AU2774602A - Use of inhibitors of cyclooxygenase in the treatment of neurodegenerative diseases - Google Patents
Use of inhibitors of cyclooxygenase in the treatment of neurodegenerative diseases Download PDFInfo
- Publication number
- AU2774602A AU2774602A AU27746/02A AU2774602A AU2774602A AU 2774602 A AU2774602 A AU 2774602A AU 27746/02 A AU27746/02 A AU 27746/02A AU 2774602 A AU2774602 A AU 2774602A AU 2774602 A AU2774602 A AU 2774602A
- Authority
- AU
- Australia
- Prior art keywords
- cox
- inhibitor
- steroid
- treatment
- prophylaxis
- 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
- 239000003112 inhibitor Substances 0.000 title claims description 52
- 238000011282 treatment Methods 0.000 title claims description 30
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 title description 13
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 title description 13
- 230000004770 neurodegeneration Effects 0.000 title description 5
- 208000015122 neurodegenerative disease Diseases 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims description 31
- 238000000034 method Methods 0.000 claims description 31
- 150000003431 steroids Chemical class 0.000 claims description 31
- 208000024827 Alzheimer disease Diseases 0.000 claims description 21
- 241000282414 Homo sapiens Species 0.000 claims description 16
- 239000003814 drug Substances 0.000 claims description 13
- 150000003839 salts Chemical class 0.000 claims description 13
- 239000000203 mixture Substances 0.000 claims description 11
- 125000001424 substituent group Chemical group 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 125000003118 aryl group Chemical group 0.000 claims description 6
- 230000000694 effects Effects 0.000 claims description 6
- 230000002496 gastric effect Effects 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 230000037396 body weight Effects 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 102000004190 Enzymes Human genes 0.000 claims description 4
- 108090000790 Enzymes Proteins 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 230000005764 inhibitory process Effects 0.000 claims description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 238000011321 prophylaxis Methods 0.000 claims 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 102100038277 Prostaglandin G/H synthase 1 Human genes 0.000 claims 1
- 108050003243 Prostaglandin G/H synthase 1 Proteins 0.000 claims 1
- 239000003260 cyclooxygenase 1 inhibitor Substances 0.000 claims 1
- 150000002431 hydrogen Chemical class 0.000 claims 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims 1
- 229920002554 vinyl polymer Polymers 0.000 claims 1
- -1 chioro Chemical group 0.000 description 21
- 201000010099 disease Diseases 0.000 description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 9
- 239000004480 active ingredient Substances 0.000 description 8
- 231100000252 nontoxic Toxicity 0.000 description 8
- 230000003000 nontoxic effect Effects 0.000 description 8
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 7
- 239000008194 pharmaceutical composition Substances 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- 239000003795 chemical substances by application Substances 0.000 description 6
- 239000000796 flavoring agent Substances 0.000 description 6
- 239000000546 pharmaceutical excipient Substances 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 239000003765 sweetening agent Substances 0.000 description 6
- 239000007859 condensation product Substances 0.000 description 5
- 235000014113 dietary fatty acids Nutrition 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 239000000194 fatty acid Substances 0.000 description 5
- 229930195729 fatty acid Natural products 0.000 description 5
- 150000004665 fatty acids Chemical class 0.000 description 5
- 235000003599 food sweetener Nutrition 0.000 description 5
- 125000001072 heteroaryl group Chemical class 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 239000007900 aqueous suspension Substances 0.000 description 4
- 125000004429 atom Chemical group 0.000 description 4
- 239000003086 colorant Substances 0.000 description 4
- 239000002270 dispersing agent Substances 0.000 description 4
- 235000013355 food flavoring agent Nutrition 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 230000001404 mediated effect Effects 0.000 description 4
- 108020004999 messenger RNA Proteins 0.000 description 4
- 239000003755 preservative agent Substances 0.000 description 4
- 239000000375 suspending agent Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 239000000080 wetting agent Substances 0.000 description 4
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 3
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 102100038280 Prostaglandin G/H synthase 2 Human genes 0.000 description 3
- 108050003267 Prostaglandin G/H synthase 2 Proteins 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 210000004556 brain Anatomy 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 125000005843 halogen group Chemical group 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 229940057995 liquid paraffin Drugs 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 235000019198 oils Nutrition 0.000 description 3
- 239000004006 olive oil Substances 0.000 description 3
- 235000008390 olive oil Nutrition 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000001593 sorbitan monooleate Substances 0.000 description 3
- 235000011069 sorbitan monooleate Nutrition 0.000 description 3
- 229940035049 sorbitan monooleate Drugs 0.000 description 3
- 210000003478 temporal lobe Anatomy 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- IZHVBANLECCAGF-UHFFFAOYSA-N 2-hydroxy-3-(octadecanoyloxy)propyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCCCCCCCCCCC IZHVBANLECCAGF-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- 235000003911 Arachis Nutrition 0.000 description 2
