CA2235855A1 - Morpholine derivatives and their use as therapeutic agents - Google Patents
Morpholine derivatives and their use as therapeutic agents Download PDFInfo
- Publication number
- CA2235855A1 CA2235855A1 CA 2235855 CA2235855A CA2235855A1 CA 2235855 A1 CA2235855 A1 CA 2235855A1 CA 2235855 CA2235855 CA 2235855 CA 2235855 A CA2235855 A CA 2235855A CA 2235855 A1 CA2235855 A1 CA 2235855A1
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- Prior art keywords
- compound
- formula
- hydrogen
- 4alkyl
- group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
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- 239000003814 drug Substances 0.000 title claims description 14
- 229940124597 therapeutic agent Drugs 0.000 title description 3
- 150000002780 morpholines Chemical class 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 192
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 56
- 239000001257 hydrogen Substances 0.000 claims abstract description 55
- -1 C16alkyl Chemical group 0.000 claims abstract description 43
- 150000003839 salts Chemical class 0.000 claims abstract description 36
- 208000002193 Pain Diseases 0.000 claims abstract description 24
- 230000002265 prevention Effects 0.000 claims abstract description 18
- 206010047700 Vomiting Diseases 0.000 claims abstract description 17
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 17
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 16
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 16
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 15
- 229920006395 saturated elastomer Polymers 0.000 claims abstract description 15
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 13
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 12
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 12
- 208000019695 Migraine disease Diseases 0.000 claims abstract description 10
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 10
- 206010027599 migraine Diseases 0.000 claims abstract description 10
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 8
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 8
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 8
- 239000001301 oxygen Substances 0.000 claims abstract description 8
- 125000001424 substituent group Chemical group 0.000 claims abstract description 7
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000005977 Ethylene Substances 0.000 claims abstract description 4
- 125000004122 cyclic group Chemical group 0.000 claims abstract description 4
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 4
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 4
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims abstract description 3
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims abstract 4
- 125000002883 imidazolyl group Chemical group 0.000 claims abstract 4
- 206010061218 Inflammation Diseases 0.000 claims abstract 3
- 230000004054 inflammatory process Effects 0.000 claims abstract 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract 2
- 239000000460 chlorine Substances 0.000 claims description 65
- 239000000203 mixture Substances 0.000 claims description 61
- 238000006243 chemical reaction Methods 0.000 claims description 50
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 41
- 238000000034 method Methods 0.000 claims description 33
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 31
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 29
- 150000002431 hydrogen Chemical group 0.000 claims description 27
- 208000035475 disorder Diseases 0.000 claims description 24
- 108060008037 tachykinin Proteins 0.000 claims description 23
- 102000003141 Tachykinin Human genes 0.000 claims description 22
- 229910052736 halogen Inorganic materials 0.000 claims description 16
- 150000002367 halogens Chemical group 0.000 claims description 16
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 15
- 239000011737 fluorine Chemical group 0.000 claims description 15
- 229910052731 fluorine Inorganic materials 0.000 claims description 15
- 229910052801 chlorine Inorganic materials 0.000 claims description 13
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
- 238000002360 preparation method Methods 0.000 claims description 9
- 230000008569 process Effects 0.000 claims description 9
- 239000003937 drug carrier Substances 0.000 claims description 8
- 125000006413 ring segment Chemical group 0.000 claims description 8
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 229940002612 prodrug Drugs 0.000 claims description 6
- 239000000651 prodrug Substances 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 125000006239 protecting group Chemical group 0.000 claims description 5
- 241000036848 Porzana carolina Species 0.000 claims description 4
- 150000001412 amines Chemical class 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 229910052701 rubidium Inorganic materials 0.000 claims description 4
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 4
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 3
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 3
- 241000689227 Cora <basidiomycete fungus> Species 0.000 claims description 3
- 206010036376 Postherpetic Neuralgia Diseases 0.000 claims description 3
- 125000003118 aryl group Chemical group 0.000 claims description 3
- 125000002971 oxazolyl group Chemical group 0.000 claims description 3
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 2
- 150000001350 alkyl halides Chemical class 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 238000002560 therapeutic procedure Methods 0.000 claims description 2
- 125000001113 thiadiazolyl group Chemical group 0.000 claims description 2
- 125000000335 thiazolyl group Chemical group 0.000 claims description 2
- 125000001425 triazolyl group Chemical group 0.000 claims description 2
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims 6
- BUDAEDKAXKWVIZ-OCBCSQNSSA-N 3-[(2r,3s)-2-[(1r)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-phenylmorpholin-4-yl]-1h-1,2,4-triazol-5-amine Chemical compound C1([C@@H]2N(CCO[C@@H]2O[C@H](C)C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)C=2N=C(N)NN=2)=CC=CC=C1 BUDAEDKAXKWVIZ-OCBCSQNSSA-N 0.000 claims 1
- KNJNSFWGFRWQCK-KBJGYGKASA-N CNN1N(NC)N(CC)N=C1N1[C@@H](C=2C=CC(F)=CC=2)[C@@H](O[C@H](C)C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)OCC1 Chemical compound CNN1N(NC)N(CC)N=C1N1[C@@H](C=2C=CC(F)=CC=2)[C@@H](O[C@H](C)C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)OCC1 KNJNSFWGFRWQCK-KBJGYGKASA-N 0.000 claims 1
- 125000001715 oxadiazolyl group Chemical group 0.000 claims 1
- 208000004296 neuralgia Diseases 0.000 abstract description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 79
- 239000000243 solution Substances 0.000 description 77
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 56
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 37
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 36
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 32
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 26
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- 239000002904 solvent Substances 0.000 description 21
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 20
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 19
- 201000010099 disease Diseases 0.000 description 17
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 16
- 239000000047 product Substances 0.000 description 16
- 239000005557 antagonist Substances 0.000 description 15
- 239000010410 layer Substances 0.000 description 15
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- 239000000839 emulsion Substances 0.000 description 14
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- 102100024304 Protachykinin-1 Human genes 0.000 description 13
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 13
- 235000019341 magnesium sulphate Nutrition 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 11
- 239000000741 silica gel Substances 0.000 description 11
- 229910002027 silica gel Inorganic materials 0.000 description 11
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
- 238000004458 analytical method Methods 0.000 description 10
- CWWARWOPSKGELM-SARDKLJWSA-N methyl (2s)-2-[[(2s)-2-[[2-[[(2s)-2-[[(2s)-2-[[(2s)-5-amino-2-[[(2s)-5-amino-2-[[(2s)-1-[(2s)-6-amino-2-[[(2s)-1-[(2s)-2-amino-5-(diaminomethylideneamino)pentanoyl]pyrrolidine-2-carbonyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-5 Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)OC)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CCCN=C(N)N)C1=CC=CC=C1 CWWARWOPSKGELM-SARDKLJWSA-N 0.000 description 10
- 239000012044 organic layer Substances 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- QDZOEBFLNHCSSF-PFFBOGFISA-N (2S)-2-[[(2R)-2-[[(2S)-1-[(2S)-6-amino-2-[[(2S)-1-[(2R)-2-amino-5-carbamimidamidopentanoyl]pyrrolidine-2-carbonyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-N-[(2R)-1-[[(2S)-1-[[(2R)-1-[[(2S)-1-[[(2S)-1-amino-4-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]pentanediamide Chemical compound C([C@@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](N)CCCNC(N)=N)C1=CC=CC=C1 QDZOEBFLNHCSSF-PFFBOGFISA-N 0.000 description 9
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- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
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Abstract
The present invention relates to compounds of formula (I) wherein X is a 5- or 6-membered C-linked heteroaromatic ring containing 1 to 4 nitrogen atoms and optionally containing in the ring one oxygen or sulphur atom; Y is a group of the formula -(CH2)nNR6R7, or a methylene- or ethylene-linked imidazolyl group; Z is hydrogen or C1-4alkyl optionally substituted by a hydroxy group; R1, R2, R3, R4, R5, R9a and R9b are a variety of substituents; R6 is hydrogen, C16alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, phenyl, or C2-4alkyl substituted by C1-4alkoxy or hydroxy; R7 is hydrogen, C1-6alkyl, C37cycloalkyl, C3-7cycloalkylC1-4alkyl, phenyl, or C2-4alkyl substituted by one or two substituents selected from C1-4alkoxy, hydroxy or a 4-, 5- or 6membered heteroaliphatic ring containing one or two heteroatoms selected from N, O and S; or R6 and R7, together with the nitrogen atom to which they are attached, form a saturated or partially saturated heterocyclic ring or a nonaromatic azabicyclic ring system; and n is zero, 1 or 2; or a pharmaceutically acceptable salt thereof. The compounds are of particular use in the treatment or prevention of pain, inflammation, migraine, emesis and postherapeutic neuralgia.
Description
CA 0223~8~ 1998-04-24 MORPHOLINI~ DERI~ATIVES AND l'~:i~l~ USE AS
THERA~I~U llC AG:~:NTS
This invention relates to a class of morpholine derivatives which are 5 useful as tachykinin antagonists.
The tachykinins are a group of naturally occurring peptides found widely distributed throughout m~mm~ n tissues, both within the central nervous system and in peripheral nervous and circulatory systems.
The tachykinins are distinguished by a conserved carboxyl-termin~l 10 sequence:
Phe-X-Gly-Leu-Met-NH2 At present, there are three known m~mm~ n tachykinins referred to as substance P, neurokinin A (NKA, substance K, neuromedin L) and neurokinin B (NKB, neuromedin K) (for review see J.E:. Maggio, Peptides (198~) 6(suppl. 3), 237-242). The current nomenclature rie.cign~tes the three tachykinin receptors me~ ing the biological actions of substance P, NKA and NKB as the NKl, NK2 and NK3 receptors, respectively.
Evidence for the usefulness of tachykinin receptor antagonists in pain, he~ .he, especially migraine, ~l~.heimer's disease, multiple sclerosis, attenuation of morphine withdrawal, cardiovascular changes, oedema, such as oedema caused by thermal injury, chronic infl~mm~tory diseases such as rheumatoid arthritis, asthma/bronchial hyperreactivity and other respiratory diseases including allergic rhinitis, infl~mm~tory diseases of the gut including ulcerative colitis and Crohn's disease, ocular 2~; injury and ocular infl~mmsltory diseases, proliferative vitreoretinopathy, irritable bowel syndrome and disorders of bladder function including cystitis and bladder detruser hyper-reflexia is reviewed in "Tachykinin Receptors and Tachykinin Receptor Antagonists", C.A. Maggi, R.
~ Patacchini, P. Rovero and A. Giachetti, J. Auto~l. Pharmcl,col. (1993) ~, 23-93.
CA 0223C78c7c, l99X-04-24 For instance, substance P is believed inter alia to be involved in the neurotr~tn~mi.c.ci--n of pain serl~tioIt~c [Otsuka et al, "Role of Substance P
as a Sensory Trz~n~mit~er in ,Spinal Cord and Sympathetic Ganglia" in 1982 Substance P in the Nervous System, Ciba Foundation Symposium 91, 13-34 (published by Pitman) and Otsuka andy~tn~t~ wa, "Does Substance P Act as a Pain Tr~n-~mttter?" TIPS (1987) 8, 506-510], specifically in the tr~tn~mi~ion of pain in migraine (B.E.B. Sandberg et al, J. Med Chem, (1982) 25, 1009) and in arthritis ~Levine et al in Science (1984) 226, 547-549]. Tachykinins have also been implicated in ga~ ,i~testinal (GI) disorders and diseases of the C~I tract such as infl~mtn~tory bowel disease ,rMantyh et al in Neuroscience (1988~ 2~(3), 817-37 and D. Regoli in "Trends in Cluster He~ t-.h~" Ed. Sicuteri et al Elsevier Scientific Publishers, Amsterdam (1987) page 85)3 and emesis rF.
D. Tattersall et al, Eur. J. Pharmacol., (1993) 250, R5-R6]. It is also hypothesised that there is a neurogenic me~.h~nt~m for arthritis in which substance P may play a role ~Kidd et al "A Neurogenic Me~h~tni~m for Symmetrical Arthritis" in The lancet, 11 November 1989 and Gronblad et al, "Neuropeptides in Synovium of Patients with Rheumatoid Arthritis and Osteoarthritis" in J. Rheumatol. (1988) 15(12), 1807-10]. Therefore, substance P is believed to be involved in the infl~mm~tory response in diseases such as rheumatoid arthritis and osteoarthritis, and fibrositis [O'Byrne et al, Arthritis and Rheumatism (1990) 33, 1023-8]. Other disease areas where tachykinin antagonists are believed to be useful are allergic conditions [Hamelet et al, Can. J. Pharmacol. Physiol. (1988) 66, 1361-7~, immunoregulation [Lotz et al, Science (1988) 241, 1218-21 and Kimball et al, J. Immunol . (1988) 141(10), 3564-9] vasodilation, bronchospasm, reflex or neuronal control of the viscera [Mantyh et al, Proc. Natl. Aca~. Sci., USA (1988) 85, 3235-9] and, possibly by arresting or slowing B-amyloid-mediated neurodegenerative changes [Yankner et al, Science (1990) 250, 279-82] in senile dementia of the Alzheimer type, Alzheimer's disease and Down's Syndrome.
CA 0223~8~ 1998-04-24 Tachykinin antagonists may also be useful in the treatment of small cell carcinomas, in particular small cell lung cancer (SCLC) [Langdon et al, Cancer Research (1992) ~, 4554-73.
Substance P may also play a role in demyelinating diseases such as 6 multiple sclerosis and amyotrophic lateral sclerosis [J. Luber-Narod et aZ, poster C.I.N.P. XVIIIth Congress, 28th June-~nd July 1992], and in disorders of bladder ~unction such as bladder detrusor hyper-reflexia (T}7,e Lancet, 16th May 1992, 1239).
It has furthermore been suggested that tachykinins have utility in 10 the following disorders: depression, dysthymic disorders, chronic obstructive airways disease, hypersen~iiLivily disorders such as poison ivy, vasospastic ~li.qe~qes such as ~ngins~ and Reynauld's disease, fibrosing and collagen diseases such as scleroderma and eosinophilic fas~irlis~qiq, re~1ex sympathetic dy~. o~hy such as shoulder/hand syndrome, addiction 15 disorders such as alcoholism, stress related somatic disorders, neuropathy, neuralgia, disorders related to immune enh~n~ement or suppression such as systemic lupus erythmatosus (European patent specification no.
0 436 334), oph~h~lmi~ disease such as conjuctivitis, vernal conjunctivitis, and the like, and cutaneous diseases such as contact dermatitis, atopic 20 derm~ti~i.q, urticaria, and other eczematoid dermatitis (European patent specification no. 0 394 989).
European patent specification no. 0 577 394 (published 5th January 1994) discloses morpholine and thiomorpholine tachykinin receptor antagonists of the general formula R X X X R~
wherein Rl is a large variety of substituents;
R2 and R3 are inter alia hydrogen;
1~4 iS inter alia R';
~R7 ~Y~
5 R5 is inter alia optionally substituted phenyl;
R6, R7 and R8 are a variety of substituents;
X is 0, S, SO or SO2;
Y is inter alia O; and ~ is hydrogen or Cl 4alkyl.
We have now found a further class of non-peptides which are potent antagonists of tachykinins, especially of substance P.
It is desirable that compounds may be ~mini~tered orally and by injection. Certain compounds have now been discovered which act as potent non-peptide tachykinin antagonists and which, by virtue of their 15 advantageous aqueous solubility, are particularly easily formulated for administration by both the oral and injection routes, for example in aqueous media.
The present invention provides compounds of the formula (I):
~RI
~R3 R9~ o ~ O
R9b J~ N
(I) CA 0223~8~ 1998-04-24 wherein X is a 5- or 6-membered C-linked heteroaromatic ring cont~ining 1 to 4 nitrogen atoms and optionally cont~inin~ in the ring one oxygen or sulphur atom;
Y is a group of the formula ~(CH2)nNR6R7~ or a methylene- or ethylene-linked imi~ 7.01yl group;
Z is hydrogen or Cl 4alkyl optionally substituted by a hydlo~y group;
Rl is hydrogen, halogen, Cl 6alkyl, Cl 6alkoxy, CF3, NO2, CN, SRa, SORa, SO2Ra, CO2Ra, CONRaRb, C2 6alkenyl, C2 6alkynyl or Cl 4alkyl substituted by Cl 4alkoxy, wherein Ra and Rb each independently represent hydrogen or Cl 4alkyl;
R2 is hydrogen, halogen, Cl 6alkyl, Cl 6alkoxy substituted by Cl q~lko~y or CF3;
R3 is hydrogen, halogen or CF3;
R4 is hydrogen, halogen, Cl.6alkyl, Cl.6alkoxy, hydlo~y, CF3, NO2, CN, SRa, SORa, SO2Ra, CO2Ra, CONRaRb, C2 6alkenyl, C2 6alkynyl or Cl 4alkyl substituted by Cl 4alkoxy, wherein Ra and Rb are as previously defined;
R5 is hydrogen, halogen, Cl 6alkyl, Cl 6alkoxy substituted by Cl ~s~lko~cy or CF3;
R6 is hydrogen, Cl 6alkyl, C3 7cycloalkyl, C3 7cycloalkylCl 4alkyl, phenyl, or C2.4alkyl substituted by Cl 4alkoxy or hydroxy;
R7 is hydrogen, Cl.6alkyl, C3.7cycloalkyl, C3.7cycloalkylCl 4alkyl, phenyl, or C2 4alkyl substituted by one or two substituents selected from Cl 4alkoxy, hydroxy or a 4, 5 or 6 membered heteroaliphatic ring cont~ining one or two heteroatoms selected from N, O and S;
or RG and R7, together with the nitrogen atom to which they are attached, form a saturated or partially saturated heterocyclic ring of 4 to 7 ring atoms, which ring may optionally contain in the ring one oxygen or sulphur atom or a group selected from NR8, S(O) or S(O)2 and which ring CA 0223~8~ 1998-04-24 may be optionally substituted by one or two groups selected fro~
hydroxyCl 4alkyl, Cl4alkoxyCl 4alkyl, oxo, CORa or CO2Ra where Ra is as previously defined;
or Rfi and R7 together with the nitrogen atom to which they are 5 attached, form a non-aromatic azabicyclic ring system of 6 to 12 ring atoms;
R8 is hydrogen, Cl 4alkyl, hy~Lo~yCl 4alkyl or Cl s~lko~ycl 4alkyl;
R9a and R9b are each independently hydrogen or Cl 4alkyl, or R9a and R9b are joined so, together with the carbon atoms to which they are 10 attached, there is formed a Cs 7 ring; and n is zero, 1 or 2;
and pharmaceutically acceptable salts thereof.
A preferred class of compounds of formula (I) is that wherein Rl is hydrogen, Cl 4alkyl, Cl 4alkoxy, halogen or CF3.
Another preferred class of compounds of formula (I) is that wherein R2 is hydrogen, Cl 4alkyl, Cl ~lkcl~y~ halogen or CF3.
Also preferred is the class of compounds of formula (I) wherein R3 is hydrogen, fluorine, chlorine or CF3.
A particularly preferred class of compounds of formula (I) is that wherein Rl is fluorine, chlorine or CF3.
Another particularly preferred class of compounds of formula (I) is that wherein R2 is hydrogen, ~1uorine, chlorine or CF3.
Also particularly preferred is the class of compounds of formula (I) wherein R3 is hydrogen, fluorine, chlorine or CF3.
2~ Pre~erably Rl and R2 are in the 3 and 5 positions of the phenyl ring More preferably Rl is 3-fluoro or 3-CF3.
More preferably R2 is 6-fluoro or 5-CF3.
More preferably R3 is hydrogeLl.
Most preferably Rl is 3-F or 3-CF3, R2 is 5-CF3 and R3 is hydrogen.
A further pre~erred class of compound of formula (I) is that wherein R~ is hydrogen.
CA 0223~8~ 1998-04-24 Another preferred class of compounds of formula (I) is that wherein R5 is hydrogen, fluorine, chlorine or CF3.
Preferably R4 is hydrogen and R~ is hydrogen or 4-fluoro.
Yet another preferred class of compounds of formula (I) is that 5 wherein R6 represents hydrogen, Cl 6alkyl or C2 4al~yl substituted by Cl 6alkoxy.
A yet further preferred class of compounds of formula (I) is that wherein R7 represents hydrogen, Cl 6alkyl or C2 4alkyl substituted by Cl 6alkoxy.
Also preferred is the class of compounds of formula (I) wherein R6 and R7, together with the nitrogen atom to which they are attached, form a saturated heterocyclic ring of 4, 5 or 6 ring atoms which may optionally contain in the ring one oxygen atom or the group NR8 (where R8 is hydrogen or methyl) and which ring may be optionally substituted by 15 hydroxyCl 4alkyl, Cl ~lko~yCl 4alkyl, oxo, CORa or CO2Ra.
In particular, the group NR6R7 preferably represents NEI2, NHCH3, N(CH3)2, azetidinyl, morpholino, thiomorpholino, piperazino, piperidino or pyrrolidino Also preferred is the class of compounds of formula (I~ wherein R9a 20 and R9b are each independently hydrogen or methyl. Preferably R9a is hydrogen. Preferably R9b is hydrogen. Most preferably R9a and R9b are both hydrogen.
From the foregoing it will be appreciated that a particularly apt sub-group of compounds of this invention are those of the formula (Ia) and 25 pharmaceutically acceptable salts thereof:
CA 02235855 l998-04-24 ~A~
~0~0 ~ N ~3 y,X
(Ia) wherein Al is fluorine or CF3;
A2 is fluorine or CF3;
A3 is fluorine or hydrogen;
and X, Y and Z are as defined in relation to formula (I).
A preferred group X for compounds of formula (I) or (Ia) is a ~-membered C-linked heteroaromatic ring cont~ining 1 to 4 nitrogen atoms and optionally con~inin~ in the ring one oxygen or sulphur atom.
Suitable groups include imi~7olyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, thiadiazolyl and o~ olyl groups.
A particularly preferred group X for compounds of formula (I) or (Ia) is a 5-membered C-linked heteroaromatic ring cont~ining 2 to 4 nitrogen atoms and optionally cont~ininF in the ring one sulphur atom.
An especially pre~erred class of compound of formula (I) or ~Ia) is that where X is an imifi~7;ol-2 yl, 1,2,4-triazol-3-yl, thiazolyl-2-yl or tetrazolyl group.
Another preferred class of compound of the present invention is that wherein Y is a group of the formula -(CHa)nNR6R7.
A preferred group Z for compounds of the formulae (I) or (Ia) is a Cl 2alkyl group optionally substituted by a hydroxy group, in particular a methyl or CH20H group, espeically a methyl group.
CA 0223~8~ 1998-04-24 WO 97/18206 PCT/GB96/0~766 Where the group NR6R7 forms a saturated heterocylic ring of 4 to 7 ring atoms which may optionally contain in the ring one oxygen or sulphur atom or a group selected from NR8, S(O) or S(0)2, suitable heterocylic groups include azetidinyl, pyrrolidino, piperidino, homopiperidino, piperazino, N-methylpiperazino, morpholino and thiomorpholino.
Suitable substituents on the saturated heterocyclic ring include CH~OH, CH20CH3, oxo, C~IO, C02H, C~02CH3, and CO2ClI2CH3.
When used herein the term "halogen" means fluorine, chlorine, bromine and iodine. The most apt halogen are fluorine and chlorine of which fluorine is preferred.
When used herein the term "alkyl" or "alkoxy" as a group or part of a group means that the group is straight or branched. ~mples of suitable alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl and t-butyl. F,~m~les of suitable al~oxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy and t-butoxy.
The term "alkenyl" as a group or part of a group means that the group is straight or branched and contains at least one double bond.
Examples of suitable alkenyl groups include vinyl and allyl.
The term "alkynyl" as a group or part of a group means that the group is straight or branched and contains at least one triple bond. An example of a suitable alkynyl group is propargyl.
Suitable cycloalkyl and cycloalkyl-alkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopLo~ llethyl and cyclobutylmethyl.
Where the group NR6R7 represents a heteroaliphatic ring of 4 to 7 ring atoms and said ring is partially saturated, a particularly preferred group is 3-pyrroline.
Where the group NR6R7 represents a non-aromatic azabicyclic ring system, such a system may contain between 6 and 12, and preferably 30 between 7 and 10, ring atoms. Suitable rings include 5-azabicyclo~2.1.1]hexyl, 5-azabicycloL2.2.1]heptyl, 6-azabicyclo~3.2.1~octyl, CA 0223~8~ 1998-04-24 2-azabicyclo~2.2.21octyl, 6-azabicyclo[3.2.2~nonyl, 6-azabicyclo[3.3.1]nonyl, 6-azabicyclo[3.3.2]decyl, 7-azabicyclo[4.3.~]decyl, 7-azabicyclo[4.4.1]undecyl and 8-azabicyclo[5.4.1]dodecyl, especially 5-azabicyclo[2.2. 1]heptyl and 6-azabicyclo[3.2. 1loctyl.
VVhere R7 represents a C2.4alkyl group substituted by a 5 or 6 membered heteroaliphatic ring col~t~inin~ one or two heteroatoms selected from N, O and S, suitable rings include pyrrolidino, piperidino, piperazino, morpholino, or thiomorpholino. Particularly preferred are nitrogen cont~ining heteroaliphatic rings, especially pyrrolidino and morpholino rings.
Specific compounds within the scope of the present invention include:
~-(5-amino-1,2,4-triazol-3-yl)-2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl) ethoxy)-3 -(S)-phenylmorpholine;
2-(~ (R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4 (2-N,N-dimethyl,qmin-)ethyl-2H-tetrazol-5-yl)-3-(S)-(4-fluorophenyl)morpholine;
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-dimethylaminomethyVthiazol-2-yl)-3-(S)-(4-fluorophenyl)morpholine;
2-(R~-(l-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydro;~yethoxy)-4-(2-amino-5-thiazolyl)-3-(S)-(4-fluorophenyl)morpholine;
and pharmaceutically acceptable salts thereof.
For use in medicine, the salts of the compounds of formula (I) will be non-toxic pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds according to the invention or of their non-toxic pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts such as those formed with hydrochloric acid, fumaric acid, p-toluenesulphonic acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Salts of amine groups may also comprise quaternary ammonium salts in which the amino nitrogen atom carries a suitable organic group such as an alkyl, CA 0223~8~ 1998-04-24 WO 97/18~06 PCT/GB96/02766 all~enyl, alkynyl or aralkyl moiety. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include metal salts such as alkali metal salts, e.g.
sodium or potassium salts; and ~lkRline earth metal salts, e.g. calcium or magnesium salts.
The pharmaceutically acceptable salts of the present invention may be formed by conventional means, such as by reacting the free base form of the product with one or more equivalents of the appropriate acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water which is removed in uacuo or by freeze drying or by e~eh~n~in~ the anions of an existing salt for another anion on a suitable ion ~r~h~nge resin.
The present invention includes within its scope prodrugs of the compounds of formula (I) above. In general, such prodrugs will be functional derivatives of the compounds of formula (I) which are readily convertible in viuo into the required compound of formula (I).
Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
A prodrug may be a pharmacologically inactive derivative of a biologically active substance (the "parent drug" or "parent molecule") that requires transformation within the body in order to release the active drug, and that has improved delivery properties over the parent drug molecule. The transformation in vivo may be, for example, as the result of some metabolic process, such as chemical or enzymatic hydrolysis of a carboxylic, phosphoric or sulphate ester, or reduction or oxidation of a susceptible functionality.
