S)-phenylmorpholine (from Step B) in 36 mL of xylenes was heated at reflux for 1.5 hours. The solution vvas cooled and concentrated in vacuo. The residue was taken up in 50 mL of 3:1 v/v hexanes/ethyl acetate vvhich caused crystallization of the product. The product was filtered and dried to afford 1.85 g of a solid. Reciystallization of the solid from 30 mL of 4:1 v/v hexanes/ethyl acetate afforded 1.19 g of pure product as a vvhite solid, mp= 156-157°C. Ali of the crystallization liquors vvere combined and concentrated in vacuo. The residue vvas purified by flash chromatography on 30 g of silica gel eiuting vvith 50:1:0.1 v/v/v methylene chioride/methanol/ammonium hydroxide to afford an additional

O. 69 g of a solid. Three recrystallizations from 20 mL of 4:1 v/v hexanes/ethyl acetate afforded an additional 0.39 g of pure product as a vvhite solid (58% total).

Mass Spectrum (FAB): m/Z 503 (M+H), 259 (55%), 226 (40%), 160 (30%).

’H NMR (CDCI₃, 400 MHz, ppm): δ 2.57 (app t, J= 9.6,1H), 2.87-2.97 (m, 2H), 3.58-3.71 (m, 3H), 4.18 (app t, J= 10.4, 1H), 4.46 (d, J= 13.6), 4.68 (d, J= 2.8, 1H), 4.85 (d, J= 13.6, 1H), 7.30-7.45 (m, 7H), 7.64 (s, 1H), 10.40 (br s, 1H), 10.73 (brs, 1H).

EXAMPLE 19

N-(2-(R)-Hvdroxvpropyl)-phenvlglvcinal, 3,5-bis(trifluoromethyQbenzvl acetal [0094] A mixture of 1.00 g (1.5 mmol) of (+/-)-a-bromo-phenylacetaldehyde, 3,5-bis(trifluoromethyl)benzyl acetal (from Example 12), 1.25 mLof (R)-1 -amino-2-propanol, 225 mg (1.5 mmol) of sodium iodide, and 3.75 mL of isopropanol vvas heated at reflux for 20 h. The solution vvas cooled and concentrated to ~25% the original voiume in vacuo. The concentrated solution was partitioned betvveen 50 mL of ether and 20 mL of 2Ņ aqueous sodium hydroxide solution and the layers vvere separated. The organic layer vvas vvashed with 20 mL of saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. Flash chromatography on 50 g of silica gel using 65:35 v/v ether/hexane as the eluant afforded 948 mg (95%) of the product as a 1:1 mixture of inseparable diastereomers.

Mass Spectrum (FAB): m/Z 664 (M+H, 25%), 420 (20%), 226 (100%).

EXAMPLE 20

N-(2-(S)-Hydroxypropvl)-phenylqlycinal, 3,5-bis(trifluoromethyl)benzyl acetal [0095] Substitution of (S)-1 -amino-2-propanol for (R)-1 -amino-2-propanol in an experiment identical to the preceding example afforded 940 mg (95%) of the product as a 1:1 mixture of diastereomers.

EXAMPLE 21

N-(2-(R)-Hydroxypropyl)-N-(prop-2-enylHR)-phenylglycinal, 3,5-bis(trifluoromethyl)benzyl acetal and N-(2-(R)Hydroxvpropyl)-N-(prop-2-envl)-(S)-phenylglvcinal, 3,5-bis(trifluoromethvl)benzyl acetal [0096] A mixture of 933 mg (1.40 mmol) of N-(2-(R)-hydroxy-propyl)-phenylglycinal, 3,5-bis(trifluoromethyl)-benzyl acetal (from Example 19), 1 mL of allyl bromide, 600 mg (4.3 mmol) of potassium carbonate, and 5 mL of ethanol vvas stirred at 60“C for 20 hours. The mixture vvas cooled, partitioned betvveen 100 mL of ethyl ether and 25 mL of vvater and the layers vvere separated. Flash chromatography on 50 g of silica gel using 20:1 v/v ether/hexanes as the eluant afforded 380 mg of the (R,R)-amino alcohol (R, = 0.72 vvith 3:2 v/v ether/hexanes as the eluant), 220 mg of the (R,S)amino alcohol (Rf = 0.62 vvith 3:2 v/v ethar/hexanes as the eluant), and 285 mg of a mixture of the disastereomeric amino alcohois.

[0097] For the (R,R)-amino alcohol:

Mass Spectrum (FAB): m/Z 704(M+H).

IR (neat) 3476, 2932, 1624,1454, 1361, 1278, 1175,1132, 760, 704, 682.

’H NMR (CDCIg, 400 MHz, ppm) 1.12 (d, 3 H, J = 6.4), 2.19 and 2.62 (dAB q, 2 H, J _AB = 13.0, J ₂,₉ = 2.3, J _{2 62} =

10.4), 2.97 (dd, 1 H. J = 14.0, 8.8), 3.25 - 3.30 (m, 1 H), 3.76 (s, 1 H), 3.77 - 3.85 (m, 1 H), 4.21 (d, ϊ H, J = 8.8), 4.49 and 4.55 (AB q, 2 H, J = 12.4), 4.86 and 4.92 (AB q. 2 H, J = 12.4), 5.27 - 5.33 (m, 2 H), 5.39 (d, 1 H, J = 8.8), 5.79 5.89 (m, 1 H), 7.21 - 7.26 (m, 4 H), 7.35 - 7.40 (m, 3 H), 7.67 (s, 1 H), 7.81 (s, 1 H), 7.85 (s, 2 H).

Analysis: Calcd for C₃₂H₂₉F₁₂NO₃: C, 54.63; H, 4.15; N. 1.99; F, 32.41. Found: C, 54.72; H, 3.94; N, 1.95; F, 32.17. [0098] For the (R,S)-amino alcohol:

Mass Spectrum (FAB): m/Z 704(M+1).

IR (neat) 3451, 2931, 1624, 1454, 1362, 1277, 704, 683.

’H NMR (CDCIg, 400 MHz, ppm) 1.09 (d, 3 H, J = 6.0), 2.48 and 2.71 (dAB q, 2 H, J _AB = 13.2, J ₂ 43 = 9-6, J ₂.62 = 3.6), 3.05 (dd, 1 H, J = 14.4, 6.8), 3.34 - 3.39 (m, 1 H), 3.35 (s, 1 H), 3.76 - 3.81 (m, 1 H). 4.21 (d, 1H, J = 8.4). 4.50 and 4.54 (AB q, 2 H, J = 12.8), 4.86 and 4.96 (AB q, 2 H, J = 12.4), 5.10 - 5.17 (m, 2 H), 5.39 (d, 1 H, J = 8.4), 5.68 5.78 (m, 1 H), 7.23 - 7.32 (m, 4 H), 7.34 - 7.39 (m, 3 H), 7.69 (s, 1 H), 7.83 (s, 1 H), 7.86 (s, 2 H).

Analysis: Calcd for C₃₂H₂₉F₁₂NO₃: C, 54.63; H, 4.15; N, 1.99; F, 32.41. Found: C, 54.80; H, 4.16; N, 1.90; F, 32.36.

EXAMPLE 22

N-(2-(S|-Hvdroxvpropyl)-N-(prop-2-envl)-(S)-phenvlqlvcinal, 3,5-bis(trifluoromethyl)benzyl acetal and N-(2-(S)Hydroxypropyl)-N-(prop-2-envl)-(R)-phenylglycinal, 3,5-bisftrifluoromethvl)benzvl acetal [0099] Substitution of 880 mg (1.33 mmol) of N-(2-(S)-hydroxypropyl)-phenylglycinal, 3,5-bis(trifluoromethyl)behzyl acetal (Example 20) for the N-(2-(R)-hydroxypropyl)-phenylglycinal, 3,5-bis(trifluoromethyl)benzyl acetal in the procedures of the preceding example afforded 281 mg of the (S.S)-amino alcohol (R, = 0.72 with 3:2 v/v ether/hexanes as the eluant), 367 mg of the (S.R)-amino alcohol (Rf = 0.62 with 3:2 v/v ether/hexanes as the eluant), and 197 mg of a mixture of the disastereomeric amino alcohois.

EXAMPLE 23

2-(R-)-3,5-Bis(trifluoromethyl)benzvloxy)-3-(R)-phenyl-6-(R)-methyl morpholine and 2-(S)-(3,5-Bis-(trifluoromethyl) benzvloxv)-3-(R)-phenvl-6-(R)-methyl morpholine

Step A 2-(R)-(3,5-Bis(trifluoromethvHbenzvloxv)-3-(R)-phenvl-4-(2-propenyl)-6-(R)-methyl morpholine and 2-(S)(3,5-bis(trifluoromethvn-benzvloxv)-3-(R)-phenvl-4-(2-propenyl)-6-(R)-methyl morpholine [0100] [0101] A solution of 355 mg (0.50 mmol) of N-(2-(R)-hydroxypropyl)-N-(2-propenyl)-(R)-phenylglycinaI, 3,5-bis(trifluoromethyl)benzyl acetal (from Example 21) and 285 mg (1.5 mmol) of p-toluensulfonic acid monohydrate in 5 mL of toluene vvas heated at reflux for 40 min. The solution was cooled and partitioned betvveen 40 mL of ether and 15 mL of saturated aqueous sodium bicarbonate solution. The layers vvere separated; the organic layer vvas washed vvith 10 mL of saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. Flash chromatography on 10 gof silica gel using 19:1 v/v hexanes/etheras the eluant afforded 122 mgof (2R,3R,6R) product (Rf=0.53 vvith 4:1 v/v hexanes/ether as the eluant) and 62 mg of the (2S, 3R.6R) product (Rf=0.23 with 4:1 v/v hexanes/ ether as the eluant).

[0102] For the (2R,3R,6R) product:

Mass Spectrum (FAB): m/Z 460 (M+H, 65%) ’H NMR (CDCIg, 400 MHz, ppm) 1.35 (d. 3 H, J = 6.4), 2.53 and 2.63 (dAB q, 2 H, J _AB = 12.0, J _2S3 = 3.2, J _{2 63} =

6.8), 2.83 - 2.96 (m, 2 H), 3.60 (d, 1 H, J = 4.0), 4.27 - 4.32 (m, 1 H), 4.57 and 4.84 (AB q, 2 H, J = 13.2), 4.87 (d, 1 H, J = 4.0), 5.08 - 5.13 (m, 2 H), 5.76 - 5.86 (m, 1 H), 7.31 - 7.37 (m, 3 H), 7.50 - 7.52 (m, 2 H), 7.58 (s, 2 H), 7.71 (s, 1 H). [0103] For the (2S,3R,6R) product:

Mass Spectrum (FAB): m/Z 460 (M+H, 65%) ’H NMR (CDCI₃, 400 MHz, ppm) 1.37 (d. 3 H, J = 6.8), 2.48 - 2.50 (m, 2 H), 2.74 and 3.01 (dtAB q, 2 H, J = 6.4, 1.2,

12.4) 3.84 (d, 1 H, J = 3.6), 3.92 - 3.99 (m, 1 H), 4.70 and 4.93 (AB q, 2 H, J = 13.6), 4.97 (d, 1 H, J = 3.6), 5.08 - 5.14 (m. 2 H), 5.74 - 5.84 (m, 1 H), 7.28 - 7.36 (m, 3 H). 7.43 - 7.46 (m, 2 H). 7.64 (s, 2 H). 7.75 (s. 1 H).

Step B 2-(R)-(3,5-Bis(trifluoromethvl)benzvloxv)-3-fR)-phenvl-6-fR)-methyl morpholine [0104] A soiution of 115 mg (0.25 mmol) of the 2-(R)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-4-(2-propenyl)6-(R)-methyl morpholine (from Example 23, Step A) and 230 mg (0.25 mmol) of tris(triphenylphosphine)rhodium chloride in 15 mL of 4:1 v/v acetonitrile/vvater vvas heated at reflux for 30 min. The reaction vvas cooled and partitioned betvveen 50 mL of ethyl acetate and 15 mL of vvater. The layers were separated and the organic layer vvas dried over magnesium sulfate. The aqueous layer vvas extracted with 2 x 25 mL of ethyl acetate; the extracts vvere dried and combined vvith the original organic layer. The combined organics were concentrated in vacuo. The residue vvas filtered through a pad of siiica gel (~ 20 g) using 2:1 v/v ether/hexanes as the solvent. The filtrate vvas concentrated; fiash chromatography on 5 g of siiica gel using 17:3 v/v hexanes/ether as the eluant afforded 67 mg (64%) of 2-(R)-(3,5-bis (trifluoromethyl)benzyloxy)-3-(R)-phenyl-6-(R)-methyl morpholine as an oil.

Mass Spectrum (FAB): m/Z 420 (M+H, 90%) ¹H NMR (CDCķ, 400 MHz, ppm) 1.21 (d, 3 H, J = 6.4), 2.02 (br s, 1 H), 2.67 and 2.77 (dAB q, 2 H, J _AB = 13.2, J ₂.₆₇ = 8.8, J ₂ 77 = 3.2), 3.89 (d, 1 H, J = 2.4), 4.07 - 4.15 (m, 1 H), 4.68 and 4.90 (AB q, 2 H, J = 12.8), 5.03 (d, 1 H, J =

2.4) , 7.28 - 7.38 (m, 3 H), 7.51 - 7.53 (m, 2 H), 7.77 (s, 2 H), 7.79 (s. 1 H).

Step C 2-(S)-(3,5-Bisftrifluoromethvl)benzvloxv)-3-(R)-phenvl-6-(R)-methvl morpholine [0105] A similar reaction was carried out using 55 mg (0.12 mmol) of 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)phenyl-4-(2-propenyl)-6-(R)-methyl morpholine (from Example 23, Step A) and 111 mg (0.12 mmol) of tris(triphenylphosphine)rhodium chloride in 12 mL of 4:1 v/v acetonitrile/vvater. Flash chromatography on 4 g of siiica gel using 50:

v/v methylene chloride/acetonitrile as the eluant afforded 14 mg (28%) of 2-(S)-(3,5-bis(trifluoromethyl)-benzyloxy)3-(R)-phenyl-6-(R)-methyl morpholine as an oil.

Mass Spectrum (FAB): m/Z 420 (M+H, 90%) ¹H NMR (CDCķ, 400 MHz, ppm) 1.39 (d, 3 H, J = 6.8), 1.92 (br s, 1 H), 2.84 and 2.95 (dAB q, 2 H, J_AB = 12.8, J ₂₈₄ = ⁶·⁴· ^J 2.9S = ³·⁶)· ^{3 93} -^{4 00} (^m· ^{1 H})· ^{4 07} (^d· 1 H, J = 2.8), 4.68 and 4.95 (AB q, 2 H, J = 13.2), 4.93 (d, 1 H, J =

2.8), 7.28 - 7.37 (m, 3 H), 7.48 - 7.52 (m, 2 H), 7.55 (s, 2 H), 7.72 (s, 1 H).

EXAMPLE 24

2-(S)-(3,5-Bis(trifluoromethv0benzvloxv)-3-(S)-phenyl-6-(S)-methyl morpholine and 2-(RH3,5-Bis-(trifluoromethyR benzyloxy)-3-(S)-phenyl-6-(S)-methvl morpholine [0106] Substitution of 350 mg of N-(2-(S)-hydroxypropyl)-N-(2-propenyl)-(S)-phenylglycinal, 3,5-bis-(trifluoromethyl) benzyl acetal (from Example 22) for N-(2-(R)-hydroxypropyl)-N-(2-propenyl)-(R)-phenylglycinal, 3,5-bis(trifluoromethyl)benzyl acetal in an experiment similar to the preceding example afforded 50 mg of 2-(S)-(3,5-bis(trifluoromethyl) benzyloxy)-3-(S)-phenyl-6-(S)-methyl morpholine and 14 mg of 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl6-(S)-methyl morpholine.

EXAMPLE 25

2-(R)-(3.5-Bis(trifluoromethvl)benzvloxv)-3-(S)-phenvl-6-(R)-methyl morpholine and 2-(S)-(3,5-Bis-(trifluoromethyl) benzyloxv)-3-(S)-phenvl-6-(R)-methyl morpholine

Step A 2-(R)-(3,5-Bis(trifluoromethyl)benzyloxv)-3-(S)-phenyl-4-(2-propeny[)-6-(R)-methyl morpholine and 2-(S)(3.5-bis(trifluoromethyl)-benzvloxv)-3-(S)-phenvl-4-(2-propenyl)-6-(R)-methvl morpholine [0107] The title compounds vvere prepared in a manner similar to Example 23, Step A. Cyclization of 300 mg (0.43 mmol) N-(2-(R)-hydroxypropyl)-N-(prop-2-enyl)-(S)-phenylglycinal, 3,5-bis(trifluoromethyl)-benzyl acetal (from Example 23) vvas effected using 246 mg (1.29 mmol) of p-toluenesulfonic acid monohydrate and 5 mL of toluene. Flash chromatography on 8 g of siiica gel using 20:1 v/v hexanes/ether as the eluant afforded 149 mg (75%) of the products as inseparable diastereomers.

Mass Spectrum (FAB): m/Z 460 (M+H, 65%).

Step B 2-(R)-(3.5-Bis(trifluoromethvl)berizvtoxv)-3-(S)-phenyl-6-(R)-methvl morpholine and 2-(S)-(3,5-Bis (trifluoromethyl)benzyloxv)-3-(S)-phenyl-6-(R)-methyl morpholine [0108] A solution of 150 mg (0.33 mmol) of 2-(R)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-4-(2-propenyl)-6(R)-methyl morpholine and 2-(S)-(3,5-bis-(trifluoromethyl)-benzyloxy)-3-(S)-phenyl-4-(2-propenyl)-6-(R)-methyl morpholine (from Example 25, Step A) and 318 mg (0.32 mmol) of tris(triphenylphosphine)-rhodium chloride in 20 mL of 4:1 v/v acetonitrile/vrater was heated at reflux for 1 h. Flash chromatography on 5 g of silica gel using 9:1 v/v hexanes/ ether as the eiuant afforded 35 mg of the products as a mixture and 26 mg of 2-(R)-(3,5-bis-(trifluoromethyl)benzyloxy)3-(S)-phenyl-6-(R)-methyi morpholine (Rf = 0.22 with 3:2 v/v hexanes/ether as the eiuant). Chromatography of the mbrture on 5 g of silica gei using 20:1 v/V afforded 14 mg of 2-{S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-6(R)-methyl morpholine (Rf=0.14 with 3:2 v/v hexanes/ether as the eiuant) and 17 mg of 2-(R)-(3,5-bis(trifluoromethyl) benzyloxy)-3-(S)-phenyl-6-(R)-methyl morpholine (41% total yield).

[0109] For the (2R.3S.6R) product: .

Mass Spectrum (FAB): m/Z 420 (M+H, 90%) ¹H NMR (CDCĻj, 400 Mhz. ppm) 1.30 (d, 3 H, J = 6.4), 1.74 (br s, 1 H), 2.73 and 2.98 (dAB q. 2 H, J _AB = 11.6, J ₂₇₃ = 10.0, J 25B = 2.4), 3.65 (d, 1 H, J = 7.2), 3.89 - 3.94 (m, 1 H), 4.45 (d, 1 H, J = 7.2), 4.53 and 4.90 (AB q, 2 H, J = 13.2), 7.28 - 7.38 (m, 3 H), 7.41 - 7.43 (m, 2 H), 7.45 (s, 2 H), 7.70 (s, 1 H).

[0110] For the (2S.3S.6R) product:

Mass Spectrum (FAB): m/Z 420 (M+H. 90%) ’H NMR (CDCIg, 400 Mhz. ppm) 1.20 (d, 3 H, J = 6.4), 2.04 (br s, 1 H), 2.84 and 3.15 (dAB q, 2 H. J _Μ = 12.8, J ₂₈₄ = 10.8, J _31S = 2.8), 4.08 (d, 1H, J = 2.8), 4.08 - 4.15 (m. 1 H), 4.53 and 4.80 (AB q, 2 H, J = 13.2), 4.79 (d, 1 H, J =

2.8), 7.28 - 7.38 (m, 5 H), 7.43 (s. 2 H), 7.70 (s, 1 H).

EXAMPLE 26

2-(S)-(3,5-Bis(trifluoromethvl)benzyloxv)-3-(R)-phenvl-e-(S)-methvl morpholine and 2-(R)-(3,5-Bis-(trifluoromethvl) benzvloxv)-3-(R)-phenyl-6-(S)-methvl morpholine [0111] Substitution of 250 mgof N-(2-(S)-hydroxy-propyl)-N-(2-propenyl)-(S)-phenylglycinal, 3,5-bis-(trifluoromethyl) benzyl acetal (from Exampie 22) for N-(2-(R)-hydroxypropyl)-N-(2-propenyl)-(R)-phenyl-glycinal, 3,5-bis(trifluoromethyl)benzyl acetal in an experiment similar to the preceding example afforded 42 mg of 2-{S)-(3,5-bis(trifluoromethyl) benzyloxy)-3-(R)-phenyl-6-(S)-methyl morpholine and 17 mg of 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl6-(S)-methyl morpholine.

EXAMPLE 27

2-(R)-(3,5-Bis(trifluoromethvl)benzvloxv)-3-(S)-phenvl-5-(R)-methvl morpholine, 2-fS)-(3.5-Bis-(trifluoromethyl) benzyloxv)-3-(S)-phenyl-5-(R)-methyl morpholine, 2-(R or S)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-5-(R)methvlmorpholine, and 2-(S or R)-(3,5-Bis(trifļuoromethvl) benzvloxv)-3-(R)-phenvl-5-(R)-methylmorpholine [0112] Execution of the sequence described in Example 19 substituting (R)-2-amino-1-propanol for (R)-1-amino2-propanol provided a mixture of 55 mg of high Rf material and 56 mg of low R, material. The high Rf material vvas processed according to Example 23, Step A above to provide 10 mg of high Rf material (2-(R)-(3,5-Bis(trifluoromethyl) benzyloxy)-3-(S)-pheny 1-5-(R)-methyl morpholine and 7 mg of tow R_f material (2-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-5-(R)-methyl morpholine. The low Rf material (after being combined with an additional 30 mg of material) was processed according to Example 23, Step A to provide 24 mg of high Rf material (2-(R or S)-(3,S-Bis (trifluoromethyl)benzyloxy)-3-(R)-phenyl-5-(R)-methyl-morpholine and 18 mg of low Rf material (2-(S or R)-(3,5-Bis (trifluoromethyl)benzyloxy)-3-(R)-phenyl-5-(R)-methylmorpholine.