- 244000105624 Arachis hypogaea Species 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 102000010907 Cyclooxygenase 2 Human genes 0.000 description 2
- 108010037462 Cyclooxygenase 2 Proteins 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 125000004414 alkyl thio group Chemical group 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 229910000389 calcium phosphate Inorganic materials 0.000 description 2
- 235000011010 calcium phosphates Nutrition 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 239000012876 carrier material Substances 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 125000006125 ethylsulfonyl group Chemical group 0.000 description 2
- 125000001207 fluorophenyl group Chemical group 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- 210000001320 hippocampus Anatomy 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 239000000787 lecithin Substances 0.000 description 2
- 235000010445 lecithin Nutrition 0.000 description 2
- 229940067606 lecithin Drugs 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000002480 mineral oil Substances 0.000 description 2
- 235000010446 mineral oil Nutrition 0.000 description 2
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 2
- 239000000346 nonvolatile oil Substances 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- YAPQBXQYLJRXSA-UHFFFAOYSA-N theobromine Chemical compound CN1C(=O)NC(=O)C2=C1N=CN2C YAPQBXQYLJRXSA-UHFFFAOYSA-N 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- UGUHFDPGDQDVGX-UHFFFAOYSA-N 1,2,3-thiadiazole Chemical compound C1=CSN=N1 UGUHFDPGDQDVGX-UHFFFAOYSA-N 0.000 description 1
- HTJMXYRLEDBSLT-UHFFFAOYSA-N 1,2,4,5-tetrazine Chemical compound C1=NN=CN=N1 HTJMXYRLEDBSLT-UHFFFAOYSA-N 0.000 description 1
- FYADHXFMURLYQI-UHFFFAOYSA-N 1,2,4-triazine Chemical compound C1=CN=NC=N1 FYADHXFMURLYQI-UHFFFAOYSA-N 0.000 description 1
- FKASFBLJDCHBNZ-UHFFFAOYSA-N 1,3,4-oxadiazole Chemical compound C1=NN=CO1 FKASFBLJDCHBNZ-UHFFFAOYSA-N 0.000 description 1
- MBIZXFATKUQOOA-UHFFFAOYSA-N 1,3,4-thiadiazole Chemical compound C1=NN=CS1 MBIZXFATKUQOOA-UHFFFAOYSA-N 0.000 description 1
- JIHQDMXYYFUGFV-UHFFFAOYSA-N 1,3,5-triazine Chemical compound C1=NC=NC=N1 JIHQDMXYYFUGFV-UHFFFAOYSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- QWENRTYMTSOGBR-UHFFFAOYSA-N 1H-1,2,3-Triazole Chemical compound C=1C=NNN=1 QWENRTYMTSOGBR-UHFFFAOYSA-N 0.000 description 1
- MSWZFWKMSRAUBD-IVMDWMLBSA-N 2-amino-2-deoxy-D-glucopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-IVMDWMLBSA-N 0.000 description 1
- BFSVOASYOCHEOV-UHFFFAOYSA-N 2-diethylaminoethanol Chemical compound CCN(CC)CCO BFSVOASYOCHEOV-UHFFFAOYSA-N 0.000 description 1
- 229940013085 2-diethylaminoethanol Drugs 0.000 description 1
- LOXBELRNKUFSRD-UHFFFAOYSA-N 2-propan-2-ylthiophene Chemical compound CC(C)C1=CC=CS1 LOXBELRNKUFSRD-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- IAMGDENNUQQLMF-UHFFFAOYSA-N 3-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)furan Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=COC=C1C1=CC=C(F)C=C1 IAMGDENNUQQLMF-UHFFFAOYSA-N 0.000 description 1
- PPANKSYRGIOHDR-UHFFFAOYSA-N 4-(2-cyclohexylthiophen-3-yl)benzenesulfonamide Chemical compound C1=CC(S(=O)(=O)N)=CC=C1C1=C(C2CCCCC2)SC=C1 PPANKSYRGIOHDR-UHFFFAOYSA-N 0.000 description 1
- SFBGMMQOTOMLPM-UHFFFAOYSA-N 4-[2-(4-fluorophenyl)-5-(2-hydroxypropan-2-yl)thiophen-3-yl]benzenesulfonamide Chemical compound S1C(C(C)(O)C)=CC(C=2C=CC(=CC=2)S(N)(=O)=O)=C1C1=CC=C(F)C=C1 SFBGMMQOTOMLPM-UHFFFAOYSA-N 0.000 description 1
- ZLHDOXPADGPKBN-UHFFFAOYSA-N 4-[3-(4-fluorophenyl)thiophen-2-yl]benzenesulfonamide Chemical compound C1=CC(S(=O)(=O)N)=CC=C1C1=C(C=2C=CC(F)=CC=2)C=CS1 ZLHDOXPADGPKBN-UHFFFAOYSA-N 0.000 description 1
- HVCNXQOWACZAFN-UHFFFAOYSA-N 4-ethylmorpholine Chemical compound CCN1CCOCC1 HVCNXQOWACZAFN-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-M 4-hydroxybenzoate Chemical compound OC1=CC=C(C([O-])=O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-M 0.000 description 1
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 description 1
- OBDSMARGWORFMU-UHFFFAOYSA-N 5,5-dimethyl-4-(4-methylsulfonylphenyl)-3-naphthalen-2-ylfuran-2-one Chemical compound CC1(C)OC(=O)C(C=2C=C3C=CC=CC3=CC=2)=C1C1=CC=C(S(C)(=O)=O)C=C1 OBDSMARGWORFMU-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 235000006491 Acacia senegal Nutrition 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 101100111459 Arabidopsis thaliana BHLH67 gene Proteins 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 108010011485 Aspartame Proteins 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- KWIUHFFTVRNATP-UHFFFAOYSA-N Betaine Natural products C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 206010012289 Dementia Diseases 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- CWYNVVGOOAEACU-UHFFFAOYSA-N Fe2+ Chemical compound [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 244000068988 Glycine max Species 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- KWIUHFFTVRNATP-UHFFFAOYSA-O N,N,N-trimethylglycinium Chemical compound C[N+](C)(C)CC(O)=O KWIUHFFTVRNATP-UHFFFAOYSA-O 0.000 description 1
- UEEJHVSXFDXPFK-UHFFFAOYSA-N N-dimethylaminoethanol Chemical compound CN(C)CCO UEEJHVSXFDXPFK-UHFFFAOYSA-N 0.000 description 1
- HTLZVHNRZJPSMI-UHFFFAOYSA-N N-ethylpiperidine Chemical compound CCN1CCCCC1 HTLZVHNRZJPSMI-UHFFFAOYSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- 238000010222 PCR analysis Methods 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- WERKSKAQRVDLDW-ANOHMWSOSA-N [(2s,3r,4r,5r)-2,3,4,5,6-pentahydroxyhexyl] (z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO WERKSKAQRVDLDW-ANOHMWSOSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- WDJHALXBUFZDSR-UHFFFAOYSA-N acetoacetic acid Chemical compound CC(=O)CC(O)=O WDJHALXBUFZDSR-UHFFFAOYSA-N 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000007131 anti Alzheimer effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 229960003121 arginine Drugs 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 239000000605 aspartame Substances 0.000 description 1
