BG62963B1 - Морфолинови антагонисти на тахикининови рецептори - Google Patents

Морфолинови антагонисти на тахикининови рецептори Download PDF

Info

Publication number: BG62963B1
Authority: BG; Bulgaria
Prior art keywords: defined above; phenyl; trifluoromethyl; benzyloxy; bis
Prior art date: 1992-06-29

Application number

BG99274A

Other languages

Bulgarian (bg)

English (en)

Other versions

BG99274A (bg

Inventor

Conrad Dorn

Jeffrey Hale

Malcolm Maccoss

Sander Mills

Tamara Ladduwahetty

Shrenik Shah

Original Assignee

Merck & Co. Inc.

Priority date (The priority date 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 date listed.)

1992-06-29

Filing date

1994-12-19

Publication date

2000-12-29

1994-12-19 Application filed by Merck & Co. Inc. filed Critical Merck & Co. Inc.

1996-04-30 Publication of BG99274A publication Critical patent/BG99274A/bg

2000-12-29 Publication of BG62963B1 publication Critical patent/BG62963B1/bg

Links

239000005557 antagonist Substances 0.000 title abstract description 15
YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 title abstract description 12
150000001875 compounds Chemical class 0.000 claims abstract description 116
208000019695 Migraine disease Diseases 0.000 claims abstract description 12
208000006673 asthma Diseases 0.000 claims abstract description 11
206010027599 migraine Diseases 0.000 claims abstract description 11
-1 isooxazolyl Chemical group 0.000 claims description 192
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 169
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 117
239000000203 mixture Substances 0.000 claims description 101
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 85
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 78
150000002367 halogens Chemical class 0.000 claims description 74
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 70
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 66
229910052736 halogen Inorganic materials 0.000 claims description 65
125000003545 alkoxy group Chemical group 0.000 claims description 64
125000000217 alkyl group Chemical group 0.000 claims description 63
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 60
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 58
125000001424 substituent group Chemical group 0.000 claims description 54
238000000034 method Methods 0.000 claims description 49
125000004093 cyano group Chemical group *C#N 0.000 claims description 45
102100024304 Protachykinin-1 Human genes 0.000 claims description 37
QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 36
229910052739 hydrogen Inorganic materials 0.000 claims description 36
239000001257 hydrogen Substances 0.000 claims description 35
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 32
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 claims description 30
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 29
101800003906 Substance P Proteins 0.000 claims description 29
SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 28
150000003839 salts Chemical class 0.000 claims description 26
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 23
125000000623 heterocyclic group Chemical group 0.000 claims description 18
FHQRDEDZJIFJAL-UHFFFAOYSA-N 4-phenylmorpholine Chemical compound C1COCCN1C1=CC=CC=C1 FHQRDEDZJIFJAL-UHFFFAOYSA-N 0.000 claims description 17
241000124008 Mammalia Species 0.000 claims description 17
238000006243 chemical reaction Methods 0.000 claims description 16
FUQXMZQIUQTJPV-UHFFFAOYSA-N 2-[[3,5-bis(trifluoromethyl)phenyl]methoxy]-3-phenylmorpholine Chemical compound FC(F)(F)C1=CC(C(F)(F)F)=CC(COC2C(NCCO2)C=2C=CC=CC=2)=C1 FUQXMZQIUQTJPV-UHFFFAOYSA-N 0.000 claims description 14
125000003342 alkenyl group Chemical group 0.000 claims description 14
239000002904 solvent Substances 0.000 claims description 14
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 14
125000002883 imidazolyl group Chemical group 0.000 claims description 13
230000036407 pain Effects 0.000 claims description 13
125000000168 pyrrolyl group Chemical group 0.000 claims description 13
230000029936 alkylation Effects 0.000 claims description 12
238000005804 alkylation reaction Methods 0.000 claims description 12
125000003386 piperidinyl group Chemical group 0.000 claims description 12
102000005962 receptors Human genes 0.000 claims description 12
108020003175 receptors Proteins 0.000 claims description 12
125000005843 halogen group Chemical group 0.000 claims description 11
125000002971 oxazolyl group Chemical group 0.000 claims description 11
125000004076 pyridyl group Chemical group 0.000 claims description 11
125000000719 pyrrolidinyl group Chemical group 0.000 claims description 11
208000002193 Pain Diseases 0.000 claims description 10
239000003795 chemical substances by application Substances 0.000 claims description 10
125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
230000000694 effects Effects 0.000 claims description 10
150000002391 heterocyclic compounds Chemical class 0.000 claims description 10
125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 9
125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 9
125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 9
102400000097 Neurokinin A Human genes 0.000 claims description 9
HEAUFJZALFKPBA-YRVBCFNBSA-N Neurokinin A Chemical compound C([C@@H](C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(N)=O)C(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CC=1NC=NC=1)C(C)O)C1=CC=CC=C1 HEAUFJZALFKPBA-YRVBCFNBSA-N 0.000 claims description 9
101800000399 Neurokinin A Proteins 0.000 claims description 9
125000005842 heteroatom Chemical group 0.000 claims description 9
125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 8
125000002541 furyl group Chemical group 0.000 claims description 8
238000002360 preparation method Methods 0.000 claims description 8
125000001544 thienyl group Chemical group 0.000 claims description 8
LEMUQYVGNWVOOC-RBUKOAKNSA-N 2-[(2s,3s)-2-[[3,5-bis(trifluoromethyl)phenyl]methoxy]-3-phenylmorpholin-4-yl]acetic acid Chemical compound O([C@H]1OCCN([C@H]1C=1C=CC=CC=1)CC(=O)O)CC1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 LEMUQYVGNWVOOC-RBUKOAKNSA-N 0.000 claims description 7
WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 7
125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 7
150000002430 hydrocarbons Chemical group 0.000 claims description 7
125000001786 isothiazolyl group Chemical group 0.000 claims description 7
229910052744 lithium Inorganic materials 0.000 claims description 7
208000033808 peripheral neuropathy Diseases 0.000 claims description 7
125000003373 pyrazinyl group Chemical group 0.000 claims description 7
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 7
125000003831 tetrazolyl group Chemical group 0.000 claims description 7
125000001113 thiadiazolyl group Chemical group 0.000 claims description 7
125000000464 thioxo group Chemical group S=* 0.000 claims description 7
125000001425 triazolyl group Chemical group 0.000 claims description 7
125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 6
UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 6
239000003153 chemical reaction reagent Substances 0.000 claims description 6
125000001715 oxadiazolyl group Chemical group 0.000 claims description 6
230000008569 process Effects 0.000 claims description 6
125000003226 pyrazolyl group Chemical group 0.000 claims description 6
229910000104 sodium hydride Inorganic materials 0.000 claims description 6
ICJXTVCDDLEZHJ-DLBZAZTESA-N (2s,3s)-2-[(3,5-dichlorophenyl)methoxy]-3-phenylmorpholine Chemical compound ClC1=CC(Cl)=CC(CO[C@@H]2[C@@H](NCCO2)C=2C=CC=CC=2)=C1 ICJXTVCDDLEZHJ-DLBZAZTESA-N 0.000 claims description 5
GSZAAEJBPFTBKG-INIZCTEOSA-N (3s)-4-benzyl-3-(4-fluorophenyl)morpholin-2-one Chemical compound C1=CC(F)=CC=C1[C@H]1C(=O)OCCN1CC1=CC=CC=C1 GSZAAEJBPFTBKG-INIZCTEOSA-N 0.000 claims description 5
125000005940 1,4-dioxanyl group Chemical group 0.000 claims description 5