The present invention includes within its scope solvates of the compounds of formula (I) and salts thereof, for example, hydrates.
The compounds according to the invention have at least three asymmetric centres, and may accordingly exist both as enantiomers and as CA 0223~8~ 1998-04-24 WO 97/18206 PCT/GB96/~2766 diastereoisomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention.
The preferred compounds of the formula (I), and (Ia) will have the 5 2- and 3- substituent cis aad the preferred stereochemistry at the 2-position is that possessed by the compound of h'.~r~mple 1 (i.e. 2-(R)-), the preferred stereochemistry of the 3-position is that possessed by the compound of ~,~s~mple 1 (i.e. 3-(S)), and the preferred stereochemistry of the carbon to which the group Z is attached is either (R) when Z is 10 Cl 4alkyl (e.g. methyl~ or (S) when Z is Cl ~alkyl substituted by hydroxy (e.g. CH20H). Thus for example as shown in formula (Ib) R9 0 ~\~/~$~ R
Rgb ", ~ R3 Y ~s (Ib) The present invention further provides pharmaceutical compositions comprising one or more compounds of formula (I) in association with a pharmaceutically acceptable carrier.
Preferably the compositions according to the invention are in unit dosage forms such as tablets, pills, capsules, powders, granules, solutions 20 or suspensions, or suppositories, for oral, parenteral or rectal ~rimini.qtration, or administration by inhalation or insllffl~t.i-n.
For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, 25 stearic acid, magnesium stearate, dicalcium phosphate or gums, and other CA 0223~8~ 1998-04-24 pharmaceutical diluents, e.g. water, to form a solid preformulation composition cor~t~ining a homogeneous mixture of a compound of the present invention, or a non-toxic pharmaceutically 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 subdivided into equally effective unit dosage forms such as tablets, pills and capsules This solid preformulation composition is then subdivided into unit dosage forms of the type described above con~ining from 0.1 to about 500 mg of the active ingredient of the present invention. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill 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 which serves to resist disintegration in the stom~(~h and permits the inner component to pass intact into the duodenum or to be delayed in release A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shell~c, cetyl alcohol and cellulose acetate.
The liquid forms in which the novel compositions of the present invention may be incorporated for ~(1mini~stration orally or by injection include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and ~:imil~r pharmaceutical vehicles. Suitable dispersing or suspending agents for - aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, ~l~in~te, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.
Preferred compositions for administration by injection include those comprising a compound of formula (I), as the active ingredient, in CA 0223~8~ 1998-04-24 WO 97/18206 PCT/(,;1,5Cf~2766 association with a surface-active agent ~or wetting agent or surfactant) or in the form of an emulsion (as a wa~er-in-oil or oil-in-water emulsion).
Suitable surface-active agents include, in particular, non-ionic agents, such as polyoxyethylenesorbitans (e.g. TvveenTM 2(), 40, 6~, 80 or 86) and other sorbitans (e.g. SpanTU 20, 40, 60, 80 or 853. Compositions with a surface-active agent wi}l conveniently comprise between 0.05 and 5% surface-active agent, and preferably between 0.1 and 2.5%. It will be appreciated that other ingredients may be added, for example m~nnitol or other pharmaceutically acceptable vehicles, if necessary.
Suitable emulsions may be prepared using commercially available fat emulsions, such as IntralipidTM, LiposynTM, InfonutrolTM, LipofundinTM
and LipiphysanTM. The active ingredient may be either dissolved in a pre-mixed emulsion composition or alternatively it may be dissolved in an oil (e.g. soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil or almondoil) and an emulsion formed upon mi~ing with a phospholipid (e.g. egg phospholipids, soybean phospholipids or soybean lecithin) and water. It will be appreciated that other ingredients may be added, for example gylcerol or glucose, to ad~ust the tonicity of the emulsion. Suitable emulsions will typically contain up to 20% oil, for example, between 5 and 20%. The fat emulsion will preferably comprise fat droplets between 0.1 and 1.0,um, particularly 0.1 and 0.511m, and have a pH in the range of 5.0 to 8Ø
ParticuIarly preferred emulsion compositions are those prepared by mi7~inF a compound of formula ~I) with IntralipidTM or the components 25 thereof (soybean oil, egg phospholipids, glycerol and water).
Compositions for inh~l~ti-~n 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.
30 Preferably the compositions are administered by the oral or nasal respiratory route for local or systemic effect. ~ompositions in preferably CA 0223~8~ l998-04-24 WO 97/lU06 PCT/GB96/02766 sterile pharmaceutically acceptable solvents may be nebulised by use of inert gases. Nebulised solutions may be breathed directly from the nebulising device or the nebulising device may be attached to a face mask, tent or intermittent positive pressure breathing m~rhine. Solution, 5 suspension or powder compositions may be R~lmini~tered, preferably orally or nasally, from devices which deliver the formulation in an appropriate m~nner The present invention futher provides a process for the preparation of a pharmaceutical composition comprising a compound of formula (I), 10 which process comprises bringing a compound of formula (I) into asso~ t.i--n with a pharmaceutically acceptable carrier or excipient.
The compounds of formula (I) are of value in the treatment of a wide variety of ~linic~l conditions which are characterised by the presence of an excess of tachykinin, in particular substance P, act*ity.
1~ Thus, for exampie, an excess of tachykinin, and in particuiar substance P, activity is implicated in a variety of disorders of the central nervous system. Such disorders include mood disorders, such as depression or more particularly depressive disorders, for example, single episodic or recurrent ma~or depressive disorders and dysthymic disorders, 20 or bipolar disorders, for example, bipolar I disorder, bipolar II disorder and cyclothymic disorder; anxiety disorders, such as panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, specific phobias, for example, specific ~nimzll phobias, social phobias, obsessive-compulsive disorder, stress disorders including post-traumatic 25 stress disorder and acute stress disorder, and generalised anxiety disorders; schizophrenia and other psychotic disorders, for example, - schizophreniform disorders, schizoaffective disorders, delusional disorders, brief psychotic disorders, shared psychotic disorders and psychotic disorders with delusions or hallll~in~tions; delerium, dementia, and 30 amnestic and other cognitive or neurodegenerative disorders, such as Alzheimer's disease, senile dementia, dementia of the Alzheimer's type, CA 0223=,8=7=, 1998-04-24 vascular dementia, and other dem~r ti~, for example, due to HIV disease, head trauma, Parkinson's ~li.ce~3~e, Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease, or due to multiple aetiologies; Parkinson's disease and other extra-pyrAmi-l~l movement disorders such as 5 medication-induced movement disorders, for example, neuroleptic-induced parkinsonism, neuroleptic m~lign~nt, syndrome, neuroleptic-induced acute dystonia, neuroleptic-induced acute ~k~t.hi~i~, neuroleptic-induced tardive dyskinesia and me~ t.ion-induced postural tremour; substance-related disorders arising from the use of alcohol, amphe~,~minf~s (or amphet~minf?-10 like substances) c~ffein~ nn~his, cocaine, hallucinogens, inh~ ntc andaerosol propellants, nicotine, opioids, phenylglycidine derivatives, sedatives, hypnotics, and anxiolytics, which substance-related disorders include dependence and abuse, into~rir.~tion, withdrawal, intoxication delerium, withdrawal delerium, persisting dementia, psychotic disorders, 15 mood disorders, anxiety disorders, sexual dysfunction and sleep disorders;
epilepsy; Down's syndrome; demyelinating ~li.ce~es such as MS and ALS
and other neuropathological disorders such as peripheral neuropathy, for example diabetic and chemotherapy-induced neuropathy, and postherpetic neuralgia, trigeminal neuralgia, segmental or intercostal neuralgia and 20 other neuralgias; and cerebral vascular disorders due to acute or chronic cerebrovascular damage such as cerebral infarction, subarachnoid haemorrhage or cerebral oedema.
Tachykinin, and in particular substance P, activity is also involved in nociception and pain. The compounds of the present invention will 25 therefore be of use in the prevention or treatment of diseases and conditions in which pain predominates, including soft tissue and peripheral damage, such as acute trauma, osteoarthritis, rheumatoid arthritis, musculo-skeletal pain, particularly after trauma, spinal pain, dental pain, myofascial pain syndromes, he~ h~, episiotomy pain, and 30 burns; deep and visceral pain, such as heart pain, muscle pain, eye pain, orofacial pain, for example, odontalgia, abdominal pain, gynaecological CA 0223~8~ 1998-04-24 WO 97/18206 PCT/GB96/0~766 pain, for example, dys~enorrhoea, and labour pain; pain associated with nerve and root damage, such as pain associated with peripheral nerve disorders, for example, nerve entrapment and brachial plexus avulsions, amputation, peripheral neuropathies, tic douloureux, atypical facial pain, 5 nerve root damage, and arachnoiditis; pain associated with carcinoma, often referred to as cancer pain; central nervous system pain, such as pain due to spinal cord or brain stem damage; low bacl~ pain; sciatica;
ankylosing spondylitis, gout; and scar pain.
Tachykinin, and in particular substance P, antagonists may also be 10 of use in the treatment of respiratory diseases, particularly those associated with excess mucus secretion, such as chronic obstructive airways disease, bronchopneumonia, chronic bronchiti.q, cystic fibrosis and asthma, adult respiratory distress syndrome, and bronchospasm;
infl:~mm~tory diseases such as infl~mm~tory bowel disease, psoriasis, 15 fibrositis, osteoarthritis, rheumatoid arthritis, pruritis and sunburn;
allergies such as eczema and rhinitis; hypersen~ ,ivi~y disorders such as poison ivy; opht.hzllmit~ diseases such as conjunctivitis, vernal conjunctivitis, and the like; opht.h~qlmi~ conditions associated with cell proliferation such as proliferative vitreoretinopathy; cutaneous diseases 20 such as contact dermatitis, atopic dermatitis, urticaria, and other eczematoid dermatitis.
Tachykinin, and in particular substance P, antagonists may also be of use in the treatment of neoplasms, including breast tumours, neuroganglioblastomas and small call carcinomas such as small cell lung 25 cancer.
Tachykinin, and in particular substance P, antagonists may also be of use in the treatment of gastrointestinal (GI) disorders, including infl~mmzltory disorders and diseases of the GI tract such as gastritis, gastroduodenal ulcers, gastric car-~in--m~.q, gastric lymphomas, disorders 30 associated with the neuronal control of viscera, ulcerative colitis, Crohn's disease, irritable bowel syndrome and emesis, including acute, delayed or CA 0223~8~ 1998-04-24 ~nt.i~iI3atory emesis such as emesis induced by chemotherapy, r~ *nn, toxins, viral or bacterial infections, pregnancy, vestibular disorders, for example, motion sickness, vertigo, ~li77.inesA and Meniere's disease~
surgery, migraine, variations in intercranial pressure, gastro-oesophageal reflux disease, acid indigestion, over indulgence in food or drink, acid stomach, waterbrash or regurgitation, heartburn, for example, episodic, nocturnal or meal-induced heartburn, and dyspepsia.
Tachykinin, and in particular substance P, antagonists may also be of use in the treatment of a variety of other conditions including stress related somatic disorders; reflex sympathetic dystrophy such as shoulder/hand syndrome; adverse immunological reactions such as rejection of transplanted tissues and disorders related to immune enh~nf ement or suppression such as systemic lupus erythematosus;
plasma extravasation resulting from cytokine chemotherapy, disorders of bladder filn~tion such as cystitis, bladder detrusor hyper-reflexia and incontinence; fibrosing and collagen diseases such as scleroderma and eosinophilic fas~ioli~Ri~; disorders of blood flow caused by vasodilation and vasospastic diseases such as ~ngin~, vascular hes~ he, migraine and Reynaud's disease; and pain or nociception attributable to or associated with any of the foregoing conditions, especially the tr~n~mi~sion of pain in mlgralne.
The compounds of formula (I~ are also of value in the treatment of a combination of the above conditions, in particular in the treatment of combined post-operative pain and post-operative nausea and vomiting.
The compounds of formula (I) are particularly useful in the treatment of emesis, including acute, delayed or anticipatory emesis~ such as emesis induced by chemotherapy, radiation, toxins, pregnancy, vestibular disorders, motion, surgery, migraine, and variations in intercranial pressure. Most especially, the compounds of formula (I) are of use in the treatment of emesis induced by antineoplastic (cytotoxic) , CA o223c,8c,c, 1998-04-24 WO 97/18206 PCT/CB9.S.~v2766 agents, including those routinely used in cancer chemotherapy, and emesis induced by other pharm~colo~ic~l agents, for example, rolipram.
F.~ mI3les of such chemotherapeutic agents include alkylating agents, for example, nitrogen mustards, ethyleneimin~ compounds, al~yl 5 sulphonates and other compounds with an alkylating action such as nitrosoureas, cisplatin and dacarbazine; antimetabolites, for example, folic acid, purine or pyrimi-lin~ antagonists; mitotic inhibitors, for example, vinca ~lk~loirl,$ and derivatives of podophyllotoxin; and cytotoxic antibiotics.
Particular examples of chemotherapeutic agents are described, for instance, by D. J. Stewart in Nausea and Vomit~ng: Recent Research and Clinical Aduances, Eds. J. Kll,h~rczyk et aZ, CRC Press Inc., Boca Raton, Florida, USA (1991) pages 177-203, especially page 188. Commonly used chemotherapeutic agents include cisplatin, dacarbazine (DTIC), dactinomycin, mechloreth~min~ (nitrogen mustard), streptozocin, cyclophosph~mi~le, carmustine (BCNU3, lomustine (CCNU3, doxorubicin (adriamycin), daunorubicin, procarbazine, mitomycin, cytarabine, - etoposide, methotrexate, 5-fluorouracil, vinblastine, vincristine, bleomycin and chlorambucil ~R. J. Gralla et al in Cancer Treatment Reports (1984) 68(1), 163-172].
The compounds of formula (I) are also of use in the treatment of emesis induced by radiation including radiation therapy such as in the treatment of cancer, or radiation sickness; and in the treatment of post-operative nausea and vomiting.
It will be appreciated that the compounds of formula (I) may be presented together with another therapeutic agent as a combined preparation for simultaneous, separate or seql~ent.izll use for the relief of emesis. Such combined preparations may be, for example, in the form of a twin pack.
A further aspect of the present invention comprises the compounds of formula (I3 in combination with a 5-HT3 antagonist, such as CA 0223~8~ 1998-04-24 ondansetron, granisetron or tropisetron, or other anti-emetic me~ m~nts, for example, a dopamine antagonist such as metoclopramide or GABAs receptor agonists such as baclofen. Additionally, a compound of formula (I) may be ~rlminiqtered in combination with an anti-5 infl~mm~tory corticosteroid, such as dexamethasone, tri~mf~in~lone,tri~mr.in-)lone acetonide, ffunisolide, budesonide, or others such as those disclosed in US patent nos. 2,7~39,118, 2,990,401, 3,048,~i81, 3,126,37~-"
THERA~I~U llC AG:~:NTS
This invention relates to a class of morpholine derivatives which are 5 useful as tachykinin antagonists.
The tachykinins are a group of naturally occurring peptides found widely distributed throughout m~mm~ n tissues, both within the central nervous system and in peripheral nervous and circulatory systems.
The tachykinins are distinguished by a conserved carboxyl-termin~l 10 sequence:
Phe-X-Gly-Leu-Met-NH2 At present, there are three known m~mm~ n tachykinins referred to as substance P, neurokinin A (NKA, substance K, neuromedin L) and neurokinin B (NKB, neuromedin K) (for review see J.E:. Maggio, Peptides (198~) 6(suppl. 3), 237-242). The current nomenclature rie.cign~tes the three tachykinin receptors me~ ing the biological actions of substance P, NKA and NKB as the NKl, NK2 and NK3 receptors, respectively.
Evidence for the usefulness of tachykinin receptor antagonists in pain, he~ .he, especially migraine, ~l~.heimer's disease, multiple sclerosis, attenuation of morphine withdrawal, cardiovascular changes, oedema, such as oedema caused by thermal injury, chronic infl~mm~tory diseases such as rheumatoid arthritis, asthma/bronchial hyperreactivity and other respiratory diseases including allergic rhinitis, infl~mm~tory diseases of the gut including ulcerative colitis and Crohn's disease, ocular 2~; injury and ocular infl~mmsltory diseases, proliferative vitreoretinopathy, irritable bowel syndrome and disorders of bladder function including cystitis and bladder detruser hyper-reflexia is reviewed in "Tachykinin Receptors and Tachykinin Receptor Antagonists", C.A. Maggi, R.
~ Patacchini, P. Rovero and A. Giachetti, J. Auto~l. Pharmcl,col. (1993) ~, 23-93.
CA 0223C78c7c, l99X-04-24 For instance, substance P is believed inter alia to be involved in the neurotr~tn~mi.c.ci--n of pain serl~tioIt~c [Otsuka et al, "Role of Substance P
as a Sensory Trz~n~mit~er in ,Spinal Cord and Sympathetic Ganglia" in 1982 Substance P in the Nervous System, Ciba Foundation Symposium 91, 13-34 (published by Pitman) and Otsuka andy~tn~t~ wa, "Does Substance P Act as a Pain Tr~n-~mttter?" TIPS (1987) 8, 506-510], specifically in the tr~tn~mi~ion of pain in migraine (B.E.B. Sandberg et al, J. Med Chem, (1982) 25, 1009) and in arthritis ~Levine et al in Science (1984) 226, 547-549]. Tachykinins have also been implicated in ga~ ,i~testinal (GI) disorders and diseases of the C~I tract such as infl~mtn~tory bowel disease ,rMantyh et al in Neuroscience (1988~ 2~(3), 817-37 and D. Regoli in "Trends in Cluster He~ t-.h~" Ed. Sicuteri et al Elsevier Scientific Publishers, Amsterdam (1987) page 85)3 and emesis rF.
D. Tattersall et al, Eur. J. Pharmacol., (1993) 250, R5-R6]. It is also hypothesised that there is a neurogenic me~.h~nt~m for arthritis in which substance P may play a role ~Kidd et al "A Neurogenic Me~h~tni~m for Symmetrical Arthritis" in The lancet, 11 November 1989 and Gronblad et al, "Neuropeptides in Synovium of Patients with Rheumatoid Arthritis and Osteoarthritis" in J. Rheumatol. (1988) 15(12), 1807-10]. Therefore, substance P is believed to be involved in the infl~mm~tory response in diseases such as rheumatoid arthritis and osteoarthritis, and fibrositis [O'Byrne et al, Arthritis and Rheumatism (1990) 33, 1023-8]. Other disease areas where tachykinin antagonists are believed to be useful are allergic conditions [Hamelet et al, Can. J. Pharmacol. Physiol. (1988) 66, 1361-7~, immunoregulation [Lotz et al, Science (1988) 241, 1218-21 and Kimball et al, J. Immunol . (1988) 141(10), 3564-9] vasodilation, bronchospasm, reflex or neuronal control of the viscera [Mantyh et al, Proc. Natl. Aca~. Sci., USA (1988) 85, 3235-9] and, possibly by arresting or slowing B-amyloid-mediated neurodegenerative changes [Yankner et al, Science (1990) 250, 279-82] in senile dementia of the Alzheimer type, Alzheimer's disease and Down's Syndrome.
CA 0223~8~ 1998-04-24 Tachykinin antagonists may also be useful in the treatment of small cell carcinomas, in particular small cell lung cancer (SCLC) [Langdon et al, Cancer Research (1992) ~, 4554-73.
Substance P may also play a role in demyelinating diseases such as 6 multiple sclerosis and amyotrophic lateral sclerosis [J. Luber-Narod et aZ, poster C.I.N.P. XVIIIth Congress, 28th June-~nd July 1992], and in disorders of bladder ~unction such as bladder detrusor hyper-reflexia (T}7,e Lancet, 16th May 1992, 1239).
It has furthermore been suggested that tachykinins have utility in 10 the following disorders: depression, dysthymic disorders, chronic obstructive airways disease, hypersen~iiLivily disorders such as poison ivy, vasospastic ~li.qe~qes such as ~ngins~ and Reynauld's disease, fibrosing and collagen diseases such as scleroderma and eosinophilic fas~irlis~qiq, re~1ex sympathetic dy~. o~hy such as shoulder/hand syndrome, addiction 15 disorders such as alcoholism, stress related somatic disorders, neuropathy, neuralgia, disorders related to immune enh~n~ement or suppression such as systemic lupus erythmatosus (European patent specification no.
0 436 334), oph~h~lmi~ disease such as conjuctivitis, vernal conjunctivitis, and the like, and cutaneous diseases such as contact dermatitis, atopic 20 derm~ti~i.q, urticaria, and other eczematoid dermatitis (European patent specification no. 0 394 989).
European patent specification no. 0 577 394 (published 5th January 1994) discloses morpholine and thiomorpholine tachykinin receptor antagonists of the general formula R X X X R~
wherein Rl is a large variety of substituents;
R2 and R3 are inter alia hydrogen;
1~4 iS inter alia R';
~R7 ~Y~
5 R5 is inter alia optionally substituted phenyl;
R6, R7 and R8 are a variety of substituents;
X is 0, S, SO or SO2;
Y is inter alia O; and ~ is hydrogen or Cl 4alkyl.
We have now found a further class of non-peptides which are potent antagonists of tachykinins, especially of substance P.
It is desirable that compounds may be ~mini~tered orally and by injection. Certain compounds have now been discovered which act as potent non-peptide tachykinin antagonists and which, by virtue of their 15 advantageous aqueous solubility, are particularly easily formulated for administration by both the oral and injection routes, for example in aqueous media.
The present invention provides compounds of the formula (I):
~RI
~R3 R9~ o ~ O
R9b J~ N
(I) CA 0223~8~ 1998-04-24 wherein X is a 5- or 6-membered C-linked heteroaromatic ring cont~ining 1 to 4 nitrogen atoms and optionally cont~inin~ in the ring one oxygen or sulphur atom;
Y is a group of the formula ~(CH2)nNR6R7~ or a methylene- or ethylene-linked imi~ 7.01yl group;
Z is hydrogen or Cl 4alkyl optionally substituted by a hydlo~y group;
Rl is hydrogen, halogen, Cl 6alkyl, Cl 6alkoxy, CF3, NO2, CN, SRa, SORa, SO2Ra, CO2Ra, CONRaRb, C2 6alkenyl, C2 6alkynyl or Cl 4alkyl substituted by Cl 4alkoxy, wherein Ra and Rb each independently represent hydrogen or Cl 4alkyl;
R2 is hydrogen, halogen, Cl 6alkyl, Cl 6alkoxy substituted by Cl q~lko~y or CF3;
R3 is hydrogen, halogen or CF3;
R4 is hydrogen, halogen, Cl.6alkyl, Cl.6alkoxy, hydlo~y, CF3, NO2, CN, SRa, SORa, SO2Ra, CO2Ra, CONRaRb, C2 6alkenyl, C2 6alkynyl or Cl 4alkyl substituted by Cl 4alkoxy, wherein Ra and Rb are as previously defined;
R5 is hydrogen, halogen, Cl 6alkyl, Cl 6alkoxy substituted by Cl ~s~lko~cy or CF3;
R6 is hydrogen, Cl 6alkyl, C3 7cycloalkyl, C3 7cycloalkylCl 4alkyl, phenyl, or C2.4alkyl substituted by Cl 4alkoxy or hydroxy;
R7 is hydrogen, Cl.6alkyl, C3.7cycloalkyl, C3.7cycloalkylCl 4alkyl, phenyl, or C2 4alkyl substituted by one or two substituents selected from Cl 4alkoxy, hydroxy or a 4, 5 or 6 membered heteroaliphatic ring cont~ining one or two heteroatoms selected from N, O and S;
or RG and R7, together with the nitrogen atom to which they are attached, form a saturated or partially saturated heterocyclic ring of 4 to 7 ring atoms, which ring may optionally contain in the ring one oxygen or sulphur atom or a group selected from NR8, S(O) or S(O)2 and which ring CA 0223~8~ 1998-04-24 may be optionally substituted by one or two groups selected fro~
hydroxyCl 4alkyl, Cl4alkoxyCl 4alkyl, oxo, CORa or CO2Ra where Ra is as previously defined;
or Rfi and R7 together with the nitrogen atom to which they are 5 attached, form a non-aromatic azabicyclic ring system of 6 to 12 ring atoms;
R8 is hydrogen, Cl 4alkyl, hy~Lo~yCl 4alkyl or Cl s~lko~ycl 4alkyl;
R9a and R9b are each independently hydrogen or Cl 4alkyl, or R9a and R9b are joined so, together with the carbon atoms to which they are 10 attached, there is formed a Cs 7 ring; and n is zero, 1 or 2;
and pharmaceutically acceptable salts thereof.
A preferred class of compounds of formula (I) is that wherein Rl is hydrogen, Cl 4alkyl, Cl 4alkoxy, halogen or CF3.
Another preferred class of compounds of formula (I) is that wherein R2 is hydrogen, Cl 4alkyl, Cl ~lkcl~y~ halogen or CF3.
Also preferred is the class of compounds of formula (I) wherein R3 is hydrogen, fluorine, chlorine or CF3.
A particularly preferred class of compounds of formula (I) is that wherein Rl is fluorine, chlorine or CF3.
Another particularly preferred class of compounds of formula (I) is that wherein R2 is hydrogen, ~1uorine, chlorine or CF3.
Also particularly preferred is the class of compounds of formula (I) wherein R3 is hydrogen, fluorine, chlorine or CF3.
2~ Pre~erably Rl and R2 are in the 3 and 5 positions of the phenyl ring More preferably Rl is 3-fluoro or 3-CF3.
More preferably R2 is 6-fluoro or 5-CF3.
More preferably R3 is hydrogeLl.
Most preferably Rl is 3-F or 3-CF3, R2 is 5-CF3 and R3 is hydrogen.
A further pre~erred class of compound of formula (I) is that wherein R~ is hydrogen.
CA 0223~8~ 1998-04-24 Another preferred class of compounds of formula (I) is that wherein R5 is hydrogen, fluorine, chlorine or CF3.
Preferably R4 is hydrogen and R~ is hydrogen or 4-fluoro.
Yet another preferred class of compounds of formula (I) is that 5 wherein R6 represents hydrogen, Cl 6alkyl or C2 4al~yl substituted by Cl 6alkoxy.
A yet further preferred class of compounds of formula (I) is that wherein R7 represents hydrogen, Cl 6alkyl or C2 4alkyl substituted by Cl 6alkoxy.
Also preferred is the class of compounds of formula (I) wherein R6 and R7, together with the nitrogen atom to which they are attached, form a saturated heterocyclic ring of 4, 5 or 6 ring atoms which may optionally contain in the ring one oxygen atom or the group NR8 (where R8 is hydrogen or methyl) and which ring may be optionally substituted by 15 hydroxyCl 4alkyl, Cl ~lko~yCl 4alkyl, oxo, CORa or CO2Ra.
In particular, the group NR6R7 preferably represents NEI2, NHCH3, N(CH3)2, azetidinyl, morpholino, thiomorpholino, piperazino, piperidino or pyrrolidino Also preferred is the class of compounds of formula (I~ wherein R9a 20 and R9b are each independently hydrogen or methyl. Preferably R9a is hydrogen. Preferably R9b is hydrogen. Most preferably R9a and R9b are both hydrogen.
From the foregoing it will be appreciated that a particularly apt sub-group of compounds of this invention are those of the formula (Ia) and 25 pharmaceutically acceptable salts thereof:
CA 02235855 l998-04-24 ~A~
~0~0 ~ N ~3 y,X
(Ia) wherein Al is fluorine or CF3;
A2 is fluorine or CF3;
A3 is fluorine or hydrogen;
and X, Y and Z are as defined in relation to formula (I).