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 1
- 235000010357 aspartame Nutrition 0.000 description 1
- 229960003438 aspartame Drugs 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- 125000005605 benzo group Chemical group 0.000 description 1
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 1
- 229960003237 betaine Drugs 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 235000019437 butane-1,3-diol Nutrition 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229960001948 caffeine Drugs 0.000 description 1
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 208000015114 central nervous system disease Diseases 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 125000004212 difluorophenyl group Chemical group 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 239000003974 emollient agent Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000002158 endotoxin Substances 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- JKFAIQOWCVVSKC-UHFFFAOYSA-N furazan Chemical compound C=1C=NON=1 JKFAIQOWCVVSKC-UHFFFAOYSA-N 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 229960002442 glucosamine Drugs 0.000 description 1
- 229940074045 glyceryl distearate Drugs 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- FBPFZTCFMRRESA-UHFFFAOYSA-N hexane-1,2,3,4,5,6-hexol Chemical compound OCC(O)C(O)C(O)C(O)CO FBPFZTCFMRRESA-UHFFFAOYSA-N 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 238000009396 hybridization Methods 0.000 description 1
- XGIHQYAWBCFNPY-AZOCGYLKSA-N hydrabamine Chemical compound C([C@@H]12)CC3=CC(C(C)C)=CC=C3[C@@]2(C)CCC[C@@]1(C)CNCCNC[C@@]1(C)[C@@H]2CCC3=CC(C(C)C)=CC=C3[C@@]2(C)CCC1 XGIHQYAWBCFNPY-AZOCGYLKSA-N 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 230000004968 inflammatory condition Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 229940102213 injectable suspension Drugs 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- 235000015110 jellies Nutrition 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 239000003226 mitogen Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- ACTNHJDHMQSOGL-UHFFFAOYSA-N n',n'-dibenzylethane-1,2-diamine Chemical compound C=1C=CC=CC=1CN(CCN)CC1=CC=CC=C1 ACTNHJDHMQSOGL-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical class 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 231100000344 non-irritating Toxicity 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 229920000768 polyamine Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002599 prostaglandin synthase inhibitor Substances 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- RZJQGNCSTQAWON-UHFFFAOYSA-N rofecoxib Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=C(C=2C=CC=CC=2)C(=O)OC1 RZJQGNCSTQAWON-UHFFFAOYSA-N 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 229910001467 sodium calcium phosphate Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 229960004559 theobromine Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
S&FRef: 370689D1
AUSTRALIA
PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT
ORIGINAL
Name and Address of Applicants: Merck Sharp Dohme Limited Hertford Road, Hoddesdon Hertfordshire EN11 9BU United Kingdom Merck Frosst Canada Co.
16711 Trans-Canada Highway Kirkland Quebec H9H 3L1 Canada Actual Inventor(s): Address for Service: Yves Ducharme, Jacques Yves Gauthier, Petpiboon Prasit, Yves Leblanc, Zhaoyin Wang, Serge Leger, Michel Therien, Raymond George Hill and Dalip Jaicaran Sastri Sirinathsinghji Spruson Ferguson St Martins Tower,Level 31 Market Street Sydney NSW 2000 (CCN 3710000177) Use of Inhibitors of Cyclooxygenase in the Treatment of Neurodegenerative Diseases Invention Title: The following statement is a full description of this invention, including the best method of performing it known to me/us:- 5845c SUse of Inhibitors of Cyclooxygenase in the Treatment of Neurodegenerative Diseases The present invention relates to a method of treating Alzheimers disease and to the use of compounds in the preparation of a medicament for the treatment of Alzheimers disease.
US Patent No. 5,192,753 states inter alia that dementia in human beings may be treated with compounds selected from the non-steroidal anti-inflammatory group of cyclooxygenase inhibitors.
The non-steroid anti-inflammatory drugs (NSAIDs) referred to in US Patent No. 5,192,753 are all agents which possess significant ability to inhibit cyclooxygenase type 1 (COX-1). A number of publications have also occurred in the scientific literature which disclose that agents such as to acetylacetic acid and indomethecin, which are generally viewed as potent inhibitors of COX-1, can be used in the treatment of Alzheimers disease; see for example: McGeer et al, Lancet, 1990:335, 1037; Rogers et al, Neurology, 1993:43, 1609-1611; McGeer et al, Neurology, 1992:42, 447-449; and is Breitner et al, Neurology, 1994, 227-232.
Cyclooxygenase (COX) exists in the human as cyclooxygenase type I (COX-I) and cyclooxygenase type II (COX-II). Hitherto there has been no suggestion that COX-II plays any role in Alzheimers disease. Indeed there has been no evidence which demonstrates that COX-II plays a part in any human central nervous system disorder. COX-II is inducible by a number of agents such as 20 mitogen, endotoxin, cytokines and the like but none of these agents which have been demonstrated as inducing COX-II have been shown to be causative in Alzheimers disease.
However, it has now been unexpectedly discovered that COX-II is found in neurons in the temporal lobes of humans suffering from Alzheimers disease.
The present invention provides a method of treating Alzheimers disease which comprises administering to a human in need thereof a therapeutically effective amount of a non-steroid COX-II inhibitor.