201000003883 Cystic fibrosis Diseases 0.000 claims description 5
108010040718 Neurokinin-1 Receptors Proteins 0.000 claims description 5
102000002002 Neurokinin-1 Receptors Human genes 0.000 claims description 5
125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 5
125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 5
125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 5
SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 claims description 5
125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 5
125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 5
239000003937 drug carrier Substances 0.000 claims description 5
125000004634 hexahydroazepinyl group Chemical group N1(CCCCCC1)* 0.000 claims description 5
125000001041 indolyl group Chemical group 0.000 claims description 5
201000001119 neuropathy Diseases 0.000 claims description 5
230000007823 neuropathy Effects 0.000 claims description 5
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
150000007524 organic acids Chemical class 0.000 claims description 5
239000003960 organic solvent Substances 0.000 claims description 5
125000004193 piperazinyl group Chemical group 0.000 claims description 5
125000000714 pyrimidinyl group Chemical group 0.000 claims description 5
125000005493 quinolyl group Chemical group 0.000 claims description 5
125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 5
125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 5
125000005958 tetrahydrothienyl group Chemical group 0.000 claims description 5
JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 5
FGNKYBCTXIEACK-DLBZAZTESA-N (2s,3s)-2-[[3,5-bis(trifluoromethyl)phenyl]methoxy]-3-(4-fluorophenyl)morpholine Chemical compound C1=CC(F)=CC=C1[C@H]1[C@@H](OCC=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)OCCN1 FGNKYBCTXIEACK-DLBZAZTESA-N 0.000 claims description 4
VQEBNTLPXZDHSZ-UHFFFAOYSA-N 4-[(3,5-ditert-butylphenyl)methoxy]-3-phenylmorpholine Chemical compound C(C)(C)(C)C=1C=C(CON2C(COCC2)C2=CC=CC=C2)C=C(C=1)C(C)(C)C VQEBNTLPXZDHSZ-UHFFFAOYSA-N 0.000 claims description 4
OZPICOPIYPCOIS-UHFFFAOYSA-N 6-[2-[3,5-bis(trifluoromethyl)phenyl]ethenyl]-5-phenylmorpholin-3-one Chemical compound FC(F)(F)C1=CC(C(F)(F)F)=CC(C=CC2C(NC(=O)CO2)C=2C=CC=CC=2)=C1 OZPICOPIYPCOIS-UHFFFAOYSA-N 0.000 claims description 4
125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 4
230000000903 blocking effect Effects 0.000 claims description 4
150000004678 hydrides Chemical class 0.000 claims description 4
239000012280 lithium aluminium hydride Substances 0.000 claims description 4
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
239000008194 pharmaceutical composition Substances 0.000 claims description 4
MQHWDFVGDXXXRC-BJKOFHAPSA-N (2s,3s)-4-benzyl-2-[[3,5-bis(trifluoromethyl)phenyl]methoxy]-3-(4-fluorophenyl)morpholine Chemical compound C1=CC(F)=CC=C1[C@@H]1N(CC=2C=CC=CC=2)CCO[C@@H]1OCC1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 MQHWDFVGDXXXRC-BJKOFHAPSA-N 0.000 claims description 3
SRIOHIXTSHGWLJ-UHFFFAOYSA-N 2-[2-[3,5-bis(trifluoromethyl)phenyl]ethyl]-3-phenylmorpholine Chemical compound FC(F)(F)C1=CC(C(F)(F)F)=CC(CCC2C(NCCO2)C=2C=CC=CC=2)=C1 SRIOHIXTSHGWLJ-UHFFFAOYSA-N 0.000 claims description 3
208000032131 Diabetic Neuropathies Diseases 0.000 claims description 3
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KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 3
239000003638 chemical reducing agent Substances 0.000 claims description 3
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238000010992 reflux Methods 0.000 claims description 3
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FQQRAUDZMUSIKP-SNVBAGLBSA-N (2R)-2-methyl-4-phenylmorpholine Chemical compound C1(=CC=CC=C1)N1CCO[C@@H](C1)C FQQRAUDZMUSIKP-SNVBAGLBSA-N 0.000 claims description 2
PUZOQLKLCNWXCR-IGNZVWTISA-N (2r,3s,5s)-2-[[3,5-bis(trifluoromethyl)phenyl]methoxy]-5-methyl-3-phenylmorpholine Chemical compound O([C@@H]1OC[C@@H](N[C@H]1C=1C=CC=CC=1)C)CC1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 PUZOQLKLCNWXCR-IGNZVWTISA-N 0.000 claims description 2
AOWGLTSPUDFTLW-UYHISHBKSA-N (2r,3s,6s)-2-[[3,5-bis(trifluoromethyl)phenyl]methoxy]-6-methyl-3-phenylmorpholine Chemical compound O([C@H]1[C@@H](NC[C@@H](O1)C)C=1C=CC=CC=1)CC1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 AOWGLTSPUDFTLW-UYHISHBKSA-N 0.000 claims description 2
AOWGLTSPUDFTLW-RZAIGCCYSA-N (2s,3r,6s)-2-[[3,5-bis(trifluoromethyl)phenyl]methoxy]-6-methyl-3-phenylmorpholine Chemical compound O([C@@H]1[C@H](NC[C@@H](O1)C)C=1C=CC=CC=1)CC1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 AOWGLTSPUDFTLW-RZAIGCCYSA-N 0.000 claims description 2
PUZOQLKLCNWXCR-UYHISHBKSA-N (2s,3s,5s)-2-[[3,5-bis(trifluoromethyl)phenyl]methoxy]-5-methyl-3-phenylmorpholine Chemical compound O([C@H]1OC[C@@H](N[C@H]1C=1C=CC=CC=1)C)CC1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 PUZOQLKLCNWXCR-UYHISHBKSA-N 0.000 claims description 2
AOWGLTSPUDFTLW-IGNZVWTISA-N (2s,3s,6s)-2-[[3,5-bis(trifluoromethyl)phenyl]methoxy]-6-methyl-3-phenylmorpholine Chemical compound O([C@@H]1[C@@H](NC[C@@H](O1)C)C=1C=CC=CC=1)CC1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 AOWGLTSPUDFTLW-IGNZVWTISA-N 0.000 claims description 2
OIYANYVIFQBNMS-LLVKDONJSA-N (3S)-4-methyl-3-phenylmorpholine Chemical compound C1(=CC=CC=C1)[C@@H]1N(CCOC1)C OIYANYVIFQBNMS-LLVKDONJSA-N 0.000 claims description 2
MDTUWBLTRPRXBX-UHFFFAOYSA-N 1,2,4-triazol-3-one Chemical compound O=C1N=CN=N1 MDTUWBLTRPRXBX-UHFFFAOYSA-N 0.000 claims description 2
LLCBKEBNBKAKRD-DNQXCXABSA-N 6-[(2s,3r)-2-[[3,5-bis(trifluoromethyl)phenyl]methoxy]-3-phenylmorpholin-4-yl]-n-methylhexanamide Chemical compound O([C@H]1OCCN([C@@H]1C=1C=CC=CC=1)CCCCCC(=O)NC)CC1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 LLCBKEBNBKAKRD-DNQXCXABSA-N 0.000 claims description 2
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DWBOMRPSOKKUJP-VJBWXMMDSA-N C1[C@@H](O[C@@H]([C@@H](N1)C2=CC=CC=C2)OCC3=CC(=CC(=C3)C(F)(F)F)C(F)(F)F)C4=CC=CC=C4 Chemical compound C1[C@@H](O[C@@H]([C@@H](N1)C2=CC=CC=C2)OCC3=CC(=CC(=C3)C(F)(F)F)C(F)(F)F)C4=CC=CC=C4 DWBOMRPSOKKUJP-VJBWXMMDSA-N 0.000 claims description 2
125000001246 bromo group Chemical group Br* 0.000 claims description 2
150000002431 hydrogen Chemical class 0.000 claims description 2
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LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 claims 1
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XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims 1
229940088368 Neurokinin 2 receptor antagonist Drugs 0.000 claims 1
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HKQKWZAMVUVBGL-VQTJNVASSA-N methyl 2-[(2s,3s)-2-[[3,5-bis(trifluoromethyl)phenyl]methoxy]-3-phenylmorpholin-4-yl]acetate Chemical compound O([C@H]1OCCN([C@H]1C=1C=CC=CC=1)CC(=O)OC)CC1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 HKQKWZAMVUVBGL-VQTJNVASSA-N 0.000 claims 1
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DUYAAUVXQSMXQP-UHFFFAOYSA-M thioacetate Chemical compound CC([S-])=O DUYAAUVXQSMXQP-UHFFFAOYSA-M 0.000 description 1
150000003573 thiols Chemical class 0.000 description 1
BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
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JLTRXTDYQLMHGR-UHFFFAOYSA-N trimethylaluminium Chemical compound C[Al](C)C JLTRXTDYQLMHGR-UHFFFAOYSA-N 0.000 description 1
RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
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Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
- C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/06—Antimigraine agents
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
- C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
- C07D265/32—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings with oxygen atoms directly attached to ring carbon atoms
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
- C07D279/12—1,4-Thiazines; Hydrogenated 1,4-thiazines not condensed with other rings
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Landscapes

Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Health & Medical Sciences (AREA)
General Health & Medical Sciences (AREA)
Veterinary Medicine (AREA)
Public Health (AREA)
Chemical Kinetics & Catalysis (AREA)
General Chemical & Material Sciences (AREA)
Medicinal Chemistry (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Bioinformatics & Cheminformatics (AREA)
Pharmacology & Pharmacy (AREA)
Life Sciences & Earth Sciences (AREA)
Animal Behavior & Ethology (AREA)
Engineering & Computer Science (AREA)
Pain & Pain Management (AREA)
Heart & Thoracic Surgery (AREA)
Pulmonology (AREA)
Cardiology (AREA)
Biomedical Technology (AREA)
Neurology (AREA)
Neurosurgery (AREA)
Rheumatology (AREA)
Vascular Medicine (AREA)
Urology & Nephrology (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Plural Heterocyclic Compounds (AREA)
Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

BG99274A 1992-06-29 1994-12-19 Морфолинови антагонисти на тахикининови рецептори BG62963B1 (bg)

Applications Claiming Priority (4)

Application Number	Priority Date	Filing Date	Title
US90597692A	1992-06-29	1992-06-29
US97144892A	1992-11-04	1992-11-04
US6191493A	1993-05-19	1993-05-19
PCT/US1993/006181 WO1994000440A1 (en)	1992-06-29	1993-06-29	Morpholine and thiomorpholine tachykinin receptor antagonists

Publications (2)

Publication Number	Publication Date
BG99274A BG99274A (bg)	1996-04-30
BG62963B1 true BG62963B1 (bg)	2000-12-29

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ID=27370159

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
BG99274A BG62963B1 (bg)	1992-06-29	1994-12-19	Морфолинови антагонисти на тахикининови рецептори

Country Status (33)

Country	Link
EP (1)	EP0577394B1 (da)
JP (1)	JP2634372B2 (da)
KR (1)	KR100301212B1 (da)
CN (1)	CN1049431C (da)
AT (1)	ATE186532T1 (da)
AU (1)	AU4656193A (da)
BG (1)	BG62963B1 (da)
BR (1)	BR1100375A (da)
CA (1)	CA2099233A1 (da)
CY (1)	CY2200B1 (da)
CZ (1)	CZ288530B6 (da)
DE (1)	DE69326977T2 (da)
DK (1)	DK0577394T3 (da)
DZ (1)	DZ1700A1 (da)
ES (1)	ES2141133T3 (da)
FI (1)	FI111363B (da)
GR (1)	GR3031824T3 (da)
HR (1)	HRP931003B1 (da)
HU (1)	HU219713B (da)
IL (1)	IL106142A (da)
LV (1)	LV12568B (da)
MX (1)	MX9303888A (da)
MY (1)	MY108836A (da)
NO (1)	NO305698B1 (da)
NZ (1)	NZ254476A (da)
RO (1)	RO114448B1 (da)
RU (1)	RU2140914C1 (da)
SI (1)	SI9300346B (da)
SK (1)	SK281093B6 (da)
TW (1)	TW358808B (da)
WO (1)	WO1994000440A1 (da)
YU (1)	YU49036B (da)
ZA (1)	ZA934624B (da)