A preferred group X for compounds of formula (I) or (Ia) is a ~-membered C-linked heteroaromatic ring cont~ining 1 to 4 nitrogen atoms and optionally con~inin~ in the ring one oxygen or sulphur atom.
Suitable groups include imi~7olyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, thiadiazolyl and o~ olyl groups.
A particularly preferred group X for compounds of formula (I) or (Ia) is a 5-membered C-linked heteroaromatic ring cont~ining 2 to 4 nitrogen atoms and optionally cont~ininF in the ring one sulphur atom.
An especially pre~erred class of compound of formula (I) or ~Ia) is that where X is an imifi~7;ol-2 yl, 1,2,4-triazol-3-yl, thiazolyl-2-yl or tetrazolyl group.
Another preferred class of compound of the present invention is that wherein Y is a group of the formula -(CHa)nNR6R7.
A preferred group Z for compounds of the formulae (I) or (Ia) is a Cl 2alkyl group optionally substituted by a hydroxy group, in particular a methyl or CH20H group, espeically a methyl group.
CA 0223~8~ 1998-04-24 WO 97/18206 PCT/GB96/0~766 Where the group NR6R7 forms a saturated heterocylic ring of 4 to 7 ring atoms which may optionally contain in the ring one oxygen or sulphur atom or a group selected from NR8, S(O) or S(0)2, suitable heterocylic groups include azetidinyl, pyrrolidino, piperidino, homopiperidino, piperazino, N-methylpiperazino, morpholino and thiomorpholino.
Suitable substituents on the saturated heterocyclic ring include CH~OH, CH20CH3, oxo, C~IO, C02H, C~02CH3, and CO2ClI2CH3.
When used herein the term "halogen" means fluorine, chlorine, bromine and iodine. The most apt halogen are fluorine and chlorine of which fluorine is preferred.
When used herein the term "alkyl" or "alkoxy" as a group or part of a group means that the group is straight or branched. ~mples of suitable alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl and t-butyl. F,~m~les of suitable al~oxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy and t-butoxy.
The term "alkenyl" as a group or part of a group means that the group is straight or branched and contains at least one double bond.
Examples of suitable alkenyl groups include vinyl and allyl.
The term "alkynyl" as a group or part of a group means that the group is straight or branched and contains at least one triple bond. An example of a suitable alkynyl group is propargyl.
Suitable cycloalkyl and cycloalkyl-alkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopLo~ llethyl and cyclobutylmethyl.
Where the group NR6R7 represents a heteroaliphatic ring of 4 to 7 ring atoms and said ring is partially saturated, a particularly preferred group is 3-pyrroline.
Where the group NR6R7 represents a non-aromatic azabicyclic ring system, such a system may contain between 6 and 12, and preferably 30 between 7 and 10, ring atoms. Suitable rings include 5-azabicyclo~2.1.1]hexyl, 5-azabicycloL2.2.1]heptyl, 6-azabicyclo~3.2.1~octyl, CA 0223~8~ 1998-04-24 2-azabicyclo~2.2.21octyl, 6-azabicyclo[3.2.2~nonyl, 6-azabicyclo[3.3.1]nonyl, 6-azabicyclo[3.3.2]decyl, 7-azabicyclo[4.3.~]decyl, 7-azabicyclo[4.4.1]undecyl and 8-azabicyclo[5.4.1]dodecyl, especially 5-azabicyclo[2.2. 1]heptyl and 6-azabicyclo[3.2. 1loctyl.
VVhere R7 represents a C2.4alkyl group substituted by a 5 or 6 membered heteroaliphatic ring col~t~inin~ one or two heteroatoms selected from N, O and S, suitable rings include pyrrolidino, piperidino, piperazino, morpholino, or thiomorpholino. Particularly preferred are nitrogen cont~ining heteroaliphatic rings, especially pyrrolidino and morpholino rings.
Specific compounds within the scope of the present invention include:
~-(5-amino-1,2,4-triazol-3-yl)-2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl) ethoxy)-3 -(S)-phenylmorpholine;
2-(~ (R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4 (2-N,N-dimethyl,qmin-)ethyl-2H-tetrazol-5-yl)-3-(S)-(4-fluorophenyl)morpholine;
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-dimethylaminomethyVthiazol-2-yl)-3-(S)-(4-fluorophenyl)morpholine;
2-(R~-(l-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydro;~yethoxy)-4-(2-amino-5-thiazolyl)-3-(S)-(4-fluorophenyl)morpholine;
and pharmaceutically acceptable salts thereof.
For use in medicine, the salts of the compounds of formula (I) will be non-toxic pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds according to the invention or of their non-toxic pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts such as those formed with hydrochloric acid, fumaric acid, p-toluenesulphonic acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Salts of amine groups may also comprise quaternary ammonium salts in which the amino nitrogen atom carries a suitable organic group such as an alkyl, CA 0223~8~ 1998-04-24 WO 97/18~06 PCT/GB96/02766 all~enyl, alkynyl or aralkyl moiety. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include metal salts such as alkali metal salts, e.g.
sodium or potassium salts; and ~lkRline earth metal salts, e.g. calcium or magnesium salts.
The pharmaceutically acceptable salts of the present invention may be formed by conventional means, such as by reacting the free base form of the product with one or more equivalents of the appropriate acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water which is removed in uacuo or by freeze drying or by e~eh~n~in~ the anions of an existing salt for another anion on a suitable ion ~r~h~nge resin.
The present invention includes within its scope prodrugs of the compounds of formula (I) above. In general, such prodrugs will be functional derivatives of the compounds of formula (I) which are readily convertible in viuo into the required compound of formula (I).
Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
A prodrug may be a pharmacologically inactive derivative of a biologically active substance (the "parent drug" or "parent molecule") that requires transformation within the body in order to release the active drug, and that has improved delivery properties over the parent drug molecule. The transformation in vivo may be, for example, as the result of some metabolic process, such as chemical or enzymatic hydrolysis of a carboxylic, phosphoric or sulphate ester, or reduction or oxidation of a susceptible functionality.
The present invention includes within its scope solvates of the compounds of formula (I) and salts thereof, for example, hydrates.
The compounds according to the invention have at least three asymmetric centres, and may accordingly exist both as enantiomers and as CA 0223~8~ 1998-04-24 WO 97/18206 PCT/GB96/~2766 diastereoisomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention.
The preferred compounds of the formula (I), and (Ia) will have the 5 2- and 3- substituent cis aad the preferred stereochemistry at the 2-position is that possessed by the compound of h'.~r~mple 1 (i.e. 2-(R)-), the preferred stereochemistry of the 3-position is that possessed by the compound of ~,~s~mple 1 (i.e. 3-(S)), and the preferred stereochemistry of the carbon to which the group Z is attached is either (R) when Z is 10 Cl 4alkyl (e.g. methyl~ or (S) when Z is Cl ~alkyl substituted by hydroxy (e.g. CH20H). Thus for example as shown in formula (Ib) R9 0 ~\~/~$~ R
Rgb ", ~ R3 Y ~s (Ib) The present invention further provides pharmaceutical compositions comprising one or more compounds of formula (I) in association with a pharmaceutically acceptable carrier.
Preferably the compositions according to the invention are in unit dosage forms such as tablets, pills, capsules, powders, granules, solutions 20 or suspensions, or suppositories, for oral, parenteral or rectal ~rimini.qtration, or administration by inhalation or insllffl~t.i-n.
For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, 25 stearic acid, magnesium stearate, dicalcium phosphate or gums, and other CA 0223~8~ 1998-04-24 pharmaceutical diluents, e.g. water, to form a solid preformulation composition cor~t~ining a homogeneous mixture of a compound of the present invention, or a non-toxic pharmaceutically 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 subdivided into equally effective unit dosage forms such as tablets, pills and capsules This solid preformulation composition is then subdivided into unit dosage forms of the type described above con~ining from 0.1 to about 500 mg of the active ingredient of the present invention. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill 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 which serves to resist disintegration in the stom~(~h and permits the inner component to pass intact into the duodenum or to be delayed in release A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shell~c, cetyl alcohol and cellulose acetate.
The liquid forms in which the novel compositions of the present invention may be incorporated for ~(1mini~stration orally or by injection include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and ~:imil~r pharmaceutical vehicles. Suitable dispersing or suspending agents for - aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, ~l~in~te, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.
Preferred compositions for administration by injection include those comprising a compound of formula (I), as the active ingredient, in CA 0223~8~ 1998-04-24 WO 97/18206 PCT/(,;1,5Cf~2766 association with a surface-active agent ~or wetting agent or surfactant) or in the form of an emulsion (as a wa~er-in-oil or oil-in-water emulsion).
Suitable surface-active agents include, in particular, non-ionic agents, such as polyoxyethylenesorbitans (e.g. TvveenTM 2(), 40, 6~, 80 or 86) and other sorbitans (e.g. SpanTU 20, 40, 60, 80 or 853. Compositions with a surface-active agent wi}l conveniently comprise between 0.05 and 5% surface-active agent, and preferably between 0.1 and 2.5%. It will be appreciated that other ingredients may be added, for example m~nnitol or other pharmaceutically acceptable vehicles, if necessary.
Suitable emulsions may be prepared using commercially available fat emulsions, such as IntralipidTM, LiposynTM, InfonutrolTM, LipofundinTM
and LipiphysanTM. The active ingredient may be either dissolved in a pre-mixed emulsion composition or alternatively it may be dissolved in an oil (e.g. soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil or almondoil) and an emulsion formed upon mi~ing with a phospholipid (e.g. egg phospholipids, soybean phospholipids or soybean lecithin) and water. It will be appreciated that other ingredients may be added, for example gylcerol or glucose, to ad~ust the tonicity of the emulsion. Suitable emulsions will typically contain up to 20% oil, for example, between 5 and 20%. The fat emulsion will preferably comprise fat droplets between 0.1 and 1.0,um, particularly 0.1 and 0.511m, and have a pH in the range of 5.0 to 8Ø
ParticuIarly preferred emulsion compositions are those prepared by mi7~inF a compound of formula ~I) with IntralipidTM or the components 25 thereof (soybean oil, egg phospholipids, glycerol and water).
Compositions for inh~l~ti-~n 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.
30 Preferably the compositions are administered by the oral or nasal respiratory route for local or systemic effect. ~ompositions in preferably CA 0223~8~ l998-04-24 WO 97/lU06 PCT/GB96/02766 sterile pharmaceutically acceptable solvents may be nebulised by use of inert gases. Nebulised solutions may be breathed directly from the nebulising device or the nebulising device may be attached to a face mask, tent or intermittent positive pressure breathing m~rhine. Solution, 5 suspension or powder compositions may be R~lmini~tered, preferably orally or nasally, from devices which deliver the formulation in an appropriate m~nner The present invention futher provides a process for the preparation of a pharmaceutical composition comprising a compound of formula (I), 10 which process comprises bringing a compound of formula (I) into asso~ t.i--n with a pharmaceutically acceptable carrier or excipient.
The compounds of formula (I) are of value in the treatment of a wide variety of ~linic~l conditions which are characterised by the presence of an excess of tachykinin, in particular substance P, act*ity.
1~ Thus, for exampie, an excess of tachykinin, and in particuiar substance P, activity is implicated in a variety of disorders of the central nervous system. Such disorders include mood disorders, such as depression or more particularly depressive disorders, for example, single episodic or recurrent ma~or depressive disorders and dysthymic disorders, 20 or bipolar disorders, for example, bipolar I disorder, bipolar II disorder and cyclothymic disorder; anxiety disorders, such as panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, specific phobias, for example, specific ~nimzll phobias, social phobias, obsessive-compulsive disorder, stress disorders including post-traumatic 25 stress disorder and acute stress disorder, and generalised anxiety disorders; schizophrenia and other psychotic disorders, for example, - schizophreniform disorders, schizoaffective disorders, delusional disorders, brief psychotic disorders, shared psychotic disorders and psychotic disorders with delusions or hallll~in~tions; delerium, dementia, and 30 amnestic and other cognitive or neurodegenerative disorders, such as Alzheimer's disease, senile dementia, dementia of the Alzheimer's type, CA 0223=,8=7=, 1998-04-24 vascular dementia, and other dem~r ti~, for example, due to HIV disease, head trauma, Parkinson's ~li.ce~3~e, Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease, or due to multiple aetiologies; Parkinson's disease and other extra-pyrAmi-l~l movement disorders such as 5 medication-induced movement disorders, for example, neuroleptic-induced parkinsonism, neuroleptic m~lign~nt, syndrome, neuroleptic-induced acute dystonia, neuroleptic-induced acute ~k~t.hi~i~, neuroleptic-induced tardive dyskinesia and me~ t.ion-induced postural tremour; substance-related disorders arising from the use of alcohol, amphe~,~minf~s (or amphet~minf?-10 like substances) c~ffein~ nn~his, cocaine, hallucinogens, inh~ ntc andaerosol propellants, nicotine, opioids, phenylglycidine derivatives, sedatives, hypnotics, and anxiolytics, which substance-related disorders include dependence and abuse, into~rir.~tion, withdrawal, intoxication delerium, withdrawal delerium, persisting dementia, psychotic disorders, 15 mood disorders, anxiety disorders, sexual dysfunction and sleep disorders;
epilepsy; Down's syndrome; demyelinating ~li.ce~es such as MS and ALS
and other neuropathological disorders such as peripheral neuropathy, for example diabetic and chemotherapy-induced neuropathy, and postherpetic neuralgia, trigeminal neuralgia, segmental or intercostal neuralgia and 20 other neuralgias; and cerebral vascular disorders due to acute or chronic cerebrovascular damage such as cerebral infarction, subarachnoid haemorrhage or cerebral oedema.
Tachykinin, and in particular substance P, activity is also involved in nociception and pain. The compounds of the present invention will 25 therefore be of use in the prevention or treatment of diseases and conditions in which pain predominates, including soft tissue and peripheral damage, such as acute trauma, osteoarthritis, rheumatoid arthritis, musculo-skeletal pain, particularly after trauma, spinal pain, dental pain, myofascial pain syndromes, he~ h~, episiotomy pain, and 30 burns; deep and visceral pain, such as heart pain, muscle pain, eye pain, orofacial pain, for example, odontalgia, abdominal pain, gynaecological CA 0223~8~ 1998-04-24 WO 97/18206 PCT/GB96/0~766 pain, for example, dys~enorrhoea, and labour pain; pain associated with nerve and root damage, such as pain associated with peripheral nerve disorders, for example, nerve entrapment and brachial plexus avulsions, amputation, peripheral neuropathies, tic douloureux, atypical facial pain, 5 nerve root damage, and arachnoiditis; pain associated with carcinoma, often referred to as cancer pain; central nervous system pain, such as pain due to spinal cord or brain stem damage; low bacl~ pain; sciatica;
ankylosing spondylitis, gout; and scar pain.
Tachykinin, and in particular substance P, antagonists may also be 10 of use in the treatment of respiratory diseases, particularly those associated with excess mucus secretion, such as chronic obstructive airways disease, bronchopneumonia, chronic bronchiti.q, cystic fibrosis and asthma, adult respiratory distress syndrome, and bronchospasm;
infl:~mm~tory diseases such as infl~mm~tory bowel disease, psoriasis, 15 fibrositis, osteoarthritis, rheumatoid arthritis, pruritis and sunburn;
allergies such as eczema and rhinitis; hypersen~ ,ivi~y disorders such as poison ivy; opht.hzllmit~ diseases such as conjunctivitis, vernal conjunctivitis, and the like; opht.h~qlmi~ conditions associated with cell proliferation such as proliferative vitreoretinopathy; cutaneous diseases 20 such as contact dermatitis, atopic dermatitis, urticaria, and other eczematoid dermatitis.
Tachykinin, and in particular substance P, antagonists may also be of use in the treatment of neoplasms, including breast tumours, neuroganglioblastomas and small call carcinomas such as small cell lung 25 cancer.
Tachykinin, and in particular substance P, antagonists may also be of use in the treatment of gastrointestinal (GI) disorders, including infl~mmzltory disorders and diseases of the GI tract such as gastritis, gastroduodenal ulcers, gastric car-~in--m~.q, gastric lymphomas, disorders 30 associated with the neuronal control of viscera, ulcerative colitis, Crohn's disease, irritable bowel syndrome and emesis, including acute, delayed or CA 0223~8~ 1998-04-24 ~nt.i~iI3atory emesis such as emesis induced by chemotherapy, r~ *nn, toxins, viral or bacterial infections, pregnancy, vestibular disorders, for example, motion sickness, vertigo, ~li77.inesA and Meniere's disease~
surgery, migraine, variations in intercranial pressure, gastro-oesophageal reflux disease, acid indigestion, over indulgence in food or drink, acid stomach, waterbrash or regurgitation, heartburn, for example, episodic, nocturnal or meal-induced heartburn, and dyspepsia.
Tachykinin, and in particular substance P, antagonists may also be of use in the treatment of a variety of other conditions including stress related somatic disorders; reflex sympathetic dystrophy such as shoulder/hand syndrome; adverse immunological reactions such as rejection of transplanted tissues and disorders related to immune enh~nf ement or suppression such as systemic lupus erythematosus;
plasma extravasation resulting from cytokine chemotherapy, disorders of bladder filn~tion such as cystitis, bladder detrusor hyper-reflexia and incontinence; fibrosing and collagen diseases such as scleroderma and eosinophilic fas~ioli~Ri~; disorders of blood flow caused by vasodilation and vasospastic diseases such as ~ngin~, vascular hes~ he, migraine and Reynaud's disease; and pain or nociception attributable to or associated with any of the foregoing conditions, especially the tr~n~mi~sion of pain in mlgralne.
The compounds of formula (I~ are also of value in the treatment of a combination of the above conditions, in particular in the treatment of combined post-operative pain and post-operative nausea and vomiting.
The compounds of formula (I) are particularly useful in the treatment of emesis, including acute, delayed or anticipatory emesis~ such as emesis induced by chemotherapy, radiation, toxins, pregnancy, vestibular disorders, motion, surgery, migraine, and variations in intercranial pressure. Most especially, the compounds of formula (I) are of use in the treatment of emesis induced by antineoplastic (cytotoxic) , CA o223c,8c,c, 1998-04-24 WO 97/18206 PCT/CB9.S.~v2766 agents, including those routinely used in cancer chemotherapy, and emesis induced by other pharm~colo~ic~l agents, for example, rolipram.
F.~ mI3les of such chemotherapeutic agents include alkylating agents, for example, nitrogen mustards, ethyleneimin~ compounds, al~yl 5 sulphonates and other compounds with an alkylating action such as nitrosoureas, cisplatin and dacarbazine; antimetabolites, for example, folic acid, purine or pyrimi-lin~ antagonists; mitotic inhibitors, for example, vinca ~lk~loirl,$ and derivatives of podophyllotoxin; and cytotoxic antibiotics.
Particular examples of chemotherapeutic agents are described, for instance, by D. J. Stewart in Nausea and Vomit~ng: Recent Research and Clinical Aduances, Eds. J. Kll,h~rczyk et aZ, CRC Press Inc., Boca Raton, Florida, USA (1991) pages 177-203, especially page 188. Commonly used chemotherapeutic agents include cisplatin, dacarbazine (DTIC), dactinomycin, mechloreth~min~ (nitrogen mustard), streptozocin, cyclophosph~mi~le, carmustine (BCNU3, lomustine (CCNU3, doxorubicin (adriamycin), daunorubicin, procarbazine, mitomycin, cytarabine, - etoposide, methotrexate, 5-fluorouracil, vinblastine, vincristine, bleomycin and chlorambucil ~R. J. Gralla et al in Cancer Treatment Reports (1984) 68(1), 163-172].
The compounds of formula (I) are also of use in the treatment of emesis induced by radiation including radiation therapy such as in the treatment of cancer, or radiation sickness; and in the treatment of post-operative nausea and vomiting.
It will be appreciated that the compounds of formula (I) may be presented together with another therapeutic agent as a combined preparation for simultaneous, separate or seql~ent.izll use for the relief of emesis. Such combined preparations may be, for example, in the form of a twin pack.
A further aspect of the present invention comprises the compounds of formula (I3 in combination with a 5-HT3 antagonist, such as CA 0223~8~ 1998-04-24 ondansetron, granisetron or tropisetron, or other anti-emetic me~ m~nts, for example, a dopamine antagonist such as metoclopramide or GABAs receptor agonists such as baclofen. Additionally, a compound of formula (I) may be ~rlminiqtered in combination with an anti-5 infl~mm~tory corticosteroid, such as dexamethasone, tri~mf~in~lone,tri~mr.in-)lone acetonide, ffunisolide, budesonide, or others such as those disclosed in US patent nos. 2,7~39,118, 2,990,401, 3,048,~i81, 3,126,37~-"
3,929,768, 3,996,369, 3,928,326 and 3,749,712. Dexamethasone (DecadronT'~1) is particularly preferred. I~urthermore, a compound of 10 formula (I) may be iq-lmini.qtered in combination with a chemotherapeutic agent such as an alkylating agent, antimetabolite, mitotic inhibitor or cytotoxic antibiotic, as described above. In general, the currently available dosage forms of the known therapeutic agents for use in such combinations will be suitable.
When tested in the ferret model of cisplatin-induced emesis described by F. D. Tattersall et al, in ~ur. J. pharmacol., (1993) 250, R5-R6, the compounds of the present invention were found to attenuate the retching and vomiting induced by cisplatin.
The compounds of formula (I) are also particularly useful in the 20 treatment of pain or nociception and/or infl~mm~tion and disorders associated therewith such as, for example, neuropathy, such as diabetic and chemotherapy-induced neuropathy, postherpetic and other neuralgias, asthma, osteroarthritis, rheumatoid arthritis, he~ he and especially migraine.
2~ The present invention further provides a compound of formula (I) for use in therapy.
According to a further or alternative aspect, the present invention provides a compound of formula (I) for use in the manufacture of a medicament for the treatment of physiological disorders associated with 30 an excess of tachykinins, especially substance P.
CA 0223~8~ 1998-04-24 The present invention also provides a method for the the treatment or prevention of physiological disorders associated with an excess of tachyk;nin.~, especially substance P, which method comprises ~mini~:tration to a patient in need thereof of a tachykinin reducing 5 amount of a compound of formula a) or a composition comprising a compound of formula (I).
For the treatment of certain conditions it may be desirable to employ a compound according to the present invention in conjunction with another pharm~cologically active agent. For example, for the treatment of 10 respiratory diseases such as asthma, a compound of formula (I) may be used in conjunction with a bronchodilator, such as a ,B2-adrenergic receptor agonist or tachykinin antagonist which acts at NK-2 receptors. The compound of formula a) and the bronchodilator may be sl~lmini.qtered to a patient simultaneously, sequentially or in combination.
Likewise, a compound of the present invention may be employed with a leukotriene antagonists, such as a leukotriene D4 antagonist such as a compound selected from those disclosed in European patent specification nos. 0 480 717 and 0 604 114 and in US patent nos. 4,859,692 and 5,270,324. This combination is particularly useful in the treatment of 20 respiratory diseases such as asthma, chronic bronchitis and cough.
The present invention accordingly provides a method for the treatment of a respiratory disease, such as asthma, which method comprises administration to a patient in need thereof of an effective amount of a compound of formula (I) and an effective amount of a 25 bronchodilator.
The present invention also provides a composition comprising a - compound of formula (I), a bronchodilator, and a pharmaceutically acceptable carrier.
It will be appreciated that for the treatment or prevention of 30 migraine, a compound of the present invention may be used in conjunction CA 0223~8~ 1998-04-24 with other anti-migraine agents, such as ergot~mines or 5-HTl agonists, especially sumatriptan, naratriptan, zolm~triptan or rizatriptan.
Likewise, for the treatment of behavioural hyperalgesia, a compound of the present invention may be used in con3unction with an 5 antagonist of N-methyl D-aspartate (N3!~DA), such as dizocilpine.
For the treatment or prevention of infl~mm~tory con~litinn~ in the lower urinary tract, especially cystitis, a compound of the present invention may be used iIl conjunction with an ~ntiinfl~mm~tory agent such as a bradykinin receptor antagonist.
It will be appreciated that for the treatment or prevention of pain or nociception, a compound of the present invention may be used in-conjunction with other analgesics, such as acet~minophen (paracetamol), aspirin and other NSAIDs and, in particular, opioid analgesics, especially morphine. Specific anti-;nfls~mm~tQry agents include diclofenac, 15 ibuprofen, indomethacin, ketoprofen, naproxen, piro~ m and sulindac.
Suitable opioid analgesics of use in conjl~nction with a compound of the present invention include morphine, codeine, dihydrocodeine, diacetylmorphine, hydrocodone, hydromorphone, levorphanol, oxymorphone, alfentanil, buprenorphine, butorphanol, fentanyl, 20 sufentanyl, meperidine, methadone, nalbuphine, propoxyphene and pentazocine; or a pharmaceutically acceptable salt thereof. Preferred salts of these opioid analgesics include morphine sulphate, morphine hydrochloride, morphine tartrate, codeine phosphate, codeine sulphate, dihydrocodeine bitartrate, diacetylmorphine hydro~hlnrifl~, hydrocodone 25 bitartrate, hydromorphone hydrochloride, levorphanol tartrate, oxymorphone hydrochloride, alfentanil hydrochloride, buprenorphine hydrochloride, butorphanol tartrate, fentanyl citrate, meperidine hydrochloride, methadone hydrochloride, nalbuphine hydrochloride, propoxyphene hydrochloride, propoxyphene napsylate 30 (2-naphthalenesulphonic acid (1:1) monohydrate), and pentazocine hydrochloride.
CA 022358C~C~ 1998-04-24 Therefore, in a further aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of the present invention and an analgesic, together with at least one pharmaceutically acceptable carrier or excipient.
In a further or alternative aspect of the present invention, there is provided a product comprising a compound of the present invention and an ~n~l~e.cic as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of pain or nociception.
It will be appreciated that for the treatment o~ depression or anxiety, a compound of the present invention may be used in conjl-nctir,n with other anti-depressant or anti-anxiety agents.
Suitable classes of anti-depressant agent include norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors (SSRIs), mono~mine oxidase inhibitors (MAOIs), reversible inhibitors of mono:~Tnine oxidase (RIl~As), serotonin and noradrenaline reuptake inhibitors (SNRIs), corticotropin rel~ing factor (CRF) antagonists, a-adrenoreceptor antagonists and atypical anti-depressants.
Suitable norepinephrine reuptal~e inhibitors include tertiary amine tricyclics and secondary amine tricyclics. Suitable examples of tertiary amine tricyclics include: amitriptyline, clomipramine, doxepin, imipramine and trimipramine, and pharmaceutically acceptable salts thereof. Suitable examples of secondary amine tricyclics include:
amoxapine, desipramine, maprotiline, nortriptyline and protriptyline, and pharmaceutically acceptable salts thereof.
Suitable selective serotonin reuptake inhibitors include: fluoxetine, fluvo~mine, paroxetine and sertraline, and pharmaceutically acceptable salts thereo~
Suitable monoamine oxidase inhibitors include: isocarboxazid, phenelzine, tranylcypromine and selegiline, and pharmaceutically acceptable salts thereof.
CA 0223C,8C,C, 1998-04-24 Suitable reversible inhibitors of monoamine oxidase include:
moclobemide, and pharmaceutically acceptable salts thereo~
Suitable serotonin and noradrenaline reuptake inhibitors of use in the present invention include: venl~f~n~, and ph~rm~ceutically 5 acceptable salts thereo~
Suitable (~RF antagonists incl~ Q those compounds described in International Patent Specification Nos. WO 94/13643, WO 94/13644, WO
94/13661, WO 94/13676 and WO 94/13677.