From another aspect this invention provides the use of a COX-II inhibitor in the manufacture of a medicament for the treatment of Alzheimers disease.
When used herein the term "treating" includes treatment of existing disease and propylactic treatment of those at risk of developing the disease.
When used herein the term "COX-II" inhibitor means a compound able to inhibit human COX-II enzyme without causing relatively significant inhibition of human COX-I enzyme. Generally compounds which bind at least 10 times as well to COX-II receptors as to COX-I receptors (ie will have a ICso COX-II receptor only one tenth the numerical value of the COX-I receptor) are chosen for use in the invention, more aptly 20 times as well, favourably 50 times as well most favourably at least .100 times as well, and preferably at least 1000 times as well.
The COX-II inhibitors for use in this invention are most aptly those which are highly brain penetrant so that the maximum concentration of COX-II inhibitor after administration of the antialzheimer effective does of COX-II inhibitors is at least the binding ICso value and preferably at least times that value for example at least 100 times the binding ICso value.
The COX-Il inhibitor may be of any structural type other than a steroid. However, most aptly the COX-Il inhibitor employed in this invention is not a carboxylic acid or a salt thereof. Most favourably it will possess a S02CH 3
NHSO
2
CH
3 SO2NH 2
SO
2
NHCH
3 or like substituent on an aromatic ring especially on a phenyl ring.
Our investigations and statements made in the more recent of the following patents indicate o1 that COX-ll inhibitors may be found in US Patent Nos. 4,375,479; 4,590,205; 4,820,827; 5,343,991; EP 0418845; WO 91/19708; WO 94/15932 and WO 94/13635. Each of the above documents is incorporated herein by cross reference.
Thus in one aspect this invention provides a method of treating Alzheimers disease which comprises administering to a patient a therapeutically effective amount of a compound generically disclosed (and preferably a compound specifically described) in US Patent Nos. 4,375,479; 4,590,205; 4,820,827; 5,344,991; EP 0418845; WO 91/19708; WO 94/15932 or WO 94/13635.
The invention also provides the use of such compounds in the manufacture of a medicament for the treatment of Alzheimers disease.
Favourably the COX-ll inhibitor employed is one described in WO 94/26751 (published S" 20 November 24,1994); WO 94/20480 (published September 15, 1994); US 5,436,265 (issued July 1995); WO 95/00501 (published January 5, 1995); WO 95/18799 (published July 13, 1995) and GB 2283745 (published May 17, 1995) all of which are included herein by cross-reference (ie may be S. read together with this Specification).
Most favourably the COX-ll inhibitor employed is one described in WO 95/00501, especially those wherein R 1 is a SO2CH 3 group.
Preferred compounds for use in this invention are compounds named in WO 95/00501.
The medicaments for treating Alzheimers disease may be formulated as described in the aforementioned referenced documents. The medicament may be employed in the doses and regimens set out in the aforementioned referenced documents with respect to the treatment of diseases which benefit from the administration of a COX-II inhibitor.
It is a great advantage of this invention that treatment may be carried out without causing gastric side effects of the type that can occur when COX-I inhibitors are used for prolonged periods.
Since neurodegenerative diseases such as Alzheimers disease are generally progressive treatment may need to take place for a number of years. Thus the provision of medicaments which are surprisingly effective without any significant tendency to cause gastric side effects at the therapeutic ,dose is of great use particularly to the elderly. The use of medicaments of this invention for the treatment of patients who are asymptomatic is also envisaged especially in those cases wlheregenetic information suggests that the patient is likely to develop Alzheimers disease.
The invention encompasses the use of a novel compound of Formula I useful in the treatment of a neurodegenerative disease such as Alzheimers disease: 0 R z x-Y or pharmaceutically acceptable salts thereof wherein: X-Y-Z-is selected from the group consisting of: -CH2CH 2
CH
2
-G(O)CH
2
CH
2 -CH2CH 2
-CR
5
(R
5
-C(O)-O-CR
5 -CH2-NR 3
-CH
2
-CR
4
=CR
4
-S-CR
4 =0R 4 'A 4 THIS PAGE HAS BEEN LEFT INTENTIONALLY BLANK
-S-N=CH-,
-CH=N-S-,
-N=CR
4 (mn) -O-CR4=N.
-N=CR
4
-NH.;
-N=CR
4 and (pY -S-CR 4
-C(O)-NR
3
-CR
5
(R.