2-(R)-(3,5-Bis(trifluoromethvl)benzvloxv)-3-(S)-phenyl-5-(R)-methvl morpholine [0113] Mass Spectrum (FAB): m/Z 420 (M+H, 100%), 227 (50%). 192 (75%), 176 (65%).

NMR (CDCI₃,400 MHz, ppm): δ0.98 (d, 3H, J= 6.3Hz), 3.16-3.20 (m, IH), 3.43-3.47(m, 1H), 3.79 (d, 1H, 1=7.5 Hz 3.91 (dd, IH, J= 3.2 &11.5 Hz), 4.51 (d, 2H, J= 13.4 Hz), 4.85 (d, 1H, J= 13.2 Hz), 7.29-7.45 (m, 7H), 7.67 (s, 1H).

2-(S)-(3,5-Bis(trifluoromethvl)benzvloxv)-3-(S)-phenvl-5-(R)-methvl morpholine [0114] Mass Spectrum (FAB): m/Z 420 (M+H, 48%), 227 (35%), 192 (39%), 176 (100%).

NMR (CDCI₃, 400 MHz, ppm): δ 1.10 (d, 3H, J= 6.4 Hz), 3.23-3.26 {m, 1H), 3.56-3.61 (m, 2H), 4.17 (d, 1H, J= 2.3 Hz), 4.51 (d, 1H, J= 13.7 Hz), 4.71 (d, 1H, J= 2.4 Hz), 4.7Θ (d, 1H, J= 13.5 Hz), 7.28-7.39 (m, 7H), 7.68 (s, 1H).

2-(R or S)-(3,5-Bis(trifluoromethyl)benzvloxv)-3-(R)-phenyl-5-(R)-methvl morpholine [0115] Mass Spectrum (FAB): m/Z 281 (35%), 221 (55%), 207 (45%), 192 (40%), 147 (100%).

NMR (CDCI₃,400 MHz, ppm): δ 1.13 (d, 3H, J= 6.6 Hz), 3.10-3.14 (m, 1H), 3.66 (dd, 1H, J= 6.6 & 11.4 Hz), 3.76 (dd, 1H, J= 3.5 & 11.2 Hz), 4.04 (d. 1H, J= 4.0 Hz), 4.61 (d, 1H, J= 13.2 Hz), 4.74 (d, 1H, J= 3.9 Hz), 4.89 (d, 1H, 13.2 Hz), 7.26-7.35 (m, 3H). 7.47-7.49 (m, 2H), 7.64 (s, 1H), 7.74 (s, 1H).

2-(R or S)-(3,5-Bis(trifluoromethyl)benzyloxv)-3-(R)-phenvl-5-(R)-methvl morpholine [0116] NMR (CDCI* 400 MHz, ppm): d 1.36 (d, 3H, J= 6.7 Hz), 3.27-3.31 (m, 1H), 3.39 (dd, 1H, J= 2.2 & 11.3 Hz), 4.16(dd, 1H, J= 3.2 & 11.0 Hz), 4.37 (d, 1H,J=2.3Hz), 4.53 (d, 1H, J=13.5Hz), 4.75 (d, 1H, J= 2.5 Hz), 4.81 (d, 1H, 13.6 Hz), 7.26-7.35 (m, 3H), 7.26-7.43 (m, 7H), 7.68 (s, 1H).

EXAMPLE 28

2-(R or S)-(3,5-Bis(trifluoromethvl)-benzyloxv)-3-(S)-phenvl-5-(S)-methylmorpholine, 2-(S or R)-(3,5-(-Bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-5-(S)-methvlmorpholine, and 2-(R)-(3,5-Bis(trifluoromethyl)benzyloxv)-3(R)-phenyl-5-(S)-methylmorpholine [0117] Execution of the sequence described in Example 19 substituting (S)-2-amino-1-propanol for (R)-1-amino2-propanol provided a mixture of 78 mg of high R, material and 70 mg of low Rf material. The high Rf material vvas processed according to Example 23, Step A above to provide less than 1 mg of high Rf material (2-(R)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(S)-phenyi-5-(S)-methylmorpholine) and 9 mg of lovv R_f material (2-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-5-(S)-methyl morpholine. The lovv Rf material vvas processed according to Example 23, Step A to provide 20 mg of high Rf material (2-{R or S)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-5-(S)-methylmorpholine and 14 mg of low Rf material (2-{S or Ρ)-(3,5-Βΐ8(1πίΙυοΓθΓΤΐβΙΙιχΙ^βηζγΙοχγ)-3-(3)-ρΙιβηχΙ-5-{3)-ιτΐθΑψΙηιθΓpholine.

2-(R or S)-(3,5-Bis(trifluoromethvnbenzvloxv)-3-(S)-phenvl-5-(S)-methvl morpholine [0118] Mass Spectrum (FAB): m/Z 420 (M+H, 60%), 227 (68%), 192 (56%), 176 (100%).

NMR (CDCI₃, 400 MHz, ppm): δ 1.12 (d, 3H, J= 6.6 Hz), 3.09-3.14 (m, 1H), 3.65 (dd, 1H, J= 6.6 & 11.0 Hz), 3.75 (dd, 1H, J= 3.6 & 11.1 Hz), 4.04 (d, 1H, J= 3.9 Hz), 4.61 (d, 1H, J= 13.2 Hz), 4.73 (d. 1H, J= 3.9 Hz), 4.89 (d, 1H, 13.2 Hz),

7.28- 7.35 (m, 3H), 7.47 (d, 2H, 7.0 Hz), 7.64 (s, 1H), 7.74 (s, 1H).

2-(S or R)-(3,5-Bis(trifluoromethvl)benzyloxv)-3-(S)-phenvl-5-(S)-methvl morpholine [0119] Mass Spectrum (FAB): m/Z 420 (M+H, 50%), 227 (45%), 192 (40%), 176 (100%).

NMR (CDCI3, 400 MHz, ppm): δ 1.36 (d, 3H, J= 6.9 Hz), 3.27-3.29 (m, 1H), 3.39 (dd, 1H, J= 2.2 & 11.1 Hz), 4.15 (dd, 1H, J= 3.3 & 11.1 Hz), 4.37 (d, 1H, J= 2.5 Hz), 4.52 (d, 1H, J= 13.3 Hz), 4.75 (d, 1H, J= 2.4 Hz), 4.81 (d, 1H, 13.5 Hz),

7.28- 7.43 (m, 7H), 7.68 (s, 1H).

2-(R)-(3,5-Bis(trifluoromethyl)benzvloxv)-3-(R)-phenvl-5-(S)-methvl morpholine [0120] NMR (CDCI3, 400 MHz, ppm): δ 1.10 (d, 3H, J= 6.4 Hz), 3.22-3.25 (m, 1H), 3.55-3.60 (m, 2H). 4.17 (d, 1H, J= 2.3 Hz), 4.51 (d, 1H, J= 13.5 Hz). 4.71 (d, 1H, J= 2.4 Hz), 4.77 (d, 1H, J= 13.6 Hz), 7.28-7.38 (m, 7H), 7.67 (s, 1H).

EXAMPLE 29

-2-(R)-(3,5-Bis(trifluoromethvl)benzyloxy)-3-(S)-phenyl-5-(R)-phenylmorpholine, 2-(S)-(3,5-Bis(trifluoromethyl) benzyloxv)-3-(S)-phenyl-5-(R)-phenylmorpholine, and 2-(R or S)-(3,5-Bis(trifluoromethyl)-benzyloxy)-3-(R)-phenyl-5iR)-phenylmorpholine [0121] Execution of the sequence described in Example 19 substituting (R)-2-amino-2-phenylethanol for (R)-1 -amino-2-propanol provided a mixture of 62 mg of high Rf material and 52 mg ot low R_f material. The high R₍ material vvas processed according to Example 23, Step A above to provide 16 mg ot high Rf material (2-(R)-(3,5-Bis(trifluoromethyl) benzyloxy) 3-(S)-phenyl-5-(R)-phenylmorpholine and 4 mg of lovv Rf material (2-(S)-(3,5-Bis(trifiuoromethyl)benzyloxy)-3-(S)-phenyl-5-(R)-phenylmorpholine. The low Rf material viras processed according to Example 23, Step A to provide 4 mg of product (2-(R or S)-(3,5-Bis(trifluoromethyl)benzyl-oxy)-3-(R)-phenyl-5-(R)-phenylmorpholine.

2-(R)-(3,5-Bis(trifiuoromethyl)benzyloxv)-3-(S)-phenyl-5-(R)-phenylmorpholine [0122] NMR (CDCl* 400 MHz, ppm): δ 3.62 (t, 1H, J= 10.7 & 21.5 Hz), 3.93 (d, 1H, J= 7.4 Hz), 3.99 (dd, 1H, J= 3.1 & 11.2 Hz), 4.18 (dd, 1H, J= 3.0 & 10.2 Hz), 4.46 (d, 1H, J= 7.4 Hz), 4.53 (d, 1H, J= 13.5 Hz), 4.89 (d, 1H, J= 13.3 Hz),

7.28-7.55 (m, 12H), 7.69 (s, 1H).

2-(S)-(3,5-Bis(trifluoromethvl)benzyloxy)-3-(S)-phenyl-5-(R)-phenvlmorpholine [0123] NMR (CDCl* 400 MHz, ppm): δ 3.67 (dd, 1H, J= 3.5 & 11.0 Hz), 3.89 (d, 1H, J= 10.8 & 21.6 Hz), 4.25 (dd. 1H, J= 3.3 & 11.0 Hz), 4.34 (d, 1H, J= 2.2 Hz), 4.52 (d, 1H, J= 13.8 Hz), 4.78-4.87 (m, 2H), 7.28-7.51 (m, 12H), 7.69 (s, IH).

2-(Ror S)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-{R)-phenyl-5-(R)-phenvlmorpholine [0124] NMR (CDCl* 400 MHz, ppm): δ 4.10-4.25 (m, 2H), 4.30-4.38 (m, 1H), 4.48-4.54 (m, 1H), 4.59-4.66 (m, 1H), 4.86-5.00 (m. 2H), 7.25-7.74 (m, 13H).

EXAMPLE 30

2-(S)-(3,5-Bis(trifluoromethvl)benzvloxy)-3-(R)-phenyl-5-(S)-phenylmorpholine, 2-fR)-f3,5-Bis(trifiuoromethvl) benzyloxy)-3-(R)-phenvl-5-(S)-phenylmorpholine, 2-(R or S)-f3,S-Bis-ftrifluoromethyl)-benzvloxv)-3-(S)-phenyl-S-(S)phenvl-morpholine, and 2-(R or S)-(3,5-Bis(trifluoromethyl)benzvloxy)-3-(S)-phenvl-5-(S)-phenvimorpholine [0125] Execution of the sequence described in Example 19 substituting (S)-2-amino-2-phenylethanoi for (R)-1 -amino-2-propanol provided a mbrture of 75 mg of high Rf material and 64 mg of iow Rf material. The high R_f material viras processed according to Example 23, Step A above to provide 23 mg of high Rf material (2-(S)-(3,5-Bis(trifluoromethyl) benzyloxy)-3-(R)-phenyl-5-(S)-phenylmorpholine [L-740,930]) and 7 mg of lovv Rf material (2-(R)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-5-(S)-phenylmorpholine. The lovir R_t material «rās processed according to ExampJe 23, Step A to provide 26 mg of higher R_f material (2-(R or S)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-5-(S)-phenylmorpholine and 6 mg of lower Rf material (2-(R or S)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-5-(S)-phenylmorpholine.

2-(S)-(3,5-Bis(trifluoromethvl)benzvloxv)-3-(R)-phenvl-5-(S)-phenvlmorpholine [0126] NMR (CDCl* 400 MHz, ppm): δ 3.60-3.74 (m. 1H), 3.94 (d, 1H, J= 7.6 Hz). 4.00 (dd, 1H, 3= 3.2 & 11.3 Hz), 4.18-4.21 (m, IH), 4.50-4.55 (m, 2H,), 4.89 (m, 1H), 7.26-7.55 (m, 12H), 7.69 (s, 1H).

2-(R)-(3,5-Bis(trifluoromethvl)benzvloxv)-3-(R)-phenvl-5-(S)-phenvlmorpholine [0127] NMR (CDCl* 400 MHz, ppm): δ 3.68 (dd, 1H, J= 3.0 & 11.0 Hz), 3.88-3.94 (m, 1H), 4.26-4.30 (m, 1H), 4.36 (s, 1H), 4.52 (d, 1H, J= 13.5 Hz), 4.77-4.86 (m, 2H), 7.27-7.51 (m, 12H), 7.69 (s, 1H).

2-(R orS)-(3,5-Bis(trifluoromethvl)benzytoxy)-3-(S)-phenyl-5-(S)-phenylmorpholine [0128] NMR (CDCl* 400 MHz, ppm): δ 3.93-3.95 (m, 1H), 4.06-4.21 (m, 2H), 4.38-4.42 (m, 1H), 4.59-4.68 (m, 2H), 4.83-4.94 (m. 2H), 7.25-7.81 (m, 13H).

2-(RorS)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-5-(S)-phenylmorpholine [0129] NMR (CDCl* 400 MHz, ppm): δ 3.43-3.59 (m, 2H), 3.82 (d, 1H, J= 7.2 Hz), 4.25 (d, 1H, J= 12.5 Hz), 4.52-4.63 (m, 3H), 4.80-4.90 (brs, 1H), 7.11-7.81 (m. 13H).

pXAMPLE 31

9-fS)-(3,5-bis(trifluoromethvl)benzvloxv)-6-(R)-methvl-3-(S)-phenvl-4-(3-(1,2.4-triazolo)methyl)-morpholine [0130] According to the procedure given in Example 17. Step B. 98 mg (0.24 mmole) of 2-(S)-(3,5-bis-(trifluoromethyl) benzyloxy)*3-(S)-phenyl-6-(R)-methyl morpholine (from Example 25 above), 38 mg (0.28 mmole) of N-formyl-2-chloroacetamidrazone (from Example 17, Step A above) and 97 mg (0.7 mmole) of anhydrous potassium carbonate gavē, after flash chromatography on 28 g of silica eluting with 1 L of 100:4:0.5 methyiene chloride:methanol: ammonia water, a iight yellow solid vvhich after recrystallization from hexanesAnethylene chloride provided 77 mg (66%) of 2-(S)-(3,5-bis (trifluoromethyl)benzyloxy)-6-(R)-methyl-3-(S)-phenyl-4-(3-(1,2,4-triazoto)methyl)-morpholine as a white povvder.

NMR (CDCI_3i 400 MHz, ppm): δ 1.17 (d, J= 6.3, 3H), 2.29 (t, J= 11.1,1H), 2.92 (d, J= 11.1,1H), 3.42 (d, J= 15.3,1H), 3.56 (s, 1H), 3.88 (d, J= 15.4, 1H), 4.20-4.33 (m, 1H). 4.43 (d, 13.5, 1H), 4.71 (d, J= 2.4, 1H), 4.74 (d, J= 13.3, 1H), 7.30-7.55 (m, 7H), 7.69 (s, 1H), 7.95 (s, 1H).

EXAMPLE 32

2-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)-6-(R)-methyl-4-(3-(5-oxo-1H, 4H-1,2,4-triazolo)methyl)-3-(S)phenvlmorpholine [0131] A mixture of 96 mg (0.23 mmole) of 2-(S)-(3,5-bis-(trifluoromethyl)benzyloxy)-3-(S)-phenyl-6-(R)-methyl morpholine (from Example 25 above), 46 mg (0.26 mmole) ot N-methylcarboxy-2-chloroacetamidrazone and 95 mg (0.69 mmole) of anhydrous potassium carbonate in 3 mL of dry DMF vvas stirred at room temperature for 20 min, at 60°C for 90 min and then at 120“C for 2 hr. The mixture vvas cooied to room temperature, taken up in 15 mL of ethyl acetate and vvas washed vvith 3x10 mL of water. The combined aqueous layers vvere back-extracted vvith 10 mL of ethyi acetate, the combined organic layers vvere vvashed vvith 10 mL of brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on 26 g of silica eluting with 1L of 100:4 methylene chloride: mēthanol to give 65 mg (55%) of 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-6-(R)-methyl-4-(3-(5-oxo-1 Η, 4H-1,2,4-triazolo)-methyl)-3-(S)-phenylmorpholine as a light yellow povvder.

NMR (CDClg, 400 MHz, ppm): δ 1.18 (d, J= 6.2, 3H), 2.15 (t, J= 11.1, 1H), 2.89 (d, J= 14, 2H), 3.49 (d, J= 2.2, 1H), 3.61 (d, J= 14.4, 1H), 4.20-4.30 (m, 1H), 4.45 (d, J= 13.6, 1H), 4.67 (d, J= 2.5, 1H), 4.79 (d, J= 13.5, 1H), 7.25-7.50 (m. 7H), 7.62 (s,1H), 10.07 (s,1H), 10.35 (s,1H).

EXAMPLE 33

2-(S)-(3,5-Bis(trifluoromethyl)benzyloxv)-3-(R)-phenylmorpholine

Step A 4-Benzvl-2-(S)-hvdroxv-3-(R)-phenylmorpholine [0132] A solution of 3.72 g (13.9 mmol) of 4-benzyl-3-(R)-phenyl-2-morpholinone, prepared from (R)-phenylglycine as described in Example 14, in 28 mL of CH₂CI₂ vvas cooled in a -78“C bath under a N₂ atmosphere and 14 mL of a 1.5 M solution of DIBAL-H (21 mmol) in toluene vvere added. After stirring the resulting solution for 0.5 h, it vvas allovved to warm to -50’C and mantained at this temperature for 0.5 h. The reaction mixture vvas quenched by adding 10 mL of aqueous potassium sodium tartarate. The mixture vvas diluted vvith CH₂CI₂ and the layers vvere separated. The aqueous layer was extracted 3 times vvith CH₂CI₂. The CH₂CI₂ layers vvere washed vvith brine, dried over Na-jSC^ and filtered. Concentration of the filtrate furnished 3.32 g (88%) of 4-benzyl-2-(S)-hydroxy-3-(R)-phenylmorpholine suitable for use in the next step.

NMR (CDCI₃) 2.28 (m, 1H), 2.71 (m, 1H), 2.91 (d, J = 13 Hz, 1H), 3.09 (d, J = 6 Hz, 1H), 3.69 (d, J = 13 Hz, 1H), 3.82 (td, J = 10 Hz and 2 Hz, 1H), 3.91 (d, J = 10 Hz, 1H), 4.73 (t, J = 6 Hz, 1H), 7.2-7.52 (m, 10H).

Step B 4-Benzyl-2-(S)-(3,5-bis(trifluoromethyl)-benzyloxv)-3-(R)-phenvlmorpholine [0133] To a suspension of 0.592 g (14.8 mmol) of NaH in 30 mL of dry THF at 0 “C vvas added 3.32 g (12.3 mmol) of 4-benzyl-2-(S)-hydroxy-3-(R)-phenylmorpholine prepared in step A. After 15 min 0.915 g of tetrabutylammonium iodide (2.47 mmol) and 2.4 mL (13 mmol) of 3,5-bis(trifluoromethyl)benzyl bromide vvere added. The resulting mixture vvas stirred at ice-bath temperature for 1 h, then poured into saturated NaHCOg solution and extracted vvith ethyi acetate (EtOAc). The organic layers were combined, vvashed vvith brine, dried over Na₂SO₄ and filtered. The filtrate was concentrated in vacuo and the resiue was chromatographed on a VVaters Prep500 HPLC system using 50% EtOAc/Hexane to isolate 3.6 g (59%) of 4-Benzyl-2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenylmorpholine.

’H NMR (CDCI₃) 2.3(td, J = 11 Hzand3Hz, IH), 2.71 (d. J= 11 Hz, 1H), 2.90 (d, J = 13 Hz, IH). 3.22 (d, J = 7.3 Hz, IH), 3.75 (m, 2H). 3.93 (m, IH), 4.43 (d, J = 13 Hz, IH), 4.45 (d, J = 7.3 Hz, 1H), 4.82 (d, J = 13 Hz, 1 H), 7.19-7.5 (m, 12H), 7.67 (s, IH).

Step C 2-(S)-(3,5-Bis(trifluoromethvl)benzvloxv)-3-(R)-phenylmorphoiine [0134] A solution of 3.6 g (7.27 mmol) of 4-benzyl-2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenylmorpholine in 100 mL of ethanol and 5 mL of vvater, containing 0.72 g of 10% Pd/C vvas hydrogenated on a Parr apparatus for 36 h. The cataiyst vvas filtered and thoroughly vvashed with EtOAc. The filtrate vvas concentrated and the residue vvas partitioned between water and EtOAc. The EtOAc layer was vvashed vvith brine, dried over N^SO₄, filtered and concentrated. The residue was purified by flash chromatography using a gradient of 10-60 % EtOAc/hexane to isolate 2.05 g (70%) of 2-(S)-(3,5-bis(trifluoromethyl)b0nzyloxy)-3-(R)-phenylmorpholine.

’H NMR (CDCI3) 1.92 (br s, 1H). 2.91 (m, 1H), 3.05 (td, J =11 HZ and 3 Hz. 1H), 3.68 (d, J = 7 Hz, 1H), 3.81 (Īd, J =

Hz and 3 Hz. 1H), 4.01 (m. 1H), 4.44 (d, J = 7 Hz), 4.5 (d. J = 13 Hz, IH). 4.85 (d, J » 13 Hz, 1 H), 7.28-7.42 (m, 7H), 7.67 (s, 1H).

EXAMPLE 34

4-(3-(1,2,4-Triazolo)methvl)-2-(S)-(3,5-bis(trifluoromethvl)benzyloxy)-3-(R)-phenvlmorpholine [0135] The title compound was prepared by the procedure of Example 17, step B employing the product of Example 33, step C as a starting material.