.Suitable atypical anti-depressants include: bupropion, lithium, 10 nefazodone, trazodone and V;ln~7in~" and ph~rmz.~eutically acceptable salts thereof.
Suitable classes of anti-anxiety agent include benzodiazepines and 5-HTlA agonists or antagonists, especially 5-HTlA partial agonists, and corticotropin releasing factor (CRF) antagonists.
Sllit~hl~ benzodiazepines include: alprazolam, chlordiazepoxide, clonazepam, chlorazepate, diazepam, halazepam, lorazepam, oxazepam and prazepam, and pharmaceutically acceptable salts thereo~
Suitable 5-~ITlA receptor agonists or antagonists include, in particular, the 5-HTlA receptor partial agonists buspirone, flesinoxan, gepirone and ipsaperone, and pharmaceutically acceptable salts thereo~
Therefore, in a further aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of the present invention and an anti-depressant or anti-anxiety agent, together with at least one pharmaceutically acceptable carrier or excipient.
In a further or alternative aspect of the present invention, there is provided a product comprising a compound of the present invention and an anti-depressant or anti-anxiety agent as a combined preparation for simultaneous, separate or sequential use for the treatment or prevention of depression and/or anxiety.
In the treatment of the conditions associated with an excess of tachykinins, a suitable dosage level is about 0.001 to 50 mg/kg per day, in , CA 0223~8~ 1998-04-24 particular about 0.01 to about 25 mgtkg, such as from about 0.05 to about 10 mgtkg per day.
For example, in the treatment of conditions involving the neurotr~n~mi~ n of pain sensations, a suitable dosage level is about 6 0.001 to 25 mgtkg per day, preferably about 0.005 to 10 mgtkg per day, and especially about 0.005 to 5 mg/kg per day. The compounds may be s~lmini~tered on a regimen of 1 to 4 times per day, preferably once or twice per day.
In the treatment of emesis using an injectable formulation, a s~ hl~ dosage level is about 0.001 to 10 mgtkg per day, preferably about 0.005 to 5 mgtkg per day, and especially 0.01 to 1 mgtkg per day; The compounds may be ~rlmini.~tered on a regimen of 1 to 4 times per day, preferably once or twice per day.
It will be appreciated that the amount of a compound of formula (I) required for use in any treatment will vary not only with the particular compounds or composition selected but also with the route of ~1mini~tration, the nature of the con-lit.ior- being treated, and the age and condition of the patient, and will ultimately be at the discretion of the attendant physician.
According to one general process (A), the compounds of formula (I), where X is a 1,2,4-triazol-3-yl group, may be prepared from compounds of formula (II) WO 97/18206 PCT/C~ 2766 ~R2 ~ ,3 R9~ ~ ~1/ ~
N~ ~R5 CN
(II) wherein Rl, R2, R3, R4, R5, R9a, R9b and Z are as defined in relation to formula (I) and R20 is phenyl or Cl.6alkyl, by reaction with hydrazine.
This reaction may be performed in a conventional n~nner, for example in a solvent such as an alcohol, for example, 2-propanol, at an elevated temperature between 50~C and 100~C, for example, at about 80~C.
According to another process (B), the compounds of formula (I) may be prepared from compounds of formula (III) r~R' ~ R2 ~<R3 R9~ o ~ O
Rgb ~ N ~
R2lo--(CH2)m~ ~ R
(III) wherein Rl R2 R3, R4, R5, R9a, R9b, X and Z are as defined in relation to formula (I) and R2l is a leaving group such as an alkyl- or CA 0223~8~ l998-04-24 WO 97/182~6 PCT/GB96/02766 aryl-sulphonyloxy group (e.g. mesylate or tosylate), and m is 1 or 2, by reaction with an amine of the formula HNR6R7 or imi~l~701~ (preferably in the form of its sodium salt).
The reaction is conveniently effected in a suitable organic solvent such as, for example, N,N-dimethylrc ~ mi-1e, preferably at elevated temperature and pressure, for example, at 60~C in a sealed vessel.
According to another process (C) the compounds of formula (I) may be prepared from compounds of formula (IV) ~R2 -~ 3 ~0~/~ R
R9~ N~ 4 Hal--(CM2)m~ ~R5R
~IV) wherein Rl, R2, R3, R4, R~, R9a, R9b, X and Z are as defined in relation to formula (I) and Hal is a halogen atom such as chlorine, bromine or iodine, especially chlorine, and m is 1 or 2, by reaction with an amine of the l~i formula HNRGR7 or imi~l~7.ole.
The reaction is conveniently effected in a suitable organic solvent such as an alcohol, for example, ethanol, preferably at ambient temperature .
According to another process (D), compounds of formula (I) may be 20 prepared by the interconversion of a compound of formula (I) in which the heteroaromatic ring represented by X is substituted by a group of the formula -(CH2)nNH2, by reaction with alkyl halides of the formula RG-Hal and R7-Hal, or a suitable ~1ih~ e designed to form a saturated heterocyclic ring, wherein R6 and R7 are as previously defined, and Hal is as previously defined, in the presence of a base.
Suitable bases of use in the reaction include alkali metal carbonates, such as, for example, potassium carbonate.
The reaction is conveniently effected in a suitable organic solvent, such as, for e~mple, N,N-dimethy~form~mitle, conveniently at a temperature between room temperature and 80~C, preferably at about 60~C.
Suitable ~lih~litles for forming a saturated heterocyclic ring include, for example, Hal-(CH2)4-Hal (to give a pyrroli~lino ring), Hal-(CHa)2O(CH2)2Hal (to give a morpholino ring), or Hal-(CHz)2NR8(CH2)2 Hal (to give a piperazino ring).
According to another process (E), compounds of formula (I) may be prepared from the compounds of formula (V) R
, :~
R9~ o ~ O
R9b ~ N ~
wherein Rl, R2, R3, R4, R5, R9a, R9b and Z are as defined in relation to formula (I), by reaction with a compound of formula (XI) 2~) Hal--X--Y
(XI) CA 02235855 l998-04-24 wherein Hal is a halogen atom such as chlorine, bromine or iodine, especially bromine.
The reaction is conveniently effected in the presence of a palladium 5 (0) catalyst, for example, tris(dibenzylidineacetone)dipalladium (O), and a catalytic amount of a co-ordinateing ligand such as 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP) or tri-o-tolylphosphine, in a suitable solvent such as tlio~ne or toluene, at an elevated temperature.
This re~ct.i~n is based upon the chemistry described by S. Buchwald in 10 Tetrahedron, vol ~;2, No 21, pp 7525-7546 and J. Am. Chem. Soc. 1996, 118,7215-7216.
The compounds of formula (II) may be prepared from an intermediate of formula (V~ by reaction with an aminocarbonimi-l~te following the procedure of P. J. Garrett, Tetrahedron (1993') ~, 165-176.
The compounds of formula (III) may be prepared by the addition of an intermediate of formula (VI) Hal-cH2(cH2)moH
(VI) where Hal and m are as previously defined, to a compound of formula (VII) ~R2 ~R3 R9~, o ~ ~
R9b~ N~
X ~R~
in the presence of a base as previously described in process (D). The resulting alcohol may then be derivatised in a conventional m~nn~r using, for example, mesyl or tosyl chloride and triethyl~rnin~ at an elevated 6 temperature, for example, at reflux.
The compounds of formula (IV) may be prepared by conventional methodology. Thus, for example, a compound of formula av) where X is a thi~ 7.01yl or oxazolyl group, may be prepared from a compound of formula (VIII) R9~ o ~ O
R9b J~ N 1 H2N Q ~5 (VIII) wherein Q is a sulphur or an oxygen atom, by reaction with a compound of the formula Hal-CH2C(O)(CH2)m-Hal where each Hal is independently as 15 previously defined, and m is as previously defined, in the presence of a base. The reaction is effected in a suitable solvent such as chloroform, conveniently at a temperature between room temperature and the reflux temperature of the chosen solvent. Suitable bases of use in the reaction include alkali metal carbonates, for example sodium bicarbonate.
Compounds of formula (VIII) where Q is S may be prepared by the reaction of a compound of formula (IX) CA 0223~8~ l998-04-24 ~R2 -~3 R9~ o ~ O R
R9b N ~1 CN l~R4 (IX) by reaction with hydrogen sulphide in the presence of a base. The reaction is conveniently effected in a suitable organic solvent such as an 5 alcohol, for example, ethanol. Suitable bases include alkali metal ~lko~i(1es, for example, potassium tert-bllto~
~ imil~rly, compounds of formula (VIII) where Q is O may be prepared by the partial hydrolysis of a cyanide of formula (IX) using conventional procedures, for example, using concentrated sulphuric acid;
10 or using formic acid and HCl or HBr; or using acetic acid and BF3.
Alternatively, compounds of formula (VIII) may be prepared by the reaction of a compound of formula (V) with an isocyanate or isothiocyanate of the formula (X) R30-N=C=Q
(X) where Q is as previously defined and R30 is a suitable amine protecting group, for example, a benzyl group or an alkyl- or aryl-sulphonyl group 20 such as a p-toluenesulphonyl group, using conventional methodology.
Compounds of formula (IX) may be prepared by the reaction of a compound of formula (V) with cyanogen bromide in the presence of a base such as an alkali metal carbonate, for example, potassium carbonate, CA 0223~8~ 1998-04-24 conveniently in an organic solvent such as N,N-dimethylform~m~-le, at a temperature between room temperature and 80~C.
Compounds of formula (VII~ may be prepared by analogous methods to those described above and those illustrated hereinafter. Such methods 5 will be readily apparent to a person skilled in the art, thus, in a further example, compounds of formula (VII) where X is a tetrazolyl group may be prepared by the reaction of a compound of formula ~IX) with a suitable azide such as sodium azide, or ammonium azide (preferably prepared in situ from sodium azide and ammonium chloride3. The reaction is 10 conveniently effected in a solvent such as N,N-dimethylformamide at an elevated temperature such as at the reflux temperature of the solvent.
The compounds of formula (V3 may be prepared as shown in the following scheme in which Arl represents the Rl, R2, R3 substituted phenyl group; Ar2 represents the R4, R5 substituted phenyl group and Ph 15 represents phenyl:
-Ar2-CH(NH~2)CO2H ~ Ar2-CH(NHCH2Ph)CO2Na BrCH2CH2Br, DMF
O O-CO~
~ NX A~ 2 (i) L-6P~ O O
Ph N A~
J
diaLl~yltitanocene Ph t~luene/THF
CHZI Z
O o~ (a) H2, Pd/C, O O~
Ar ethyl acetate/IPA
~N J~ A~.2 or (b) (i) BH3 ~ ,2 J (~) H2O2, NaOH
Ph (iii) H2, PdlC, (V) ethyl acetate/IPA
(Z = H or Cl 3alkyl) The following references describe methods which may be applied by the skilled worker to the chemical synthesis set forth above once the sl~lled worker has read the disclosure herein.
(i) D.A. Evans et al., J. Am. Chem. Soc., 112, 4011 (1990).
(ii) y~n~ ?wa~ I. et al., ~7. Med. Chem., 27, 849 (1984).
(iii) Duschinsky, R. et al., J. Am. Chem. Soc., ~, 657 (1948).
(iv) Tebbe F. N. et al., J. Am. Chem. Soc., 100, 3611 (1978).
(v) Petasis, N. A. et al., J. Am. Chem. Soc., 112, 6532 (1990).
(vi) Takai, K. et al., ~J. Org. Chem., ~, 4412 (1987).
Compounds of formulae (VI), (X) and (XI) are either known compounds or may be prepared by methods which will be readily apparent ~ to one skilled in the art.
The ~ mples disclosed herein produce predominently the preferred isomers. The unfavoured isomers are also produced on minor components.
WO 97/18206 PCT/(iL~!;G~ 766 If desired they may be isolated and employed to prepare the various stereoisomers in conventional m~nner, for example chromatographv using an appropriate chiral column. However, the skilled worker will appreciate that although the ~.~mples have been optimized to the production of the pre~erred isomers, v~r;~tion in solvent, reagents, chromatography etc can be readily employed to yield the other isomers.
L-Selectride is lithium tri-sec-butylborohydride.
Where they are not commercially available, the intermediates above may be prepared by the procedures described in the accompanying ~ mples or by alternative procedures which will be readily apparent to one skilled in the art.
During any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or react*e groups on any of the molecules concerned. This may be achieved by means of convent - n~l protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis~ John Wiley & Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.
The exemplified compounds of this invention were tested by the methods set out at pages 36 to 39 of International Patent Specification No.
WO 93/01165. The compounds were found to be active with ICso at the NKl receptor of less than 100nM.
The following ~mples i'lustrate the preparation of compounds 2~ according to the present invention:
(Sl-(4-Fluorophenvl)~lvcine Via Chiral Svnthesis:
SteP A: 3-(4-FluoroPhenvl)acetvl-4-(S)-benzvl-2-oxazQlidinone CA 0223~8~ 1998-04-24 AI1 oven-dried, 1 L 3-necked flask, equipped with a septum, nitrogen inlet, thermometer, and a magnetic stirring bar, was flushed with nitrogen and charged with a solution of 5.09g (33.0mmol) of 4~fluorophenylacetic acid in lOOml of anhydrous ether. The solution was cooled to -10~C and treated with 5.60ml (40.0mmol) of triethylamine followed by 4.30ml (35.0mmol) of trimethylacetyl chloride. A white precipitate formed immediately. The resulting mixture was stirred at -10~C for 40 minutes, then cooled to -78~C.
An oven-dried, 250ml round bottom flask, equipped with a septum and a magnetic stirring bar, was flushed with nitrogen and charged with a solution of 5.31g (30.0mmol) of 4-(S)-benzyl-2-oxazolidinone in 40ml of dry THF. The solution was stirred in a dry ice/acetone bath for 10 minutes, then 18.8ml of 1.6M n-butyllithium solution in hexanes was slowly added.
After 10 minutes, the l~thi~ted oxazolidinone solution was added, via i~ cannuia, to the above mixture in the 3-necked ~as~. The cooiing bath was removed from the resulting mixture and the temperature was allowed to rise to 0~C. The reaction was quenched with lOOml of saturated aqueous ammonium chloride solution, transferred to a 11 flask, and the ether and THF were removed i77, uacuo. The concentrated mixture was partitioned between 300ml of methylene chloride and 50ml of water and the layers were separated. The organic layer was washed with lOOml of 2N aqueous hydrochloric acid solution, 300ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate and concentrated i7~ vacuo. Flash chromatography on 400g of silica gel using 3:2 v/v hexanes/ether as the eluant afforded 8.95g of an oil that slowly solidified on st~n~ing.
Recrystallisation from 10:1 hexanes/ether afforded 7.89g (83%) of the title compound as a white solid: mp 64-66~C. MS (FAB): m/z 314 (M++H, 100%), 177 (M-ArCH2CO+H, 85%). lH NMR (400MHz, CDC13) ~ 2.76 (lH, dd, ~=13.2, 9.2Hz), 3.26 ~dd, J=13.2, 3.2Hz), 4.16-4.34 (4H, m), 4.65 (lH, m), 7.02-7.33 (9H, m).
CA 0223~8~ 1998-04-24 Analysis Calcd. for ClsH16FNO3: C, 69.00; H, 5.15; N, 4.47; F, 6.06;
Found: C, 68.86; ~I, 5.14; N, 4.48; F, 6.08%.
SteP B: 3-(~S~-Azido-(4-fluoroPhenvl)~acetYl-4-(S)-benzvl-2-oxazolidinone An oven-dried, 1l 3-necked flask, e~uipped with a septum, nitrogen inlet, thermometer, and a magnetic stirring bar, was flushed with nitrogen and charged with a solution of 58.0ml of lM potassium bis(trimethylsilyl)amide solution in toluene and 85ml of THF and was cooled to -78~C. An oven-dried 250ml round-bottomed ~lask, equipped with lO a septum and a magnetic stirring bar, was flushed with nitrogen and charged with a solution of 7.20g (23.0mmoV of 3-(4-fluorophenyl~acetyl-4-(S)-benzyl-2-oxazolidinone (from Step A) in 40ml of THF. The acyl oxazolidinone solution was stirred in a dry ice/acetone bath for 10 minutes, then transferred, via cannula, to the potassium bis(trimethylsilyl)amide 15 solution at such a rate that the internal temperature of the mixture was maintained below -70~C. The acyl oxazolidinone flask was rinsed with 15ml of THF and the rinse was added, via cannula, to the reaction mixture and the resulting mixture was stirred at -78~C for 30 minutes. An oven-dried, 250ml round-bottomed flask, equipped with a septum and a 20 magnetic stirring bar, was ~ushed with nitrogen and charged with a solution of 10.89g (35.0mmol) of 2,4,6-triisopropylphenylsulfonyl azide in 40ml of TH~. The azide solution was stirred in a dry ice/acetone bath for 10 minutes, then transferred, via cannula, to the reaction mixture at such a rate that the internal temperature of the mixture was maintained below 25 -70~C. After 2 minutes, the reaction was quenched with 6.0ml of glacial acetic acid, the cooling bath was removed and the mixture was stirred at room temperature for 18 hours. The quenched reaction mixture was partitioned between 300ml of ethyl acetate and 300ml of 50% saturated aqueous sodium bicarbonate solution. The organic layer was separated, 30 dried over magnesium sulfate, and concentrated in vacuo. Flash chromatography on 500g of silica gel using 2:1 v/v, then 1:1 v/v CA 0223~8~ l998-04-24 he~ne~/methylene ~hlori~e as the eluant afforded 5.45g (67%) of the title compound as an oil. IR Spectrum (neat, cm-l): 2104, 1781, 1702. IH NMR
(400MHz, CDCl3) ~ 2.86 (lH, dd, ~=13.2, ~.6Hz), 3.40 (lH, dd, J=13.2, 3.2Hz), 4.09-4.19 (2H, m), 4.62-4.68 (lH, m), 6.14 (lH, s), 7.07-7.47 (9H, 5 m)-Analysis Calcd. for ClsHlsFN4O3: C 61.01; H, 4.27; N, 15.81; F, 5.36;
Found: C, 60.99; H, 4.19; N, 15.80; F, 5.34%.
~ten C: (S)-Azido-(4-fluoroPhenvl)acetic acid A solution of 5.40g (15.2mmol) of 3-((S)-azido-(4-fluorophenyl))acetyl-4-(S)-benzyl-2-oxazoli-linc ll~ (from Step B) in 200ml of 3: 1 v/v THF/water was stirred in an ice bath for 10 minutes. 1.28g (30.4mmoV of lithium hydroxide monohydrate was added in one portion and the resulting mixture was stirred cold for 30 minutes. The reaction mixture was partitioned between lOOml of methylene chloride and lOOml of 25% saturated aqueous sodium bicarbonate solution and the layers were separated. The aqueous layer was washed with 2 x lOOml of methylene chloride and acidified to pH 2 with 2N a~ueous hydrochloric acid solution.
The resulting mixture was extracted with 2 x lOOml of ethyl acetate; the extracts were combined, washed with 50ml of saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated i77, vacuo to afford 2.30g (77%) of the title compound as an oil that was used in the following step without further purification. IR Spectrum (neat, cm~
2111, 1724. lH NMR (400MHz, CDCl3) ~ 5.06 (lH, s), 7.08-7.45 (4H, m), 8.75 (lH, br s).
SteP D: (S3-(4-FluoroPhenYl)~lYcine A mixture of 2.30g (11.8mmol) of (S)-azido-(4-fluorophenyl)acetic acid (from Step C), 2.50mg 10% palladium on carbon catalyst and 160ml 30 3: 1 v/v water/acetic acid was stirred under an al;mosphere of hydrogen for 18 hours. The reaction mixture was filtered through Cclite and the flask CA 0223~8~ 1998-04-24 and filter cake were rinsed well with about 1 litre of 3:1 vlv water/acetic acid. The filtrate was concer~trated in uacuo to about 50ml of volume.
300ml 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 1.99g (100%) of the title compound. lH NMR (400MHz, D20+
NaOD) ~ 3.97 (1~, s), 6.77 (2H, app t, J=8.8Hz), 7.01 (2H, app t, J=5.6Hz).
Via ~esolution:
SteP A' ~4-FluoroPhenvl)acetvl chloride A solution of 150g (0.974mol) of 4-(fluorophenyl)acetic acid and lml of N,N-dimethylform~mi(lr~ in 500ml of toluene at 40~C was treated with 20ml of thionyl chloride and heated to 40~C. An ~(1(1itional 61.2ml of thionyl chloride was added dropwise over 1.5 hours. After the addition, the solution was heated at 50~C for 1 hour, the solvent was removed in 15 vacuo and the residual oil was distilled at reduced pressure (1.5mm~g) to afford 150.4g (89.5%) of the title compound, bp = 68-70~C.
SteP B': Methyl 2-bromo-3-(4-fluorophenvl)acetate A mixture of 150.4g (0.872moV of 4-(fluorophenyl)acetyl chloride 20 (from Step A') and 174.5g (1.09mol~ of bromine was irradiated at 40-50~C
with a quartz lamp for 6 hours. The reaction mixture was added dropwise to 400ml of methanol and the solution was stirred for 16 hours. The solvent was removed ill vacuo and the residual oil was distilled at reduced pressure (1.5mm~g) to afford 198.5g (92%) of the title compound, bp =
25 106- 110~C.
Step C': Methvl (~-(4-fluorophenvl)~lvcine A solution of 24.7g (0.lmol) of methyl 2-bromo-2-(4-fluorophenyl)acetate (from Step B') and 2.28g (0.01mol) of benzyl 30 triethylammonium chloride in 25ml of methanol was treated with 6.8g (0.105mol) of sodium azide and the resulting mixture was stirred for 20 CA 0223~8~ 1998-04-24 hours at room temperature. The reaction mixture was filtered; the filtrate was diluted with 50ml of methanol and hydrogenated in the presence of 0.5g of 10% Pd/C at 50 psi for 1 hour. The solution was filtered and the solvent removed in vacuo. The residue was partitioned between 10%
6 aqueous sodium carbonate solution and ethyl acetate. The organic phase was washed with water, saturated aqueous sodium chloride solution dried over magnesium sulfate and concentrated in vacuo to afford 9.8g of the title compound as an oil.
10 SteD D': MethYl (O-(4-fluorol~henvl)~lYcinate A solution of 58.4g of methyl ( I ) 4-(fluorophenyl)glycinate ~from Step C') in 110ml of 7:1 v/v ethanol/water was mixed with a solution of 28.6g (0.0799moV of O,O'-(+)-dibenzoyltartaric acid ((+)-DBT) (28.6g, 0.0799mol) in 110ml of 7:1 v/v e~h~nol water and the resulting solution 15 was allowed to age at room temperature. Ethyl acetate (220ml) was added after crys~lli.c~tinn was complete and the resulting mixture was cooled to -20~C and filtered to afford 32.4g of methyl (S)-(4-fluorophenyVglycinate, (+)-DBT salt (ee = 93.2%). The mother liquors were concentrated in uacuo and the free base was liberated by partitioning between ethyl acetate and 20 aqueous sodium carbonate solution. A solution of free base, so obtained, in 110ml of 7:1 v/v ethanol/water was mixed with a solution of 28.6g (0.0799mol) of O,O'-(-)-dibenzoyltartaric acid ((-)-DBT) (28.6g, 0.0799mol) in llOml of 7:1 v/v ethanol:water and the resulting solution was allowed to age at room temperature. Ethyl acetate (220ml) was added after crysallisation was complete and the resulting mixture was cooled to -20~C
and filtered to afford 47.0g of methyl (R)-(4-fluorophenyl)glycinate, (-)-DBT
salt (ee = 75.8%). Recycling of the mother liquors and addition of (+)-DBT
gave a second crop of 7.4g of (S)-(4-fluorophenyl)glycinate, (~)-DBT salt (ee = 96.4%). The two crops of the (st-amino ester (39.8g) were combined in 200ml of 7:1 v/v ethanollwater, heated for 30 minutes and cooled to room temperature. Addition of ethyl acetate, cooling, and filtration afforded 31.7g of (S)-(4-fluorophenyVglycinate, (+~-DBT salt (ee > 98%).
l~.n~nti~ ric excess was determin~rl by chiral HPLC (Crownpak CR(+) 5%
MeOH in aq HCl04 pH2 1.5mlfmin 40~C 200nm).
A mixture of 17.5g of ~S)-(4-~Luorophenyl)glycinate, (+)-DBT salt and 6 32ml of 5.5N HCl (32ml) was heated at reflux for 1.5 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in 40ml of water. The aqueous solution was washed (3 x 30ml of ethyl acetate) and the layers were separated. The pH of the aqueous layer was adjusted to 7 using ammonium hydroxide and the precipitated solid was filtered to afford 7.4g of the title compound (ee = 98.8%).
When tested in the ferret model of cisplatin-induced emesis described by F. D. Tattersall et al, in ~ur. J. pharmacol., (1993) 250, R5-R6, the compounds of the present invention were found to attenuate the retching and vomiting induced by cisplatin.
The compounds of formula (I) are also particularly useful in the 20 treatment of pain or nociception and/or infl~mm~tion and disorders associated therewith such as, for example, neuropathy, such as diabetic and chemotherapy-induced neuropathy, postherpetic and other neuralgias, asthma, osteroarthritis, rheumatoid arthritis, he~ he and especially migraine.
2~ The present invention further provides a compound of formula (I) for use in therapy.
According to a further or alternative aspect, the present invention provides a compound of formula (I) for use in the manufacture of a medicament for the treatment of physiological disorders associated with 30 an excess of tachykinins, especially substance P.
CA 0223~8~ 1998-04-24 The present invention also provides a method for the the treatment or prevention of physiological disorders associated with an excess of tachyk;nin.~, especially substance P, which method comprises ~mini~:tration to a patient in need thereof of a tachykinin reducing 5 amount of a compound of formula a) or a composition comprising a compound of formula (I).
For the treatment of certain conditions it may be desirable to employ a compound according to the present invention in conjunction with another pharm~cologically active agent. For example, for the treatment of 10 respiratory diseases such as asthma, a compound of formula (I) may be used in conjunction with a bronchodilator, such as a ,B2-adrenergic receptor agonist or tachykinin antagonist which acts at NK-2 receptors. The compound of formula a) and the bronchodilator may be sl~lmini.qtered to a patient simultaneously, sequentially or in combination.
Likewise, a compound of the present invention may be employed with a leukotriene antagonists, such as a leukotriene D4 antagonist such as a compound selected from those disclosed in European patent specification nos. 0 480 717 and 0 604 114 and in US patent nos. 4,859,692 and 5,270,324. This combination is particularly useful in the treatment of 20 respiratory diseases such as asthma, chronic bronchitis and cough.
The present invention accordingly provides a method for the treatment of a respiratory disease, such as asthma, which method comprises administration to a patient in need thereof of an effective amount of a compound of formula (I) and an effective amount of a 25 bronchodilator.
The present invention also provides a composition comprising a - compound of formula (I), a bronchodilator, and a pharmaceutically acceptable carrier.
It will be appreciated that for the treatment or prevention of 30 migraine, a compound of the present invention may be used in conjunction CA 0223~8~ 1998-04-24 with other anti-migraine agents, such as ergot~mines or 5-HTl agonists, especially sumatriptan, naratriptan, zolm~triptan or rizatriptan.
