CA2287487A1 - Use of nk-1 receptor antagonists for treating eating disorders - Google Patents
Use of nk-1 receptor antagonists for treating eating disorders Download PDFInfo
- Publication number
- CA2287487A1 CA2287487A1 CA002287487A CA2287487A CA2287487A1 CA 2287487 A1 CA2287487 A1 CA 2287487A1 CA 002287487 A CA002287487 A CA 002287487A CA 2287487 A CA2287487 A CA 2287487A CA 2287487 A1 CA2287487 A1 CA 2287487A1
- Authority
- CA
- Canada
- Prior art keywords
- phenyl
- 4alkyl
- group
- 6alkyl
- hydrogen
- 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
Links
- 108010040718 Neurokinin-1 Receptors Proteins 0.000 title claims abstract description 115
- 102000002002 Neurokinin-1 Receptors Human genes 0.000 title claims abstract description 115
- 239000002464 receptor antagonist Substances 0.000 title claims abstract description 112
- 229940044551 receptor antagonist Drugs 0.000 title claims abstract description 112
- 235000014632 disordered eating Nutrition 0.000 title claims abstract description 51
- 208000030814 Eating disease Diseases 0.000 title claims abstract description 41
- 208000019454 Feeding and Eating disease Diseases 0.000 title claims abstract description 41
- 238000011282 treatment Methods 0.000 claims abstract description 74
- 238000000034 method Methods 0.000 claims abstract description 57
- 229940125709 anorectic agent Drugs 0.000 claims abstract description 51
- 239000002830 appetite depressant Substances 0.000 claims abstract description 51
- 230000002265 prevention Effects 0.000 claims abstract description 47
- 239000003814 drug Substances 0.000 claims abstract description 18
- 238000004519 manufacturing process Methods 0.000 claims abstract description 15
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 12
- 239000001257 hydrogen Substances 0.000 claims description 102
- 229910052739 hydrogen Inorganic materials 0.000 claims description 102
- 150000001875 compounds Chemical class 0.000 claims description 97
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 97
- 125000005843 halogen group Chemical group 0.000 claims description 68
- 125000001424 substituent group Chemical group 0.000 claims description 62
- -1 C-6alkoxy Chemical group 0.000 claims description 61
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 59
- 150000003839 salts Chemical class 0.000 claims description 54
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 50
- 239000000203 mixture Substances 0.000 claims description 50
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 40
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 40
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 39
- 150000002431 hydrogen Chemical group 0.000 claims description 38
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 38
- 125000000217 alkyl group Chemical group 0.000 claims description 37
- 239000000460 chlorine Substances 0.000 claims description 30
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 30
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 28
- 125000000623 heterocyclic group Chemical group 0.000 claims description 28
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 27
- 125000004432 carbon atom Chemical group C* 0.000 claims description 25
- 229960004597 dexfenfluramine Drugs 0.000 claims description 25
- 238000002360 preparation method Methods 0.000 claims description 25
- 125000003118 aryl group Chemical group 0.000 claims description 23
- DBGIVFWFUFKIQN-VIFPVBQESA-N (+)-Fenfluramine Chemical compound CCN[C@@H](C)CC1=CC=CC(C(F)(F)F)=C1 DBGIVFWFUFKIQN-VIFPVBQESA-N 0.000 claims description 22
- KWTSXDURSIMDCE-QMMMGPOBSA-N (S)-amphetamine Chemical compound C[C@H](N)CC1=CC=CC=C1 KWTSXDURSIMDCE-QMMMGPOBSA-N 0.000 claims description 21
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 21
- 125000004076 pyridyl group Chemical group 0.000 claims description 21
- 125000001624 naphthyl group Chemical group 0.000 claims description 20
- 208000008589 Obesity Diseases 0.000 claims description 19
- 125000001072 heteroaryl group Chemical group 0.000 claims description 19
- 235000020824 obesity Nutrition 0.000 claims description 19
- 229910052760 oxygen Inorganic materials 0.000 claims description 19
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 17
- 239000011737 fluorine Substances 0.000 claims description 17
- 229910052731 fluorine Inorganic materials 0.000 claims description 17
- 125000001153 fluoro group Chemical group F* 0.000 claims description 17
- 229910052736 halogen Inorganic materials 0.000 claims description 17
- 150000002367 halogens Chemical class 0.000 claims description 17
- 229910052757 nitrogen Inorganic materials 0.000 claims description 17
- DBGIVFWFUFKIQN-UHFFFAOYSA-N (+-)-Fenfluramine Chemical compound CCNC(C)CC1=CC=CC(C(F)(F)F)=C1 DBGIVFWFUFKIQN-UHFFFAOYSA-N 0.000 claims description 16
- 229960001582 fenfluramine Drugs 0.000 claims description 16
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 16
- 125000001544 thienyl group Chemical group 0.000 claims description 16
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 14
- 125000003386 piperidinyl group Chemical group 0.000 claims description 14
- 230000002829 reductive effect Effects 0.000 claims description 13
- 206010006550 Bulimia nervosa Diseases 0.000 claims description 12
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 12
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 12
- 125000002541 furyl group Chemical group 0.000 claims description 12
- 239000001301 oxygen Substances 0.000 claims description 12
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 12
- 150000003254 radicals Chemical group 0.000 claims description 12
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 11
- 239000003937 drug carrier Substances 0.000 claims description 11
- 208000010235 Food Addiction Diseases 0.000 claims description 10
- 125000002252 acyl group Chemical group 0.000 claims description 10
- 239000011203 carbon fibre reinforced carbon Substances 0.000 claims description 10
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 10
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 10
- 125000006413 ring segment Chemical group 0.000 claims description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 9
- 125000002883 imidazolyl group Chemical group 0.000 claims description 9
- 229910052717 sulfur Inorganic materials 0.000 claims description 9
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 8
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 8
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 claims description 8
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 8
- 125000002971 oxazolyl group Chemical group 0.000 claims description 8
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 8
- DHHVAGZRUROJKS-UHFFFAOYSA-N phentermine Chemical compound CC(C)(N)CC1=CC=CC=C1 DHHVAGZRUROJKS-UHFFFAOYSA-N 0.000 claims description 8
- 125000005493 quinolyl group Chemical group 0.000 claims description 8
- 125000000335 thiazolyl group Chemical group 0.000 claims description 8
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 7
- 125000001041 indolyl group Chemical group 0.000 claims description 7
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 7
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 7
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 7
- 125000001425 triazolyl group Chemical group 0.000 claims description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- 125000002837 carbocyclic group Chemical group 0.000 claims description 6
- 125000004122 cyclic group Chemical group 0.000 claims description 6
- DLNKOYKMWOXYQA-UHFFFAOYSA-N dl-pseudophenylpropanolamine Natural products CC(N)C(O)C1=CC=CC=C1 DLNKOYKMWOXYQA-UHFFFAOYSA-N 0.000 claims description 6
- DLNKOYKMWOXYQA-APPZFPTMSA-N phenylpropanolamine Chemical compound C[C@@H](N)[C@H](O)C1=CC=CC=C1 DLNKOYKMWOXYQA-APPZFPTMSA-N 0.000 claims description 6
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 6
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 6
- ZCKAMNXUHHNZLN-UHFFFAOYSA-N Chlorphentermine Chemical compound CC(C)(N)CC1=CC=C(Cl)C=C1 ZCKAMNXUHHNZLN-UHFFFAOYSA-N 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 125000001246 bromo group Chemical group Br* 0.000 claims description 5
- 229950007046 chlorphentermine Drugs 0.000 claims description 5
- TZWKUQDQKPYNLL-UHFFFAOYSA-N cloforex Chemical compound CCOC(=O)NC(C)(C)CC1=CC=C(Cl)C=C1 TZWKUQDQKPYNLL-UHFFFAOYSA-N 0.000 claims description 5
- 229950008294 cloforex Drugs 0.000 claims description 5
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims description 5
- 125000002346 iodo group Chemical group I* 0.000 claims description 5
- 125000004043 oxo group Chemical group O=* 0.000 claims description 5
- PZJBWSQQDMRZHY-UHFFFAOYSA-N picilorex Chemical compound CC1NC(C2CC2)CC1C1=CC=C(Cl)C=C1 PZJBWSQQDMRZHY-UHFFFAOYSA-N 0.000 claims description 5
- 229950003624 picilorex Drugs 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
- UNAANXDKBXWMLN-UHFFFAOYSA-N sibutramine Chemical compound C=1C=C(Cl)C=CC=1C1(C(N(C)C)CC(C)C)CCC1 UNAANXDKBXWMLN-UHFFFAOYSA-N 0.000 claims description 5
- 229960004425 sibutramine Drugs 0.000 claims description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- 239000005864 Sulphur Substances 0.000 claims description 4
- 229940025084 amphetamine Drugs 0.000 claims description 4
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical compound C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- HXCXASJHZQXCKK-UHFFFAOYSA-N clortermine Chemical compound CC(C)(N)CC1=CC=CC=C1Cl HXCXASJHZQXCKK-UHFFFAOYSA-N 0.000 claims description 4
- 229950000649 clortermine Drugs 0.000 claims description 4
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 4
- 125000005842 heteroatom Chemical group 0.000 claims description 4
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 claims description 4
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 4
- 125000001715 oxadiazolyl group Chemical group 0.000 claims description 4
- 229960003562 phentermine Drugs 0.000 claims description 4
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 4
- 229920006395 saturated elastomer Polymers 0.000 claims description 4
- 125000003107 substituted aryl group Chemical group 0.000 claims description 4
- 239000011593 sulfur Substances 0.000 claims description 4
- 125000001113 thiadiazolyl group Chemical group 0.000 claims description 4
- YAGBSNMZQKEFCO-SNVBAGLBSA-N (2r)-n-ethyl-1-phenylpropan-2-amine Chemical compound CCN[C@H](C)CC1=CC=CC=C1 YAGBSNMZQKEFCO-SNVBAGLBSA-N 0.000 claims description 3
- OOBHFESNSZDWIU-GXSJLCMTSA-N (2s,3s)-3-methyl-2-phenylmorpholine Chemical compound C[C@@H]1NCCO[C@H]1C1=CC=CC=C1 OOBHFESNSZDWIU-GXSJLCMTSA-N 0.000 claims description 3
- KWTSXDURSIMDCE-MRVPVSSYSA-N (R)-amphetamine Chemical compound C[C@@H](N)CC1=CC=CC=C1 KWTSXDURSIMDCE-MRVPVSSYSA-N 0.000 claims description 3
- MFKDAOCUEASALN-QQTNTEGQSA-N 1-[5-[[(2r,3s)-2-[(1r)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-phenylmorpholin-4-yl]methyl]-2h-triazol-4-yl]-n,n-dimethylmethanamine Chemical compound O([C@@H]([C@@H]1C=2C=CC=CC=2)O[C@H](C)C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)CCN1CC1=NNN=C1CN(C)C MFKDAOCUEASALN-QQTNTEGQSA-N 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- MFOCDFTXLCYLKU-CMPLNLGQSA-N Phendimetrazine Chemical compound O1CCN(C)[C@@H](C)[C@@H]1C1=CC=CC=C1 MFOCDFTXLCYLKU-CMPLNLGQSA-N 0.000 claims description 3
- 125000002947 alkylene group Chemical group 0.000 claims description 3
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 3
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 3
- YXKTVDFXDRQTKV-HNNXBMFYSA-N benzphetamine Chemical compound C([C@H](C)N(C)CC=1C=CC=CC=1)C1=CC=CC=C1 YXKTVDFXDRQTKV-HNNXBMFYSA-N 0.000 claims description 3
- 229960002837 benzphetamine Drugs 0.000 claims description 3
- 229960003609 cathine Drugs 0.000 claims description 3
- 229960002492 clobenzorex Drugs 0.000 claims description 3
- LRXXRIXDSAEIOR-ZDUSSCGKSA-N clobenzorex Chemical compound C([C@H](C)NCC=1C(=CC=CC=1)Cl)C1=CC=CC=C1 LRXXRIXDSAEIOR-ZDUSSCGKSA-N 0.000 claims description 3
- 229960000632 dexamfetamine Drugs 0.000 claims description 3
- XXEPPPIWZFICOJ-UHFFFAOYSA-N diethylpropion Chemical compound CCN(CC)C(C)C(=O)C1=CC=CC=C1 XXEPPPIWZFICOJ-UHFFFAOYSA-N 0.000 claims description 3
- 229960004890 diethylpropion Drugs 0.000 claims description 3
- 229960001003 etilamfetamine Drugs 0.000 claims description 3
- IQUFSXIQAFPIMR-UHFFFAOYSA-N fenproporex Chemical compound N#CCCNC(C)CC1=CC=CC=C1 IQUFSXIQAFPIMR-UHFFFAOYSA-N 0.000 claims description 3
- 229960005231 fenproporex Drugs 0.000 claims description 3
- DLGIIZAHQPTVCJ-UHFFFAOYSA-N furfenorex Chemical compound C=1C=COC=1CN(C)C(C)CC1=CC=CC=C1 DLGIIZAHQPTVCJ-UHFFFAOYSA-N 0.000 claims description 3
- 229950005457 furfenorex Drugs 0.000 claims description 3
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 3
- 229950005223 levamfetamine Drugs 0.000 claims description 3
- XXVROGAVTTXONC-UHFFFAOYSA-N mefenorex Chemical compound ClCCCNC(C)CC1=CC=CC=C1 XXVROGAVTTXONC-UHFFFAOYSA-N 0.000 claims description 3
- 229960001468 mefenorex Drugs 0.000 claims description 3
- KBHMHROOFHVLBA-UHFFFAOYSA-N metamfepramone Chemical compound CN(C)C(C)C(=O)C1=CC=CC=C1 KBHMHROOFHVLBA-UHFFFAOYSA-N 0.000 claims description 3
- 229950001413 metamfepramone Drugs 0.000 claims description 3
- 229960001252 methamphetamine Drugs 0.000 claims description 3
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 claims description 3
- 125000002757 morpholinyl group Chemical group 0.000 claims description 3
- UMWAUEZOGHNSCH-UHFFFAOYSA-N pentorex Chemical compound CC(N)(C)C(C)C1=CC=CC=C1 UMWAUEZOGHNSCH-UHFFFAOYSA-N 0.000 claims description 3
- 229950000821 pentorex Drugs 0.000 claims description 3
- 229960000436 phendimetrazine Drugs 0.000 claims description 3
- 229960003209 phenmetrazine Drugs 0.000 claims description 3
- 229960000395 phenylpropanolamine Drugs 0.000 claims description 3
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 3
- 125000000464 thioxo group Chemical group S=* 0.000 claims description 3
- 125000002861 (C1-C4) alkanoyl group Chemical group 0.000 claims description 2
- USRYEHHMJIRICK-ZNZBMKLDSA-N 1-[5-[[(2r,3s)-2-[(1r)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholin-4-yl]methyl]-2h-triazol-4-yl]-n,n-dimethylmethanamine Chemical compound O([C@@H]([C@@H]1C=2C=CC(F)=CC=2)O[C@H](C)C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)CCN1CC1=NNN=C1CN(C)C USRYEHHMJIRICK-ZNZBMKLDSA-N 0.000 claims description 2
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 claims description 2
- VBZDETYCYXPOAK-UHFFFAOYSA-N 2,2,2-trichloro-n-(1-phenylpropan-2-yl)ethanimine Chemical compound ClC(Cl)(Cl)C=NC(C)CC1=CC=CC=C1 VBZDETYCYXPOAK-UHFFFAOYSA-N 0.000 claims description 2
- AGJJTKRYTPXPGM-UHFFFAOYSA-N 2-cyclohexyl-n-methylpropan-1-amine Chemical compound CNCC(C)C1CCCCC1 AGJJTKRYTPXPGM-UHFFFAOYSA-N 0.000 claims description 2
- CXLOIJUDIPVKOU-UHFFFAOYSA-N Fludorex Chemical compound CNCC(OC)C1=CC=CC(C(F)(F)F)=C1 CXLOIJUDIPVKOU-UHFFFAOYSA-N 0.000 claims description 2
- ZPXSCAKFGYXMGA-UHFFFAOYSA-N Mazindol Chemical compound N12CCN=C2C2=CC=CC=C2C1(O)C1=CC=C(Cl)C=C1 ZPXSCAKFGYXMGA-UHFFFAOYSA-N 0.000 claims description 2
- 125000004442 acylamino group Chemical group 0.000 claims description 2
- 125000004423 acyloxy group Chemical group 0.000 claims description 2
- 125000004450 alkenylene group Chemical group 0.000 claims description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 2
- 125000000278 alkyl amino alkyl group Chemical group 0.000 claims description 2
- 125000004414 alkyl thio group Chemical group 0.000 claims description 2
- IYABWNGZIDDRAK-UHFFFAOYSA-N allene Chemical group C=C=C IYABWNGZIDDRAK-UHFFFAOYSA-N 0.000 claims description 2
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 2
- SYAKTDIEAPMBAL-UHFFFAOYSA-N aminorex Chemical group O1C(N)=NCC1C1=CC=CC=C1 SYAKTDIEAPMBAL-UHFFFAOYSA-N 0.000 claims description 2
- 229950002544 aminorex Drugs 0.000 claims description 2
- 125000003705 anilinocarbonyl group Chemical group O=C([*])N([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 150000001450 anions Chemical class 0.000 claims description 2
- 125000003435 aroyl group Chemical group 0.000 claims description 2
- 125000005116 aryl carbamoyl group Chemical group 0.000 claims description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
- 150000001721 carbon Chemical group 0.000 claims description 2
- HAHOPPGVHWVBRR-UHFFFAOYSA-N clominorex Chemical compound O1C(N)=NCC1C1=CC=C(Cl)C=C1 HAHOPPGVHWVBRR-UHFFFAOYSA-N 0.000 claims description 2
- 229950000352 clominorex Drugs 0.000 claims description 2
- 125000006254 cycloalkyl carbonyl group Chemical group 0.000 claims description 2
- 125000003678 cyclohexadienyl group Chemical group C1(=CC=CCC1)* 0.000 claims description 2
- 125000004985 dialkyl amino alkyl group Chemical group 0.000 claims description 2
- UHZJPVXMMCFPNR-UHFFFAOYSA-N difemetorex Chemical compound OCCN1CCCCC1C(C=1C=CC=CC=1)C1=CC=CC=C1 UHZJPVXMMCFPNR-UHFFFAOYSA-N 0.000 claims description 2
- 229950011229 difemetorex Drugs 0.000 claims description 2
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- BAQKJENAVQLANS-UHFFFAOYSA-N fenbutrazate Chemical compound C=1C=CC=CC=1C(CC)C(=O)OCCN(C1C)CCOC1C1=CC=CC=C1 BAQKJENAVQLANS-UHFFFAOYSA-N 0.000 claims description 2
- 229960002533 fenbutrazate Drugs 0.000 claims description 2
- 229950000734 fenisorex Drugs 0.000 claims description 2
- HEXAHJRXDZDVLR-HZPDHXFCSA-N fenisorex Chemical compound C1([C@@H]2C3=CC(F)=CC=C3C[C@@H](O2)NC)=CC=CC=C1 HEXAHJRXDZDVLR-HZPDHXFCSA-N 0.000 claims description 2
- 229950002723 fludorex Drugs 0.000 claims description 2
- NMGYDYBWRZHLHR-UHFFFAOYSA-N fluminorex Chemical compound O1C(N)=NCC1C1=CC=C(C(F)(F)F)C=C1 NMGYDYBWRZHLHR-UHFFFAOYSA-N 0.000 claims description 2
- 229950007852 fluminorex Drugs 0.000 claims description 2
- 125000004970 halomethyl group Chemical group 0.000 claims description 2
- 125000004475 heteroaralkyl group Chemical group 0.000 claims description 2
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 claims description 2
- 229950004771 levofacetoperane Drugs 0.000 claims description 2
- BKPLVPRTTWIDNL-ZIAGYGMSSA-N levofacetoperane Chemical compound C([C@@H]1[C@H](OC(=O)C)C=2C=CC=CC=2)CCCN1 BKPLVPRTTWIDNL-ZIAGYGMSSA-N 0.000 claims description 2
- 229960000299 mazindol Drugs 0.000 claims description 2
- WCYWZMWISLQXQU-UHFFFAOYSA-N methyl Chemical compound [CH3] WCYWZMWISLQXQU-UHFFFAOYSA-N 0.000 claims description 2
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 2
- 125000005646 oximino group Chemical group 0.000 claims description 2
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 2
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 2
- 150000003413 spiro compounds Chemical class 0.000 claims description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 2
- 125000004853 tetrahydropyridinyl group Chemical group N1(CCCC=C1)* 0.000 claims description 2
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 16
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims 6
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims 4
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims 4
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 3
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims 3
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 3
- 125000000027 (C1-C10) alkoxy group Chemical group 0.000 claims 2
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims 2
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims 2
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- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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Abstract
The present invention provides the use of an NK-1 receptor antagonist, optionally with an anorectic agent, for the manufacture of a medicament for the treatment or prevention of eating disorders, methods of treatment using the NK-1 receptor antagonist and pharmaceutical compositions and products containing it.
Description
TREATING EATING DISORDERS
This invention relates to the treatment or prevention of eating disorders by the administration of a N:K-1 receptor antagonist, optionally in combination with an anorectic agent.
Eating disorders commonly arise through an imbalance in a subject's appetite, or desire to eat. It is recognised that appetite is influenced by the interaction of central and peripheral systems, most likely acting through the effects of neuropeptides on the so-called feeding and safety centres in the hypothalamus region of the brain. For instance, neuropeptides released by the gut in rEaponse to a meal may serve to modulate the intake of further food.
Alterations of appetite may lead to eating disorders including obesity, bulimia nervosa, and compulsive eating disorders.
Obesity is a chronic disease that is highly prevalent in modern society and is associated not only with a social stigma, but also with decreased life span and numerous medical problems, including adverse psychological development, reproductive disorders such as polycystic ovarian disease, dermatological disorders such as infections, varicose veins, Acanthosis nigricans, and eczema, exercise intolerance, diabetes mellitus, insulin resistance, hypertension, hypercholesterolemia, cholelithiasis, osteoarthritis, orthopedic injury, thromboembolic disease, cancer, and coronary heart disease. Rissanen et al, British Medical Journal, 301:$35-837 (1990).
Bulimia nervosa is characterised by recurrent episodes of overeating, or binges, followed by severe dieting often associated with self induced vomiting, abuse of laxatives or diuretics, or excessive exercise to avoid weight gain. Frequent vomiting or purging may result in electrolyte disturbances and erosion of dental enamel.
This invention relates to the treatment or prevention of eating disorders by the administration of a N:K-1 receptor antagonist, optionally in combination with an anorectic agent.
Eating disorders commonly arise through an imbalance in a subject's appetite, or desire to eat. It is recognised that appetite is influenced by the interaction of central and peripheral systems, most likely acting through the effects of neuropeptides on the so-called feeding and safety centres in the hypothalamus region of the brain. For instance, neuropeptides released by the gut in rEaponse to a meal may serve to modulate the intake of further food.
Alterations of appetite may lead to eating disorders including obesity, bulimia nervosa, and compulsive eating disorders.
Obesity is a chronic disease that is highly prevalent in modern society and is associated not only with a social stigma, but also with decreased life span and numerous medical problems, including adverse psychological development, reproductive disorders such as polycystic ovarian disease, dermatological disorders such as infections, varicose veins, Acanthosis nigricans, and eczema, exercise intolerance, diabetes mellitus, insulin resistance, hypertension, hypercholesterolemia, cholelithiasis, osteoarthritis, orthopedic injury, thromboembolic disease, cancer, and coronary heart disease. Rissanen et al, British Medical Journal, 301:$35-837 (1990).
Bulimia nervosa is characterised by recurrent episodes of overeating, or binges, followed by severe dieting often associated with self induced vomiting, abuse of laxatives or diuretics, or excessive exercise to avoid weight gain. Frequent vomiting or purging may result in electrolyte disturbances and erosion of dental enamel.
Complusive eating disorders may or may not be associated with other neurological disorders. One well characterised compulsive eating disorder is Prader-Willi syndrome, a congential disorder characterised by infantile hypotonia, hypogonadism and facial dysmorphism, with subsequent development of hyperplagia and abnormalities of behaviour and intellect.
Treatment regimens for eating disorders typically include the use of anorectic agents, such as amphetamine derivatives.
p-Chloroamphetamine and other halogenated amphetamines promote serotonin (5-hydroxytryptamine; 5-HT) release from platelets and neurons.
A rapid release of serotonin is followed by a prolonged and selective depletion of serotonin in the brain. The most widely used example of this class of compound is fenfluramine and its (S'~-isomer, dexfenfluramine.
The precise mechanism of action of these compounds is uncertain, however, fenfluramine and dexfenfluramine are both useful in the treatment of bulimia nervosa and obesity, and fenfluramine has also produced promising results in the management of Prader-Willi syndrome.
Neurokinin 1 (NK-l; substance P) receptor antagonists are being developed for the treatment of a number of physiological disorders associated with an excess or imbalance of tachykinins, and in particular substance P. Examples of such conditions include disorders of the central nervous system such as anxiety, depression and psychosis (see, for instance, International (PCT) patent specification Nos. WO 95/16679, WO
95/18124 and WO 95/23798).
We have now found that NK-1 receptor antagonists are effective in the treatment of eating disorders, as evidenced by their activity in vivo in a model of diet-induced obesity.
Furthermore, a combination of an anorectic agent with a NK-1 receptor antagonist may provide an enhanced anorectic effect. They may also provide for a rapid onset of action to combat eating disorders thereby enabling prescription on an "as-needed" basis.
WO 98!47513 PCTlGB98/01161 A particularly preferred class of NK-1 receptor antagonists of use in the present invention are those which a.re able to cross the blood-brain barrier, otherwise known as CNS- or br ain-penetrant compounds.
The present invention accordingly provides the use of a NK-1 receptor antagonist for the manufacturE: of a medicament for the treatment or prevention of eating disorders.
The present invention also provides a method for the treatment or prevention of eating disorders, which method comprises administration to a patient in need of such treatment an Effective amount of a NK-1 receptor antagonist.
In a further aspect of the present invention, there is provided a pharmaceutical composition for the treatment or prevention of eating disorders comprising a NK-1 receptor antagonist, together with at least one pharmaceutically acceptable carrier or excipient.
In a further embodiment of the present invention there is provided the use of a NK-1 receptor antagonist fcrr the manufacture of a medicament for the treatment or prevention of obesity.
The present invention also provides a method for the treatment or prevention of obesity, which method comprises administration to a patient in need of such treatment an effective amount of a NK-1 receptor antagonist.
In an alternative embodiment of the present invention there is provided the use of a NK-1 receptor antagonist for the manufacture of a medicament for the treatment or prevention of bulimia nervosa.
The present invention also provides a method for the treatment or prevention of bulimia nervosa, which method comprises administration to a patient in need of such treatment an Effective amount of a NK-1 receptor antagonist.
In a further embodiment of the present invention there is provided the use of a NK-1 receptor antagonist for the manufacture of a medicament for the treatment or prevention of compulsive eating disorders.
The present invention also provides a method for the treatment or prevention of compulsive eating disorders, which method comprises administration to a patient in need of such treatment an effective amount of a NK-1 receptor antagonist.
In an alternative embodiment of the present invention there is provided the use of a NK-1 receptor antagonist for the manufacture of a medicament for reducing the total body fat mass in an obese mammal, especially a human.
The present invention also provides a method for reducing the total body fat mass in an obese mammal, especially a human, which method comprises administration to a patient in need of such treatment an effective amount of a NK-1 receptor antagonist.
The present invention further provides the use of a NK-1 receptor antagonist and an anorectic agent for the manufacture of a medicament for the treatment or prevention of eating disorders.
The present invention also provides a method for the treatment or prevention of eating disorders, which method comprises administration to a patient in need of such treatment an amount of a NK-1 receptor antagonist and an amount of an anorectic agent, such that together they give effective relief.
In a further aspect of the present invention, there is provided a pharmaceutical composition comprising a NK-1 receptor antagonist and an anorectic agent, together with at least one pharmaceutically acceptable carrier or excipient.
It will be appreciated that the NK-1 receptor antagonist and anorectic agent may be present as a combined preparation for simultaneous, separate or sequential use for the treatment or prevention of eating disorders. Such combined preparations may be, for example, in the form of a twin pack.
Treatment regimens for eating disorders typically include the use of anorectic agents, such as amphetamine derivatives.
p-Chloroamphetamine and other halogenated amphetamines promote serotonin (5-hydroxytryptamine; 5-HT) release from platelets and neurons.
A rapid release of serotonin is followed by a prolonged and selective depletion of serotonin in the brain. The most widely used example of this class of compound is fenfluramine and its (S'~-isomer, dexfenfluramine.
The precise mechanism of action of these compounds is uncertain, however, fenfluramine and dexfenfluramine are both useful in the treatment of bulimia nervosa and obesity, and fenfluramine has also produced promising results in the management of Prader-Willi syndrome.
Neurokinin 1 (NK-l; substance P) receptor antagonists are being developed for the treatment of a number of physiological disorders associated with an excess or imbalance of tachykinins, and in particular substance P. Examples of such conditions include disorders of the central nervous system such as anxiety, depression and psychosis (see, for instance, International (PCT) patent specification Nos. WO 95/16679, WO
95/18124 and WO 95/23798).
We have now found that NK-1 receptor antagonists are effective in the treatment of eating disorders, as evidenced by their activity in vivo in a model of diet-induced obesity.
Furthermore, a combination of an anorectic agent with a NK-1 receptor antagonist may provide an enhanced anorectic effect. They may also provide for a rapid onset of action to combat eating disorders thereby enabling prescription on an "as-needed" basis.
WO 98!47513 PCTlGB98/01161 A particularly preferred class of NK-1 receptor antagonists of use in the present invention are those which a.re able to cross the blood-brain barrier, otherwise known as CNS- or br ain-penetrant compounds.
The present invention accordingly provides the use of a NK-1 receptor antagonist for the manufacturE: of a medicament for the treatment or prevention of eating disorders.
The present invention also provides a method for the treatment or prevention of eating disorders, which method comprises administration to a patient in need of such treatment an Effective amount of a NK-1 receptor antagonist.
In a further aspect of the present invention, there is provided a pharmaceutical composition for the treatment or prevention of eating disorders comprising a NK-1 receptor antagonist, together with at least one pharmaceutically acceptable carrier or excipient.
In a further embodiment of the present invention there is provided the use of a NK-1 receptor antagonist fcrr the manufacture of a medicament for the treatment or prevention of obesity.
The present invention also provides a method for the treatment or prevention of obesity, which method comprises administration to a patient in need of such treatment an effective amount of a NK-1 receptor antagonist.
In an alternative embodiment of the present invention there is provided the use of a NK-1 receptor antagonist for the manufacture of a medicament for the treatment or prevention of bulimia nervosa.
The present invention also provides a method for the treatment or prevention of bulimia nervosa, which method comprises administration to a patient in need of such treatment an Effective amount of a NK-1 receptor antagonist.
In a further embodiment of the present invention there is provided the use of a NK-1 receptor antagonist for the manufacture of a medicament for the treatment or prevention of compulsive eating disorders.
The present invention also provides a method for the treatment or prevention of compulsive eating disorders, which method comprises administration to a patient in need of such treatment an effective amount of a NK-1 receptor antagonist.
In an alternative embodiment of the present invention there is provided the use of a NK-1 receptor antagonist for the manufacture of a medicament for reducing the total body fat mass in an obese mammal, especially a human.
The present invention also provides a method for reducing the total body fat mass in an obese mammal, especially a human, which method comprises administration to a patient in need of such treatment an effective amount of a NK-1 receptor antagonist.
The present invention further provides the use of a NK-1 receptor antagonist and an anorectic agent for the manufacture of a medicament for the treatment or prevention of eating disorders.
The present invention also provides a method for the treatment or prevention of eating disorders, which method comprises administration to a patient in need of such treatment an amount of a NK-1 receptor antagonist and an amount of an anorectic agent, such that together they give effective relief.
In a further aspect of the present invention, there is provided a pharmaceutical composition comprising a NK-1 receptor antagonist and an anorectic agent, together with at least one pharmaceutically acceptable carrier or excipient.
It will be appreciated that the NK-1 receptor antagonist and anorectic agent may be present as a combined preparation for simultaneous, separate or sequential use for the treatment or prevention of eating disorders. Such combined preparations may be, for example, in the form of a twin pack.
In a further or alternative aspect of the present invention, there is therefore provided a product comprising a NK-1 receptor antagonist and an anorectic agent as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of eating disorders.
In a further embodiment of the present invention there is provided the use of a NK-1 receptor antagonist and an anorectic agent for the manufacture of a medicament for the treatment or prevention of obesity.
The present invention also provides a method for the treatment or prevention of obesity, which method comprises administration to a patient in need of such treatment an amount o:f a NK-1 receptor antagonist and an amount of an anorectic agent, such that together they give effective relief.
It will be appreciated that the NK-1 receptor antagonist and anorectic agent may be present as a combined preparation for simultaneous, separate or sequential use for the treatment or prevention of obesity. Such combined preparations may be, for example, in the form of a twin pack.
In a further or alternative aspect of the present invention, there is therefore provided a product comprising a NK-1 receptor antagonist and an anorectic agent as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of obesity.
In an alternative embodiment of the present invention there is provided the use of a NK-1 receptor antagonist and an anorectic agent for the manufacture of a medicament for the treatment or prevention of bulimia nervosa.
The present invention also provides a method for the treatment or prevention of bulimia nervosa, which method comprises administration to a patient in need of such treatment an amount of a NK-1 receptor antagonist and an amount of an anorecaic agent, such that together they give effective relief.
It will be appreciated that the NK-1 receptor antagonist and anorectic agent may be present as a combined preparation for simultaneous, separate or sequential use for the treatment or prevention of bulimia nervosa. Such combined preparations may be, for example, in the form of a twin pack.
In a further or alternative aspect of the present invention, there is therefore provided a product comprising a NK-1 receptor antagonist and an anorectic agent as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of bulimia nervosa.
In a further embodiment of the present invention there is provided the use of a NK-1 receptor antagonist and an anorectic agent for the manufacture of a medicament for the treatment or prevention of compulsive eating disorders.
The present invention also provides a method for the treatment or prevention of compulsive eating disorders, which method comprises administration to a patient in need of such treatment an amount of a NK-1 receptor antagonist and an amount of an anorectic agent, such that together they give effective relief.
It will be appreciated that the NK-1 receptor antagonist and anorectic agent may be present as a combined preparation for simultaneous, separate or sequential use for the treatment or prevention of compulsive eating disorders. Such combined preparations may be, for example, in the form of a twin pack.