’H NMR (CDCI3) 1.75 (br s, 1 H), 2.61 (td, J =12 Hz and 2 Hz, 1H), 2.83 (d. J = 12 Hz, 1H), 3.33 (d, J = 7 Hz, 1H), 3.48 (d, J = 15 Hz, 1H), 3.78 (d, J = 15 Hz, 1H), 3.85 (m, 1H), 3.99 (m, 1H), 4.44 (d, J = 13 Hz, 1 H), 4.49 (d, J = 7Hz, 1H), 4.81 (d, J = 13 Hz, 1H), 7.23-7.45 (m, 7H), 7.67 (s, 1H), 7.96 (s,1H).

EXAMPLE 35

4-(3-(5-Oxo-1H,4H-1,2,4-triazolo)methyl)-2-(S)-(3,5-bis-(trifluoromethyl) benzytoxy)-3-(R)-phenylmorpholine [0136] The title compound vvas prepared by the procedure of Example 18, steps B & C employing the product of Example 33, step C as a starting material.

EXAMPLE 36

4-(2-(lmidazolo)methvl)-2-(S)-(3,5-bis(trifluoromethvl)benzvloxv)-3-(S)-phenylmorpholine [0137] A solution of 101 mg (0.25 mmol) of 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenylmorpholine (Exam pie 15), 98 mg (1.0 mmol) of imidazoie-2-carboxaldehyde, and 5 drops of glacial acetic acid in 3 ml of methanol wa treated with 1.5 ml of 1M sodium cyanoborohydride solution in THF. After 16 hr, the reaction vvas quenched vvith 5 rr of saturated aqueous sodium bicarbonate solution and partitioned betvveen 40 ml of ethyl acetate and 20 ml of wate The organic iayer vvas separated, dried over magnēsium sulfate, and concentrated in vacuo. Flash chromatograpl· on 8 g of silica gel using 50:1:0.1 methylene chloride/methanol/amonium hydroxide as the eluent afforded 54 mg (44' yield) of the title compound as a vvhite solid.

’H NMR (CDCI3) 2.60 (dt, J = 3.2 Hz and 12.4 Hz, 1H), 2.85 (d, J =12.4 Hz, 1H), 3.28 (d, J = 14.4 Hz, 1H), 3.59 (d =2.8 Hz, 1H), 3.66 (dd, J =2.0,11.6 Hz, 1H), 3.84 (d, J =14.4 Hz, 1H), 3.94 (app s, 2H), 4.14 (dt. J = 2.0,12.0 Hz, 114.43 (d, J = 13.6 Hz, 1H), 4.71 (d, J = 2.8 Hz, 1H), 4.78 (d, J = 13.6 Hz, 1H), 6.99 (app s, 2H), 7.25-7.48 (m, 6H), 7/ (s, 1H). Mass spectrum (FAB): m/z 486 (100%, M+H)

EXAMPLE 37

4-(2-(lmidazolo)methyl)-2-(S)-(3,5-bis(trifluoromethvl)benzyloxy)-3-(R)-phenylmorpholine [0138] The tītie compound was prepared by the procedure of Example 36 employing appropriate starting mater ’H NMR (CDCI₃) 2.53 (td, J = 11 Hz and 3 Hz, 1H), 2.74 (d, J =12 Hz, 1H), 3.23 (d, J = 7Hz, 1H), 3.32 (d, J =15 1H), 3.66 (d, J =15 Hz, 1H), 3.77 (td, J =11 Hz and 2 Hz, 1H), 3.99 (m, 1H). 4.44 (m, 2H), 4.8 (d, J = 13 Hz, 1H), <

(s, 2H), 7.2-7.45 (m, 7H), 7.67 (s, 1H).

EXAMPLE 38

4-(5-(lmidazolo)methvl)-2-(S)-(3,5-bis(1rifluoromethvl)benzvloxv)-3-(R)-phenvlmorpholine [0139] The title compound vvas prepared by the procedure of Example 36 emptoying appropriate starting materiāls. ’H NMR (CDCI₃) 2.47 (td, J = 12 Hz and 3 Hz. 1H), 2.83 (d, J = 12 Hz, 1H), 3,2 (m, 2H), 3.61 (d, J =14 Hz, 1H), 3.79 (td, J =12 Hz and 2 Hz, 1H), 3,96 (m, IH), 4.44 (m, 2H). 4.80 (d, J =13 Hz, 1H), 6.81 (s, 1H), 7.28-7.45 (m, 7H), 7.60 (s, 1H), 7.66 (s, 1H).

EXAMPLE 39

4-(Aminocarbonylmethyl)-2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenylmorpholine [0140] The title compound vvas prepared by the procedure of Example 15 employing appropriate starting materiāls. ’H NMR (CDCI3) 2.54 (td, J = 11 Hz and 2 Hz, 1H), 2.64 (d, J = 17 Hz, 1H), 2.93 (d, J 12 Hz, 1H), 3.14 (d, J = 17 Hz, 1H), 3.27 (d, J =7 Hz, 1H), 3.83 (td, J = 11 Hz and 2 Hz, 1H), 4.05 (m, 1H), 4.46 (m, 2H), 4.81 (d, J =13 Hz, 1H), 5.62 (br s, 1H), 6.80 (br s, 1H), 7.28-7.32 (m, 7H), 7.67 (s, 1H).

EXAMPLES 40-43

4-(3-(1,2,4-Triazolo)methyO-2-(3-ftert-butvl)-5-methvlbenzyloxv)-3-phenyl-morpholine, 4-(3-(5-Oxo-1 H,4H1,2,4-triazolo)methyl)-2-(3-(tert-butvh-5-mBthylbenzvloxy)-3-phenyl-morpholine, 4-(2-(lmidazolo)methyl)-2-(3-(tertbutvl)-5-methylbenzyloxy)-3-phenyl-morpholine, 4-(4-(lmidazoto)-methyl)-2-(3-(tert-butyl)-5-methyl-benzyloxv)3- phenvl-morpholine [0141] The title compounds are each prepared by the procedures of Examples 15,17 & 18 empioying appropriately substituted starting materiāls and reaģents.

EXAMPLE 44

2-(S)-(3,5-Dichlorobenzvloxv)-3-(S)-phenylmorpholine

Step A: 3,5-Dichlorobenzvl aicohol, trifluoromethanesulfonate ester [0142] A solution of 6.09 g (34.4 mmole) of 3,5-dichlorobenzyl aicohol and 8.48 g (41.3 mmole) of 2,6-di4-butyl4- methylpyridine in 280 mL of dry carbon tetrachloride under a nitrogen atmosphere vvas treated vvith 5.95 mL (35.4 mmole) of trifluoromethanesulfonic anhydride at room temperature. A vvhite precipitate formed shortly after the addition of the anhydride. After 90 min, the slurry was filtered under nitrogen vvith a Schlenk filter, and the filtrate was concentrated in vacuo. The residue, vvhich vvas a tvvo-phase oil, vvas dissolved under nitrogen in 60 mL of dry toluene. The resulting solution was used immediately in Step B belovv.

Step B: 4-Benzyl-2-(S)-(3,5-dichlorobenzyloxy)-3-(S)-phenylmorpholine [0143] A solution of 5.11 g (19.1 mmole) of N-benzyl-3-(S)-phenylmorpholin-2-one (from Example 14) in 100 mL of dry THF was cooled to -75“C under nitrogen and vvas treated dropvvise with 20.5 mL (20.5 mmole) of a 1M solution of lithium tri(sec-butyl)-borohydride (L-Selectride®) in THF. After stirring the solution at -75’C for 30 min, a solution of 3,5-dichlorobenzyl aicohol, trifluoromethanesulfonate ester in toluene (from Example 44, Step A) vvas added by cannula so that the internai temperature was maintained belovv -60’C. The resulting solution vvas stirred betvveen -38’C and -50’C for 9 hr, and vvas then treated vvith 14 mL of aqueous ammonia and stored at -20°C for 12 hours. The solution vvas then poured into a mixture of 50 mL of ethyl acetate and 100 mL of water, and the layers vvere separated. The aqueous phase was extracted vvith 2x100 mL of ethyl acetate, each extract was vvashed with brine, the combined organic layers vvere dried over sodium sulfate, the mixture vvas filtered and the filtrate concentrated in vacuo. The residue was purified by flash chromatography on 235 g of silica eluting vvith 1.5 L of 100:2 hexanes:ethyl acetate, then 1.5 L of 100:3 hexanes: ethyl acetate and then 1.9 L of 100:5 hexanes:ethyi acetate to give 4.4 g (54%) of an oil, vvhich by ¹H NMR is a 8:1 mixture of cis:trans morpholines.

Mass Spectrum (FAB): m/Z 430,428,426 (M+H, —60%), 268 (M-ArCH₂,100%), 252 (M-ArCH₂O, 75%), 222(20%), 159 (45%).

’H NMR (CDCI3, 400 MHz, ppm): δ major (cis) isomer: 2.32 (td, J= 12, 3.6, 1H), 2.84 (app t, J= 13, 2H), 3.52 (d, J=

2.6, 1H), 3.55 (dq, J= 11.3, 1.6, 1H), 3.91 (d, J= 13.3, 1H), 4.12 (td, J= 11.6, 2.4, 1H), 4.29 (d, J= 13.6,1H), 4.59 (d.

J= 2.9.1H), 4.60 (d, J= 13.6), 6.70 (s. 2H), 7.13 (t, J= 1.9, 1H), 7.2-7.6 (m, 8H), 7.53 (brd. 2H).

Step C: 2-(S)-(3.5-Dichtorobenzvloxy)-3-fS)-phenylmorpholine [0144] A solution of 0.33 g (0.77 mmole) of 4-benzyl-2-(S)-(3,5-dichlorobenzytexy)-3-(S)-phenylmorpholine (from Example 44, Step B) and 0.22 g (1.54 mmole) of 1-chtoroethyl chloroformate in 4.5 mL of 1,2-dichioroethane vvas placed in a pressure vial vvhich was lovvered into an oil bath which vvas heated to 110*C. After stirring for 60 hr the solution vvas cooled and concentrated in vacuo. The residue vvas dissolved in 7 mL of methanol and the resulting solution was heated at reflux tor 30 min. The mixture was cooled and treated with several drops of concentrated aqueous ammonia and the solution was concentrated. The residue was partly purified by flash chromatography on 67 g of silica eluting with 1.5 L of 100:1 methylene chloride: methanol, and the rich cuts vvere purified by flash chormatography on 32 g of silica eluting with 50:50 hexanes: ethyl acetate and then 50:50:5 hexanes:ethyl acetate.methanol to give 0.051 g (20%) of an oil, vvhich by ¹H NMR was pure cis morpholine.

Mass Spectrum (FAB): m/Z 468,466,464 (max 8%)), 338,340 (M+H, 25%), 176 (20%). 162 (100%), 132 (20%),.

¹H NMR (CDCI₃, 400 MHz, ppm): 5 1.89 (br s, 1H), 3.08 (dd, J= 12.5, 2.9, 1H), 3.23 (td, J= 12.2, 3.6,1H), 3.59 (dd,

J= 11.3, 2.5, 1H), 4.03 (td, J= 11.7, 3, 1H), 4.09 (d. J= 2.4, IH), 4.37 (d, J= 13.5, 1H), 4.62 (d, J= 13.3, 1H), 4.67 (d,

J= 2.5,1H), 6.72 (d, J= 1.8, 2H), 7.14 (t, J= 1.8, 1H), 7.25-7.40 (m, 5H).

EKAMPLE 45

2-(S)-(3,5-dichlorobenzvloxy)-4-(3-(5-oxo-1,2,4-triazolo)methvl)-3-(S)-phenylmorpholine

Step A N-Methvlcarboxv-2-chloroacetamidrazone [0145] A solution of 5.0 g (66.2 mmol) of chloroacetonitrile in 35 mL of dry methanol was cooled to 0*C and was treated vvith 0.105 g (1.9 mmol) of sodium methaxide. The ice-bath was removed and the mixture vvas alowed to stir at room temperature for 30 minūtes. To the reaction vvas then added 0.110 mL (1.9 mmol) of acetic acid and then 5.8 g (64.9 mmol) of methyl hydrazinecarboxylate. After stirring 30 minūtes at room temperature, the suspension vvas concentrated in vacuo, and placed on the high-vac line overnight, to give 10.5 g (98%) of a yeliow povvder, a portion of which vvas employed in Step C belovv.

Step B: 4-(2-(N-Methylcarboxv-acetamidrazono)-2-(S)-(3,5-dichlorobenzvloxv)-3-(S)-phenvlmorpholine [0146] A solution of 0.050 g (0.15 mmol) of 2-(S)-(3,5-dichlorobenzyloxy)-3-(S)-phenylmorpholine (from Example

44, Step C), 0.034 g (0.21 mmol) of N-methylcarboxy-2-chloroacteamidrazone (from Step A), and 0.044 mL (0.25 | mmol) N,N-diisopropylethylamine in 1 mL of acetonitrile was stirred at room temperature for 3 hours. The mixture vvas =? , partitioned betvveen 20 mL of methylene chloride and 10 mL of vvater. The layers vvere separated, the organic layer vvas dried over sodium sulfate and vvas then concentrated in vacuo. The residue vvas purified by flash chromatography on 35 g of silica eluting vvith 1L of 50:1: methyfene chlorideZmethanol then 500 mL of 25:1:0.05 methylene chloride:

methanol:aqueous ammonia to give 70 mg (~100%) of the product as a white solid.

Mass Spectrum (FAB): m/Z 469 (M+H, 60%), 467 (M+H, 100%),291 (40%), 160 (20%), 158 (25%).

¹H NMR (CDCI₃, 400 MHz, ppm): δ 2.48 (td, J= 3.5,12.2,1H), 2.53 (d, J= 14.6,1H), 2.90 (d, J= 11.6,1H), 3.37 (d, J=

14.6,1H), 3.52 (d, J= 2.8), 1H), 3.62 (dm, J= 11.4,1H), 3.75 (s, 3H), 4.14 (td, J= 2.2, 11.8,1H), 4.28 (d, J= 13.5, 1H),

4.58 (d, J= 13.6), 4.60 (d, J= 2.8, 1H), 5.45 (brs, 2H), 6.74 (d, J= 1.9, 2H), 7.15 (t, J= 1.9,1H), 7.30-7.46 (m, 6H).

Step C: 2-(S)-(3,5-Dichtorobenzyloxy)-4-(3-(5-oxo-1,2,4-triazoto)methyl)-3-(S)-phenylmorpholine [0147] A solution of 0.069 g (0.15 mmol) of 4-(2-(N-methylcarboxy-acetamidrazono)-2-(S)-(3,5-dichiorobenzyloxy)

3-(S)-phenylmorpholine (from Step B) in 6 mL of xylenes vvas heated at reflux for 2 hours. The solution vvas coolec and concentrated in vacuo. The residue vvas purified by flash chromatography on 35 g of silica gel eluting vvith 500 mi of 50:1:0.1 methylene chloride/methanol/aqueous ammonia then 500 mL of 20:1:0.1 methylene chloride/methanol aqueous ammonia to give 56 mg (8B%) of the product as a vvhite povvder.

Mass Spectrum (FAB): m/Z 437 (M+H, 65%), 435 (M+H, 100%), 259 (85%), 161 (55%).

’H NMR (CDCI₃, 400 MHz, ppm): δ 2.53 (t, J= 11.7, 3.6, 1H), 2.88 (d,J= 11.6, 1H), 2.96 (d, J= 14.3,1H), 3.54 (d, J 2.6,1H), 3.63 (dd, J= 11.6, 1.9,1H), 3.68 (d, J= 14.6,1H), 4.16 (t, J= 11.7, 2.2, IH), 4.30 (d, J= 13.6), 4.58 (d, J= 2.7 1H), 4.67 (d, J= 13.6,1H), 6.65 (d, J= 1.8,2H), 7.07 (t, J= 1.9,1H), 7.29-7.44 (m, 5H), 10.25 (brs, 1H), 10.75 (brs, 1H

ΕΧΑΜΡΙ,Ε 46

2-(S)-(3,5-Bis(trifluoromethvnbenzvloxv)-4-(methoxycarbonylmethyl)-3-(S)-phenvlmorpholine [0148] Α solution of 300 mg (0.74 mmole) of 2-(S)-(3,5-bis(trifluoromethyi)benzyloxy)-3-(S)-phenylmorpholine (from Example 15, Step C) and 0.35 mL (2.0 mmole) of DIEA in 5 mL of acetonitrile was treated vvith 0.19 mL (2.0 mmole) of methyl bromoacetate and the mixture vvas stirred for 16 hr at room temperature. The solution vvas then concentrated in vacuo and the residue partitioned betvveen 30 mL of ether and 15 mL of 0.5 N aqueous KHSO₄. The layers vvere separated and the organic phase was vvashed with 10 mL of brine and dried over magnesium sulfate. Follovving filtration, the organic phase vvas concentrated in vacuo and the residue purified by flash chromatography on 20 g of silica eluting with 80:20 hexanes:ether to give 351 mg (99%) of the product [a]_D = +147.3* (c= 1.6. CHCI3).

Mass Spectrum (FAB): m/Z 478 (M+H, 40%), 477 (65%), 418 (50%). 250 (95%), 234 (90%), 227 (100%).

¹H NMR (CDCI₃, 400 MHz, ppm): δ 3.02 (br d, 2H), 3.13 (d, J= 16.9,1H), 3.36 (d, J= 16.8), 3.62 (s. 3H), 3.69 (dt J=

11.7, 2.2, 1H), 4.03 (br s, 1H), 4.23-4.32 (m, 1H), 4.44 (d. J= 13.3, 1H), 4.68, (d, J= 2.6, 1H), 4.81 (d, J= 13.5, 1H), 7.30-7.38 (m, 3H). 7.4-7.5 (m, 3H), 7.70 (s, 1H).

Analysis:
Ceilcd for Cļ>gHgļ FgNO^ Found	c-55.35 C-55.09	H-4.43 H-4.43	N-2.93 N-2.83	F-23.88 F-24.05

EXAMPLE 47

2- (SM3,5-Bis(trifluoromethvl)benzvloxv)-4-(carboxvmethvl)-3-(S)-phenvlmorpholine [0149] A solution of 0.016 g (0.034 mmole) of 2-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)-4-(methoxycarbonylmethyl)3- (S)-phenylmorpholine (from Example 46) in 2 mL of THF and 0.5 mL of vvater vvas treated vvith 0.027 mL (0.067 mmole) of 2.5 N aqueous sodium hydroxide and the mixture vvas stirred at room temperature for 5 hr. The mixture vvas treated vvith 2 drops of 2N aqueous HCl and 3 mL of vvater and the solution vvas extracted with 15 mL of 1:1 hexanes: ethyt acetate. The organic phase was dried over magnesium sulfate. filtered and concentrated in vacuo. The residue vvas purified by flash chormatography on 13 g of silica eluting vvith 250 mL of 100:3:0.1 methylene chloride:methanol: acetic acid then 100 mL of 50:2:0.1 methylene chloride: methanokacetic acid to give 0.014 g (90%) of an oil.

Mass Spectrum (FAB): m/Z 464 (M+H, 90%), 420 (M-CO₂, 10%), 227 (ArCH₂, 35%), 220 (M-OCH^r, 100%), 161 (20%).

¹H NMR (CDCI₃, 400 MHz, ppm): 52.9 (app d, 2H), 3.03 (d. 1H), 3.33 (d, 1H), 3.72 (d, 1H), 3.90 (d, 1H), 4.25 (t, 1H),

4.44 (d, 1H), 4.71 (d, 1H), 4.79 (d, 1H), 7.3-7.4 (m, 5H), 7.44 (s, 2H), 7.71 (s, 1H).

EXAMPLE 48

2-fS1-(3,5-Bis(trifluoromethv0benzvloxv)-4-((2-aminoethv0aminocarbonylmethvD-3-(S)-phenvlmorpholine hydrochloride [0150] A solution of 54 mg (0.11 mmole) of 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-4-(carboxymethyl)-3-(S)-phenylmorpholine (from Example 46) and 0.15 mL of ethylenediamine (2.3 mmole) in 1 mL of mēthanol was stirred at 55°C for 48 hr. The mixture vvas concentrated and the residue purified by flash chromatography on 16 g of silica eluting vvith 500 mL of 50:4:0.1 methylene chtoride:methanol: aqueous ammonia to provide 57 mg(100%) of an oil. The oil vvas dissolved in ether and was treated vvith ether saturated vvith gaseous HCl. After concentration in vacuo, 58 mg (95%) of a rigid oil vvas obtained.

Mass Spectrum (FAB; free base): m/Z 506 (M+H, 100%), 418 (15%), 262(35%), 227 (30%), 173 (40%) ¹H NMR (CDClg, 400 MHz, ppm): δ 2.56 (d, J= 15.5, 1H), 2.59 (td, J= 12.0, 3.6, 1H), 2.82 (t, J= 6.5, 2H), 2.96 (d, J=

11.8, 1H). 3.21 (d, J= 15.8, 1H), 3.25-3.40 (m, 2H), 3.65 (d, J= 2.6, 1H), 3.67 (app dt. J= 11.4, ~2, 1H), 4.18 (td, J=

11.8, 2.6. 1H). 4.33 (d. J= 13.5. 1H),4.69 (d. J= 2.7, 1H), 4.79 (d, J= 13.5, 1H), 7.25-7.40 (m, 5H), 7.46 (s, 2H), 7.59 (brt, 1H). 7.71 (s, 1H).

EXAMPLE 49

2-(S)-(3,5-Bis(trifluoromethvl)benzvloxv)-4-((3-aminopropvl)aminocarbonytmethyl)-3-(S)-phenylmorpholine hvdrochloride [0151] A solution of 59 mg (0.12 mmole) of 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-4-(carboxymethyl)-3-(S)-phenylmorpholine (from Example 46) and 0.21 mL of 1,3-propylenediamine (2.5 mmole) in 1 mL of methanol was stirred at 55’C for 72 hr. The mčcture vizas concentrated and the residue purified by flash chromatography on 16 g of siiica eluting with 500 mL of 10:1:0.05 methylene chloride:methanol: aqueous ammonia to provide 56 mg (88%) of an oil. The oil was dissolved in methylene chloride and was treated with methylene chloride saturated with gaseous HCI. After concentration in vacuo, a white pasta was obtained.