Likewise, for the treatment of behavioural hyperalgesia, a compound of the present invention may be used in con3unction with an 5 antagonist of N-methyl D-aspartate (N3!~DA), such as dizocilpine.
For the treatment or prevention of infl~mm~tory con~litinn~ in the lower urinary tract, especially cystitis, a compound of the present invention may be used iIl conjunction with an ~ntiinfl~mm~tory agent such as a bradykinin receptor antagonist.
It will be appreciated that for the treatment or prevention of pain or nociception, a compound of the present invention may be used in-conjunction with other analgesics, such as acet~minophen (paracetamol), aspirin and other NSAIDs and, in particular, opioid analgesics, especially morphine. Specific anti-;nfls~mm~tQry agents include diclofenac, 15 ibuprofen, indomethacin, ketoprofen, naproxen, piro~ m and sulindac.
Suitable opioid analgesics of use in conjl~nction with a compound of the present invention include morphine, codeine, dihydrocodeine, diacetylmorphine, hydrocodone, hydromorphone, levorphanol, oxymorphone, alfentanil, buprenorphine, butorphanol, fentanyl, 20 sufentanyl, meperidine, methadone, nalbuphine, propoxyphene and pentazocine; or a pharmaceutically acceptable salt thereof. Preferred salts of these opioid analgesics include morphine sulphate, morphine hydrochloride, morphine tartrate, codeine phosphate, codeine sulphate, dihydrocodeine bitartrate, diacetylmorphine hydro~hlnrifl~, hydrocodone 25 bitartrate, hydromorphone hydrochloride, levorphanol tartrate, oxymorphone hydrochloride, alfentanil hydrochloride, buprenorphine hydrochloride, butorphanol tartrate, fentanyl citrate, meperidine hydrochloride, methadone hydrochloride, nalbuphine hydrochloride, propoxyphene hydrochloride, propoxyphene napsylate 30 (2-naphthalenesulphonic acid (1:1) monohydrate), and pentazocine hydrochloride.
CA 022358C~C~ 1998-04-24 Therefore, in a further aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of the present invention and an analgesic, together with at least one pharmaceutically acceptable carrier or excipient.
In a further or alternative aspect of the present invention, there is provided a product comprising a compound of the present invention and an ~n~l~e.cic as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of pain or nociception.
It will be appreciated that for the treatment o~ depression or anxiety, a compound of the present invention may be used in conjl-nctir,n with other anti-depressant or anti-anxiety agents.
Suitable classes of anti-depressant agent include norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors (SSRIs), mono~mine oxidase inhibitors (MAOIs), reversible inhibitors of mono:~Tnine oxidase (RIl~As), serotonin and noradrenaline reuptake inhibitors (SNRIs), corticotropin rel~ing factor (CRF) antagonists, a-adrenoreceptor antagonists and atypical anti-depressants.
Suitable norepinephrine reuptal~e inhibitors include tertiary amine tricyclics and secondary amine tricyclics. Suitable examples of tertiary amine tricyclics include: amitriptyline, clomipramine, doxepin, imipramine and trimipramine, and pharmaceutically acceptable salts thereof. Suitable examples of secondary amine tricyclics include:
amoxapine, desipramine, maprotiline, nortriptyline and protriptyline, and pharmaceutically acceptable salts thereof.
Suitable selective serotonin reuptake inhibitors include: fluoxetine, fluvo~mine, paroxetine and sertraline, and pharmaceutically acceptable salts thereo~
Suitable monoamine oxidase inhibitors include: isocarboxazid, phenelzine, tranylcypromine and selegiline, and pharmaceutically acceptable salts thereof.
CA 0223C,8C,C, 1998-04-24 Suitable reversible inhibitors of monoamine oxidase include:
moclobemide, and pharmaceutically acceptable salts thereo~
Suitable serotonin and noradrenaline reuptake inhibitors of use in the present invention include: venl~f~n~, and ph~rm~ceutically 5 acceptable salts thereo~
Suitable (~RF antagonists incl~ Q those compounds described in International Patent Specification Nos. WO 94/13643, WO 94/13644, WO
94/13661, WO 94/13676 and WO 94/13677.
.Suitable atypical anti-depressants include: bupropion, lithium, 10 nefazodone, trazodone and V;ln~7in~" and ph~rmz.~eutically acceptable salts thereof.
Suitable classes of anti-anxiety agent include benzodiazepines and 5-HTlA agonists or antagonists, especially 5-HTlA partial agonists, and corticotropin releasing factor (CRF) antagonists.
Sllit~hl~ benzodiazepines include: alprazolam, chlordiazepoxide, clonazepam, chlorazepate, diazepam, halazepam, lorazepam, oxazepam and prazepam, and pharmaceutically acceptable salts thereo~
Suitable 5-~ITlA receptor agonists or antagonists include, in particular, the 5-HTlA receptor partial agonists buspirone, flesinoxan, gepirone and ipsaperone, and pharmaceutically acceptable salts thereo~
Therefore, in a further aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of the present invention and an anti-depressant or anti-anxiety agent, together with at least one pharmaceutically acceptable carrier or excipient.
In a further or alternative aspect of the present invention, there is provided a product comprising a compound of the present invention and an anti-depressant or anti-anxiety agent as a combined preparation for simultaneous, separate or sequential use for the treatment or prevention of depression and/or anxiety.
In the treatment of the conditions associated with an excess of tachykinins, a suitable dosage level is about 0.001 to 50 mg/kg per day, in , CA 0223~8~ 1998-04-24 particular about 0.01 to about 25 mgtkg, such as from about 0.05 to about 10 mgtkg per day.
For example, in the treatment of conditions involving the neurotr~n~mi~ n of pain sensations, a suitable dosage level is about 6 0.001 to 25 mgtkg per day, preferably about 0.005 to 10 mgtkg per day, and especially about 0.005 to 5 mg/kg per day. The compounds may be s~lmini~tered on a regimen of 1 to 4 times per day, preferably once or twice per day.
In the treatment of emesis using an injectable formulation, a s~ hl~ dosage level is about 0.001 to 10 mgtkg per day, preferably about 0.005 to 5 mgtkg per day, and especially 0.01 to 1 mgtkg per day; The compounds may be ~rlmini.~tered on a regimen of 1 to 4 times per day, preferably once or twice per day.
It will be appreciated that the amount of a compound of formula (I) required for use in any treatment will vary not only with the particular compounds or composition selected but also with the route of ~1mini~tration, the nature of the con-lit.ior- being treated, and the age and condition of the patient, and will ultimately be at the discretion of the attendant physician.
According to one general process (A), the compounds of formula (I), where X is a 1,2,4-triazol-3-yl group, may be prepared from compounds of formula (II) WO 97/18206 PCT/C~ 2766 ~R2 ~ ,3 R9~ ~ ~1/ ~
N~ ~R5 CN
(II) wherein Rl, R2, R3, R4, R5, R9a, R9b and Z are as defined in relation to formula (I) and R20 is phenyl or Cl.6alkyl, by reaction with hydrazine.
This reaction may be performed in a conventional n~nner, for example in a solvent such as an alcohol, for example, 2-propanol, at an elevated temperature between 50~C and 100~C, for example, at about 80~C.
According to another process (B), the compounds of formula (I) may be prepared from compounds of formula (III) r~R' ~ R2 ~<R3 R9~ o ~ O
Rgb ~ N ~
R2lo--(CH2)m~ ~ R
(III) wherein Rl R2 R3, R4, R5, R9a, R9b, X and Z are as defined in relation to formula (I) and R2l is a leaving group such as an alkyl- or CA 0223~8~ l998-04-24 WO 97/182~6 PCT/GB96/02766 aryl-sulphonyloxy group (e.g. mesylate or tosylate), and m is 1 or 2, by reaction with an amine of the formula HNR6R7 or imi~l~701~ (preferably in the form of its sodium salt).
The reaction is conveniently effected in a suitable organic solvent such as, for example, N,N-dimethylrc ~ mi-1e, preferably at elevated temperature and pressure, for example, at 60~C in a sealed vessel.
According to another process (C) the compounds of formula (I) may be prepared from compounds of formula (IV) ~R2 -~ 3 ~0~/~ R
R9~ N~ 4 Hal--(CM2)m~ ~R5R
~IV) wherein Rl, R2, R3, R4, R~, R9a, R9b, X and Z are as defined in relation to formula (I) and Hal is a halogen atom such as chlorine, bromine or iodine, especially chlorine, and m is 1 or 2, by reaction with an amine of the l~i formula HNRGR7 or imi~l~7.ole.
The reaction is conveniently effected in a suitable organic solvent such as an alcohol, for example, ethanol, preferably at ambient temperature .
According to another process (D), compounds of formula (I) may be 20 prepared by the interconversion of a compound of formula (I) in which the heteroaromatic ring represented by X is substituted by a group of the formula -(CH2)nNH2, by reaction with alkyl halides of the formula RG-Hal and R7-Hal, or a suitable ~1ih~ e designed to form a saturated heterocyclic ring, wherein R6 and R7 are as previously defined, and Hal is as previously defined, in the presence of a base.
Suitable bases of use in the reaction include alkali metal carbonates, such as, for example, potassium carbonate.
The reaction is conveniently effected in a suitable organic solvent, such as, for e~mple, N,N-dimethy~form~mitle, conveniently at a temperature between room temperature and 80~C, preferably at about 60~C.
Suitable ~lih~litles for forming a saturated heterocyclic ring include, for example, Hal-(CH2)4-Hal (to give a pyrroli~lino ring), Hal-(CHa)2O(CH2)2Hal (to give a morpholino ring), or Hal-(CHz)2NR8(CH2)2 Hal (to give a piperazino ring).
According to another process (E), compounds of formula (I) may be prepared from the compounds of formula (V) R
, :~
R9~ o ~ O
R9b ~ N ~
wherein Rl, R2, R3, R4, R5, R9a, R9b and Z are as defined in relation to formula (I), by reaction with a compound of formula (XI) 2~) Hal--X--Y
(XI) CA 02235855 l998-04-24 wherein Hal is a halogen atom such as chlorine, bromine or iodine, especially bromine.
The reaction is conveniently effected in the presence of a palladium 5 (0) catalyst, for example, tris(dibenzylidineacetone)dipalladium (O), and a catalytic amount of a co-ordinateing ligand such as 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP) or tri-o-tolylphosphine, in a suitable solvent such as tlio~ne or toluene, at an elevated temperature.
This re~ct.i~n is based upon the chemistry described by S. Buchwald in 10 Tetrahedron, vol ~;2, No 21, pp 7525-7546 and J. Am. Chem. Soc. 1996, 118,7215-7216.
The compounds of formula (II) may be prepared from an intermediate of formula (V~ by reaction with an aminocarbonimi-l~te following the procedure of P. J. Garrett, Tetrahedron (1993') ~, 165-176.
The compounds of formula (III) may be prepared by the addition of an intermediate of formula (VI) Hal-cH2(cH2)moH
(VI) where Hal and m are as previously defined, to a compound of formula (VII) ~R2 ~R3 R9~, o ~ ~
R9b~ N~
X ~R~
in the presence of a base as previously described in process (D). The resulting alcohol may then be derivatised in a conventional m~nn~r using, for example, mesyl or tosyl chloride and triethyl~rnin~ at an elevated 6 temperature, for example, at reflux.
The compounds of formula (IV) may be prepared by conventional methodology. Thus, for example, a compound of formula av) where X is a thi~ 7.01yl or oxazolyl group, may be prepared from a compound of formula (VIII) R9~ o ~ O
R9b J~ N 1 H2N Q ~5 (VIII) wherein Q is a sulphur or an oxygen atom, by reaction with a compound of the formula Hal-CH2C(O)(CH2)m-Hal where each Hal is independently as 15 previously defined, and m is as previously defined, in the presence of a base. The reaction is effected in a suitable solvent such as chloroform, conveniently at a temperature between room temperature and the reflux temperature of the chosen solvent. Suitable bases of use in the reaction include alkali metal carbonates, for example sodium bicarbonate.
Compounds of formula (VIII) where Q is S may be prepared by the reaction of a compound of formula (IX) CA 0223~8~ l998-04-24 ~R2 -~3 R9~ o ~ O R
R9b N ~1 CN l~R4 (IX) by reaction with hydrogen sulphide in the presence of a base. The reaction is conveniently effected in a suitable organic solvent such as an 5 alcohol, for example, ethanol. Suitable bases include alkali metal ~lko~i(1es, for example, potassium tert-bllto~
~ imil~rly, compounds of formula (VIII) where Q is O may be prepared by the partial hydrolysis of a cyanide of formula (IX) using conventional procedures, for example, using concentrated sulphuric acid;
10 or using formic acid and HCl or HBr; or using acetic acid and BF3.
Alternatively, compounds of formula (VIII) may be prepared by the reaction of a compound of formula (V) with an isocyanate or isothiocyanate of the formula (X) R30-N=C=Q
(X) where Q is as previously defined and R30 is a suitable amine protecting group, for example, a benzyl group or an alkyl- or aryl-sulphonyl group 20 such as a p-toluenesulphonyl group, using conventional methodology.
Compounds of formula (IX) may be prepared by the reaction of a compound of formula (V) with cyanogen bromide in the presence of a base such as an alkali metal carbonate, for example, potassium carbonate, CA 0223~8~ 1998-04-24 conveniently in an organic solvent such as N,N-dimethylform~m~-le, at a temperature between room temperature and 80~C.
Compounds of formula (VII~ may be prepared by analogous methods to those described above and those illustrated hereinafter. Such methods 5 will be readily apparent to a person skilled in the art, thus, in a further example, compounds of formula (VII) where X is a tetrazolyl group may be prepared by the reaction of a compound of formula ~IX) with a suitable azide such as sodium azide, or ammonium azide (preferably prepared in situ from sodium azide and ammonium chloride3. The reaction is 10 conveniently effected in a solvent such as N,N-dimethylformamide at an elevated temperature such as at the reflux temperature of the solvent.
The compounds of formula (V3 may be prepared as shown in the following scheme in which Arl represents the Rl, R2, R3 substituted phenyl group; Ar2 represents the R4, R5 substituted phenyl group and Ph 15 represents phenyl:
-Ar2-CH(NH~2)CO2H ~ Ar2-CH(NHCH2Ph)CO2Na BrCH2CH2Br, DMF
O O-CO~
~ NX A~ 2 (i) L-6P~ O O
Ph N A~
J
diaLl~yltitanocene Ph t~luene/THF
CHZI Z
O o~ (a) H2, Pd/C, O O~
Ar ethyl acetate/IPA
~N J~ A~.2 or (b) (i) BH3 ~ ,2 J (~) H2O2, NaOH
Ph (iii) H2, PdlC, (V) ethyl acetate/IPA
(Z = H or Cl 3alkyl) The following references describe methods which may be applied by the skilled worker to the chemical synthesis set forth above once the sl~lled worker has read the disclosure herein.
(i) D.A. Evans et al., J. Am. Chem. Soc., 112, 4011 (1990).
(ii) y~n~ ?wa~ I. et al., ~7. Med. Chem., 27, 849 (1984).
(iii) Duschinsky, R. et al., J. Am. Chem. Soc., ~, 657 (1948).
(iv) Tebbe F. N. et al., J. Am. Chem. Soc., 100, 3611 (1978).
(v) Petasis, N. A. et al., J. Am. Chem. Soc., 112, 6532 (1990).
(vi) Takai, K. et al., ~J. Org. Chem., ~, 4412 (1987).
Compounds of formulae (VI), (X) and (XI) are either known compounds or may be prepared by methods which will be readily apparent ~ to one skilled in the art.
The ~ mples disclosed herein produce predominently the preferred isomers. The unfavoured isomers are also produced on minor components.
WO 97/18206 PCT/(iL~!;G~ 766 If desired they may be isolated and employed to prepare the various stereoisomers in conventional m~nner, for example chromatographv using an appropriate chiral column. However, the skilled worker will appreciate that although the ~.~mples have been optimized to the production of the pre~erred isomers, v~r;~tion in solvent, reagents, chromatography etc can be readily employed to yield the other isomers.
L-Selectride is lithium tri-sec-butylborohydride.
Where they are not commercially available, the intermediates above may be prepared by the procedures described in the accompanying ~ mples or by alternative procedures which will be readily apparent to one skilled in the art.
During any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or react*e groups on any of the molecules concerned. This may be achieved by means of convent - n~l protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis~ John Wiley & Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.
The exemplified compounds of this invention were tested by the methods set out at pages 36 to 39 of International Patent Specification No.
WO 93/01165. The compounds were found to be active with ICso at the NKl receptor of less than 100nM.
The following ~mples i'lustrate the preparation of compounds 2~ according to the present invention:
(Sl-(4-Fluorophenvl)~lvcine Via Chiral Svnthesis:
SteP A: 3-(4-FluoroPhenvl)acetvl-4-(S)-benzvl-2-oxazQlidinone CA 0223~8~ 1998-04-24 AI1 oven-dried, 1 L 3-necked flask, equipped with a septum, nitrogen inlet, thermometer, and a magnetic stirring bar, was flushed with nitrogen and charged with a solution of 5.09g (33.0mmol) of 4~fluorophenylacetic acid in lOOml of anhydrous ether. The solution was cooled to -10~C and treated with 5.60ml (40.0mmol) of triethylamine followed by 4.30ml (35.0mmol) of trimethylacetyl chloride. A white precipitate formed immediately. The resulting mixture was stirred at -10~C for 40 minutes, then cooled to -78~C.
An oven-dried, 250ml round bottom flask, equipped with a septum and a magnetic stirring bar, was flushed with nitrogen and charged with a solution of 5.31g (30.0mmol) of 4-(S)-benzyl-2-oxazolidinone in 40ml of dry THF. The solution was stirred in a dry ice/acetone bath for 10 minutes, then 18.8ml of 1.6M n-butyllithium solution in hexanes was slowly added.
After 10 minutes, the l~thi~ted oxazolidinone solution was added, via i~ cannuia, to the above mixture in the 3-necked ~as~. The cooiing bath was removed from the resulting mixture and the temperature was allowed to rise to 0~C. The reaction was quenched with lOOml of saturated aqueous ammonium chloride solution, transferred to a 11 flask, and the ether and THF were removed i77, uacuo. The concentrated mixture was partitioned between 300ml of methylene chloride and 50ml of water and the layers were separated. The organic layer was washed with lOOml of 2N aqueous hydrochloric acid solution, 300ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate and concentrated i7~ vacuo. Flash chromatography on 400g of silica gel using 3:2 v/v hexanes/ether as the eluant afforded 8.95g of an oil that slowly solidified on st~n~ing.
Recrystallisation from 10:1 hexanes/ether afforded 7.89g (83%) of the title compound as a white solid: mp 64-66~C. MS (FAB): m/z 314 (M++H, 100%), 177 (M-ArCH2CO+H, 85%). lH NMR (400MHz, CDC13) ~ 2.76 (lH, dd, ~=13.2, 9.2Hz), 3.26 ~dd, J=13.2, 3.2Hz), 4.16-4.34 (4H, m), 4.65 (lH, m), 7.02-7.33 (9H, m).
CA 0223~8~ 1998-04-24 Analysis Calcd. for ClsH16FNO3: C, 69.00; H, 5.15; N, 4.47; F, 6.06;
Found: C, 68.86; ~I, 5.14; N, 4.48; F, 6.08%.
SteP B: 3-(~S~-Azido-(4-fluoroPhenvl)~acetYl-4-(S)-benzvl-2-oxazolidinone An oven-dried, 1l 3-necked flask, e~uipped with a septum, nitrogen inlet, thermometer, and a magnetic stirring bar, was flushed with nitrogen and charged with a solution of 58.0ml of lM potassium bis(trimethylsilyl)amide solution in toluene and 85ml of THF and was cooled to -78~C. An oven-dried 250ml round-bottomed ~lask, equipped with lO a septum and a magnetic stirring bar, was flushed with nitrogen and charged with a solution of 7.20g (23.0mmoV of 3-(4-fluorophenyl~acetyl-4-(S)-benzyl-2-oxazolidinone (from Step A) in 40ml of THF. The acyl oxazolidinone solution was stirred in a dry ice/acetone bath for 10 minutes, then transferred, via cannula, to the potassium bis(trimethylsilyl)amide 15 solution at such a rate that the internal temperature of the mixture was maintained below -70~C. The acyl oxazolidinone flask was rinsed with 15ml of THF and the rinse was added, via cannula, to the reaction mixture and the resulting mixture was stirred at -78~C for 30 minutes. An oven-dried, 250ml round-bottomed flask, equipped with a septum and a 20 magnetic stirring bar, was ~ushed with nitrogen and charged with a solution of 10.89g (35.0mmol) of 2,4,6-triisopropylphenylsulfonyl azide in 40ml of TH~. The azide solution was stirred in a dry ice/acetone bath for 10 minutes, then transferred, via cannula, to the reaction mixture at such a rate that the internal temperature of the mixture was maintained below 25 -70~C. After 2 minutes, the reaction was quenched with 6.0ml of glacial acetic acid, the cooling bath was removed and the mixture was stirred at room temperature for 18 hours. The quenched reaction mixture was partitioned between 300ml of ethyl acetate and 300ml of 50% saturated aqueous sodium bicarbonate solution. The organic layer was separated, 30 dried over magnesium sulfate, and concentrated in vacuo. Flash chromatography on 500g of silica gel using 2:1 v/v, then 1:1 v/v CA 0223~8~ l998-04-24 he~ne~/methylene ~hlori~e as the eluant afforded 5.45g (67%) of the title compound as an oil. IR Spectrum (neat, cm-l): 2104, 1781, 1702. IH NMR
(400MHz, CDCl3) ~ 2.86 (lH, dd, ~=13.2, ~.6Hz), 3.40 (lH, dd, J=13.2, 3.2Hz), 4.09-4.19 (2H, m), 4.62-4.68 (lH, m), 6.14 (lH, s), 7.07-7.47 (9H, 5 m)-Analysis Calcd. for ClsHlsFN4O3: C 61.01; H, 4.27; N, 15.81; F, 5.36;
Found: C, 60.99; H, 4.19; N, 15.80; F, 5.34%.
~ten C: (S)-Azido-(4-fluoroPhenvl)acetic acid A solution of 5.40g (15.2mmol) of 3-((S)-azido-(4-fluorophenyl))acetyl-4-(S)-benzyl-2-oxazoli-linc ll~ (from Step B) in 200ml of 3: 1 v/v THF/water was stirred in an ice bath for 10 minutes. 1.28g (30.4mmoV of lithium hydroxide monohydrate was added in one portion and the resulting mixture was stirred cold for 30 minutes. The reaction mixture was partitioned between lOOml of methylene chloride and lOOml of 25% saturated aqueous sodium bicarbonate solution and the layers were separated. The aqueous layer was washed with 2 x lOOml of methylene chloride and acidified to pH 2 with 2N a~ueous hydrochloric acid solution.
The resulting mixture was extracted with 2 x lOOml of ethyl acetate; the extracts were combined, washed with 50ml of saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated i77, vacuo to afford 2.30g (77%) of the title compound as an oil that was used in the following step without further purification. IR Spectrum (neat, cm~
2111, 1724. lH NMR (400MHz, CDCl3) ~ 5.06 (lH, s), 7.08-7.45 (4H, m), 8.75 (lH, br s).
SteP D: (S3-(4-FluoroPhenYl)~lYcine A mixture of 2.30g (11.8mmol) of (S)-azido-(4-fluorophenyl)acetic acid (from Step C), 2.50mg 10% palladium on carbon catalyst and 160ml 30 3: 1 v/v water/acetic acid was stirred under an al;mosphere of hydrogen for 18 hours. The reaction mixture was filtered through Cclite and the flask CA 0223~8~ 1998-04-24 and filter cake were rinsed well with about 1 litre of 3:1 vlv water/acetic acid. The filtrate was concer~trated in uacuo to about 50ml of volume.
300ml 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 1.99g (100%) of the title compound. lH NMR (400MHz, D20+
NaOD) ~ 3.97 (1~, s), 6.77 (2H, app t, J=8.8Hz), 7.01 (2H, app t, J=5.6Hz).
Via ~esolution:
SteP A' ~4-FluoroPhenvl)acetvl chloride A solution of 150g (0.974mol) of 4-(fluorophenyl)acetic acid and lml of N,N-dimethylform~mi(lr~ in 500ml of toluene at 40~C was treated with 20ml of thionyl chloride and heated to 40~C. An ~(1(1itional 61.2ml of thionyl chloride was added dropwise over 1.5 hours. After the addition, the solution was heated at 50~C for 1 hour, the solvent was removed in 15 vacuo and the residual oil was distilled at reduced pressure (1.5mm~g) to afford 150.4g (89.5%) of the title compound, bp = 68-70~C.
SteP B': Methyl 2-bromo-3-(4-fluorophenvl)acetate A mixture of 150.4g (0.872moV of 4-(fluorophenyl)acetyl chloride 20 (from Step A') and 174.5g (1.09mol~ of bromine was irradiated at 40-50~C
with a quartz lamp for 6 hours. The reaction mixture was added dropwise to 400ml of methanol and the solution was stirred for 16 hours. The solvent was removed ill vacuo and the residual oil was distilled at reduced pressure (1.5mm~g) to afford 198.5g (92%) of the title compound, bp =
25 106- 110~C.
Step C': Methvl (~-(4-fluorophenvl)~lvcine A solution of 24.7g (0.lmol) of methyl 2-bromo-2-(4-fluorophenyl)acetate (from Step B') and 2.28g (0.01mol) of benzyl 30 triethylammonium chloride in 25ml of methanol was treated with 6.8g (0.105mol) of sodium azide and the resulting mixture was stirred for 20 CA 0223~8~ 1998-04-24 hours at room temperature. The reaction mixture was filtered; the filtrate was diluted with 50ml of methanol and hydrogenated in the presence of 0.5g of 10% Pd/C at 50 psi for 1 hour. The solution was filtered and the solvent removed in vacuo. The residue was partitioned between 10%
6 aqueous sodium carbonate solution and ethyl acetate. The organic phase was washed with water, saturated aqueous sodium chloride solution dried over magnesium sulfate and concentrated in vacuo to afford 9.8g of the title compound as an oil.
10 SteD D': MethYl (O-(4-fluorol~henvl)~lYcinate A solution of 58.4g of methyl ( I ) 4-(fluorophenyl)glycinate ~from Step C') in 110ml of 7:1 v/v ethanol/water was mixed with a solution of 28.6g (0.0799moV of O,O'-(+)-dibenzoyltartaric acid ((+)-DBT) (28.6g, 0.0799mol) in 110ml of 7:1 v/v e~h~nol water and the resulting solution 15 was allowed to age at room temperature. Ethyl acetate (220ml) was added after crys~lli.c~tinn was complete and the resulting mixture was cooled to -20~C and filtered to afford 32.4g of methyl (S)-(4-fluorophenyVglycinate, (+)-DBT salt (ee = 93.2%). The mother liquors were concentrated in uacuo and the free base was liberated by partitioning between ethyl acetate and 20 aqueous sodium carbonate solution. A solution of free base, so obtained, in 110ml of 7:1 v/v ethanol/water was mixed with a solution of 28.6g (0.0799mol) of O,O'-(-)-dibenzoyltartaric acid ((-)-DBT) (28.6g, 0.0799mol) in llOml of 7:1 v/v ethanol:water and the resulting solution was allowed to age at room temperature. Ethyl acetate (220ml) was added after crysallisation was complete and the resulting mixture was cooled to -20~C
and filtered to afford 47.0g of methyl (R)-(4-fluorophenyl)glycinate, (-)-DBT
salt (ee = 75.8%). Recycling of the mother liquors and addition of (+)-DBT
gave a second crop of 7.4g of (S)-(4-fluorophenyl)glycinate, (~)-DBT salt (ee = 96.4%). The two crops of the (st-amino ester (39.8g) were combined in 200ml of 7:1 v/v ethanollwater, heated for 30 minutes and cooled to room temperature. Addition of ethyl acetate, cooling, and filtration afforded 31.7g of (S)-(4-fluorophenyVglycinate, (+~-DBT salt (ee > 98%).
l~.n~nti~ ric excess was determin~rl by chiral HPLC (Crownpak CR(+) 5%
MeOH in aq HCl04 pH2 1.5mlfmin 40~C 200nm).