Families Citing this family (118)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
US5637699A (en) *	1992-06-29	1997-06-10	Merck & Co., Inc.	Process for preparing morpholine tachykinin receptor antagonists
US5719147A (en) *	1992-06-29	1998-02-17	Merck & Co., Inc.	Morpholine and thiomorpholine tachykinin receptor antagonists
US6048859A (en)	1992-06-29	2000-04-11	Merck & Co., Inc.	Morpholine and thiomorpholine tachykinin receptor antagonists
IL111960A (en) *	1993-12-17	1999-12-22	Merck & Co Inc	Morpholines and thiomorpholines their preparation and pharmaceutical compositions containing them
IL112134A (en) *	1993-12-29	1999-12-22	Merck Sharp & Dohme	Substituted morpholine derivatives their preparation and pharmaceutical compositions containing them
US5610165A (en) *	1994-02-17	1997-03-11	Merck & Co., Inc.	N-acylpiperidine tachykinin antagonists
IL112778A0 (en) *	1994-03-04	1995-05-26	Merck & Co Inc	Substituted heterocycles, their preparation and pharmaceutical compositions containing them
WO1995030674A1 (en) *	1994-05-05	1995-11-16	Merck Sharp & Dohme Limited	Morpholine derivatives and their use as antagonists of tachikinins
US5824678A (en) *	1994-08-15	1998-10-20	Merck Sharp & Dohme Ltd.	Morpholine derivatives and their use as therapeutic agents
GB9417956D0 (en) *	1994-09-02	1994-10-26	Merck Sharp & Dohme	Therapeutic agents
US5457107A (en) *	1994-09-16	1995-10-10	Merck & Co., Inc.	Polymorphic form of a tachykinin receptor antagonist
FR2728165A1 (fr) *	1994-12-19	1996-06-21	Oreal	Utilisation d'un antagoniste de substance p pour le traitement des rougeurs cutanees d'origine neurogene
GB9426102D0 (en) *	1994-12-23	1995-02-22	Merck Sharp & Dohme	Pharmacuetical compositions
GB9426103D0 (en) *	1994-12-23	1995-02-22	Merck Sharp & Dohme	Therapeutic agents
FR2729954B1 (fr) *	1995-01-30	1997-08-01	Sanofi Sa	Composes heterocycliques substitues, procede pour leur preparation et compositions pharmaceutiques les contenant
DE19504627A1 (de) *	1995-02-13	1996-08-14	Bayer Ag	Verfahren und neue Zwischenprodukte zur Herstellung von Triazolinonen
GB9505491D0 (en) *	1995-03-18	1995-05-03	Merck Sharp & Dohme	Therapeutic agents
GB9505492D0 (en) *	1995-03-18	1995-05-03	Merck Sharp & Dohme	Therapeutic agents
ES2153031T4 (es) *	1995-04-20	2001-05-16	Pfizer	Derivados del acido arilsulfonil hidroxamico como inhibidores de mmp y tnf.
GB9511031D0 (en) *	1995-06-01	1995-07-26	Merck Sharp & Dohme	Chemical process
GB9513118D0 (en) *	1995-06-28	1995-08-30	Merck Sharp & Dohme	Therapeutic agents
GB9513121D0 (en) *	1995-06-28	1995-08-30	Merck Sharp & Dohme	Therapeutic agents
GB9513117D0 (en) *	1995-06-28	1995-08-30	Merck Sharp & Dohme	Therapeutic agents
GB9523244D0 (en) *	1995-11-14	1996-01-17	Merck Sharp & Dohme	Therapeutic agents
DK0785198T3 (da) *	1996-01-19	2000-11-13	Lonza Ag	Fremgangsmåde til fremstilling af optisk aktiv 3-quinuclidinol
GB9603136D0 (en) *	1996-02-15	1996-04-17	Merck Sharp & Dohme	Therapeutic agents
GB9603137D0 (en) *	1996-02-15	1996-04-17	Merck Sharp & Dohme	Therapeutic agents
UA56185C2 (uk) *	1996-09-30	2003-05-15	Пфайзер Інк.	Аралкіл- та аралкіліденгетероциклічні лактами та іміди, фармацевтична композиція та спосіб лікування
US6423708B1 (en)	1996-09-30	2002-07-23	Pfizer Inc	Aralkyl and aralkylidene heterocyclic lactams and imides
US6117855A (en)	1996-10-07	2000-09-12	Merck Sharp & Dohme Ltd.	Use of a NK-1 receptor antagonist and an antidepressant and/or an anti-anxiety agent
DE69736390T2 (de) *	1996-10-07	2007-07-26	Merck Sharp & Dohme Ltd., Hoddesdon	Zns-penetrierende nk-1 rezeptorantagonisten als antidepressivum und / oder anxiolytikum
US5750549A (en) *	1996-10-15	1998-05-12	Merck & Co., Inc.	Cycloalkyl tachykinin receptor antagonists
JP2001504848A (ja) *	1996-12-02	2001-04-10	メルクシヤープエンドドームリミテツド	重症不安障害の治療のためのｎｋ−１受容体拮抗薬の使用
US5977104A (en) *	1996-12-02	1999-11-02	Merck Sharp & Dohme Ltd.	Use of NK-1 receptor antagonists for treating bipolar disorders
US6100256A (en) *	1996-12-02	2000-08-08	Merck Sharp & Dohme Ltd.	Use of NK-1 receptors antagonists for treating schizophrenic disorders
JP2001504851A (ja) *	1996-12-02	2001-04-10	メルクシヤープエンドドームリミテツド	性的機能不全の治療のためのｎｋ−１受容体拮抗薬の使用
EP0942730A1 (en) *	1996-12-02	1999-09-22	MERCK SHARP & DOHME LTD.	Use of nk-1 receptor antagonists for treating bipolar disorders
CA2273853A1 (en) *	1996-12-02	1998-06-11	Merck Sharp & Dohme Limited	Use of nk-1 receptor antagonists for treating cognitive disorders
DE69730515T2 (de) *	1996-12-02	2005-09-01	Merck Sharp & Dohme Ltd., Hoddesdon	Die verwendung von nk-1 rezeptor antagonisten für die behandlungen von stress störungen
US6613765B1 (en)	1996-12-02	2003-09-02	Merck Sharp & Dohme Limited	Use of NK-1 receptor antagonists for treating major depressive disorders
WO1998024444A1 (en) *	1996-12-02	1998-06-11	Merck Sharp & Dohme Limited	Use of nk-1 receptor antagonists for treating substance use disorders