In a further or alternative aspect of the present invention, there is therefore provided a product comprising a NK-1 receptor antagonist and an anorectic agent as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of compulsive eating disorders.
In an alternative embodiment of the present invention there is provided the use of a NK-1 receptor antagonist and an anorectic agent for the manufacture of a medicament for reducing the total body fat mass in an obese mammal, especially a human.
_ 7 .
The present invention also provides a method for reducing the total body fat mass in an obese mammal, especially a human, which method comprises administration to a patient in need of such treatment an amount of a NK-1 receptor antagonist and an amount of an anorectic agent, such that together they give effective relief. _ It will be appreciated that the NK-1 receptor antagonist and anorectic agent may be present as a combined preparation for simultaneous, separate or sequential use for reducing the total body fat mass in an obese mammal, especially a human. Such combined preparations may be, for example, in the form of a twin pack.
In a further or alternative aspect; of the present invention, there is therefore provided a product comprising a NK-1 receptor antagonist and an anorectic agent as a combined preparation for simultaneous, separate or sequential use in reducing the total body fat mass in an obese mammal, especially a human.
It will be appreciated that when using a combination of the present invention, both the NK-1 receptor antagonist and the anorectic agent will be administered to a patient, within a reasonable period of time. The compounds may be in the same pharmaceutically acceptable carrier and therefore administered simultaneously. They may be in separate pharmaceutical carriers such as conventional oral dosage forms which are taken simultaneously. The term "combination" also refers to the case where the compounds are provided in separate dosage forms and are administered sequentially. Therefore, by way of example, the anorectic agent may be administered as a tablet and then, within a reasonable period of time, the NK-1 receptor antagonist may be administered either as an oral dosage form such as a tablet or a fast-dissolving oral dosage form. By a "fast dissolving oral formulation" is meant, an oral delivery form which when placed on the tongue of a patient, dissolves within about 10 seconds.
_g-By "reasonable period of time" is meant a time period that is not in excess of about 1 hour. That is, for example, if the anorectic agent is provided as a tablet, then within one hour, the NK-1 receptor antagonist should be administered, either in the same type of dosage form, or another dosage form which provides effective delivery of the medicament.
The compositions of the present invention are useful for the prevention or treatment of eating disorders. As used herein, the term "eating disorders" includes obesity, bulimia nervosa and compulsive eating disorders.
As used herein "obesity" refers to a condition whereby a mammal has a Body Mass Index (BMI), which is calculated as weight per height squared (kg/m2), of at least 25.9. Conventionally, those persons with normal weight, have a BMI of 19.9 to less than 25.9.
The obesity herein may be due to any cause, whether genetic or environmental. Examples of disorders that may result in obesity or be the cause of obesity include overeating and bulimia, polycystic ovarian disease, craniopharyngioma, the Prader-Willi Syndrome, Frohlich's syndrome, Type II diabetes, GH-deficient subjects, normal variant short stature, Turner's syndrome, and other pathological conditions showing reduced metabolic activity or a decrease in resting energy expenditure as a percentage of total fat-free mass, e.g, children with acute lymphoblastic leukemia.
"Treatment" refers to reducing the BMI of the mammal to less than about 25.9, and maintaining that weight for at least 6 months. The treatment suitably results in a reduction in food or calorie intake by the mammal.
"Prevention" refers to preventing obesity from occurring if the treatment is administered prior to the onset of the obese condition.
Moreover, if treatment is commenced in already obese subjects, such treatment is expected to prevent, or to prevent the progression of, the medical sequelae of obesity, such as, e.g., arteriosclerosis, Type II
diabetes, WO 98/4'I513 PCT/GB98/01161 _g_ polycycstic ovarian disease, cardiovascular diseases, osteoarthritis, dermatological disorders, hypertension, insulin resistance, hypercholesterolezriia, hypertriglyceridemia, and cholelithiasis.
Thus, in one aspect, this invention relates to the inhibition and/or complete suppression of lipogenesis in obese mammals, i.e., the excessive accumulation of lipids in fat cells, which is one of the major features of human and animal obesity, as well as loss of total body weight. In another aspect, the invention ameliorates the conditions that are a consequence of the disease, such as preventing or arresting the progression of polycystic ovarian disease so that the patient is no longer infertile, and increasing the insulin sensitivity andlor decreasing or eliminating the need or usage of insulin in a diabetic patient, e.g., one with adult-onset diabetes or Type II diabetes.
"Mammals" include animals of economic importance such as bovine, ovine, and porcine animals, especially those that produce meat, as well as domestic animals, sports animals, zoo animals, and humans, the latter being preferred.
The compositions of the present invention are especially useful for the treatment of or prevention of eating disorders where the use of an anorectic agent is generally prescribed. By the use of a combination of a NK-1 receptor antagonist and an anorectic agent in accordance with the present invention, it is now also possible to treat or prevent eating disorders in patients for whom conventional anorectic therapy might not be wholly successful or where dependance upon the anorectic therapy is prevalent.
Suitable anoretic agents of use in the combinations of the present invention include, but are not limited t;o, aminorex, amphechloral, amphetamine, benzphetamine, chlorphentermine, clobenzorex, cloforex, clominorex, clortermine, cyclexedrine, dexfenfluramine, dextroamphetamine, diethylpropion, diphemethoxidine, N-ethylamphetamine, fenbutrazate, fenfluramine, fenisorex, fenproporex, fludorex, fluminorex, furfurylmethylamphetamine, levamfetamine, levophacetoperane, mazindol, mefenorex, metamfepramone, methamphetamine, norpseudoephedrine, pentorex, phendimetrazine, phenmetrazine, phentermine, phenylpropanolamine, picilorex and sibutramine; and pharmaceutically acceptable salts thereof.
Particularly preferred anorectic agents include amphetamine and derivatives thereof such as amphetamine, benzphetamine, chlorphentermine, clobenzorex, cloforex, clotermine, dexfenfluramine, dextroamphetamine, diethylpropion, N ethylamphetamine, fenfluramine, fenproporex, furfurylmethylamphetamine, levamfetamine, mefenorex, metamfepramone, methamphetamine, norpseudoephedrine, pentorex, phendimetrazine, phenmetrazine, phentermine, phenylpropanolamine, picilorex and sibutramine; and pharmaceutically acceptable salts thereof.
A particularly suitable class of anorectic agent are the halogenated amphetamine derivatives, including chlorphentermine, cloforex, clortermine, dexfenfluramine, fenfluramine, picilorex and sibutramine;
and pharmaceutically acceptble salts thereof;
Particularly preferred halogenated amphetamine derivatives of use in the present invention include: fenfluramine and dexfenfluramine, and pharmaceutically acceptable salts thereof.
Another particularly preferred anorectic agent is phentermine.
NK-1 receptor antagonists of use in the present invention are described in published European Patent Specification Nos. 0 360 390, 0 394 989, 0 429 366, 0 443 132, 0 482 539, 0 512 901, 0 512 902, 0 514 273, 0 514 275, 0 517 589, 0 520 555, 0 522 808, 0 528 495, 0 532 456, 0 533 280, 0 536 817, 0 545 478, 0 577 394, 0 590 152, 0 599 538, 0 610 793, 0 634 402, 0 686 629, 0 693 489, 0 694 535, 0 699 655, 0 699 674, 0 707 006, 0 708 101, 0 714 891, 0 723 959, 0 733 632 and 0 776 893; and in International Patent Specification Nos. 90/05525, 90/05729, 91/09844, 91/18899, 92/01688, 92/06079, 92/12151, 92/15585, 92/17449, 92/20661, 92/20676, 92/21677, 93/00330, 93/00331, 93/01159, -lL-93/01165, 93/01169, 93/01170, 93/06099, 93/09116, 93/10073, 93/14113, 93/18023, 93/19064, 93/21155, 9321181, 93/23380, 93/24465, 94/01402, 94/02461, 94/03429, 94/03445, 94/04494, 94/04496, 94/05625, 94/07843, 94/10165, 94/10167, 94/10168, 94/101'd0, 94/11368, 94/13639, 94/13663, 94/14767, 94/15903, 94/19320, 94/19323, 94/20500, 94/26735, 94/26740, 94/29309, 95/02595, 95/04040, 95/04042, 95/06645, 95/07886, 95/07908, 95/08549, 95/11880, 95/14017, 95/1537_1, 95/16679, 95/17382, 95/18124, 95/18129, 95/19344, 95/20575, 95/21819, 96/22525, 95/23798, 95/26338, 95/28418, 95/30674, 95/30687, 96/05193, 96/05203, 96/06094, 96/07649, 96//0562, 96/16939, 96/18643, 96/20197, 96/21661, 96/29304, 96/29317, 96/29326, 96/29328, 96/31214, 96/32385, 96/37489, 97/01553, 97/01554, 97/03066, 97/08144, 97/14671, 97//7362, 97/18206, 97/19084, 97/19942 and 97/21702; and in British Patent Specification Nos. 2 266 529, 2 268 931, 2 269 170, 2 269 590, 2 271 774, 2 292 144, 2 293 168, 2 293 169, and 2 302 689.
Particularly preferred NK-1 receptor antagonists are those described in European Patent Specific<~tion No. 0 577 394, i.e. compounds of formula (I):
(I) y R
or a pharmaceutically acceptable salt thereof, wherein:
Rl is selected from the group consisting of:
(1) hydrogen;
(2) C1-salkyl, unsubstituted or substituted with one or more of the substituents selected from:
(a) hydroxy, (b) oxo, (c) C1-ealkoxy, (d) phenyl-Ci.salkoxy, (e) phenyl, (f) -CN, (g) halo, (h) -NR~RI~, wherein R9 and Rl~ are independently __ selected from:
(i) hydrogen, (ii) C1-calkyl, (iii) hydroxy-Ci_calkyl, and (iv) phenyl, (i) -NR~COR1~, wherein R~ and R1~ are as defined above, (j) -NR9COzRl~, wherein R9 and Rl~ are as defined above, (k) -CONR9R1~, wherein R9 and Rl~ are as defined above, (1) -COR9, wherein R9 is as defined above, (m) -COzR9, wherein R~ is as defined above, (n) heterocycle, wherein the heterocycle is selected from the group consisting of:
(A) benzimidazolyl, (B) benzofuranyl, (C) benzthiophenyl, (D) benzoxazolyl, (E) furanyl, (F) imidazolyl, (G) indolyl, (H) isoxazolyl, (I) isothiazolyl, (J) oxadiazolyl, (K) oxazolyl, (L) pyrazinyl, (M) pyrazolyl, (N) pyridyl, WO 98/47513 PCT/GB98l01161 -13- _ (O} pyrimidyl, (P) pyrrolyl, (fa) quinolyl, (R) tetrazolyl, (S) thiadiazolyl, (T) thiazolyl, (U) thienyl, triazolyl, (V~ azetidinyl, (X) 1,4-dioxanyl, hexahydroazepinyl, (Z) oxanyl, (AA) piperazinyl, (AB) piperidinyl, (AC) pyrrolidinyl, (AD) tetrahydrofuranyl, and (AE) tetrahydrothienyl, and wherein the heterocylcle is unsubstituted or substituted with one or more substituent(s) selected from:
(i) Ci.salkyl, unsubstituted or substituted with halo, -CFs, -OCHs, or phenyl, (ii) C1-salkoxy, (iii) oxo, (iv) hydroxy, (v) thioxo, (vi) -SRS, wherein R'' is as defined above, (vii) halo, (viii) cyano, (ix) phenyl, {x) trifluoromethyl, (xi) -(CHz)m-NR9Rlo, wherein m is 0, 1 or 2, and Ro and Rlo are as defined above, (xii) -NRgCORlo, wherein R~ and Rlo are as defined above, (xiii) -CONR9Rlo, wherein R9 and Rlo are as defined above, (xiv) -COzR~, wherein R9 is as defined above, and (xv) -(CH2)m-OR9, wherein m and R9 are as defined above;
(3) Cz-salkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:
(a) hydroxy, (b) oxo, (c) Ci-salkoxy, (d) phenyl-C1-salkoxy, (e) phenyl, {f) -CN, (g) halo, (h) -CONR9Rls, wherein Ro and Rlo are as defined above, (i) -COR9, wherein Ro is as defined above, (j) -COzR~, wherein R9 is as defined above, (k) heterocycle, wherein the heterocycle is as defined above;
(4) CZ-salkynyl;
(5) phenyl, unsubstitued or substituted with one or more of the substituent(s) selected from:
(a) hydroxy, (b) Ci-salkoxy, (c) C i-salkyl, (d) C2-salkenyl, (e) halo, -CN, (g) -NOa, (h) -CFs, (i) -(CH2)m-NR9R1~, wherein m, Rs and Rls are as defined above, (j) -NR~CORI~, wherein R~ and Rl~ are as defined above, (k) -NR9COZRls, wherein R~ and Rz~ are as defined above, (1) -CONRsRIa, wherein R9 and Rls are as defined above, (m) -COzNR~RIS, wherein R~ and Rls are as defined above, (n) -COR9, wherein R~ is as defined above, (o) -COzR9, wherein R9 is as defined above;
R2 and R3 are independently selected from the group consisting of:
(1} hydrogen;
(2) Ci-salkyl, unsubstituted or substituted with one or more of the substituents selected from:
(a) hydroxy, (b) oxo, (c) C1-salkoxy, (d) phenyl-C1-salkoxy, (e) phenyl, (fj -CN, (g} halo, (h) -NR9Rls, wherein R"~ and Rls are independentlv selected from:
(i) -NR~CORIS, wherein R9 and Rls are as defined above, (j) -NR~COzRIS, wherein R9 and R1~ are as defined above, (k) -CONR~Rls, wherein R~ and Rls are as defined above, (1) -COR9, wherein R~ i.s as defined above, and (m) -COzR9, wherein R~ is as defined above;
(3) Cz.salkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:
(a) hydroxy, (b) oxo, (c) Ci-salkoxy, (d) phenyl-C1-salkoxy, (e) phenyl, (f) -CN, (g) halo, .
(h) -CONR9R1~ wherein R9 and Rl~ are as defined above, (i) -COR9, wherein R~ is as defined above, (j) -COzR9, wherein R9 is as defined above;
(4) C2-salkynyl;
(5) phenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:
(a) hydroxy, (b) C i-salkoxy, (c) Ci-salkyl, (d) Cz-salkenyl, (e) halo, (f) -CN, (g) -NOz (h) -CFs, (i) -(CHZ)m-NR9Rls, wherein m, Rs and Rls are as defined above, (j) -NR9COR1~, wherein R9 and Rl~ are as defined above, (k) -NR9C02R1~, wherein R9 and Rl~ are as defined above, (1) -CONR~Rls, wherein Rs and Rls are as defined above, (m) -COaNR9Rl~, wherein R9 and Rl~ are as defined above, (n) -CORs, wherein R9 is as defined above, (o) -COzR~, wherein Rs is as defined above;
and the groups R1 and RZ may be joined together to form a heterocyclic ring selected from the group consisting of:
(a) pyrrolidinyl, (b) piperidinyl, (c) pyrrolyl, (d) pyridinyl, (e) imidazolyl, (f) oxazolyl, and (g) thiazolyl, and wherein the heterocyclic ring is unsubstituted or substituted with one or more substituent(s) selected from:
(i) C l.salkyl, (ii) oxo, (iii) Ci-salkoxy, (iv) -NR~RIS, wherein 1~,~ and Rl~ are as defined above, (v) halo, and (vi) trifluoromethyl;
and the groups RZ and R3 may be joined together to form a carbocyclic ring selected from the group consisting of:
(a) cyclopentyl, (b) cyclohexyl, (c) phenyl, and wherein the carbocyclic ring is unsubstituted or substituted with one or more substituents selected from:
(i) C1-salkyl, (ii) C1-salkoxy, (iii) -NRsRl~, wherein Fps and Rls are as defined above, (iv) halo, and (v) trifluoromethyl;
and the groups R2 and R3 may be joined together to form a heterocyclic ring selected from the group consisting of:
(a) pyrrolidinyl, (b) piperidinyl, (c) pyrrolyl, (d) pyridinyl, (e) imidazolyl, (f) furanyl, (g) oxazolyl, (h) thienyl, and (i) thiazolyl, and wherein the heterocyclic ring is unsubstituted or substituted with one or more substituent(s) selected from:
(i) C1_~alkyl, (11) OXO, (iii) Ci.~alkoxy, (iv) -NR~RI~, wherein R~ and Rl~ are as defined above, (v) halo, and (vi) trifluoromethyl;
X is selected from the group consisting of:
(1) -O-, (2) -S-, (3) -SO-, and (4) -SOZ-;
R4 is selected from the group consisting o~
(1) R~
i R' ,Y w Ra (2) -Y-C1-salkyl, wherein alkyl is unsubstituted or substituted with one or more of the substituents selected from:
- 1~ _ _ (a) hydroxy, (b) oxo, (c) C1-salkoxy, (d) phenyl-Ci.3alkoxy, (e) phenyl, (fj -CN, (g) halo, (h) -NR9R10, wherein 1~,9 and R10 are as defined above, (i) -NRsCORIS, wherein R~ and Rls are as defined above, (j) -NR9COzRls, wherein R~ and Ri~ are as defined above, (k) -CONRsRIS, wherein R9 and R1~ are as defined above, (1) -COR9, wherein R~ is as defined above, (m) -COzR9, wherein R9 is as defined above;
(3) -Y-CZ.salkenyl, wherein the a.lkenyl is unsubstituted or substituted with one or more of the substituent(s) selected from:
(a) hydroxy, (b) oxo, (c) Ci-salkoxy, (d) phenyl-Ci-aalkoxy, (e) phenyl, (fj -CN, (g) halo, (h) -CONRsRIS, wherein R~ and Rls are as defined above, (i) -CORs, wherein R~ is as defined above, (j) -COzR~, wherein Rs is as defined above, (4) -O(CO)-phenyl, wherein the phenyl is unsubstituted or substituted with one or more of Rs, R7and R8;
Re is selected from the group consisting of:
(1) phenyl, unsubstituted or substituted with one or more of Rll, Riz and Rls ;
(2) C1-salkyl, unsubstituted or substituted with one or more of the substituent(s) selected from:
(a) hydroxy, (b) oxo, (c) C1-salkoxy, (d) phenyl-Ci-salkoxy, (e) phenyl, (fj -CN, (g) halo, (h) -NR~RI~, wherein R~ and Rls are as defined above, (i) -NR~COR1~, wherein R~ and Rls are as defined above, (j) -NR9COzRl~, wherein Rs and Rls are as defined above, (k) -CONR9R1~, wherein R9 and Rl~ are as defined above, (1) -COR9, wherein R~ is as defined above, (m) -COaR9, wherein R~ is as defined above;
(3) Cz-salkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:
(a) hydroxy, (b) oxo, (c) C1-salkoxy, (d) phenyl-C1-salkoxy, (e) phenyl, (fj -CN, (g) halo, (h) -CONR~RI~, wherein R9 and Rls are as defined above, (i) -CORs, wherein Rs is as defined above, (j) -COaR9, wherein R~ is as defined above;
(4) heterocycle, wherein the heterocycle is as defined above;
Rs, R7 and Rg are independently selected from the group consisting of:
(1) hydrogen;
(2) C1-salkyl, unsubstituted or substituted with one or more of the substituents selected from:
(a) hydroxy, (b) oxo, (c) Ci-salkoxy, __ (d} phenyl-Ci-salkoxy, (e) phenyl, (fj -CN, (g) halo, (h) -NR9Rlo, wherein Rs and Rla are as defined above, (i) -NR9CORla, wherein Rs and Rl~ are as defined above, (j) -NR9C02R1~, wherein R9 and RI~ are as defined above, (k) -CONR9R1~, wherein R9 and Rl~ are as defined above, (1) -COR9, wherein R9 is as defined above, and (m) -COaRs, wherein R'~ is as defined above;
(3} Ca-salkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:
(a) hydroxy, (b) oxo, (c) C1-salkoxy, (d) phenyl-Cl.salkoxy, (e) phenyl, (fj -CN, (g) halo, (h) -CONR9Rlo wherein R9 and Rl~ are as defined above, (i) -COR9 wherein Rs is as defined above, (j) -COZR9, wherein R~ is as defined above;
(4) CZ-salkynyl;
(5) phenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:
(a) hydroxy, (b) C 1-salkoxy, (c) C l.salkyl, (d) Cz-salkenyl, (e) halo, (fj -CN, (g) -NOa, (h) -CFs, (i) -(CH2)m-NR9Rls, wherein m, Rs and Ri~ are as defined above, (j) -NR9CORls, wherein R~ and Rls are as defined above, (k) -NRsCOzRI~, wherein R9 and Rla are as defined above, (1) -CONR~Rl~, wherein Rs and Ri~ are as defined above, (m} -COaNR9Rl~, wherein R9 and Rl~ are as defined above, (n) -COR9, wherein R9 is as defined above;
(o) -COzR9, wherein R9 is as defined above;
(6) halo, (7) - CN, (8) - CFs, (9) - NOz, (10) -SR14, wherein R14 is hydrogen or Ci-salkyl, (11) -SOR14, wherein R14 is as defined above, (12) -SOzRl4, wherein R14 is as defined above, (13) NR~CORIS, wherein R9 and Rls are as defined above, (14) CONR~CORl~, wherein R9 and Rl~ are as defined above, (15) NR9R1~, wherein R9 and Rl~ are as defined above, (16) NR~COaRis, wherein R~ and Rl~ are as defined above, (17) hydroxy, (18) Cl.salkoxy, (19) COR9, wherein R9 is as defined above, (20) COzRs, wherein R9 is as defined above, Rii, Riz and R13 are independently selected from the definitions of R~, R7 and R8, or -OX;
Y is selected from the group consisting of:
(1) a single bond, __ (2) -O-, (3) -S-, (4) -CO-, (5) -CHZ-, (6) -CHRlb-, and (7) -CRl5Rm-, wherein Rl~ and ltl~ are independently selected from the group consisting of:
(a) Ci-salkyl, unsubstii;uted or substituted with one or more of the substituents selected from:
(i) hydroxy, (ii) oxo, (iii) Ci-salkoxy, (iv) phenyl-C1-salkoxy, (v) phenyl, (vi) -CN, (vii) halo, (viii) -NR9R1~, wherein R~ and Rl~ are as defined above, (ix) -NR~COR1~, wherein R~ and Rl~ are as defined above, (x) -NR~COzRI~, wherein R9 and Rl~ are as defined above, (xi) -CONR9R1~, wherein R~ and Rl~ are as defined above, (xii) -CORD, wherein R~ is as defined above, and (xiii) -COzR~, wherein R'3 is as defined above;
(b) phenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:
(i) hydroxy, (ii) C i-salkoxy, (iii) C i.salkyl, (iv) Cz-salkenyl, (v) halo, (vi) -CN, (vii) -N02, (viii) -CFa, (ix) -(CH2)m-NR9R1~, wherein m, Rs and Rl~ are as defined above, (x) -NR9COR1~, wherein Rs and Rl~ are as defined above, (xi) -NR9COZR1~, wherein R9 and Rl~ are as defined above, (xii) -CONR9R1~, wherein R9 and Rl~ are as defined above, (xiii) -COZNR9R1~, wherein R9 and Rl~ are as defined above, (xiv) -COR9, wherein Rs is as defined above, and (xv) -COzR~, wherein R9 is as defined above;
Z is selected from:
(1) hydrogen, (2) Ci-4alkyl, and (3) hydroxy, with the proviso that if Y is -O-, Z is other than hydroxy, or if Y is -CHR15-, then Z and R15 may be joined together to form a double bond.
Particularly preferred compounds of formula (I) are those wherein:
Rl is selected from the group consisting of:
(1) Ci-salkyl, substituted with one or more of the substituents selected from:
(a) heterocycle, wherein the heterocycle is selected from the group consisting o~
(A) benzimidazolyl, (B) imidazolyl, (C) isoxazolyl, (D) isothiazolyl, (E) oxadiazolyl, (F) pyrazinyl, (G) pyrazolyl, (H) pyridyl, (I) pyrrolyl, __ (J) tetrazolyl, (K) thiadiazolyl, (L) triazolyl, and (M) piperidinyl, and wherein the heterocycle is unsubstituted or substituted with one or more substituent(s) selected from:
(i) C1-salkyl, unsubstituted or substituted with halo, -CFs, -OCHa, or phenyl, (ii) C i-salkoxy, (iii) oxo, (1V) th10X0, (v) cyano, (Vl) -SCH3, (vii) phenyl, (viii) hydroxy, (ix) trifluoromethyl, (x) -(CHa)m-NR9Rlo, wherein m is 0, 1 or 2, and R9 and Rlo areindependently selected from:
(I) hydrogen, (II} C1-salkyl, (III} hydroxyCl-salkyl, and (I~ phenyl, (xi) -NRoCORIO, wherein R9 and Rlo are as defined above, and (xii) -CONRsRlo, wherein R9 and Rlo are as defined above, R2 and R3 are independently selected from the group consisting of:
(1) hydrogen;
(2) Ci-salkyl (3) C2-salkenyl, and (5) phenyl;
X is -O-;
R4 is Rs i R' ,Y ~ ' Rs R~ is phenyl, unsubstituted or substituted with halo;
R~, R7 and R8 are independently selected from the group consisting of:
(1) hydrogen, {2) C1-salkyl, (3) halo, and (4) -CFs;
Y is -O-; and Z is hydrogen or Cl.4alkyl;
and pharmaceutically acceptable salts thereof.
Particularly preferred compounds of formula (I) are:
4-(3-(1,2, 4-triazolo)methyl)-2(S)-(3, 5-bis(trifluoromethyl)benzyloxy)-3(S)-phenyl-morpholine;
4-(3-(1,2,4-triazolo)methyl)-2(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3(R)-phenyl-morpholine;
4-(3-(5-oxo-1H,4H-1, 2,4-triazolo)methyl)-2(S)-(3, 5-bis(trifluoromethyl)benzyloxy)-3(S)-phenyl-morpholine; and 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-{S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine; or a pharmaceutically acceptable salt thereof.
Further preferred NK-1 receptor antagonists are those described in International (PCT) Patent Specification No. WO 95/18124, i.e. compounds of formula (II):
R' RZ _ Rsa O O
R3 (II) sb N i R i -~~R4 ,X
Rs Rs or a pharmaceutically acceptable salt or prodrug thereof, wherein R1 is hydrogen, halogen, C1-salkyl, C1-salkoxy, CFs, NOz, CN, SRa, SORa, SOaRa, COzRa, CONRaRb, CZ.salkenyl, Cz-salkynyl or Ci-4alkyl substituted by Cl.4alkoxy, where Ra and Rb each independently represent hydrogen or C1-4alkyl;
R2 is hydrogen, halogen, Cl.salkyl, C1-salkoxy substituted by C1-4alkoxy or CFs;
R3 is hydrogen, halogen or CF3;
R4 is hydrogen, halogen, Ci-salkyl, Cl.salkoxy, CFs, NOz, CN, SRe, SORa, SOzRa, C02Ra, CONRaRb, Ca-salkenyl, C2.salkynyl or C1-alkyl substituted by C1-4alkoxy, where R$ and Rb each independently represent hydrogen or C1-4alkyl;
R5 is hydrogen, halogen, C1-salkyl, Ci-salkoxy substituted by C1-4alkoxy or CFs;
Rs is a 5-membered or 6-membe:red heterocyclic ring containing 2 or 3 nitrogen atoms optionally substituted by =O, =S or a Cl.4alkyl group, and optionally substituted by a group of the formula ZNR7R8 where Z is C1-salkylene or Cs.scycloalkylene;
R7 is hydrogen, Cl.4alkyl, Cs-~cyc:loalkyl or Cs-7cycloalkylC~_.~alkyl, or CZ-4alkyl substituted by Ci-4alkoxy or hydroxyl;
R$ is hydrogen, Ci-4alkyl, Cs_7cycloalkyl or Cs-7cyclo-alkylCi.4alkyl, or C2-4alkyl substituted by one or two substituents selected from Ci-4alkoxy, hydroxyl or a 4, 5 or 6 membered heteroaliphatic ring containing one or two heteroatoms selected from N, O and S;
or R7, R8 and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms, optionally substituted by a hydroxy group, and optionally containing a double bond, which ring may optionally contain an oxygen or sulphur ring atom, a group S(O) or S(O)z or a second nitrogen atom which will be part of a NH or NR~ moiety where R~ is C1-4alkyl optionally substituted by hydroxy or C1-4alkoxy;
or R7, R8 and the nitrogen atom to which they are attached form a non-aromatic azabicyclic ring system of 6 to 12 ring atoms;
or Z, R7 and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms which may optionally contain an oxygen ring atom;
R~~ and R9b are each independently hydrogen or C1-4alkyl, or Rya and Rib are joined so, together with the carbon atoms to which they are attached, there is formed a Cs-7 ring;
X is an alkylene chain of 1 to 4 carbon atoms optionally substituted by oxo; and Y is a Ci-4alkyl group optionally substituted by a hydroxyl group;
with the proviso that if Y is Ci-4alkyl, R~ is susbstituted at least by a group of formula ZNR7R$ as defined above.
Particularly preferred compounds of formula (II) are those of formula (IIa) and pharmaceutically acceptable salts thereof:
A' Y
O O~ I ~ z C A
N
i RsiX w s A
(IIa) wherein:
A1 is fluorine or CFs;
AZ is fluorine or CFa;
A3 is fluorine or hydrogen;
and X, Y and R~ are as defined in relation to formula (II).
Particularly preferred compounds of formula (II) include:
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(dimethylamino) methyl-1,2,3-triazol-4-yl)methyl-3-(S)-phenylmorpholine;
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(dimethylamino) methyl-1,2,3-triazol-4-yl)methyl-3-(S)-(4-fluorophenyl)morpholine;
and pharmaceutically acceptable salts thereof.
Further preferred NK-1 receptor antagonists are those described in European Patent Spec~cation No. WO 95/23798, i.e. compounds of formula (III):
Rs i R3 X Y w , R' Rz N . / Z R$ (III) Rm (O)a A , Ri3 Ria or a pharmaceutically acceptable salt thereof, wherein:
WO 98/47513 PCTlGB98/01161 RZ and R3 are independently selected from the group consisting of (1) hydrogen, (2) Ci-salkyl, unsubstituted or substituted with one or more of the substituents selected from:
(a) hydroxy, (b) oxo, (c) C1-salkoxy, (d) phenyl-C1-salkoxy, (e) phenyl, (f) -CN, (g) halo, (h) -NR~Rls, wherein R9 and Rls are independently selected from:
(i) hydrogen, (ii) C1-salkyl, (iii) hydroxy-C1-salkyl, and (iv) phenyl, (i) -NR~COR1~, wherein R~ and Rls are as defined above, (j) -NR~C02Rls, wherein R9 and R1~ are as defined above, (k) -CONR~RIS, wherein Rs and Rls are as defined above, (1) -COR9, wherein Rs is as defined above, and (m) -COzRs, wherein R~ is as defined above;
(3) Cz-salkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:
(a) hydroxy, (b) oxo, (c) Ci-salkoxy, (d) phenyl-C1-salkoxy, (e) phenyl, (f) -CN, (g) halo, WO 98!47513 PCT/GB98101161 (h) -CONR9R1~ wherein R9 and Rl~ are as defined above, (i) -CORs wherein R9 is as defined above, (j) -C02R~, wherein R~ is as defined above;
(4) Cz-salkynyl;
(5) phenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:
(a) hydroxy, (b) C1-salkoxy, (c) Ci-salkyl, (d) Cz-salkenyl, (e) halo, (f) -CN, (g} -NO2, (h) -CFa, (i) -(CHz)m-NR9R1~, wherein m, Rs and Rl~ are as defined above, (j) -NR9COR1~, wherein Rs and R1~ are as defined above, (k) -NR9COzRla, wherein R~ and Rl~ are as defined above, (1) -CONR9R1~, wherein R~ and Rl~ are as defined above, (m) -C02NRsRl~, wherein Rs and Rl~ are as defined above, (n) -COR9, wherein Rs is as defined above, (o) -COzRs, wherein Rs is as defined above;
and the groups RZ and R3 may be joined together to form a carbocyclic ring selected from the group consisting of:
(a) cyclopentyl, (b) cyclohexyl, - (c) phenyl, and wherein the carbocyclic ring is unsubstituted or substituted with one or more substituents selected from:
(i) C 1-salkyl, (ii) Ci-salkoxy, (iii) -NR~RIS, wherein R~ and Rls are as defined above, (iv) halo, and (v) trifluoromethyl;
and the groups RZ and R3 may be joined together to form a heterocyclic ring selected from the group consisting of:
(a) pyrrolidinyl, (b) piperidinyl, (c) pyrrolyl, (d) pyridinyl, (e) imidazolyl, (f) furanyl, (g) oxazolyl, (h) thienyl, and (i) thiazolyl, and wherein the heterocyclic ring is unsubstituted or substituted with one or more substituent(s) selected from:
(i) Ci-salkyl, (ii) oxo, (iii) C1-salkoxy, (iv) -NReRI~, wherein Rs and Rls are as defined above, (v) halo, and (vi) trifluoromethyl;
Rs, R7 and R8 are independently selected from the group consisting of:
(1) hydrogen;
(2) Cl.salkyl, unsubstituted or substituted with one or more of the substituents selected from:
(a) hydroxy, (b) oxo, (c) C i-salkoxy, (d) phenyl-C1-salkoxy, (e) phenyl, . (fj -CN, (g) halo, _.
(h) -NR,sg,io, wherein R~ and Rls are as defined above, (i) -NR9COR1~, wherein Rs and Rl~ are as defined above, (j) -NR9C02R1o, wherein Rs and Rl~ are as defined above, (k) -CONR9Rlo, wherein R9 and Rla are as defined above, (1) -CORs, wherein Rs is as defined above, and (m) -COaRs, wherein Rs is as defined above;
(3) Cz-salkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:
(a) hydroxy, (b) oxo, (c) C l.salkoxy, (d) phenyl-C1-salkoxy, (e) phenyl, (f) -CN, (g) halo, (h) -CONR9R1~ wherein Rs and Rls are as defined above, (i) -CORs wherein R9 is as defined above, (j) -C02Rs, wherein R'~ is as defined above;
(4) Cz-salkynyl;
(5) phenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:
(a) hydroxy, (b) C1-salkoxy, (c) Ci-salkyl, (d) Ca.salkenyl, (e) halo, WO 98/47513 PCTlGB98/01161 (~ -CN, (g) -NOz, (h) -CFs, (i) -(CHz)m-NR9Rls, wherein m, Rs and Rl~ are as defined above, (j) -NR9COR1~, wherein R9 and Rl~ are as defined above, (k) -NR~COaRi~, wherein R9 and Rls are as defined above, (1) -CONR9R1~, wherein R9 and R1~ are as defined above, (m) -COzNR9Rl~, wherein R9 and Rl~ are as defined above, (n) -COR9, wherein R~ is as defined above, (o) -COzR9, wherein R~ is as defined above;
(6) halo, (7) -CN, (8) -CFs, (9) -NOz, (10) -SR14, wherein R14 is hydrogen or Cl.salkyl, (I1) -SOR14, wherein R14 is as defined above, (12) -SOzRl4, wherein R14 is as defined above, (13) NR9COR1~, wherein Rs and Rl~ are as defined above, (14) CONR9CORls, wherein R~ and Rls are as defined above, (15) NR9R1~, wherein R9 and Rl~ are as defined above , (16) NR9C02R1~, wherein R9 and Rl~ are as defined above, (17) hydroxy, (18) Ci-salkoxy, {19) COR9, wherein R9 is as defined above, (20) COzR9, wherein R~ is as defined above, (21) 2-pyridyl, (22) 3-pyridyl, (23) 4-pyridyl, (24) 5-tetrazolyl, (25) 2-oxazolyl, and (26) 2-thiazolyl;
Rll, R12 and R13 are independently selected from the definitions of Rs, R7 and R8, or -OX;
_.