A mixture of 17.5g of ~S)-(4-~Luorophenyl)glycinate, (+)-DBT salt and 6 32ml of 5.5N HCl (32ml) was heated at reflux for 1.5 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in 40ml of water. The aqueous solution was washed (3 x 30ml of ethyl acetate) and the layers were separated. The pH of the aqueous layer was adjusted to 7 using ammonium hydroxide and the precipitated solid was filtered to afford 7.4g of the title compound (ee = 98.8%).
4-Benzvl-3-(S)-(4-fluoro~henvl~-2-mor~hoIinone SteP A: N-Benzvl-~S)-(4-fluoro~henvl)~Ivcine A solution of 1.87g (11.05mmol) of (S)-(4-~1uorophenyl)-glycine (from Description 1) and 1.12ml (11.lmmol) of benzaldehyde in 11.1ml of lN
aqueous sodium hydroxide solution and 11ml of methanol at 0~C was treated with 165mg (4.4mmol) of sodium borohydride. The cooling bath was removed and the resulting mixture was stirred at room temperature for 30 minutes. Second portions of benzaldehyde (1.12ml (11. lmmol)) and sodium borohydride (165mg (4.4mmol) were added to the reaction mixture and stirring was continued for 1.5hours. The reaction mixture was partitioned between 100ml of ether and 50ml of water and the layers were separated. The aqueous layer was separated and filtered to remove a small amount of insoluble material. The filtrate was acidified to pH 5 with 2N aqueous hydrochloric acid solution and the solid that had precipitated was filtered, rinsed well with water, then ether, and dried to afford 1.95g of the title compound. lH NMR (400MHz, D20 + NaOD) 3.33 (2H, AB q, J=8.4Hz), 3.85 (lH, s), 6.79-7.16 (4H, m).
CA 0223~8~ l998-04-24 Step B: 4-Benzvl-3-(S)-(4-fluorophenvl)-2-morpholinone A mixture of 1.95g (7.5mmol) of N-benzyl (S)-(4-fluorophenyVglycine, 3.90ml (22.5mmol) of N,N-diisopropyl-ethyl~mine, 6.~0ml (75.0mmol) of ~,2-dibromoethane and 40ml of N,N-5 dimethylform~mi~le was stirred at 100~C for 20 hours (dissolution of allsolids occurred on warming). The reaction mixture was cooled and concentrated in vacuo. The residue was partitioned between 250ml of ether and 100ml of 0.6N potassium hydrogen sulfate solution and the layers were separated. The organic layer was washed with 100ml of 10 saturated aqueous sodium bicarbonate solution, 3 x 150ml of water, dried over magnesium sulfate, and concentrated in uacuo. Flash chromatography on 125g of silica gel using 3:1 v/v hex~n~s/ether as the eluant afEorded 1.58g (74%) of the title compound as an oil. lH NMR
(400MHz, CDCl3) ~ 2.65 (lH, dt, J=3.2, 12.8Hz), 3.00 (lH, dt, J=12.8, 2.8Hz), 3.16 (1~, d, J=13.6Hz), 3.76 (lH, d, J=13.6Hz), 4.24 (lH, s~, 4.37 (lH, dt, ~=13.2, 3.2Hz), 4.54 (lH, dt, J=2.8, 13.2Hz), 7.07-7.56 (9H, m).
DESC~l~IPTION 3 4-BenzYl-2-~R)-(3.5-bis~trifluoromethvl)benzovloxy)-3-(S)-~4-fluoroPhenYl)morPholine A solution of 2.67g (10.Ommol) of 4-benzyl-3-(S)-(4-fluorophenyl)-2-morpholinone (Description 2) in 40ml of dry THF was cooled to -78~C. The cold solution was treated with 12.5ml of 1.0M L-Selectride~) solution in THF, m~int~ining the internal reaction temperature below -70~C. The resulting solution was stirred cold for 45 minutes and the reaction was charged with 3.60ml(20.0mmol) of 3,5-bis(trifluoromethyl)benzoyl chloride.
The resulting yellow mixture was stirred cold for 30 minutes and the reaction was quenched with 50ml of saturated aqueous sodium bicarbonate solution. The quenched mixture was partitioned between 300ml of ether and 50ml of water and the layers were separated. The organic layer was dried over magnesium sulfate. The aqueous layer was extracted with 300ml of ether; the extract was dried and combined with the original organic layer. The combined organics were concentrated i vacuo. Flash chromatography on 150g of silica gel using 37:3 v/v heX~n ether as the eluant afforded 4.06g (80%) of the title compound as a solid.
lH NMR (200MHz, CDCl3) ~ 2.50 (lH, dt, J=3.4, 12.0Hz), 2.97 (lH, app d, J=12.0Hz), 2.99 (lH, d, J=13.6~z), 3.72-3.79 (lH, m), 3.82 (lH, d, J=2.6Hz~, 4.00 (lH, d, ~=13.6Hz), 4.20 (dt, J=2.4, 11.6Hz), 6.22 (lH, d, J=2.6Hz), 7.22.7.37 (7H, m), 7.57 (2H, app d, J=6.8Hz), 8.07 (lH, s), 8.47 (2H, s). MS (FAB) m/~ 528 (M+H, 25%), 270 ~100%~.
Analysis Calcd. for C26H20F7NO3: C, 59.21; H, 3.82; N, 2.66; F, 25.21;
Found: C, 59.06; H, 4.05; N, 2.50; F, 25.18%.
4-Benzvl-2-(R)-(1-(3~ 5-bis(trifluoromethvl)PhenYl~ethenYloxY)-3-(s)-(4 fluoro~henvl)morPholine Ste~ A: Dimethvl titanocene A solution of 2.49g (lO.OmmoV of titanocene dichloride in 50ml of ether in the dark at 0~C was treated with 17.~ml of 1.4M methyllithium solution in ether maint~ining the internal temperature below 5~C~ The resulting yellowlorange mixture was stirred at room temperature for 30 minutes and the reaction was quenched by slowly adding 25g of ice. The quenched reaction mixture was diluted with 50ml of ether and 25ml of water and the layers were separated. The organic layer was dried over magnesium sulfate and concentrated in vacuo to afford 2.03g (98%) of the title compound as a light-sensitive solid. The dimethyl titanocene could be stored as a solution in toluene at 0~C for at least 2 wee~s without apparent r.hemi~ l degradation. lH NMR (200MHz, (~DCl3) ~ -0.15 (6H, s), 6.06 (lOH, s).
Ste~ B: 4-Benzvl-2-(R)-(1-(3.5-bis(tri~uoromethvl)phenvl)ethenvloxv)-3-(S)-(4-fluorophenvl)morpholine A solution of the compound of Description 3 (2.50g, 4.9mmol) and 2.50g (12.0mmoV of dimethyl titanocene (from Step A) in 35ml of 1:1 v/v THF/toluene was stirred in an oil bath at 80~C for 16 hours. The reaction ~i~ture was cooled and concentrated in vacuo. Flash chromatography on 150g of silica gel using 3:1 v/v hexanes/methylene chloride as the eluant afforded 1.71g (69%) of the title compound as a solid. An analytical sample was obtained via recryst~ ti~ n from isopropanol: lH NMR
(400MHz, CDCl3) o 2.42 (lH, dt, J=3.6, 12.0Hz), 2.90 (lH, app d, J=12.0Hz), 2.91 (lH, d, J=13.6Hz), 3.62-3.66 (lH, m), 3.~2 (lH, d, J=2.6Hz), 3.94 (lH, d, J=13.6Hz), 4.09 (lH, dt, J=2.4, 12.0Hz), 4.75 (lH, d, J=3.2Hz), 4.82 (lH, d, J=3.2Hz), 5.32 (lH, d, J=2.6Hz), 7.09 (2H, t, J=8.8Hz), 7.24-7.33 (5H, m), 7.58-7.62 (2H, m), 7.80 (lH, s), 7.90 (2H, s);
MS (FAB) 526 (M~H, 75%), 270 (100%).
Analysis (:~alcd. for C27H22F7NO2: C, 61.72; H, 4.22; N, 2.67; F, 25.31;
Found: C, 61.79; H, 4.10; N, 2.65; F, 25.27%.
2~ -(1-(R)-(3~5-Bis(tri~uoromethYlh~henYl~ethoxY)-3-(O-(4-fluoro~henvl)morpholine The compound of Description 4 (4.0g) was dissolved in ethyl acetate (50ml) and isopropanol (16ml). To this solution was added palladium on charcoal (1.5g) and the mixture was hydrogenated at 40 psi for 36h. The catalyst was removed by filtration through Celite and the solvents were removed in uacuo. The residue was purified by ~lash chromatography on silica using 100% ethyl acetate and then 1-10% methanol in ethyl acetate.
This afforded isomer A 500mg (15%) and isomer B 2.6g (80%) as clear oils -isomer B crystal~ised on st~nr1ing. For the title compound: IH NMR
(400MHz, CDCl3) ~ 1.16 (3H, d, J=6.8MHz), 1.80 (lH, br s), 3.13 (lH, dd, J=3.2, 12.4Hz), 3.23 (lH, dt, J=3.6, 12.4Hz), 3.63 (lH, dd, J=2.4, 11.2Hz), 4.01 (lH, d, 3=2.4Hz), 4.13 (lH, dt, J=3.2, 12.0Hz), 4.42 (lH, d, J=2.4Hz), 4.19 ~lH, q, J=6.8Hz), 7.04-7.09 (2H, m~, 7.27-7.40 (4H, m), 7.73 (lH, s);
MS (FAB) 438 (M~H, 75%), 180 (100%).
HCl salt formation. To a solution of the free base (0.77g) in diethyl ether (lOmV was added lM-HCl in methanol (1.75ml). The solution was evaporated to dryness and on ~ iti~)n of diethyl ether crystals formed.
The solution was filtered and the residue washed with diethyl ether to give the title com~ound hvdrochlori-le salt mp 248-250~C.
Analysis Calcd. for C20HlsF7NO2.HCl: C, 50.70; H, 4.04; N, 2.96; Cl, 7.48;
Found: C, 50.46; H, 3.85; N, 3.01; Cl, 7.31%.
D:@~SCRIPTION 6 4-Benzyl-3-(S)-phenvl-2-morPholinone Ste~ A: N-Benzvl-(S)-phen~l~lYcine A solution of 1.51g (lO.Ommol) of (S)-phenylglycine in 5ml of 2N
aqueous sodium hydroxide solution was treated with l.Oml (lO.Ommol) of ben7~1-1ehyde and stirred at room temperature for 20 minutes. The solution was diluted with 5ml of meth~n(-l, cooled to 0~C, and carefully treated with 200mg (5.3mmol) of sodium horohydride. The cooling bath was removed and the reaction mixture was stirred at room temperature for 1.5 hours. The reaction was diluted with 20ml of water and extracted with 2 x 25ml of methylene chloride. The aqueous layer was acidified with concentrated hydrochloric acid to pH 6 and the solid that precipitated was filtered, washed with 50ml of water, 50ml of 1:1 v/v methanollethyl ether and 50ml of ether, and dried to afford 1.83g (76%) of product~ mp 230-232~C.
Analysis Calcd. for Cl~HlsNO2: C, 74.66; H, 6.27; N, 5.81;
Found: C, 74.17; H, 6.19; N, 5.86%.
_ _ CA 0223~8~ 1998-04-24 WO 97/18206 PCT/(~L5 ''02766 Ste~ B: 4-Benzyl-3-(S)-Phenvl-2-morPholinone A mixture of 4.00g ~16.6mmoV of N-benzyl-(S)-phenylglycine (from Step A) 5.00g (36.0mmoV of potassium carbonate, lO.Oml of 1,2-dibromoethane and 25ml of N,N-dimethylformslmill~ was stirred at 5 100~C for 20 hours. The mixture was cooled and partitioned between 200ml of ethyl ether and 100ml of water. The layers were separated and the organic layer was washed with 3 x 50ml of water, dried over m~gnQsium sulfate and concentrated in vacuo. The residue was purit;ed by ~ash chromatography on 125g of silica gel eluting with 9:1 v/v, then 4:1 he~ne~/ethyl ether to af~ord 2.41g (54%) of the product as a solid, mp 98-100~C. lH NMR (250MHz, CDCl3) ~ 2.54-2.68 (lH, m), 2.96 (lH, dt, J=12.8, 2.8Hz), 3.14 (lH, d, ~=13.3Hz), 3.75 (lH, d, J=13.3~Iz), 4.23 (l~I, s), 4.29-4.37 (lH, m), 4.53 (dt, ~=3.2, ll.OHz), 7.20-7.56 (lOH, m). MS
(FAB): m/z 268 (M+H; 100%).
4-13enzYl-2-¢R)-(3,6-bis(trifluoromethvl)benzovloxv) -3-(S)-phenvlmor~holine A solution of 2.67g (lO.Ommol) of the compound of Description 6 in 20 40ml of dry THF was cooled to -78~C. The cold solution was treated with 12.5ml of 1.0M L-Selectride(g) solution in THF, maint~ining the internal reaction temperature below -70~C. The resulting solution was stirred cold for 45 minutes and the reaction was charged with 3.60ml (20.0mmol) of 3,5-bis(trifluoromethyl)benzoyl chloride. The resulting yellow mixture was 25 stirred cold for 30 minutes and the reaction was quenched with 50ml of saturated aqueous sodium bicarbonate solution. The quenched mixture was partitioned between 300ml of ether and 50ml of water and the layers were separated. The organic layer was dried over magnesium sulfate.
~ The aqueous layer was extracted with 300ml of ether; the extract was 30 dried and combined with the original organic layer. The combined organics were concentrated in vacuo. Flash chromatography on 150g of silica gel using 37:3 v/v h~ne~/ether as the eluant afforded 4.06g (80%) of the title compound as a solid. lH NMR (200MHz, CDCl3) ~ 2.50 (lE, dt, J--3.4, 12.0Hz), 2.97 (lH, app d, J= 12.0EIz), 2.99 (lH, d, J=13.6Hz), 3.72-3.79 (lH, m), 3.82 (lH, d, J=2.6Hz), 4.00 (lH, d, J=13.6Hz), 4.20 (dt, J=2.4, 11.6Hz), 6.22 (lH, d, J=2.6Hz), 7.22-7.37 (7H, m), 7.57 (2H, app d, J=6.8Hz), 8.07 (lH, s), 8.47 (2H, s).
Analysis Calcd. for C26H2lF6NOs: C, 61.29; H, 4.16; N, 2.75; F, 22.38;
Found: C, 61.18; H, 4.14; N, 2.70; F, 22.13%.
4-Benzvl-2-(R)-(1-(3~5-bis(trifluoromethvl)phenyl) ethenvloxv)-3-(S)-phenvlmorpholine A solution of 2.50g (4.9mmol) of the compound of Description 7 and 2.50g (12.0mmol) of dimethyl titanocene (Description 4a), in 35ml of 1:1 v/v THF/toluene was stirred in an oil bath at 80~C for 16 hours. The reaction mixture was cooled and concentrated in vaCUo. Flash chromatography on 150g of silica gel using 3:1 v/v hç~s~nes/methylene chloride as the eluant afforded 1.71g (69%) of the title compound as a solid. lH NMR (400MHz, CDCl3) ~ 2.42 (lH, dt, J=3.6, 12.0Hz), 2.89 (app d, J--11.6Hz), 2.92 (lH, d, J=13.6Hz), 3.61-3.66 (lH, m), 3.73 ~lH, d, J=2.8Hz), 4.00 (lH, d, J=13.6EIz), 4.09 (lH, dt, J=2.4, 11.6Hz), 4.75 (lH, d, J=2.8Hz), 4.79 (lH, d, J=2.8Hz), 5.36 (lH, d, J--2.4Hz), 7.23-7.41 (7H, m), 7.63 (lH, app d, J=7.2Hz), 7.79 (lH, s), 7.91 (2H, s). MS (FAB) m/z 508 (M:+l, 25%).
Analysis Calcd. for C27H23FGNO2: C, 63.90; H, 4.57; N, 2.76; F, 22.46;
Found: C, 63.71; H, 4.53; N, 2.68; F, 22.66%.
2-(R~-(l-(R)-(3.5-Bis(trifluoromethYl)~henvl)ethoxy~-3-(S)-phenylmorpholine A mixture of the compound of Description 8 (1.5g) and 10%
palladium on carbon catalyst (750mg) in a mixture of isopropano~/ethyl acetate (25ml, 3:2 v/v) was stirred under an atmosphere of hydrogen for 48h. The catalyst was removed by filtration through celite and the reaction flask and filter pad were rinsed with ethyl acetate (500ml). The filtrate was concentrated in vacuo, flash chromatography afforded epimer A (106mg) and epimer B (899mg) as clear oils. The title compound, epimer B had the following analysis:
lH NMR (CDCl3, 400MHz) ~ 1.46 (3H, d, J=6.8Hz), 1.92 (lH, br s), 3.13 (lH, dd, J=3.0, 12.6Hz), 3.24 (lH, dt, J=3.6, 12.6Hz), 3.62 (lH, dd, J=3.6, 11.2Hz), 4.04 (lH, d, J=2.4Hz), 4.14 (lH, dt, J=3.0, 11.2Hz), 4.48 (lH, d, J=2.4Hz), 4.90 (lH, q, J=6.8Hz), 7.21-7.32 (7H, m), 7.64 (lH, s). MS (CI+) m/z 420 (M++1, 20%), 178 (100%).
Analysis Calcd. for C20HIsF6NO2: C, 57.28; H, 4.57; N, 3.34; F, 27.18;
Found: C, 57.41; H, 4.~i1; N, 3.29; F, 27.23%.
(N-Phenvlcvanocarbonimi-l~te 2-~ (1-(R)-(3,5-bis(trifluoromethvl)-phenvl)ethoxy)-3-($)-PhenYlmorPholine The title compound was synthesised ~ollowing the procedure of Garrett P.J. 'retrcrhedro~ (1993) 49, 165-176. The product of Description 9 (2.0g, 0.45mmol) was dissolved in 2-propanol (40ml), diphenvl aminocarbonimitl~te (2.18g, 0.9mmol) was added and the reaction heated to 80~C for 16h. The solvent was then removed and the product purified on silica eluting with hexane-ethyl acetate mixtures to give the title compound as an oil (1.2g).
2-(R)-(l-(R)-(3,5-Bis(trifluoromethvl)nhenyl)ethoxv)-4-cvano-3-(S)-(4-fluoroPhenyl)mor~holine CA 0223~8~ 1998-04-24 WO 97/18206 PCT/~1~5G~1~2766 The product of Description 5 (2.0g, 4.57mmol) was dissolved in dimethylform~mi~e (20ml), cyanogen bromide (727mg, 6.86mmol) was added followed by potassium carbonate (1.89g, 13.7mmol) and the reaction heated to 60~C for 16h. The reaction was then poured into ethyl acetate 5 and washed with water and brine, dried (MgSO4) and evaporated to dryness. Purification on silica eluting with h~ ne ethyl acetate ~ixtures gave the title compound (2.01g). lH NMR (250MHz, CDCI3) ~ 1.51 (3H, d, ~=6.6Hz), 3.42-3.60 (2H, m), 3.63-3.71 (lH, m), 4.22 (lH, d, J=2.6Hz), 4.25-4.34 (lH, m), 4.37 (lH, d, J=2.6Hz), 4.88 ~lH, q, J=6.6Hz), 7.09 (2H, t, J=8.6Hz), 7.22 (2H, s), 7.40-7.46 (2H, m), 7.67 (lH, s).
2-(R~-(l-(R)-(3~ 5-Bis(trifluoromethvl)Phenvl)ethoxY)-3-(S)-(4-f~uoro~henvl)-4-tetrazol- 5 -vl-mor~holine The product of Description 11 (280mg, 0.6mmol) was dissolved in dimethylform~mitle (15ml), sodium azide (78~g, 1.2mmol) was added followed by ammonium chloride (64mg, 1.2mmol) and the reaction heated to 160~C for 16h. The reaction was then poured into ethyl acetate, washed with water and brine, dried (~g~O4) and evaporated to dryness.
Purification on silica eluting with he~ne ethyl acetate mixtures gave the title compound. IH NMR (2~i0MHz, CDCl3) ~ 1.35 (3H, d, ~=6.6Hz), 3.44-3.58 (lH, m), 3.70-3.80 (2H, m), 4.60 (lH, d, J=3.3Hz), 4.78 (lH, d, J=3.3H~), 4.95 (lH, q, J=6.5Hz), 6.82-6.94 (2H, m), 7.39 (2H, s), 7.40-7.52 (2H, m), 7.67 (lH, s).
2-(R)-l-(R~-3,5-Bis(trifluoromethYl)phenvl)ethoxy)-3-(S)-(4-fluoro~henvl)-4-(2-hvdroxyethyl-2H-tetrazol-5-Yl)mor~holine The product of Description 12 (610mg, 1.21mmol) was dissolved in diemthylformamide (5ml). Potassium carbonate (757mg, 5.47mmol) was added followed by 2-bromoethanol (256~1, 3.62mmol) and the reaction CA 0223~8~ 1998-04-24 heated to 60~C for 16h. The reaction was then poured into ethyl acetate and washed with water and brine, dried (MgSO4) and evaporated to drvness. pllrifi~tion on silica eluting with h~n~-ethyl acetate gave the title compound (335mg). lH NMR (250MHz, CDCl3) ~ 1.44 (3H, d, J=6.6Hz), 2.26 (lH, br t), 3.62-3.66 (2H, m), 3.79-3.89 (lH, m), 3.95-4.01 (2H, m), 4.22-4.29 (lH, m), 4.45-4.52 (2H, m), 4.68 (lH, d, J=3.3Hz), 4.85 (lH, d, J=3.3Hz), 5.05 (lH, q, J=6.5Hz), 6.99 (2H, t, J=8.7Hz), 7.53-7.59 (4H, m), 7.76 (lH, s).
2-(R)-(l-~R)-(3,5-Bis(trifluoromethvl)Phenyl)ethoxv)-3-(S)-(4-fluorophenvl)-4-(2-p-toluenesulPhonvlethvl-2H-tetrazol-5-vl)morpholine The product of Description 13 (335mg, 0.61mmol) was dissolved in dichloromethane (lOmV, tosyl chloride (232mg, l ~.~.mmol) was added followed by triethylamine (171,u1, 2.34mmol) and the reaction heated to reflux for l~h. The solvent was then removed and the residue redissolved in ethyl acetate and washed with water and brine, dried (MgSO4) and evaporated to dryness. Purification on silica eluting with hexane-ethyl acetate gave the title compound (0.25g). lH NMR (250MHz, CDCl3) ~ 1.44 (3H, d, J=6.6Hz), 2.41 (3H, s), 3.46-3.63 (2H, m), 3.78-3.87 (lH, dt, J=3.9 and 10.2Hz), 4.19-4.24 (lH, dt, J=3.3 and 11.3Hz), 4.41 (2H, t, J=5.2Hz), 4.58 (2H, t, J=5.7Hz), 4.70 (lH, d, ~r=3.3Hz), 4.89 (lH, d, J=3.34Hz), 5.05-5.08 (lH, q, J=6.5Hz), 6.97 (2H, t, J=8.7Hz), 7.27 (2H, d, J=7.87Hz), 7.55-7.61 (4H, m), 7.67 (2H, d, J=6.6Hz), 7.77 (lH, s).
4-(5-Amino-1~2,4-triazol-3-vl)-2-(R)-(l-(R~-(3.6-bis(trifluoromethvl)phenyl) ethoxv)-3-(S)-~henYlmorPholine The product of Description 10 (1.80g, 1.85mmol) was dissolved in 2-propanol (30ml), hydrazine (180~1, 3.7mmol) was added and the reaction heated to 80~C for 16h. The solvent was then removed and the residue purified on silica eluting with dichloromethane-methanol mixtures to give the title compound (0.4g). lH NMR (250MHz, CDCl3) ~ 1.31 ~3H, d, J=6.5Hz), 3.22-3.40 (2H, m), 3.71-3.74 (lH, dt, ~=7.2 and 3.7~z), 3.94-4.00 (lH~ m), 4.50 (3H, m), 4.90 (lH, q, ~=6.5Hz), 4.96-~i.04 (2H, m), 6.90 (2H, t, J=17.6Hz), 7.50-7.64 (5H, m). MIS M+ 502.
2-(R)-l-(R)-(3~5-Bis(trifLuoromethvl)phenyl)ethoxv)-4-(2-N,N-dimethvl~minoethvl-2H-tetrazol-5-vl)-3-(S)-(4-fluoroPhenvl)morPholine The product of Description 14 (250mg, 0.355mmol) was dissolved in dimethylform~mi~le (lOml), dimethyl~mine (2ml) was added and the reaction heated in a sealed tube at 60~C for 16h. The reaction was then poured into ethyl acetate and washed with water and brine, dried (MgSO4) and evaporated to dryness. Purification on silica eluting with dichloromethane-methanol mixtures gave the title compound (0.13g).
lH NMR (250MHz, CDGl3) o 1.37 (3H, d, J=6.6Hz), 2.14 (6H, s), 2.67-2.71 (2H, dt, ~=1.6 and 6.65Hz), 3.43-3.59 (2H, m), 3.72-3.80 (lH, dt, J=3.7 and 9.9Hz), 4.12-4.19 (lH, m), 4.61 (lH, d, J=3.3Hz), 4.82 (lH, d, J=3.3Hz), 4.99 (lH, q, J=6.5Hz), 6.86-6.94 (2H, m), 7.50-7.55 (4H, m), 7.70 (lH, s,).
M/S M+ 577.
2-(R)-(l-(R)-(3,5-Bis(trifluoromethvl)phenvl~ethoxv)-4-(4-N,N-dimethvl~minomethvl)thiazol-2-vl)-3-(S)-(4-fluoroPhenvl)morPholine a) 2-(R)-(l-(R)-(3~5-Bis(trifluoromethyl)phenyl)ethoxy)-4-aminothiocarbonvl-3-(0-(4-~luorophenvl)mor~holine Through a solution of the product of Description 11 (1.07g) in ethanol (25ml) was bubbled hydrogen sulphide for 10 minutes. Potassium 30 tert-butoxide (0.05g) was added and addition of hydrogen sulphide was continued for 16 hours whilst the solution was heated at 50~C. Glacial acetic acid (O.lml) was added and the solvent was evaporated in vacuo.