AU734872B2 (en) *	1996-12-02	2001-06-21	Merck Sharp & Dohme Limited	Use of NK-1 receptor antagonists for treating movement disorders
US6114315A (en) *	1996-12-02	2000-09-05	Merck Sharp & Dohme Ltd.	Use of NK-1 receptor antagonists for treating major depressive disorders with anxiety
EP0942735A1 (en) *	1996-12-02	1999-09-22	MERCK SHARP & DOHME LTD.	Use of nk-1 receptor antagonists for treating schizophrenic disorders
DE69732492T2 (de) *	1996-12-02	2006-03-30	Merck Sharp & Dohme Ltd., Hoddesdon	Verwendung von nk-1 rezeptorantagonisten zur behandlung von schweren depressionen, die von angstzuständen begleitet werden
CA2273810A1 (en) *	1996-12-02	1998-06-11	Merck Sharp & Dohme Limited	Use of nk-1 receptor antagonists for treating major depressive disorders
ATE206047T1 (de) *	1997-01-09	2001-10-15	Bifodan As	Verwendung von dichlorobenzyl alkohol zur herstellung einer zusammenstellung zur topischen behandlung von entzündungen
JP2001524960A (ja) *	1997-04-24	2001-12-04	メルクシヤープエンドドームリミテツド	摂食障害を治療するためのｎｋ−１受容体拮抗薬の使用
ZA985765B (en)	1997-07-02	1999-08-04	Merck & Co Inc	Polymorphic form of a tachykinin receptor antagonist.
AU738047B2 (en) *	1997-08-04	2001-09-06	Merck Sharp & Dohme Limited	Use of NK-1 receptor antagonists for treating mania
CA2298779A1 (en) *	1997-08-04	1999-02-18	Merck Sharp & Dohme Limited	Use of nk-1 receptor antagonists for treating aggressive behaviour disorders
GB9716457D0 (en) *	1997-08-04	1997-10-08	Merck Sharp & Dohme	Therapeutic agents
GB9716463D0 (en) *	1997-08-04	1997-10-08	Merck Sharp & Dohme	Therapeutic agents
US6271230B1 (en)	1997-12-01	2001-08-07	Merck Sharp & Dohme Limited	Use of NK-1 receptor antagonists for treating cognitive disorders
US6087348A (en) *	1997-12-01	2000-07-11	Merck Sharp & Dohme Ltd.	Use of NK-1 receptor antagonists for treating stress disorders
US6156749A (en) *	1997-12-01	2000-12-05	Merck Sharp & Dohme Limited	Use of NK-1 receptor antagonists for treating movement disorders
GB9810920D0 (en) *	1998-05-21	1998-07-22	Merck Sharp & Dohme	Therapeutic use
GB9816897D0 (en) *	1998-08-04	1998-09-30	Merck Sharp & Dohme	Therapeutic use
GB9819888D0 (en) *	1998-09-11	1998-11-04	Merck Sharp & Dohme	Chemical synthesis
US6218390B1 (en) *	1998-12-17	2001-04-17	Synaptic Pharmaceutical Corporation	Morpholinone and morpholine derivatives and uses thereof
EP1041070B1 (en) *	1999-03-30	2004-09-22	Pfizer Products Inc.	Process for preparing cyclic thioamides
US7163949B1 (en)	1999-11-03	2007-01-16	Amr Technology, Inc.	4-phenyl substituted tetrahydroisoquinolines and use thereof
MXPA02004330A (es)	1999-11-03	2004-07-30	Albany Molecular Res Inc	Tetrahidroisoquinolinas aril-y heteroaril-sustituidas y uso de las mismas para bloquear la recaptacion de norepinefrina, dopamina y serotonina..
SI1103545T1 (en) *	1999-11-29	2004-02-29	F. Hoffmann-La Roche Ag	2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide
KR100821410B1 (ko)	2000-07-11	2008-04-10	에이엠알 테크놀로지, 인크.	4-페닐 치환된 테트라하이드로이소퀴놀린 및 이의치료학적 용도
GB0022988D0 (en) *	2000-09-19	2000-11-01	Merck Sharp & Dohme	Therapeutic agents
DE10116978A1 (de) *	2001-04-05	2002-10-10	Merck Patent Gmbh	Kappa-Opiatagonisten für die Behandlung von Erkrankungen der Blase
US20030083345A1 (en) *	2001-07-10	2003-05-01	Torsten Hoffmann	Method of treatment and/or prevention of brain, spinal or nerve injury
US6638981B2 (en)	2001-08-17	2003-10-28	Epicept Corporation	Topical compositions and methods for treating pain
BR0315247A (pt) *	2002-10-11	2005-08-30	Cytokinetics Inc	Composição, composição farmacêutica, método de tratamento para uma doença proliferativa celular, e, kit
KR20060124770A (ko)	2004-03-17	2006-12-05	화이자 프로덕츠 인코포레이티드	벤질(이덴)-락탐 유도체
NZ552397A (en)	2004-07-15	2011-04-29	Amr Technology Inc	Aryl-and heteroaryl-substituted tetrahydroisoquinolines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
ES2382814T3 (es)	2005-05-17	2012-06-13	Merck Sharp & Dohme Ltd.	Ácido cis-4-[(4-clorofenil)sulfonil]-4-(2,5-difluorofenil)ciclohexanopropanoico para el tratamiento del cáncer
KR101594898B1 (ko)	2005-07-15	2016-02-18	알바니 몰레큘라 리써치, 인크.	아릴- 및 헤테로아릴-치환된 테트라히드로벤자제핀, 및 노르에피네프린, 도파민 및 세로토닌의 재흡수를 차단하기 위한 용도
EP1940842B1 (en)	2005-09-29	2012-05-30	Merck Sharp & Dohme Corp.	Acylated spiropiperidine derivatives as melanocortin-4 receptor modulators
GB0603041D0 (en)	2006-02-15	2006-03-29	Angeletti P Ist Richerche Bio	Therapeutic compounds
US8173629B2 (en)	2006-09-22	2012-05-08	Merck Sharp & Dohme Corp.	Method of treatment using fatty acid synthesis inhibitors
US20110218176A1 (en)	2006-11-01	2011-09-08	Barbara Brooke Jennings-Spring	Compounds, methods, and treatments for abnormal signaling pathways for prenatal and postnatal development
JP4611444B2 (ja)	2007-01-10	2011-01-12	イステイチユート・デイ・リチエルケ・デイ・ビオロジア・モレコラーレ・ピ・アンジエレツテイ・エツセ・ピー・アー	ポリ（ａｄｐ−リボース）ポリメラーゼ（ｐａｒｐ）阻害剤としてのアミド置換インダゾール
EP2117538A1 (en)	2007-01-24	2009-11-18	Glaxo Group Limited	Pharmaceutical compositions comprising 2-methoxy-5- (5-trifluoromethyl-tetrazol-i-yl-benzyl) - (2s-phenyl-piperidin-3s-yl-)