A is selected from the group consisting of:
(1) C1-salkyl, unsubstituted or substituted with one or more of the substituents selected from:
(a) hydroxy, to (b) oxo, (c) C1-salkoxy, (d) phenyl-C1-3alkoxy, (e) phenyl, (f) -CN, (g) halo, wherein halo i.s fluoro, chloro, bromo or iodo, (h) -NR9R1~, wherein R~ and Rl~ are as defined above, (i) -NR9COR1~, wherein R~ and Rl~ are as defined above, (j) -NR~COzRI~, wherein R~ and Rl~ are as defined above, (k) -CONR9R1~, wherein R9 and Rl~ are as defined above, (1) -CORD, wherein Rs :is as defined above, and (m) -COzR~, wherein R~ is as defined above;
(2) C2-salkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:
(a) hydroxy, (b) oxo, (c) Cl.salkoxy, (d) phenyl-C1-salkoxy, (e) phenyl, (fj -CN, (g) halo, (h) -CONR9R1~ wherein R~ and R1~ are as defined above, (i) -CORD wherein R~ is as defined above, and (j) -COzR~, wherein R~ is as defined above; and (3) C2-salkynyl;
B is a heterocycle, wherein the heterocycle is selected from the group consisting of:
N N 'X X~ g X~ H
N-N N-N N-N
N O ~N~O WN~O WN~S
X H
N_~ X
N-N N-N _ X
S ~ S / O,X N N
X ~N~S X
~1 N
N-N
N_NX ~_~ ~ N / ,N
N N ~N.
N i X X X
X ~ X
N=N ' ' ,N- / N~ ~C / N
N X ~~C N
X
rHr ~ / ' _.
.~~ / .X / X -N S ~ ~ . ~ S- N
X N N X
-~N,X N ~~ N
X N X
N N~ N
i i i X X X
and wherein the heterocycle may be substituted in addition to -X with one or more substituent(s) selected from:
(i) C1-salkyl, unsubstituted or substituted with halo, -CFs, -OCHs, or phenyl, (ii) C i.calkoxy, (iii) oxo, (iv) hydroxy, (v) thioxo, (vi) -SRo, wherein R9 is as defined above, (vii) halo, (viii) cyano, . (ix) phenyl, (x) trifluoromethyl, (xi) -(CHz)m-NR9Rlo, wherein m is 0, 1 or 2, and R~ and Rlo are as defined above, -3 - _ (xii) -NR9COR1~, wherein R9 and Rl~ are as defined above, (xiii) -CONR9R1~, wherein R9 and Rl~ are as defined above, (xiv) -COZR9, wherein R~ is as defined above, and (xv) -(CH2)m-OR9, wherein m and R9 are as defined above;
pis0orl;
X is selected from:
(a) -PO(OH)O- ~ M+, wherein M+ is a pharmaceutically acceptable monovalent counterion, (b) -PO(O-)2 ~ 2M+, (c) -PO(O-)2 ~ D2+, wherein DZ+ is a pharmaceutically acceptable divalent counterion, (d) -CH(R4)-PO(OH)O- ~ M+, wherein R4 is hydrogen or Ci-aalkyl, (e) -CH(R,4)-PO(O-)2 ~ 2M+, (fj -CH(R4)-PO(O-)a ~ DZ+~
(g) -SOs- ~ M+, (h) -CH(R4)-SOs- ~ M+, (i) -CO-CH2CHz-C02- ~ M+, (j) -CH(CHs)-O-CO-R5, wherein R~ is selected from the group consisting o~
( ) \ O ~~ NH3+ M
HZ+ M.
(u) \O~.N.Rs \O~COZ M+
CO 2 M+
(iv) \ O CO . M+
2 ' \ ~~ COa (v) O
C02 M+
(vi) - O ' CO2 M
COZ M+
COZ M+
(vii) ~ O ~ ( ; and \
(k} hydrogen, with the proviso that if p is 0 and none of Rll, Riz or R13 are -OX, then X is other than hydrogen;
Y is selected from the group consisting of:
(1) a single bond, (2) -O-, (3) -S-, (4) -CO-, (5) -CHz-, (6) -CHR15- , and (7) -CRlSRIS_, wherein Rls and Rls are independently selected from the group consisting of (a) C1-salkyl, unsubstituted or substituted with one or more of the substituents selected from:
(i) hydroxy, (ii) oxo, (iii) C1-salkoxy, {iv) phenyl-C1-salkoxy, (v) phenyl, (vi) -CN, (vii) halo, (viii) -NR9R1~, wherein Rs and RIS are as defined above , (ix) -NR~CORl~, wherein R9 and Rls are as defined above, (x) -NR9COzRls, wherein Rs and Rl~ are as defined above, (xi) -CONR9R1~, wherein Rs and R1~ are as defined above, (xii) -COR9, wherein R~ is as defined above, and (xiii) -COzR~, wherein Rs is as defined above;
(b) phenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:
(i) hydroxy, (ii) C1-salkoxy, (iii) C1-salkyl, (iv) Cz-salkenyl, (v) halo, (vi) -CN, (vii) -NOz, (viii) -CFs, (ix) -(CHz)m-NRgRIS, wherein m, R~ and Rls are as defined above, (x) -NRsCORIa, wherein Rs and Rl~ are as defined above, (xi) -NR9C02R1~, wherein Rs and Rls are as defined above, (xii) -CONR9R1~, wherein Rs and Rl~ are as defined above, (xiii) -C02NR9R1~, wherein R9 and Rl~ are as defined above, (xiv) -CORD, wherein R~ :is as defined above, and _ (xv) -COzR9, wherein R~ is as defined above;
Z is selected from:
(1) hydrogen, (2) Cl.salkyl, and (3) hydroxy, with the proviso that if Y is -O-, Z is other than hydroxy, or if Y is -CHRI~-, then Z and R15 may be joined together to form a double bond.
Particularly preferred compounds of formula (III) are those wherein:
Rz and R3 are independently selected from the group consisting o~
(1) hydrogen, (2) Cl.salkyl, (3) Cz-salkenyl, and (4) phenyl;
Rs, R7 and R$ are independently selected from the group consisting o~
(1) hydrogen, (2) C1-salkyl, (3) fluoro, (4) chloro, (5) bromo, (6) iodo, and (7) -CFa;
Rll, Rlz and R13 are independently selected from the group consisting of:
(1) fluoro, (2) chloro, (3) bromo, and (4) iodo;
A is unsubstituted i-salkyl;
B is selected from the group consisting o~
N- N X X, X
N N N-~ N-N . _ N O ~N~O WN~O WN~S
X H
N_~ X
N-N N-N _ X
N S ~ S ~ O,X N N X
X H N ~N S.
N-NX ~ , ~ N
N N
N X X
X N X
/ N ~~O / N
N
H X H S
H
/ N\ X / N X
N S ~~~0, ~~~S, N N
X
pis0orl;
X is selected from:
(a) -PO(OH)O- ~ M+, wherein M+ is a pharmaceutically acceptable monovalent counterion, (b) -PO(O-)z ~ 2M+, (c) -PO(O-)z ' D2+, wherein D2+ is a pharmaceutically acceptable divalent counterion, (d) -CH(R4)-PO(OH)O- ~ M+, wherein R~ is hydrogen or Ci-salkyl, (e) -CH(R4)-PO(O-)z ~ 2M+, (f) -CH(R4)-PO(O-)z ~ Dz+, (i) -CO-CH2CHz-COz- ~ M+, (j) -CH(CHs)-0-CO-R5, wherein R5 is selected from the group consisting of: -(i) ~ O ~. NH 3+ M- , HZ+ M-\O~~N~OH
\O~CC)2 M+ , CGZ M+
(iv) ~ O CCI - M+
~O~.CO2 (V) , C02 M+
(vi) -O C02-M+
COZ- M+
CC)2 M+
(vii) ~O ~ I ; and Y is -0-;
Z is hydrogen or Ci-calkyl;
and pharmaceutically acceptable salts thereof.
Particularly preferred compounds of formula (III) include:
(1) 2-(S)-(3,5-bis(tri.fluoromethyl)benzyloxy)-3-(S)-phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine N-oxide;
(2) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-4-(3-(4-(ethoxycarbonyloxy-1-ethyl)-5-oxo-1H-1,2,4-triazolo)methyl)morpholine;
(3) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(4-monophosphoryl-5-oxo-1H-1, 2, 4-triazolo)methyl)morpholine;
(4) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(1-monophosphoryl-5-oxo-1H-1,2,4-triazolo)methyl)morpholine;
(5) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(2-monophosphoryl-5-oxo-1H-1, 2, 4-triazolo)methyl)morpholine;
(6) 2-(R)-(1-(R,)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxyphosphoryl-1H-1, 2,4-triazolo)methyl)morpholine;
(7) 2-(S)-(1-(R)-(3,5-bis(trifiuoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(1-monophosphoryl-5-oxo-4H-1, 2, 4-triazolo)methyl)morpholine;
and pharmaceutically acceptable salts thereof.
Further preferred NK-1 receptor antagonists are those described in European Patent Specification No. WO 96/05181, i.e. compounds of formula (I~:
Rl //
Y
R9a O O Rs R9b / ~~ __ N
-~ R4 s R
X
wherein X is a group of the formula NRsR7 or a C- or N-linked imidazolyl ring;
Y is hydrogen or C1-4alkyl optionally substituted by a hydroxy group;
Rl is hydrogen, halogen, C1-salkyl, Cl.salkoxy, CFs, NOa, CN, SRa, SORa, SOaRa, C02Ra, CONRaRb, CZ-salkenyl, Cz-salkynyl or Ci-9alkyl substituted by C1-4alkoxy, wherein Ra and Rb each independently represent hydrogen or Ci-4alkyl;
RZ is hydrogen, halogen, C1-salkyl, Ci.salkoxy substituted by C1-4alkoxy or CFs;
R3 is hydrogen, halogen or CFs;
R4 is hydrogen, halogen, Cl.salkyl, C1-salkoxy, hydroxy, CFs, N02, CN, SRa, SORB, SOzRa, C02Ra, CONRaRb, Cz-salkenyl, Ca.salkynyl or C1-4alkyl substituted by C1-4alkoxy, wherein R$ and Rb are as previously defined;
R5 is hydrogen, halogen, Ci-salkyl, C1-salkoxy substituted by Ci-4alkoxy or CFa;
Rs is hydrogen, C1-salkyl, Cs-7cycloalkyl, Cs-7cycloalkylCi-4alkyl, phenyl, or Ca.4alkyl substituted by Ci-4alkoxy or hydroxy;
R7 is hydrogen, C1_salkyl, Cs-7cycloalkyl, Cs-~cycloalkylCl-nalkyl, phenyl, or Ca.4alkyl substituted by one or two substituents selected from C1-aalkoxy, hydroxy or a 4, 5 or 6 membered heteroaliphatic ring containing one or two heteroatoms selected from N, O and S;
or R~ 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 NRB, S(O) or S(O)a and which ring may be optionally substituted by one or two groups selected from hydroxyCl-4alkyl, C1-4alkoxyCl-4alkyl, oxo, CORa or COaRa 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, C1-4alkyl, hydroxyCi-4alkyl or C1-4alkoxyCi-4alkyl;
and R9a and R9b are each independently hydrogen or C1-4alkyl, or Rya and R9b are joined so, together with the carbon atoms to which they are attached, there is formed a Cs-7 ring;
and pharmaceutically acceptable salts thereof.
Particularly preferred compounds of formula (IV) are those of formula (IVa) and pharmaceutically acceptable salts thereof:
A' i z A
O O
IVa N
w A3 X
wherein A1 is fluorine or CFs;
A2 is fluorine or CFs;
A3 is fluorine or hydrogen; , and X and Y are as defined in relation t,o formula (I).
Specific compounds of formula (I'~ of use in the present invention include:
2-(R)-(1-(R)-(3, 5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(4-morpholinobut-2-yn-yl)morpholine;;
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-N,N-dimethylaminobut-2-yn-yl)-3-(S)-(4-fluorophenyl)morpholine;
4-(4-azetidinylbut-2-yn-yl)-2-(R)-(1-(R)-1;3,5-bis(trifluoromethyl)phenyl}
ethoxy)-3-(S)-(4-fluorophenyl)morpholine;
2-(R)-{1-(R)-(3, 5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(4-imidazolylbut-2-yn-yl)morphaline;
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(4-(N-methylpiperazinyl)but-2-yn-yl)morpholine;
4-(4-bis(2-methoxyethyl)aminobut-2-yn-yl)-2-(R)-(1-(R)-(3, 5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S;)-(4-fluorophenyl)morpholine;
2-(R)-(1-(R)-(3, 5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(4-pyrrolidinobut-2-yn-yl)morpholine;
3-(S)-(4-fluarophenyl)-2-(R}-(1-(R)-(3-fluoro-5-(trifluoromethyl)phenyl) ethoxy)-4-(4-morpholinobut-2-yn-yl)morpholine;
3-(S)-(4-fluorophenyl)-4-(4-morpholinob ut-2-yn-yl)-2-(R)-(1-(R)-(3-(trifluoromethyl)phenyl)ethoxy)morpholine;
4-(4-azetidinylbut-2-yn-yl}-3-(S)-(4-fluorophenyl}-2-(R)-(1-(R)-(3-(trifluoromethyl)phenyl)ethoxy)morpho:line;
2-(R)-{1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-(N-(2-methoxyethyl)-N-methyl)aminobut-2-yn-yl)-3-(S)-phenylmorpholine;
2-(R)-(1-(R}-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-(N-cyclopropyl-N-{2-methoxyethyl)amino}but-2-yn-yl)-3-(S)-phenylmorpholine;
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-(N-isopropyl-N-(2-methoxyethyl)amino)but-2-yn-yl)-3-(S)-phenylmorpholine;
4-(4-(N,N-dimethylamino)but-2-yn-yl)-3-(S)-(4-fluorophenyl)-2-(R)-(1-(S)-(3-fluoro-5-(trifluoromethyl)phenyl-2-hydroxyethoxy)morpholine;
4-(4-azetidinylbut-2yn-yl)-3-(S)-(4-fluorophenyl)-2-(R)-(1-(S)-(3-fluoro-5-(trifluoromethyl)phenyl)-2-hydroxyethoxy)morpholine;
2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-4-(4-(N,N-dimethylamino)but-2-yn-yl)-3-(S)-(4-fluorophenyl)morpholine;
4-(4-azetidinylbut-2-yn-yl)-2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)morpholine;
4-(4-N-bis(2-methoxy)ethyl-N-methylamino)but-2-yn-yl)-2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)morpholine;
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(4-(2-(S)-(methoxymethyl)pyrrolidino)but-2-yn-yl)morphoiine;
4-(4-(7-azabicyclo[2.2.1]heptano)but-2-yn-yl)-2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)morpholine;
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-diisopropylaminobut-2-yn-yl)-3-(S)-(4-fluorophenyl)morpholine;
2-(R)-(1-(R)-(3-fluoro-5-(trifluoromethyl)phenyl)ethoxy)-4-(4-(2-(S)-(methoxymethyl)pyrrolidino)but-2-yn-yl)-3-(S)-phenylmorpholine;
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-{4-{2-(S)-(hydroxymethyl)pyrrolidino)but-2-yn-yl)morpholine;
and pharmaceutically acceptable salts thereof.
Another class of NK-1 receptor antagonists of use in the present invention is that described in European Patent Specification No.
0 436 334, i.e. compounds of formula (~:
R' Ra Ri Y ~ (VI
N
Re- (~) Is -49~-or a pharmaceutically acceptable salt thereof, wherein Y is (CH2)n wherein n is an integer from 1 to 4, and wherein any one of the carbon-carbon single bonds in said (CHz)n may optionally be replaced by a carbon-carbon double bond, and wherein any one of the carbon atoms of said (CHa)n may optionally be substituted with R4, an~i wherein any one of the carbon atoms of said (CHa)n may optionally be substituted with R7;
Z is (CHz)m wherein m is an integer from 0 to 6, and wherein any one of the carbon-carbon single bonds of (CHz)m may optionally be replaced by a carbon-carbon double bond or a carbon-carbon triple bond, and any one of the carbon atoms of said (CHz)m may optionally be substituted with R8~
Rl is hydrogen or C1-aalkyl optionally substituted with hydroxy, C1-4alkoxy or fluoro;
RZ is a radical selected from hydrogen, C1-s straight or branched alkyl, Cs-7cycloalkyl wherein one of the CHz groups in said cycloalkyl may optionally be replaced by NH, oxygen or sulphur; aryl selected from phenyl and naphthyl; heteroaryl selected from i.ndanyl, thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; phenyl-Cz-salkyl, benzhydryl and benzyl, wherein each of said aryl and heteroaryl groups and the phenyl moieties of said benzyl, phenyl -Cz-salkyl and benzhydryl may optionally be substituted with one or more substituents independently selected from halo, nitro, C1-s alkyl, Cl.salkoxy, trifluoromethyl, amino, C1-salkylamino, Cl.salkyl-O-CO, C1-salkyl-O-CO-C1-salkyl, C1-salkyl-CO-O, C1-salkyl-CO-Ci-salkyl-O-, Cl.salkyl-CO, Ci_salkyl-CO-C1-salkyl-, di-C1-salkylamino, -CONH-Ci-salkyl, C1-salkyl-CO-NH-C1-salkyl, -NHCOH and -NHCO-Cl.salkyl; and wherein one of the phenyl moieties of said benzhydryl may optionally be replaced by naphthyl, thienyl, furyl or pyridyl;
R5 is hydrogen, phenyl or Cl.salkyl;
or Rz and Rs together with the carbon to which they are attached, form a saturated ring having from 3 to 7 carbon atoms wherein one of the CHZ groups in said ring may optionally be replaced by oxygen, NH or sulfur;
R3 is aryl selected from phenyl and naphthyl; heteroaryl selected from indanyl, thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; and cycloalkyl having 3 to 7 carbon atoms wherein one of the (CHz) groups in said cycloalkyl may optionally be replaced by NH, oxygen or sulphur;
wherein each of said aryl and heteroaryl groups may optionally be substituted with one or more substituents, and said Cs-7cycloalkyl may optionally be substituted with one or two substituents, each of said substituents being independently selected from halo, nitro, Cl.salkyl, Cl.salkoxy, trifluoromethyl, amino, C1-salkylamino, -CO-NH- C1-salkyl, Ci-salkyl-CO-NH-C1-salkyl, -NHCOH and -NHCO-Ci-salkyl;
R4 and R7 are each independently selected from hydroxy, halogen, halo, amino, oxo, cyano, methylene, hydroxymethyl, halomethyl, C1_salkylamino, di-Ci-salkylamino, C1-salkoxy, C1-salkyl-O-CO, Ci.salkyl-O-CO-C1-salkyl, Cl.salkyl-CO-O, Cl.salkyl-CO-Ci-salkyl-O-, C1-salkyl-CO-, C1-salkyl-CO-Cl.salkyl, and the radicals set forth in the definition of R2;
Rs is -NHCOR~, -NHCHzR9, SOzRB or one of the radicals set forth in any of the definitions of R2, R4 and R7;
R8 is oximino (=NOH) or one of the radicals set forth in any of the definitions of R2, R4 and R7;
R~ is C1-salkyl, hydrogen, phenyl or phenylCl-salkyl;
with the proviso that (a) when m is 0, R8 is absent, (b) when R4, Rs, R~ or R8 is as defined in Rz, it cannot form together with the carbon to which it is attached ,a ring with R5, and (c) when R4 and R~ are attached to the same carbon atom, then either each of R4 and R7 is independently selected from hydrogen, fluoro and C1-salkyl, or R~ and R~, together with the carbon to which they are attached, for a Cs.s sai;urated carbocyclic ring that forms a spiro compound with the nitrogen-containing ring to which they are attached.
A particularly preferred compound of formula (~ is (2S,3S)-cis-3-(2-methoxybenzylamino)-2-phenylpiperidine; or a pharmaceutically acceptable salt thereof.
Another class of NK-1 receptor antagonists of use in the present invention is that described in International Patent Specification No. WO
93/21155, i.e. compounds of formula (VI):
R R
O
NCH-R1 (VI) Rs Iz R
R3 R' or a pharmaceutically acceptable salt thereof, wherein radicals R are phenyl radicals optionally 2- or 3-substituted by a halogen atom or a methyl radical;
Rl is optionally substituted phenyl, cyclohexadienyl, naphthyl, indenyl or optionally substituted heterocycle;
RZ is H, halogen, OH, alkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkyloxy, alkylthio, acyloxy, carboxy, optionally substituted alkyloxycarbonyl, benzyloxycarbonyl, amino or acylamino;
R3 is optionally 2-substituted phenyl;
R4 is OH or fluorine when R5 is H;
or R4 and R5 are OH ;
or R~ and R5 together form a bond.
A particularly preferred compound of formula (VI) is (3aS, 4S, 7aS)-7,7-diphenyl-4-(2-methoxyphenyl)-2-[(2S)-(2-methoxyphenyl)propionyl]
perhydroisoindol-4-0l; or a pharmaceutically acceptable salt thereof.
Another class of NK-1 receptor antagonists of use in the present invention is that described in European Patent Specification No.
0 591 040, i.e. compounds of formula (VII):
R Q
Ar-T-CO-~-CH2-~-CHZ-CHZ-Am +, A - (VII) __ Are wherein Ar represents an optionally substituted mono-, di- or tricyclic aromatic or heteroaromatic group;
T represents a bond, a hydroxymethylene group, a C1-4alkoxymethylene group or a Ci-salkylene group;
Ar' represents a phenyl group which is unsubstituted or substituted by one or more substituents selected from halogen, preferably chlorine or fluorine, trifluoromethyl, C1-4alkoxy, Ci-4alkyl where the said substituents may be the same or different; a thienyl group; a benzothienyl group; a naphthyl group; or an indolyl group;
R represents hydrogen, C1-4alkyl, w-C1-4alkoxyCl-4alkyl, or cu-Cz-4alkanoyloxyC2-4alkyl;
Q represents hydrogen;
or (a and R together form a 1,2-ethylene, 1,3-propylene or 1,4-butylene group;
Am+ represents the radical ~.z---N
in which Xi, X2 and Xs, together with the nitrogen atom to which they are attached, form an azabicyclic or azatricyclic ring system optionally substituted by a phenyl or benzyl group; and A- represents a pharmaceutically acceptable anion.
-53~-A particularly preferred compound of formula (VII) is (+) 1-[2-[3-(3,4-dichlorophenyl)-1-[(3-isopropoxyphenyl)acetyl]-3-piperidinyl]ethyl]-4-phenyl-1-azabicyclo[2,2,2]octane; or a pharmaceutically acceptable salt, especially the chloride, thereof.
Another class of NK-1 receptor antagonists of use in the presenf invention is that described in European Patent Specification No.
0 532 456, i.e. compounds of formula (VIII):
Rl--N X -X -Ra (VIII) a i R Xi or a pharmaceutically acceptable salt thereof, wherein R1 represents an optionally substituted aralkyl, aryloxyalykl, heteroaralkyl, aroyl, heteroaroyl, cycloalkylcarbonyl, aralkanoyl, heteroarylalkanoyl, aralkoxycarbonyl or arylcarbamoyl group or the acyl group of an a-amino acid optionally N-substituted by a lower alkanoyl or carbamoyl-lower alkanoyl group;
RZ represents cycloalkyl or an optionally substituted aryl or heteroaryl group;
R3 represents hydrogen, alkyl, carbamoyl or an alkanoyl or alkenoyl group optionally substituted by carboxy or esterified or amidated carboxy;
R4 represents an optionally substituted aryl group or an optionally partially saturated heteroaryl group;
Xl represents methylene, ethylene, a bond, an optionally ketalised carbonyl group or an optionally etherified hydroxymethylene group;
X2 represents alkylene, carbonyl gar a bond; and Xs represents carbonyl, oxo-lower alkyl, oxo(aza)-lower alkyl, or an alkyl group optionally substituted by phenyl, hydroxymethyl, optionally esterified or amidated carboxy, or (in other than the a-position) hydroxy.
A particularly preferred compound of formula (VIII) is (2R*, 4S*)-2-benzyl-1-(3, 5-dimethylbenzoyl}-N-(4-qui.nolinylmethyl)-4-piperidineamine;
or a pharmaceutically acceptable salt thereof.
Another class of NK-1 receptor antagonists of use in the present invention is that described in European Patent Specification No.
0 443 132, i.e. compounds of formula (IX) i \
a /
CHz R1-Y-A- N -1---CONHCHCON ~ (IX) R"
or a pharmaceutically acceptable salt thereof, wherein RI is aryl, or a group of the formula:
i \ ,x z X is CH or N; and Z is O or N-Rb, in which R5 is hydrogen or lower alkyl;
R2 is hydroxy or lower alkoxy;
R3 is hydrogen or optionally substituted lower alkyl;
R4 is optionally substituted ar(lower)alkyl;
A is carbonyl or sulfonyl; and Y is a bond or lower alkenylene.
A particularly preferred compound of formula (IX) is the compound of formula (IXa) HO
O
N \ ~
_N
(IXa) O CH3 \
O
N
or a pharmaceutically acceptable salt thereof.
Another class of NK-1 receptor antagonists of use in the present invention is that described in International Patent Specification No. WO
92/17449, i.e. compounds of the formula (X) ,~~~ ~~ g,' __ N J.,,. R
H
(X) or a pharmaceutically acceptable salt thereof, wherein Rl is aryl selected from indanyl, phenyl and naphthyl; heteroaryl selected from thienyl, furyl, pyridyl and quinolyl; and cycloalkyl having 3 to 7 carbon atoms, wherein one of said carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; wherein each of said aryl and heteroaryl groups may optionally be substituted with one or more substituents, and said Ca-7cycloalkyl may optionally be substituted with one or two substituents, said substituents being independently selected from chloro, fluoro, bromo, iodo, nitro, Ci.loalkyl optionally substituted with from one to three fluoro groups, Cl..loalkoxy optionally substituted with from one to three fluoro groups, amino, Ci-ioalkyl-S-, Ci-ioalkyl-S(O)-, C1-loalkyl-SOa-, phenyl, phenoxy, Cl.ioalkyl-SOzNH-, Ci-ioalkyl-SOzNH-C1-loakyl-, C1-loalkyla:mino-diCl-ioalkyl-, cyano, hydroxy, cycloalkoxy having 3 to 7 carbon atoms, Ci.calkylamino, C1-sdialkylamino, HC(O)NH- and Cl.loalkyl-C(O)NH-; and Rz is thienyl, benzhydryl, naphth;yl or phenyl optionally substituted with from one to three substituents independently selected from chloro, bromo, fluoro, iodo, cycloalkoxy having 3 to ? carbon atoms, C1-ioalkyl optionally substituted with from one to three fluoro groups and Ci-loalkoxy optionally substituted with from one to three fluoro groups.
A particularly preferred compound of formula (X) is (2S,3S)-3-(2-methoxy-5-trifluoromethoxybenzyl)-ami.no-2-phenylpiperidine; or a pharmaceutically acceptable salt thereof.
Another class of NK-1 receptor antagonists of use in the present invention is that described in International Patent Specification No. WO
95/08549, i.e. compounds of formula (XI) (CHa)X ._ N ~ i R
R~
N
H
R
(XI) or a pharmaceutically acceptable salt thereof, wherein R1 is a C1-4alkoxy group;
N
N
N-N ' R3 is a hydrogen or halogen atom;
R4 and R~ may each independently represent a hydrogen or halogen atom, or a Ci-4alkyl, C1-4alkoxy or trifluoromethyl group;
R~ is a hydrogen atom, a C1-4alkyl, (CHz)mcyclopropyl, -S(O)"C1_ aalkyl, phenyl, NR7R8, CHzC(O)CFs or trifluoromethyl group;
R7 and R$ may each independently represent a hydrogen atom, or a Ci-4alkyl or acyl group;
x represents zero or 1;
n represents zero, 1 or 2; and m represents zero or 1.
Particularly preferred compounds of formula (~I) are (2-methoxy-5-tetrazol-1-yl-benzyl)-([2S,3S]-2-phenyl-piperidin-3-yl)-amine; and [2-methoxy-5-(5-trifluoromethyl-tetrazol-1-yl)-benzyl]-([2S,3S]-2-phenyl-piperidin-3-yl)-amine; or a pharmaceutically acceptable salt thereof.
- 57 _ Another class of tachykinin antagonists of use in the present invention is that described in International Patent Specification No. WO
95/14017, i.e. compounds of formula (XII) R$ R4 R- (CHZ)n- C - CHZ - N- (CH2)o- R3 __ NH R
(CO)P
(CH2)m Rl (XII) or a pharmaceutically acceptable salt thereof, wherein m is zero, 1, 2 or 3;
n is zero or 1;
o is zero, 1 or 2;
p is zero or 1;
R is phenyl, 2- or 3-indolyl, 2- or 3-indolinyl, benzothienyl, benzofuranyl, or naphthyl;
which R groups may be substituted with one or two halo, C1-salkoxy, trifluoromethyl, C1-4alkyl, phenyl-Ci-salkoxy, or C1-4alkanoyl groups;
Rl is trityl, phenyl, diphenylmethyl, phenoxy, phenylthio, piperazinyl, piperidinyl, pyrrolidinyl, m.orpholinyl, indolinyl, indolyl, benzothienyl, hexamethyleneiminyl, benzofuranyl, tetrahydropyridinyl, quinolinyl, isoquinolinyl, reduced quinolinyl, reduced isoquinolinyl, phenyl-(Ci-4alkyl)-, phenyl-(C1-4alkoxy)-, quinolinyl-(Ci-4alkyl)-, isoquinolinyl-(C1-4alkyl)-, reduced quniolinyl-(Ci-4alkyl)-, reduced isoquinolinyl-(C1-4alkyl)-, benzoyl-(Ci-salkyl)-, Ci.4alkyl, or -NH-CHa-R5;
any one of which Rl groups may be substituted with halo, C1-4alkyl, C1-4alkoxy, trifluoromethyl, amino, Cl.4alkylamino, di(C1-4alkyl)amino, or C2-4alkanoylamino;
or any one of which Rl groups may be substituted with phenyl, piperazinyl, Cs.acycloalkyl, benzyl, Ci-4alkyl, piperidinyl, pyridinyl, pyrimidinyl, Cz-~alkanoylamino, pyrrolidinyl, Cz-calkanoyl, .or C1-4alkoxycarbonyl;
any one of which groups may be substituted with halo, Ci-alkyl, C1-4alkoxy, trifluoromethyl, amino, Ci-4alkylamino, di{Ci-4alkyl)amino, or Cz-4alkanoylamino;
or Rl is amino, a leaving group, hydrogen, C1-4alkylamino, or di(C1-4alkyl)amino;
R5 is pyridyl, anilino-(C1-salkyl)-, or anilinocarbonyl;
R2 is hydrogen, C1-4alkyl, Ci_4alkylsulfonyl, carboxy-(C1-salkyl)-, C1-aalkoxycarbonyl-(C1-salkyl)-, or -CO-R6;
R~ is hydrogen, C1-4alkyl, Ci-shaloalkyl, phenyl, Ci-salkoxy, Ci-shydroxyalkyl, amino, Ci-4alkylamino, di(Ci-aalkyl)amino, or -(CHa)Q-R~;
q is zero to 3;
R7 is carboxy, C1-4alkoxycarbonyl, C1-4alkylcarbonyloxy, amino, Ci-4alkylamino, di(Ci-4alkyl)amino, Ci-calkoxycarbonylamino, or phenoxy, phenylthio, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, indolinyl, indolyl, benzothienyl, benzofuranyl, quinolinyl, phenyl-(Ci-4alkyl)-, quinolinyl-(Ci.4alkyl)-, isoquinolinyl-(Ci-4alkyl)-, reduced quinolinyl-(Ci-4alkyl)-, reduced isoquinolinyl-(Cl.4alkyl)-, benzoyl-Ci.salkyl;
any one of which aryl or heterocyclic R7 groups may be substituted with halo, trifluoromethyl, C1-4alkoxy, C1-4alkyl, amino, Ci-4alkylamino, di(C1-4alkyl)amino, or Cz-4alkanoylamino;
or any one of which R7 groups may be substituted with phenyl, piperazinyl, Cs-scycloalkyl, benzyl, piperidinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, Cz-ealkanoyl, or Ci-4alkoxycarbonyl;
any of which groups may be substituted with halo, trifluoromethyl, amino, C1-4alkoxy, C1-4alkyl, C1-4alkylamino, di(C1-4alkyl)amino, or C2-~alkanoylamino;
Rs is hydrogen or Ci-alkyl;
R3 is phenyl, phenyl-(C1-alkyl)-, Cs-scycloalkyl, C~-scycloalkenyl, Ci-salkyl, naphthyl, C2-salkenyl, or hydrogen;
any one or which groups except hydrogen may be substituted with one or two halo, C1-salkoxy, C1-aalkylthio, nitro, trifluoromethyl, or C1-salkyl groups; and R4 is hydrogen or C1-aalkyl;
with the proviso that if Rl is hydrogen or halo, R3 is phenyl, . __ phenyl-(Ci-salkyl)-, Cs.scYcloalkyl, Cs.scYcloalkenyl, or naphthyl.
A particularly preferred compound of formula (XII) is [N-(2-methoxybenzyl)acetylamino]-3-(1H-indoa-3-yl)-2-[N-(2-(4-piperidin-1-yl)piperidin-1-yl)acetylamino]propane; o:r a pharmaceutically acceptable salt thereof.