5
-R
3 N-CH=CH- provided Plis not -S(O)2Me 1o
-CH=CH-NR
3 provided Rlis not -S(O)2Me when side b is a double bond, and sides a an c are, single bonds; and X-Y-Z-is selected from the group consisting of: is =CH-O-CH=, and
=CH-NR
3
-CH=,
=N-S-CH=,
=CH-S-N=,
=N-O-CH=,
when sides a and c are double bonds and side b is a single bond; R1 is selected from the group consisting of S(O)2CH3, S(O)2NH2, S(O)2NHC(O)CF3, S(O)(NH)CH3, S(O)(NH)NH2,
S(O)(NH)NHC(O)CF
3 P(O)(CH3)OH, and P(O)(CH3)NH2,
R
2 is selected from the group consisting of C 1-6alkyl, C3, C4, C5, C6, and C7, cycloalkyl, mono-, di- or tn-substituted phenyl or naphthyl wherein the substituent is selected from the group consisting of -6 hydrogen, halo, C1.6alkoxy, C 1-6alkyl thio0,
CN,
CF3, N3, -CO2H, (10) -C02-CI-4alkyl, (12) -C(R 5
)(R
6 1-alky1, and (13) -CI-6alkyl-002-R 5 mono-, dli- or tri-substituted heteroaryl wherein the heteroaryl is a monocyclic aromatic ring of 5 atoms, said ring having one hetero atom which is S, 0, or N, and optionally 1, 2, or 3 additionally N atoms; or the heteroaryl is a rndnocychc ring of 6 atoms, said ring having one hetero atom which is N, and optionally 1, 2, 3, or 4 additional N atoms; said substituents are selected from the group consisting of hydrogen, halo, including fluoro, chioro, bromo and iodo, (3 C 9.lkl C1-Galkoxy, Cl-Calkylthio,
CN,
CF3, N3, *0 30 -C(R 5
)(R
6 and
-C(R
5
)(R
6 14alkyl; benzoheteroaryl which includes the benzo fused analogs of
R
3 is selected from the group consisting of hydrogen, CF3,
CN,
.7- (h)
R
4 and R 4 (a) (b) (c) (d) (e) (h) CI-6alkyl, hydlroxyC 1-Galkyl, 1-Galkyl, optionally substituted -C 1-5 alkyl-Q, -CI-3alkyl-O-C1..3alkyl-Q, -C1..3alkyl-S-CI-3alkyl-Q, -C i-5 alkyl-O-Q, or wherein the substituent resides on the alkyl. and the substituent is C 1-3alkyl;
-Q
are each independently selected from the group consisting of hydrogen, CF3,
CN,
CI-Galkyl, and optionally substituted -Cl-s alkyl-Q, -0-C I-5 alkyl-Q, -SC. alkyl--1.3lylQ -CI.3alkyl-S-Cl.3alkyl-Q, -CI-5 alkyl-0-Q, -Cl-s alkyl-S-Q, wherein the substituent resides on the alkyl and the substituent is C1-3alky1, and
R
7 and R 8 are each independently selected from the group 0~
R
5
R
5
RG
consisting of hydrogen, or R 5 and R 6 or R 7 and R 8 together with the carbon to which they are attached form a saturated monocyclic carbon ring of 3, 4, 6 or 7 atoms; Q is CO2H, C02-C 1-4alky1, tetrazolyl-5-yl, C(R 7
)(R
8 or provided that when X-Y-Z is -S-CR 4
CR
4 then R 4 and R 4 are other than CF3.
On~e Class within this embodiment are the compounds 'of formula I bZ
-Y
or pharmacetically acceptable salts thereof wherein: X-Y-Z- is selected from the group consisti ng of -C(O)-O-CR 5
(R
5 when side b is a double bond, and sides a and c are single bonds; and
R
1 is selected from the group consisting of S(O)2QH3, S(O)2NH2,
R
2 is selected from the group consisting of Cl-ralkyl, C3, C4, C5, C6, and cycloalkyl, heteroaryl benzoheteroaryl mono- or di-substituted phenyl wherein the substituent is selected from the group consisting of :*see* 2 hydrogen, halo, Cl.Galkoxy, C 1-alkylthio,
CN,
CF3, Cl.6alkyl, N3, -9- -C02H1, -CO2-C 1-4alkyl, (11) -C(R 5 )cRG)-OH, (12) -C(R 5
)(R
6 3)-O-C1..4alkyl, and (13) -Cl-Galkyl-CO2-R 5
R
5 R1 5 and RG are each independently selected from the group consisting of hydrogen, Cl..6alkyl, or R 5 and R 6 together with the carbon to which they are attached form a'saturated monocycdic carbon ring of 3, 4, 5, 6 or 7 atoms.
For purposes of this specification alkyl is defined to include linear, branched, and cyclic structures, 'With C 1-6alkyl including including methyl, ethyl, propyl, 2-propyl, s- and t-butyl, butyl, pentyl, hexyl, 1,1dimethylethyl, cyclopropyl, cyclobutyl, cyclopen tyl and cyc] ohexyl.
Similarly, Cl-Galkoxy is intended to include alkoxy groups of from 1 to 6 carbon atoms of a straight, branched, or cyclic config-uration. Examples of 20 lower alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy, and the like. Likewise, C1.6alkylthio is intended to include alkylthio groups of from I to 6 carbon atoms of a straight, branched or cyclic configuration. Examples of lower alkylthio :groups include methylthio, propylthio, isopropylthio, cycloheptylthio, etc.
By way of illustration, the propylthio group signifies -SCH 2
CH
2
CH
3 Heteroaryl includes furan, thiophene, pyrrole, isoxazole, isothiazole, pyrazole, oxazole, thiazole, imidazole, 1,2 ,3-oxa-diazole, 1,2,3 thiadiazole, 1,2,3-triazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,3,4triazole, 1,2,5-oxadiazole, 1,2,5-thiadiazo le, pyridine, pyridazine, :30 pyrimidine, pyrazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,4,5-tetrazine, and the like.
Benzoheteroaryl includes the above hieteroaryi ings to which it is possible to fuse a benzene ring.