Mass Spectrum (FAB; free base): m/Z 520 (M+H, 100%), 418 (10%), 276(30%), 227 (20%), 174 (30%) ’H NMR (CDCĻ 400 MHz, ppm): 51.64 (pentet, J= 6.6,2H), 2.53 (d, J= 15.5,1H), 2.58 (td, J= 12.0,3.6,1H), 2.73 (t, J= 6.5, 2H), 2.92 (d, J= 11.8,1H), 3.19 (d, J= 15.8,1H), 3.25-3.40 (m, 2H), 3.62 (d, J= 2.6,1H), 3.65 (app dt, J= 11.4, ~2,1H), 4.16 (td, J= 11.8,2.6,1H). 4.41 (d, J= 13.5,1H),4.68 (d, J= 2.7,1H), 4.79 (d, J= 13.5,1H), 7.25-7.40 (m, 5H),

7.45 (s, 2H), 7.57 (br t, 1H), 7.70 (s, IH).

EXAMPLE 50

4-benzvl-5-(S),6-(R)-dimethvl-3-(S)-phenylmorpholinone and 4-benzyl-5-(R),6-(S)-dimethyl-3-(S)phenvlmorpholinone [0152] To a suspension of 1.7 g (7.0 mmole) of N-benzyl-(S)-phenylglycine (Exampie 13) in 15 ml of methylene chloride at 0*C was added 6.9 ml (13.9 mmole) of trimethylaluminum (2.0 M in toluene). After one hour at 0*C, 0.625 ml (7.0 mmole) of (+/-)-trans-2,3-epoxy butane (dissolved in 2.0 ml of methylene chloride) vizas added dropvvise and then allovved to stir at 22“C for 16 hours. The reaction was then transferred to another flask containing 30 ml of 1:1 hexane:methylene chloride and 30 ml of 1M potassium sodium tartrate and stirred at 22*C for 2 hours. The layers vvere separated, and the aqueous layer vvas extracted with methylene chloride (3 x 100 ml). The combined organic layers vizere vvashed vvith 25 ml of a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo.

[0153] The crude alcohol was dissolved in 25 ml of toluene, treated vvith 93 mg (0.49 mmole) of p-toluenesulfonic acid and heated at 50^eC for 20 hours. The reaction was then cooled and concentrated in vacuo. The residue was partitioned betvveen 15 ml of diethyl ether and 10 mi of saturated sodium bicarbonate. The Iayers vvere separated, and the organic layer vvas washed vvith vvater (3x10 ml). The combined organic layers vvere vvashed vvith 25 ml of a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography on 145 g of silica gel using 1:4 v/v ethyl acetate/ hexane as the eluant afforded 567 mg of the high Rf lactone (Isomer A) and 388 mg of the low Rf lactone (Isomer B).

¹ H-NMR (400 MHz, CDCIg) δ Isomer A: 1.04 (d, 3H, J = 8.0 Hz), 1.24 (d, 3H, J = 8.0 Hz), 2.92 (br qd, 1H), 3.41 (d, 1H, J= 16.0Hz), 3.62(d, 1H,J=16.0Hz), 4.36 (s, 1H), 4.96(brqd, IH), 7.20-7.42(m, 8H), 7.58-7.64(m, 2H); Isomer Β: 1.04 (d, 3H, J = 10.0 Hz). 1.39 (d, 3H. J = 10.0 Hz), 3.06 (br qd, 1H), 3.53 (d, 1H, J = 16.0 Hz), 3.81 (d, 1H, J = 16.0 Hz), 4.33 (s, 1H), 4.67 (brqd, 1H), 7.18-7.50 (m, 10H).

Mass Spectrum (FAB): m/z Isomer A: 296 (M+H, 100%), 294 (50%); Isomer B: 296 (M+H, 100%), 294 (50%).

EXAMPLE 51

2-(R)-(3,5-Bis(trifluoromethyl)benzyloxv)-f5-(S),6-(R) or5-(R),6-(S)-dimethyn-3-(S)-phenylmofpholinone

Step A: 4-Benzvl-2-(R)-(3,5-bis(trifluoromethyl) benzyloxy)-f5-(S),6-(R) or 5-(R),6-(S)-dimethyli-3-(S)phenylmorpholinone [0154] According to the procedure in Example 15, Step B, 251 mg (0.85 mmole) of Isomer A from Example (4-benzyl-[5-(S),6-(R) or 5-(R)-6-(S)-dimethyl]-3-(S)-phenylmorpholinone) provided 238 mg (53%) of the product an oil.

’H-NMR (400 MHz, CDCI₃) δ 1.03 (d, 3H, J = 6.7 Hz), 1.13 (d, 3H, J = 6.6 Hz), 2.61 (qd, 1H, J = 2.2 & 6.6 Hz), 3 (d, 1H, J = 13.9 Hz), 3.55 (d, 1H, J = 13.9 Hz), 3.63 (d, 1H, J = 7.6 Hz), 4.01 (qd, 1H, J = 2.3 & 6.6 Hz), 4.44 (d, 1H = 13.1 Hz). 4.53 (d, 1H, J = 7.7 Hz), 4.71 (s, 1H), 4.85 (d, 1H, J = 13.2 Hz), 7.20-7.35 (m, 9H). 7.46-7.48 (m, 2H), 7 (s, 1H), 7.81 (s, 1H).

Mass Spectrum (FAB): m/z 523 (M+H, 100%), 296 (95%), 280 (40%), 227 (50%).

Step B: 2-(R)-(3,5-Bis(trifluoromethyl)benzvloxv)-f5-(S).6-(R) or 5-(R),6-(S)-dimethvH-3-(S)-phenvlmorpholinone [0155] According to the procedure in Example 15, Step C, 260 mg of starting material from Step A [derived from Isomer A in Example 50 (4-Benzyl-2-(R)-(3,5-bis(trifluoromethyl)benzyloxy)-[5-(S),6-(R) or 5-(R),6-(S)-dimethyl]-3-(S)phenylmorpholinone)] provided 122 mg (57%) of the product as an oil.

H-NMR (400 MHz, CDCI₃) δ 1.19 (d, 3H. J = 6.5 Hz), 1.27 (d, 3H, J = 6.7 Hz), 2.97 (qd, 1H, J = 2.9 & 6.9 Hz), 3.96 (d, 1H, J = 7.7 Hz), 4.08-4.11 (m, 2H), 4.39 (d, 1H, J = 7.7 Hz), 4.50 (d, 1H, J = 13.3 Hz), 4.88 (d, 1H, J = 13.2 Hz), 7.27-7.33 (m, 3H), 7.40-7.42 (m, 4H), 7.67 (s, 1H).

Mass Spectrum (FAB): m/z 434 (M+H, 45%), 227 (35%), 206 (40%), 190 (100%).

EXAMPLE 52

2-(S)-(3,5-Bis(trifluoromethvl)benzyloxy)-f5-(R),6-(S) or 5-(S),6-(R)-dimethyn-3-(S)-phenylmorpholinone

Step A~ 4-Benzyl-2-(S)-(3,5-bis(trifluoromethyl)-benzvloxy)-f5-(R).6-(S) or 5-(S),6-(R)-dimethylļ-3-(S)phenvlmorpholinone [0156] According to the procedure in Example 15, Step B, 449 mg (1.52 mmole) of Isomer B from Example 50 (4-benzyl-[5-(R),6-(S) or 5-(S)-6-(R)-dimethyl]-3-(S)-phenylmorpholinone) provided 400 mg (51%) of the product as an oil.

¹ H-NMR (400 MHz, CDCI₃) δ 0.90 (d, 3H, J = 6.8 Hz). 1.37 (d, 3H, J = 6.6 Hz), 2.86-2.89 (br qd, 1H), 3.47 (d, 1H, J = 15.0 Hz), 3.82-3.85 (m, 2H), 3.99-4.02 (br qd, 1H), 4.45 (d, 1H, 3 = 13.6 Hz), 4.81 (d, 1H, J = 2.0 Hz), 4.87 (d, 1H, J = 13.5 Hz), 7.17-7.83 (m, 13H).

Step B: 2-(S)-(3,5-Bis(trifluoromethvl)benzvloxv)-f5-(S),6-(R) or 5-(R),6-(S)-dimethvn-3-(S)-phenylmorpholinone [0157] According to the procedure in Example 15, Step C, 400 mg of starting material from Step A [derived from Isomer B in Example 50 (4-Benzyl-2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-[5-(R),6-(S) or5-(S),6-(R)-dimethyl]-3-(S)phenylmorpholinone)] provided 230 mg (69%) of the product as an oil.

¹ H-NMR (400 MHz, CDCI₃) δ 1.08 (d, 3H, J = 6.7 Hz), 1.38 (d, 3H, J = 7.0 Hz), 3.41-3.45 (brqd, 1H), 3.85-3.89 (brqd, 1H), 4.16 (d, 1H, J = 2.9 Hz), 4.49 (d, 1H, J = 13.6 Hz), 4.71 (d, 1H, J = 2.9 Hz), 4.82 (d, 1H, J = 13.6 Hz), 7.25-7.36 (m, 7H), 7.66 (s, 1H).

Mass Spectrum (FAB): m/z 434 (M+H, 35%), 227 (40%), 206 (40%), 190 (100%).

EXAMPLE 53

2-(R)-f3,5-Bis(trifluoromethvl)benzyloxv)-4-(3-(1,2,4-triazolo)methvl)-[5-(S),6-(R) or 5-(R),6-(S)-dimethvn-3-(S)phenvlmorpholinone [0158] A mixture of 62 mg (0.14 mmole) of 2-(R)-(3,5-Bis(trifIuoromethyl)benzyloxy)-[5-(S),6-(R) or 5-(R),6-(S)-dimethyl]-3-(S)-phenylmorpholinone (from Example 51, Step B), 62 mg (0.45 mmole) of anhydrous potassium carbonate and 26 mg (0.19 mmole) of N-formyl-2-chloroacetamidrazone (from Example 17, Step A) in 2.0 ml of N,N-dimethylformamide was heated to 60’C for 2 hours and then 118°C for 1.5 hours. The mixture was then allovved to cool to room temperature and then quenched vvith 5 mis of water and diluted vvith 15 mis of ethyl acetate. The layers vvere separated and the organic layer vvas vvashed vvith ethyt acetate (2 x 10 mis). The combined organic layers were vvashed vvith 10 mis of brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography on 42 g of silica gel using 95:5 v/v methylene chloride/ methanol as the eluant afforded 42 mg (57%) of a clear oil.

¹ H-NMR (400 MHz, CDCI₃) δ 1.13 (d, 3H, J = 6.5 Hz), 1.19 (d, 3H, J = 6.5 Hz), 2.65 (qd, 1H, J = 1.9 & 6.5 Hz), 3.58 (d, 1H, J = 15.5 Hz), 3.65 (d, 1H, J = 7.7 Hz), 3.75 (d, 1H, J = 15.4 Hz), 4.06 (qd, 1H, J = 2.2 & 6.6 Hz), 4.45 (d, 1H, J = 13.2 Hz), 4.54 (d, 1H, J = 7.7 Hz), 4.84 (d, 1H, J = 13.2 Hz), 7.28-7.37 (m, 7H), 7.67 (s, 1H), 7.89 (s, 1H).

Mass Spectrum (FAB): m/z 516 (M+H, 52%), 287 (28%), 271 (100%), 227 (40%), 202 (38%).

EXAMPLE 54

2-(R)-(3,5-Bis(trifluoromethvl)benzyloxv)-4-(3-(5-oxo-1,2,4-triazolo) methyl)-f5-(S),6-(R) or 5-(R),6-(S)-dimethvn-3(S)-phenvlmorpholinone [0159] A solution of 96 mg (0.22 mmole) of 2-(R)-(3,5-Bis(trifluoromethyl)benzyloxy)-[5-(S),6-(R) or 5-(R),6-(S)-dime55 thyl]-3-(S)-phenylmorpholinone (from Example 51, Step B), 92 mg (0.66 mmole) of potassium carbonate and 48 mg (0.29 mmole) of N-methylcarboxy-2-chloroacetamidrazone (from Example 18, Step A) in 4 mL of DMF viras heated at 60*C for 1.5 hr and at 120*C tor 3.5 hr. The mbtture was cooled to room temperature and vvas partitioned betvveen 15 mL of vvater and 25 mL of ethyl acetate. The aqueous layer vvas extracted vvith 3x10 mL of ethyl acetate, the combined organic iayers vvere vvashed vvith 10 mL of brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue vvas partly purified by flash chromatography on 42 g of silica gel using 2L of 98:2 v/v methylene chloride/ methanol as the eluant and the rich cuts vvere purified under the same conditions to give 38 mg (33%) of a clear oil.

¹ H-NMR (400 MHZ, C0CI₃) δ 1.09 (d, 3H, J = 6.5 Hz), 1.20 (d, 3H, J = 6.6 Hz), 2.64 (qd, 1H. J = 2.4 & 6.6 Hz). 3.33 (s, 1H), 3.56 (d, 1H, J = 7.6 Hz), 4.11 (qd, 1H, J = 2.4 & 6.6 Hz), 4.41 (d, 1H, J = 13.2 Hz), 4.57 (d, 1H, J = 7.7 Hz), 4.82 (d. 1H. J = 13.2 Hz), 7.25-7.30 (m, 5H). 7.40 (d. 2H, J = 5.7 Hz), 7.65 (s, 1H), 9.46 (s, 1H), 10.51 (s, 1H).

Mass Spectrum (FAB): m/z 531 (M+H, 98%), 287 (100%), 227 (80%), 189 (65%).

EXAMPLE 55

2-(S)-(3,5-Bisftrifluoromethvl)benzvloxv)-4-(3-(1.2,4-triazolo)methvl)-f5-(R),6-(S) or 5-(S),6-(R)-dimethylļ-3-(SIphenvimorpholinone [0160] According to the procedure in Example 53,75 mg (0.17 mmole) of 2-(S)-(3,5-Bis(trifluoromethyl)-benzyloxy)[5-(R),6-(S) or 5-(S),6-(R)-dimethyl]-3-(S)-phenylmorpholinone (from Example 52, Step B) provided, after flash chromatography on 73 g of silica gel using 98:2 v/v methylene chloride/ methanol as the eluant, 46 mg (52%) of a yellow oil.

’H-NMR (400 MHz. CDCI3) δ 1.04 (d, 3H, J = 6.6 Hz). 1.46 (d, 3H, J = 6.7 Hz), 3.05-3.08 (m, 1H), 3.74-3.81 (m, 2H), 3.91-3.95 (m, 2H), 4.41 (d, 1H, J = 13.2 Hz), 4.69 (d, 1H, J = 3.2 Hz), 4.82 (d, 1H, J = 13.5 Hz), 7.31-7.35 (m, 5H), 7.43-7.45 (m, 2H), 7.68 (s, 1H), 7.91 (s, 1H).

Mass Spectrum (El): m/z 432 (36%), 287 (60%), 270 (65%), 227 (30%), 187 (48%), 83 (100%).

EXAMPLE 56

2-f S)-(3,5-Bis(trifluoromethvl)benzyloxv1-4-(3-(5-oxo-1,2.4-triazolo) methvD-f5-(R).6-fS) or 5-fS).6-(R)-dimethyn-3(S)-phenvlmorpholinone [0161] According to the procedure in Example 54,86 mg (0.2 mmole) of 2-(S)-(3,5-Bis(trifluoromethyl)-benzylūxy)(5-(R),6-(S) or 5-(S),6-(R)-dimethyl]-3-(S)-phenylmorpholinone (from Example 47, Step B) provided, after flash chromatography on 73 g of silica gel using 95:5 v/v methylene chloride/ methanol as the eluant, 32 mg (30%) ot a yellow oil. ¹ H-NMR (400 MHz, CDCI₃) δ 1.03 (d, 3H, J = 6.7 Hz). 1.40 (d, 3H. J = 6.8 Hz), 3.00 (qd. 1H, J = 3.8 & 6.8 Hz),⁵3.44 (d, 1H, J = 16.1 Hz), 3.63 (d, 1H. J = 16.0 Hz), 3.82 (d, 1H, J = 3.3 Hz), 3.95 (qd, 1H. J = 3.7 & 6.7 Hz), 4.43 (d, 1H, J = 13.5 Hz), 4.73 (d, 1H, J = 3.3 Hz), 4.84 (d, 1H, J = 13.6 Hz), 7.28-7.47 (m, 7H), 7.68 (s, 1H), 9.52 (d, 2H).

Mass Spectrum (FAB): m/z 531 (M+H, 100%), 287 (55%), 227 (25%), 147 (50%).

EXAMPLE 57

2-(S)-(3,5-Bis(trifluoromethyl)benzvloxy)-4-(2-(1-(4-benzyl)piperidino) ethyl)-3-(S)-phenylmorpholine [0162] To a solution of 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenylmorpholine (50 mg, 0.12 mmol) and

4-benzyl-1-(2-chtoroethyl)piperidine hydrochioride (50 mg, 0.18 mmol) in acetonitrile (0.5 mL) vvas added diisopropylethyiamine (0.065 mL, 0.36 mmol) at room temperature. After 60 hours, TLC (5% MeOH/2% Et₃N/93% EtOAc) indicated that the reaction vvas only partially complete. The reaction vvas diluted with methylene chloride and vvashed vvith vvater, then brine, dried over sodium sulfate and evaporated. Prep TLC (5% MeOH/2% Et₃N/93% EtOAc) afforded 36 mc (50%) of the title compound as an oil.

¹ H-NMR (400 MHz, CDCI₃) δ 1.1-1.4 (m, 2 H), 1.4-1.65 (2 m, 4 H), 1.65-2.05 (m. 3 H), 2.05-2.3 (m, 1H), 2.35-2.5 (n and d, J = 7 Hz, 3 H), 2.55 (br t, J = 11 Hz. 1 H), 2.65-2.8 (m, 2 H), 3.09 (d, J = 11 Hz, 1 H). 3.50 (d, J = 2.5 Hz, 1 H) 3.66 (dd. J = 2 and 11 Hz, 1 H), 4.15 (dt, J = 2 and 12 Hz, 1 H), 4.38 and 4.75 (AB q, J = 13 Hz, 2 H), 4.61 (d, J = 2.5 Hz, 1 H), 7.06 (d, J = 7 Hz, 2 H), 7.15 (t, J = 7 Hz, 1 H), 7.2-7.35 (m, 5 H). 7.36 (m, 4 H), 7.75 (s, 1H).

ΕΧΑΜΡΙ,Ε 58 (S)-(4-Fluorophenyl)qlycine

Step A: 3-(4-Fluorophenvl)acetvl-4-(S)-benzyl-2-oxazolidinone [0163] An oven-dried, 1 L 3-necked flask, equipped vvith a septum, nitrogen inlet, thermometer, and a magnetic stirring bar, vvas flushed vvith nitrogen and charged vvith a solution of 5.09 g (33.0 mmol) of 4-fluoropheny!acetic acid in 100 mL of anhydrous ether. The solution was cooled to -10’C and treated vvith 5.60 mL (40.0 mmol) of triethylamine followed by 4.30 mL (35.0 mmol) of trimethylacetyl chloride. A white precipitate formed immediateķ The resulting mixture vvas stirred at -10’C for 40 minūtes, then cooled to -7B’C.

[0164] An oven-dried, 250 mL round bottom flask, equipped vvith a septum and a magnetic stirring bar, vvas flushed vvith nitrogen and charged vvith a solution of 5.31 g (30.0 mmol) of 4-(S)-benzyl-2-oxazolidinone in 40 mL of dry THF. The solution vvas stirred in a dry ice/acetone bath for 10 minūtes, then 18.8 mL of 1.6 M n-butyllithium solution in hexanes vvas slowiy added. After 10 minūtes, the lithiated oxazolidinone solution vvas added, via cannula, to the mixture in the 3-necked flask. The cooling bath was removed from the resulting mixture and the temperature vvas allovved to rise to 0’C. The reaction was quenched vvith 100 mL of saturated aqueous ammonium chloride solution, transferred to a 1 L flask, and the ether and THF vvere removed in vacuo. The concentrated mixture vvas partitioned betvveen 300 mL of methylene chloride and 50 mL of vvater and the layers vvere separated. The organic layer vvas washed vvith 200 mL of 2 Ņ aqueous hydrochloric acid solution, 300 mL of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate and concentrated in vacuo. Flash chromatography on 400 g of silica gel using 3:2 v/v hexanes/ ether as the eluant afforded 8.95 g of an oil that slowly solidified on standing. Recrystallization from 10:1 hexanes/ ether afforded 7.89 g (83%) of the title compound as a vvhite solid, mp 64-66’C.

Mass Spectrum (FAB): m/Z 314 (M+H, 100%), 177 (M-ArCH₂CO+H, 85%).

¹H-NMR (400 MHZ, CDCI₃): δ 2.76 (dd, 1 H, J = 13.2, 9.2), 3.26 (dd, J = 13.2, 3.2), 4.16-4.34 (m. 4 H), 4.65-4.70 (m, 1 H), 7.02-7.33 (m, 9 H).