The preferred compounds of formulae (I), (II), (III} and (I~ will have the 2- and 3-substituents on the morpholine ring in the cis arrangement, the preferred stereochemistry being as shown in the following general formula:
i O ,~,0~ w ~.2 a R
Where the benzyloxy moiety is a-substituted, the preferred stereochemistry of the a-carbon is either (R) when the substituent is an alkyl (e.g. methyl) group or (,S~ when the substituent is a hydroxyalkyl (e.g. hydroxymethyl) group.
Unless otherwise defined herein, suitable alkyl groups include straight-chained and branched alkyl groups containing from 1 to 6 carbon atoms. Typical examples include methyl and ethyl groups, and straight-chained or branched propyl and butyl groups. Particular alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl and tert-butyl.
Unless otherwise defined herein, suitable alkenyl groups include straight-chained and branched alkenyl groups containing from 2 to 6 carbon atoms. Typical examples include vinyl and allyl groups.
Unless otherwise defined herein, suitable alkynyl groups include straight-chained and branched alkynyl groups containing from 2 to 6 ._ carbon atoms. Typical examples include ethynyl and propargyl groups.
Unless otherwise defined herein, suitable cycloalkyl groups include groups containing from 3 to 7 carbon atoms. Particular cycloalkyl groups are cyclopropyl and cyclohexyl.
Unless otherwise defined herein, suitable aryl groups include phenyl and naphthyl groups.
A particular aryl-Cl.~alkyl, e.g. phenyl-Cl.salkyl, group is benzyl.
Unless otherwise defined herein, suitable heteroaryl groups include pyridyl, quinolyl, isoquinolyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, furyl, benzofuryl, thienyl, benzthienyl, imidazolyl, oxadiazolyl and thiadiazolyl groups.
The term "halogen" as used herein includes fluorine, chlorine, bromine and iodine.
The compounds of use in this invention may have one or more asymmetric centres and can therefore exist as enantiomers and possibly as diastereoisomers. It is to be understood that the present invention relates to the use of all such isomers and mixtures thereof.
Suitable pharmaceutically acceptable salts of the NK-1 receptor antagonists of use in the present invention include acid addition salts which may, for example, be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable non-toxic acid such as hydrochloric acid, fumaric acid, malefic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid or sulphuric acid. Salts of amine groups may also comprise the quaternary ammonium salts in which the amino nitrogen atom carries an alkyl, alkenyl, alkynyl or aralkyl group. Where the compound carries an acidic group, for example a carboxylic acid group, the present invention also contemplates salts thereof, preferably non-toxic pharmaceutically acceptable salts thereof, such as the sodium, potassium and calcium salts thereof.
Suitable pharmaceutically acceptable salts of the anorectic agent of use in the combinations of the present invention include those salts . _.
described above in relation to the salts of NK-1 receptor antagonists.
The present invention accordingly provides the use of a NK-1 receptor antagonist selected from the compounds of formulae (I), (II), (III), (IV), (~, (VI), (VII), (VIII), (IX), (X), (Xl:) and (XII), for the manufacture of a medicament for the treatment or prevention of eating disorders.
The present invention also provides a method for the treatment or prevention of eating disorders, which method comprises administration to a patient in need of such treatment an effective amount of a NK-1 receptor antagonist selected from the compounds of formulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) and (XI:f).
In a further aspect of the present; invention, there is provided a pharmaceutical composition for the treatment or prevention of eating disorders comprising a NK-1 receptor antagonist selected from the compounds of formulae (I), (II), (III}, (IV), (V}, (VI}, (VII), (VIII), (IX), (X), (XI) and (XII), together with at least one pharmaceutically acceptable carrier or excipient.
It will be appreciated that the NK-1 receptor antagonist selected from the compounds of formulae (I), (II), (III}, (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) and (XII) may be used in combination with an anorectic agent, present as a combined preparation for simultaneous, separate or sequential use for the treatment or prevention of eating disorders. Such combined preparations may be, for example, in the form of a twin pack.
In a further or alternative aspect; of the present invention, there is therefore provided a product comprising a NK-1 receptor antagonist selected from the compounds of formulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) and (XII) and an anorectic agent as a combined WO 98!47513 PCT/GB98/01161 preparation for simultaneous, separate or sequential use in the treatment or prevention of eating disorders.
In a preferred aspect, the present invention accordingly provides the use of a NK-1 receptor antagonist selected from the compounds of formulae (I), (II), (III), (IV), (~, (VI), (VII), {VIII), (IX), (X), (XI) and (XII) and a __ halogenated amphetamine derivative for the manufacture of a medicament for the treatment or prevention of eating disorders.
The present invention also provides a method for the treatment or prevention of eating disorders, which method comprises administration to a patient in need of such treatment an amount of a NK-1 receptor antagonist selected from the compounds of formulae (I), (II), (III), (IV), (V), {VI), (VII), (VIII), (IX), {X), (XI) and (XII) and a halogenated amphetamine derivative such that together they give effective relief.
In a further aspect of the present invention, there is provided a pharmaceutical composition comprising a NK-1 receptor antagonist selected from the compounds of formulae (I), {II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) and (XII) and a halogenated amphetamine derivative 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 NK-1 receptor antagonist selected from the compounds of formulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), {X), (XI) and (XII) and a halogenated amphetamine derivative as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of eating disorders.
Particularly preferred halogenated amphetamine derivatives are selected from the group consisting of fenfluramine and dexfenfluramine.
Thus in a further preferred aspect, the present invention accordingly provides the use of a NK-1 receptor antagonist selected from the compounds of formulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) and (XII) and a halogenated amphetamine derivative selected from the group consisting of fenfluramine and dexfenfluramine; for the manufacture of a medicament for the treatment or prevention of eating disorders.
The present invention also provides a method for the treatment or prevention of eating disorders, which method comprises administration to a patient in need of such treatment an amount of a NK-1 receptor antagonist selected from the compounds of formulae (I), (iI), (III), (IV), (~, (VI), (VII), (VIII), (IX), (X), (XI) and (XII) and an amount of a halogenated amphetamine derivative selected from the group consisting of fenfluramine and dexfenfluramine, such that together they give effective relief.
In a further aspect of the present invention, there is provided a pharmaceutical composition comprising a NK-1 receptor antagonist selected from the compounds of formulae (I), (II), (III), (IV), (V), (VI}, (VII), (VIII), (IX), (X), (XI) and (XII) and a halogenated amphetamine derivative selected from the group consisting of fenfluramine and dexfenfluramine, 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 NK-1 receptor antagonist selected from the compounds of formulae (I), (II), (III), (IV), (V}, (VI), (VII), (VIII), (IX), (X), (XI) and (XII) and a halogenated amphetamine derivative selected from the group consisting of fenfluramine and dexfenfluramine, as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of eating disorders.
As stated above, the NK-1 receptor antagonist and the anorectic agent may be formulated in a single pharmaceutical composition or alternatively in individual pharmaceutical compositions for simultaneous, separate or sequential use in accordancE: with the present invention.
Preferably the compositions according to the present invention are in unit dosage forms such as tablets, pills, capsules, powders, granules, solutions or suspensions, or suppositories, for oral, parenteral or rectal administration, by inhalation or insufflation or administration by trans-dermal patches or by buccal cavity absorption wafers. Oral dosage forms are particularly preferred (e.g. tablets, capsules, pills or wafers).
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, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing 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 containing 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 stomach 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 shellac, cetyl alcohol and cellulose acetate.
The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions vvith edible oils such as cottonseed oil, sesame oil, coconut oil, peanut oil or soybean oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.
Preferred compositions for administration by injection include those comprising a NK-1 receptor antagonist as the active ingredient, in association with a surface-active agent (or wetting agent or surfactant) or in the form of an emulsion (as a water-:in-oil or oil-in-water emulsion).
Suitable surface-active agents include, in particular, non-ionic agents, such as polyoxyethylenesorbitans (e.g. TweenT"" 20, 40, 60, 80 or 85) and other sorbitans (e.g. SpanT"' 20, 40, 60, 80 or 85). Compositions with a surface-active agent will 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 mannitol or other pharmaceutically acceptable vehicles, if necessary.
Suitable emulsions may be prep;~red using commercially available fat emulsions, such as IntralipidT"", LiposynT"", InfonutrolT"", LipofundinT°"
and LipiphysanT"". 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 almond oil) and an emulsion formed upon mixing 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 glycerol or glucose, to adjust the tonicity of the emulsion. Suitable emulsions will typically contain up to 20% oil, for example, between 5 and 20%. The fat emulsion will preferably comprise fat droplets between 0.1 and 1.0~m, particularly 0.1 and 0.5~m, and have a pH in the range of 5.5 to 8Ø
Particularly preferred emulsion compositions are those prepared by mixing a NK-1 receptor antagonist selected from the compounds of formulae (I), (II), (III), (IV), (~, (VI), (VII), (VIII), (IX), (X), (XI) and (XII) with IntralipidT"" or the components thereof (soybean oil, egg phospholipids, glycerol and water).
Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as set out above.
Preferably the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably sterile pharmaceutically acceptable solvents may be 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 machine. Solution, suspension or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.
Compositions of the present invention may also be presented for administration in the form of trans-dermal patches using conventional technology. The compositions may also be administered via the buccal cavity using, for example, absorption wafers.
The present invention further provides a process for the preparation of a pharmaceutical composition comprising a NK-1 receptor antagonist and an anorectic agent, which process comprises bringing a NK-1 receptor antagonist and an anorectic agent, into association with a pharmaceutically acceptable carrier or excipient.
When administered in combination, either as a single or as separate pharmaceutical composition(s), the NK-1 receptor antagonist and an anorectic agent, are presented in a ratio which is consistent with the manifestation of the desired effect. In particular, the ratio by weight of the NK-1 receptor antagonist and the anorectic agent will suitably be between 0.001 to 1 and 1000 to 1, and especially between 0.01 to 1 and 100 to 1.
A suitable dosage level for the NK-1 receptor antagonist about 0.05 to I500mg per day, preferably about 0.25 to I500mg per day, and especially about 0.25 to 500mg/kg per day. The compounds may be administered on a regimen of up to 6 tines per day, preferably 1 to 4 times per day, especially 1 or 2 times daily.
A suitable dosage level for the anorectic agent is about 0.5 to 1500mg per day, preferably about 2.5 to 1000mg per day, and especially about 2.5 to 500mg per day. The compounds may be administered on a regimen of up to 6 times per day, preferably 1 to 4 times per day, especially 1 or 2 times daily.
It will be appreciated that the amount of the NK-1 receptor antagonist and (where present) the anorectic agent required for use in the treatment or prevention of eating disorders will vary not only with the particular compounds or compositions selected but also with the route of administration, the nature of the condition being treated, and the age and condition of the patient, and will ultimately be at the discretion of the patient's physician or pharmacist.
The compounds of formulae (I), (I:I), (III), (IV), (~, (VI), (VII), (VIII), (IX), (X), (XI) and (XII) may be preparect by the methods described in EP-A-0 577 394 (or WO 95/16679), WO 95/18124, WO 95/23798, WO 96/05181, EP-A-0 436 334, WO 93/:?1155, EP-A-0 591 040, EP-A-0 532 456, EP-A-0 443 132, WO 92/17449, WO 95/08549 and WO 95//4017, respectively.
Particularly preferred NK-1 receptor antagonists of the formulae (I), (II), (III}, (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) and (XII) for use in the present invention are compounds which. are potent NK-1 receptor antagonists, i.e. compounds with an NK-I receptor affinity (ICso) of less than 100nM.
Even more preferred NK-1 receptor antagonists of use in the present invention are compounds which are potent NK-1 receptor antagonists with an NK-1 receptor affinity (ICSo) of less than IOnM, favourably less than 2nM and preferably less than lnM.
5 Especially preferred NK-1 receptor antagonists of use in the prQSent invention are orally active, long acting, CNS-penetrant NK-1 receptor antagonists, identified using a combination of the following assays:
ASSAY 1: NK-1 Receptor bindin~~
10 NK-1 receptor binding assays are performed in intact Chinese hamster ovary (CHO) cells expressing the human NK-1 receptor using a modification of the assay conditions described by Cascieri et al, J.
Pharmacol. Exp. Ther., 1992, 42, 458. Typically, the receptor is expressed at a level of 3x105 receptors per cell. Cells are grown in monolayer culture, 15 detached from the plate with enzyme-free dissociation solution (Speciality Media Inc.), and washed prior to use in the assay. laSl-~,r8-substance P
(O.lnM, 2000Ci/mmol; New England Nuclear) is incubated in the presence or absence of test compounds (dissolved in 5~1 dimethylsulphoxide, DMSO) with 5x104 CHO cells. Ligand binding is performed in 0.25m1 of 50mM
20 Tris-HCI, pH7.5, containing 5mM MnClz, 150mM NaCl, 0.02% bovine serum albumin (Sigma), 50p.g/ml chymostatin (Peninsula), O.lnM
phenylmethylsulphonyl fluoride, 2~g/ml pepstatin, 2~.g1m1 leupeptin and 2.8~g/ml furoyl saccharine. The incubation proceeds at room temperature until equilibrium is achieved (>40 minutes) and the receptor-ligand 25 complex is harvested by filtration over GF/C filters pre-soaked in 0.1%
polyethylenimine using a Tomtek 96-well harvester. Non-specific binding is determined using excess substance P (1~,M) and represents <10% of total binding.
ASSAY 2: Gerbil Foot-Tapping CNS-penetrant NK-1 receptor antagonists for use in the present invention can be identified by their ability to inhibit foot tapping in gerbils induced by anxiogenic agents (such as pentagastrin) or central infusion of NK-1 receptor agonists such as GR736;32, or caused by aversive _.
stimulation such as foot shock or single housing, based on the method of Rupniak & Williams, Eur. J. Pharmacvl., 1994, 265, 179.
Male or female Mongolian gerbils (35-70g) are anaesthetised by inhalation of an isoflurane/oxygen mixi;ure to permit exposure of the jugular vein in order to permit administration of test compounds or vehicle in an injection volume of approximately 5mllkg i.v. Alternatively, test compounds may be administered orally or by subcutaneous or intraperitoneal routes. A skin incision is then made in the midline of the scalp to expose the skull. An anxiogenic agent (e.g. pentagastrin) or a selective NK-I receptor agonist (e.g. G1~,73632 (d Ala[L-Pro9,Me-Leulo]-substance P-(7-1I)) is infused directly into the cerebral ventricles (e.g.
3pmo1 in 5~,1 i.c.v., depending on test substance) by vertical insertion of a cuffed 27 gauge needle to a depth of 4.5mm below bregma. The scalp incision is closed and the animal allowE~d to recover from anaesthesia in a clear perspex observation box (approximately 25cm x 20cm x 20cm). The duration and/or intensity of hind foot tapping is then recorded continuously for approximately 5 minutes. Alternatively, the ability of test compounds to inhibit foot tapping evoked by aversive stimulation, such as foot shock or single housing, may be studied using a similar method of quantification.
ASSAY 3: Ferret Emesis Individually housed male ferrets (1.0 -2.5 kg) are dosed orally by gavage with test compound. Ten minui;es later they are fed with approximately 100g of tinned cat food. At 60 minutes following oral dosing, cisplatin (lOmg/kg) is given i.v. uia a jugular vein catheter inserted under a brief period of halothane anaesthesia. The catheter is then removed, the jugular vein ligated and the skin incision closed. The ferrets recover rapidly from the anaesthetic and are mobile within 10-20 minutes. The animals are observed continuously during recovery from the anaesthetic and for 4 hours following the cisplatin injection, after which time the animals are killed humanely. The numbers of retches and vomits occurring during the 4 hours after cisplatin administration are recorded by trained observers.
ASSAY 4: Separation-Induced Vocalisation Male and female guinea-pigs pups are housed in family groups with their mothers and littermates throughout the study. Experiments are commenced after weaning when the pups are at least 2 weeks old. Before entering an experiment, the pups may be screened to ensure that a vigorous vocalisation response is reproducibly elicited following maternal separation. The pups are placed individually in an observation cage (approximately 55cm x 39cm x l9cm) in a room physically isolated from the home cage for approximately 15 minutes and the duration and/or number of vocalisation during this baseline period is recorded. Those animals which vocalise for longer than 5 minutes are employed for drug challenge studies (approximately 50% of available pups may fail to reach this criterion). On test days each pup receives an oral dose or an s.c. or i.p.
injection of test compound or vehicle and is then immediately returned to the home cage with its mother and siblings for at least 30 to 60 minutes (or for up to 4 hours following an oral dose, dependent upon the oral pharmacokinetics of the test compound) before social isolation for 15 minutes as described above. The duration and/or number of vocalisation on drug treatment days may be expressed as a percentage of the pre-treatment baseline value for each animal or compared with values obtained in vehicle-treated animals. The same subjects may be retested once weekly for up to 6 weeks. Between 6 and 8 animals receive each test WO 98/47513 PCTlGB98/01161 compound at each dose tested.
A suitable selection cascade for NKl antagonists of use according to the present invention is as follows:
(i) Determine affinity for human NKl receptor in radioligand . _.
binding studies (Assay 1); select compounds with ICso <_ lOnM, preferably ICso <_ 2nM, especially ICso _< lnM.
(ii) Determine ability of compounds to penetrate CNS by their ability to inhibit foot tapping in gerbils induced by central injection of an NKi agonist (Assay 2); select compounds that inhibit foot tapping with IDso _< 3mg/kg i.v., and preferably IDso ~ lmglkg i.v. when administered immediately prior to central NKl agonist challenge, or IDso <_ 30mg/kg p.o., and preferably IDso <_ lOmglkg p.o. 1 hour prior to challenge.
(iii) Determine central duration of action of compounds in gerbil foot tapping assay following intravenous administration 24 hours prior to central NKl agonist challenge; select compounds showing <_ 25-fold loss of potency compared with IDso determined in step (ii) above with the proviso that IDso <_ l0mg/kg i.v., and preferably _< 5mglkg i.v. after 24 hour pre-treatment.
(iv) Determine oral bioavailabilii;y of compounds by pharmacokinetic analysis, activity in gerbil foot tapping assay following oral administration and/or by ability to inhibit cisplatin-induced emesis in ferrets (Assay 3); select compounds with IDso 5 3mg/kg p.o., and preferably IDso _< 1mg/kg p.o.
Particularly preferred compounds of use in the present invention are identified using steps (i) to (iv) followed by step (v):
(v) Determine activity of compounds in assays sensitive to conventional serotonergic drugs (inhibi.tion of pharmacologically evoked foot tapping in gerbils and/or inhibition of distress vocalisations in guinea-pig pups (Assay 4)). Select compounds with IDso < 20mg/kg, and preferably .
IDso _< lOmg/kg.
Yet further preferred compounds of use in the present invention may be selected from those compounds which satisfy the NK-1 receptor binding criteria of step (i) which, in addition, have < 5-fold shift in affinity when incubated in the presence of human serum albumin (HSA) to show non-specific protein binding.
One example of a NK-1 receptor antagonist of use in the present invention is the compound 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)-ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)-morpholine, the preparation of which is described in International Patent Specification No. WO 95/16679. In the aforementioned assays, this compound has the following activity:
human NK-1 receptor binding: ICso=O.lnM
gerbil foot-tapping (5 minx.): IDso=0.36mg/kg i.v.
gerbil foot-tapping (24 hrs.): IDso=0.33mg/kg i.v.
ferret emesis: IDoo<3mg/kg p.o.
guinea-pig vocalisation IDso=0.73mg/kg p.o.
(4hrs. pretreatment) Another example of a NK-1 receptor antagonist of use in the present invention is the compound 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(N, N-dimethylamino)methyl-1,2, 3-triazol-4-yl)methyl-3-(S)-phenylmorpholine, the preparation of which is described in International Patent Specification No. WO 95/18124. In the aforementioned assays, this compound has the following activity:
human NK-1 receptor binding: ICso=0.25nM
gerbil foot-tapping (5 rains.): ID~o=0.12mg/kg i.v.
gerbil foot-tapping (24 hrs.): IDSO=0.17mg/kg i.v.
guinea-pig vocalisation: IDso=0.5mg/kg s:c.
The following assay has been used to demonstrate the potentiation of the anorectic effects of dexfenfluramine in diet-induced obese mice when co-administered with a NK-1 receptor antagonist. __ Evaluation of the Interaction of NK-1 Antagonists and Anorectic Aeents on Food Intake and Bod Wei,~ht in Diet-Induced Obese Mice.
Mice:
Male C57BL/J mice were obtained from Jackson Labs at 3 weeks of age. Half the mice were maintained an a wet diet consisting of sweetened condensed milk and standard ground rodent chow (70%:30%, voi:vol).
Fresh wet chow was provided daily. These mice will be referred to as diet-induced obese (DIO). The other half was maintained on just ground rodent chow. These will be referred to as Non-Obese Littermates (NOL). Both food and water were supplied czd libiturrx. Mice were housed with a 12 hour light/dark cycle (4.OOam lights on) through out the course of the described studies.
Mice were weighed bi-weekly until a paint that both DIO and NOL
mice were weight stable (approximately 20 weeks). At this time, DIO mice weighed significantly more than NOL mice (p20.01). DIO mice also exhibited elevated insulin and glucose levels, as well as polyuria.
Food Intake:
(All food intake studies were peri:ormed on weight stable DIO mice.
Both food and water were available before treatment.) The effect that the anorectic agent, dexfenflur amine had on food intake in DIO mice was determined previously (ED~o = 3 mg/kg, ip}. The combined effect that [2-methoxy-5-(5-trifluoromethyl-tetrazol-1-y~1)-benzyl]-([2S,3Sj-2-phenyl-piperidin-3-yl)amine (GR205171) and dexfenfluramine WO. 98/47513 PCT/GB98/01161 -74- _ had on food consumption was examined by observing the resulting changes in food intake observed after treatment with dexfenfluramine, GR205171, or combinations of dexfenfluramine with decreasing doses of GR 205171.
Mice were randomly assigned to one of the following treatment groups:
~ SalinelSaline ~ Saline/GR 205171@20 mg/kg ~ Dexfenfluramine @ 3 mg/kg/ GR 205171@20 mg/kg Dexfenfluramine @ 3 mg/kg/ GR 205171@10 mg/kg ~ Dexfenfluramine @ 3 mg/kg/ GR 205171@ 5 mg/kg Mice received two injections approximately 30 wins apart. All injections were administered ip., in a volume of 0.2 ml between 3.OOpm and 3.30pm. Fresh chow was provided at the time of injection. Food intake was measured 16 hours post-injection for each mouse.
Results shown in Figure 1 are expressed as inhibition of food intake relative to that of saline treated animals.
Body Wed (All weight studies are performed on DIO mice) The effect that the combination of anorectic agents and NK-1 antagonists have on weight are examined using a chronic dosing regimen.
Mice are treated with dexfenfluramine, GR 205171, or combinations of dexfenfluramine with decreasing doses of GR 205171, similar to those used in the evaluation of food intake. Mice are dosed once daily, for 7 days with body weights being measured at the start and conclusion of the study.
Changes in body weight are compared with that of saline treated mice.
Concurrent daily food intake measurements may be taken at this time.
The following examples illustrate pharmaceutical compositions according to the invention.
These formulations may be prepared with separate active ingredients or with a combination of active ingredients in one composition.
In such combined preparations, the ratio of the NK-1 receptor antagonist and the anorectic agent will depend upon the choice of active ingredients.
EXAMPLE 1 Tablets containing 50-300mg of NK-1 antagonist and l5mg of dexfenfluramine Amount mg NK-1 antagonist 50.0 100.0 300.0 dexfenfluramine 15.0 15.0 15.0 Microcrystalline cellulose80.0 80.0 80.0 Modified food corn 80.0 80.0 80.0 starch Lactose 174.5 124.5 124.5 Magnesium Stearate 0.5 0.5 0.5 EXAMPLE 2 Tablets containin~,50-300mg of NK-1 antagonist and 60mg of fenfluramine Amount mg NK-1 antagonist 50.0 100.0 300.0 fenfluramine 60.0 60.0 60.0 Microcrystalline cellulose$0.0 80.0 80.0 Modified food corn starch80.0 80.0 80.0 Lactose 129.5 179.5 129.5 Magnesium Stearate 0.5 0.5 0.5 The active ingredients 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 remainder of the corn starch and the magnesium stearate. The resulting granulation is WO. 98/47513 PCT/GB98/01161 then compressed into tablets containing 50mg, 100mg and 300mg of the NK-1 receptor antagonist per tablet.
EXAMPLE 3 Parenteral injection Amount Active Ingredients 10 to 300mg Citric Acid Monohydrate 0.75mg Sodium Phosphate 4.5mg Sodium Chloride 9mg Water for injection to lOml The sodium phosphate, citric acid monohydrate and sodium chloride are dissolved in a portion of the water. The active ingredients are dissolved or suspended in the solution and made up to volume.
In a further embodiment of the present invention there is provided the use of a NK-1 receptor antagonist and an anorectic agent for the manufacture of a medicament for the treatment or prevention of obesity.
The present invention also provides a method for the treatment or prevention of obesity, which method comprises administration to a patient in need of such treatment an amount o:f a NK-1 receptor antagonist and an amount of an anorectic agent, such that together they give effective relief.
It will be appreciated that the NK-1 receptor antagonist and anorectic agent may be present as a combined preparation for simultaneous, separate or sequential use for the treatment or prevention of obesity. Such combined preparations may be, for example, in the form of a twin pack.
In a further or alternative aspect of the present invention, there is therefore provided a product comprising a NK-1 receptor antagonist and an anorectic agent as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of obesity.
In an alternative embodiment of the present invention there is provided the use of a NK-1 receptor antagonist and an anorectic agent for the manufacture of a medicament for the treatment or prevention of bulimia nervosa.
The present invention also provides a method for the treatment or prevention of bulimia nervosa, which method comprises administration to a patient in need of such treatment an amount of a NK-1 receptor antagonist and an amount of an anorecaic agent, such that together they give effective relief.
It will be appreciated that the NK-1 receptor antagonist and anorectic agent may be present as a combined preparation for simultaneous, separate or sequential use for the treatment or prevention of bulimia nervosa. Such combined preparations may be, for example, in the form of a twin pack.
In a further or alternative aspect of the present invention, there is therefore provided a product comprising a NK-1 receptor antagonist and an anorectic agent as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of bulimia nervosa.
In a further embodiment of the present invention there is provided the use of a NK-1 receptor antagonist and an anorectic agent for the manufacture of a medicament for the treatment or prevention of compulsive eating disorders.
The present invention also provides a method for the treatment or prevention of compulsive eating disorders, which method comprises administration to a patient in need of such treatment an amount of a NK-1 receptor antagonist and an amount of an anorectic agent, such that together they give effective relief.
It will be appreciated that the NK-1 receptor antagonist and anorectic agent may be present as a combined preparation for simultaneous, separate or sequential use for the treatment or prevention of compulsive eating disorders. Such combined preparations may be, for example, in the form of a twin pack.
In a further or alternative aspect of the present invention, there is therefore provided a product comprising a NK-1 receptor antagonist and an anorectic agent as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of compulsive eating disorders.
In an alternative embodiment of the present invention there is provided the use of a NK-1 receptor antagonist and an anorectic agent for the manufacture of a medicament for reducing the total body fat mass in an obese mammal, especially a human.
_ 7 .
The present invention also provides a method for reducing the total body fat mass in an obese mammal, especially a human, which method comprises administration to a patient in need of such treatment an amount of a NK-1 receptor antagonist and an amount of an anorectic agent, such that together they give effective relief. _ It will be appreciated that the NK-1 receptor antagonist and anorectic agent may be present as a combined preparation for simultaneous, separate or sequential use for reducing the total body fat mass in an obese mammal, especially a human. Such combined preparations may be, for example, in the form of a twin pack.
In a further or alternative aspect; of the present invention, there is therefore provided a product comprising a NK-1 receptor antagonist and an anorectic agent as a combined preparation for simultaneous, separate or sequential use in reducing the total body fat mass in an obese mammal, especially a human.
It will be appreciated that when using a combination of the present invention, both the NK-1 receptor antagonist and the anorectic agent will be administered to a patient, within a reasonable period of time. The compounds may be in the same pharmaceutically acceptable carrier and therefore administered simultaneously. They may be in separate pharmaceutical carriers such as conventional oral dosage forms which are taken simultaneously. The term "combination" also refers to the case where the compounds are provided in separate dosage forms and are administered sequentially. Therefore, by way of example, the anorectic agent may be administered as a tablet and then, within a reasonable period of time, the NK-1 receptor antagonist may be administered either as an oral dosage form such as a tablet or a fast-dissolving oral dosage form. By a "fast dissolving oral formulation" is meant, an oral delivery form which when placed on the tongue of a patient, dissolves within about 10 seconds.
_g-By "reasonable period of time" is meant a time period that is not in excess of about 1 hour. That is, for example, if the anorectic agent is provided as a tablet, then within one hour, the NK-1 receptor antagonist should be administered, either in the same type of dosage form, or another dosage form which provides effective delivery of the medicament.
The compositions of the present invention are useful for the prevention or treatment of eating disorders. As used herein, the term "eating disorders" includes obesity, bulimia nervosa and compulsive eating disorders.
As used herein "obesity" refers to a condition whereby a mammal has a Body Mass Index (BMI), which is calculated as weight per height squared (kg/m2), of at least 25.9. Conventionally, those persons with normal weight, have a BMI of 19.9 to less than 25.9.
The obesity herein may be due to any cause, whether genetic or environmental. Examples of disorders that may result in obesity or be the cause of obesity include overeating and bulimia, polycystic ovarian disease, craniopharyngioma, the Prader-Willi Syndrome, Frohlich's syndrome, Type II diabetes, GH-deficient subjects, normal variant short stature, Turner's syndrome, and other pathological conditions showing reduced metabolic activity or a decrease in resting energy expenditure as a percentage of total fat-free mass, e.g, children with acute lymphoblastic leukemia.
"Treatment" refers to reducing the BMI of the mammal to less than about 25.9, and maintaining that weight for at least 6 months. The treatment suitably results in a reduction in food or calorie intake by the mammal.
"Prevention" refers to preventing obesity from occurring if the treatment is administered prior to the onset of the obese condition.
Moreover, if treatment is commenced in already obese subjects, such treatment is expected to prevent, or to prevent the progression of, the medical sequelae of obesity, such as, e.g., arteriosclerosis, Type II
diabetes, WO 98/4'I513 PCT/GB98/01161 _g_ polycycstic ovarian disease, cardiovascular diseases, osteoarthritis, dermatological disorders, hypertension, insulin resistance, hypercholesterolezriia, hypertriglyceridemia, and cholelithiasis.
Thus, in one aspect, this invention relates to the inhibition and/or complete suppression of lipogenesis in obese mammals, i.e., the excessive accumulation of lipids in fat cells, which is one of the major features of human and animal obesity, as well as loss of total body weight. In another aspect, the invention ameliorates the conditions that are a consequence of the disease, such as preventing or arresting the progression of polycystic ovarian disease so that the patient is no longer infertile, and increasing the insulin sensitivity andlor decreasing or eliminating the need or usage of insulin in a diabetic patient, e.g., one with adult-onset diabetes or Type II diabetes.
"Mammals" include animals of economic importance such as bovine, ovine, and porcine animals, especially those that produce meat, as well as domestic animals, sports animals, zoo animals, and humans, the latter being preferred.
The compositions of the present invention are especially useful for the treatment of or prevention of eating disorders where the use of an anorectic agent is generally prescribed. By the use of a combination of a NK-1 receptor antagonist and an anorectic agent in accordance with the present invention, it is now also possible to treat or prevent eating disorders in patients for whom conventional anorectic therapy might not be wholly successful or where dependance upon the anorectic therapy is prevalent.
Suitable anoretic agents of use in the combinations of the present invention include, but are not limited t;o, aminorex, amphechloral, amphetamine, benzphetamine, chlorphentermine, clobenzorex, cloforex, clominorex, clortermine, cyclexedrine, dexfenfluramine, dextroamphetamine, diethylpropion, diphemethoxidine, N-ethylamphetamine, fenbutrazate, fenfluramine, fenisorex, fenproporex, fludorex, fluminorex, furfurylmethylamphetamine, levamfetamine, levophacetoperane, mazindol, mefenorex, metamfepramone, methamphetamine, norpseudoephedrine, pentorex, phendimetrazine, phenmetrazine, phentermine, phenylpropanolamine, picilorex and sibutramine; and pharmaceutically acceptable salts thereof.
Particularly preferred anorectic agents include amphetamine and derivatives thereof such as amphetamine, benzphetamine, chlorphentermine, clobenzorex, cloforex, clotermine, dexfenfluramine, dextroamphetamine, diethylpropion, N ethylamphetamine, fenfluramine, fenproporex, furfurylmethylamphetamine, levamfetamine, mefenorex, metamfepramone, methamphetamine, norpseudoephedrine, pentorex, phendimetrazine, phenmetrazine, phentermine, phenylpropanolamine, picilorex and sibutramine; and pharmaceutically acceptable salts thereof.
A particularly suitable class of anorectic agent are the halogenated amphetamine derivatives, including chlorphentermine, cloforex, clortermine, dexfenfluramine, fenfluramine, picilorex and sibutramine;
and pharmaceutically acceptble salts thereof;
Particularly preferred halogenated amphetamine derivatives of use in the present invention include: fenfluramine and dexfenfluramine, and pharmaceutically acceptable salts thereof.
Another particularly preferred anorectic agent is phentermine.
NK-1 receptor antagonists of use in the present invention are described in published European Patent Specification Nos. 0 360 390, 0 394 989, 0 429 366, 0 443 132, 0 482 539, 0 512 901, 0 512 902, 0 514 273, 0 514 275, 0 517 589, 0 520 555, 0 522 808, 0 528 495, 0 532 456, 0 533 280, 0 536 817, 0 545 478, 0 577 394, 0 590 152, 0 599 538, 0 610 793, 0 634 402, 0 686 629, 0 693 489, 0 694 535, 0 699 655, 0 699 674, 0 707 006, 0 708 101, 0 714 891, 0 723 959, 0 733 632 and 0 776 893; and in International Patent Specification Nos. 90/05525, 90/05729, 91/09844, 91/18899, 92/01688, 92/06079, 92/12151, 92/15585, 92/17449, 92/20661, 92/20676, 92/21677, 93/00330, 93/00331, 93/01159, -lL-93/01165, 93/01169, 93/01170, 93/06099, 93/09116, 93/10073, 93/14113, 93/18023, 93/19064, 93/21155, 9321181, 93/23380, 93/24465, 94/01402, 94/02461, 94/03429, 94/03445, 94/04494, 94/04496, 94/05625, 94/07843, 94/10165, 94/10167, 94/10168, 94/101'd0, 94/11368, 94/13639, 94/13663, 94/14767, 94/15903, 94/19320, 94/19323, 94/20500, 94/26735, 94/26740, 94/29309, 95/02595, 95/04040, 95/04042, 95/06645, 95/07886, 95/07908, 95/08549, 95/11880, 95/14017, 95/1537_1, 95/16679, 95/17382, 95/18124, 95/18129, 95/19344, 95/20575, 95/21819, 96/22525, 95/23798, 95/26338, 95/28418, 95/30674, 95/30687, 96/05193, 96/05203, 96/06094, 96/07649, 96//0562, 96/16939, 96/18643, 96/20197, 96/21661, 96/29304, 96/29317, 96/29326, 96/29328, 96/31214, 96/32385, 96/37489, 97/01553, 97/01554, 97/03066, 97/08144, 97/14671, 97//7362, 97/18206, 97/19084, 97/19942 and 97/21702; and in British Patent Specification Nos. 2 266 529, 2 268 931, 2 269 170, 2 269 590, 2 271 774, 2 292 144, 2 293 168, 2 293 169, and 2 302 689.