The residue was chromatographed on silica gel eluting successively with 20% and 50% ethyl acetate in petroleum ether (bp 60-80~C) to give the title compound (0.57g). lH NMR(CDCl3, 250MHz) â 7.68 (lH,s), 7.31-7.72 (4H,m), 7.02 (2H,t, J=8.6Hz~, 5.51 (2H,br. s), 5.21 (lh,d, J=4.1Hz), 4.9Ei-4.90 (2H,m), 4.6 (lH,d, J=4.2Hz), 4.0-3.8 (3H,m), 1.38 (3H,d, J=6.6Hz).
b) 2-(R)-(1-(R)-(3.5-Bis(tri uoromethyl)phenvl3ethoxy)-4-(4-chloromethvl)thiazol-2-Yl) -3-~S)-(4-fluorophenvl)morpholine To a solution of the product of step (a) (0.534g) in chloroform (20ml) was added sodium bicarbonate (0.39g) and 1,3-dichloroacetone (0.165g).
The solution was stirred at 50~C for 3 hours followed by heating at reflux in a Dean and Stark apparatus cont~ining 3A molecular sieves for 2 hours.
The cooled solution was evaporated and the residue purified on silica gel eluting with 15% ethyl acetate in petroleum ether (bp 60-80~C) to give the title compound (0.487g). lH NMR(CDCl3, 250MHz) ~ 7.77 (lH,s), 7.61-7.54 (4H,m), 7.02 (2H,td, J=8.6Hz and 2.1Hz), 6.48 (lH,s), 5.04 (lH,q, J=6.6Hz), 4.87 (lH,d, J--3.4Hz), 4.66 ~lH,d, J=3.46Hz), 4.44 (2H,d, J=0.64Hz), 4.19 (2H,dt, J=11.3Hz and 3.32Hz), 3.92-3.62 (3H,m), 1.46 (3H,d, J=6.6Hz).
c) 2-(R)-(l-(R)-~3~5-:~is(trifluoromethvl)~henyl)ethoxy)-4-(4-N~N-dimethvlaminomethvl)thiazol-2-vl)-3-(S)-(4-fluoroPhenYl)morPholine Through a solution of the product of step (b) (0.109g) in ethanol (5ml) was passed diethylamine gas until saturated. The flask was sealed for 16 hours whereupon the solvent was removed in vacuo and the residue ~ purified on silica gel eluting with 2U% methanol in ethyl acetate. The residue after evaporation (0.063g) was dissolved in lM HCl in methanol ~ (lml), evaporated to dryness and washed with hexane. After drying i7il, 30 uacuo this gave the title compound as a foam. lH NMR(CDCl3, 360MHz) 7.76 (lH,s), 7.5 (4H,m), 7.01 (2H,t, J=8.7Hz), 6.8 ~lH,s), 5.0 (lH,q, J=6.5Hz), 4.85 (lH,d, J=3.5Hz), 4.65 (lH,d, J=3.6Hz), 4.22 (lH,dt, J=ll.OHz), 3.91-3.79 (4H,m), 3.6 (lH,ddd), 2.62 (6H,s), 1.44 (3H,d, J=6.6Hz). MS m/z (CI~ 578 (M+H).
li~XAlVI PLE 4 2-(R)-(l-(S)-(3.5-Bis(trifluorometh~l)phenvl)-2-hvdloxv~thoxv)-4-(2-amino-5-thiazolvl)-3-(0-(4-fluoroPhenvl)morpholine To a degassed solution of 2-~R~-(1-(S)-(3,5-bis(~i~uoromethyl3-phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)morpholine (0.2g), 2-amino-5-bromot.hi~7.ol~ (0.14g), sodium tert-butoxide (0.0105g) and tri-o-tolylphosphine (0.007g) in dioxane (4mV was added tris(dibenzylideneacetone)dipalladium (O) (0.02g). The solution was degassed and then heated at 80~C for 24h under an atmosphere of nitrogen. The solvent was removed in vacuo and the residue partitioned between ethyl acetate and water. The organic layer was dried (MgS04) and after evaporation of the solvent the residue was chromatographed on silica (eluting with gradient of 2% -4% methanol/ammonia (100:3) in dichloromethane) to give the title compound. lH NMR (360MHz, CDCl3) 3.11 (lH, td, J=11.7Hz, 3.5Hz), 3.19 (lH, bd J=11.4Hz), 3.61 (lH, dd, J=12.2Hz and 3.3Hz), 3.67-3.81 (3H, m), 4.47 (lH, d, J=2.8Hz), 4.54 (lH, td, J=11.7Hz and 2.8Hz), 4.80 (2H, bs), 4.92 (lH, dd, J=7.8Hz and 3.1Hz), 6.97 (2H, t, J=8.7Hz), 7.09 (lH, s), 7.14 (2H, s), 4.91 (lH, dd, J=7.8Hz and 3.1Hz), 7.67 (lH, s); m/z EI' 552(M~H).
The following examples illustrate pharmaceutical compositions according to the invention.
E~MPLE 5A Tablets cont~inin~ 1-25m~ of compound Amount m~
Compound offormula (I) 1.0 2.0 25.0 Microcrystalline cellulose 20.0 20.0 20.0 CA0223~8~ 1998-04-24 Modified food corn starch 20.0 20.0 20.0 Lactose 58.5 57.5 34.5 - Mz~nesium stearate 0.5 0.5 0-5 5 E~MPLE 5B Tablets cont~inin~ 26-lOOm~ of comPound Amount m~
Compound of formula (I) 26.0 50.0 100.0 Microcrystalline cellulose 80.0 80.0 80.0 Modified foodcorn starch 80.0 80.0 80.0 Lactose 213.5 189.5 13~.5 M~gnesium stearate 0.5 0.5 0 5 The compound of formula (I), cellulose, lactose and a portion of the corn starch are mixed and granulated with 10% corn starch paste. The resulting granulation is sieved, dried and blended with the rern~inller of 15 the corn starch and the magnesium stearate. The resulting granulation is then compressed into tablets cont~ining l.Omg, 2.0mg, 25.0mg, 26.0mg, 50.0mg and lOOmg of the active compound per tablet.
EXAMPLE 6 Parenteral iniection Amount m~
Compound of formula ~I) 1 to lOOmg Citric acid monohydrate 0.75mg Sodium phosphate 4.5mg Sodium chloride 9mg Water for injection to 10ml The sodium phosphate, citric acid monohydrate and sodium chloride are dissolved in a portion of the water. The compound of formula (I~ is dissolved or suspended in the solution and made up to volume.
EXAMPLE 7 Topical formulation Amount m~
Compound of formula (I) 1-lOg Emulsifying wax 30g Liquid paraffin 20g White soft paraffin to 100g The white soft paraffin is heated until molten. The liquid paraf~n and emulsifying wax are incorporated and st~rred until dissolved. The compound of formula (I) is added and stirring continued until dispersed.
The mixture is then cooled until solid.
EXAMPLE 8A - (Surface-Active A~ent) Iniection Formulation Compound of formula (I) up to 10mg/kg Tween 80TM up to 2.~%
[in 5% aqueous mzlnni~ol (isotonic)~
The compound of formula (I) is dissolved directly in a solution of the commercially available Tween 80TM (polyoxyethylenesorbitan monooleate) and 5% aqueous mannitol (isotonic).
EXAMPLE 8~ - (Emulsion) Iniection Formulation Compound of formula (I) up to 30mg/ml IntralipidTM (10-20%) The compound of formula (I) is dissolved directly in the commercially available IntralipidTM (10 or 20%) to form an emulsion.
CA 02235855 l998-04-24 EXAMPLE 8C - Alternative (Emulsion) Iniectable Formulation Amount (~ompound of formula (I) 0.1 - lOmg Soybean oil lOOmg Egg phospholipid 6mg Glycerol 22mg Water for injection to lml All materials are sterilized and pyrogen free. The compound of formula (I) 10 is dissolved in soybean oil. An emulsion is then formed by mi~ing this solution with the egg phospholipid, glycerol and water. The emulsion is then sealed in sterile vials.
aqueous sodium hydroxide solution and 11ml of methanol at 0~C was treated with 165mg (4.4mmol) of sodium borohydride. The cooling bath was removed and the resulting mixture was stirred at room temperature for 30 minutes. Second portions of benzaldehyde (1.12ml (11. lmmol)) and sodium borohydride (165mg (4.4mmol) were added to the reaction mixture and stirring was continued for 1.5hours. The reaction mixture was partitioned between 100ml of ether and 50ml of water and the layers were separated. The aqueous layer was separated and filtered to remove a small amount of insoluble material. The filtrate was acidified to pH 5 with 2N aqueous hydrochloric acid solution and the solid that had precipitated was filtered, rinsed well with water, then ether, and dried to afford 1.95g of the title compound. lH NMR (400MHz, D20 + NaOD) 3.33 (2H, AB q, J=8.4Hz), 3.85 (lH, s), 6.79-7.16 (4H, m).
CA 0223~8~ l998-04-24 Step B: 4-Benzvl-3-(S)-(4-fluorophenvl)-2-morpholinone A mixture of 1.95g (7.5mmol) of N-benzyl (S)-(4-fluorophenyVglycine, 3.90ml (22.5mmol) of N,N-diisopropyl-ethyl~mine, 6.~0ml (75.0mmol) of ~,2-dibromoethane and 40ml of N,N-5 dimethylform~mi~le was stirred at 100~C for 20 hours (dissolution of allsolids occurred on warming). The reaction mixture was cooled and concentrated in vacuo. The residue was partitioned between 250ml of ether and 100ml of 0.6N potassium hydrogen sulfate solution and the layers were separated. The organic layer was washed with 100ml of 10 saturated aqueous sodium bicarbonate solution, 3 x 150ml of water, dried over magnesium sulfate, and concentrated in uacuo. Flash chromatography on 125g of silica gel using 3:1 v/v hex~n~s/ether as the eluant afEorded 1.58g (74%) of the title compound as an oil. lH NMR
(400MHz, CDCl3) ~ 2.65 (lH, dt, J=3.2, 12.8Hz), 3.00 (lH, dt, J=12.8, 2.8Hz), 3.16 (1~, d, J=13.6Hz), 3.76 (lH, d, J=13.6Hz), 4.24 (lH, s~, 4.37 (lH, dt, ~=13.2, 3.2Hz), 4.54 (lH, dt, J=2.8, 13.2Hz), 7.07-7.56 (9H, m).
DESC~l~IPTION 3 4-BenzYl-2-~R)-(3.5-bis~trifluoromethvl)benzovloxy)-3-(S)-~4-fluoroPhenYl)morPholine A solution of 2.67g (10.Ommol) of 4-benzyl-3-(S)-(4-fluorophenyl)-2-morpholinone (Description 2) in 40ml of dry THF was cooled to -78~C. The cold solution was treated with 12.5ml of 1.0M L-Selectride~) solution in THF, m~int~ining the internal reaction temperature below -70~C. The resulting solution was stirred cold for 45 minutes and the reaction was charged with 3.60ml(20.0mmol) of 3,5-bis(trifluoromethyl)benzoyl chloride.
The resulting yellow mixture was stirred cold for 30 minutes and the reaction was quenched with 50ml of saturated aqueous sodium bicarbonate solution. The quenched mixture was partitioned between 300ml of ether and 50ml of water and the layers were separated. The organic layer was dried over magnesium sulfate. The aqueous layer was extracted with 300ml of ether; the extract was dried and combined with the original organic layer. The combined organics were concentrated i vacuo. Flash chromatography on 150g of silica gel using 37:3 v/v heX~n ether as the eluant afforded 4.06g (80%) of the title compound as a solid.
lH NMR (200MHz, CDCl3) ~ 2.50 (lH, dt, J=3.4, 12.0Hz), 2.97 (lH, app d, J=12.0Hz), 2.99 (lH, d, J=13.6~z), 3.72-3.79 (lH, m), 3.82 (lH, d, J=2.6Hz~, 4.00 (lH, d, ~=13.6Hz), 4.20 (dt, J=2.4, 11.6Hz), 6.22 (lH, d, J=2.6Hz), 7.22.7.37 (7H, m), 7.57 (2H, app d, J=6.8Hz), 8.07 (lH, s), 8.47 (2H, s). MS (FAB) m/~ 528 (M+H, 25%), 270 ~100%~.
Analysis Calcd. for C26H20F7NO3: C, 59.21; H, 3.82; N, 2.66; F, 25.21;
Found: C, 59.06; H, 4.05; N, 2.50; F, 25.18%.
4-Benzvl-2-(R)-(1-(3~ 5-bis(trifluoromethvl)PhenYl~ethenYloxY)-3-(s)-(4 fluoro~henvl)morPholine Ste~ A: Dimethvl titanocene A solution of 2.49g (lO.OmmoV of titanocene dichloride in 50ml of ether in the dark at 0~C was treated with 17.~ml of 1.4M methyllithium solution in ether maint~ining the internal temperature below 5~C~ The resulting yellowlorange mixture was stirred at room temperature for 30 minutes and the reaction was quenched by slowly adding 25g of ice. The quenched reaction mixture was diluted with 50ml of ether and 25ml of water and the layers were separated. The organic layer was dried over magnesium sulfate and concentrated in vacuo to afford 2.03g (98%) of the title compound as a light-sensitive solid. The dimethyl titanocene could be stored as a solution in toluene at 0~C for at least 2 wee~s without apparent r.hemi~ l degradation. lH NMR (200MHz, (~DCl3) ~ -0.15 (6H, s), 6.06 (lOH, s).
Ste~ B: 4-Benzvl-2-(R)-(1-(3.5-bis(tri~uoromethvl)phenvl)ethenvloxv)-3-(S)-(4-fluorophenvl)morpholine A solution of the compound of Description 3 (2.50g, 4.9mmol) and 2.50g (12.0mmoV of dimethyl titanocene (from Step A) in 35ml of 1:1 v/v THF/toluene was stirred in an oil bath at 80~C for 16 hours. The reaction ~i~ture was cooled and concentrated in vacuo. Flash chromatography on 150g of silica gel using 3:1 v/v hexanes/methylene chloride as the eluant afforded 1.71g (69%) of the title compound as a solid. An analytical sample was obtained via recryst~ ti~ n from isopropanol: lH NMR
(400MHz, CDCl3) o 2.42 (lH, dt, J=3.6, 12.0Hz), 2.90 (lH, app d, J=12.0Hz), 2.91 (lH, d, J=13.6Hz), 3.62-3.66 (lH, m), 3.~2 (lH, d, J=2.6Hz), 3.94 (lH, d, J=13.6Hz), 4.09 (lH, dt, J=2.4, 12.0Hz), 4.75 (lH, d, J=3.2Hz), 4.82 (lH, d, J=3.2Hz), 5.32 (lH, d, J=2.6Hz), 7.09 (2H, t, J=8.8Hz), 7.24-7.33 (5H, m), 7.58-7.62 (2H, m), 7.80 (lH, s), 7.90 (2H, s);
MS (FAB) 526 (M~H, 75%), 270 (100%).
Analysis (:~alcd. for C27H22F7NO2: C, 61.72; H, 4.22; N, 2.67; F, 25.31;
Found: C, 61.79; H, 4.10; N, 2.65; F, 25.27%.
2~ -(1-(R)-(3~5-Bis(tri~uoromethYlh~henYl~ethoxY)-3-(O-(4-fluoro~henvl)morpholine The compound of Description 4 (4.0g) was dissolved in ethyl acetate (50ml) and isopropanol (16ml). To this solution was added palladium on charcoal (1.5g) and the mixture was hydrogenated at 40 psi for 36h. The catalyst was removed by filtration through Celite and the solvents were removed in uacuo. The residue was purified by ~lash chromatography on silica using 100% ethyl acetate and then 1-10% methanol in ethyl acetate.
This afforded isomer A 500mg (15%) and isomer B 2.6g (80%) as clear oils -isomer B crystal~ised on st~nr1ing. For the title compound: IH NMR
(400MHz, CDCl3) ~ 1.16 (3H, d, J=6.8MHz), 1.80 (lH, br s), 3.13 (lH, dd, J=3.2, 12.4Hz), 3.23 (lH, dt, J=3.6, 12.4Hz), 3.63 (lH, dd, J=2.4, 11.2Hz), 4.01 (lH, d, 3=2.4Hz), 4.13 (lH, dt, J=3.2, 12.0Hz), 4.42 (lH, d, J=2.4Hz), 4.19 ~lH, q, J=6.8Hz), 7.04-7.09 (2H, m~, 7.27-7.40 (4H, m), 7.73 (lH, s);
MS (FAB) 438 (M~H, 75%), 180 (100%).
HCl salt formation. To a solution of the free base (0.77g) in diethyl ether (lOmV was added lM-HCl in methanol (1.75ml). The solution was evaporated to dryness and on ~ iti~)n of diethyl ether crystals formed.
The solution was filtered and the residue washed with diethyl ether to give the title com~ound hvdrochlori-le salt mp 248-250~C.
Analysis Calcd. for C20HlsF7NO2.HCl: C, 50.70; H, 4.04; N, 2.96; Cl, 7.48;
Found: C, 50.46; H, 3.85; N, 3.01; Cl, 7.31%.
D:@~SCRIPTION 6 4-Benzyl-3-(S)-phenvl-2-morPholinone Ste~ A: N-Benzvl-(S)-phen~l~lYcine A solution of 1.51g (lO.Ommol) of (S)-phenylglycine in 5ml of 2N
aqueous sodium hydroxide solution was treated with l.Oml (lO.Ommol) of ben7~1-1ehyde and stirred at room temperature for 20 minutes. The solution was diluted with 5ml of meth~n(-l, cooled to 0~C, and carefully treated with 200mg (5.3mmol) of sodium horohydride. The cooling bath was removed and the reaction mixture was stirred at room temperature for 1.5 hours. The reaction was diluted with 20ml of water and extracted with 2 x 25ml of methylene chloride. The aqueous layer was acidified with concentrated hydrochloric acid to pH 6 and the solid that precipitated was filtered, washed with 50ml of water, 50ml of 1:1 v/v methanollethyl ether and 50ml of ether, and dried to afford 1.83g (76%) of product~ mp 230-232~C.
Analysis Calcd. for Cl~HlsNO2: C, 74.66; H, 6.27; N, 5.81;
Found: C, 74.17; H, 6.19; N, 5.86%.
_ _ CA 0223~8~ 1998-04-24 WO 97/18206 PCT/(~L5 ''02766 Ste~ B: 4-Benzyl-3-(S)-Phenvl-2-morPholinone A mixture of 4.00g ~16.6mmoV of N-benzyl-(S)-phenylglycine (from Step A) 5.00g (36.0mmoV of potassium carbonate, lO.Oml of 1,2-dibromoethane and 25ml of N,N-dimethylformslmill~ was stirred at 5 100~C for 20 hours. The mixture was cooled and partitioned between 200ml of ethyl ether and 100ml of water. The layers were separated and the organic layer was washed with 3 x 50ml of water, dried over m~gnQsium sulfate and concentrated in vacuo. The residue was purit;ed by ~ash chromatography on 125g of silica gel eluting with 9:1 v/v, then 4:1 he~ne~/ethyl ether to af~ord 2.41g (54%) of the product as a solid, mp 98-100~C. lH NMR (250MHz, CDCl3) ~ 2.54-2.68 (lH, m), 2.96 (lH, dt, J=12.8, 2.8Hz), 3.14 (lH, d, ~=13.3Hz), 3.75 (lH, d, J=13.3~Iz), 4.23 (l~I, s), 4.29-4.37 (lH, m), 4.53 (dt, ~=3.2, ll.OHz), 7.20-7.56 (lOH, m). MS
(FAB): m/z 268 (M+H; 100%).
4-13enzYl-2-¢R)-(3,6-bis(trifluoromethvl)benzovloxv) -3-(S)-phenvlmor~holine A solution of 2.67g (lO.Ommol) of the compound of Description 6 in 20 40ml of dry THF was cooled to -78~C. The cold solution was treated with 12.5ml of 1.0M L-Selectride(g) solution in THF, maint~ining the internal reaction temperature below -70~C. The resulting solution was stirred cold for 45 minutes and the reaction was charged with 3.60ml (20.0mmol) of 3,5-bis(trifluoromethyl)benzoyl chloride. The resulting yellow mixture was 25 stirred cold for 30 minutes and the reaction was quenched with 50ml of saturated aqueous sodium bicarbonate solution. The quenched mixture was partitioned between 300ml of ether and 50ml of water and the layers were separated. The organic layer was dried over magnesium sulfate.
~ The aqueous layer was extracted with 300ml of ether; the extract was 30 dried and combined with the original organic layer. The combined organics were concentrated in vacuo. Flash chromatography on 150g of silica gel using 37:3 v/v h~ne~/ether as the eluant afforded 4.06g (80%) of the title compound as a solid. lH NMR (200MHz, CDCl3) ~ 2.50 (lE, dt, J--3.4, 12.0Hz), 2.97 (lH, app d, J= 12.0EIz), 2.99 (lH, d, J=13.6Hz), 3.72-3.79 (lH, m), 3.82 (lH, d, J=2.6Hz), 4.00 (lH, d, J=13.6Hz), 4.20 (dt, J=2.4, 11.6Hz), 6.22 (lH, d, J=2.6Hz), 7.22-7.37 (7H, m), 7.57 (2H, app d, J=6.8Hz), 8.07 (lH, s), 8.47 (2H, s).
Analysis Calcd. for C26H2lF6NOs: C, 61.29; H, 4.16; N, 2.75; F, 22.38;
Found: C, 61.18; H, 4.14; N, 2.70; F, 22.13%.
4-Benzvl-2-(R)-(1-(3~5-bis(trifluoromethvl)phenyl) ethenvloxv)-3-(S)-phenvlmorpholine A solution of 2.50g (4.9mmol) of the compound of Description 7 and 2.50g (12.0mmol) of dimethyl titanocene (Description 4a), in 35ml of 1:1 v/v THF/toluene was stirred in an oil bath at 80~C for 16 hours. The reaction mixture was cooled and concentrated in vaCUo. Flash chromatography on 150g of silica gel using 3:1 v/v hç~s~nes/methylene chloride as the eluant afforded 1.71g (69%) of the title compound as a solid. lH NMR (400MHz, CDCl3) ~ 2.42 (lH, dt, J=3.6, 12.0Hz), 2.89 (app d, J--11.6Hz), 2.92 (lH, d, J=13.6Hz), 3.61-3.66 (lH, m), 3.73 ~lH, d, J=2.8Hz), 4.00 (lH, d, J=13.6EIz), 4.09 (lH, dt, J=2.4, 11.6Hz), 4.75 (lH, d, J=2.8Hz), 4.79 (lH, d, J=2.8Hz), 5.36 (lH, d, J--2.4Hz), 7.23-7.41 (7H, m), 7.63 (lH, app d, J=7.2Hz), 7.79 (lH, s), 7.91 (2H, s). MS (FAB) m/z 508 (M:+l, 25%).
Analysis Calcd. for C27H23FGNO2: C, 63.90; H, 4.57; N, 2.76; F, 22.46;
Found: C, 63.71; H, 4.53; N, 2.68; F, 22.66%.
2-(R~-(l-(R)-(3.5-Bis(trifluoromethYl)~henvl)ethoxy~-3-(S)-phenylmorpholine A mixture of the compound of Description 8 (1.5g) and 10%
palladium on carbon catalyst (750mg) in a mixture of isopropano~/ethyl acetate (25ml, 3:2 v/v) was stirred under an atmosphere of hydrogen for 48h. The catalyst was removed by filtration through celite and the reaction flask and filter pad were rinsed with ethyl acetate (500ml). The filtrate was concentrated in vacuo, flash chromatography afforded epimer A (106mg) and epimer B (899mg) as clear oils. The title compound, epimer B had the following analysis:
lH NMR (CDCl3, 400MHz) ~ 1.46 (3H, d, J=6.8Hz), 1.92 (lH, br s), 3.13 (lH, dd, J=3.0, 12.6Hz), 3.24 (lH, dt, J=3.6, 12.6Hz), 3.62 (lH, dd, J=3.6, 11.2Hz), 4.04 (lH, d, J=2.4Hz), 4.14 (lH, dt, J=3.0, 11.2Hz), 4.48 (lH, d, J=2.4Hz), 4.90 (lH, q, J=6.8Hz), 7.21-7.32 (7H, m), 7.64 (lH, s). MS (CI+) m/z 420 (M++1, 20%), 178 (100%).
Analysis Calcd. for C20HIsF6NO2: C, 57.28; H, 4.57; N, 3.34; F, 27.18;
Found: C, 57.41; H, 4.~i1; N, 3.29; F, 27.23%.
(N-Phenvlcvanocarbonimi-l~te 2-~ (1-(R)-(3,5-bis(trifluoromethvl)-phenvl)ethoxy)-3-($)-PhenYlmorPholine The title compound was synthesised ~ollowing the procedure of Garrett P.J. 'retrcrhedro~ (1993) 49, 165-176. The product of Description 9 (2.0g, 0.45mmol) was dissolved in 2-propanol (40ml), diphenvl aminocarbonimitl~te (2.18g, 0.9mmol) was added and the reaction heated to 80~C for 16h. The solvent was then removed and the product purified on silica eluting with hexane-ethyl acetate mixtures to give the title compound as an oil (1.2g).
2-(R)-(l-(R)-(3,5-Bis(trifluoromethvl)nhenyl)ethoxv)-4-cvano-3-(S)-(4-fluoroPhenyl)mor~holine CA 0223~8~ 1998-04-24 WO 97/18206 PCT/~1~5G~1~2766 The product of Description 5 (2.0g, 4.57mmol) was dissolved in dimethylform~mi~e (20ml), cyanogen bromide (727mg, 6.86mmol) was added followed by potassium carbonate (1.89g, 13.7mmol) and the reaction heated to 60~C for 16h. The reaction was then poured into ethyl acetate 5 and washed with water and brine, dried (MgSO4) and evaporated to dryness. Purification on silica eluting with h~ ne ethyl acetate ~ixtures gave the title compound (2.01g). lH NMR (250MHz, CDCI3) ~ 1.51 (3H, d, ~=6.6Hz), 3.42-3.60 (2H, m), 3.63-3.71 (lH, m), 4.22 (lH, d, J=2.6Hz), 4.25-4.34 (lH, m), 4.37 (lH, d, J=2.6Hz), 4.88 ~lH, q, J=6.6Hz), 7.09 (2H, t, J=8.6Hz), 7.22 (2H, s), 7.40-7.46 (2H, m), 7.67 (lH, s).
2-(R~-(l-(R)-(3~ 5-Bis(trifluoromethvl)Phenvl)ethoxY)-3-(S)-(4-f~uoro~henvl)-4-tetrazol- 5 -vl-mor~holine The product of Description 11 (280mg, 0.6mmol) was dissolved in dimethylform~mitle (15ml), sodium azide (78~g, 1.2mmol) was added followed by ammonium chloride (64mg, 1.2mmol) and the reaction heated to 160~C for 16h. The reaction was then poured into ethyl acetate, washed with water and brine, dried (~g~O4) and evaporated to dryness.
Purification on silica eluting with he~ne ethyl acetate mixtures gave the title compound. IH NMR (2~i0MHz, CDCl3) ~ 1.35 (3H, d, ~=6.6Hz), 3.44-3.58 (lH, m), 3.70-3.80 (2H, m), 4.60 (lH, d, J=3.3Hz), 4.78 (lH, d, J=3.3H~), 4.95 (lH, q, J=6.5Hz), 6.82-6.94 (2H, m), 7.39 (2H, s), 7.40-7.52 (2H, m), 7.67 (lH, s).