Analysis:
Calcd for C18H16FNO3 | C-69.00 Found i C-68.86	H-5.15 H-5.14	N-4.47 N-4.48	F-6.06 F-6.08

Step B: 3-((S)-Azido-(4-fluorophenyl))acetyl-4-(S)-benzyl-2-oxazolidinone [0165] An oven-dried, 1 L 3-necked flask, equipped vvith a septum, nitrogen inlet, thermometer, and a magnetic stirring bar, vvas flushed vvith nitrogen and charged vvith a solution of 58.0 mL of 1 M potassium bis(trimethylsilyl)amide solution in toluene and 85 mL of THF and was cooled to -78’C. An oven-dried, 250 mL round-bottomed flask, equipped vvith a septum and a magnetic stirring bar, vvas flushed vvith nitrogen and charged with a solution of 7.20 g (23.0 mmol) of 3-(4-fluorophenyl)acetyl-4-(S)-benzyl-2-oxazolidinone (from Example 58, Step A) in 40 mL of THF. The acyl oxazolidinone solution vvas stirred in a dry ice/acetone bath for 10 minūtes, then transferred, via cannula, to the potassium bis(trimethylsilyl)amide solution at such a rāte that the internai temperature of the mixture vvas maintained belovv -70“C. The acyl oxazolidinone flask was rinsed vvith 15 mL of THF and the rinse vvas added, via cannula, to the reaction mixture and the resulting mixture vvas stirred at -78’C for 30 minūtes. An oven-dried, 250 mL round-bottomed flask, equipped vvith a septum and a magnetic stirring bar, vvas flushed vvith nitrogen and charged vvith a solution of 10.89 g (35.0 mmol) of 2,4,6-triisopropylphenylsulfonyl azide in 40 mL of THF. The azide solution vvas stirred in a dry ice/ acetone bath for 10 minūtes, then transferred, via cannula, to the reaction mixture at such a rāte that the internai temperature of the mixture vvas maintained belovv -70’C. After 2 minūtes, the reaction vvas quenched vvith 6.0 mL of glacial acetic acid, the cooling bath vvas removed and the mixture vvas stirred at room temperature for 18 hours. The quenched reaction mixture vvas partitioned betvveen 300 mL of ethyl acetate and 300 mL of 50% saturated aqueous sodium bicarbonate solution. The organic layer vvas separated, dried over magnesium sulfate, and concentrated in vacuo. Flash chromatography on 500 g of silica gel using 2:1 v/v, then 1:1 v/v hexanes/methylene chloride as the eluant afforded 5.45 g (67%) of the title compound as an oil.

IR Spectrum (neat, cm'¹): 2104,1781, 1702.

’H-NMR (400 MHz, CDCI₃): δ 2.86 (dd, 1 H, J = 13.2, 9.6), 3.40 (dd, 1 H, J = 13.2, 3.2), 4.09-4.19 (m, 2 H), 4.62-4.68 (m, 1 H), 6.14 (s, 1 H), 7.07-7.47 (m, 9 H).

Analysis:
Calcd for | C61,01	H-4.27	N-15.81	F-5.36
Found ļ C-60.99	H-4.19	N-15.80	F-5.34

Step C: fS)-Azido-(4-fluorophenvl)acetic acid [0166] A solution of 5.40 g (15.2 mmol) of 3-((S)-azido-(4-fluorophenyl))acetyl-4-(S)-benzyt-2-oxazlidinone (from Example 58, Step B) in 200 mL of 3.Ί vN THF/water was stirred in an ice bath for 10 minūtes. 1.28 g (30.4 mmot) of lithium hydroxide monohydrate vvas added in one portion and the resulting mixture vvas stirred cold for 30 minūtes. The reaction mixture was partitioned between 100 mL of methylene chloride and 100 mL of 25% saturated aqueous sodium bicarbonate solution and the layers were separated. The aqueous layer was vvashed with 2 x 100 ml of methylene chloride and acidified to pH 2 with 2Ņ aqueous hydrochloric acid solution. The resulting mixture vvas extracted vvith 2 x 100 mL of ethyl acetate; the extracts vvere combined, vvashed with 50 mL of saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo to afford 2.30 g (77%) of the title compound as an oil that vvas used in the follovving step vvithout further purification.

IR Spectrum (neat, cm-1): 2111,1724.

¹ H-NMR (400 MHz, CDCI₃): δ 5.06 (s, 1 H), 7.08-7.45 (m, 4 H), 8.75 (br s, 1 H).

Step D: fS)-(4-Fluorophenvl)glycine [0167] A mixture of 2.30 g (11.6 mmol) of (S)-azido-(4-fluorophenyl)acetic acid (from Exampie 58, Step C), 250 mg 10% palladium on carbon catalyst and 160 mL 3:1 v/v water/acetic acid vvas stirred under an atmosphere of hydrogen for 18 hours. The reaction mixture vvas filtered through Celite and the flask and filter cake vvere rinsed vvell with — 1L of 3:1 v/v vvater/acetic acid. The filtrate was concentrated in vacuo to about 50 mL of volume. 300 mL of toluene was added and the mixture concentrated to afford a solid. The solid was suspended in 1:1 v/v methanol/ether, filtered and dried to afford 1.99 g (100%) of the title compound.

¹H-NMR (400 MHz, DjjO + NaOD): δ 3.97 (s, 1 H), 6.77 (app t, 2 H, J = 8.8), 7.01 (app t, 2 H, J = 5.6).

ΕΧΑΜΡΙΕ 59

3-(S)-(4-Fluorophenyl)-4-benzyl-2-morpholinone

Step A: N-Benzyl fS)-(4-fluorophenvl)qlycine [0168] A solution of 1.87 g (11.05 mmol) of (S)-(4-fiuorophenyl)glycine (from Example 58) and 1.12 mL (11;1 mmol) of benzaldehyde in 11.1 mL of 1Ņ aqueous sodium hydroxide solution and 11 mL of methanol at 0^aC vvas treated with 165 mg (4.4 mmol) of sodium borohydride. The cooling bath vvas removed and the resulting mixture vvas stirred at room temperature for 30 minūtes. Second portions of benzaldehyde (1.12 mL (11.1 mmol}) and sodium borohydride 165 mg (4.4 mmol) were added to the reaction mixture and stirring vvas continued for 1.5 hours. The reaction mixture was partitioned betvveen 100 mL of ether and 50 mL of vvater and the layers vvere separated. The aqueous layer was separated and filtered to remove a small amount of insoluble material. The filtrate was acidified to pH 5 vvith 2 N aqueous hydrochioric acid solution and the solid that had precipitated vvas filtered, rinsed vvell vvith vvater, then ether, and dried to afford 1.95 g of the title compound.

¹ H-NMR (400 MHz, DgO + NaOD): δ 3.33 (AB q, 2 H, J = 8.4), 3.85 (s, 1 H), 6.79-7.16 (m, 4 H).

Step B: 3-fSl-(4-Fluorophenyl)-4-benzvl-2-morpholinone [0169] A mixture of 1.95 g (7.5 mmol) of N-benzyl (S)-(4-fluorophenyl)glycine, 3.90 mL (22.5 mmol) of N,N-diisopropylethylamine, 6.50 mL (75.0 mmol) of 1,2-dibromoethane and 40 mL of N,N-dimethylformamide vvas stirred at 100’C for 20 hours (dissolution of all solids occurred on warming). The reaction mixture was cooled and concentrated in vacuo. The residue was partitioned betvveen 250 mL of ether and 100 ml of 0.5Ņ potassium hydrogen sulfate solution and the layers vvere separated. The organic layer was vvashed 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 125 g of siiica gel using 3:1 v/v hexanes/ether as the eluant afforded 1.58 g (74%) of the title compound as an oil. ¹H-NMR (400 MHz, CDCI₃): δ 2.65 (dt, 1 H, J = 3.2,12.8), 3.00 (dt, 1 H, J = 12.8,2.8), 3.16 (d, 1 H, J = 13.6), 3.76 (d, 1 H, J = 13.6), 4.24 (s, 1 H), 4.37 (dt, 1 H, J = 13.2, 3.2), 4.54 (dt, 1 H, J = 2.8,13.2), 7.07-7.56 (m, 9 H).

ΕΧΑΜΡΙ,Ε 60

2-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(S)-(4-fluorophenyl)-4-benzvlmorpholine [0170] The title compound was prepared in 72% yield from 3-(S)-(4-fluorophenyl)-4-benzyl-2-morpholinone (from Example 59) using procedures analogous to those in Example 15, Steps A and B.

’H-NMR (200 MHz. CDCI₃): δ 2.37 (dt, 1 H, J = 3.6, 11.8), 2,83-2.90 (m, 2 H), 3.55-3.63 (m, 2 H), 3.85 (d, 1 H, J = 13.4), 4.14 (dt, 1 H, J = 2.0,11.8), 4.44 (d, 1 H, J = 13.6), 4.66 (d, 1 H, J = 2.8), 4.79 (d, 1 H, J = 13.4), 7.00-7.70 (12 H).

ΕΧΑΜΡΙ,Ε 61

2-(S)-(3,5-Bis(trifluoromethvl)benzvloxy)-3-(S)-(4-fluorophenyl) morpholine [0171] The title compound vvas prepared in 70% yiefd from 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-(4-fluorophenyl)-4-benzylmorpholine (from Example 60) using a procedure analogous to that in Example 15, Step C.

Mass Spectrum (FAB): m/Z 424 (M+H, 40%), ’ H-NMR (400 MHz, CDCI₃): δ 1 ,B0 (br s, 1 H), 3.11 (app dd, 1 H, J = 2.2,12.4), 3.25 (dt, 1 H, J = 3.6,12.4), 3.65 (app dd, 1 H, J = 3.6,11.4), 4.05 (dt, 1 H, J = 2.2, 11.8), 4.11 (d. 1 H, J = 2.2), 4.53 (d, 1 H, J = 13.6), 4.71 (d, 1 H, J = 2.2), 4.83 (d, 1 H, J = 13.6), 7.04 (t, 2 H. J = 7.2), 7.33-7.37 (m, 2 H), 7.42 (s, 2 H), 7.72 (s, 1 H).

EXAMPLE 62

2-(S)-(3,5-Bis(trifluoromethvl)benzvloxv)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methylmorpholine [0172] Tha title compound vvas prepared in 69% yield from 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-(4-fluorophenyl)morpholine (from Example 61) using a procedure analogous to that in Example 18.

Mass Spectrum (FAB): m/Z 521 (M+H, 100%).

’H-NMR (400 MHz, CDCI₃): δ 2.55 (dt, 1 H, J = 3.6, 12.0), 2.91 (d, 1 H, J = 11.6), 2.93 (d, 1 H, J = 14.4), 3.57 (d, 1 H, J = 2.8), 3.59 (d, 1 H, J = 14.4), 3.67-3.70 (m, 1 H), 4.18 (dt, 1 H, J = 2.4, 11.6), 4.48 (d, 1 H, J = 13.6), 4.65 (d, 1 H, J = 2.8), 4.84 (d, 1 H, J = 13.6), 7.07 (t, 2 H, J = 8.4), 7.40 (s, 2 H), 7.45-7.48 (m, 2 H), 7.68 (s, 1 H), 10.04 (br s, 1 H), 10.69 (brs, 1 H).

Analysis:
Calcd for C22H19F7N4O3 ļ C-50.78	H-3.68	N-10.77	F-25.55
Found ļ C-50.89	H-3.76	N-10.62	F-25.56

ΕΧΑΜΡΙΕ 63

2-(S)-(3,5-Bis(trifluoromethvl)benzvloxv)-4-((3-pvridvl)methvtcarbonyl)-3-(R)-phenvlmorpholine [0173] A solution of 55 mg (0.315 mfnol) of 4-pyridylacetic acid in 1 mL of CH₂CI₂, containing 0.079 mL (0.715 mmol) of N-methylmorpholine, 53 mg (0.37 mmol) of HOBt and 73 mg (0.37 mmol) of EDC was stirred for 10 min. A soiution of 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenylmorpholine (from Example 33) in 1 mLof CHgC^ vvas added. After stirring the mixture for 2 h, it vvas partitioned betvveen vvater and CH₂CI₂. The organic layer was vvashed with vvater, brine and dried by filtering through Na₂SO₄. The filtrate vvas concentrated and the residue vvas purified by flash chromatography using 70% EtOAc/hexane to furnish 152 mg (100 % yield) of the product.

¹H-NMR (400 MHz, CDCI₃): δ 3.0-3.85 (m, 5H), 3.95 & 4.4 (br s, 1H), 4.66 (d, J = 13 Hz, 1H), 4.82 (d, J = 13 Hz, 1H), 5.0 & 5.9 (br s, 1H), 5.23 (s, 1H), 7.1-7.65 (m, 7H), 7.8 (m, 3 H), 8.43 (br s, 2H).

-EXAMPLE 64 ž-(S)-(3,5-Bis(trifiuoromethyl)benzyloxv)-4-(methoxvcarbonylpentvl)-3-(R)-phenvlmorpholine (0174] To a solution of 0.259 g (0.64 mmol) of 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenylmorpholine (from example 33) in 2 mL of DMF were added 0.16 g (0.77 mmol) of methyl 6-bromohexanoate, 0.155 g (1.12 mmol) of K₂CO₃ and 2 crystals of nBu₄NI. The resulting solution vvas heated in a 60’C bath for 36 h, at vvhich time a tic indicated incomplete reaction. The bath temperature was raised to 100’C. After 3 h the reaction mixture vvas cooled and diluted vzith EtOAc. The EtOAc solution was washed with water (2x), brine and dried over NagSO^ The filtrate was concentrated and the residue was chromatographed using 30% EtOAc/hexane to isolate 220 mg (65%) ot the product ’H-NMR (400 MHz, CDCI₃): δ 1.0-1.4 (m, 4 H), 1.47 (m, J = 8 Hz, 2H), 1.95 (m, 1H), 2.2 (t, J = θ Hz, 2H), 2.35 (m, 2H), 2.9 (d. J = 13 Hz, 1H), 3.07 (d, J = 7 Hz, 1H), 3.62 (s. 3H). 3.81 (td, J = 8 Hz and 2 Hz, 1 H), 4.04 (dd, J = 10 Hz and 2 Hz, 1H), 4.36 (d, J = 7 Hz, 1H), 4.4 (d, J = 13 Hz, 1H), 4.79 (d, J = 13 Hz, 1H), 7.2-7.4 (m, 7H), 7.66 (s, 1H).

EXAMPLE 65

2-(S)-(3.5-Bisftrifluoromethvl)benzvloxy)-4-(carboxvpentyl)-3-(R)-phenylroorpholine [0175] A solution of 0.15 g (0.28 mmol) of 2-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)-4-(methoxycarbonylpentyl)-3(R)-phenylmorpholine (from Example 64) in 3 mL of MeOH vvas saponified by treating vvith 0.5 mL of 5 N NaOH for 40 min at 65*C. The solution vvas cooled, concentrated and the residue was diluted vzith vvater. The aqueous solution vzas adjusted to pH 6 by adding 2 N HCI and it vzas extracted with EtOAc. The organic layer was vzashed vvith brine, dried and concentrated. The residue upon chromatography on a flash column vzith 50% EtOAc/hexane fumished 0.13g (89%) of the product ’H-NMR (400 MHz. CDClj): δ 1.0-1.5 (m, 4H). 1.5 (m, 2H), 2.2 (m, 2H), 2.35 (m, 2H). 2.9 (d, J = 13 Hz, 1H), 3.08 (d, J = 7 Hz, 1H), 3.B2 (t, J = 8 Hz, 1H), 4.09 (d, J = 7 Hz, 1H), 4.38 (s, 1H), 4.4 (d, J = 13 Hz, 1H), 4.79 (d, J = 13 Hz, 1H), 7.2-7.4 (m, 7H), 7.66 (s, 1H).

EXAMPLE 66

2-(S)-(3,5-Bis(trifluoromethvl)benzyloxy)-4-(methvlaminocarbonvlpentvl)-6-oxo-hexyO-3-(R)-phenylmorpholine [0176] A solution of 116 mg (0.22 mmol) of 2-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)-4-(carboxypentyl)-3-(R)-phenylmorpholine (from Example 65) in 1 mL of CHjCIg vzas treated vzith 40 mg (0.29 mmol) of HOBt, 57 mg (0.29 mmol) of EDC and 0.037 mL of N-methylmorpholine. After 10 min 0.027 mL (0.3 mmol) of aqueous methylamine (40%) vzas added and the resulting mixture vzas stirred for 4 h. The reaction mixture vzas diluted vzith vzater and extracted vzith CH₂CI₂. The combined layer was vzashed vvith vzater, brine and dried over Na₂SO₄, and the filtrate vvas concentrated. Purification of the residue on a flash column vzith EtOAc fumished 0.10 g of the product.

’H-NMR (400 MHz. CDCI₃): δ 1.0-1.4 (m, 4 H), 1.47 (m, 2H), 1.95 (m, 1H), 2.04 (t, J = 8 Hz. 2H), 2.35 (m, 2H), 2. 74 (d, J = 5 Hz, 3 H), 2.89(d, J =12 Hz, 1H) 3.08 (d, J = 7 Hz, 1H), 3.81 (t, J = 7 Hz, 1H), 4.02 (d, J = 11 Hz, 1H), 4.36 (d, J > 7 Hz, 1H), 4.39 (d, J = 13 Hz, 1H), 4.79 (d, J =13 Hz, 1H), 5.03 (br s, 1H), 7.2-7.4 (m. 7H). 7.65 (s, 1H).

EXAMPLE 67

Tvpical Pharmaceutical Compositions Containing a Compound of the Invention

A: Drv Filled Capsules Containing 50 mg of Active Ingredient Per Capsuie [0177]

Ingredient	Amount per capsuie (mg)
Active ingredient	50
Lactose	149
Magnesium stearate	1
Capsuie (size No. 1)	200

[0178] The active ingredient can be reduced to a No. 60 povzder and the lactose and magnesium stearate can then be passed through a No. 60 blotting cloth onto the povzder. The combined ingredients can then be mixed for about 10 minūtes and filled into a No. 1 dry gelatin capsuie.

B: Tablet [0179] A typical tablet vvould contain the active ingredient (25 mg), pregelatinized starch USP (82 mg), microcrystalline cellulose (82 mg) and magnesium stearate (1 mg).

C: Suppositorv [0180] Typical suppository formulations for reetal administration contain the active ingredient (0.08-1.0 mg), disodium calcium edetate (0.25-0.5 mg), and polyethylene glycol (775-1500 mg). Other suppository formulations can be made by substituting, for example, butylated hydroxytoluene (0.04-0.08 mg) for the disodium calcium edetate and a hydrogenated vegetable oil (675-1400 mg) such as Suppocire L, Wecobee FS, Wecobee M, Witepsols, and the like, for the polyethylene glycol.

D: Injection [0181] A typical injectible formulation contains the acting ingredient sodium phosphate dibasic anhydrous (11.4 mg), benzyl alcohol (0.01 ml) and vvater for injection (1.0 ml).

[0182] While the foregoing specification teaches the principles of the present invention, vvith examples provided for the purpose of illustration, it vvill be understood that the practice of the invention encompasses ali of the casual variations, adaptations, modifications, deletions, or additions of procedures and protocols described herein, as come vvithin the scope of the follovving ciaims and its eguivalents.

Claims (84)

1. Izgudrojuma formula

   1. Savienojums ar struktūrformulu un tā farmaceitiski pieņemamās sālis, kur

   R¹ ir ņemts no rindas:

   (1) ūdeņraža atoms;
2. (2) Ci^alkilgrupa, neobligāti aizvietota ar vienu vai vairākiem aizvietotājiem no rindas:

   (a) hidroksilgrupa, (b) oksogrupa, (c) Ci-ealkoksigrupa, (d) fenil-Ci-3alkoksigrupa, (e) fenilgrupa, (f) ciāngrupa, (g) halogēna atoms, (h) -NR$R¹⁰, kur R⁹ un R¹⁰, neatkarīgi viens no otra, ir ņemti no rindas:

   (i) ūdeņraža atoms, (ii) Ci^alkilgrupa, (iii) hidroksi-Ci^alkilgrupa, (iv) fenilgrupa, (i) -NR⁹COR¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (j) -NR⁹CO2R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (k) -CONR⁹R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (l) -COR⁹, kur R⁹ ir ar augstāk definēto nozīmi, (m) -CO2R⁹, kur R⁹ ir ar augstāk definēto nozīmi, (n) heterocikliska grupa, kurā heterocikls ņemts no rindas:

   (A) benzimidazols, (B) benzofurāns, (C) benzotiofēns, (D) benzoksazols, (E) furāns, (F) imidazols, (G) indols, (H) izoksazols, (I) izotiazols, (J) oksadiazols, (K) oksazols, (L) pirazīns, (M) pirazois, (N) piridīns.