Particularly preferred NK-1 receptor antagonists are those described in European Patent Specific<~tion No. 0 577 394, i.e. compounds of formula (I):
(I) y R
or a pharmaceutically acceptable salt thereof, wherein:
Rl is selected from the group consisting of:
(1) hydrogen;
(2) C1-salkyl, unsubstituted or substituted with one or more of the substituents selected from:
(a) hydroxy, (b) oxo, (c) C1-ealkoxy, (d) phenyl-Ci.salkoxy, (e) phenyl, (f) -CN, (g) halo, (h) -NR~RI~, wherein R9 and Rl~ are independently __ selected from:
(i) hydrogen, (ii) C1-calkyl, (iii) hydroxy-Ci_calkyl, and (iv) phenyl, (i) -NR~COR1~, wherein R~ and R1~ are as defined above, (j) -NR9COzRl~, wherein R9 and Rl~ are as defined above, (k) -CONR9R1~, wherein R9 and Rl~ are as defined above, (1) -COR9, wherein R9 is as defined above, (m) -COzR9, wherein R~ is as defined above, (n) heterocycle, wherein the heterocycle is selected from the group consisting of:
(A) benzimidazolyl, (B) benzofuranyl, (C) benzthiophenyl, (D) benzoxazolyl, (E) furanyl, (F) imidazolyl, (G) indolyl, (H) isoxazolyl, (I) isothiazolyl, (J) oxadiazolyl, (K) oxazolyl, (L) pyrazinyl, (M) pyrazolyl, (N) pyridyl, WO 98/47513 PCT/GB98l01161 -13- _ (O} pyrimidyl, (P) pyrrolyl, (fa) quinolyl, (R) tetrazolyl, (S) thiadiazolyl, (T) thiazolyl, (U) thienyl, triazolyl, (V~ azetidinyl, (X) 1,4-dioxanyl, hexahydroazepinyl, (Z) oxanyl, (AA) piperazinyl, (AB) piperidinyl, (AC) pyrrolidinyl, (AD) tetrahydrofuranyl, and (AE) tetrahydrothienyl, and wherein the heterocylcle is unsubstituted or substituted with one or more substituent(s) selected from:
(i) Ci.salkyl, unsubstituted or substituted with halo, -CFs, -OCHs, or phenyl, (ii) C1-salkoxy, (iii) oxo, (iv) hydroxy, (v) thioxo, (vi) -SRS, wherein R'' is as defined above, (vii) halo, (viii) cyano, (ix) phenyl, {x) trifluoromethyl, (xi) -(CHz)m-NR9Rlo, wherein m is 0, 1 or 2, and Ro and Rlo are as defined above, (xii) -NRgCORlo, wherein R~ and Rlo are as defined above, (xiii) -CONR9Rlo, wherein R9 and Rlo are as defined above, (xiv) -COzR~, wherein R9 is as defined above, and (xv) -(CH2)m-OR9, wherein m and R9 are as defined above;
(3) Cz-salkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:
(a) hydroxy, (b) oxo, (c) Ci-salkoxy, (d) phenyl-C1-salkoxy, (e) phenyl, {f) -CN, (g) halo, (h) -CONR9Rls, wherein Ro and Rlo are as defined above, (i) -COR9, wherein Ro is as defined above, (j) -COzR~, wherein R9 is as defined above, (k) heterocycle, wherein the heterocycle is as defined above;
(4) CZ-salkynyl;
(5) phenyl, unsubstitued or substituted with one or more of the substituent(s) selected from:
(a) hydroxy, (b) Ci-salkoxy, (c) C i-salkyl, (d) C2-salkenyl, (e) halo, -CN, (g) -NOa, (h) -CFs, (i) -(CH2)m-NR9R1~, wherein m, Rs and Rls are as defined above, (j) -NR~CORI~, wherein R~ and Rl~ are as defined above, (k) -NR9COZRls, wherein R~ and Rz~ are as defined above, (1) -CONRsRIa, wherein R9 and Rls are as defined above, (m) -COzNR~RIS, wherein R~ and Rls are as defined above, (n) -COR9, wherein R~ is as defined above, (o) -COzR9, wherein R9 is as defined above;
R2 and R3 are independently selected from the group consisting of:
(1} hydrogen;
(2) Ci-salkyl, unsubstituted or substituted with one or more of the substituents selected from:
(a) hydroxy, (b) oxo, (c) C1-salkoxy, (d) phenyl-C1-salkoxy, (e) phenyl, (fj -CN, (g} halo, (h) -NR9Rls, wherein R"~ and Rls are independentlv selected from:
(i) -NR~CORIS, wherein R9 and Rls are as defined above, (j) -NR~COzRIS, wherein R9 and R1~ are as defined above, (k) -CONR~Rls, wherein R~ and Rls are as defined above, (1) -COR9, wherein R~ i.s as defined above, and (m) -COzR9, wherein R~ is as defined above;
(3) Cz.salkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:
(a) hydroxy, (b) oxo, (c) Ci-salkoxy, (d) phenyl-C1-salkoxy, (e) phenyl, (f) -CN, (g) halo, .
(h) -CONR9R1~ wherein R9 and Rl~ are as defined above, (i) -COR9, wherein R~ is as defined above, (j) -COzR9, wherein R9 is as defined above;
(4) C2-salkynyl;
(5) phenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:
(a) hydroxy, (b) C i-salkoxy, (c) Ci-salkyl, (d) Cz-salkenyl, (e) halo, (f) -CN, (g) -NOz (h) -CFs, (i) -(CHZ)m-NR9Rls, wherein m, Rs and Rls are as defined above, (j) -NR9COR1~, wherein R9 and Rl~ are as defined above, (k) -NR9C02R1~, wherein R9 and Rl~ are as defined above, (1) -CONR~Rls, wherein Rs and Rls are as defined above, (m) -COaNR9Rl~, wherein R9 and Rl~ are as defined above, (n) -CORs, wherein R9 is as defined above, (o) -COzR~, wherein Rs is as defined above;
and the groups R1 and RZ may be joined together to form a heterocyclic ring selected from the group consisting of:
(a) pyrrolidinyl, (b) piperidinyl, (c) pyrrolyl, (d) pyridinyl, (e) imidazolyl, (f) oxazolyl, and (g) thiazolyl, and wherein the heterocyclic ring is unsubstituted or substituted with one or more substituent(s) selected from:
(i) C l.salkyl, (ii) oxo, (iii) Ci-salkoxy, (iv) -NR~RIS, wherein 1~,~ and Rl~ are as defined above, (v) halo, and (vi) trifluoromethyl;
and the groups RZ and R3 may be joined together to form a carbocyclic ring selected from the group consisting of:
(a) cyclopentyl, (b) cyclohexyl, (c) phenyl, and wherein the carbocyclic ring is unsubstituted or substituted with one or more substituents selected from:
(i) C1-salkyl, (ii) C1-salkoxy, (iii) -NRsRl~, wherein Fps and Rls are as defined above, (iv) halo, and (v) trifluoromethyl;
and the groups R2 and R3 may be joined together to form a heterocyclic ring selected from the group consisting of:
(a) pyrrolidinyl, (b) piperidinyl, (c) pyrrolyl, (d) pyridinyl, (e) imidazolyl, (f) furanyl, (g) oxazolyl, (h) thienyl, and (i) thiazolyl, and wherein the heterocyclic ring is unsubstituted or substituted with one or more substituent(s) selected from:
(i) C1_~alkyl, (11) OXO, (iii) Ci.~alkoxy, (iv) -NR~RI~, wherein R~ and Rl~ are as defined above, (v) halo, and (vi) trifluoromethyl;
X is selected from the group consisting of:
(1) -O-, (2) -S-, (3) -SO-, and (4) -SOZ-;
R4 is selected from the group consisting o~
(1) R~
i R' ,Y w Ra (2) -Y-C1-salkyl, wherein alkyl is unsubstituted or substituted with one or more of the substituents selected from:
- 1~ _ _ (a) hydroxy, (b) oxo, (c) C1-salkoxy, (d) phenyl-Ci.3alkoxy, (e) phenyl, (fj -CN, (g) halo, (h) -NR9R10, wherein 1~,9 and R10 are as defined above, (i) -NRsCORIS, wherein R~ and Rls are as defined above, (j) -NR9COzRls, wherein R~ and Ri~ are as defined above, (k) -CONRsRIS, wherein R9 and R1~ are as defined above, (1) -COR9, wherein R~ is as defined above, (m) -COzR9, wherein R9 is as defined above;
(3) -Y-CZ.salkenyl, wherein the a.lkenyl is unsubstituted or substituted with one or more of the substituent(s) selected from:
(a) hydroxy, (b) oxo, (c) Ci-salkoxy, (d) phenyl-Ci-aalkoxy, (e) phenyl, (fj -CN, (g) halo, (h) -CONRsRIS, wherein R~ and Rls are as defined above, (i) -CORs, wherein R~ is as defined above, (j) -COzR~, wherein Rs is as defined above, (4) -O(CO)-phenyl, wherein the phenyl is unsubstituted or substituted with one or more of Rs, R7and R8;
Re is selected from the group consisting of:
(1) phenyl, unsubstituted or substituted with one or more of Rll, Riz and Rls ;
(2) C1-salkyl, unsubstituted or substituted with one or more of the substituent(s) selected from:
(a) hydroxy, (b) oxo, (c) C1-salkoxy, (d) phenyl-Ci-salkoxy, (e) phenyl, (fj -CN, (g) halo, (h) -NR~RI~, wherein R~ and Rls are as defined above, (i) -NR~COR1~, wherein R~ and Rls are as defined above, (j) -NR9COzRl~, wherein Rs and Rls are as defined above, (k) -CONR9R1~, wherein R9 and Rl~ are as defined above, (1) -COR9, wherein R~ is as defined above, (m) -COaR9, wherein R~ is as defined above;
(3) Cz-salkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:
(a) hydroxy, (b) oxo, (c) C1-salkoxy, (d) phenyl-C1-salkoxy, (e) phenyl, (fj -CN, (g) halo, (h) -CONR~RI~, wherein R9 and Rls are as defined above, (i) -CORs, wherein Rs is as defined above, (j) -COaR9, wherein R~ is as defined above;
(4) heterocycle, wherein the heterocycle is as defined above;
Rs, R7 and Rg are independently selected from the group consisting of:
(1) hydrogen;
(2) C1-salkyl, unsubstituted or substituted with one or more of the substituents selected from:
(a) hydroxy, (b) oxo, (c) Ci-salkoxy, __ (d} phenyl-Ci-salkoxy, (e) phenyl, (fj -CN, (g) halo, (h) -NR9Rlo, wherein Rs and Rla are as defined above, (i) -NR9CORla, wherein Rs and Rl~ are as defined above, (j) -NR9C02R1~, wherein R9 and RI~ are as defined above, (k) -CONR9R1~, wherein R9 and Rl~ are as defined above, (1) -COR9, wherein R9 is as defined above, and (m) -COaRs, wherein R'~ is as defined above;
(3} Ca-salkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:
(a) hydroxy, (b) oxo, (c) C1-salkoxy, (d) phenyl-Cl.salkoxy, (e) phenyl, (fj -CN, (g) halo, (h) -CONR9Rlo wherein R9 and Rl~ are as defined above, (i) -COR9 wherein Rs is as defined above, (j) -COZR9, wherein R~ is as defined above;
(4) CZ-salkynyl;
(5) phenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:
(a) hydroxy, (b) C 1-salkoxy, (c) C l.salkyl, (d) Cz-salkenyl, (e) halo, (fj -CN, (g) -NOa, (h) -CFs, (i) -(CH2)m-NR9Rls, wherein m, Rs and Ri~ are as defined above, (j) -NR9CORls, wherein R~ and Rls are as defined above, (k) -NRsCOzRI~, wherein R9 and Rla are as defined above, (1) -CONR~Rl~, wherein Rs and Ri~ are as defined above, (m} -COaNR9Rl~, wherein R9 and Rl~ are as defined above, (n) -COR9, wherein R9 is as defined above;
(o) -COzR9, wherein R9 is as defined above;
(6) halo, (7) - CN, (8) - CFs, (9) - NOz, (10) -SR14, wherein R14 is hydrogen or Ci-salkyl, (11) -SOR14, wherein R14 is as defined above, (12) -SOzRl4, wherein R14 is as defined above, (13) NR~CORIS, wherein R9 and Rls are as defined above, (14) CONR~CORl~, wherein R9 and Rl~ are as defined above, (15) NR9R1~, wherein R9 and Rl~ are as defined above, (16) NR~COaRis, wherein R~ and Rl~ are as defined above, (17) hydroxy, (18) Cl.salkoxy, (19) COR9, wherein R9 is as defined above, (20) COzRs, wherein R9 is as defined above, Rii, Riz and R13 are independently selected from the definitions of R~, R7 and R8, or -OX;
Y is selected from the group consisting of:
(1) a single bond, __ (2) -O-, (3) -S-, (4) -CO-, (5) -CHZ-, (6) -CHRlb-, and (7) -CRl5Rm-, wherein Rl~ and ltl~ are independently selected from the group consisting of:
(a) Ci-salkyl, unsubstii;uted or substituted with one or more of the substituents selected from:
(i) hydroxy, (ii) oxo, (iii) Ci-salkoxy, (iv) phenyl-C1-salkoxy, (v) phenyl, (vi) -CN, (vii) halo, (viii) -NR9R1~, wherein R~ and Rl~ are as defined above, (ix) -NR~COR1~, wherein R~ and Rl~ are as defined above, (x) -NR~COzRI~, wherein R9 and Rl~ are as defined above, (xi) -CONR9R1~, wherein R~ and Rl~ are as defined above, (xii) -CORD, wherein R~ is as defined above, and (xiii) -COzR~, wherein R'3 is as defined above;
(b) phenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:
(i) hydroxy, (ii) C i-salkoxy, (iii) C i.salkyl, (iv) Cz-salkenyl, (v) halo, (vi) -CN, (vii) -N02, (viii) -CFa, (ix) -(CH2)m-NR9R1~, wherein m, Rs and Rl~ are as defined above, (x) -NR9COR1~, wherein Rs and Rl~ are as defined above, (xi) -NR9COZR1~, wherein R9 and Rl~ are as defined above, (xii) -CONR9R1~, wherein R9 and Rl~ are as defined above, (xiii) -COZNR9R1~, wherein R9 and Rl~ are as defined above, (xiv) -COR9, wherein Rs is as defined above, and (xv) -COzR~, wherein R9 is as defined above;
Z is selected from:
(1) hydrogen, (2) Ci-4alkyl, and (3) hydroxy, with the proviso that if Y is -O-, Z is other than hydroxy, or if Y is -CHR15-, then Z and R15 may be joined together to form a double bond.
Particularly preferred compounds of formula (I) are those wherein:
Rl is selected from the group consisting of:
(1) Ci-salkyl, substituted with one or more of the substituents selected from:
(a) heterocycle, wherein the heterocycle is selected from the group consisting o~
(A) benzimidazolyl, (B) imidazolyl, (C) isoxazolyl, (D) isothiazolyl, (E) oxadiazolyl, (F) pyrazinyl, (G) pyrazolyl, (H) pyridyl, (I) pyrrolyl, __ (J) tetrazolyl, (K) thiadiazolyl, (L) triazolyl, and (M) piperidinyl, and wherein the heterocycle is unsubstituted or substituted with one or more substituent(s) selected from:
(i) C1-salkyl, unsubstituted or substituted with halo, -CFs, -OCHa, or phenyl, (ii) C i-salkoxy, (iii) oxo, (1V) th10X0, (v) cyano, (Vl) -SCH3, (vii) phenyl, (viii) hydroxy, (ix) trifluoromethyl, (x) -(CHa)m-NR9Rlo, wherein m is 0, 1 or 2, and R9 and Rlo areindependently selected from:
(I) hydrogen, (II} C1-salkyl, (III} hydroxyCl-salkyl, and (I~ phenyl, (xi) -NRoCORIO, wherein R9 and Rlo are as defined above, and (xii) -CONRsRlo, wherein R9 and Rlo are as defined above, R2 and R3 are independently selected from the group consisting of:
(1) hydrogen;
(2) Ci-salkyl (3) C2-salkenyl, and (5) phenyl;
X is -O-;
R4 is Rs i R' ,Y ~ ' Rs R~ is phenyl, unsubstituted or substituted with halo;
R~, R7 and R8 are independently selected from the group consisting of:
(1) hydrogen, {2) C1-salkyl, (3) halo, and (4) -CFs;
Y is -O-; and Z is hydrogen or Cl.4alkyl;
and pharmaceutically acceptable salts thereof.
Particularly preferred compounds of formula (I) are:
4-(3-(1,2, 4-triazolo)methyl)-2(S)-(3, 5-bis(trifluoromethyl)benzyloxy)-3(S)-phenyl-morpholine;
4-(3-(1,2,4-triazolo)methyl)-2(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3(R)-phenyl-morpholine;
4-(3-(5-oxo-1H,4H-1, 2,4-triazolo)methyl)-2(S)-(3, 5-bis(trifluoromethyl)benzyloxy)-3(S)-phenyl-morpholine; and 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-{S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine; or a pharmaceutically acceptable salt thereof.
Further preferred NK-1 receptor antagonists are those described in International (PCT) Patent Specification No. WO 95/18124, i.e. compounds of formula (II):
R' RZ _ Rsa O O
R3 (II) sb N i R i -~~R4 ,X
Rs Rs or a pharmaceutically acceptable salt or prodrug thereof, wherein R1 is hydrogen, halogen, C1-salkyl, C1-salkoxy, CFs, NOz, CN, SRa, SORa, SOaRa, COzRa, CONRaRb, CZ.salkenyl, Cz-salkynyl or Ci-4alkyl substituted by Cl.4alkoxy, where Ra and Rb each independently represent hydrogen or C1-4alkyl;
R2 is hydrogen, halogen, Cl.salkyl, C1-salkoxy substituted by C1-4alkoxy or CFs;
R3 is hydrogen, halogen or CF3;
R4 is hydrogen, halogen, Ci-salkyl, Cl.salkoxy, CFs, NOz, CN, SRe, SORa, SOzRa, C02Ra, CONRaRb, Ca-salkenyl, C2.salkynyl or C1-alkyl substituted by C1-4alkoxy, where R$ and Rb each independently represent hydrogen or C1-4alkyl;
R5 is hydrogen, halogen, C1-salkyl, Ci-salkoxy substituted by C1-4alkoxy or CFs;
Rs is a 5-membered or 6-membe:red heterocyclic ring containing 2 or 3 nitrogen atoms optionally substituted by =O, =S or a Cl.4alkyl group, and optionally substituted by a group of the formula ZNR7R8 where Z is C1-salkylene or Cs.scycloalkylene;
R7 is hydrogen, Cl.4alkyl, Cs-~cyc:loalkyl or Cs-7cycloalkylC~_.~alkyl, or CZ-4alkyl substituted by Ci-4alkoxy or hydroxyl;
R$ is hydrogen, Ci-4alkyl, Cs_7cycloalkyl or Cs-7cyclo-alkylCi.4alkyl, or C2-4alkyl substituted by one or two substituents selected from Ci-4alkoxy, hydroxyl or a 4, 5 or 6 membered heteroaliphatic ring containing one or two heteroatoms selected from N, O and S;
or R7, R8 and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms, optionally substituted by a hydroxy group, and optionally containing a double bond, which ring may optionally contain an oxygen or sulphur ring atom, a group S(O) or S(O)z or a second nitrogen atom which will be part of a NH or NR~ moiety where R~ is C1-4alkyl optionally substituted by hydroxy or C1-4alkoxy;
or R7, R8 and the nitrogen atom to which they are attached form a non-aromatic azabicyclic ring system of 6 to 12 ring atoms;
or Z, R7 and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms which may optionally contain an oxygen ring atom;
R~~ and R9b are each independently hydrogen or C1-4alkyl, or Rya and Rib are joined so, together with the carbon atoms to which they are attached, there is formed a Cs-7 ring;
X is an alkylene chain of 1 to 4 carbon atoms optionally substituted by oxo; and Y is a Ci-4alkyl group optionally substituted by a hydroxyl group;
with the proviso that if Y is Ci-4alkyl, R~ is susbstituted at least by a group of formula ZNR7R$ as defined above.
Particularly preferred compounds of formula (II) are those of formula (IIa) and pharmaceutically acceptable salts thereof:
A' Y
O O~ I ~ z C A
N
i RsiX w s A
(IIa) wherein:
A1 is fluorine or CFs;
AZ is fluorine or CFa;
A3 is fluorine or hydrogen;
and X, Y and R~ are as defined in relation to formula (II).
Particularly preferred compounds of formula (II) include:
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(dimethylamino) methyl-1,2,3-triazol-4-yl)methyl-3-(S)-phenylmorpholine;
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(dimethylamino) methyl-1,2,3-triazol-4-yl)methyl-3-(S)-(4-fluorophenyl)morpholine;
and pharmaceutically acceptable salts thereof.
Further preferred NK-1 receptor antagonists are those described in European Patent Spec~cation No. WO 95/23798, i.e. compounds of formula (III):
Rs i R3 X Y w , R' Rz N . / Z R$ (III) Rm (O)a A , Ri3 Ria or a pharmaceutically acceptable salt thereof, wherein:
WO 98/47513 PCTlGB98/01161 RZ and R3 are independently selected from the group consisting of (1) hydrogen, (2) Ci-salkyl, unsubstituted or substituted with one or more of the substituents selected from:
(a) hydroxy, (b) oxo, (c) C1-salkoxy, (d) phenyl-C1-salkoxy, (e) phenyl, (f) -CN, (g) halo, (h) -NR~Rls, wherein R9 and Rls are independently selected from:
(i) hydrogen, (ii) C1-salkyl, (iii) hydroxy-C1-salkyl, and (iv) phenyl, (i) -NR~COR1~, wherein R~ and Rls are as defined above, (j) -NR~C02Rls, wherein R9 and R1~ are as defined above, (k) -CONR~RIS, wherein Rs and Rls are as defined above, (1) -COR9, wherein Rs is as defined above, and (m) -COzRs, wherein R~ is as defined above;
(3) Cz-salkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:
(a) hydroxy, (b) oxo, (c) Ci-salkoxy, (d) phenyl-C1-salkoxy, (e) phenyl, (f) -CN, (g) halo, WO 98!47513 PCT/GB98101161 (h) -CONR9R1~ wherein R9 and Rl~ are as defined above, (i) -CORs wherein R9 is as defined above, (j) -C02R~, wherein R~ is as defined above;
(4) Cz-salkynyl;
(5) phenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:
(a) hydroxy, (b) C1-salkoxy, (c) Ci-salkyl, (d) Cz-salkenyl, (e) halo, (f) -CN, (g} -NO2, (h) -CFa, (i) -(CHz)m-NR9R1~, wherein m, Rs and Rl~ are as defined above, (j) -NR9COR1~, wherein Rs and R1~ are as defined above, (k) -NR9COzRla, wherein R~ and Rl~ are as defined above, (1) -CONR9R1~, wherein R~ and Rl~ are as defined above, (m) -C02NRsRl~, wherein Rs and Rl~ are as defined above, (n) -COR9, wherein Rs is as defined above, (o) -COzRs, wherein Rs is as defined above;
and the groups RZ and R3 may be joined together to form a carbocyclic ring selected from the group consisting of:
(a) cyclopentyl, (b) cyclohexyl, - (c) phenyl, and wherein the carbocyclic ring is unsubstituted or substituted with one or more substituents selected from:
(i) C 1-salkyl, (ii) Ci-salkoxy, (iii) -NR~RIS, wherein R~ and Rls are as defined above, (iv) halo, and (v) trifluoromethyl;
and the groups RZ and R3 may be joined together to form a heterocyclic ring selected from the group consisting of:
(a) pyrrolidinyl, (b) piperidinyl, (c) pyrrolyl, (d) pyridinyl, (e) imidazolyl, (f) furanyl, (g) oxazolyl, (h) thienyl, and (i) thiazolyl, and wherein the heterocyclic ring is unsubstituted or substituted with one or more substituent(s) selected from:
(i) Ci-salkyl, (ii) oxo, (iii) C1-salkoxy, (iv) -NReRI~, wherein Rs and Rls are as defined above, (v) halo, and (vi) trifluoromethyl;
Rs, R7 and R8 are independently selected from the group consisting of:
(1) hydrogen;
(2) Cl.salkyl, unsubstituted or substituted with one or more of the substituents selected from:
(a) hydroxy, (b) oxo, (c) C i-salkoxy, (d) phenyl-C1-salkoxy, (e) phenyl, . (fj -CN, (g) halo, _.
(h) -NR,sg,io, wherein R~ and Rls are as defined above, (i) -NR9COR1~, wherein Rs and Rl~ are as defined above, (j) -NR9C02R1o, wherein Rs and Rl~ are as defined above, (k) -CONR9Rlo, wherein R9 and Rla are as defined above, (1) -CORs, wherein Rs is as defined above, and (m) -COaRs, wherein Rs is as defined above;
(3) Cz-salkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:
(a) hydroxy, (b) oxo, (c) C l.salkoxy, (d) phenyl-C1-salkoxy, (e) phenyl, (f) -CN, (g) halo, (h) -CONR9R1~ wherein Rs and Rls are as defined above, (i) -CORs wherein R9 is as defined above, (j) -C02Rs, wherein R'~ is as defined above;
(4) Cz-salkynyl;
(5) phenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:
(a) hydroxy, (b) C1-salkoxy, (c) Ci-salkyl, (d) Ca.salkenyl, (e) halo, WO 98/47513 PCTlGB98/01161 (~ -CN, (g) -NOz, (h) -CFs, (i) -(CHz)m-NR9Rls, wherein m, Rs and Rl~ are as defined above, (j) -NR9COR1~, wherein R9 and Rl~ are as defined above, (k) -NR~COaRi~, wherein R9 and Rls are as defined above, (1) -CONR9R1~, wherein R9 and R1~ are as defined above, (m) -COzNR9Rl~, wherein R9 and Rl~ are as defined above, (n) -COR9, wherein R~ is as defined above, (o) -COzR9, wherein R~ is as defined above;
(6) halo, (7) -CN, (8) -CFs, (9) -NOz, (10) -SR14, wherein R14 is hydrogen or Cl.salkyl, (I1) -SOR14, wherein R14 is as defined above, (12) -SOzRl4, wherein R14 is as defined above, (13) NR9COR1~, wherein Rs and Rl~ are as defined above, (14) CONR9CORls, wherein R~ and Rls are as defined above, (15) NR9R1~, wherein R9 and Rl~ are as defined above , (16) NR9C02R1~, wherein R9 and Rl~ are as defined above, (17) hydroxy, (18) Ci-salkoxy, {19) COR9, wherein R9 is as defined above, (20) COzR9, wherein R~ is as defined above, (21) 2-pyridyl, (22) 3-pyridyl, (23) 4-pyridyl, (24) 5-tetrazolyl, (25) 2-oxazolyl, and (26) 2-thiazolyl;
Rll, R12 and R13 are independently selected from the definitions of Rs, R7 and R8, or -OX;
_.
A is selected from the group consisting of:
(1) C1-salkyl, unsubstituted or substituted with one or more of the substituents selected from:
(a) hydroxy, to (b) oxo, (c) C1-salkoxy, (d) phenyl-C1-3alkoxy, (e) phenyl, (f) -CN, (g) halo, wherein halo i.s fluoro, chloro, bromo or iodo, (h) -NR9R1~, wherein R~ and Rl~ are as defined above, (i) -NR9COR1~, wherein R~ and Rl~ are as defined above, (j) -NR~COzRI~, wherein R~ and Rl~ are as defined above, (k) -CONR9R1~, wherein R9 and Rl~ are as defined above, (1) -CORD, wherein Rs :is as defined above, and (m) -COzR~, wherein R~ is as defined above;
(2) C2-salkenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:
(a) hydroxy, (b) oxo, (c) Cl.salkoxy, (d) phenyl-C1-salkoxy, (e) phenyl, (fj -CN, (g) halo, (h) -CONR9R1~ wherein R~ and R1~ are as defined above, (i) -CORD wherein R~ is as defined above, and (j) -COzR~, wherein R~ is as defined above; and (3) C2-salkynyl;
B is a heterocycle, wherein the heterocycle is selected from the group consisting of:
N N 'X X~ g X~ H
N-N N-N N-N
N O ~N~O WN~O WN~S
X H
N_~ X
N-N N-N _ X
S ~ S / O,X N N
X ~N~S X
~1 N
N-N
N_NX ~_~ ~ N / ,N
N N ~N.
N i X X X
X ~ X
N=N ' ' ,N- / N~ ~C / N
N X ~~C N
X
rHr ~ / ' _.
.~~ / .X / X -N S ~ ~ . ~ S- N
X N N X
-~N,X N ~~ N
X N X
N N~ N
i i i X X X
and wherein the heterocycle may be substituted in addition to -X with one or more substituent(s) selected from:
(i) C1-salkyl, unsubstituted or substituted with halo, -CFs, -OCHs, or phenyl, (ii) C i.calkoxy, (iii) oxo, (iv) hydroxy, (v) thioxo, (vi) -SRo, wherein R9 is as defined above, (vii) halo, (viii) cyano, . (ix) phenyl, (x) trifluoromethyl, (xi) -(CHz)m-NR9Rlo, wherein m is 0, 1 or 2, and R~ and Rlo are as defined above, -3 - _ (xii) -NR9COR1~, wherein R9 and Rl~ are as defined above, (xiii) -CONR9R1~, wherein R9 and Rl~ are as defined above, (xiv) -COZR9, wherein R~ is as defined above, and (xv) -(CH2)m-OR9, wherein m and R9 are as defined above;
pis0orl;
X is selected from:
(a) -PO(OH)O- ~ M+, wherein M+ is a pharmaceutically acceptable monovalent counterion, (b) -PO(O-)2 ~ 2M+, (c) -PO(O-)2 ~ D2+, wherein DZ+ is a pharmaceutically acceptable divalent counterion, (d) -CH(R4)-PO(OH)O- ~ M+, wherein R4 is hydrogen or Ci-aalkyl, (e) -CH(R,4)-PO(O-)2 ~ 2M+, (fj -CH(R4)-PO(O-)a ~ DZ+~
(g) -SOs- ~ M+, (h) -CH(R4)-SOs- ~ M+, (i) -CO-CH2CHz-C02- ~ M+, (j) -CH(CHs)-O-CO-R5, wherein R~ is selected from the group consisting o~
( ) \ O ~~ NH3+ M
HZ+ M.
(u) \O~.N.Rs \O~COZ M+
CO 2 M+
(iv) \ O CO . M+
2 ' \ ~~ COa (v) O
C02 M+
(vi) - O ' CO2 M
COZ M+
COZ M+
(vii) ~ O ~ ( ; and \
(k} hydrogen, with the proviso that if p is 0 and none of Rll, Riz or R13 are -OX, then X is other than hydrogen;
Y is selected from the group consisting of:
(1) a single bond, (2) -O-, (3) -S-, (4) -CO-, (5) -CHz-, (6) -CHR15- , and (7) -CRlSRIS_, wherein Rls and Rls are independently selected from the group consisting of (a) C1-salkyl, unsubstituted or substituted with one or more of the substituents selected from:
(i) hydroxy, (ii) oxo, (iii) C1-salkoxy, {iv) phenyl-C1-salkoxy, (v) phenyl, (vi) -CN, (vii) halo, (viii) -NR9R1~, wherein Rs and RIS are as defined above , (ix) -NR~CORl~, wherein R9 and Rls are as defined above, (x) -NR9COzRls, wherein Rs and Rl~ are as defined above, (xi) -CONR9R1~, wherein Rs and R1~ are as defined above, (xii) -COR9, wherein R~ is as defined above, and (xiii) -COzR~, wherein Rs is as defined above;
(b) phenyl, unsubstituted or substituted with one or more of the substituent(s) selected from:
(i) hydroxy, (ii) C1-salkoxy, (iii) C1-salkyl, (iv) Cz-salkenyl, (v) halo, (vi) -CN, (vii) -NOz, (viii) -CFs, (ix) -(CHz)m-NRgRIS, wherein m, R~ and Rls are as defined above, (x) -NRsCORIa, wherein Rs and Rl~ are as defined above, (xi) -NR9C02R1~, wherein Rs and Rls are as defined above, (xii) -CONR9R1~, wherein Rs and Rl~ are as defined above, (xiii) -C02NR9R1~, wherein R9 and Rl~ are as defined above, (xiv) -CORD, wherein R~ :is as defined above, and _ (xv) -COzR9, wherein R~ is as defined above;
Z is selected from:
(1) hydrogen, (2) Cl.salkyl, and (3) hydroxy, with the proviso that if Y is -O-, Z is other than hydroxy, or if Y is -CHRI~-, then Z and R15 may be joined together to form a double bond.
Particularly preferred compounds of formula (III) are those wherein:
Rz and R3 are independently selected from the group consisting o~
(1) hydrogen, (2) Cl.salkyl, (3) Cz-salkenyl, and (4) phenyl;
Rs, R7 and R$ are independently selected from the group consisting o~
(1) hydrogen, (2) C1-salkyl, (3) fluoro, (4) chloro, (5) bromo, (6) iodo, and (7) -CFa;
Rll, Rlz and R13 are independently selected from the group consisting of:
(1) fluoro, (2) chloro, (3) bromo, and (4) iodo;
A is unsubstituted i-salkyl;
B is selected from the group consisting o~
N- N X X, X
N N N-~ N-N . _ N O ~N~O WN~O WN~S
X H
N_~ X
N-N N-N _ X
N S ~ S ~ O,X N N X
X H N ~N S.