2-(R)-l-(R~-3,5-Bis(trifluoromethYl)phenvl)ethoxy)-3-(S)-(4-fluoro~henvl)-4-(2-hvdroxyethyl-2H-tetrazol-5-Yl)mor~holine The product of Description 12 (610mg, 1.21mmol) was dissolved in diemthylformamide (5ml). Potassium carbonate (757mg, 5.47mmol) was added followed by 2-bromoethanol (256~1, 3.62mmol) and the reaction CA 0223~8~ 1998-04-24 heated to 60~C for 16h. The reaction was then poured into ethyl acetate and washed with water and brine, dried (MgSO4) and evaporated to drvness. pllrifi~tion on silica eluting with h~n~-ethyl acetate gave the title compound (335mg). lH NMR (250MHz, CDCl3) ~ 1.44 (3H, d, J=6.6Hz), 2.26 (lH, br t), 3.62-3.66 (2H, m), 3.79-3.89 (lH, m), 3.95-4.01 (2H, m), 4.22-4.29 (lH, m), 4.45-4.52 (2H, m), 4.68 (lH, d, J=3.3Hz), 4.85 (lH, d, J=3.3Hz), 5.05 (lH, q, J=6.5Hz), 6.99 (2H, t, J=8.7Hz), 7.53-7.59 (4H, m), 7.76 (lH, s).
2-(R)-(l-~R)-(3,5-Bis(trifluoromethvl)Phenyl)ethoxv)-3-(S)-(4-fluorophenvl)-4-(2-p-toluenesulPhonvlethvl-2H-tetrazol-5-vl)morpholine The product of Description 13 (335mg, 0.61mmol) was dissolved in dichloromethane (lOmV, tosyl chloride (232mg, l ~.~.mmol) was added followed by triethylamine (171,u1, 2.34mmol) and the reaction heated to reflux for l~h. The solvent was then removed and the residue redissolved in ethyl acetate and washed with water and brine, dried (MgSO4) and evaporated to dryness. Purification on silica eluting with hexane-ethyl acetate gave the title compound (0.25g). lH NMR (250MHz, CDCl3) ~ 1.44 (3H, d, J=6.6Hz), 2.41 (3H, s), 3.46-3.63 (2H, m), 3.78-3.87 (lH, dt, J=3.9 and 10.2Hz), 4.19-4.24 (lH, dt, J=3.3 and 11.3Hz), 4.41 (2H, t, J=5.2Hz), 4.58 (2H, t, J=5.7Hz), 4.70 (lH, d, ~r=3.3Hz), 4.89 (lH, d, J=3.34Hz), 5.05-5.08 (lH, q, J=6.5Hz), 6.97 (2H, t, J=8.7Hz), 7.27 (2H, d, J=7.87Hz), 7.55-7.61 (4H, m), 7.67 (2H, d, J=6.6Hz), 7.77 (lH, s).
4-(5-Amino-1~2,4-triazol-3-vl)-2-(R)-(l-(R~-(3.6-bis(trifluoromethvl)phenyl) ethoxv)-3-(S)-~henYlmorPholine The product of Description 10 (1.80g, 1.85mmol) was dissolved in 2-propanol (30ml), hydrazine (180~1, 3.7mmol) was added and the reaction heated to 80~C for 16h. The solvent was then removed and the residue purified on silica eluting with dichloromethane-methanol mixtures to give the title compound (0.4g). lH NMR (250MHz, CDCl3) ~ 1.31 ~3H, d, J=6.5Hz), 3.22-3.40 (2H, m), 3.71-3.74 (lH, dt, ~=7.2 and 3.7~z), 3.94-4.00 (lH~ m), 4.50 (3H, m), 4.90 (lH, q, ~=6.5Hz), 4.96-~i.04 (2H, m), 6.90 (2H, t, J=17.6Hz), 7.50-7.64 (5H, m). MIS M+ 502.
2-(R)-l-(R)-(3~5-Bis(trifLuoromethvl)phenyl)ethoxv)-4-(2-N,N-dimethvl~minoethvl-2H-tetrazol-5-vl)-3-(S)-(4-fluoroPhenvl)morPholine The product of Description 14 (250mg, 0.355mmol) was dissolved in dimethylform~mi~le (lOml), dimethyl~mine (2ml) was added and the reaction heated in a sealed tube at 60~C for 16h. The reaction was then poured into ethyl acetate and washed with water and brine, dried (MgSO4) and evaporated to dryness. Purification on silica eluting with dichloromethane-methanol mixtures gave the title compound (0.13g).
lH NMR (250MHz, CDGl3) o 1.37 (3H, d, J=6.6Hz), 2.14 (6H, s), 2.67-2.71 (2H, dt, ~=1.6 and 6.65Hz), 3.43-3.59 (2H, m), 3.72-3.80 (lH, dt, J=3.7 and 9.9Hz), 4.12-4.19 (lH, m), 4.61 (lH, d, J=3.3Hz), 4.82 (lH, d, J=3.3Hz), 4.99 (lH, q, J=6.5Hz), 6.86-6.94 (2H, m), 7.50-7.55 (4H, m), 7.70 (lH, s,).
M/S M+ 577.
2-(R)-(l-(R)-(3,5-Bis(trifluoromethvl)phenvl~ethoxv)-4-(4-N,N-dimethvl~minomethvl)thiazol-2-vl)-3-(S)-(4-fluoroPhenvl)morPholine a) 2-(R)-(l-(R)-(3~5-Bis(trifluoromethyl)phenyl)ethoxy)-4-aminothiocarbonvl-3-(0-(4-~luorophenvl)mor~holine Through a solution of the product of Description 11 (1.07g) in ethanol (25ml) was bubbled hydrogen sulphide for 10 minutes. Potassium 30 tert-butoxide (0.05g) was added and addition of hydrogen sulphide was continued for 16 hours whilst the solution was heated at 50~C. Glacial acetic acid (O.lml) was added and the solvent was evaporated in vacuo.
The residue was chromatographed on silica gel eluting successively with 20% and 50% ethyl acetate in petroleum ether (bp 60-80~C) to give the title compound (0.57g). lH NMR(CDCl3, 250MHz) â 7.68 (lH,s), 7.31-7.72 (4H,m), 7.02 (2H,t, J=8.6Hz~, 5.51 (2H,br. s), 5.21 (lh,d, J=4.1Hz), 4.9Ei-4.90 (2H,m), 4.6 (lH,d, J=4.2Hz), 4.0-3.8 (3H,m), 1.38 (3H,d, J=6.6Hz).
b) 2-(R)-(1-(R)-(3.5-Bis(tri uoromethyl)phenvl3ethoxy)-4-(4-chloromethvl)thiazol-2-Yl) -3-~S)-(4-fluorophenvl)morpholine To a solution of the product of step (a) (0.534g) in chloroform (20ml) was added sodium bicarbonate (0.39g) and 1,3-dichloroacetone (0.165g).
The solution was stirred at 50~C for 3 hours followed by heating at reflux in a Dean and Stark apparatus cont~ining 3A molecular sieves for 2 hours.
The cooled solution was evaporated and the residue purified on silica gel eluting with 15% ethyl acetate in petroleum ether (bp 60-80~C) to give the title compound (0.487g). lH NMR(CDCl3, 250MHz) ~ 7.77 (lH,s), 7.61-7.54 (4H,m), 7.02 (2H,td, J=8.6Hz and 2.1Hz), 6.48 (lH,s), 5.04 (lH,q, J=6.6Hz), 4.87 (lH,d, J--3.4Hz), 4.66 ~lH,d, J=3.46Hz), 4.44 (2H,d, J=0.64Hz), 4.19 (2H,dt, J=11.3Hz and 3.32Hz), 3.92-3.62 (3H,m), 1.46 (3H,d, J=6.6Hz).
c) 2-(R)-(l-(R)-~3~5-:~is(trifluoromethvl)~henyl)ethoxy)-4-(4-N~N-dimethvlaminomethvl)thiazol-2-vl)-3-(S)-(4-fluoroPhenYl)morPholine Through a solution of the product of step (b) (0.109g) in ethanol (5ml) was passed diethylamine gas until saturated. The flask was sealed for 16 hours whereupon the solvent was removed in vacuo and the residue ~ purified on silica gel eluting with 2U% methanol in ethyl acetate. The residue after evaporation (0.063g) was dissolved in lM HCl in methanol ~ (lml), evaporated to dryness and washed with hexane. After drying i7il, 30 uacuo this gave the title compound as a foam. lH NMR(CDCl3, 360MHz) 7.76 (lH,s), 7.5 (4H,m), 7.01 (2H,t, J=8.7Hz), 6.8 ~lH,s), 5.0 (lH,q, J=6.5Hz), 4.85 (lH,d, J=3.5Hz), 4.65 (lH,d, J=3.6Hz), 4.22 (lH,dt, J=ll.OHz), 3.91-3.79 (4H,m), 3.6 (lH,ddd), 2.62 (6H,s), 1.44 (3H,d, J=6.6Hz). MS m/z (CI~ 578 (M+H).
li~XAlVI PLE 4 2-(R)-(l-(S)-(3.5-Bis(trifluorometh~l)phenvl)-2-hvdloxv~thoxv)-4-(2-amino-5-thiazolvl)-3-(0-(4-fluoroPhenvl)morpholine To a degassed solution of 2-~R~-(1-(S)-(3,5-bis(~i~uoromethyl3-phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)morpholine (0.2g), 2-amino-5-bromot.hi~7.ol~ (0.14g), sodium tert-butoxide (0.0105g) and tri-o-tolylphosphine (0.007g) in dioxane (4mV was added tris(dibenzylideneacetone)dipalladium (O) (0.02g). The solution was degassed and then heated at 80~C for 24h under an atmosphere of nitrogen. The solvent was removed in vacuo and the residue partitioned between ethyl acetate and water. The organic layer was dried (MgS04) and after evaporation of the solvent the residue was chromatographed on silica (eluting with gradient of 2% -4% methanol/ammonia (100:3) in dichloromethane) to give the title compound. lH NMR (360MHz, CDCl3) 3.11 (lH, td, J=11.7Hz, 3.5Hz), 3.19 (lH, bd J=11.4Hz), 3.61 (lH, dd, J=12.2Hz and 3.3Hz), 3.67-3.81 (3H, m), 4.47 (lH, d, J=2.8Hz), 4.54 (lH, td, J=11.7Hz and 2.8Hz), 4.80 (2H, bs), 4.92 (lH, dd, J=7.8Hz and 3.1Hz), 6.97 (2H, t, J=8.7Hz), 7.09 (lH, s), 7.14 (2H, s), 4.91 (lH, dd, J=7.8Hz and 3.1Hz), 7.67 (lH, s); m/z EI' 552(M~H).
The following examples illustrate pharmaceutical compositions according to the invention.
E~MPLE 5A Tablets cont~inin~ 1-25m~ of compound Amount m~
Compound offormula (I) 1.0 2.0 25.0 Microcrystalline cellulose 20.0 20.0 20.0 CA0223~8~ 1998-04-24 Modified food corn starch 20.0 20.0 20.0 Lactose 58.5 57.5 34.5 - Mz~nesium stearate 0.5 0.5 0-5 5 E~MPLE 5B Tablets cont~inin~ 26-lOOm~ of comPound Amount m~
Compound of formula (I) 26.0 50.0 100.0 Microcrystalline cellulose 80.0 80.0 80.0 Modified foodcorn starch 80.0 80.0 80.0 Lactose 213.5 189.5 13~.5 M~gnesium stearate 0.5 0.5 0 5 The compound of formula (I), cellulose, lactose and a portion of the corn starch are mixed and granulated with 10% corn starch paste. The resulting granulation is sieved, dried and blended with the rern~inller of 15 the corn starch and the magnesium stearate. The resulting granulation is then compressed into tablets cont~ining l.Omg, 2.0mg, 25.0mg, 26.0mg, 50.0mg and lOOmg of the active compound per tablet.
EXAMPLE 6 Parenteral iniection Amount m~
Compound of formula ~I) 1 to lOOmg Citric acid monohydrate 0.75mg Sodium phosphate 4.5mg Sodium chloride 9mg Water for injection to 10ml The sodium phosphate, citric acid monohydrate and sodium chloride are dissolved in a portion of the water. The compound of formula (I~ is dissolved or suspended in the solution and made up to volume.
EXAMPLE 7 Topical formulation Amount m~
Compound of formula (I) 1-lOg Emulsifying wax 30g Liquid paraffin 20g White soft paraffin to 100g The white soft paraffin is heated until molten. The liquid paraf~n and emulsifying wax are incorporated and st~rred until dissolved. The compound of formula (I) is added and stirring continued until dispersed.
The mixture is then cooled until solid.
EXAMPLE 8A - (Surface-Active A~ent) Iniection Formulation Compound of formula (I) up to 10mg/kg Tween 80TM up to 2.~%
[in 5% aqueous mzlnni~ol (isotonic)~
The compound of formula (I) is dissolved directly in a solution of the commercially available Tween 80TM (polyoxyethylenesorbitan monooleate) and 5% aqueous mannitol (isotonic).
EXAMPLE 8~ - (Emulsion) Iniection Formulation Compound of formula (I) up to 30mg/ml IntralipidTM (10-20%) The compound of formula (I) is dissolved directly in the commercially available IntralipidTM (10 or 20%) to form an emulsion.
CA 02235855 l998-04-24 EXAMPLE 8C - Alternative (Emulsion) Iniectable Formulation Amount (~ompound of formula (I) 0.1 - lOmg Soybean oil lOOmg Egg phospholipid 6mg Glycerol 22mg Water for injection to lml All materials are sterilized and pyrogen free. The compound of formula (I) 10 is dissolved in soybean oil. An emulsion is then formed by mi~ing this solution with the egg phospholipid, glycerol and water. The emulsion is then sealed in sterile vials.
Claims (25)
1. A compound of the formula (I):
wherein X is a 5- or 6-membered C-linked heteroaromatic ring containing 1 to 4 nitrogen atoms and optionally containing in the ring one oxygen or sulphur atom;
Y is a group of the formula -(CH2)nNR6R7, or a methylene- or ethylene-linked imidazolyl group;
Z is hydrogen or Cl 4alkyl optionally substituted by a hydroxy group;
R1 is hydrogen, halogen, Cl Galkyl, Cl.6alkoxy, CF3, NO2, CN, SRa, SORa, So2Ra, CO2Ra, CONRaRb, C2 6alkenyl, C2 6alkynyl or C1 4alkyl substituted by Cl 4alkoxy, wherein Ra and Rb each independently represent hydrogen or Cl 4alkyl;
R2 is hydrogen, halogen, Cl 6alkyl, Cl Galkoxy substituted by Cl 4alkoxy or CF3;
R3 is hydrogen, halogen or CF3;
R4 is hydrogen, halogen, Cl Galkyl, Cl Galkoxy, hydroxy, CF3, NO2, CN, SRa, SORa, SO2Ra, CO2Ra, CONRaRb, C2 Galkenyl, C2 Galkynyl or Cl-4alkyl substituted by Cl-4lkoxy wherein Ra and Rb are as previously defined;
R5 is hydrogen, halogen, Cl-6alkyl, Cl-6alkoxy substituted by Cl-4alkoxy or CF3;
R6 is hydrogen, Cl-6alkyl, C3.7cycloalkyl, C3 7cycloalkylCl 4alkyl, phenyl, or C2 4alkyl substituted by Cl-4alkoxy or hydroxy;
R7 is hydrogen, Cl 6alkyl, C3 7cycloalkyl, C3 7cycloalkylCl 4alkyl, phenyl, or C2 4alkyl substituted by one or two substituents selected from Cl-4alkoxy, hydroxy or a 4, 5 or 6 membered heteroaliphatic ring containing one or two heteroatoms selected from N, O and S;
or R6 and R7, together with the nitrogen atom to which they are attached, form a saturated or partially saturated heterocyclic ring of 4 to 7 ring atoms, which ring may optionally contain in the ring one oxygen or sulphur atom or a group selected from NR8, S(O) or S(0)2 and which ring may be optionally substituted by one or two groups selected from hydroxyCl 4alkyl, Cl 4alkoxyCl 4alkyl, oxo, CORa or CO2Ra where Ra is as previously defined;
or R6 and R7 together with the nitrogen atom to which they are attached, form a non-aromatic azabicyclic ring system of 6 to 12 ring atoms;
R8 is hydrogen, Cl-4alkyl, hydroxyCl 4alkyl or Cl-4alkoxyCl 4alkyl;
R9a and R9b are each independently hydrogen or Cl-4alkyl, or R9a and R9b are joined so, together with the carbon atoms to which they are attached, there is formed a C5.7 ring; and n is zero, 1 or 2;
or a pharmaceutically acceptable salt thereof.
wherein X is a 5- or 6-membered C-linked heteroaromatic ring containing 1 to 4 nitrogen atoms and optionally containing in the ring one oxygen or sulphur atom;
Y is a group of the formula -(CH2)nNR6R7, or a methylene- or ethylene-linked imidazolyl group;
Z is hydrogen or Cl 4alkyl optionally substituted by a hydroxy group;
R1 is hydrogen, halogen, Cl Galkyl, Cl.6alkoxy, CF3, NO2, CN, SRa, SORa, So2Ra, CO2Ra, CONRaRb, C2 6alkenyl, C2 6alkynyl or C1 4alkyl substituted by Cl 4alkoxy, wherein Ra and Rb each independently represent hydrogen or Cl 4alkyl;
R2 is hydrogen, halogen, Cl 6alkyl, Cl Galkoxy substituted by Cl 4alkoxy or CF3;
R3 is hydrogen, halogen or CF3;
R4 is hydrogen, halogen, Cl Galkyl, Cl Galkoxy, hydroxy, CF3, NO2, CN, SRa, SORa, SO2Ra, CO2Ra, CONRaRb, C2 Galkenyl, C2 Galkynyl or Cl-4alkyl substituted by Cl-4lkoxy wherein Ra and Rb are as previously defined;
R5 is hydrogen, halogen, Cl-6alkyl, Cl-6alkoxy substituted by Cl-4alkoxy or CF3;
R6 is hydrogen, Cl-6alkyl, C3.7cycloalkyl, C3 7cycloalkylCl 4alkyl, phenyl, or C2 4alkyl substituted by Cl-4alkoxy or hydroxy;
R7 is hydrogen, Cl 6alkyl, C3 7cycloalkyl, C3 7cycloalkylCl 4alkyl, phenyl, or C2 4alkyl substituted by one or two substituents selected from Cl-4alkoxy, hydroxy or a 4, 5 or 6 membered heteroaliphatic ring containing one or two heteroatoms selected from N, O and S;
or R6 and R7, together with the nitrogen atom to which they are attached, form a saturated or partially saturated heterocyclic ring of 4 to 7 ring atoms, which ring may optionally contain in the ring one oxygen or sulphur atom or a group selected from NR8, S(O) or S(0)2 and which ring may be optionally substituted by one or two groups selected from hydroxyCl 4alkyl, Cl 4alkoxyCl 4alkyl, oxo, CORa or CO2Ra where Ra is as previously defined;
or R6 and R7 together with the nitrogen atom to which they are attached, form a non-aromatic azabicyclic ring system of 6 to 12 ring atoms;
R8 is hydrogen, Cl-4alkyl, hydroxyCl 4alkyl or Cl-4alkoxyCl 4alkyl;
R9a and R9b are each independently hydrogen or Cl-4alkyl, or R9a and R9b are joined so, together with the carbon atoms to which they are attached, there is formed a C5.7 ring; and n is zero, 1 or 2;
or a pharmaceutically acceptable salt thereof.
2. A compound a claimed in Claim 1 wherein Rl is hydrogen, Cl-4alkyl, C1-4alkoxy, halogen or CF3.
3. A compound as claimed in Claim 1 or Claim 2 wherein R2 is hydrogen, Cl-4alkyl, C1-4alkoxy, halogen or CF3.
4. A compound as claimed in any one of Claims 1 to 3 wherein R3 is hydrogen, fluorine, chlorine or CF3.
5. A compound as claimed in any one of Claims 1 to 4 wherein R4 is hydrogen.
6. A compound as claimed in any one of Claims 1 to 5 wherein R5 is hydrogen, fluorine, chlorine or CF3.
7. A compound as claimed in any one of Claims 1 to 6 wherein R9a and R9b are each independently hydrogen or methyl.
8. A compound of the formula (ra):
wherein Al is fluorine or CF3;
A2 is fluorine or CF3;
A3 is fluorine or hydrogen;
X is a 5- or 6- membered C-linked heteroaromatic ring containing 1 to 4 nitrogen atoms and optionally containing in the ring one oxygen or sulphur atom;
Y is a group of the formula -(CH2)nNR6R7, or a methylene- or ethylene-linked imidazolyl group;
Z is hydrogen or C1-4alkyl optionally substituted by a hydroxy group;
or a pharmaceutically acceptable salt thereof.
wherein Al is fluorine or CF3;
A2 is fluorine or CF3;
A3 is fluorine or hydrogen;
X is a 5- or 6- membered C-linked heteroaromatic ring containing 1 to 4 nitrogen atoms and optionally containing in the ring one oxygen or sulphur atom;
Y is a group of the formula -(CH2)nNR6R7, or a methylene- or ethylene-linked imidazolyl group;
Z is hydrogen or C1-4alkyl optionally substituted by a hydroxy group;
or a pharmaceutically acceptable salt thereof.
9. A compound as claimed in any one of Claims 1 to 8 wherein X
is selected from imidazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, thiadiazolyl and oxadiazolyl.
is selected from imidazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, thiadiazolyl and oxadiazolyl.
10. A compound as claimed in any one of Claims 1 to 9 wherein Y
is a group of the formula -(CH2)nNR6R7.
is a group of the formula -(CH2)nNR6R7.
11. A compound as claimed in any one of Claims 1 to 10 wherein Z is a C1-2alkyl group optionally substituted by a hydroxy group.
12. A compound selected from:
4-(5-amino-1,2,4-triazol-3-yl)-2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl) ethoxy)-3-(S)-phenylmorpholine;
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(2-N,N-dimethylaminoethyl-2H-tetrazol-5-yl)-3-(S)-(4-fluorophenyl)morpholine;
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-dimethylaminomethyl)thiazol-2-yl)-3-(S)-(4-fluorophenyl)morpholine;
or a pharmaceutically acceptable salt thereof.
4-(5-amino-1,2,4-triazol-3-yl)-2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl) ethoxy)-3-(S)-phenylmorpholine;
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(2-N,N-dimethylaminoethyl-2H-tetrazol-5-yl)-3-(S)-(4-fluorophenyl)morpholine;
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-dimethylaminomethyl)thiazol-2-yl)-3-(S)-(4-fluorophenyl)morpholine;
or a pharmaceutically acceptable salt thereof.
13. A compound as claimed in any preceding claim for use in therapy.
14. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 12 in association with a pharmaceutically acceptable carrier or excipient.
15. A method for the treatment or prevention of physiological disorders associated with an excess of tachykinins, which method comprises administration to a patient in need thereof of a tachykinin reducing amount of a compound according to claim 1.
16. A method according to claim 15 for the treatment or prevention of pain or inflammation.
17. A method according to claim 15 for the treatment or prevention of migraine.
18. A method according to claim 15 for the treatment or prevention of emesis.
19. A method according to claim 15 for the treatment or prevention of postherpetic neuralgia.
20. The use of a compound as claimed in any one of claims 1 to 1 for the manufacture of a medicament for the treatment or prevention of a physiological disorder associated with an excess of tachykinins.
21. The use of a compound as claimed in any one of claims 1 to 12 for the manufacture of a medicament for the treatment or prevention of pain or inflammation.
22. The use of a compound as claimed in any one of claims 1 to 12 for the manufacture of a medicament for the treatment or prevention of migraine.
23. The use of a compound as claimed in any one of claims 1 to 12 for the manufacture of a medicament for the treatment or prevention of emesis.
24. The use of a compound as claimed in any one of claims 1 to 12 for the manufacture of a medicament for the treatment or prevention of postherpetic neuralgia.
25. A process for the preparation of a compound as claimed in Claim 1 which comprises:
(A), reaction of formula (II) wherein Rl R2, R3, R4, R5, R9a, R9b and Z are as defined in Claim 1 and R20 is phenyl or Cl-6alkyl, with hydrazine; or (B), reaction of a compound of formula (III) wherein R1, R2, R3, R4, R5, R9a, R9b, X and Z are as defined in Claim 1, R21 is a leaving group, and m is 1 or 2, with an amine of the formula HNR6R7 or imidazole; or (C), reaction of a compound of formula (IV) wherein R1, R2, R3, R4, R5, R9a, R9b, X and Z are as defined Claim 1 and Hal is a halogen atom and m is 1 or 2, with an amine of the formula HNR6R7 or imidazole; or (D), interconversion of a compound of formula (1) in which the heteroaromatic ring represented by X is substituted by a group of the formula -(CH2)nNH2, by reaction with alkyl halides of the formula R6-Hal and R7-Hal, or a suitable dihalide to form a saturated heterocyclic ring, wherein R6 and R7 are as defined in Claim 1, and Hal is as previously defined, in the presence of a base;
(E), reaction of a compound of formula (V) wherein Rl, R2, R3, R4, R5, R9a, R9b and Z are as defined in Claim 1, with a compound of formula (XI) wherein Hal is a halogen atom;
each process being followed, where necessary, by the removal of any protecting group where present;
and when the compound of formula (I) is obtained as a mixture of enantiomers or diastereoisomers, optionally resolving the mixture to obtain the desired enantiometer;
and/or, if desired, covering the resulting compound of formula (I) or a salt thereof, into a pharmaceutically acceptable salt or prodrug thereof.
(A), reaction of formula (II) wherein Rl R2, R3, R4, R5, R9a, R9b and Z are as defined in Claim 1 and R20 is phenyl or Cl-6alkyl, with hydrazine; or (B), reaction of a compound of formula (III) wherein R1, R2, R3, R4, R5, R9a, R9b, X and Z are as defined in Claim 1, R21 is a leaving group, and m is 1 or 2, with an amine of the formula HNR6R7 or imidazole; or (C), reaction of a compound of formula (IV) wherein R1, R2, R3, R4, R5, R9a, R9b, X and Z are as defined Claim 1 and Hal is a halogen atom and m is 1 or 2, with an amine of the formula HNR6R7 or imidazole; or (D), interconversion of a compound of formula (1) in which the heteroaromatic ring represented by X is substituted by a group of the formula -(CH2)nNH2, by reaction with alkyl halides of the formula R6-Hal and R7-Hal, or a suitable dihalide to form a saturated heterocyclic ring, wherein R6 and R7 are as defined in Claim 1, and Hal is as previously defined, in the presence of a base;
(E), reaction of a compound of formula (V) wherein Rl, R2, R3, R4, R5, R9a, R9b and Z are as defined in Claim 1, with a compound of formula (XI) wherein Hal is a halogen atom;
each process being followed, where necessary, by the removal of any protecting group where present;
and when the compound of formula (I) is obtained as a mixture of enantiomers or diastereoisomers, optionally resolving the mixture to obtain the desired enantiometer;
and/or, if desired, covering the resulting compound of formula (I) or a salt thereof, into a pharmaceutically acceptable salt or prodrug thereof.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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GBGB9523244.3A GB9523244D0 (en) | 1995-11-14 | 1995-11-14 | Therapeutic agents |
GB9523244.3 | 1995-11-14 | ||
PCT/GB1996/002766 WO1997018206A1 (en) | 1995-11-14 | 1996-11-13 | Morpholine derivatives and their use as therapeutic agents |
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CA2235855A1 true CA2235855A1 (en) | 1997-05-22 |
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CA 2235855 Abandoned CA2235855A1 (en) | 1995-11-14 | 1996-11-13 | Morpholine derivatives and their use as therapeutic agents |
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Country | Link |
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CA (1) | CA2235855A1 (en) |
-
1996
- 1996-11-13 CA CA 2235855 patent/CA2235855A1/en not_active Abandoned
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