Exemplifying the invention are: 3-(4-(Aminosulfonyl)phenyl)-2-(4-fluorophenyl)-5-(2hydroxy-2-propyl)thiophene, 3 (Aminosulfonyl)ph enyl) -2 (4 -flu oroph enyl)thiophene, 3 -(4-(Aminosulfonyl)ph enyl) fluorop henyl) (2 propyl)thiophene, 3-(4-(Aminosulfonyl)phenyl)-2-cyclohexylthiophene, 5-(4-Carboxyphenyl)-4-(4- (methylsulfonylphenyl)thiophene-2 -carboxylic acid, orophenyl)- 2 -methyl- 5 (methylsulfonyl)phenyl)thiazole, 2-(4-Fluorophenyl)-3 ethylsulfonyl)phenyl)-2 cyclopenten- 1-one 4-(4-(Methylsulfonyl)phenyl)5-(4-fluorophenyl)isothiazole, 3-(4.Fluorophenyl)-4-(4-(methyiufonyI)phelyl)-2-(5THfuranone, 3-(4.Fluorophenyl)4-(4-(aminosulfonyl)phenyl)-2-(5H)furan one, 3-(4-Fluorophenyl)-4-(4-(methylsulfonyl)phenyl)furan, ,5-Dimethyl-3-(4-fluorophenyl)-4-(4methylsulfonyl)phenyl) (511)-furan one, (in) 2-(4-(Aminosulfonyl)phenyl)- 3-(4 -fluorophenyl)thiophene, an) d3(4-(Trifluoroacetylaminosufony)phenyl)-2 fluoroph enyl) thioph en e, 3 -Flu orophenyl)- 4-(4 -(methvlsulfonyl)p henyl)-2 furanone, 5 ,5-Dimethyl-3 -(3-fluorophenyl)-4 m methylsulfonyl)ph enyl) 2 -(511) -furan one, 5 ,5-Dimethyl-3-(3-chlorophenyl)-4-(4m ethylsulfonyl)ph en yl) -2 -furan one, 3-(3,4.Difluorophenyl).4-(4.(inethylsulfonyl)phenyl)- 2 3-(3,4-Dichlorophenyl)-4-(4.(inethylsulfonyl)phenyl)- 2 5,5-Dimethyl-3-(3,4-difluorophenyl)-4-(4- 5,5.Dimethylb3-(3,4-dichlorophenyl)-4-(4- 5,5-Dimethyl-3-(4-chlorophenyl)-4-(4-methylsulfonyl)phenyl)-2(5H)-furanone, 3-(2-Naphthyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone, 5,5-Dimethyl-3-(2-naphthyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone, 3-phenyl-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone.
Some of the compounds described herein contain one or more asymmetric centres and may thus give rise to diastereomers and optical isomers. The present invention is meant to comprehend such possible diastereomers as well as their racemic and resolved, enantiomerically pure forms and pharmaceutically acceptable salts thereof.
Some of the compounds described herein contain olefinic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers.
In a second embodiment, the invention encompasses pharmaceutical compositions for inhibiting cyclooxygenase and for treating cyclooxygenase mediated diseases as disclosed herein comprising a pharmaceutically acceptable carrer and a non-toxic therapeutically effective amount of compound of formula I as described above.
Within this embodiment the invention encompasses pharmaceutical compositions for inhibiting cyclooxygenase-2 and for treating cyclooxygenase-2 mediated diseases as disclosed herein comprising a pharmaceutically acceptable carrier and a non-toxic therapeutically effective amount of a compound of formula I as described above.
In a third embodiment, the invention encompasses a method of inhibiting cyclooxygenase and treating cyclooxygenase mediated diseases, advantageously treated by an active agent that selectively inhibits COX-2 in preference to COX-1 as disclosed herein comprising: administration to a patient in need of such treatment of a non-toxic therapeutically effective amount of a compound of Formula I as disclosed herein.
For the purposes of this specification a preferred compound is said to selectively inhibit COX-2 in preference to COX-1 if the ratio of the 12 concentration for COX-1 inhibition to COX-2 inhibition is 100 or greater.
The pharmaceutical compositions used in the present invention comprise a compound of Formula I as an active ingredient or a pharmaceutically acceptable salt thereof, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic.
ingredients. Th6 term "pharmaceutically acceptable-salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N--dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, 20 glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
It will be understood that in the discussion of methods of 25 treatment which follows, references to the compounds of Formula I are meant to also include the pharmaceutically acceptable salts.
For the treatment of any of these cyclooxygenase mediated diseases, compounds of formula I may be administered orally, topically, parenterally, by inhalation spray or rectally in dosage unit formulations 30 containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.
The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
13- Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredierit in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example, magnesium stearate, stearic acid ortalc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay Smaterial such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the technique described in the U.S.
Patent 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic 20 tablets for control release.
o oi Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredients is mixed with water 25 or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethyl-cellulose, methylcellulose, hydroxy-propylmethycellulose, 30 sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene-oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene 14oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or npropyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.
Oify suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned 20 above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
The pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for 25 example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene 30 sorbitan monooleate. The emulsions may also contain sweetening and flavouring agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable 15 dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation ofinjectables.
Compounds of formula I may also be administered in the form of a suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable nonirritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the Sdrug. Such materials are cocoa butter and polyethylene glycols.
For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compound of Formula I are employed.
(For purposes of this application, topical application shall include mouth 20 washes and gargles.) Dosage levels of the order of from about 0.01 mg to about 140 mg/kg of body weight per day are useful in the treatment of the aboveindicated conditions, or alternatively about 0.5 mg to about 7 g per patient per day. For example, inflammation may be effectively treated by the administration of from about 0.01 to 50 mg of the compound per kilogram of body weight per day, or alternatively about 0.5 mg to about 3.5 g per patient per day.
The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a formulation intended for the oral administration of humans may contain from 0.5 mg to 5 g of active agent compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient, typically 25mg, 50mg, 100mg, 200mg, 300mg, 400mg, 500mg, 600mg,,800mg or 1000mg.
It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
Example Using PCR analysis of mRNA extracted from the post-mortem hippocampus of 7 AD patients and 6 age-matched control patients (with no history of neurological or neuropsychiatric diseases, we o1 found COX-II mRNA in 6 AD patients. Four of the control patients showed no COX-II mRNA. In situ hybridisation histochemistry also showed COX-II mRNA in the hippocampus of 4 AD patients but not in 5 control patients. Westem blot analysis of temporal lobe cortex showed COX-II protein in 3 AD patients but not in 3 control patients.
These results show that COX-II is induced in the medial temporal lobe of AD patients, a brain region most severely affected during Alzheimers disease process. The results indicate that the inflammatory condition associated with AD involves COX-II in its aetiology and show that treating AD patients with brain penetrant selective COX-II inhibitors will be effective.