N-NX ~ , ~ N
N N
N X X
X N X
/ N ~~O / N
N
H X H S
H
/ N\ X / N X
N S ~~~0, ~~~S, N N
X
pis0orl;
X is selected from:
(a) -PO(OH)O- ~ M+, wherein M+ is a pharmaceutically acceptable monovalent counterion, (b) -PO(O-)z ~ 2M+, (c) -PO(O-)z ' D2+, wherein D2+ is a pharmaceutically acceptable divalent counterion, (d) -CH(R4)-PO(OH)O- ~ M+, wherein R~ is hydrogen or Ci-salkyl, (e) -CH(R4)-PO(O-)z ~ 2M+, (f) -CH(R4)-PO(O-)z ~ Dz+, (i) -CO-CH2CHz-COz- ~ M+, (j) -CH(CHs)-0-CO-R5, wherein R5 is selected from the group consisting of: -(i) ~ O ~. NH 3+ M- , HZ+ M-\O~~N~OH
\O~CC)2 M+ , CGZ M+
(iv) ~ O CCI - M+
~O~.CO2 (V) , C02 M+
(vi) -O C02-M+
COZ- M+
CC)2 M+
(vii) ~O ~ I ; and Y is -0-;
Z is hydrogen or Ci-calkyl;
and pharmaceutically acceptable salts thereof.
Particularly preferred compounds of formula (III) include:
(1) 2-(S)-(3,5-bis(tri.fluoromethyl)benzyloxy)-3-(S)-phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine N-oxide;
(2) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-4-(3-(4-(ethoxycarbonyloxy-1-ethyl)-5-oxo-1H-1,2,4-triazolo)methyl)morpholine;
(3) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(4-monophosphoryl-5-oxo-1H-1, 2, 4-triazolo)methyl)morpholine;
(4) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(1-monophosphoryl-5-oxo-1H-1,2,4-triazolo)methyl)morpholine;
(5) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(2-monophosphoryl-5-oxo-1H-1, 2, 4-triazolo)methyl)morpholine;
(6) 2-(R)-(1-(R,)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxyphosphoryl-1H-1, 2,4-triazolo)methyl)morpholine;
(7) 2-(S)-(1-(R)-(3,5-bis(trifiuoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(1-monophosphoryl-5-oxo-4H-1, 2, 4-triazolo)methyl)morpholine;
and pharmaceutically acceptable salts thereof.
Further preferred NK-1 receptor antagonists are those described in European Patent Specification No. WO 96/05181, i.e. compounds of formula (I~:
Rl //
Y
R9a O O Rs R9b / ~~ __ N
-~ R4 s R
X
wherein X is a group of the formula NRsR7 or a C- or N-linked imidazolyl ring;
Y is hydrogen or C1-4alkyl optionally substituted by a hydroxy group;
Rl is hydrogen, halogen, C1-salkyl, Cl.salkoxy, CFs, NOa, CN, SRa, SORa, SOaRa, C02Ra, CONRaRb, CZ-salkenyl, Cz-salkynyl or Ci-9alkyl substituted by C1-4alkoxy, wherein Ra and Rb each independently represent hydrogen or Ci-4alkyl;
RZ is hydrogen, halogen, C1-salkyl, Ci.salkoxy substituted by C1-4alkoxy or CFs;
R3 is hydrogen, halogen or CFs;
R4 is hydrogen, halogen, Cl.salkyl, C1-salkoxy, hydroxy, CFs, N02, CN, SRa, SORB, SOzRa, C02Ra, CONRaRb, Cz-salkenyl, Ca.salkynyl or C1-4alkyl substituted by C1-4alkoxy, wherein R$ and Rb are as previously defined;
R5 is hydrogen, halogen, Ci-salkyl, C1-salkoxy substituted by Ci-4alkoxy or CFa;
Rs is hydrogen, C1-salkyl, Cs-7cycloalkyl, Cs-7cycloalkylCi-4alkyl, phenyl, or Ca.4alkyl substituted by Ci-4alkoxy or hydroxy;
R7 is hydrogen, C1_salkyl, Cs-7cycloalkyl, Cs-~cycloalkylCl-nalkyl, phenyl, or Ca.4alkyl substituted by one or two substituents selected from C1-aalkoxy, hydroxy or a 4, 5 or 6 membered heteroaliphatic ring containing one or two heteroatoms selected from N, O and S;
or R~ 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 NRB, S(O) or S(O)a and which ring may be optionally substituted by one or two groups selected from hydroxyCl-4alkyl, C1-4alkoxyCl-4alkyl, oxo, CORa or COaRa 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, C1-4alkyl, hydroxyCi-4alkyl or C1-4alkoxyCi-4alkyl;
and R9a and R9b are each independently hydrogen or C1-4alkyl, or Rya and R9b are joined so, together with the carbon atoms to which they are attached, there is formed a Cs-7 ring;
and pharmaceutically acceptable salts thereof.
Particularly preferred compounds of formula (IV) are those of formula (IVa) and pharmaceutically acceptable salts thereof:
A' i z A
O O
IVa N
w A3 X
wherein A1 is fluorine or CFs;
A2 is fluorine or CFs;
A3 is fluorine or hydrogen; , and X and Y are as defined in relation t,o formula (I).
Specific compounds of formula (I'~ of use in the present invention include:
2-(R)-(1-(R)-(3, 5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(4-morpholinobut-2-yn-yl)morpholine;;
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-N,N-dimethylaminobut-2-yn-yl)-3-(S)-(4-fluorophenyl)morpholine;
4-(4-azetidinylbut-2-yn-yl)-2-(R)-(1-(R)-1;3,5-bis(trifluoromethyl)phenyl}
ethoxy)-3-(S)-(4-fluorophenyl)morpholine;
2-(R)-{1-(R)-(3, 5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(4-imidazolylbut-2-yn-yl)morphaline;
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(4-(N-methylpiperazinyl)but-2-yn-yl)morpholine;
4-(4-bis(2-methoxyethyl)aminobut-2-yn-yl)-2-(R)-(1-(R)-(3, 5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S;)-(4-fluorophenyl)morpholine;
2-(R)-(1-(R)-(3, 5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(4-pyrrolidinobut-2-yn-yl)morpholine;
3-(S)-(4-fluarophenyl)-2-(R}-(1-(R)-(3-fluoro-5-(trifluoromethyl)phenyl) ethoxy)-4-(4-morpholinobut-2-yn-yl)morpholine;
3-(S)-(4-fluorophenyl)-4-(4-morpholinob ut-2-yn-yl)-2-(R)-(1-(R)-(3-(trifluoromethyl)phenyl)ethoxy)morpholine;
4-(4-azetidinylbut-2-yn-yl}-3-(S)-(4-fluorophenyl}-2-(R)-(1-(R)-(3-(trifluoromethyl)phenyl)ethoxy)morpho:line;
2-(R)-{1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-(N-(2-methoxyethyl)-N-methyl)aminobut-2-yn-yl)-3-(S)-phenylmorpholine;
2-(R)-(1-(R}-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-(N-cyclopropyl-N-{2-methoxyethyl)amino}but-2-yn-yl)-3-(S)-phenylmorpholine;
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-(N-isopropyl-N-(2-methoxyethyl)amino)but-2-yn-yl)-3-(S)-phenylmorpholine;
4-(4-(N,N-dimethylamino)but-2-yn-yl)-3-(S)-(4-fluorophenyl)-2-(R)-(1-(S)-(3-fluoro-5-(trifluoromethyl)phenyl-2-hydroxyethoxy)morpholine;
4-(4-azetidinylbut-2yn-yl)-3-(S)-(4-fluorophenyl)-2-(R)-(1-(S)-(3-fluoro-5-(trifluoromethyl)phenyl)-2-hydroxyethoxy)morpholine;
2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-4-(4-(N,N-dimethylamino)but-2-yn-yl)-3-(S)-(4-fluorophenyl)morpholine;
4-(4-azetidinylbut-2-yn-yl)-2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)morpholine;
4-(4-N-bis(2-methoxy)ethyl-N-methylamino)but-2-yn-yl)-2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)morpholine;
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(4-(2-(S)-(methoxymethyl)pyrrolidino)but-2-yn-yl)morphoiine;
4-(4-(7-azabicyclo[2.2.1]heptano)but-2-yn-yl)-2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)morpholine;
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-diisopropylaminobut-2-yn-yl)-3-(S)-(4-fluorophenyl)morpholine;
2-(R)-(1-(R)-(3-fluoro-5-(trifluoromethyl)phenyl)ethoxy)-4-(4-(2-(S)-(methoxymethyl)pyrrolidino)but-2-yn-yl)-3-(S)-phenylmorpholine;
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-{4-{2-(S)-(hydroxymethyl)pyrrolidino)but-2-yn-yl)morpholine;
and pharmaceutically acceptable salts thereof.
Another class of NK-1 receptor antagonists of use in the present invention is that described in European Patent Specification No.
0 436 334, i.e. compounds of formula (~:
R' Ra Ri Y ~ (VI
N
Re- (~) Is -49~-or a pharmaceutically acceptable salt thereof, wherein Y is (CH2)n wherein n is an integer from 1 to 4, and wherein any one of the carbon-carbon single bonds in said (CHz)n may optionally be replaced by a carbon-carbon double bond, and wherein any one of the carbon atoms of said (CHa)n may optionally be substituted with R4, an~i wherein any one of the carbon atoms of said (CHa)n may optionally be substituted with R7;
Z is (CHz)m wherein m is an integer from 0 to 6, and wherein any one of the carbon-carbon single bonds of (CHz)m may optionally be replaced by a carbon-carbon double bond or a carbon-carbon triple bond, and any one of the carbon atoms of said (CHz)m may optionally be substituted with R8~
Rl is hydrogen or C1-aalkyl optionally substituted with hydroxy, C1-4alkoxy or fluoro;
RZ is a radical selected from hydrogen, C1-s straight or branched alkyl, Cs-7cycloalkyl wherein one of the CHz groups in said cycloalkyl may optionally be replaced by NH, oxygen or sulphur; aryl selected from phenyl and naphthyl; heteroaryl selected from i.ndanyl, thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; phenyl-Cz-salkyl, benzhydryl and benzyl, wherein each of said aryl and heteroaryl groups and the phenyl moieties of said benzyl, phenyl -Cz-salkyl and benzhydryl may optionally be substituted with one or more substituents independently selected from halo, nitro, C1-s alkyl, Cl.salkoxy, trifluoromethyl, amino, C1-salkylamino, Cl.salkyl-O-CO, C1-salkyl-O-CO-C1-salkyl, C1-salkyl-CO-O, C1-salkyl-CO-Ci-salkyl-O-, Cl.salkyl-CO, Ci_salkyl-CO-C1-salkyl-, di-C1-salkylamino, -CONH-Ci-salkyl, C1-salkyl-CO-NH-C1-salkyl, -NHCOH and -NHCO-Cl.salkyl; and wherein one of the phenyl moieties of said benzhydryl may optionally be replaced by naphthyl, thienyl, furyl or pyridyl;
R5 is hydrogen, phenyl or Cl.salkyl;
or Rz and Rs together with the carbon to which they are attached, form a saturated ring having from 3 to 7 carbon atoms wherein one of the CHZ groups in said ring may optionally be replaced by oxygen, NH or sulfur;
R3 is aryl selected from phenyl and naphthyl; heteroaryl selected from indanyl, thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; and cycloalkyl having 3 to 7 carbon atoms wherein one of the (CHz) groups in said cycloalkyl may optionally be replaced by NH, oxygen or sulphur;
wherein each of said aryl and heteroaryl groups may optionally be substituted with one or more substituents, and said Cs-7cycloalkyl may optionally be substituted with one or two substituents, each of said substituents being independently selected from halo, nitro, Cl.salkyl, Cl.salkoxy, trifluoromethyl, amino, C1-salkylamino, -CO-NH- C1-salkyl, Ci-salkyl-CO-NH-C1-salkyl, -NHCOH and -NHCO-Ci-salkyl;
R4 and R7 are each independently selected from hydroxy, halogen, halo, amino, oxo, cyano, methylene, hydroxymethyl, halomethyl, C1_salkylamino, di-Ci-salkylamino, C1-salkoxy, C1-salkyl-O-CO, Ci.salkyl-O-CO-C1-salkyl, Cl.salkyl-CO-O, Cl.salkyl-CO-Ci-salkyl-O-, C1-salkyl-CO-, C1-salkyl-CO-Cl.salkyl, and the radicals set forth in the definition of R2;
Rs is -NHCOR~, -NHCHzR9, SOzRB or one of the radicals set forth in any of the definitions of R2, R4 and R7;
R8 is oximino (=NOH) or one of the radicals set forth in any of the definitions of R2, R4 and R7;
R~ is C1-salkyl, hydrogen, phenyl or phenylCl-salkyl;
with the proviso that (a) when m is 0, R8 is absent, (b) when R4, Rs, R~ or R8 is as defined in Rz, it cannot form together with the carbon to which it is attached ,a ring with R5, and (c) when R4 and R~ are attached to the same carbon atom, then either each of R4 and R7 is independently selected from hydrogen, fluoro and C1-salkyl, or R~ and R~, together with the carbon to which they are attached, for a Cs.s sai;urated carbocyclic ring that forms a spiro compound with the nitrogen-containing ring to which they are attached.
A particularly preferred compound of formula (~ is (2S,3S)-cis-3-(2-methoxybenzylamino)-2-phenylpiperidine; or a pharmaceutically acceptable salt thereof.
Another class of NK-1 receptor antagonists of use in the present invention is that described in International Patent Specification No. WO
93/21155, i.e. compounds of formula (VI):
R R
O
NCH-R1 (VI) Rs Iz R
R3 R' or a pharmaceutically acceptable salt thereof, wherein radicals R are phenyl radicals optionally 2- or 3-substituted by a halogen atom or a methyl radical;
Rl is optionally substituted phenyl, cyclohexadienyl, naphthyl, indenyl or optionally substituted heterocycle;
RZ is H, halogen, OH, alkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkyloxy, alkylthio, acyloxy, carboxy, optionally substituted alkyloxycarbonyl, benzyloxycarbonyl, amino or acylamino;
R3 is optionally 2-substituted phenyl;
R4 is OH or fluorine when R5 is H;
or R4 and R5 are OH ;
or R~ and R5 together form a bond.
A particularly preferred compound of formula (VI) is (3aS, 4S, 7aS)-7,7-diphenyl-4-(2-methoxyphenyl)-2-[(2S)-(2-methoxyphenyl)propionyl]
perhydroisoindol-4-0l; or a pharmaceutically acceptable salt thereof.
Another class of NK-1 receptor antagonists of use in the present invention is that described in European Patent Specification No.
0 591 040, i.e. compounds of formula (VII):
R Q
Ar-T-CO-~-CH2-~-CHZ-CHZ-Am +, A - (VII) __ Are wherein Ar represents an optionally substituted mono-, di- or tricyclic aromatic or heteroaromatic group;
T represents a bond, a hydroxymethylene group, a C1-4alkoxymethylene group or a Ci-salkylene group;
Ar' represents a phenyl group which is unsubstituted or substituted by one or more substituents selected from halogen, preferably chlorine or fluorine, trifluoromethyl, C1-4alkoxy, Ci-4alkyl where the said substituents may be the same or different; a thienyl group; a benzothienyl group; a naphthyl group; or an indolyl group;
R represents hydrogen, C1-4alkyl, w-C1-4alkoxyCl-4alkyl, or cu-Cz-4alkanoyloxyC2-4alkyl;
Q represents hydrogen;
or (a and R together form a 1,2-ethylene, 1,3-propylene or 1,4-butylene group;
Am+ represents the radical ~.z---N
in which Xi, X2 and Xs, together with the nitrogen atom to which they are attached, form an azabicyclic or azatricyclic ring system optionally substituted by a phenyl or benzyl group; and A- represents a pharmaceutically acceptable anion.
-53~-A particularly preferred compound of formula (VII) is (+) 1-[2-[3-(3,4-dichlorophenyl)-1-[(3-isopropoxyphenyl)acetyl]-3-piperidinyl]ethyl]-4-phenyl-1-azabicyclo[2,2,2]octane; or a pharmaceutically acceptable salt, especially the chloride, thereof.
Another class of NK-1 receptor antagonists of use in the presenf invention is that described in European Patent Specification No.
0 532 456, i.e. compounds of formula (VIII):
Rl--N X -X -Ra (VIII) a i R Xi or a pharmaceutically acceptable salt thereof, wherein R1 represents an optionally substituted aralkyl, aryloxyalykl, heteroaralkyl, aroyl, heteroaroyl, cycloalkylcarbonyl, aralkanoyl, heteroarylalkanoyl, aralkoxycarbonyl or arylcarbamoyl group or the acyl group of an a-amino acid optionally N-substituted by a lower alkanoyl or carbamoyl-lower alkanoyl group;
RZ represents cycloalkyl or an optionally substituted aryl or heteroaryl group;
R3 represents hydrogen, alkyl, carbamoyl or an alkanoyl or alkenoyl group optionally substituted by carboxy or esterified or amidated carboxy;
R4 represents an optionally substituted aryl group or an optionally partially saturated heteroaryl group;
Xl represents methylene, ethylene, a bond, an optionally ketalised carbonyl group or an optionally etherified hydroxymethylene group;
X2 represents alkylene, carbonyl gar a bond; and Xs represents carbonyl, oxo-lower alkyl, oxo(aza)-lower alkyl, or an alkyl group optionally substituted by phenyl, hydroxymethyl, optionally esterified or amidated carboxy, or (in other than the a-position) hydroxy.
A particularly preferred compound of formula (VIII) is (2R*, 4S*)-2-benzyl-1-(3, 5-dimethylbenzoyl}-N-(4-qui.nolinylmethyl)-4-piperidineamine;
or a pharmaceutically acceptable salt thereof.
Another class of NK-1 receptor antagonists of use in the present invention is that described in European Patent Specification No.
0 443 132, i.e. compounds of formula (IX) i \
a /
CHz R1-Y-A- N -1---CONHCHCON ~ (IX) R"
or a pharmaceutically acceptable salt thereof, wherein RI is aryl, or a group of the formula:
i \ ,x z X is CH or N; and Z is O or N-Rb, in which R5 is hydrogen or lower alkyl;
R2 is hydroxy or lower alkoxy;
R3 is hydrogen or optionally substituted lower alkyl;
R4 is optionally substituted ar(lower)alkyl;
A is carbonyl or sulfonyl; and Y is a bond or lower alkenylene.
A particularly preferred compound of formula (IX) is the compound of formula (IXa) HO
O
N \ ~
_N
(IXa) O CH3 \
O
N
or a pharmaceutically acceptable salt thereof.
Another class of NK-1 receptor antagonists of use in the present invention is that described in International Patent Specification No. WO
92/17449, i.e. compounds of the formula (X) ,~~~ ~~ g,' __ N J.,,. R
H
(X) or a pharmaceutically acceptable salt thereof, wherein Rl is aryl selected from indanyl, phenyl and naphthyl; heteroaryl selected from thienyl, furyl, pyridyl and quinolyl; and cycloalkyl having 3 to 7 carbon atoms, wherein one of said carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; wherein each of said aryl and heteroaryl groups may optionally be substituted with one or more substituents, and said Ca-7cycloalkyl may optionally be substituted with one or two substituents, said substituents being independently selected from chloro, fluoro, bromo, iodo, nitro, Ci.loalkyl optionally substituted with from one to three fluoro groups, Cl..loalkoxy optionally substituted with from one to three fluoro groups, amino, Ci-ioalkyl-S-, Ci-ioalkyl-S(O)-, C1-loalkyl-SOa-, phenyl, phenoxy, Cl.ioalkyl-SOzNH-, Ci-ioalkyl-SOzNH-C1-loakyl-, C1-loalkyla:mino-diCl-ioalkyl-, cyano, hydroxy, cycloalkoxy having 3 to 7 carbon atoms, Ci.calkylamino, C1-sdialkylamino, HC(O)NH- and Cl.loalkyl-C(O)NH-; and Rz is thienyl, benzhydryl, naphth;yl or phenyl optionally substituted with from one to three substituents independently selected from chloro, bromo, fluoro, iodo, cycloalkoxy having 3 to ? carbon atoms, C1-ioalkyl optionally substituted with from one to three fluoro groups and Ci-loalkoxy optionally substituted with from one to three fluoro groups.
A particularly preferred compound of formula (X) is (2S,3S)-3-(2-methoxy-5-trifluoromethoxybenzyl)-ami.no-2-phenylpiperidine; or a pharmaceutically acceptable salt thereof.
Another class of NK-1 receptor antagonists of use in the present invention is that described in International Patent Specification No. WO
95/08549, i.e. compounds of formula (XI) (CHa)X ._ N ~ i R
R~
N
H
R
(XI) or a pharmaceutically acceptable salt thereof, wherein R1 is a C1-4alkoxy group;
N
N
N-N ' R3 is a hydrogen or halogen atom;
R4 and R~ may each independently represent a hydrogen or halogen atom, or a Ci-4alkyl, C1-4alkoxy or trifluoromethyl group;
R~ is a hydrogen atom, a C1-4alkyl, (CHz)mcyclopropyl, -S(O)"C1_ aalkyl, phenyl, NR7R8, CHzC(O)CFs or trifluoromethyl group;
R7 and R$ may each independently represent a hydrogen atom, or a Ci-4alkyl or acyl group;
x represents zero or 1;
n represents zero, 1 or 2; and m represents zero or 1.
Particularly preferred compounds of formula (~I) are (2-methoxy-5-tetrazol-1-yl-benzyl)-([2S,3S]-2-phenyl-piperidin-3-yl)-amine; and [2-methoxy-5-(5-trifluoromethyl-tetrazol-1-yl)-benzyl]-([2S,3S]-2-phenyl-piperidin-3-yl)-amine; or a pharmaceutically acceptable salt thereof.
- 57 _ Another class of tachykinin antagonists of use in the present invention is that described in International Patent Specification No. WO
95/14017, i.e. compounds of formula (XII) R$ R4 R- (CHZ)n- C - CHZ - N- (CH2)o- R3 __ NH R
(CO)P
(CH2)m Rl (XII) or a pharmaceutically acceptable salt thereof, wherein m is zero, 1, 2 or 3;
n is zero or 1;
o is zero, 1 or 2;
p is zero or 1;
R is phenyl, 2- or 3-indolyl, 2- or 3-indolinyl, benzothienyl, benzofuranyl, or naphthyl;
which R groups may be substituted with one or two halo, C1-salkoxy, trifluoromethyl, C1-4alkyl, phenyl-Ci-salkoxy, or C1-4alkanoyl groups;
Rl is trityl, phenyl, diphenylmethyl, phenoxy, phenylthio, piperazinyl, piperidinyl, pyrrolidinyl, m.orpholinyl, indolinyl, indolyl, benzothienyl, hexamethyleneiminyl, benzofuranyl, tetrahydropyridinyl, quinolinyl, isoquinolinyl, reduced quinolinyl, reduced isoquinolinyl, phenyl-(Ci-4alkyl)-, phenyl-(C1-4alkoxy)-, quinolinyl-(Ci-4alkyl)-, isoquinolinyl-(C1-4alkyl)-, reduced quniolinyl-(Ci-4alkyl)-, reduced isoquinolinyl-(C1-4alkyl)-, benzoyl-(Ci-salkyl)-, Ci.4alkyl, or -NH-CHa-R5;
any one of which Rl groups may be substituted with halo, C1-4alkyl, C1-4alkoxy, trifluoromethyl, amino, Cl.4alkylamino, di(C1-4alkyl)amino, or C2-4alkanoylamino;
or any one of which Rl groups may be substituted with phenyl, piperazinyl, Cs.acycloalkyl, benzyl, Ci-4alkyl, piperidinyl, pyridinyl, pyrimidinyl, Cz-~alkanoylamino, pyrrolidinyl, Cz-calkanoyl, .or C1-4alkoxycarbonyl;
any one of which groups may be substituted with halo, Ci-alkyl, C1-4alkoxy, trifluoromethyl, amino, Ci-4alkylamino, di{Ci-4alkyl)amino, or Cz-4alkanoylamino;
or Rl is amino, a leaving group, hydrogen, C1-4alkylamino, or di(C1-4alkyl)amino;
R5 is pyridyl, anilino-(C1-salkyl)-, or anilinocarbonyl;
R2 is hydrogen, C1-4alkyl, Ci_4alkylsulfonyl, carboxy-(C1-salkyl)-, C1-aalkoxycarbonyl-(C1-salkyl)-, or -CO-R6;
R~ is hydrogen, C1-4alkyl, Ci-shaloalkyl, phenyl, Ci-salkoxy, Ci-shydroxyalkyl, amino, Ci-4alkylamino, di(Ci-aalkyl)amino, or -(CHa)Q-R~;
q is zero to 3;
R7 is carboxy, C1-4alkoxycarbonyl, C1-4alkylcarbonyloxy, amino, Ci-4alkylamino, di(Ci-4alkyl)amino, Ci-calkoxycarbonylamino, or phenoxy, phenylthio, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, indolinyl, indolyl, benzothienyl, benzofuranyl, quinolinyl, phenyl-(Ci-4alkyl)-, quinolinyl-(Ci.4alkyl)-, isoquinolinyl-(Ci-4alkyl)-, reduced quinolinyl-(Ci-4alkyl)-, reduced isoquinolinyl-(Cl.4alkyl)-, benzoyl-Ci.salkyl;
any one of which aryl or heterocyclic R7 groups may be substituted with halo, trifluoromethyl, C1-4alkoxy, C1-4alkyl, amino, Ci-4alkylamino, di(C1-4alkyl)amino, or Cz-4alkanoylamino;
or any one of which R7 groups may be substituted with phenyl, piperazinyl, Cs-scycloalkyl, benzyl, piperidinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, Cz-ealkanoyl, or Ci-4alkoxycarbonyl;
any of which groups may be substituted with halo, trifluoromethyl, amino, C1-4alkoxy, C1-4alkyl, C1-4alkylamino, di(C1-4alkyl)amino, or C2-~alkanoylamino;
Rs is hydrogen or Ci-alkyl;
R3 is phenyl, phenyl-(C1-alkyl)-, Cs-scycloalkyl, C~-scycloalkenyl, Ci-salkyl, naphthyl, C2-salkenyl, or hydrogen;
any one or which groups except hydrogen may be substituted with one or two halo, C1-salkoxy, C1-aalkylthio, nitro, trifluoromethyl, or C1-salkyl groups; and R4 is hydrogen or C1-aalkyl;
with the proviso that if Rl is hydrogen or halo, R3 is phenyl, . __ phenyl-(Ci-salkyl)-, Cs.scYcloalkyl, Cs.scYcloalkenyl, or naphthyl.
A particularly preferred compound of formula (XII) is [N-(2-methoxybenzyl)acetylamino]-3-(1H-indoa-3-yl)-2-[N-(2-(4-piperidin-1-yl)piperidin-1-yl)acetylamino]propane; o:r a pharmaceutically acceptable salt thereof.
The preferred compounds of formulae (I), (II), (III} and (I~ will have the 2- and 3-substituents on the morpholine ring in the cis arrangement, the preferred stereochemistry being as shown in the following general formula:
i O ,~,0~ w ~.2 a R
Where the benzyloxy moiety is a-substituted, the preferred stereochemistry of the a-carbon is either (R) when the substituent is an alkyl (e.g. methyl) group or (,S~ when the substituent is a hydroxyalkyl (e.g. hydroxymethyl) group.
Unless otherwise defined herein, suitable alkyl groups include straight-chained and branched alkyl groups containing from 1 to 6 carbon atoms. Typical examples include methyl and ethyl groups, and straight-chained or branched propyl and butyl groups. Particular alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl and tert-butyl.
Unless otherwise defined herein, suitable alkenyl groups include straight-chained and branched alkenyl groups containing from 2 to 6 carbon atoms. Typical examples include vinyl and allyl groups.
Unless otherwise defined herein, suitable alkynyl groups include straight-chained and branched alkynyl groups containing from 2 to 6 ._ carbon atoms. Typical examples include ethynyl and propargyl groups.
Unless otherwise defined herein, suitable cycloalkyl groups include groups containing from 3 to 7 carbon atoms. Particular cycloalkyl groups are cyclopropyl and cyclohexyl.
Unless otherwise defined herein, suitable aryl groups include phenyl and naphthyl groups.
A particular aryl-Cl.~alkyl, e.g. phenyl-Cl.salkyl, group is benzyl.
Unless otherwise defined herein, suitable heteroaryl groups include pyridyl, quinolyl, isoquinolyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, furyl, benzofuryl, thienyl, benzthienyl, imidazolyl, oxadiazolyl and thiadiazolyl groups.
The term "halogen" as used herein includes fluorine, chlorine, bromine and iodine.
The compounds of use in this invention may have one or more asymmetric centres and can therefore exist as enantiomers and possibly as diastereoisomers. It is to be understood that the present invention relates to the use of all such isomers and mixtures thereof.
Suitable pharmaceutically acceptable salts of the NK-1 receptor antagonists of use in the present invention include acid addition salts which may, for example, be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable non-toxic acid such as hydrochloric acid, fumaric acid, malefic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid or sulphuric acid. Salts of amine groups may also comprise the quaternary ammonium salts in which the amino nitrogen atom carries an alkyl, alkenyl, alkynyl or aralkyl group. Where the compound carries an acidic group, for example a carboxylic acid group, the present invention also contemplates salts thereof, preferably non-toxic pharmaceutically acceptable salts thereof, such as the sodium, potassium and calcium salts thereof.
Suitable pharmaceutically acceptable salts of the anorectic agent of use in the combinations of the present invention include those salts . _.
described above in relation to the salts of NK-1 receptor antagonists.
The present invention accordingly provides the use of a NK-1 receptor antagonist selected from the compounds of formulae (I), (II), (III), (IV), (~, (VI), (VII), (VIII), (IX), (X), (Xl:) and (XII), for the manufacture of a medicament for the treatment or prevention of eating disorders.
The present invention also provides a method for the treatment or prevention of eating disorders, which method comprises administration to a patient in need of such treatment an effective amount of a NK-1 receptor antagonist selected from the compounds of formulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) and (XI:f).
In a further aspect of the present; invention, there is provided a pharmaceutical composition for the treatment or prevention of eating disorders comprising a NK-1 receptor antagonist selected from the compounds of formulae (I), (II), (III}, (IV), (V}, (VI}, (VII), (VIII), (IX), (X), (XI) and (XII), together with at least one pharmaceutically acceptable carrier or excipient.
It will be appreciated that the NK-1 receptor antagonist selected from the compounds of formulae (I), (II), (III}, (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) and (XII) may be used in combination with an anorectic agent, present as a combined preparation for simultaneous, separate or sequential use for the treatment or prevention of eating disorders. Such combined preparations may be, for example, in the form of a twin pack.
In a further or alternative aspect; of the present invention, there is therefore provided a product comprising a NK-1 receptor antagonist selected from the compounds of formulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) and (XII) and an anorectic agent as a combined WO 98!47513 PCT/GB98/01161 preparation for simultaneous, separate or sequential use in the treatment or prevention of eating disorders.
In a preferred aspect, the present invention accordingly provides the use of a NK-1 receptor antagonist selected from the compounds of formulae (I), (II), (III), (IV), (~, (VI), (VII), {VIII), (IX), (X), (XI) and (XII) and a __ halogenated amphetamine derivative for the manufacture of a medicament for the treatment or prevention of eating disorders.
The present invention also provides a method for the treatment or prevention of eating disorders, which method comprises administration to a patient in need of such treatment an amount of a NK-1 receptor antagonist selected from the compounds of formulae (I), (II), (III), (IV), (V), {VI), (VII), (VIII), (IX), {X), (XI) and (XII) and a halogenated amphetamine derivative such that together they give effective relief.
In a further aspect of the present invention, there is provided a pharmaceutical composition comprising a NK-1 receptor antagonist selected from the compounds of formulae (I), {II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) and (XII) and a halogenated amphetamine derivative 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 NK-1 receptor antagonist selected from the compounds of formulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), {X), (XI) and (XII) and a halogenated amphetamine derivative as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of eating disorders.
Particularly preferred halogenated amphetamine derivatives are selected from the group consisting of fenfluramine and dexfenfluramine.
Thus in a further preferred aspect, the present invention accordingly provides the use of a NK-1 receptor antagonist selected from the compounds of formulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) and (XII) and a halogenated amphetamine derivative selected from the group consisting of fenfluramine and dexfenfluramine; for the manufacture of a medicament for the treatment or prevention of eating disorders.
The present invention also provides a method for the treatment or prevention of eating disorders, which method comprises administration to a patient in need of such treatment an amount of a NK-1 receptor antagonist selected from the compounds of formulae (I), (iI), (III), (IV), (~, (VI), (VII), (VIII), (IX), (X), (XI) and (XII) and an amount of a halogenated amphetamine derivative selected from the group consisting of fenfluramine and dexfenfluramine, such that together they give effective relief.
In a further aspect of the present invention, there is provided a pharmaceutical composition comprising a NK-1 receptor antagonist selected from the compounds of formulae (I), (II), (III), (IV), (V), (VI}, (VII), (VIII), (IX), (X), (XI) and (XII) and a halogenated amphetamine derivative selected from the group consisting of fenfluramine and dexfenfluramine, 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 NK-1 receptor antagonist selected from the compounds of formulae (I), (II), (III), (IV), (V}, (VI), (VII), (VIII), (IX), (X), (XI) and (XII) and a halogenated amphetamine derivative selected from the group consisting of fenfluramine and dexfenfluramine, as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of eating disorders.
As stated above, the NK-1 receptor antagonist and the anorectic agent may be formulated in a single pharmaceutical composition or alternatively in individual pharmaceutical compositions for simultaneous, separate or sequential use in accordancE: with the present invention.
Preferably the compositions according to the present invention are in unit dosage forms such as tablets, pills, capsules, powders, granules, solutions or suspensions, or suppositories, for oral, parenteral or rectal administration, by inhalation or insufflation or administration by trans-dermal patches or by buccal cavity absorption wafers. Oral dosage forms are particularly preferred (e.g. tablets, capsules, pills or wafers).
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, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing 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 containing 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 stomach 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 shellac, cetyl alcohol and cellulose acetate.
The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions vvith edible oils such as cottonseed oil, sesame oil, coconut oil, peanut oil or soybean oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.
Preferred compositions for administration by injection include those comprising a NK-1 receptor antagonist as the active ingredient, in association with a surface-active agent (or wetting agent or surfactant) or in the form of an emulsion (as a water-:in-oil or oil-in-water emulsion).
Suitable surface-active agents include, in particular, non-ionic agents, such as polyoxyethylenesorbitans (e.g. TweenT"" 20, 40, 60, 80 or 85) and other sorbitans (e.g. SpanT"' 20, 40, 60, 80 or 85). Compositions with a surface-active agent will 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 mannitol or other pharmaceutically acceptable vehicles, if necessary.