JP5319518B2 (ja)	2007-04-02	2013-10-16	Ｍｓｄ株式会社	インドールジオン誘導体
WO2008130616A2 (en) *	2007-04-19	2008-10-30	Schering Corporation	Diaryl morpholines as cb1 modulators
AU2008269154B2 (en)	2007-06-27	2014-06-12	Merck Sharp & Dohme Llc	4-carboxybenzylamino derivatives as histone deacetylase inhibitors
CA2716080C (en)	2008-02-20	2016-12-13	Targia Pharmaceuticals	Cns pharmaceutical compositions and methods of use
AU2009222122A1 (en)	2008-03-03	2009-09-11	Tiger Pharmatech	Tyrosine kinase inhibitors
WO2009124756A1 (en) *	2008-04-08	2009-10-15	European Molecular Biology Laboratory (Embl)	Use of aprepitant and derivatives thereof for the treatment of cancer
AR071997A1 (es)	2008-06-04	2010-07-28	Bristol Myers Squibb Co	Forma cristalina de 6-((4s)-2-metil-4-(2-naftil)-1,2,3,4-tetrahidroisoquinolin-7-il)piridazin-3-amina
US9156812B2 (en)	2008-06-04	2015-10-13	Bristol-Myers Squibb Company	Crystalline form of 6-[(4S)-2-methyl-4-(2-naphthyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]pyridazin-3-amine
WO2010114780A1 (en)	2009-04-01	2010-10-07	Merck Sharp & Dohme Corp.	Inhibitors of akt activity
AU2010247735B2 (en)	2009-05-12	2015-07-16	Albany Molecular Research, Inc.	Crystalline forms of (S)-7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)- 1,2,3,4-tetrahydroisoquinoline and use thereof
AU2010247763B2 (en)	2009-05-12	2015-12-24	Albany Molecular Research, Inc.	7-([1,2,4,]triazolo[1,5,-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4- tetrahydroisoquinoline and use thereof
WO2010132437A1 (en)	2009-05-12	2010-11-18	Albany Molecular Research, Inc.	Aryl, heteroaryl, and heterocycle substituted tetrahydroisoquinolines and use thereof
PE20121172A1 (es)	2009-10-14	2012-09-05	Merck Sharp & Dohme	Piperidinas sustituidas con actividad en la hdm2
WO2011163330A1 (en)	2010-06-24	2011-12-29	Merck Sharp & Dohme Corp.	Novel heterocyclic compounds as erk inhibitors
EP3330377A1 (en)	2010-08-02	2018-06-06	Sirna Therapeutics, Inc.	Rna interference mediated inhibition of catenin (cadherin-associated protein), beta 1 (ctnnb1) gene expression using short interfering nucleic acid (sina)
US9029341B2 (en)	2010-08-17	2015-05-12	Sirna Therapeutics, Inc.	RNA interference mediated inhibition of hepatitis B virus (HBV) gene expression using short interfering nucleic acid (siNA)
US8883801B2 (en)	2010-08-23	2014-11-11	Merck Sharp & Dohme Corp.	Substituted pyrazolo[1,5-a]pyrimidines as mTOR inhibitors
EP2613782B1 (en)	2010-09-01	2016-11-02	Merck Sharp & Dohme Corp.	Indazole derivatives useful as erk inhibitors
US9242981B2 (en)	2010-09-16	2016-01-26	Merck Sharp & Dohme Corp.	Fused pyrazole derivatives as novel ERK inhibitors
WO2012058210A1 (en)	2010-10-29	2012-05-03	Merck Sharp & Dohme Corp.	RNA INTERFERENCE MEDIATED INHIBITION OF GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACIDS (siNA)
WO2012087772A1 (en)	2010-12-21	2012-06-28	Schering Corporation	Indazole derivatives useful as erk inhibitors
AU2012245971A1 (en)	2011-04-21	2013-10-17	Piramal Enterprises Limited	A crystalline form of a salt of a morpholino sulfonyl indole derivative and a process for its preparation
EP2770987B1 (en)	2011-10-27	2018-04-04	Merck Sharp & Dohme Corp.	Novel compounds that are erk inhibitors
US20150299696A1 (en)	2012-05-02	2015-10-22	Sirna Therapeutics, Inc.	SHORT INTERFERING NUCLEIC ACID (siNA) COMPOSITIONS
RU2660429C2 (ru)	2012-09-28	2018-07-06	Мерк Шарп И Доум Корп.	Новые соединения, которые являются ингибиторами erk
RS56680B1 (sr)	2012-11-28	2018-03-30	Merck Sharp & Dohme	Kompozicije i postupci za lečenje kancera
KR102196882B1 (ko)	2012-12-20	2020-12-30	머크 샤프 앤드 돔 코포레이션	Hdm2 억제제로서의 치환된 이미다조피리딘
WO2014120748A1 (en)	2013-01-30	2014-08-07	Merck Sharp & Dohme Corp.	2,6,7,8 substituted purines as hdm2 inhibitors
WO2015034925A1 (en)	2013-09-03	2015-03-12	Moderna Therapeutics, Inc.	Circular polynucleotides
EP3525785B1 (en)	2016-10-12	2025-08-27	Merck Sharp & Dohme LLC	Kdm5 inhibitors
US10947234B2 (en)	2017-11-08	2021-03-16	Merck Sharp & Dohme Corp.	PRMT5 inhibitors
EP3706747B1 (en)	2017-11-08	2025-09-03	Merck Sharp & Dohme LLC	Prmt5 inhibitors
US12173026B2 (en)	2018-08-07	2024-12-24	Merck Sharp & Dohme Llc	PRMT5 inhibitors
EP3833668B1 (en)	2018-08-07	2025-03-19	Merck Sharp & Dohme LLC	Prmt5 inhibitors
US11981701B2 (en)	2018-08-07	2024-05-14	Merck Sharp & Dohme Llc	PRMT5 inhibitors
CA3173697A1 (en)	2020-04-03	2021-10-07	Mike TROWER	An nk-1 receptor antagonist for treating a disease selecting from sepsis, septic shock, acute respiratory distress syndrome (ards) or multiple organ dysfunction syndrome (mods)
CA3177477A1 (en)	2020-06-02	2021-12-09	Nerre Therapeutics Limited	Neurokinin (nk)-1 receptor antagonists for use in the treatment of pulmonary fibrosis conditions promoted by mechanical injury to the lungs
CN115650969B (zh) *	2022-10-29	2024-10-01	河南师范大学	一种α-取代-β-胺氧基取代吗啉类化合物的合成方法