Claims (25)
1. A method for the treatment of prophylaxis of Alzheimers disease in a human requiring said treatment or prophylaxis, which method comprises administering to said human an effective amount of at least one non-steroid COX-II inhibitor without causing gastric side effects of the type that can occur when COX-I inhibitors are used for prolonged periods; with the proviso that the at least one non-steroid COX-II inhibitor is not a compound of the formula Y Arl Ar 2 wherein to Y is O or S Arl is NHS(0) 2 CH 3 0O Ar2 0 Aris C B 15 wherein A, B and C are each independently selected from the group consisting of: hydrogen, F, CI, Br or l, methyl or ethyl, CF 3 20 vinyl or -C=CH, OCH3 or OCF 3 SCH 3 or SCF3, CN, N3, but wherein at least one of A, B and C must be hydrogen; wherein the term COX-II inhibitor means a compound able to inhibit human COX-II enzyme without causing relatively significant inhibition of human COX-I enzyme. SI 18 C 2. The method as claimed in claim 1, wherein the non-steroid COX-II inhibitor istifrrulated for oral administration.
3. The method as claimed in claim 1 or claim 2, wherein the non-steroid COX-II inhibitor is formulated as a tablet. S4. The method as claimed in any one of claims 1 to 3, wherein the non-steroid COX-II inhibitor will bind at least 10 times as well to COX-II as to COX-I. The method as claimed in any one of claims 1 to 3, wherein the non-steroid COX-II inhibitor will bind at least 20 times as well to COX-II as to COX-I.
6. The method as claimed in any one of claims 1 to 3, wherein the non-steroid COX-II inhibitor will bind at least 50 times as well to COX-II as to COX-I.
7. The method as claimed in any one of claims 1 to 3, wherein the non-steroid COX-II inhibitor will bind at least 100 times as well to COX-II as to COX-I.
8. The method as claimed in any one of claims 1 to 3, wherein the non-steroid COX-II inhibitor will bind at least 1,000 times as well to COX-II as to COX-I. Is 9. The method as claimed in any one of the preceding claims, wherein the non-steroid COX-II inhibitor is administered at a dosage level of from about 0.01mg to about 140mg/kg of body weight per day.
10. The method as claimed in any one of claims 1 to 8, wherein the non-steroid COX-II inhibitor is administered at a dosage level of about 0.5 to about 7g per patient per day. 20 11. The method as claimed in any one of claims 1 to 10, wherein the non-steroid COX-II inhibitor is not a carboxylic acid or a salt thereof.
12. The method as claimed in any one of claims 1 to 10, wherein the non-steroid COX-II inhibitor possesses an SO2CH 3 NHSO 2 CH 3 SO 2 NH 2 or SO2NHCH 3 substituent on an aromatic ring.
13. The method as claimed in claim 12, wherein the aromatic ring is a phenyl ring.
14. The method as claimed in any one of claims 1 to 10, wherein the non-steroid COX-II inhibitor is a compound of Formula I as hereinbefore defined. The method as claimed in claim 14, wherein R 1 in the compound of Formula I is S02CH 3 -16. The method as claimed in claim 14, wherein the compound of formula I is 3-phenyl-4-(4-
17. At least one non-steroid COX-II inhibitor as defined in claim 1, when used for the treatment or prophylaxis of Alzheimers disease in a human requiring said treatment or prophylaxis without causing gastric side effects of the type that can occur when COX-I inhibitors are used for prolonged periods.
18. Use of at least one non-steroid COX-II inhibitor as defined in claim 1, in the manufacture of a medicament for the treatment or prophylaxis of Alzheimers disease in a human requiring said 'treatment or prophylaxis. 19 1 19. The use as claimed in claim 18, wherein the medicament is adapted'-for oral administration. The use as claimed in claim 18 or claim 19, wherein the medicament is in the form of a tablet.
21. The use as claimed in any one of claims 18 to 20, wherein the non-steroid COX-II inhibitor will bind at least 10 times as well to COX-II as to COX-1.
22. The use as claimed in any one of claims 18 to 20, wherein the non-steroid COX-II inhibitor will bind at least 20 times as well to COX-II as to COX-I.
23. The use as claimed in any one of claims 18 to 20, wherein the non-steroid COX-II o1 inhibitor will bind at least 50 times as well to COX-II as to COX-I.
24. The use as claimed in any one of claims 18 to 20, wherein the non-steroid COX-II inhibitor will bind at least 100 times as well to COX-II as to COX-I. The use as claimed in any one of claims 18 to 20, wherein the non-steroid COX-II inhibitor will bind at least 1,000 times as well to COX-II as to COX-I. Is 26. The use as claimed in any one of claims 18 to 25, wherein the non-steroid COX-II inhibitor is administered at a dosage level of from about 0.01mg to about 140mg/kg of body weight per day.
27. The use as claimed in any one of claims 18 to 25, wherein the non-steroid COX-II inhibitor is administered at a dosage level of about 0.5 to about 7g per patient per day. 20 28. The use as claimed in any one of claims 18 to 27, wherein the non-steroid COX-II inhibitor is not a carboxylic acid or a salt thereof.
29. The use as claimed in any one of claims 18 to 27, wherein the non-steroid COX-II inhibitor possesses an S02CH 3 NHSO2CH 3 S0 2 NH 2 or S02NHCH3 substituent on an aromatic ring.
30. The use as claimed in claim 29, wherein the aromatic ring is a phenyl ring.
31. The use as claimed in any one of claims 18 to 27, wherein the non-steroid COX-II inhibitor is a compound of Formula I as hereinbefore defined.