Suitable emulsions may be prep;~red using commercially available fat emulsions, such as IntralipidT"", LiposynT"", InfonutrolT"", LipofundinT°"
and LipiphysanT"". 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 almond oil) and an emulsion formed upon mixing 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 glycerol or glucose, to adjust the tonicity of the emulsion. Suitable emulsions will typically contain up to 20% oil, for example, between 5 and 20%. The fat emulsion will preferably comprise fat droplets between 0.1 and 1.0~m, particularly 0.1 and 0.5~m, and have a pH in the range of 5.5 to 8Ø
Particularly preferred emulsion compositions are those prepared by mixing a NK-1 receptor antagonist selected from the compounds of formulae (I), (II), (III), (IV), (~, (VI), (VII), (VIII), (IX), (X), (XI) and (XII) with IntralipidT"" or the components thereof (soybean oil, egg phospholipids, glycerol and water).
Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as set out above.
Preferably the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably sterile pharmaceutically acceptable solvents may be 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 machine. Solution, suspension or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.
Compositions of the present invention may also be presented for administration in the form of trans-dermal patches using conventional technology. The compositions may also be administered via the buccal cavity using, for example, absorption wafers.
The present invention further provides a process for the preparation of a pharmaceutical composition comprising a NK-1 receptor antagonist and an anorectic agent, which process comprises bringing a NK-1 receptor antagonist and an anorectic agent, into association with a pharmaceutically acceptable carrier or excipient.
When administered in combination, either as a single or as separate pharmaceutical composition(s), the NK-1 receptor antagonist and an anorectic agent, are presented in a ratio which is consistent with the manifestation of the desired effect. In particular, the ratio by weight of the NK-1 receptor antagonist and the anorectic agent will suitably be between 0.001 to 1 and 1000 to 1, and especially between 0.01 to 1 and 100 to 1.
A suitable dosage level for the NK-1 receptor antagonist about 0.05 to I500mg per day, preferably about 0.25 to I500mg per day, and especially about 0.25 to 500mg/kg per day. The compounds may be administered on a regimen of up to 6 tines per day, preferably 1 to 4 times per day, especially 1 or 2 times daily.
A suitable dosage level for the anorectic agent is about 0.5 to 1500mg per day, preferably about 2.5 to 1000mg per day, and especially about 2.5 to 500mg per day. The compounds may be administered on a regimen of up to 6 times per day, preferably 1 to 4 times per day, especially 1 or 2 times daily.
It will be appreciated that the amount of the NK-1 receptor antagonist and (where present) the anorectic agent required for use in the treatment or prevention of eating disorders will vary not only with the particular compounds or compositions selected but also with the route of administration, the nature of the condition being treated, and the age and condition of the patient, and will ultimately be at the discretion of the patient's physician or pharmacist.
The compounds of formulae (I), (I:I), (III), (IV), (~, (VI), (VII), (VIII), (IX), (X), (XI) and (XII) may be preparect by the methods described in EP-A-0 577 394 (or WO 95/16679), WO 95/18124, WO 95/23798, WO 96/05181, EP-A-0 436 334, WO 93/:?1155, EP-A-0 591 040, EP-A-0 532 456, EP-A-0 443 132, WO 92/17449, WO 95/08549 and WO 95//4017, respectively.
Particularly preferred NK-1 receptor antagonists of the formulae (I), (II), (III}, (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) and (XII) for use in the present invention are compounds which. are potent NK-1 receptor antagonists, i.e. compounds with an NK-I receptor affinity (ICso) of less than 100nM.
Even more preferred NK-1 receptor antagonists of use in the present invention are compounds which are potent NK-1 receptor antagonists with an NK-1 receptor affinity (ICSo) of less than IOnM, favourably less than 2nM and preferably less than lnM.
5 Especially preferred NK-1 receptor antagonists of use in the prQSent invention are orally active, long acting, CNS-penetrant NK-1 receptor antagonists, identified using a combination of the following assays:
ASSAY 1: NK-1 Receptor bindin~~
10 NK-1 receptor binding assays are performed in intact Chinese hamster ovary (CHO) cells expressing the human NK-1 receptor using a modification of the assay conditions described by Cascieri et al, J.
Pharmacol. Exp. Ther., 1992, 42, 458. Typically, the receptor is expressed at a level of 3x105 receptors per cell. Cells are grown in monolayer culture, 15 detached from the plate with enzyme-free dissociation solution (Speciality Media Inc.), and washed prior to use in the assay. laSl-~,r8-substance P
(O.lnM, 2000Ci/mmol; New England Nuclear) is incubated in the presence or absence of test compounds (dissolved in 5~1 dimethylsulphoxide, DMSO) with 5x104 CHO cells. Ligand binding is performed in 0.25m1 of 50mM
20 Tris-HCI, pH7.5, containing 5mM MnClz, 150mM NaCl, 0.02% bovine serum albumin (Sigma), 50p.g/ml chymostatin (Peninsula), O.lnM
phenylmethylsulphonyl fluoride, 2~g/ml pepstatin, 2~.g1m1 leupeptin and 2.8~g/ml furoyl saccharine. The incubation proceeds at room temperature until equilibrium is achieved (>40 minutes) and the receptor-ligand 25 complex is harvested by filtration over GF/C filters pre-soaked in 0.1%
polyethylenimine using a Tomtek 96-well harvester. Non-specific binding is determined using excess substance P (1~,M) and represents <10% of total binding.
ASSAY 2: Gerbil Foot-Tapping CNS-penetrant NK-1 receptor antagonists for use in the present invention can be identified by their ability to inhibit foot tapping in gerbils induced by anxiogenic agents (such as pentagastrin) or central infusion of NK-1 receptor agonists such as GR736;32, or caused by aversive _.
stimulation such as foot shock or single housing, based on the method of Rupniak & Williams, Eur. J. Pharmacvl., 1994, 265, 179.
Male or female Mongolian gerbils (35-70g) are anaesthetised by inhalation of an isoflurane/oxygen mixi;ure to permit exposure of the jugular vein in order to permit administration of test compounds or vehicle in an injection volume of approximately 5mllkg i.v. Alternatively, test compounds may be administered orally or by subcutaneous or intraperitoneal routes. A skin incision is then made in the midline of the scalp to expose the skull. An anxiogenic agent (e.g. pentagastrin) or a selective NK-I receptor agonist (e.g. G1~,73632 (d Ala[L-Pro9,Me-Leulo]-substance P-(7-1I)) is infused directly into the cerebral ventricles (e.g.
3pmo1 in 5~,1 i.c.v., depending on test substance) by vertical insertion of a cuffed 27 gauge needle to a depth of 4.5mm below bregma. The scalp incision is closed and the animal allowE~d to recover from anaesthesia in a clear perspex observation box (approximately 25cm x 20cm x 20cm). The duration and/or intensity of hind foot tapping is then recorded continuously for approximately 5 minutes. Alternatively, the ability of test compounds to inhibit foot tapping evoked by aversive stimulation, such as foot shock or single housing, may be studied using a similar method of quantification.
ASSAY 3: Ferret Emesis Individually housed male ferrets (1.0 -2.5 kg) are dosed orally by gavage with test compound. Ten minui;es later they are fed with approximately 100g of tinned cat food. At 60 minutes following oral dosing, cisplatin (lOmg/kg) is given i.v. uia a jugular vein catheter inserted under a brief period of halothane anaesthesia. The catheter is then removed, the jugular vein ligated and the skin incision closed. The ferrets recover rapidly from the anaesthetic and are mobile within 10-20 minutes. The animals are observed continuously during recovery from the anaesthetic and for 4 hours following the cisplatin injection, after which time the animals are killed humanely. The numbers of retches and vomits occurring during the 4 hours after cisplatin administration are recorded by trained observers.
ASSAY 4: Separation-Induced Vocalisation Male and female guinea-pigs pups are housed in family groups with their mothers and littermates throughout the study. Experiments are commenced after weaning when the pups are at least 2 weeks old. Before entering an experiment, the pups may be screened to ensure that a vigorous vocalisation response is reproducibly elicited following maternal separation. The pups are placed individually in an observation cage (approximately 55cm x 39cm x l9cm) in a room physically isolated from the home cage for approximately 15 minutes and the duration and/or number of vocalisation during this baseline period is recorded. Those animals which vocalise for longer than 5 minutes are employed for drug challenge studies (approximately 50% of available pups may fail to reach this criterion). On test days each pup receives an oral dose or an s.c. or i.p.
injection of test compound or vehicle and is then immediately returned to the home cage with its mother and siblings for at least 30 to 60 minutes (or for up to 4 hours following an oral dose, dependent upon the oral pharmacokinetics of the test compound) before social isolation for 15 minutes as described above. The duration and/or number of vocalisation on drug treatment days may be expressed as a percentage of the pre-treatment baseline value for each animal or compared with values obtained in vehicle-treated animals. The same subjects may be retested once weekly for up to 6 weeks. Between 6 and 8 animals receive each test WO 98/47513 PCTlGB98/01161 compound at each dose tested.
A suitable selection cascade for NKl antagonists of use according to the present invention is as follows:
(i) Determine affinity for human NKl receptor in radioligand . _.
binding studies (Assay 1); select compounds with ICso <_ lOnM, preferably ICso <_ 2nM, especially ICso _< lnM.
(ii) Determine ability of compounds to penetrate CNS by their ability to inhibit foot tapping in gerbils induced by central injection of an NKi agonist (Assay 2); select compounds that inhibit foot tapping with IDso _< 3mg/kg i.v., and preferably IDso ~ lmglkg i.v. when administered immediately prior to central NKl agonist challenge, or IDso <_ 30mg/kg p.o., and preferably IDso <_ lOmglkg p.o. 1 hour prior to challenge.
(iii) Determine central duration of action of compounds in gerbil foot tapping assay following intravenous administration 24 hours prior to central NKl agonist challenge; select compounds showing <_ 25-fold loss of potency compared with IDso determined in step (ii) above with the proviso that IDso <_ l0mg/kg i.v., and preferably _< 5mglkg i.v. after 24 hour pre-treatment.
(iv) Determine oral bioavailabilii;y of compounds by pharmacokinetic analysis, activity in gerbil foot tapping assay following oral administration and/or by ability to inhibit cisplatin-induced emesis in ferrets (Assay 3); select compounds with IDso 5 3mg/kg p.o., and preferably IDso _< 1mg/kg p.o.
Particularly preferred compounds of use in the present invention are identified using steps (i) to (iv) followed by step (v):
(v) Determine activity of compounds in assays sensitive to conventional serotonergic drugs (inhibi.tion of pharmacologically evoked foot tapping in gerbils and/or inhibition of distress vocalisations in guinea-pig pups (Assay 4)). Select compounds with IDso < 20mg/kg, and preferably .
IDso _< lOmg/kg.
Yet further preferred compounds of use in the present invention may be selected from those compounds which satisfy the NK-1 receptor binding criteria of step (i) which, in addition, have < 5-fold shift in affinity when incubated in the presence of human serum albumin (HSA) to show non-specific protein binding.
One example of a NK-1 receptor antagonist of use in the present invention is the compound 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)-ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)-morpholine, the preparation of which is described in International Patent Specification No. WO 95/16679. In the aforementioned assays, this compound has the following activity:
human NK-1 receptor binding: ICso=O.lnM
gerbil foot-tapping (5 minx.): IDso=0.36mg/kg i.v.
gerbil foot-tapping (24 hrs.): IDso=0.33mg/kg i.v.
ferret emesis: IDoo<3mg/kg p.o.
guinea-pig vocalisation IDso=0.73mg/kg p.o.
(4hrs. pretreatment) Another example of a NK-1 receptor antagonist of use in the present invention is the compound 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(N, N-dimethylamino)methyl-1,2, 3-triazol-4-yl)methyl-3-(S)-phenylmorpholine, the preparation of which is described in International Patent Specification No. WO 95/18124. In the aforementioned assays, this compound has the following activity:
human NK-1 receptor binding: ICso=0.25nM
gerbil foot-tapping (5 rains.): ID~o=0.12mg/kg i.v.
gerbil foot-tapping (24 hrs.): IDSO=0.17mg/kg i.v.
guinea-pig vocalisation: IDso=0.5mg/kg s:c.
The following assay has been used to demonstrate the potentiation of the anorectic effects of dexfenfluramine in diet-induced obese mice when co-administered with a NK-1 receptor antagonist. __ Evaluation of the Interaction of NK-1 Antagonists and Anorectic Aeents on Food Intake and Bod Wei,~ht in Diet-Induced Obese Mice.
Mice:
Male C57BL/J mice were obtained from Jackson Labs at 3 weeks of age. Half the mice were maintained an a wet diet consisting of sweetened condensed milk and standard ground rodent chow (70%:30%, voi:vol).
Fresh wet chow was provided daily. These mice will be referred to as diet-induced obese (DIO). The other half was maintained on just ground rodent chow. These will be referred to as Non-Obese Littermates (NOL). Both food and water were supplied czd libiturrx. Mice were housed with a 12 hour light/dark cycle (4.OOam lights on) through out the course of the described studies.
Mice were weighed bi-weekly until a paint that both DIO and NOL
mice were weight stable (approximately 20 weeks). At this time, DIO mice weighed significantly more than NOL mice (p20.01). DIO mice also exhibited elevated insulin and glucose levels, as well as polyuria.
Food Intake:
(All food intake studies were peri:ormed on weight stable DIO mice.
Both food and water were available before treatment.) The effect that the anorectic agent, dexfenflur amine had on food intake in DIO mice was determined previously (ED~o = 3 mg/kg, ip}. The combined effect that [2-methoxy-5-(5-trifluoromethyl-tetrazol-1-y~1)-benzyl]-([2S,3Sj-2-phenyl-piperidin-3-yl)amine (GR205171) and dexfenfluramine WO. 98/47513 PCT/GB98/01161 -74- _ had on food consumption was examined by observing the resulting changes in food intake observed after treatment with dexfenfluramine, GR205171, or combinations of dexfenfluramine with decreasing doses of GR 205171.
Mice were randomly assigned to one of the following treatment groups:
~ SalinelSaline ~ Saline/GR 205171@20 mg/kg ~ Dexfenfluramine @ 3 mg/kg/ GR 205171@20 mg/kg Dexfenfluramine @ 3 mg/kg/ GR 205171@10 mg/kg ~ Dexfenfluramine @ 3 mg/kg/ GR 205171@ 5 mg/kg Mice received two injections approximately 30 wins apart. All injections were administered ip., in a volume of 0.2 ml between 3.OOpm and 3.30pm. Fresh chow was provided at the time of injection. Food intake was measured 16 hours post-injection for each mouse.
Results shown in Figure 1 are expressed as inhibition of food intake relative to that of saline treated animals.
Body Wed (All weight studies are performed on DIO mice) The effect that the combination of anorectic agents and NK-1 antagonists have on weight are examined using a chronic dosing regimen.
Mice are treated with dexfenfluramine, GR 205171, or combinations of dexfenfluramine with decreasing doses of GR 205171, similar to those used in the evaluation of food intake. Mice are dosed once daily, for 7 days with body weights being measured at the start and conclusion of the study.
Changes in body weight are compared with that of saline treated mice.
Concurrent daily food intake measurements may be taken at this time.
The following examples illustrate pharmaceutical compositions according to the invention.
These formulations may be prepared with separate active ingredients or with a combination of active ingredients in one composition.
In such combined preparations, the ratio of the NK-1 receptor antagonist and the anorectic agent will depend upon the choice of active ingredients.
EXAMPLE 1 Tablets containing 50-300mg of NK-1 antagonist and l5mg of dexfenfluramine Amount mg NK-1 antagonist 50.0 100.0 300.0 dexfenfluramine 15.0 15.0 15.0 Microcrystalline cellulose80.0 80.0 80.0 Modified food corn 80.0 80.0 80.0 starch Lactose 174.5 124.5 124.5 Magnesium Stearate 0.5 0.5 0.5 EXAMPLE 2 Tablets containin~,50-300mg of NK-1 antagonist and 60mg of fenfluramine Amount mg NK-1 antagonist 50.0 100.0 300.0 fenfluramine 60.0 60.0 60.0 Microcrystalline cellulose$0.0 80.0 80.0 Modified food corn starch80.0 80.0 80.0 Lactose 129.5 179.5 129.5 Magnesium Stearate 0.5 0.5 0.5 The active ingredients 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 remainder of the corn starch and the magnesium stearate. The resulting granulation is WO. 98/47513 PCT/GB98/01161 then compressed into tablets containing 50mg, 100mg and 300mg of the NK-1 receptor antagonist per tablet.
EXAMPLE 3 Parenteral injection Amount Active Ingredients 10 to 300mg Citric Acid Monohydrate 0.75mg Sodium Phosphate 4.5mg Sodium Chloride 9mg Water for injection to lOml The sodium phosphate, citric acid monohydrate and sodium chloride are dissolved in a portion of the water. The active ingredients are dissolved or suspended in the solution and made up to volume.
Claims (28)
1. Use of a NK-1 receptor antagonist for the manufacture of a medicament for the treatment or prevention of eating disorders.
2. Use according to claim 1 which further comprises the simultaneous, separate or sequential administration of an anorectic agent.
3. A pharmaceutical composition for the treatment or prevention of eating disorders comprising a NK-1 receptor antagonist, together with at least one pharmaceutically acceptable carrier or excipient.
4. A composition according to claim 3 which further comprises an anorectic agent.
5. A product comprising a NK-1 receptor antagonist and an anorectic agent as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of eating disorders.
6. A method for the treatment or prevention of eating disorders, which method comprises administration to a patient in need of such treatment of an effective amount of a NK-1 receptor antagonist.
7. A method for the treatment or prevention of eating disorders, which method comprises administration to a patient in need of such treatment of an amount of a NK-1 receptor antagonist and an amount of an anorectic agent, such that together they give effective relief.
8. A use according to claim 1 or 2, a composition according to claim 3 or 4, a product according to claim 5 or a method according to claim 6 or 7 wherein the NK-1 receptor antagonist is a compound of formula I:
wherein R1 is selected from the group consisting of:
(1) C1-6alkyl, substituted with one or more of the substituents selected from:
(a) heterocycle, wherein the heterocycle is selected from the group consisting of:
(A) benzimidazolyl, (B) imidazolyl, (C) isoxazolyl, (D) isothiazolyl, (E) oxadiazolyl, (F) pyrazinyl, (G) pyrazolyl, (H) pyridyl, (I) pyrrolyl, (J) tetrazolyl, (K) thiadiazolyl, (L) triazolyl, and (M) piperidinyl, and wherein the heterocycle is unsubstituted or substituted with one or more substituent(s) selected from:
(i) C1-6 alkyl, unsubstituted or substituted with halo, -CF3, -OCH3, or phenyl, (ii) C1-6alkoxy, (iii) oxo, (iv) thioxo, (v) cyano, (vi) -SCH3, (vii) phenyl, (viii) hydroxy, (ix) trifluoromethyl, (x) -(CH2)m-NR9R10, wherein m is 0, 1 or 2, and R9 and R10 areindependently selected from:
(I) hydrogen, (II) C1-6alkyl, (III) hydroxy C1-6alkyl, and (IV) phenyl, (xi) -NR9COR10, wherein R9 and R10 are as defined above, and (xii) -CONR9R10, wherein R9 and R10 are as defined above, R2 and R3 are independently selected from the group consisting of:
(1) hydrogen;
(2) C1-6alkyl (3) C2-6alkenyl, and (5) phenyl;
X is -O-;
R4 is , R5 is phenyl, unsubstituted or substituted with halo;
R6, R7 and R8 are independently selected from the group consisting of:
(1) hydrogen, (2) C1-6alkyl, (3) halo, and (4) -CF3;
Y is -O-; and Z is hydrogen or C1-4alkyl;
or a pharmaceutically acceptable salt thereof.
wherein R1 is selected from the group consisting of:
(1) C1-6alkyl, substituted with one or more of the substituents selected from:
(a) heterocycle, wherein the heterocycle is selected from the group consisting of:
(A) benzimidazolyl, (B) imidazolyl, (C) isoxazolyl, (D) isothiazolyl, (E) oxadiazolyl, (F) pyrazinyl, (G) pyrazolyl, (H) pyridyl, (I) pyrrolyl, (J) tetrazolyl, (K) thiadiazolyl, (L) triazolyl, and (M) piperidinyl, and wherein the heterocycle is unsubstituted or substituted with one or more substituent(s) selected from:
(i) C1-6 alkyl, unsubstituted or substituted with halo, -CF3, -OCH3, or phenyl, (ii) C1-6alkoxy, (iii) oxo, (iv) thioxo, (v) cyano, (vi) -SCH3, (vii) phenyl, (viii) hydroxy, (ix) trifluoromethyl, (x) -(CH2)m-NR9R10, wherein m is 0, 1 or 2, and R9 and R10 areindependently selected from:
(I) hydrogen, (II) C1-6alkyl, (III) hydroxy C1-6alkyl, and (IV) phenyl, (xi) -NR9COR10, wherein R9 and R10 are as defined above, and (xii) -CONR9R10, wherein R9 and R10 are as defined above, R2 and R3 are independently selected from the group consisting of:
(1) hydrogen;
(2) C1-6alkyl (3) C2-6alkenyl, and (5) phenyl;
X is -O-;
R4 is , R5 is phenyl, unsubstituted or substituted with halo;
R6, R7 and R8 are independently selected from the group consisting of:
(1) hydrogen, (2) C1-6alkyl, (3) halo, and (4) -CF3;
Y is -O-; and Z is hydrogen or C1-4alkyl;
or a pharmaceutically acceptable salt thereof.
9. A use according to claim 1 or 2, a composition according to claim 3 or 4, a product according to claim 5 or a method according to claim 6 or 7 wherein the NK-1 receptor antagonist is a compound of formula IIa:
wherein:
A1 is fluorine or CF3;
A2 is fluorine or CF3;
A3 is fluorine or hydrogen;
R6 is a 5-membered or 6-membered heterocyclic ring containing 2 or 3 nitrogen atoms optionally substituted by =O, =S or a C1-4alkyl group, and optionally substituted by a group of the formula ZNR7R8 where Z is C1-6alkylene or C3-6cycloalkylene;
R7 is hydrogen, C1-4alkyl, C3-7cycloalkyl or C3-7cycloalkylC1-4alkyl, or C2-4alkyl substituted by C1-4alkoxy or hydroxyl;
R8 is hydrogen, C1-4alkyl, C3-7cycloalkyl or C3-7cycloalkylC1-4alkyl, or C2-4alkyl substituted by one or two substituents selected from C1-4alkoxy, hydroxyl or a 4, 5 or 6 membered heteroaliphatic ring containing one or two heteroatoms selected from N, O and S;
or R7, R8 and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms, optionally substituted by a hydroxy group, and optionally containing a double bond, which ring may optionally contain an oxygen or sulphur ring atom, a group S(O) or S(O)2 or a second nitrogen atom which will be part of a NH or NR c moiety where R c is C1-4alkyl optionally substituted by hydroxy or C1-4alkoxy;
or R7, R8 and the nitrogen atom to which they are attached form a non-aromatic azabicyclic ring system of 6 to 12 ring atoms;
or Z, R7 and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms which may optionally contain an oxygen ring atom;
or a pharmaceutically acceptable salt thereof.
wherein:
A1 is fluorine or CF3;
A2 is fluorine or CF3;
A3 is fluorine or hydrogen;
R6 is a 5-membered or 6-membered heterocyclic ring containing 2 or 3 nitrogen atoms optionally substituted by =O, =S or a C1-4alkyl group, and optionally substituted by a group of the formula ZNR7R8 where Z is C1-6alkylene or C3-6cycloalkylene;
R7 is hydrogen, C1-4alkyl, C3-7cycloalkyl or C3-7cycloalkylC1-4alkyl, or C2-4alkyl substituted by C1-4alkoxy or hydroxyl;
R8 is hydrogen, C1-4alkyl, C3-7cycloalkyl or C3-7cycloalkylC1-4alkyl, or C2-4alkyl substituted by one or two substituents selected from C1-4alkoxy, hydroxyl or a 4, 5 or 6 membered heteroaliphatic ring containing one or two heteroatoms selected from N, O and S;
or R7, R8 and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms, optionally substituted by a hydroxy group, and optionally containing a double bond, which ring may optionally contain an oxygen or sulphur ring atom, a group S(O) or S(O)2 or a second nitrogen atom which will be part of a NH or NR c moiety where R c is C1-4alkyl optionally substituted by hydroxy or C1-4alkoxy;
or R7, R8 and the nitrogen atom to which they are attached form a non-aromatic azabicyclic ring system of 6 to 12 ring atoms;
or Z, R7 and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms which may optionally contain an oxygen ring atom;
or a pharmaceutically acceptable salt thereof.
10. A use according to claim 1 or 2, a composition according to claim 3 or 4, a product according to claim 5 or a method according to claim 6 or 7 wherein the NK-1 receptor antagonist is a compound of formula III:
wherein:
R2 and R3 are independently selected from the group consisting of:
(1) hydrogen, (2) C1-6alkyl, (3) C2-6alkenyl, and (4) phenyl;
R6, R7 and R8 are independently selected from the group consisting of:
(1) hydrogen, (2) C1-6alkyl, (3) fluoro, (4) chloro, (5) bromo, (6) iodo, and (7) -CF3;
R11, R12 and R13 are independently selected from the group consisting of:
(1) fluoro, (2) chloro, (3) bromo, and (4) iodo;
A is unsubstituted 1-6alkyl;
B is selected from the group consisting of:
p is 0 or 1;
X is selected from:
(a) -PO(OH)O- ~ M+, wherein M+ is a pharmaceutically acceptable monovalent counterion, (b) -PO(O-)2 ~ 2M+, (c) -PO(O-)2 ~ D2+, wherein D2+ is a pharmaceutically acceptable divalent counterion, (d) -CH(R4)-PO(OH)O- ~ M+, wherein R4 is hydrogen or C1-3alkyl, (e) -CH(R4)-PO(O-)2 ~ 2M+, (f) -CH(R4)-PO(O-)2 ~ D2+, (i) -CO-CH2CH2-CO2- ~ M+, (j) -CH(CH3)-O-CO-R5, wherein R5 is selected from the group consisting of:
Y is -O-;
Z is hydrogen or C1-6alkyl;
or a pharmaceutically acceptable salt thereof.
wherein:
R2 and R3 are independently selected from the group consisting of:
(1) hydrogen, (2) C1-6alkyl, (3) C2-6alkenyl, and (4) phenyl;
R6, R7 and R8 are independently selected from the group consisting of:
(1) hydrogen, (2) C1-6alkyl, (3) fluoro, (4) chloro, (5) bromo, (6) iodo, and (7) -CF3;
R11, R12 and R13 are independently selected from the group consisting of:
(1) fluoro, (2) chloro, (3) bromo, and (4) iodo;
A is unsubstituted 1-6alkyl;
B is selected from the group consisting of:
p is 0 or 1;
X is selected from:
(a) -PO(OH)O- ~ M+, wherein M+ is a pharmaceutically acceptable monovalent counterion, (b) -PO(O-)2 ~ 2M+, (c) -PO(O-)2 ~ D2+, wherein D2+ is a pharmaceutically acceptable divalent counterion, (d) -CH(R4)-PO(OH)O- ~ M+, wherein R4 is hydrogen or C1-3alkyl, (e) -CH(R4)-PO(O-)2 ~ 2M+, (f) -CH(R4)-PO(O-)2 ~ D2+, (i) -CO-CH2CH2-CO2- ~ M+, (j) -CH(CH3)-O-CO-R5, wherein R5 is selected from the group consisting of:
Y is -O-;
Z is hydrogen or C1-6alkyl;
or a pharmaceutically acceptable salt thereof.
11. A use according to claim 1 or 2, a composition according to claim 3 or 4, a product according to claim 5 or a method according to claim 6 or 7 wherein the NK-1 receptor antagonist is a compound of formula IVa:
wherein A1 is fluorine or CF3;
A2 is fluorine or CF3;
A3 is fluorine or hydrogen;
X is a group of the formula NR6R7 or a C- or N-linked imidazolyl ring;
Y is hydrogen or C1-4alkyl optionally substituted by a hydroxy group;
R6 is hydrogen, C1-6alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, phenyl, or C2-4alkyl substituted by C1-4alkoxy or hydroxy;
R7 is hydrogen, C1-6alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, phenyl, or C2-4alkyl substituted by one or two substituents selected from C1-4alkoxy, 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(O)2 and which ring may be optionally substituted by one or two groups selected from hydroxyC1-4alkyl, C1-4alkoxyC1-4alkyl, oxo, COR a or CO2R a where R a is hydrogen or C1-4alkyl;
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; and R8 is hydrogen, C1-4alkyl, hydroxyC1-4alkyl or C1-4alkoxyC1-4alkyl;
or a pharmaceutically acceptable salt thereof.
wherein A1 is fluorine or CF3;
A2 is fluorine or CF3;
A3 is fluorine or hydrogen;
X is a group of the formula NR6R7 or a C- or N-linked imidazolyl ring;
Y is hydrogen or C1-4alkyl optionally substituted by a hydroxy group;
R6 is hydrogen, C1-6alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, phenyl, or C2-4alkyl substituted by C1-4alkoxy or hydroxy;
R7 is hydrogen, C1-6alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, phenyl, or C2-4alkyl substituted by one or two substituents selected from C1-4alkoxy, 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(O)2 and which ring may be optionally substituted by one or two groups selected from hydroxyC1-4alkyl, C1-4alkoxyC1-4alkyl, oxo, COR a or CO2R a where R a is hydrogen or C1-4alkyl;
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; and R8 is hydrogen, C1-4alkyl, hydroxyC1-4alkyl or C1-4alkoxyC1-4alkyl;
or a pharmaceutically acceptable salt thereof.
12. A use according to claim 1 or 2, a composition according to claim 3 or 4, a product according to claim 5 or a method according to claim 6 or 7 wherein the NK-1 receptor antagonist is a compound of formula V:
wherein:
Y is (CH2)n wherein n is an integer from 1 to 4, and wherein any one of the carbon-carbon single bonds in said (CH2)n may optionally be replaced by a carbon-carbon double bond, and wherein any one of the carbon atoms of said (CH2)n may optionally be substituted with R4, and wherein any one of the carbon atoms of said (CH2)n may optionally be substituted with R7;
Z is (CH2)m wherein m is an integer from 0 to 6, and wherein any one of the carbon-carbon single bonds of (CH2)m may optionally be replaced by a carbon-carbon double bond or a carbon-carbon triple bond, and any one of the carbon atoms of said (CH2)m may optionally be substituted with R8.
R1 is hydrogen or C1-8alkyl optionally substituted with hydroxy, C1-4alkoxy or fluoro;
R2 is a radical selected from hydrogen, C1-6 straight or branched alkyl, C3-7cycloalkyl wherein one of the CH2 groups in said cycloalkyl may optionally be replaced by NH, oxygen or sulphur; aryl selected from phenyl and naphthyl; heteroaryl selected from indanyl, thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; phenyl-C2-6alkyl, benzhydryl and benzyl, wherein each of said aryl and heteroaryl groups and the phenyl moieties of said benzyl, phenyl-C2-6alkyl and benzhydryl may optionally be substituted with one or more substituents independently selected from halo, nitro, C1-6 alkyl, C-6alkoxy, trifluoromethyl, amino, C1-6alkylamino, C1-6alkyl-O-CO, C1-6alkyl-O-CO-C1-6alkyl, C1-6alkyl-CO-O, C1-6alkyl-CO-C1-6alkyl-O-, C1-6alkyl-CO, C1-6alkyl-CO-C1-6alkyl-, di-C1-6alkylamino, -CONH-C1-6alkyl, C1-6alkyl-CO-NH-C1-6alkyl, -NHCOH and -NHCO-C1-6alkyl; and wherein one of the phenyl moieties of said benzhydryl may optionally be replaced by naphthyl, thienyl, furyl or pyridyl;
R5 is hydrogen, phenyl or C1-6alkyl;
or R2 and R5 together with the carbon to which they are attached, form a saturated ring having from 3 to 7 carbon atoms wherein one of the CH2 groups in said ring may optionally be replaced by oxygen, NH or sulfur;
R3 is aryl selected from phenyl and naphthyl; heteroaryl selected from indanyl, thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; and cycloalkyl having 3 to 7 carbon atoms wherein one of the (CH2) groups in said cycloalkyl may optionally be replaced by NH, oxygen or sulphur;
wherein each of said aryl and heteroaryl groups may optionally be substituted with one or more substituents, and said C3-7cycloalkyl may optionally be substituted with one or two substituents, each of said substituents being independently selected from halo, nitro, C1-6alkyl, C1-6alkoxy, trifluoromethyl, amino, C1-6alkylamino, -CO-NH- C1-6alkyl, C1-6alkyl-CO-NH-C1-6alkyl, -NHCOH and -NHCO-C1-6alkyl;
R4 and R7 are each independently selected from hydroxy, halogen, halo, amino, oxo, cyano, methylene, hydroxymethyl, halomethyl, C1-6alkylamino, di-C1-6alkylamino, C1-6alkoxy, C1-6alkyl-O-CO, C1-6alkyl-O-CO-C1-6alkyl, C1-6alkyl-CO-O, C1-6alkyl-CO-C1-6alkyl-O-, C1-6alkyl-CO-, C1-6alkyl-CO-C1-6alkyl, and the radicals set forth in the definition of R2;
R6 is -NHCOR9, -NHCH2R9, SO2R8 or one of the radicals set forth in any of the definitions of R2, R4 and R7;
R8 is oximino (=NOH) or one of the radicals set forth in any of the definitions of R2, R4 and R7;
R9 is C1-6alkyl, hydrogen, phenyl or phenylC1-6alkyl;
with the proviso that (a) when m is 0, R8 is absent, (b) when R4, R6, R7 or R8 is as defined in R2, it cannot form together with the carbon to which it is attached ,a ring with R5, and (c) when R4 and R7 are attached to the same carbon atom, then either each of R4 and R7 is independently selected from hydrogen, fluoro and C1-6alkyl, or R4 and R7, together with the carbon to which they are attached, for a C3-6 saturated carbocyclic ring that forms a spiro compound with the nitrogen-containing ring to which they are attached;
or a pharmaceutically acceptable salt thereof.
wherein:
Y is (CH2)n wherein n is an integer from 1 to 4, and wherein any one of the carbon-carbon single bonds in said (CH2)n may optionally be replaced by a carbon-carbon double bond, and wherein any one of the carbon atoms of said (CH2)n may optionally be substituted with R4, and wherein any one of the carbon atoms of said (CH2)n may optionally be substituted with R7;
Z is (CH2)m wherein m is an integer from 0 to 6, and wherein any one of the carbon-carbon single bonds of (CH2)m may optionally be replaced by a carbon-carbon double bond or a carbon-carbon triple bond, and any one of the carbon atoms of said (CH2)m may optionally be substituted with R8.