   (O) pirimidīns, (P) pirols, (Q) hinolīns, (R) tetrazols, (S) tiadiazols, (T) tiazols, (U) tiofēns, (V) triazols, (W) azetidīns, (X) 1,4-dioksāns, (Y) heksahidroazepīns, (Z) oksāns, (AA) piperazīns, (AB) piperidīns, (AC) pirolidīns, (AD) tetrahidrofurāns, (AE) tetrahidrotiofēns, pie tam heterocikls ir neobligāti aizvietots ar vienu vai vairākiem aizvietotājiem no rindas:

   (i) Ci^alkilgrupa, neobligāti aizvietota ar halogēna atomu, trifluormetilgrupu, metoksigrupu vai fenilgrupu, (ii) Ci-ealkoksigrupa, (iii) oksogrupa, (iv) hidroksilgrupa, (v) tioksogrupa, (vi) -SR⁹, kur R⁹ ir ar jau minēto nozīmi, (vii) halogēna atoms, (viii) ciāngrupa, (ix) fenilgrupa, (x) trifluormetilgrupa, (xi) -(CH₂)_m-NR⁹R¹⁰, kur m ir 0,1 vai 2, R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (xii) -NR⁹COR¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (xiii) -CONR⁹R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (xiv) -CO2R⁹, kur R⁹ ir ar augstāk definēto nozīmi, (xv) -(CH₂)_m-OR⁹, kur m un R⁹ ir ar jau minētām nozīmēm;
3. (3) C₂-6alkenilgrupa, neobligāti aizvietota ar vienu vai vairākiem aizvietotājiem no rindas;

   (a) hidroksilgrupa, (b) oksogrupa, (c) Cļ^alkoksigrupa, (d) fenil-Ci.₃alkoksigrupa, (e) fenilgrupa, (f) ciāngrupa, (g) halogēna atoms, (h) -CONR⁹R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (i) -COR⁹, kur R⁹ ir ar augstāk definēto nozīmi, (j) -CO2R⁹, kur R⁹ ir ar augstāk definēto nozīmi, (k) heterocikliska grupa ar augstāk definēto nozīmi;
4. (4) C₂.6alkinilgrupa;
5. (5) fenilgrupa, neobligāti aizvietota ar vienu vai vairākiem aizvietotājiem no rindas:

   (a) hidroksilgrupa, (b) C-i^alkoksigrupa, (c) C^alkilgrupa, (d) C2-5alkenilgrupa, (e) halogēna atoms, (f) ciāngrupa, (g) nitrogrupa, (h) trifluormetilgrupa, (i) -(CH₂)_m-NR⁹R¹°, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (j) -NR⁹COR¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (k) -NR⁹CO2R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (l) -CONR⁹R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (m) -CO₂NR⁹R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (n) -COR⁹, kur R⁹ ir ar augstāk definēto nozīmi, (0) -CO₂R⁹, kur R⁹ ir ar augstāk definēto nozīmi,

   R² un R³, neatkarīgi viens no otra, ir ņemti no rindas:

   (1) ūdeņraža atoms, (2) Ci.₆alkilgnjpa, neobligāti aizvietota ar vienu vai vairākiem aizvietotājiem no rindas:

   (a) hidroksilgrupa, (b) oksogrupa, (c) Ci^alkoksigrupa, (d) fenil-Ci-3alkoksigrupa, (e) fenilgrupa, (f) ciāngrupa, (g) halogēna atoms, (h) -NR⁹R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (i) -NR⁹COR¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (j) -NR⁹CO₂R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (k) -CONR⁹R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (l) -COR⁹, kur R⁹ ir ar augstāk definēto nozīmi, (m) -CO₂R⁹, kur R⁹ ir ar augstāk definēto nozīmi;

   (3) C₂-6alkenilgrupa, neobligāti aizvietota ar vienu vai vairākiem aizvietotājiem no rindas:

   (a) hidroksilgrupa, (b) oksogrupa, (c) Ci-ealkoksigrupa, (d) fenil-Ci.₃alkoksigrupa, (e) fenilgrupa, (f) ciāngrupa, (g) halogēna atoms, (h) -CONR⁹R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (i) -COR⁹, kur R⁹ ir ar augstāk definēto nozīmi, (j) -CO₂R⁹, kur R⁹ ir ar augstāk definēto nozīmi;

   (4) C₂-6alkinilgrupa;

   (5) fenilgrupa, neobligāti aizvietota ar vienu vai vairākiem aizvietotājiem no rindas:

   (a) hidroksilgrupa, (b) Ci-ealkoksigrupa, (c) C-i-ealkilgrupa, (d) C₂.₅alkenilgrupa, (e) halogēna atoms, (f) ciāngrupa, (g) nitrogrupa, (h) trifluormetilarupa, (i) -(CH₂)_m-NR⁹R , kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (j) -NR⁹COR¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (k) -NR⁹CO₂R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (l) -CONR⁹R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (m) -CO₂NR⁹R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (n) -COR⁹, kur R⁹ ir ar augstāk definēto nozīmi, (o) -CO₂R⁹, kur R⁹ ir ar augstāk definēto nozīmi;

   pie tam aizvietotāji R¹ un R² var būt savstarpēji savienoti, veidojot heterociklisku grupu, kur heterocikls ņemts no rindas:

   (a) pirolidīns, (b) piperidīns, (c) pirols, (d) piridīns, (e) imidazols, (f) oksazols, (g) tiazols, pie kam heterocikls ir neobligāti aizvietots ar vienu vai vairākiem aizvietotājiem no rindas:

   (i) Cļ-ealkilgrupa, (ii) oksogrupa, (iii) C-i^alkoksigrupa, (iv) -NR⁹R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (v) halogēna atoms, (vi) trifiuormetilgrupa;

   pie tam aizvietotāji R² un R³ var būt savstarpēji savienoti, veidojot karbociklisku grupu, kas ņemta no rindas:

   (a) ciklopentiigrupa, (b) cikloheksilgrupa, (c) fenilgrupa, pie kam karbocikliskā grupa ir neobligāti aizvietota ar vienu vai vairākiem aizvietotājiem no rindas:

   (i) C-i-galkilgrupa, (ii) C^alkoksigrupa, (iii) -NR⁹R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (iv) halogēna atoms, (v) trifiuormetilgrupa;

   pie tam aizvietotāji R² un R³ var būt savstarpēji savienoti, veidojot heterociklisku grupu, kur heterocikls ņemts no rindas:

   (a) pirolidīns, (b) piperidīns, (c) pirols, (d) piridīns, (e) imidazois, (f) furāns, (g) oksazols, (h) tiofens, (i) tiazols, pie kam heterocikls ir neobligāti aizvietots ar vienu vai vairākiem aizvietotājiem no rindas:

   (i) C-i^alkilgrupa, (ii) oksogrupa, (iii) Ci^alkoksigrupa, (iv) -NR⁹R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (v) halogēna atoms, (vi) trifiuormetilgrupa;

   X ir-O-;

   (2) -Y-Ci^alkilgrupa, kur alkilgrupa ir neobligāti aizvietota ar vienu vai vairākiem aizvietotājiem no rindas:

   (a) hidroksilgrupa, (b) oksogrupa, (c) C-i-ealkoksigrupa, (d) fenil-Ci.3alkoksigrupa, (e) fenilgrupa, (f) ciāngrupa, (g) halogēna atoms, (h) -NR⁹R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (i) -NR⁹COR¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (j) -NR⁹CO₂R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (k) -CONR⁹R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (l) -COR⁹, kur R⁹ ir ar augstāk definēto nozīmi, (m) -CO2R⁹, kur R⁹ ir ar augstāk definēto nozīmi;

   (3) -Y-C2-6alkenilgrupa, kur alkenilgrupa neobligāti aizvietota ar vienu vai vairākiem aizvietotājiem no rindas:

   (a) hidroksilgrupa, (b) oksogrupa, (c) Ci_₆alkoksigrupa, (d) fenil-Ci.₃aikoksigrupa, (e) fenilgrupa, (f) ciāngrupa, (g) halogēna atoms, (h) -CONR⁹R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (i) -COR⁹, kur R⁹ ir ar augstāk definēto nozīmi, (j) -CO₂R⁹, kur R⁹ ir ar augstāk definēto nozīmi;

   (4) -O(CO)-fenilgrupa, kur fenilgrupa neobligāti aizvietota ar vienu vai vairākiem aizvietotājiem R⁶ , R⁷ un R^S:

   R⁵ ir fenilgrupa, neobligāti aizvietota ar vienu vai vairākiem aizvietotājiem R¹¹, R¹² un R¹ ,

   R⁶, R⁷ un R⁸, neatkarīgi viens no otra, ņemti no rindas:

   (1) ūdeņraža atoms;

   (2) C-i-ealkilgrupa, neobligāti aizvietota ar vienu vai vairākiem aizvietotājiem no rindas:

   (a) hidroksilgrupa, (b) oksogrupa, (c) Ci^alkoksigrupa, (d) fenil-Cļ-salkoksigrupa, (e) fenilgrupa, (f) ciāngrupa, (g) halogēna atoms, (h) -NR⁹R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (i) -NR⁹COR¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (j) -NR⁹CO2R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (k) -CONR⁹R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (l) -COR⁹, kur R⁹ ir ar augstāk definēto nozīmi, (m) -CO₂R⁹, kur R⁹ ir ar augstāk definēto nozīmi;

   (3) C2-6alkenilgrupa, neobligāti aizvietota ar vienu vai vairākiem aizvietotājiem no rindas:

   (a) hidroksilgrupa, (b) oksogrupa, (c) C-i-ealkoksigrupa, (d) fenil-Ci.3alkoksigrupa, (e) fenilgrupā, (f) ciāngrupa, (g) halogēna atoms, (h) -CONR⁹R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (i) -COR⁹, kur R⁹ ir ar augstāk definēto nozīmi, (j) -CO₂R⁹, kur R⁹ ir ar augstāk definēto nozīmi;

   (4) C₂.₆alkinilgrupa;

   (5) fenilgrupā, neobligāti aizvietota ar vienu vai vairākiem aizvietotājiem no rindas:

   (a) hidroksilgrupa, (b) C-i^alkoksigrupa, (c) Ci^alkilgrupa, (d) C₂-5alkenilgrupa, (e) halogēna atoms, (f) ciāngrupa, (g) nitrogrupa, (h) trifluormetiigrupa, (i) -(CH₂)_m-NR⁹R , kur m, R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (j) -NR⁹COR¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (k) -NR⁹CO₂R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (l) -CONR⁹R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (m) -CO₂NR⁹R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (n) -COR⁹, kur R⁹ ir araugstākdefinēto nozīmi, (o) -CO₂R⁹, kur R⁹ ir ar augstāk definēto nozīmi;
6. (6) halogēna atoms, (7) ciāngrupa, (8) trifluormetiigrupa, (9) nitrogrupa, (10) -SR , kurā R¹⁴ ir ūdeņraža atoms vai Ci^alkilgrupa, (11) -SOR¹⁴, kurā R¹⁴ nozīme ir jau minētā, (12) -SO₂R¹⁴, kurā R¹⁴ nozīme ir jau minētā, (13) NR⁹COR¹⁰, kurā R⁹ un R¹⁰ nozīmes ir jau minētās, (14) CONR⁹COR¹⁰, kurā R⁹ un R¹⁰ nozīmes ir jau minētās, (15) NR⁹R¹⁰, kurā R⁹ un R¹⁰ nozīmes ir jau minētās, (16) NR⁹CO₂R¹⁰, kurā R⁹ un R¹⁰ nozīmes ir jau minētās, (17) hidroksilgrupa, (18) C^alkoksigrupa, (19) COR⁹, kurā R⁹ nozīme ir jau minētā, (20) CO₂R⁹ kurā R⁹ nozīme ir jau minētā;

   R¹¹, R¹² un R¹³, neatkarīgi viens no otra, ir ņemti no rindas R⁶, R⁷ un R⁸;

   Y ir ņemts no rindas:

   (1) vienkāršā saite, (2) -0-.

   (3) -S-, (4) -CO-, (5) -CH₂-, (6) -CHR¹⁵-, (7)-CR¹⁵R¹⁶-, kurā R¹⁵ un R¹⁶, neatkarīgi viens no otra, ir ņemti no rindas:

   (a) Ci.₆alkilgrupa, neobligāti aizvietota ar vienu vai vairākiem aizvietotājiem no rindas:

   (i) hidroksilgrupa, (ii) oksogrupa, (iii) Ci-6alkoksigrupa, (iv) fenil-Ci-3alkoksigrupa, (v) feniigrupa, (vi) ciāngrupa, (vii) halogēna atoms, (viii) -NR⁹R¹⁰, kur R⁹ un R¹⁰ nozīmes ir jau minētās, (ix) -NR⁹COR¹⁰, kur R⁹ un R¹⁰ nozīmes ir jau minētās, (x) -NR⁹CO2R¹⁰, kur R⁹ un R¹⁰ nozīmes ir jau minētās, (xi) -CONR⁹R¹⁰, kur R⁹ un R¹⁰ nozīmes ir jau minētās, (xii) -COR⁹, kur R⁹ nozīme ir jau minētā, (xiii) -CO2R⁹, kur R⁹ ir ar augstāk definēto nozīmi;

   (b) fenilgrupa, neobligāti aizvietota ar vienu vai vairākiem aizvietotājiem no rindas:

   (i) hidroksilgrupa, (ii) Ci-₆alkoksigrupa, (iii) C^alkiigrupa, (iv) C₂-5alkenilgrupa, (v) halogēna atoms, (vi) ciāngrupa, (vii) nitrogrupa, (viii) trifluormetilgrupa, (ix) -(CH₂)_m-NR⁹R °, kur R⁹ un R¹⁰ nozīmes ir jau minētās;

   (x) -NR⁹COR¹⁰, kur R⁹ un. R¹⁰ nozīmes ir jau minētās, (xi) -NR⁹CO₂R¹⁰, kur R⁹ un R¹⁰ nozīmes ir jau minētās, (xii) -CONR⁹R¹⁰, kur R⁹ un R¹⁰ nozīmes ir jau minētās, (xiii) -CO₂NR⁹R¹⁰, kur R⁹ un R¹⁰ nozīmes ir jau minētās, (xiv) -COR⁹, kur R⁹ nozīme ir jau minētā, (xv) -CO2R⁹, kur R⁹ nozīme ir jau minētā;

   Z ir ņemts no rindas:

   (1) ūdeņraža atoms, (2) C-Malkilgrupa, (3) hidroksilgrupa, ar noteikumu, ka Z nav hidroksilgrupa, kad Y ir -O-, un Z un R¹⁵ var būt savienoti savā starpā, veidojot divkāršo saiti, kad Y ir -CHR¹⁵-.

   2. Savienojums pēc 1. punkta, kurā:

   R¹ ir ņemts no rindas:

   (1) Ci^alkilgrupa, aizvietota ar vienu vai vairākiem aizvietotājiem no rindas:

   (a) heterocikliska grupa, kurā heterocikls ņemts no rindas:

   (A) benzimidazols, (B) imidazols, (C) izoksazols, (D) izotiazols, (E) oksadiazols, (F) pirazīns, (G) pirazols, (H) piridīns.

   (I) pirols, (J) tetrazols, (K) tiadiazols, (L) tiazols, (M) piperidīns, pie tam heterocikls ir neobligāti aizvietots ar vienu vai vairākiem aizvietotājiem no rindas:

   (i) Ci^alkilgrupa, neobligāti aizvietota ar halogēna atomu, trifluormetilgrupu, metoksigrupu vai fenilgrupu, (ii) C^alkoksigrupa, (iii) oksogrupa, (iv) tioksogrupa, (v) ciāngrupa, (vi) -SCH₃, (vii) fenilgrupa, (viii) hidroksilgrupa, (ix) trifluormetilgrupa, (x) -(CH₂)_m-NRV⁰, kur m ir 0, 1 vai 2, R⁹ un R¹⁰, neatkarīgi viens no otra, ņemti no rindas:

   (I) ūdeņraža atoms, (II) Ci^alkilgrupa, (III) hidroksi-Ci^alkilgrupa, (IV) fenilgrupa;

   (xi) -NR⁹COR , kurā R⁹ un R¹⁰ nozīmes ir jau minētās, (xii) -CONR⁹R¹⁰, kurā R⁹ un R¹⁰ nozīmes ir jau minētās:

   R² un R³, neatkarīgi viens no otra, ir ņemti no rindas:

   (1) ūdeņraža atoms, (2) C^alkilgrupa, (3) C2-ealkenilgrupa,

   R⁵ ir fenilgrupa, neobligāti aizvietota ar halogēna atomu; R⁶ , R⁷ un R , neatkarīgi viens no otra, ņemti no rindas:

   (1) ūdeņraža atoms;

   (2) Ci^alkilgrupa, (3) halogēna atoms, (4) trifluormetilgrupa;

   X ir -O-;

   Z ir ūdeņraža atoms vai Ci^alkilgrupa.

   3. Savienojums pēc 1. punkta, kurā R¹ ir ņemts no rindas:

   4. Savienojums pēc 1. punkta ar formulu (III)

   III vai tā farmaceitiski pieņemamās sālis, kur R¹, R², R³, R⁶, R⁷, R⁸, R¹¹, R¹², R¹³ un Z ir ar 1. punktā minētajām nozīmēm.

   5. Savienojums pēc 1. punkta, kas ņemts no rindas:

   1) 2-(3,5-bis(trifluormetil)benziloksi]-3-fenilmorfolīns;

   2) 2(R,S)-[3,5-bis(trifluormetil)benziloksi]-3(R)-fenil-6(R)-metilmorfolīns;

   3) 2(R_IS)-[3,5-bis(trifluormetil)benziloksij-3(S)-fenil-6(R)-metilmorfolīns;

   4) (+/-)-2-(3,5-bis(trifluormetil)benziloksi]-3-fenil-4-metilkarboksamidomorfolīns;

   5) (+/-)-2-(3,5-bis(trifluormetil)benziloksi]-3-fenil-4-metoksikarbonilmetilmorfolīns;

   6) 2-{2-[3,5-bis(trifluormetil)fenil]etenil}-3-fenil-5-oksomorfolīns:
7. 7) 3-fenil-2-{2-[3,5-bis(trifluormetil)fenil]etil}morfolīns;
8. 8) 2(R)-(3,5-bis(trifluormetil)benziloksi]-3(R)-fenil-6(S)-metiImorfolīns;
9. 9) 2(R)-[3,5-bis(trifluormetil)benziloksi]-3(S)-fenil-6(S)-metilmorfolīns;
10. 10) 2(S)-[3,5-bis(trifluormetil)benziloksi]-3(R)-fenil-6(S)-metilmorfolīns;
11. 11) 2(S)-[3,5-bis(trifluormetil)benziloksij-3(S)-fenil-6(S)-metilmorfotīns;
12. 12) 2(R)-[3,5-bis(trifluormetil)benziloksi]-3(R)-feniI-5(R)-metilmorfolīns;
13. 13) 2(R)-[3,5-bis(trifluormetil)benziloksi]-3(S)-fenil-5(R)-metilmorfolīns;
14. 14) 2(S)-[3,5-bis(trifluormetil)benziloksi]-3(R)-fenil-5(R)-rnetilmorfolīns;
15. 15) 2(S)-[3,5-bis(trifluormetil)benziloksij-3(S)-fenil-5(R)-metilmorfolīns;
16. 16) 2(S)-[3,5-bis(trifluormetil)benziloksij-3(S)-fenilmorfolīns;
17. 17) 4-(1,2,4-triazol-3-il )metil-2(S )-[3,5-bis(trifluormetil)benziloksi]-3(S)fenilmorfolīns;
18. 18) 4-(5-okso-1 H.4H-1,2,4-triazol-3-il)metil-2(S)-[3,5-bis(trifluormetil)benziloksi]-3(S)-fenilmorfolīns;
19. 19) 2(R)-[3,5-bis(trifluormetil)benziloksi]-3(R)-fenil-6(R)-metilmorfolīns;
20. 20) 2(S)-(3,5-bis(trifluorrnetil)benziloksi]-3(R)-fenil-6(R)-metilmorfolīns;
21. 21) 2(R)-[3,5-bis(trifIuormetil)benziloksi]-3(S)-fenil-6(R)-metilmorfolīns;
22. 22) 2(S)-[3,5-bis(trifluormetil)benziloksi]-3(S)-fenil-6(R)-metilmorfolTns;
23. 23) 2(R)-[3,5-bis(trifluormetil)benziloksi]-3(S)-fenil-5(S)-metiimorfolīns;
24. 24) 2(S)-[3,5-bis(trifluormetil)benziloksi]-3(S)-fenil-5(S)-metilmorfoR'ns;
25. 25) 2(R)-[3,5-bis(trifluormetil)benziloksi]-3(R)-fenil-5(S)-metilmorfolīns;
26. 26) 2(R)-[3,5-bis(trifluormetil)benziloksi]-3(S)-fenil-5(R)-fenilmorfon'ns;
27. 27) 2(S)-[3,5-bis(trifluormetil)benziloksi]-3(S)-fenil-5(R)-fenilmorfolīns;
28. 28) 2(S)-[3,5-bis(trifluormetil)benziloksi]-3(R)-fenil-5(S)-fenilmorfolīns;
29. 29) 2(R)-[3,5-bis(trifluormetil)benziloksi]-3(R)-fenil-5(S)-fenilmorfolTns;
30. 30) 2(S)-[3,5-bis(trifIuormetil)benziloksi]-6(R)-metil-3(S)-fenil-4-[(1,2,4-triazol3-il)metil]morfolīns;
31. 31) 2(S)-[3,5-bis(trifluormetil)benziloksi]-6-(R)metil-4-[(5-okso-1 H.4H-1,2,4triazol-3-il)-metil]-3(S)-fenilmorforins;
32. 32) 2(S)-[3,5-bis(trifluormetil)benziloksi]-3(R)-fenilmorfolīns;
33. 33) 4-[(1,2,4-triazol-3-il)metil]-2(S)-[3,5-bis(trifluormetii)benziloksi]-3(R)-fenilmorfolīns;
34. 34) 4-[(5-okso-1 H.4H-1,2,4-triazol-3-il)metil]-2(S)-[3,5-bis(trifIuormetil)benziloksi]-3(R)-fenil-morfolīns;
35. 35) 4-[(imidazol-2-il)metil]-2(S)-[3,5-bis(trifluoimetil)benziloksi]-3(R)-fenilmorfolīns;
36. 36) 4-[(imidazol-4-il)metil]-2(S)-[3,5-bis(trifluormetil)benziloksi]-3(R)-fenilmorfolTns;
37. 37) 4-(aminokarbonilmetil)-2(S)-[3,5-bis(trifluormetil)benziloksi]-3(R)-fenilmorfolīns;
38. 38) 4-[(imidazol-2-il)metil]-2(S)-[3,5-bis(trifluormetil)benziloksi]-3(S)-fenilmorfolīns;
39. 39) 4-[(imidazol-4-il)metil]-2(S)-[3,5-bis(trifluormetil)benziloksi]-3(S)-fenilmorfolīns;
40. 40) 4-[(imidazol-2-il)metil]-2(S)-[3,5-bis(trifluormetil)benziloksi]-3(S)-fenil-6(R) metilmorfofiīts;
41. 41) 4-[(imidazol-4-il)metil]-2(S)-[3,5-bis(trifluormetil)benziloksi]-3(S)-fenil-6(R) metilmorfolīns;
42. 42) 2(S)-[3,5-bis(trifluormetil)benziIoksi]-4-(6-hidroksiheksil)-3(R)-fenilmorfolīns;
43. 43) 2(S)-[3,5-bis(trifluormetil)benziloksi)-4-[5-(metilaminokarbonil)pentil]-3(R)fenilmorfolīns;
44. 44) 4-(1,2,4-triazol-3-il)metil-2-(3,5-dimetilbenziloksi)-3-fenilmorforrns;
45. 45) 4-[(5-okso-1 H,4H-1,2,4-triazol-3-il)metil]-2-[3,5-bis(trifluormetil)benziloksi]-3-fenilmorfolīns;
46. 46) 4-(1,2,4-triazol-3-il)metil-2-[3,5-di(t-butil)benziloksi]-3-fenilmorfolTns;
47. 47) 4-[(5-okso-1 H.4H-1,2,4-triazol-3-ii)metil]-2-[3,5-di(t-butil)benziloksi]-3fenilmorfolīns;
48. 48) 4-(1,2,4-triazol-3-il)metil-2-[3-(t-butil)-5-metilbenziloksi]-3-fenilmorfolīns;
49. 49) 4-[(5-okso-1 H.4H-1,2,4-triazol-3-il)metil]-2-[3-(t-butil)-5-metiibenziloksi]-3fenilmorfolīns;
50. 50) 4-(1,2,4-triazol-3-il)metil-2-[3-trifluormetil-5-metilbenziloksi]-3-fenilmorfolīns;
51. 51) 4-[(5-okso-1 H.4H-1,2,4-triazol-3-il)metil]-2-[3-trifluormetil-5-metilbenziloksi]-3-fenilmorfolīns;
52. 52) 4-(1,2,4-triazol-3-il)metil-2-[3-(t-butil)-5-trifIuormetilbenziloksi]-3-fenilmorfolīns;
53. 53) 4-[(5-okso-1 H,4H-1,2,4-triazol-3-il)metil]-2-[3-(t-butil)-5-trifluormetilbenziloksi]-3-fenil-morfolīns;
54. 54) 4-((imidazol-2-il)metill-2-(3,5-dimetilbenziloksi)-3-fenilmorfolīns;
55. 55) 4-[(imidazol-4-il)metil]-2-(3,5-dimetilbenziloksi)-3-fenilmorfolīns;
56. 56) 4-[(imidazol-2-il)metil]-2-[3,5-di(t-butil)benziloksi]-3-fenilmorfolīns;
57. 57) 4-[(imidazol-4-il)metil]-2-[3,5-di(t-butil)benziloksij-3-fenilmorfolīns;
58. 58) 4-[(imidazol-2-il)metil]-2-[3-(t-butil)-5-metilbenziloksi]-3-fenilmorfolīns;
59. 59) 4-[(imidazol-4-il)metil]-2-[3-(t-butii)-5-metilbenziloksi]-3-fenilmorfolīns;
60. 60) 4-[(imidazol-2-il)metili-2-[3-trifluormetil-5-metilbenziloksi]-3-fenilmorfolīns;
61. 61) 4-i(imidazol-4-il)metil]-2-[3-trifluormetil-5-metilbenziloksij-3-fenilmorfolīns;
62. 62) 4-[(imidazol-2-il)metil]-2-[3-(t-butii)-5-trifluormetil-benziloksi]-3-fenilmorfolīns;
63. 63) 2(S)-(3,5)-dihlorbenziloksi)-3-fenil-morfolīns;
64. 64) 2(S)-(3,5-dihlorbenziloksi)-4-[(5-okso-1,2,4-triazol-3-il)metil]-3(S)fenilmorfolīns;
65. 65) 2(S)-[3,5-bis(trifluormetil)benziloksi]-4-metoksikarbonilmetil-3(S)-fenilmorfolīns;
66. 66) 2(S)-[3,5-bis(trifiuormetil)benziloksi]-4-karboksimetil-3(S)-fenil-morfolīns;
67. 67) 2(S)-[3,5-bis(trifluormetil)benziloksi]-4-[(2-aminoetil)aminokarbonilmetil]3(S)-fenil-morfolīns;
68. 68) 2(S)-[3,5-bis(trifluormetil)benziloksi]-4-[(3-aminpropil)aminokarbonilmetil]3(S)-fenil-morfolīns;
69. 69) 4-benzil-5(S),6(R)-dimetil-3(S)-fenilmorfolinons un 4-benzil-5(R),6(S)dimetil-3(S)-fenilmorfolinons
70. 70) 2(R)-[3,5-bis(trifluormetil)benziloksi]-[5(S),6(R)- vai 5(R),6(S)- jdimetil3(S)-fenilmorfolinons;
71. 71) 2(R)-[3,5-bis(trifluormetil)benziloksi]-[5(R),6(S)- vai 5(S),6(R)- Jdimetil3(S)-fenilmorfolinons;
72. 72) 2(S)-[3,5-bis(trifIuormetil)benziloksi]-4-[(1,2,4-triazol-3-il)metil]-[5(S),6(R)vai 5(R),6(S)- ]dimetil-3(S)-fenilmorfolinons;
73. 73) 2(R)-[3,5-bis(trifIuormetil)benziloksi]-4-[(5-okso-1,2,4-triazol-3-il)metil][5(S),6(R)- vai 5(R),6(S)- ]dimetil-3(S)-fenilmorfolinons;
74. 74) 2(R)-[3,5-bis(trifIuormetil)benziloksi]-4-[(1,2,4-triazol-3-il)metil]-[5(R),6(S)vai 5(S),6(R)- ]dimetil-3(S)-feniimorfolinons;
75. 75) 2(S)-[3,5-bis(trifluormetil)benziloksi]-4-[(5-okso-1,2,4-triazol-3-il)metil][5(R),6(S)- vai 5(S),6(R)- ]dimetil-3(S)-fenilmorfolinons;
76. 76) 2(S)-[3,5-bis(trifIuormetil)benziloksi]-4-[2-(4-benzilpiperidin-1-il)etil]”3(S)feniimorfolīns;
77. 77) 3(S)-(4-fluorfenil)-4-benzil-morfolin-2-ons;
78. 78) 2(S)-[3,5-bis(trifluormetil)benziloksi]-3(S)-(4-fluorfenil)-4-benzilmorfolīns;
79. 79) 2(S)-[3,5-bis(trifluormetil)benziloksij-3(S)-(4-fluorfenil)morfolīns;
80. 80) 2(SH3,5-bis(trifluormetil)benziloksi]-3(S)-(4-fluorfenil)4-[(5-okso-1H,4H1,2,4-triazol-3-il)metil]morforins;
81. 81) 2(S)-[3,5-bis(trifluormetil)benziloksi]-4-[(piridin-3-il)metilkarbonil]-3(R)fenilmorfolīns;
82. 82) 2(S)-[3,5-bis(trifIuormetil)benziloksi]-4-metoksikarbonilpentil-3(R)fenilmorfolīns;
83. 83) 2(S)-[3,5-bis(trifluormetil)benziloksi]-4-karboksipentil-3(R)-fenilmorfolīns;
84. 84) 2(S)-[3,5-bis(trifluormetil)benziioksi]-4-[(metilaminokarboksipentil-6-oksoheksil]-3(R)-fenilmorfolīns;