32. The use as claimed in claim 31, wherein R 1 in the compound of Formula I is S 2 OCH 3
33. The use as claimed in claim 31, wherein the compound of formula I is 3-phenyl-4-(4-
34. A method for the treatment or prophylaxis of Alzheimers disease in a human requiring said treatment or prophylaxis, which method comprises administering to said human an effective amount of at least one non-steroid COX-II inhibitor which is substantially as hereinbefore described with reference to any one of the Examples, without causing gastric side effects of the type that can occur when COX-I inhibitors are used for prolonged periods.
35. At least one non-steroid COX-II inhibitor which is substantially as hereinbefore described Vwith reference to any one of the Examples, when used for the treatment or prophylaxis of Alzheimers disease in a human requiring said treatment or prophylaxis without causing gastric side effects of the type that can occur when COX-1 inhibitors are used for prolonged periods.
36. Use of at least one non-steroid COX-II inhibitor which is substantially as hereinbefore described with reference to any one of the Examples, in the manufacture of a medicament for the s treatment or prophylaxis of Alzheimers disease in a human requiring said treatment or prophylaxis.
37. The method as claimed in any one of claims 1 to 16 or 34 wherein said inhibitor is administered combined with a pharmaceutically acceptable carrier or diluent in the form of a composition. Dated 27 March, 2002 Merck Sharp Dohme Limited Merck Frosst Canada Co. Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON S S *go e* 0 o
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU27746/02A AU2774602A (en) | 1993-03-12 | 2002-03-27 | Use of inhibitors of cyclooxygenase in the treatment of neurodegenerative diseases |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US030924 | 1993-03-12 | ||
AU27746/02A AU2774602A (en) | 1993-03-12 | 2002-03-27 | Use of inhibitors of cyclooxygenase in the treatment of neurodegenerative diseases |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
AU36139/95A Division AU715676B2 (en) | 1993-03-12 | 1995-10-09 | Use of inhibitors of cyclooxygenase in the treatment of neurodegenerative diseases |
Publications (1)
Publication Number | Publication Date |
---|---|
AU2774602A true AU2774602A (en) | 2002-05-16 |
Family
ID=3716057
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
AU27746/02A Abandoned AU2774602A (en) | 1993-03-12 | 2002-03-27 | Use of inhibitors of cyclooxygenase in the treatment of neurodegenerative diseases |
Country Status (1)
Country | Link |
---|---|
AU (1) | AU2774602A (en) |
-
2002
- 2002-03-27 AU AU27746/02A patent/AU2774602A/en not_active Abandoned
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20040147581A1 (en) | Method of using a Cox-2 inhibitor and a 5-HT1A receptor modulator as a combination therapy | |
JP2002528498A (en) | Migraine treatment method and pharmaceutical composition | |
WO2003059271A2 (en) | Treatment involving peroxisome proliferator-activated receptor-gamma agonist and cyclooxygenase-2 selective inhibitors | |
AU2003207535A2 (en) | Combinations of peroxisome proliferator-activated receptor-alpha agonists and cyclooxygenase-2 selective inhibitors and therapeutic uses therefor | |
WO2005021004A1 (en) | Method for preventing or treating an optic neuropathy | |
US20040235925A1 (en) | Method for the treatment, prevention, or inhibition of a CNS disorder and/or pain and inflammation using a combination of duloxetine, venlafaxine or atomoxetine and a cyclooxygenase-2 selective inhibitor and compositions thereof | |
US20030157061A1 (en) | Combinations of a cyclooxygenase-2 selective inhibitor and a TNFalpha antagonist and therapeutic uses therefor | |
US20030114416A1 (en) | Method and compositions for the treatment and prevention of pain and inflammation with a cyclooxygenase-2 selective inhibitor and chondroitin sulfate | |
EP0109036A1 (en) | Anti-inflammatory/analgesic combination of alpha-fluoromethylhistidine and a selected non-steroidal anti-inflammatory drug (NSAID) | |
US20030114418A1 (en) | Method for the treatment and prevention of pain and inflammation with glucosamine and a cyclooxygenase-2 selective inhibitor and compositions therefor | |
WO1996011676A1 (en) | Use of inhibitors of cyclooxygenase in the treatment of neurodegenerative diseases | |
US20030207846A1 (en) | Treatment of pain, inflammation, and inflammation-related disorders with a combination of a cyclooxygenase-2 selective inhibitor and aspirin | |
WO2005020926A2 (en) | Treatment or prevention of vascular disorders with cox-2 inhibitors in combination with cyclic amp-specific phosphodiesterase inhibitors | |
AU715676B2 (en) | Use of inhibitors of cyclooxygenase in the treatment of neurodegenerative diseases | |
AU2774602A (en) | Use of inhibitors of cyclooxygenase in the treatment of neurodegenerative diseases | |
WO1997011701A1 (en) | Compositions for treating inflammation containing certain prostaglandins and a selective cyclooxygenase-2 inhibitor | |
WO2003094924A1 (en) | Combination therapy for treating cyclooxygenase-2 mediated diseases in patients at risk of thrombotic cardiovascular events | |
MXPA05006681A (en) | Combination of reboxetine and a cyclooxygenase-2 inhibitor. | |
CA2202173A1 (en) | Use of inhibitors of cyclooxygenase in the treatment of neurodegenerative diseases | |
WO2004110378A2 (en) | Treatment alzheimer's disease with r(-) 2-arylproponic acid nsaid alone or in combination with selective cox-2 inhibitor | |
JP2005503346A (en) | Methods and compositions for treating migraine | |
US20050215611A1 (en) | Combination therapy for treating cyclooxygenase-2 mediated diseases in patients at risk of thrombotic cardiovascular events | |
KR20040063112A (en) | Compositions for the treatment and prevention of pain and inflammation with a cyclooxygenase-2 selective inhibitor and glucosamine |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
MK1 | Application lapsed section 142(2)(a) - no request for examination in relevant period |