R1 is hydrogen or C1-8alkyl optionally substituted with hydroxy, C1-4alkoxy or fluoro;
R2 is a radical selected from hydrogen, C1-6 straight or branched alkyl, C3-7cycloalkyl wherein one of the CH2 groups in said cycloalkyl may optionally be replaced by NH, oxygen or sulphur; aryl selected from phenyl and naphthyl; heteroaryl selected from indanyl, thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; phenyl-C2-6alkyl, benzhydryl and benzyl, wherein each of said aryl and heteroaryl groups and the phenyl moieties of said benzyl, phenyl-C2-6alkyl and benzhydryl may optionally be substituted with one or more substituents independently selected from halo, nitro, C1-6 alkyl, C-6alkoxy, trifluoromethyl, amino, C1-6alkylamino, C1-6alkyl-O-CO, C1-6alkyl-O-CO-C1-6alkyl, C1-6alkyl-CO-O, C1-6alkyl-CO-C1-6alkyl-O-, C1-6alkyl-CO, C1-6alkyl-CO-C1-6alkyl-, di-C1-6alkylamino, -CONH-C1-6alkyl, C1-6alkyl-CO-NH-C1-6alkyl, -NHCOH and -NHCO-C1-6alkyl; and wherein one of the phenyl moieties of said benzhydryl may optionally be replaced by naphthyl, thienyl, furyl or pyridyl;
R5 is hydrogen, phenyl or C1-6alkyl;
or R2 and R5 together with the carbon to which they are attached, form a saturated ring having from 3 to 7 carbon atoms wherein one of the CH2 groups in said ring may optionally be replaced by oxygen, NH or sulfur;
R3 is aryl selected from phenyl and naphthyl; heteroaryl selected from indanyl, thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; and cycloalkyl having 3 to 7 carbon atoms wherein one of the (CH2) groups in said cycloalkyl may optionally be replaced by NH, oxygen or sulphur;
wherein each of said aryl and heteroaryl groups may optionally be substituted with one or more substituents, and said C3-7cycloalkyl may optionally be substituted with one or two substituents, each of said substituents being independently selected from halo, nitro, C1-6alkyl, C1-6alkoxy, trifluoromethyl, amino, C1-6alkylamino, -CO-NH- C1-6alkyl, C1-6alkyl-CO-NH-C1-6alkyl, -NHCOH and -NHCO-C1-6alkyl;
R4 and R7 are each independently selected from hydroxy, halogen, halo, amino, oxo, cyano, methylene, hydroxymethyl, halomethyl, C1-6alkylamino, di-C1-6alkylamino, C1-6alkoxy, C1-6alkyl-O-CO, C1-6alkyl-O-CO-C1-6alkyl, C1-6alkyl-CO-O, C1-6alkyl-CO-C1-6alkyl-O-, C1-6alkyl-CO-, C1-6alkyl-CO-C1-6alkyl, and the radicals set forth in the definition of R2;
R6 is -NHCOR9, -NHCH2R9, SO2R8 or one of the radicals set forth in any of the definitions of R2, R4 and R7;
R8 is oximino (=NOH) or one of the radicals set forth in any of the definitions of R2, R4 and R7;
R9 is C1-6alkyl, hydrogen, phenyl or phenylC1-6alkyl;
with the proviso that (a) when m is 0, R8 is absent, (b) when R4, R6, R7 or R8 is as defined in R2, it cannot form together with the carbon to which it is attached ,a ring with R5, and (c) when R4 and R7 are attached to the same carbon atom, then either each of R4 and R7 is independently selected from hydrogen, fluoro and C1-6alkyl, or R4 and R7, together with the carbon to which they are attached, for a C3-6 saturated carbocyclic ring that forms a spiro compound with the nitrogen-containing ring to which they are attached;
or a pharmaceutically acceptable salt thereof.
13. A use according to claim 1 or 2, a composition according to claim 3 or 4, a product according to claim 5 or a method according to claim 6 or 7 wherein the NK-1 receptor antagonist is a compound of formula VI:
wherein:
radicals R are phenyl radicals optionally 2- or 3-substituted by a halogen atom or a methyl radical;
R1 is optionally substituted phenyl, cyclohexadienyl, naphthyl, indenyl or optionally substituted heterocycle;
R2 is H, halogen, OH, alkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkyloxy, alkylthio, acyloxy, carboxy, optionally substituted alkyloxycarbonyl, benzyloxycarbonyl, amino or acylamino;
R3 is optionally 2-substituted phenyl;
R4 is OH or fluorine when R5 is H;
or R4 and R5 are OH;
or R4 and R5 together form a bond;
or a pharmaceutically acceptable salt thereof.
wherein:
radicals R are phenyl radicals optionally 2- or 3-substituted by a halogen atom or a methyl radical;
R1 is optionally substituted phenyl, cyclohexadienyl, naphthyl, indenyl or optionally substituted heterocycle;
R2 is H, halogen, OH, alkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkyloxy, alkylthio, acyloxy, carboxy, optionally substituted alkyloxycarbonyl, benzyloxycarbonyl, amino or acylamino;
R3 is optionally 2-substituted phenyl;
R4 is OH or fluorine when R5 is H;
or R4 and R5 are OH;
or R4 and R5 together form a bond;
or a pharmaceutically acceptable salt thereof.
14. A use according to claim 1 or 2, a composition according to claim 3 or 4, a product according to claim 5 or a method according to claim 6 or 7 wherein the NK-1 receptor antagonist is a compound of formula VII:
wherein:
Ar represents an optionally substituted mono-, di- or tricyclic aromatic or heteroaromatic group;
T represents a bond, a hydroxymethylene group, a C1-4alkoxymethylene group or a C1-5alkylene group;
Ar' represents a phenyl group which is unsubstituted or substituted by one or more substituents selected from halogen, preferably chlorine or fluorine, trifluoromethyl, C1-4alkoxy, C1-4alkyl where the said substituents may be the same or different; a thienyl group; a benzothienyl group; a naphthyl group; or an indolyl group;
R represents hydrogen, C1-4alkyl, .omega.-C-4alkoxyC1-4alkyl, or .omega.-C2-4alkanoyloxyC2-4alkyl;
Q represents hydrogen;
or Q and R together form a 1,2-ethylene, 1,3-propylene or 1,4-butylene group;
Am+ represents the radical in which X1, X2 and X3, together with the nitrogen atom to which they are attached, form an azabicyclic or azatricyclic ring system optionally substituted by a phenyl or benzyl group; and A- represents a pharmaceutically acceptable anion.
wherein:
Ar represents an optionally substituted mono-, di- or tricyclic aromatic or heteroaromatic group;
T represents a bond, a hydroxymethylene group, a C1-4alkoxymethylene group or a C1-5alkylene group;
Ar' represents a phenyl group which is unsubstituted or substituted by one or more substituents selected from halogen, preferably chlorine or fluorine, trifluoromethyl, C1-4alkoxy, C1-4alkyl where the said substituents may be the same or different; a thienyl group; a benzothienyl group; a naphthyl group; or an indolyl group;
R represents hydrogen, C1-4alkyl, .omega.-C-4alkoxyC1-4alkyl, or .omega.-C2-4alkanoyloxyC2-4alkyl;
Q represents hydrogen;
or Q and R together form a 1,2-ethylene, 1,3-propylene or 1,4-butylene group;
Am+ represents the radical in which X1, X2 and X3, together with the nitrogen atom to which they are attached, form an azabicyclic or azatricyclic ring system optionally substituted by a phenyl or benzyl group; and A- represents a pharmaceutically acceptable anion.
15. A use according to claim 1 or 2, a composition according to claim 3 or 4, a product according to claim 5 or a method according to claim 6 or 7 wherein the NK-1 receptor antagonist is a compound of formula VIII
wherein:
R1 represents an optionally substituted aralkyl, aryloxyalykl, heteroaralkyl, aroyl, heteroaroyl, cycloalkylcarbonyl, aralkanoyl, heteroarylalkanoyl, aralkoxycarbonyl or arylcarbamoyl group or the acyl group of an .alpha.-amino acid optionally N-substituted by a lower alkanoyl or carbamoyl-lower alkanoyl group;
R2 represents cycloalkyl or an optionally substituted aryl or heteroaryl group;
R3 represents hydrogen, alkyl, carbamoyl or an alkanoyl or alkenoyl group optionally substituted by carboxy or esterified or amidated carboxy;
R4 represents an optionally substituted aryl group or an optionally partially saturated heteroaryl group;
X1 represents methylene, ethylene, a bond, an optionally ketalised carbonyl group or an optionally etherified hydroxymethylene group;
X2 represents alkylene, carbonyl or a bond; and X3 represents carbonyl, oxo-lower alkyl, oxo(aza)-lower alkyl, or an alkyl group optionally substituted by phenyl, hydroxymethyl, optionally esterified or amidated carboxy, or (in other than the .alpha.-position) hydroxy;
or a pharmaceutically acceptable salt thereof.
wherein:
R1 represents an optionally substituted aralkyl, aryloxyalykl, heteroaralkyl, aroyl, heteroaroyl, cycloalkylcarbonyl, aralkanoyl, heteroarylalkanoyl, aralkoxycarbonyl or arylcarbamoyl group or the acyl group of an .alpha.-amino acid optionally N-substituted by a lower alkanoyl or carbamoyl-lower alkanoyl group;
R2 represents cycloalkyl or an optionally substituted aryl or heteroaryl group;
R3 represents hydrogen, alkyl, carbamoyl or an alkanoyl or alkenoyl group optionally substituted by carboxy or esterified or amidated carboxy;
R4 represents an optionally substituted aryl group or an optionally partially saturated heteroaryl group;
X1 represents methylene, ethylene, a bond, an optionally ketalised carbonyl group or an optionally etherified hydroxymethylene group;
X2 represents alkylene, carbonyl or a bond; and X3 represents carbonyl, oxo-lower alkyl, oxo(aza)-lower alkyl, or an alkyl group optionally substituted by phenyl, hydroxymethyl, optionally esterified or amidated carboxy, or (in other than the .alpha.-position) hydroxy;
or a pharmaceutically acceptable salt thereof.
16. A use according to claim 1 or 2, a composition according to claim 3 or 4, a product according to claim 5 or a method according to claim 6 or 7 wherein the NK-1 receptor antagonist is a compound of formula IX:
wherein:
R1 is aryl, or a group of the formula:
X is CH or N; and Z is O or N-R5, in which R5 is hydrogen or lower alkyl;
R2 is hydroxy or lower alkoxy;
R3 is hydrogen or optionally substituted lower alkyl;
R4 is optionally substituted ar(lower)alkyl;
A is carbonyl or sulfonyl; and Y is a bond or lower alkenylene;
or a pharmaceutically acceptable salt thereof.
wherein:
R1 is aryl, or a group of the formula:
X is CH or N; and Z is O or N-R5, in which R5 is hydrogen or lower alkyl;
R2 is hydroxy or lower alkoxy;
R3 is hydrogen or optionally substituted lower alkyl;
R4 is optionally substituted ar(lower)alkyl;
A is carbonyl or sulfonyl; and Y is a bond or lower alkenylene;
or a pharmaceutically acceptable salt thereof.
17. A use according to claim 1 or 2, a composition according to claim 3 or 4, a product according to claim 5 or a method according to claim 6 or 7 wherein the NK-1 receptor antagonist is a compound of formula X:
wherein:
R1 is aryl selected from indanyl, phenyl and naphthyl; heteroaryl selected from thienyl, furyl, pyridyl and quinolyl; and cycloalkyl having 3 to 7 carbon atoms, wherein one of said carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; wherein each of said aryl and heteroaryl groups may optionally be substituted with one or more substituents, and said C1-7cycloalkyl may optionally be substituted with one or two substituents, said substituents being independently selected from chloro, fluoro, bromo, iodo, nitro, C1-10alkyl optionally substituted with from one to three fluoro groups, C1-10alkoxy optionally substituted with from one to three fluoro groups, amino, C1-10alkyl-S-, C1-10alkyl-S(O)-, C1-10alkyl-SO2-, phenyl, phenoxy, C1-10alkyl-SO2NH-, C1-10alkyl-SO2NH-C1-10akyl-, C1-10alkylamino-diC1-10alkyl-, cyano, hydroxy, cycloalkoxy having 3 to 7 carbon atoms, C1-6alkylamino, C1-6dialkylamino, HC(O)NH- and C1-10alkyl-C(O)NH-; and R2 is thienyl, benzhydryl, naphthyl or phenyl optionally substituted with from one to three substituents independently selected from chloro, bromo, fluoro, iodo, cycloalkoxy having 3 to 7 carbon atoms, C1-10alkyl optionally substituted with from one to three fluoro groups and C1-10alkoxy optionally substituted with from one to three fluoro groups;
or a pharmaceutically acceptable salt thereof.
wherein:
R1 is aryl selected from indanyl, phenyl and naphthyl; heteroaryl selected from thienyl, furyl, pyridyl and quinolyl; and cycloalkyl having 3 to 7 carbon atoms, wherein one of said carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; wherein each of said aryl and heteroaryl groups may optionally be substituted with one or more substituents, and said C1-7cycloalkyl may optionally be substituted with one or two substituents, said substituents being independently selected from chloro, fluoro, bromo, iodo, nitro, C1-10alkyl optionally substituted with from one to three fluoro groups, C1-10alkoxy optionally substituted with from one to three fluoro groups, amino, C1-10alkyl-S-, C1-10alkyl-S(O)-, C1-10alkyl-SO2-, phenyl, phenoxy, C1-10alkyl-SO2NH-, C1-10alkyl-SO2NH-C1-10akyl-, C1-10alkylamino-diC1-10alkyl-, cyano, hydroxy, cycloalkoxy having 3 to 7 carbon atoms, C1-6alkylamino, C1-6dialkylamino, HC(O)NH- and C1-10alkyl-C(O)NH-; and R2 is thienyl, benzhydryl, naphthyl or phenyl optionally substituted with from one to three substituents independently selected from chloro, bromo, fluoro, iodo, cycloalkoxy having 3 to 7 carbon atoms, C1-10alkyl optionally substituted with from one to three fluoro groups and C1-10alkoxy optionally substituted with from one to three fluoro groups;
or a pharmaceutically acceptable salt thereof.
18. A use according to claim 1 or 2, a composition according to claim 3 or 4, a product according to claim 5 or a method according to claim 6 or 7 wherein the NK-1 receptor antagonist is a compound of formula XI:
wherein:
R1 is a C1-4alkoxy group;
R2 is R3 is a hydrogen or halogen atom;
R4 and R5 may each independently represent a hydrogen or halogen atom, or a C1-4alkyl, C1-4alkoxy or trifluoromethyl group;
R6 is a hydrogen atom, a C1-4alkyl, (CH2)m cyclopropyl, -S(O)n C1-4alkyl, phenyl, NR7R8, CH2C(O)CF3 or trifluoromethyl group;
R7 and R8 may each independently represent a hydrogen atom, or a C1-4alkyl or acyl group;
x represents zero or 1;
n represents zero, 1 or 2; and m represents zero or 1;
or a pharmaceutically acceptable salt thereof.
wherein:
R1 is a C1-4alkoxy group;
R2 is R3 is a hydrogen or halogen atom;
R4 and R5 may each independently represent a hydrogen or halogen atom, or a C1-4alkyl, C1-4alkoxy or trifluoromethyl group;
R6 is a hydrogen atom, a C1-4alkyl, (CH2)m cyclopropyl, -S(O)n C1-4alkyl, phenyl, NR7R8, CH2C(O)CF3 or trifluoromethyl group;
R7 and R8 may each independently represent a hydrogen atom, or a C1-4alkyl or acyl group;
x represents zero or 1;
n represents zero, 1 or 2; and m represents zero or 1;
or a pharmaceutically acceptable salt thereof.
19. A use according to claim 1 or 2, a composition according to claim 3 or 4, a product according to claim 5 or a method according to claim 6 or 7 wherein the NK-1 receptor antagonist is a compound of formula XII:
wherein:
m is zero, 1, 2 or 3;
n is zero or 1;
o is zero, 1 or 2;
p is zero or 1;
R is phenyl, 2- or 3-indolyl, 2- or 3-indolinyl, benzothienyl, benzofuranyl, or naphthyl;
which R groups may be substituted with one or two halo, C1-3alkoxy, trifluoromethyl, C1-4alkyl, phenyl-C1-3alkoxy, or C1-4alkanoyl groups;
R1 is trityl, phenyl, diphenylmethyl, phenoxy, phenylthio, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, indolinyl, indolyl, benzothienyl, hexamethyleneiminyl, benzofuranyl, tetrahydropyridinyl, quinolinyl, isoquinolinyl, reduced quinolinyl, reduced isoquinolinyl, phenyl-(C1-4alkyl)-, phenyl-(C1-4alkoxy)-, quinolinyl-(C1-4alkyl)-, isoquinolinyl-(C1-4alkyl)-, reduced quniolinyl-(C1-4alkyl)-, reduced isoquinolinyl-(C1-4alkyl)-, benzoyl-(C1-3alkyl)-, C1-4alkyl, or -NH-CH2-R5;
any one of which R1 groups may be substituted with halo, C1-4alkyl, C1-4alkoxy, trifluoromethyl, amino, C1-4alkylamino, di(C1-4alkyl)amino, or C2-4alkanoylamino;
or any one of which R1 groups may be substituted with phenyl, piperazinyl, C3-8cycloalkyl, benzyl, C1-4alkyl, piperidinyl, pyridinyl, pyrimidinyl, C2-6alkanoylamino, pyrrolidinyl, C2-6alkanoyl, or C1-4alkoxycarbonyl;
any one of which groups may be substituted with halo, C1-4alkyl, C1-4alkoxy, trifluoromethyl, amino, C1-4alkylamino, di(C1-4alkyl)amino, or C2-4alkanoylamino;
or R1 is amino, a leaving group, hydrogen, C1-4alkylamino, or di(C1-4alkyl)amino;
R5 is pyridyl, anilino-(C1-3alkyl)-, or anilinocarbonyl;
R2 is hydrogen, C1-4alkyl, C1-4alkylsulfonyl, carboxy-(C1-3alkyl)-, C1-3alkoxycarbonyl-(C1-3alkyl)-, or -CO-R6;
R6 is hydrogen, C1-4alkyl, C1-3haloalkyl, phenyl, C1-3alkoxy, C1-3hydroxyalkyl, amino, C1-4alkylamino, di(C1-4alkyl)amino, or -(CH2)q-R7;
q is zero to 3;
R7 is carboxy, C1-4alkoxycarbonyl, C1-4alkylcarbonyloxy, amino, C1-4alkylamino, di(C1-4alkyl)amino, C1-6alkoxycarbonylamino, or phenoxy, phenylthio, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, indolinyl, indolyl, benzothienyl, benzofuranyl, quinolinyl, phenyl-(C1-4alkyl)-, quinolinyl-(C1-4alkyl)-, isoquinolinyl-(C1-4alkyl)-, reduced quinolinyl-(C1-4alkyl)-, reduced isoquinolinyl-(C1-4alkyl)-, benzoyl-C1-3alkyl;
any one of which aryl or heterocyclic R7 groups may be substituted with halo, trifluoromethyl, C1-4alkoxy, C1-4alkyl, amino, C1-4alkylamino, di(C1-4alkyl)amino, or C2-4alkanoylamino;
or any one of which R7 groups may be substituted with phenyl, piperazinyl, C3-8cycloalkyl, benzyl, piperidinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, C2-6alkanoyl, or C1-4alkoxycarbonyl;
any of which groups may be substituted with halo, trifluoromethyl, amino, C1-4alkoxy, C1-4alkyl, C1-4alkylamino, di(C1-4alkyl)amino, or C2-4alkanoylamino;
R6 is hydrogen or C1-6alkyl;
R3 is phenyl, phenyl-(C1-6alkyl)-, C3-8cycloalkyl, C5-8cycloalkenyl, C1-8alkyl, naphthyl, C2-8alkenyl, or hydrogen;
any one or which groups except hydrogen may be substituted with one or two halo, C1-3alkoxy, C1-3alkylthio, nitro, trifluoromethyl, or C1-3alkyl groups; and R4 is hydrogen or C1-3alkyl;
with the proviso that if R1 is hydrogen or halo, R3 is phenyl, phenyl-(C1-6alkyl)-, C3-8cycloalkyl, C5-8cycloalkenyl, or naphthyl;
or a pharmaceutically acceptable salt thereof.
wherein:
m is zero, 1, 2 or 3;
n is zero or 1;
o is zero, 1 or 2;
p is zero or 1;
R is phenyl, 2- or 3-indolyl, 2- or 3-indolinyl, benzothienyl, benzofuranyl, or naphthyl;
which R groups may be substituted with one or two halo, C1-3alkoxy, trifluoromethyl, C1-4alkyl, phenyl-C1-3alkoxy, or C1-4alkanoyl groups;
R1 is trityl, phenyl, diphenylmethyl, phenoxy, phenylthio, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, indolinyl, indolyl, benzothienyl, hexamethyleneiminyl, benzofuranyl, tetrahydropyridinyl, quinolinyl, isoquinolinyl, reduced quinolinyl, reduced isoquinolinyl, phenyl-(C1-4alkyl)-, phenyl-(C1-4alkoxy)-, quinolinyl-(C1-4alkyl)-, isoquinolinyl-(C1-4alkyl)-, reduced quniolinyl-(C1-4alkyl)-, reduced isoquinolinyl-(C1-4alkyl)-, benzoyl-(C1-3alkyl)-, C1-4alkyl, or -NH-CH2-R5;
any one of which R1 groups may be substituted with halo, C1-4alkyl, C1-4alkoxy, trifluoromethyl, amino, C1-4alkylamino, di(C1-4alkyl)amino, or C2-4alkanoylamino;
or any one of which R1 groups may be substituted with phenyl, piperazinyl, C3-8cycloalkyl, benzyl, C1-4alkyl, piperidinyl, pyridinyl, pyrimidinyl, C2-6alkanoylamino, pyrrolidinyl, C2-6alkanoyl, or C1-4alkoxycarbonyl;
any one of which groups may be substituted with halo, C1-4alkyl, C1-4alkoxy, trifluoromethyl, amino, C1-4alkylamino, di(C1-4alkyl)amino, or C2-4alkanoylamino;
or R1 is amino, a leaving group, hydrogen, C1-4alkylamino, or di(C1-4alkyl)amino;
R5 is pyridyl, anilino-(C1-3alkyl)-, or anilinocarbonyl;
R2 is hydrogen, C1-4alkyl, C1-4alkylsulfonyl, carboxy-(C1-3alkyl)-, C1-3alkoxycarbonyl-(C1-3alkyl)-, or -CO-R6;
R6 is hydrogen, C1-4alkyl, C1-3haloalkyl, phenyl, C1-3alkoxy, C1-3hydroxyalkyl, amino, C1-4alkylamino, di(C1-4alkyl)amino, or -(CH2)q-R7;
q is zero to 3;
R7 is carboxy, C1-4alkoxycarbonyl, C1-4alkylcarbonyloxy, amino, C1-4alkylamino, di(C1-4alkyl)amino, C1-6alkoxycarbonylamino, or phenoxy, phenylthio, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, indolinyl, indolyl, benzothienyl, benzofuranyl, quinolinyl, phenyl-(C1-4alkyl)-, quinolinyl-(C1-4alkyl)-, isoquinolinyl-(C1-4alkyl)-, reduced quinolinyl-(C1-4alkyl)-, reduced isoquinolinyl-(C1-4alkyl)-, benzoyl-C1-3alkyl;
any one of which aryl or heterocyclic R7 groups may be substituted with halo, trifluoromethyl, C1-4alkoxy, C1-4alkyl, amino, C1-4alkylamino, di(C1-4alkyl)amino, or C2-4alkanoylamino;
or any one of which R7 groups may be substituted with phenyl, piperazinyl, C3-8cycloalkyl, benzyl, piperidinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, C2-6alkanoyl, or C1-4alkoxycarbonyl;
any of which groups may be substituted with halo, trifluoromethyl, amino, C1-4alkoxy, C1-4alkyl, C1-4alkylamino, di(C1-4alkyl)amino, or C2-4alkanoylamino;
R6 is hydrogen or C1-6alkyl;
R3 is phenyl, phenyl-(C1-6alkyl)-, C3-8cycloalkyl, C5-8cycloalkenyl, C1-8alkyl, naphthyl, C2-8alkenyl, or hydrogen;
any one or which groups except hydrogen may be substituted with one or two halo, C1-3alkoxy, C1-3alkylthio, nitro, trifluoromethyl, or C1-3alkyl groups; and R4 is hydrogen or C1-3alkyl;
with the proviso that if R1 is hydrogen or halo, R3 is phenyl, phenyl-(C1-6alkyl)-, C3-8cycloalkyl, C5-8cycloalkenyl, or naphthyl;
or a pharmaceutically acceptable salt thereof.
20. A use, composition, product or method according to any one of the preceding claims wherein the NK-1 receptor antagonist is orally active, long acting and CNS-penetrant.
21. A use according to claim 1 or 2, a composition according to claim 3 or 4, a product according to claim 5 or a method according to claim 6 or 7 wherein the NK-1 receptor antagonist is selected from the classes of compounds described in EP-A-0577394, WO-A-9508549, WO-A-9518124, WO-A-9523798 and WO-A-9605181.
22. A use according to claim 1 or 2, a composition according to claim 3 or 4, a product according to claim 5 or a method according to claim 6 or 7 wherein the NK-1 receptor antagonist is selected from 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine;
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)-3-(S)-phenyl-morpholine;
2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-4-(3-(5-oxo-1H,4H-1,2, 4-triazolo)methyl)-3-(S)-phenyl-morpholine;
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine;
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(N,N-dimethylamino)methyl-1,2,3-triazol-4-yl)methyl-3-(S)-phenylmorpholine;
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(N,N-dimethylamino)methyl-1,2,3-triazol-4-yl)methyl-3-(S)-(4-fluorophenyl)morpholine;
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(4-monophosphoryl-5-oxo-1H-1,2,4-triazolo)methyl)morpholine;
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(1-monophosphoryl-5-oxo-1H-1,2,4-triazolo)methyl)morpholine;
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(2-monophosphoryl-5-oxo-1H-1,2,4-triazolo)methyl)morpholine;
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxyphosphoryl-1H-1,2,4-triazolo)methyl)morpholine;
2-(S)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(1-monophosphoryl-5-oxo-4H-1,2,4-triazolo)methyl)morpholine;
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-N,N-dimethylaminobut-2-yn-yl)-3-(S)-(4-fluorophenyl)morpholine;
or a pharmaceutically acceptable salt thereof.
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)-3-(S)-phenyl-morpholine;
2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-4-(3-(5-oxo-1H,4H-1,2, 4-triazolo)methyl)-3-(S)-phenyl-morpholine;
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine;
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(N,N-dimethylamino)methyl-1,2,3-triazol-4-yl)methyl-3-(S)-phenylmorpholine;
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(N,N-dimethylamino)methyl-1,2,3-triazol-4-yl)methyl-3-(S)-(4-fluorophenyl)morpholine;
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(4-monophosphoryl-5-oxo-1H-1,2,4-triazolo)methyl)morpholine;
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(1-monophosphoryl-5-oxo-1H-1,2,4-triazolo)methyl)morpholine;
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(2-monophosphoryl-5-oxo-1H-1,2,4-triazolo)methyl)morpholine;
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxyphosphoryl-1H-1,2,4-triazolo)methyl)morpholine;
2-(S)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(1-monophosphoryl-5-oxo-4H-1,2,4-triazolo)methyl)morpholine;
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-N,N-dimethylaminobut-2-yn-yl)-3-(S)-(4-fluorophenyl)morpholine;
or a pharmaceutically acceptable salt thereof.
23. A use, composition, product or method according to any one of the preceding claims wherein the anorectic agent is selected from aminorex, amphechloral, amphetamine, benzphetamine, chlorphentermine, clobenzorex, cloforex, clominorex, clortermine, cyclexedrine, dexfenfluramine, dextroamphetamine, diethylpropion, diphemethoxidine, N-ethylamphetamine, fenbutrazate, fenfluramine, fenisorex, fenproporex, fludorex, fluminorex, furfurylmethylamphetamine, levamfetamine, levophacetoperane, mazindol, mefenorex, metamfepramone, methamphetamine, norpseudoephedrine, pentorex, phendimetrazine, phenmetrazine, phentermine, phenylpropanolamine, picilorex and sibutramine; or a pharmaceutically acceptable salt thereof.
24. A use, composition, product or method according to any one of the preceding claims wherein the anorectic agent is a halogenated amphetamine derivative.
25. A use, composition, product or method according to claim 24 wherein the amphetamine derivative is selected from chlorphentermine, cloforex, clortermine, dexfenfluramine, fenfluramine, picilorex and sibutramine; or a pharmaceutically acceptable salt thereof.
26. A use, composition, product or method according to any one of claims 1 to 25 wherein the eating disorder is obesity.
27. A use, composition, product or method according to any one of claims 1 to 25 wherein the eating disorder is bulimia nervosa.
28. A use, composition, product or method according to any one of claims 1 to 25 wherein the eating disorder is a compulsive eating disorder.
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB9708289.5 | 1997-04-24 | ||
GBGB9708289.5A GB9708289D0 (en) | 1997-04-24 | 1997-04-24 | Therapeutic use |
GBGB9721265.8A GB9721265D0 (en) | 1997-10-07 | 1997-10-07 | Therapeutic use |
GB9721265.8 | 1997-10-07 | ||
PCT/GB1998/001161 WO1998047513A1 (en) | 1997-04-24 | 1998-04-22 | Use of nk-1 receptor antagonists for treating eating disorders |
Publications (1)
Publication Number | Publication Date |
---|---|
CA2287487A1 true CA2287487A1 (en) | 1998-10-29 |
Family
ID=26311439
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002287487A Abandoned CA2287487A1 (en) | 1997-04-24 | 1998-04-22 | Use of nk-1 receptor antagonists for treating eating disorders |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP0977572A1 (en) |
JP (1) | JP2001524960A (en) |
AU (1) | AU744261B2 (en) |
CA (1) | CA2287487A1 (en) |
WO (1) | WO1998047513A1 (en) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2003519087A (en) * | 1999-03-19 | 2003-06-17 | クノール・ゲー・エム・ベー・ハー | How to treat eating disorders |
AU7750100A (en) * | 1999-10-13 | 2001-04-23 | Glaxo Group Limited | Method for the treatment of obesity |
MXPA03008484A (en) * | 2001-03-21 | 2003-12-08 | Pharmacopeia Inc | Aryl and biaryl compounds having mch modulatory activity. |
DE10311984A1 (en) * | 2003-03-12 | 2004-09-23 | Freie Universität Berlin | Using neutral endopeptidase-associated molecules for treatment, diagnosis, prophylaxis and monitoring of eating and metabolic disorders and dementia, also for drug development |
CN106290894A (en) * | 2016-07-21 | 2017-01-04 | 浙江理工大学 | A kind of leukemia detection kit based on NK1R albumen |
Family Cites Families (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB8929070D0 (en) * | 1989-12-22 | 1990-02-28 | Fujisawa Pharmaceutical Co | Peptide compounds,processes for preparation thereof and pharmaceutical composition comprising the same |
WO1991009844A1 (en) * | 1990-01-04 | 1991-07-11 | Pfizer Inc. | Substance p antagonists |
RU2105001C1 (en) * | 1991-03-26 | 1998-02-20 | Пфайзер Инк. | Method of synthesis of substituted 3-aminopiperidine |
MY110227A (en) * | 1991-08-12 | 1998-03-31 | Ciba Geigy Ag | 1-acylpiperindine compounds. |
FR2689888B1 (en) * | 1992-04-10 | 1994-06-10 | Rhone Poulenc Rorer Sa | NOVEL PERHYDROISOINDOLE DERIVATIVES, THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. |
CA2099233A1 (en) * | 1992-06-29 | 1993-12-30 | Conrad P. Dorn | Morpholine and thiomorpholine tachykinin receptor antagonists |
FR2696178B1 (en) * | 1992-09-30 | 1994-12-30 | Sanofi Elf | Quaternary basic amides, process for their preparation and pharmaceutical compositions containing them. |
IS4208A (en) * | 1993-09-22 | 1995-03-23 | Glaxo Group Limited | 3- (tetrazolyl-benzyl) amino-piperadidine derivatives |
US6403577B1 (en) * | 1993-11-17 | 2002-06-11 | Eli Lilly And Company | Hexamethyleneiminyl tachykinin receptor antagonists |
SG52217A1 (en) * | 1993-12-29 | 1998-09-28 | Merck Sharp & Dohme | Substituted morpholine derivatives and their use as therapeutic agents |
IL112778A0 (en) * | 1994-03-04 | 1995-05-26 | Merck & Co Inc | Substituted heterocycles, their preparation and pharmaceutical compositions containing them |
JP2002502351A (en) * | 1994-08-15 | 2002-01-22 | メルク シヤープ エンド ドーム リミテツド | Morpholine derivatives and their use as therapeutics |
AU4918796A (en) * | 1995-02-10 | 1996-08-27 | Eli Lilly And Company | Methods of treating or preventing psychiatric disorders |
AU6025296A (en) * | 1995-05-25 | 1996-12-11 | Biofrontiers, Inc. | Pharmaceutical compositions containing calcium sulfate |
ZA966891B (en) * | 1995-08-21 | 1998-02-16 | Lilly Co Eli | 2-acylaminopropanamines as growth hormone secretagogues. |
AU2611297A (en) * | 1996-04-12 | 1997-11-07 | Eli Lilly And Company | Bisindoles for treating pain or nociception |
PL330235A1 (en) * | 1996-06-21 | 1999-05-10 | Merck Sharp & Dohme | Derivatives of spiropiperidine and their application as therapeutic agents |
GB9613969D0 (en) * | 1996-07-03 | 1996-09-04 | Merck Sharp & Dohme | Therapeutic agents |
-
1998
- 1998-04-22 EP EP98917425A patent/EP0977572A1/en not_active Withdrawn
- 1998-04-22 AU AU70657/98A patent/AU744261B2/en not_active Ceased
- 1998-04-22 WO PCT/GB1998/001161 patent/WO1998047513A1/en not_active Application Discontinuation
- 1998-04-22 JP JP54529098A patent/JP2001524960A/en active Pending
- 1998-04-22 CA CA002287487A patent/CA2287487A1/en not_active Abandoned
Also Published As
Publication number | Publication date |
---|---|
AU7065798A (en) | 1998-11-13 |
AU744261B2 (en) | 2002-02-21 |
EP0977572A1 (en) | 2000-02-09 |
JP2001524960A (en) | 2001-12-04 |
WO1998047513A1 (en) | 1998-10-29 |
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