    vai tā farmaceitiski pieņemamā sāls.

    6. Farmaceitiskā kompozīcija, kas ietver farmaceitiski pieņemamu nesēju un iedarbīgu daudzumu savienojuma pēc 1. punkta.

    7. Savienojuma pēc jebkura no 1. līdz 5. punktam pielietojums medikamenta ražošanai, kas paredzēts tādu fizioloģisku traucējumu ārstēšanai zīdītājiem, kuri saistīti ar tahikinīnu pārpilnību vai tahikinīna receptoru blokādi.

    8. Paņēmiens savienojuma vai tā farmaceitiski pieņemamas sāls ar formulu (IV)

    IV kur:

    R¹ ir ņemts no rindas:

    (1) ūdeņraža atoms;

    (2) Cvsalkilgrupa, neobligāti aizvietota ar vienu vai vairākiem aizvietotājiem no rindas:

    (a) hidroksiigrupa, (b) oksogrupa, (c) C-t-salkoksigrupa, (d) fenil-Ci.₃alkoksigrupa, (e) feniigrupa, (f) ciāngrupa, (g) halogēna atoms, (h) -NR^R¹⁰, kur R⁹ un R¹⁰, neatkarīgi viens no otra, ir ņemti no rindas:

    (i) ūdeņraža atoms, (ii) C-i-salkilgrupa, (iii) hidroksi-C-i-ealkilgrupa, (iv) feniigrupa, (i) -NR⁹COR¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (j) -NR⁹CO₂R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (k) -CONR⁹R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (l) -COR⁹, kur R⁹ ir ar augstāk definēto nozīmi, (m) -CO₂R⁹, kur R⁹ ir ar augstāk definēto nozīmi, (n) heterocikliska grupa, kurā heterocikls ņemts no rindas:

    (A) benzimidazols, (B) benzofurāns, (C) benzotiofēns, (D) benzoksazols, (E) furāns, (F) imidazols, (G) indols, (H) izoksazols, (I) izotiazols, (J) oksadiazols, (K) oksazols, (L) pirazīns, (M) pirazols, (N) piridīns.

    (O) pirimidīns, (P) pirols, (Q) hinolīns, (R) tetrazols, (S) tiadiazols, (T) tiazols, (U) tiofēns, (V) triazols, (W) azetidīns, (X) 1,4-dioksāns, (Y) heksahidroazepīns, (Z) oksāns, (AA) piperazīns, (AB) piperidīns, (AC) pirolidīns, (AD) tetrahidrofurāns, (AE) tetrahidrotiofēns, pie tam heterocikls ir neobligāti aizvietots ar vienu vai vairākiem aizvietotājiem no rindas:

    (i) C-i-ealkilgrupa, neobligāti aizvietota ar halogēna atomu, trifluormetilgrupu, metoksigrupu vai fenilgrupu, (ii) C-i_₆alkoksigrupa, (iii) oksogrupa, (iv) hidroksilgrupa, (v) tioksogrupa, (vi) -SR⁹, kur R⁹ ir ar jau minēto nozīmi, (vii) halogēna atoms, (viii) ciāngrupa, (ix) fenilgrupa, (x) trifluormetilgrupa, (xi) -(CH_₂)_m-NR⁹R¹⁰, kur m ir Ο, 1 vai 2, R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (xii) -NR⁹COR¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (xiii) -CONR⁹R¹°, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (xiv) -CO2R⁹, kur R⁹ ir ar augstāk definēto nozīmi, (xv) -(CH₂)_m-OR⁹, kur m un R⁹ ir ar jau minētajām nozīmēm;

    (3) C₂-6alkenilgrupa, neobligāti aizvietota ar vienu vai vairākiem aizvietotājiem no rindas:

    (a) hidroksilgrupa, (b) oksogrupa, (c) Cļ-eaikoksigrupa, (d) fenil-Ci-3alkoksigrupa, (e) fenilgrupa, (f) ciāngrupa, (g) halogēna atoms, (h) -CONR⁹R-, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (i) -COR⁹, kur R⁹ ir ar augstāk definēto nozīmi, (j) -CO₂R⁹, kur R⁹ ir ar augstāk definēto nozīmi, (k) heterocikliska grupa ar augstāk definēto nozīmi;

    (4) C₂-6alkinilgrupa;

    (5) fenilgrupa, neobligāti aizvietota ar vienu vai vairākiem aizvietotājiem no rindas:

    (a) hidroksilgrupa, (b) Ci^alkoksigrupa, (c) C-i-ealkilgrupa, (d) C₂-5alkenilgrupa, (e) halogēna atoms, (f) ciāngrupa, (g) nitrogrupa, (h) trifiuormetilgrupa, (i) -(CH₂)_m-NR⁹R , kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (j) -NR⁹COR¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (k) -NR⁹CO₂R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (!) -CONR⁹R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (m) -CO₂NR⁹R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (n) -COR⁹, kur R⁹ ir ar augstāk definēto nozīmi, (0) -CO₂R⁹, kur R⁹ ir ar augstāk definēto nozīmi,

    R² un R³, neatkarīgi viens no otra, ir ņemti no rindas:

    (1) ūdeņraža atoms, (2) Ci-6alkilgrupa, neobligāti aizvietota ar vienu vai vairākiem aizvietotājiem no rindas:

    (a) hidroksilgrupa, (b) oksogrupa, (c) Ci-6alkoksigrupa, (d) fenil-Ci-3alkoksigrupa, (e) fenilgrupa, (f) ciāngrupa, (g) halogēna atoms, (h) -NR⁹R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (i) -NR⁹COR¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi,

    0) -NR⁹CO2R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (k) -CONR⁹R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (l) -COR⁹, kur R⁹ ir ar augstāk definēto nozīmi, (m) -CO2R⁹, kur R⁹ ir ar augstāk definēto nozīmi;

    (3) C2-6alkenilgrupa, neobligāti aizvietota ar vienu vai vairākiem aizvietotājiem no rindas:

    (a) hidroksilgrupa, (b) oksogrupa, (c) C-i-ealkoksigrupa, (d) fenil-Ci_3alkoksigrupa, (e) fenilgrupa, (f) ciāngrupa, (g) halogēna atoms, (h) -CONR⁹R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (i) -COR⁹, kur R⁹ ir ar augstāk definēto nozīmi, (j) -CO₂R⁹, kur R⁹ ir ar augstāk definēto nozīmi;

    (4) C2-6alkinilgrupa;

    (5) fenilgrupa, neobligāti aizvietota ar vienu vai vairākiem aizvietotājiem no rindas:

    (a) hidroksilgrupa, (b) C-i-ealkoksigrupa, (c) C-i-ealkilgrupa, (d) C2-5alkenilgrupa, (e) halogēna atoms, (f) ciāngrupa, (g) nitrogrupa, (h) trifluormetilgrupa, (i) -(CH₂)m-NR⁹R , kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (j) -NR⁹COR¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (k) -NR⁹CO₂R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (l) -CONR⁹R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (m) -CO2NR⁹R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (n) -COR⁹, kur R⁹ ir ar augstāk definēto nozīmi, (o) -CO2R⁹, kur R⁹ ir ar augstāk definēto nozīmi;

    pie tam aizvietotāji R¹ un R² var būt savstarpēji savienoti, veidojot heterociklisku grupu, kur heterocikls ņemts no rindas:

    (a) pirolidīns, (b) piperidīns, (c) pirols, (d) piridīns, (e) imidazols, (f) oksazols, (g) tiazols, pie kam heterocikls ir neobligāti aizvietots ar vienu vai vairākiem aizvietotājiem no rindas:

    (i) Ci-6alkilgrupa, (ii) oksogrupa, (iii) C-|.₆alkoksigrupa, (iv) -NR⁹R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (v) halogēna atoms, (vi) trifluormetilgrupa;

    pie tam aizvietotāji R² un R³ var būt savstarpēji savienoti, veidojot karbociklisku grupu, kas ņemta no rindas:

    (a) ciklopentilgrupa, (b) cikloheksilgrupa, (c) fenilgrupa, pie kam karbocikliskā grupa ir neobligāti aizvietota ar vienu vai vairākiem aizvietotājiem no rindas:

    (i) C-i-ealkilgrupa, (ii) Ct-6alkoksigrupa, (iii) -NR⁹R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (iv) halogēna atoms, (v) trifluormetilgrupa;

    pie tam aizvietotāji R² un R³ var būt savstarpēji savienoti, veidojot heterociklisku grupu, kur heterocikls ņemts no rindas:

    (a) pirolidīns, (b) piperidīns, (c) pirols, (d) piridīns, (e) imidazols, (f) furāns, (g) oksazols, (h) tiofēns, (i) tiazols, pie kam heterocikls ir neobligāti aizvietots ar vienu vai vairākiem aizvietotājiem no rindas:

    (i) C^alkilgrupa, (ii) oksogrupa, (iii) C-i-ealkoksigrupa, (iv) -NR⁹R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (v) halogēna atoms, (i) trifluormetilgrupa;

    R⁶, R⁷ un R⁸, neatkarīgi viens no otra, ņemti no rindas:

    (1) ūdeņraža atoms;

    (2) Ci-₆alkilgrupa, neobligāti aizvietota ar vienu vai vairākiem aizvietotājiem no rindas:

    (a) hidroksilgrupa, (b) oksogrupa, (c) Ci-6alkoksigrupa, (d) fenil-Ci-3alkoksigrupa, (e) fenilgrupa, (f) ciāngrupa, (g) halogēna atoms, (h) -NR⁹R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (i) -NR⁹COR¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (j) -NR⁹CO2R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (k) -CONR⁹R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (l) -COR⁹, kur R⁹ ir ar augstāk definēto nozīmi, (m) -CO2R⁹, kur R⁹ ir ar augstāk definēto nozīmi;

    (3) C2^alkenilgrupa, neobligāti aizvietota ar vienu vai vairākiem aizvietotājiem no rindas:

    (a) hidroksilgrupa, (b) oksogrupa, (c) C-i^alkoksigrupa, (d) fenil-Ci-3alkoksigrupa, (e) fenilgrupa, (f) ciāngrupa, (g) halogēna atoms, (h) -CONR⁹R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (i) -COR⁹, kur R⁹ ir ar augstāk definēto nozīmi, (j) -CO₂R⁹, kur R⁹ ir ar augstāk definēto nozīmi;

    (4) C₂-6alkinilgrupa;

    (5) fenilgrupa, neobligāti aizvietota ar vienu vai vairākiem aizvietotājiem no rindas:

    (a) hidroksilgrupa, (b) C-i-ealkoksigrupa, (c) Ci-ealkilgrupa, (d) C₂-5aikenilgrupa, (e) halogēna atoms, (f) ciāngrupa, (g) nitrogrupa, (h) trifluormetilgrupa, (i) -(CH₂)_m-NR^āR¹°, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi,

    0) -NR⁹COR¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (k) -NR⁹CO2R¹°, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (l) -CONR⁹R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (m) -CO2NR⁹R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (n) -COR⁹, kur R⁹ ir ar augstāk definēto nozīmi, (o) -CO2R⁹, kur R⁹ ir ar augstāk definēto nozīmi;

    (6) halogēna atoms, (7) ciāngrupa, (8) trifluormetilgrupa, (9) nitrogrupa, (10) -SR¹⁴, kurā R¹⁴ ir ūdeņraža atoms vai C-i-6alkilgrupa, (11) -SOR¹⁴, kurā R¹⁴ nozīme ir jau minētā, (12) -SO₂R¹⁴, kurā R¹⁴ nozīme ir jau minētā, (13) NR⁹COR¹⁰, kurā R⁹ un R¹⁰ nozīmes ir jau minētās, (14) CONR⁹COR¹⁰, kurā R⁹ un R¹⁰ nozīmes ir jau minētās, (15) NR⁹R¹⁰, kurā R⁹ un R¹⁰ nozīmes ir jau minētās, (16) NR⁹CO₂R¹⁰, kurā R⁹ un R¹⁰ nozīmes ir jau minētās, (17) hidroksilgrupa, (18) Ci.₆alkoksignjpa, (19) COR⁹, kurā R⁹ nozīme ir jau minētā, (20) CO₂R⁹ kurā R⁹ nozīme ir jau minētā;

    R¹¹, R¹² un R¹³, neatkarīgi viens no otra, ir ņemti no rindas R⁶, R⁷ un R⁸; Y ir -O-,

    Z ir ūdeņraža atoms vai C-Malkilgrupa, iegūšanai, kas paredz savienojuma ar formulu (V) kurā R¹, R², R³, R⁶, R⁷, R⁸, R¹¹, R¹² un R¹³ ir ar jau minētām nozīmēm, apstrādāšanu pietiekoši ilgu laiku ar neorganisku vai organisku skābi no rindas: toluolsuifoskābe, metānsulfoskābe, sērskābe, sālskābe vai to maisījumi, aprotonā šķīdinātājā no rindas: toluols, benzols, dimetilformamīds, tetrahidrofurāns, dietilēteris, dimetoksietāns, etilacetāts un to maisījumi, pie temperatūras no 0 °C līdz šķīdinātāja viršanas temperatūrai, veidojot savienojumu ar formulu (IV).

    9. Paņēmiens savienojuma vai tā farmaceitiski pieņemamās sāls ar formulu (VI)

    VI kurā:

    R¹ ir ņemts no rindas:

    (1) ūdeņraža atoms;

    (2) Cļ-ealkilgrupa, neobligāti aizvietota ar vienu vai vairākiem aizvietotājiem no rindas:

    (a) hidroksilgrupa, (b) oksogrupa, (c) C-i-galkoksigrupa, (d) fenil-Ci-3alkoksigrupa, (e) fenilgrupa, (f) ciāngrupa, (g) halogēna atoms, (h) -NRSR¹⁰, kur R⁹ un R¹⁰, neatkarīgi viens no otra, ir ņemti no rindas:

    (i) ūdeņraža atoms, (ii) C-i-galkilgrupa, (iii) hidroksi-Ci.₆alkilgrupa, (iv) fenilgrupa, (i) -NR⁹COR¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (j) -NR⁹CO2R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (k) -CONR⁹R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (l) -COR⁹, kur R⁹ ir ar augstāk definēto nozīmi, (m) -CO2R⁹, kur R⁹ ir ar augstāk definēto nozīmi, (n) heterocikliska grupa, kurā heterocikls ņemts no rindas:

    (A) benzimidazols, (B) benzofurāns, (C) benzotiofēns, (D) benzoksazols, (E) furāns, (F) imidazols, (G) indols, (H) izoksazols, (I) izotiazols, (J) oksadiazols, (K) oksazols, (L) pirazīns, (M) pirazols, (N) piridīns.