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
US4476311A (en) *	1980-03-12	1984-10-09	The Purdue Frederick Company	Analgesic 4-carboxy-pyrrolidin-2-one compound
JPS5739599A (en) *	1980-08-20	1982-03-04	Fuji Machine Mfg	Method and device for automatically mounting leadless electronic part on printed board or like
FR2534915B1 (fr) *	1982-10-26	1985-10-25	Lafon Labor	Nouveaux derives de 2-(phenoxymethyl)-morpholine, utilisation en therapeutique et procede de preparation
UA41251C2 (uk) *	1990-01-04	2001-09-17	Пфайзер, Інк.	Гідровані азотвмісні гетероциклічні сполуки, похідні піперидину, фармацевтична композиція та спосіб пригнічення активності речовини р в організмі
EP0600952B1 (en) *	1991-08-20	1996-04-17	MERCK SHARP & DOHME LTD.	Azacyclic compounds, processes for their preparation and pharmaceutical compositions containing them

1993
- 1993-06-25 IL IL106142A patent/IL106142A/xx not_active IP Right Cessation
- 1993-06-25 CA CA002099233A patent/CA2099233A1/en not_active Abandoned
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- 1993-06-29 CN CN93109517A patent/CN1049431C/zh not_active Expired - Lifetime
- 1993-06-29 KR KR1019940704776A patent/KR100301212B1/ko not_active Expired - Lifetime
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- 1993-06-29 DE DE69326977T patent/DE69326977T2/de not_active Expired - Lifetime
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- 1993-06-29 AU AU46561/93A patent/AU4656193A/en not_active Abandoned
- 1993-06-29 AT AT93305086T patent/ATE186532T1/de active
- 1993-06-29 RU RU94046364A patent/RU2140914C1/ru active
- 1993-06-29 DZ DZ930080A patent/DZ1700A1/fr active
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- 1993-06-29 WO PCT/US1993/006181 patent/WO1994000440A1/en not_active Ceased
- 1993-06-29 CZ CZ19943330A patent/CZ288530B6/cs not_active IP Right Cessation
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1994
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1997
- 1997-04-30 BR BR1100375-8A patent/BR1100375A/pt active IP Right Grant
1999
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2000
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Also Published As