    (O) pirimidīns, (P) pirols, (Q) hinolīns, (R) tetrazols, (S) tiadiazols, (T) tiazols, (U) tiofēns, (V) triazols, (VV) azetidīns, (X) 1,4-dioksāns, (Y) heksahidroazepīns, (Z) oksāns, (AA) piperazīns, (ΑΒ) piperidīns, (AC) pirolidīns, (AD) tetrahidrofurāns, (AE) tetrahidrotiofēns, pie tam heterocikls ir neobligāti aizvietots ar vienu vai vairākiem aizvietotājiem no rindas:

    (i) Cļ-ealkilgrupa, neobligāti aizvietota ar halogēna atomu, trifluormetilgrupu, metoksigrupu vai fenilgrupu, (ii) Cļ^alkoksigrupa, (iii) oksogrupa, (iv) hidroksilgrupa, (v) tioksogrupa, (vi) -SR⁹, kur R⁹ ir ar jau minēto nozīmi, (vii) halogēna atoms, (viii) ciāngrupa, (ix) fenilgrupa, (x) trifluormetilgrupa, (xi) -(CH₂)m-NR⁹R¹⁰, kur m ir 0, 1 vai 2, R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (xii) -NR⁹COR¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (xiii) -CONR⁹R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (xiv) -CO2R⁹, kur R⁹ ir ar augstāk definēto nozīmi, (xv) -(CH₂)m-OR⁹, kur m un R⁹ ir ar jau minētām nozīmēm;

    (3) C₂-6alkenilgrupa, neobligāti aizvietota ar vienu vai vairākiem aizvietotājiem no rindas:

    (a) hidroksilgrupa, (b) oksogrupa, (c) Ci-galkoksigrupa, (d) fenil-C₁.₃alkoksigrupa, (e) fenilgrupa, (f) ciāngrupa, (g) halogēna atoms, (h) -CONR⁹R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (i) -COR⁹, kur R⁹ ir ar augstāk definēto nozīmi, (j) -CO₂R⁹, kur R⁹ ir ar augstāk definēto nozīmi, (k) heterocikliska grupa ar augstāk definēto nozīmi;

    (4) C₂-6alkinilgrupa;

    (5) fenilgrupa, neobligāti aizvietota ar vienu vai vairākiem aizvietotājiem no rindas:

    (a) hidroksilgrupa, (b) Ci-salkoksigrupa, (c) Ci.₆alkilgrupa, (d) C₂-5alkenilgrupa, (e) halogēna atoms, (f) ciāngrupa, (g) nitrogrupa, (h) trifluormetilarupa, (i) -(CH₂)_m-NR⁹R , kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (j) -NR⁹COR¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (k) -NR⁹CO2R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (l) -CONR⁹R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (m) -CO₂NR⁹R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (n) -COR⁹, kur R⁹ ir ar augstāk definēto nozīmi, (o) -CO2R⁹, kur R⁹ ir ar augstāk definēto nozīmi,

    R² un R³, neatkarīgi viens no otra, ir ņemti no rindas:

    (1) ūdeņraža atoms, (2) Cvsalkilgrupa, neobligāti aizvietota ar vienu vai vairākiem aizvietotājiem no rindas:

    (a) hidroksiigrupa, (b) oksogrupa, (c) C^alkoksigrupa, (d) fenil-Cv3alkoksigrupa, (e) feniigrupa, (f) ciāngrupa, (g) halogēna atoms, (h) -NR⁹R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (i) -NR⁹COR¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (j) -NR⁹CO₂R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (k) -CONR⁹R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (l) -COR⁹, kur R⁹ ir ar augstāk definēto nozīmi, (m) -CO2R⁹, kur R⁹ ir ar augstāk definēto nozīmi;

    (3) C₂^alkenilgrupa, neobligāti aizvietota ar vienu vai vairākiem aizvietotājiem no rindas:

    (a) hidroksiigrupa, (b) oksogrupa, (c) C^alkoksigrupa, (d) fenil-Cv3alkoksigrupa, (e) feniigrupa, (f) ciāngrupa, (g) halogēna atoms, (h) -CONR⁹R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (i) -COR⁹, kur R⁹ ir ar augstāk definēto nozīmi, (j) -CO2R⁹, kur R⁹ ir ar augstāk definēto nozīmi;

    (4) C₂-6alkinilgrupa;

    (5) feniigrupa, neobligāti aizvietota ar vienu vai vairākiem aizvietotājiem no rindas:

    (a) hidroksiigrupa, (b) C^alkoksigrupa, (c) C-i-salkilgrupa, (d) C₂-5alkenilgrupa, (e) halogēna atoms, (f) ciāngrupa, (g) nitrogrupa, (h) trifluormetilarupa, (i) -(CH₂)_m-NR⁹R , kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi,

    0) -NR⁹COR¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (k) -NR⁹CO2R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (l) -CONR⁹R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (m) -CO₂NR⁹R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (n) -COR⁹, kur R⁹ ir ar augstāk definēto nozīmi, (o) -CO2R⁹, kur R⁹ ir ar augstāk definēto nozīmi;

    pie tam aizvietotāji R¹ un R² var būt savstarpēji savienoti, veidojot heterociklisku grupu, kur heterocikls ņemts no rindas:

    (a) pirolidīns, (b) piperidīns, (c) pirols, (d) piridīns, (e) imidazols, (f) oksazols, (g) tiazols, pie kam heterocikls ir neobligāti aizvietots ar vienu vai vairākiem aizvietotājiem no rindas:

    (i) C-i-ealkilgrupa, (ii) oksogrupa, (iii) Ci^alkoksigrupa, (iv) -NR⁹R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (v) halogēna atoms, (vi) trifluormetilgrupa;

    pie tam aizvietotāji R² un R³ var būt savstarpēji savienoti, veidojot karbociklisku grupu, kas ņemta no rindas:

    (a) ciklopentilgrupa, (b) cikloheksilgrupa, (c) fenilgrupa, pie kam karbocikliskā grupa ir neobligāti aizvietota ar vienu vai vairākiem aizvietotājiem no rindas:

    (i) Ci-ealkilgrupa, (ii) Ci-ealkoksigrupa, (iii) -NR⁹R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (iv) halogēna atoms, (v) trifluormetilgrupa;

    pie tam aizvietotāji R² un R³ var būt savstarpēji savienoti, veidojot heterociklisku grupu, kur heterocikls ņemts no rindas:

    (a) pirolidīns, (b) piperidīns, (c) pirols, (d) piridīns, (e) imidazols, (f) furāns, (g) oksazols, (h) tiofēns, (i) tiazols, pie kam heterocikls ir neobligāti aizvietots ar vienu vai vairākiem aizvietotājiem no rindas:

    (i) Ci.₆alkilgrupa, (ii) oksogrupa, (iii) C-i-ealkoksigrupa, (iv) -NR⁹R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (v) halogēna atoms, (vi) trifluormetilgrupa;

    R⁶, R⁷ un R⁸, neatkarīgi viens no otra ņemti no rindas:

    (1) ūdeņraža atoms;

    (2) C-i-ealkilgrupa, neobligāti aizvietota ar vienu vai vairākiem aizvietotājiem no rindas:

    (a) hidroksilgrupa, (b) oksogrupa, (c) C-i-ealkoksigrupa, (d) fenil-Ci-3alkoksigrupa, (e) fenilgrupa, (f) ciāngrupa, (g) halogēna atoms, (h) -NR⁹R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (i) -NR⁹COR¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (j) -NR⁹CO2R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (k) -CONR⁹R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (l) -COR⁹, kur R⁹ ir ar augstāk definēto nozīmi, (m) -CO2R⁹, kur R⁹ ir ar augstāk definēto nozīmi;

    (3) C2-6alkenilgrupa, neobligāti aizvietota ar vienu vai vairākiem aizvietotājiem no rindas:

    (a) hidroksilgrupa, (b) oksogrupa, (c) Ci^alkoksigrupa, (d) fenil-Ci.3alkoksigrupa, (e) fenilgrupa, (f) ciāngrupa, (g) halogēna atoms, (h) -CONR⁹R¹⁰, kur R⁹ un R¹⁰ nozīmes ir jau minētās, (i) -COR⁹, kur R⁹ nozīme ir jau minētā, (j) -CO2R⁹, kur R⁹ nozīme ir jau minētā;

    (4) C2-6alkinilgrupa;

    (5) fenilgrupa, neobligāti aizvietota ar vienu vai vairākiem aizvietotājiem no rindas:

    (a) hidroksilgrupa, (b) Ci-ealkoksigrupa, (c) Ci^alkilgrupa, (d) C2.5alkenilgrupa, (e) halogēna atoms, (f) ciāngrupa, (g) nitrogrupa, (h) trifluormetilarupa, (i) -(ΟΗ₂)πγΝΡί3¹⁰, kur R⁹ un R¹⁰ nozīmes ir jau minētās, (j) -NR⁹COR¹⁰, kur R⁹ un R¹⁰ nozīmes ir jau minētās, (k) -NR⁹CO2R¹⁰, kur R⁹ un R¹⁰ nozīmes ir jau minētās, (l) -CONR⁹R¹⁰, kur R⁹ un R¹⁰ nozīmes ir jau minētās, (m) -CO₂NR⁹R¹⁰, kur R⁹ un R¹⁰ nozīmes ir jau minētās, (n) -COR⁹, kur R⁹ nozīme ir jau minētā, (o) -CO2R⁹, kur R⁹ nozīme ir jau minētā;

    (6) halogēna atoms, (7) ciāngrupa, (8) trifluormetilgrupa, (9) nitrogrupa, (10) -SR¹⁴, kurā R¹⁴ ir ūdeņraža atoms vai Ci^alkilgrupa, (11) -SOR¹⁴, kurā R¹⁴ nozīme ir jau minētā, (12) -SO2R¹⁴, kurā R¹⁴ nozīme ir jau minētā, (13) NR⁹COR¹⁰, kurā R⁹ un R¹⁰ nozīmes ir jau minētās, (14) CONR⁹COR¹⁰, kurā R⁹ un R¹⁰ nozīmes ir jau minētās, (15) NR⁹R¹⁰, kurā R⁹ un R¹⁰ nozīmes ir jau minētās, (16) NR⁹CO₂R¹⁰, kurā R⁹ un R¹⁰ nozīmes ir jau minētās, (17) hidroksilgrupa, (18) Ci-₆alkoksigrupa, (19) COR⁹, kurā R^ģ nozīme ir jau minētā, (20) CO₂R⁹ kurā R⁹ nozīme ir jau minētā;

    R¹¹, R¹² un R¹³, neatkarīgi viens no otra, ir ņemti no rindas R⁶, R⁷ un R⁸;

    iegūšanai, kas paredz savienojuma ar formulu (VII) kurā R¹, R², R³, R¹¹, R¹² un R¹³ ir ar jau minētām nozīmēm, apstrādāšanu ar hidrida tipa reducētāju no rindas: diizobutilalumohidrīds, litija tri(sbutil)borhidrīda un litija alumohidrīds, organiskā šķīdinātājā zemā temperatūrā, radušās spirta izolēšanu un tā alkilēšanu pietiekoši ilgu laiku organiskā šķīdinātājā ar benzilhalogenīdu (kurā fenilgrupa ir aizvietota R⁶, R⁷ un R⁸, kur R⁶, R⁷ un R⁸ nozīmes ir jau minētās) nātrija hidrida klātienē, iegūstot savienojumu ar formulu VI.

    10. Paņēmiens savienojuma ar formulu (VIII)

    VIII vai tā farmaceitiski pieņemamas sāls,

    R¹ ir ņemts no rindas:

    (1) ūdeņraža atoms;

    (2) Ci.₆alkilgrupa, neobligāti aizvietota ar vienu vai vairākiem aizvietotājiem no rindas:

    (a) hidroksilgrupa, (b) oksogrupa, (c) C-i-galkoksigrupa, (d) fenil-Cļ^alkoksigrupa, (e) fenilgrupa, (f) ciāngrupa, (g) halogēna atoms, (h) -NR^¹⁰, kur R⁹ un R¹⁰, neatkarīgi viens no otra, ir ņemti no rindas:

    (i) ūdeņraža atoms, (ii) C-i-salkilgrupa, (iii) hidroksi-C-|.₆alkilgrupa, (iv) fenilgrupa, (i) -NR⁹COR¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (j) -NR⁹CO2R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (k) -CONR⁹R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (l) -COR⁹, kur R⁹ ir ar augstāk definēto nozīmi, (m) -CO2R⁹, kur R⁹ ir ar augstāk definēto nozīmi, (n) heterocikliska grupa, kurā heterocikls ņemts no rindas:

    (A) benzimidazols, (B) benzofurāns, (C) benzotiofēns, (D) benzoksazols, (E) furāns, (F) imidazols, (G) indols, (H) izoksazols, (I) izotiazols, (J) oksadiazols, (K) oksazols, (L) pirazīns, (M) pirazols, (N) piridīns.

    (O) pirimidīns, (P) pirols, (Q) hinolīns, (R) tetrazols, (S) tiadiazols, (T) tiazols, (U) tiofēns, (V) triazols, (W) azetidīns, (X) 1,4-dioksāns, (Y) heksahidroazepīns, (Z) oksāns, (AA) piperazīns, (AB) piperidīns, (AC) pirolidīns, (AD) tetrahidrofurāns, (AE) tetrahidrotiofēns, pie tam heterocikls ir neobligāti aizvietots ar vienu vai vairākiem aizvietotājiem no rindas:

    (i) C-i-6alkilgrupa, neobligāti aizvietota ar halogēna atomu, trifluormetilgrupu, metoksigrupu vai fenilgrupu, (ii) C^alkoksigrupa, (iii) oksogrupa, (iv) hidroksilgrupa, (v) tioksogrupa, (vi) -SR⁹, kur R⁹ ir ar jau minēto nozīmi, (vii) halogēna atoms, (viii) ciāngrupa, (ix) fenilgrupā, (x) trifluormetiigrupa, (xi) -(CH₂)m-NR⁹R¹⁰, kur m ir 0, 1 vai 2, R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (xii) -NR⁹COR¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (xiii) -CONR⁹R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (xiv) -CO₂R⁹, kur R⁹ ir ar augstāk definēto nozīmi, (xv) -(CH₂)_m-OR⁹, kur m un R⁹ ir ar jau minētām nozīmēm;

    (3) C2-6alkenilgrupa, neobligāti aizvietota ar vienu vai vairākiem aizvietotājiem no rindas:

    (a) hidroksilgrupa, (b) oksogrupa, (c) Ci-ealkoksigrupa, (d) fenil-C-i-3alkoksigrupa, (e) fenilgrupā, (f) ciāngrupa, (g) halogēna atoms, (h) -CONR⁹R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (i) -COR⁹, kur R⁹ ir ar augstāk definēto nozīmi, (j) -CO₂R⁹, kur R⁹ ir ar augstāk definēto nozīmi, (k) heterocikliska grupa ar augstāk definēto nozīmi;

    (4) C₂-6alkinilgrupa;

    (5) fenilgrupā, neobligāti aizvietota ar vienu vai vairākiem aizvietotājiem no rindas:

    (a) hidroksilgrupa, (b) Ci-ealkoksigrupa, (c) Ci-6alkilgrupa, (d) C₂-5alkenilgrupa, (e) halogēna atoms, (f) ciāngrupa, (g) nitrogrupa, (h) trifluormetilgrupa, (i) -(CH2)_m-NR®R , kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (j) -NR⁹COR¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (k) -NR⁹CO₂R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (l) -CONR⁹R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (m) -CO₂NR⁹R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (n) -COR⁹, kur R⁹ ir ar augstāk definēto nozīmi, (o) -CO₂R⁹, kur R⁹ ir ar augstāk definēto nozīmi,

    R² un R³, neatkarīgi viens no otra, ir ņemti no rindas:

    (1) ūdeņraža atoms, (2) C^alkilgrupa, neobligāti aizvietota ar vienu vai vairākiem aizvietotājiem no rindas:

    (a) hidroksilgrupa, (b) oksogrupa, (c) C^alkoksigrupa, (d) fenil-Ci.₃alkoksigrupa, (e) fenilgrupa, (f) ciāngrupa, (g) halogēna atoms, (h) -NR⁹R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (i) -NR⁹COR¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi,

    0) -NR⁹CO2R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (k) -CONR⁹R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (i) -COR⁹, kur R⁹ ir ar augstāk definēto nozīmi, (m) -CO2R⁹, kur R⁹ ir ar augstāk definēto nozīmi;

    (3) C₂-6alkenilgrupa, neobligāti aizvietota ar vienu vai vairākiem aizvietotājiem no rindas:

    (a) hidroksilgrupa, (b) oksogrupa, (c) Ci^alkoksigrupa, (d) fenil-Ci-3alkoksigrupa, (e) fenilgrupa, (f) ciāngrupa, (g) halogēna atoms, (h) -CONR⁹R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (i) -COR⁹, kur R⁹ ir ar augstāk definēto nozīmi, (j) -CO2R⁹, kur R⁹ ir ar augstāk definēto nozīmi;

    (4) C2-6alkinilgrupa;

    (5) feniigrupa, neobligāti aizvietota ar vienu vai vairākiem aizvietotājiem no rindas:

    (a) hidroksilgrupa, (b) C-i-₆alkoksignjpa, (c) Ci.₆alkilgrupa, (d) C2-5alkenilgrupa, (e) halogēna atoms, (f) ciāngrupa, (g) nitrogrupa, (h) trifluormetilgrupa, (i) -(CH₂)_m-NR$R , kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (j) -NR⁹COR¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (k) -NR⁹CO₂R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (l) -CONR⁹R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (m) -CO₂NR⁹R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (n) -COR⁹, kur R⁹ ir ar augstāk definēto nozīmi, (o) -CO₂R⁹, kur R⁹ ir ar augstāk definēto nozīmi;

    pie tam aizvietotāji R¹ un R² var būt savstarpēji savienoti, veidojot heterociklisku grupu, kur heterocikls ņemts no rindas:

    (a) pirolidīns, (b) piperidīns, (c) pirols, (d) piridīns, (e) imidazols, (f) oksazols, (g) tiazols, pie kam heterocikls ir neobligāti aizvietots ar vienu vai vairākiem aizvietotājiem no rindas:

    (i) C^alkilgrupa, (ii) oksogrupa, (iii) Ci^alkoksigrupa, (iv) -NR⁹R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (v) halogēna atoms, (vi) trifluormetilgrupa;

    pie tam aizvietotāji R² un R³ var būt savstarpēji savienoti, veidojot karbociklisku grupu, kas ņemta no rindas:

    (a) ciklopentilgrupa, (b) cikloheksilgrupa, (c) fenilgrupa, pie kam karbocikliskā grupa ir neobligāti aizvietota ar vienu vai vairākiem aizvietotājiem no rindas:

    (i) C^alkilgrupa, (ii) Ci.₆alkoksigrupa, (iii) -NR⁹R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (iv) halogēna atoms, (v) trifluormetilgrupa;

    pie tam aizvietotāji R² un R³ var būt savstarpēji savienoti, veidojot heterociklisku grupu, kur heterocikls ņemts no rindas:

    (a) pirolidīns, (b) piperidīns, (c) pirols, (d) piridīns, (e) imidazols, (f) furāns, (g) oksazols, (h) tiofēns, (i) tiazols, pie kam heterocikls ir neobligāti aizvietots ar vienu vai vairākiem aizvietotājiem no rindas:

    (i) Ci_₆alkilgrupa, (ii) oksogrupa, (iii) Ci^alkoksigrupa, (iv) -NR⁹R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (v) halogēna atoms, (ii) trifluormetilgrupa;

    R⁶ , R⁷ un R⁸, neatkarīgi viens no otra, ņemti no rindas:

    (1) ūdeņraža atoms;

    (2) Ci^alkilgrupa, neobligāti aizvietota ar vienu vai vairākiem aizvietotājiem no rindas:

    (a) hidroksilgrupa, (b) oksogrupa, (c) C-|.₆alkoksigrupa, (d) fenil-Ci-3alkoksigrupa, (e) fenilgrupa, (f) ciāngrupa, (g) halogēna atoms, (h) -NR⁹R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (i) -NR⁹COR^w, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (j) -NR⁹CO2R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (k) -CONR⁹R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (l) -COR⁹, kur R⁹ ir ar augstāk definēto nozīmi, (m) -CO₂R⁹, kur R⁹ ir ar augstāk definēto nozīmi;

    (3) C₂-6alkenilgrupa, neobligāti aizvietota ar vienu vai vairākiem aizvietotājiem no rindas:

    (a) hidroksilgrupa, (b) oksogrupa, (c) C^alkoksigrupa, (d) fenil-Ci-3alkoksigrupa, (e) fenilgrupa, (f) ciāngrupa, (g) halogēna atoms, (h) -CONR⁹R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (i) -COR⁹, kur R⁹ ir ar augstāk definēto nozīmi, (j) -CO2R⁹, kur R⁹ ir ar augstāk definēto nozīmi;

    (4) C₂-6alkinilgrupa;

    (5) fenilgrupa, neobligāti aizvietota ar vienu vai vairākiem aizvietotājiem no rindas:

    (a) hidroksilgrupa, (b) Ci._salkoksigrupa, (c) Ci^alkilgrupa, (d) C₂-5alkenilgrupa, (e) halogēna atoms, (f) ciāngrupa, (g) nitrogrupa, (h) trifluormetilarupa, (i) -(CH₂)m-NR^sR¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (j) -NR⁹COR¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (k) -NR⁹CO₂R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (l) -CONR⁹R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (m) -CO₂NR⁹R¹⁰, kur R⁹ un R¹⁰ ir ar augstāk definēto nozīmi, (n) -COR⁹, kur R⁹ ir ar augstāk definēto nozīmi, (o) -CO₂R⁹, kur R⁹ ir ar augstāk definēto nozīmi;

    (6) halogēna atoms, (7) ciāngrupa, (8) trifiuormetilgrupa, (9) nitrogrupa, (10) -SR¹⁴, kurā R¹⁴ ir ūdeņraža atoms vai C-i-ealkilgrupa, (11) -SOR¹⁴, kurā R¹⁴ nozīme ir jau minētā, (12) -SO₂R¹⁴, kurā R¹⁴ nozīme ir jau minētā, (13) NR⁹COR¹⁰, kurā R⁹ un R¹⁰ nozīmes ir jau minētās, (14) CONR⁹COR¹⁰, kurā R⁹ un R¹⁰ nozīmes ir jau minētās, (15) NR⁹R¹⁰, kurā R⁹ un R¹⁰ nozīmes ir jau minētās, (16) NR⁹CO₂R¹⁰, kurā R⁹ un R¹⁰ nozīmes ir jau minētās, (17) hidroksilgrupa, (18) Ci-₆alkoksigrupa, (19) COR⁹, kurā R^ģ nozīme ir jau minētā, (20) CO₂R⁹ kurā R⁹ nozīme ir jau minētā;

    R¹¹, R¹² un R¹³, neatkarīgi viens no otra, ir ņemti no rindas R⁶, R⁷ un R⁸; iegūšanai, kas paredz savienojuma ar formulu (IX)

    P'

    R

    R¹³ R¹²

    IX kurā R¹, R², R³, R¹¹, R¹² un R¹³ ir ar jau minētām nozīmēm, apstrādāšanu ar hidrīda tipa reducētāju no rindas: diizobutilalumohidrīds, litija tri(sbutil)borhidrīda un litija alumohidrīds, organiskajā šķīdinātājā zemā temperatūrā, radušās spirta/aikoholāta alkilēšanu organiskajā šķīdinātājā zemā temperatūrā pietiekoši ilgu laiku ar benzilgrupas pārneses reaģentu (kurā fenilgrupa ir aizvietota R , R⁷ un R⁸, kur R , R⁷ un R⁸ nozīmes ir jau minētās), kura aizejošā grupa ņemta no rindas: triflāta grupa, mezilāta grupa, tozilāta grupa, p-nitrofenilsulfonāta grupa, broms un jods, iegūstot savienojumu ar formulu VIII.