Publication number	Publication date
JPH06172178A (ja)	1994-06-21
ZA934624B (en)	1994-06-20
CY2200B1 (en)	2002-11-08
SI9300346A (sl)	1993-12-31
RU94046364A (ru)	1996-10-10
HK1009268A1 (en)	1999-05-28
IL106142A (en)	1997-03-18
KR100301212B1 (ko)	2001-10-22
ATE186532T1 (de)	1999-11-15
TW358808B (en)	1999-05-21
DE69326977T2 (de)	2000-06-08
NO305698B1 (no)	1999-07-12
RO114448B1 (ro)	1999-04-30
DK0577394T3 (da)	2000-03-27
ES2141133T3 (es)	2000-03-16
HRP931003A2 (en)	1995-02-28
CA2099233A1 (en)	1993-12-30
NO945064D0 (no)	1994-12-28
SI9300346B (sl)	2003-10-31
GR3031824T3 (en)	2000-02-29
CN1049431C (zh)	2000-02-16
FI946133A0 (fi)	1994-12-28
CZ288530B6 (cs)	2001-07-11
BG99274A (bg)	1996-04-30
FI111363B (fi)	2003-07-15
MY108836A (en)	1996-11-30
BR1100375A (pt)	2000-03-14
LV12568A (en)	2000-11-20
LV12568B (lv)	2001-04-20
NZ254476A (en)	1996-09-25
HUT71809A (en)	1996-02-28
FI946133L (fi)	1994-12-28
RU2140914C1 (ru)	1999-11-10
DE69326977D1 (de)	1999-12-16
SK281093B6 (sk)	2000-11-07
YU49036B (sh)	2003-07-07
HU9403804D0 (en)	1995-02-28
HRP931003B1 (en)	2000-10-31
AU4656193A (en)	1994-01-24
IL106142A0 (en)	1993-10-20
SK160094A3 (en)	1995-07-11
CZ333094A3 (en)	1995-09-13
EP0577394B1 (en)	1999-11-10
NO945064L (no)	1995-02-28
YU45293A (sh)	1996-10-18
MX9303888A (es)	1994-03-31
AU663595B2 (en)	1995-10-12
EP0577394A1 (en)	1994-01-05
HU219713B (hu)	2001-06-28
AU4156893A (en)	1994-01-06
JP2634372B2 (ja)	1997-07-23
CN1087902A (zh)	1994-06-15
KR950702193A (ko)	1995-06-19
WO1994000440A1 (en)	1994-01-06
DZ1700A1 (fr)	2002-02-17

Publication	Publication Date	Title
EP0577394B1 (en)	1999-11-10	Morpholine and thiomorpholine tachykinin receptor antagonists
US5637699A (en)	1997-06-10	Process for preparing morpholine tachykinin receptor antagonists
EP0734381B1 (en)	2000-07-05	Morpholine tachykinin receptor antagonists
US5512570A (en)	1996-04-30	Treatment of emesis with morpholine tachykinin receptor antagonists
US5872116A (en)	1999-02-16	Morpholine and thiomorpholine tachykinin receptor antagonists
US6235735B1 (en)	2001-05-22	Morpholine and thiomorpholine tachykinin receptor antagonists
HK1009268B (en)	2001-01-12	Morpholine and thiomorpholine tachykinin receptor antagonists
HK1009046B (en)	2001-05-11	Morpholine tachykinin receptor antagonists