CN101754774B - Vr-1拮抗剂和cox-2抑制剂的协同组合 - Google Patents
Vr-1拮抗剂和cox-2抑制剂的协同组合 Download PDFInfo
- Publication number
- CN101754774B CN101754774B CN2008800249638A CN200880024963A CN101754774B CN 101754774 B CN101754774 B CN 101754774B CN 2008800249638 A CN2008800249638 A CN 2008800249638A CN 200880024963 A CN200880024963 A CN 200880024963A CN 101754774 B CN101754774 B CN 101754774B
- Authority
- CN
- China
- Prior art keywords
- alkyl
- pain
- antagonist
- cox
- hydroxyl
- 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.)
- Expired - Fee Related
Links
- 239000011885 synergistic combination Substances 0.000 title claims abstract description 25
- 239000005557 antagonist Substances 0.000 title abstract description 63
- 229940111134 coxibs Drugs 0.000 title description 43
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 title description 43
- 150000001875 compounds Chemical class 0.000 claims abstract description 55
- 150000003839 salts Chemical class 0.000 claims abstract description 31
- 239000012453 solvate Substances 0.000 claims abstract description 22
- 238000002360 preparation method Methods 0.000 claims description 38
- 229960001259 diclofenac Drugs 0.000 claims description 17
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 claims description 17
- JFPXRFIBKKSHGY-UHFFFAOYSA-N 4-(7-hydroxy-4-oxo-2-propan-2-ylquinazolin-3-yl)benzonitrile Chemical compound CC(C)C1=NC2=CC(O)=CC=C2C(=O)N1C1=CC=C(C#N)C=C1 JFPXRFIBKKSHGY-UHFFFAOYSA-N 0.000 claims description 13
- 239000003814 drug Substances 0.000 claims description 10
- 230000001404 mediated effect Effects 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Substances N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 4
- KQWCLZDEKIKCND-UHFFFAOYSA-N CC(C)c1nc2cc(O)ccc2c(=O)n1-c1ccccc1C#N Chemical compound CC(C)c1nc2cc(O)ccc2c(=O)n1-c1ccccc1C#N KQWCLZDEKIKCND-UHFFFAOYSA-N 0.000 claims description 2
- 229940127555 combination product Drugs 0.000 claims 5
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 abstract description 46
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 abstract description 46
- 108010025083 TRPV1 receptor Proteins 0.000 abstract description 31
- 208000002193 Pain Diseases 0.000 description 43
- 230000036407 pain Effects 0.000 description 39
- 108010062740 TRPV Cation Channels Proteins 0.000 description 38
- 102000011040 TRPV Cation Channels Human genes 0.000 description 37
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 27
- 230000000694 effects Effects 0.000 description 24
- 229910052739 hydrogen Inorganic materials 0.000 description 22
- 239000001257 hydrogen Substances 0.000 description 22
- 241001597008 Nomeidae Species 0.000 description 21
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 19
- 229910052736 halogen Inorganic materials 0.000 description 16
- 201000010099 disease Diseases 0.000 description 15
- 230000003203 everyday effect Effects 0.000 description 15
- 150000002367 halogens Chemical class 0.000 description 14
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 14
- 238000000034 method Methods 0.000 description 13
- 208000035475 disorder Diseases 0.000 description 12
- 150000002431 hydrogen Chemical class 0.000 description 12
- 238000012856 packing Methods 0.000 description 12
- 239000000556 agonist Substances 0.000 description 11
- 239000000203 mixture Substances 0.000 description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 10
- 239000007788 liquid Substances 0.000 description 10
- 230000036470 plasma concentration Effects 0.000 description 10
- 239000003826 tablet Substances 0.000 description 10
- MIMJSJSRRDZIPW-UHFFFAOYSA-N tilmacoxib Chemical compound C=1C=C(S(N)(=O)=O)C(F)=CC=1C=1OC(C)=NC=1C1CCCCC1 MIMJSJSRRDZIPW-UHFFFAOYSA-N 0.000 description 10
- 238000010171 animal model Methods 0.000 description 9
- 239000003795 chemical substances by application Substances 0.000 description 9
- 230000000875 corresponding effect Effects 0.000 description 9
- 239000003112 inhibitor Substances 0.000 description 9
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 8
- 241001465754 Metazoa Species 0.000 description 8
- YKPUWZUDDOIDPM-SOFGYWHQSA-N capsaicin Chemical compound COC1=CC(CNC(=O)CCCC\C=C\C(C)C)=CC=C1O YKPUWZUDDOIDPM-SOFGYWHQSA-N 0.000 description 8
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 8
- -1 Pyridine radicals Chemical class 0.000 description 7
- 230000001154 acute effect Effects 0.000 description 7
- 230000001684 chronic effect Effects 0.000 description 7
- 230000002757 inflammatory effect Effects 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- WVTKBKWTSCPRNU-KYJUHHDHSA-N (+)-Tetrandrine Chemical compound C([C@H]1C=2C=C(C(=CC=2CCN1C)OC)O1)C(C=C2)=CC=C2OC(=C2)C(OC)=CC=C2C[C@@H]2N(C)CCC3=CC(OC)=C(OC)C1=C23 WVTKBKWTSCPRNU-KYJUHHDHSA-N 0.000 description 6
- GPRYKVSEZCQIHD-UHFFFAOYSA-N 1-(4-aminophenyl)ethanone Chemical compound CC(=O)C1=CC=C(N)C=C1 GPRYKVSEZCQIHD-UHFFFAOYSA-N 0.000 description 6
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 125000000217 alkyl group Chemical group 0.000 description 6
- 230000001754 anti-pyretic effect Effects 0.000 description 6
- 239000002221 antipyretic Substances 0.000 description 6
- CNBGNNVCVSKAQZ-UHFFFAOYSA-N benzydamine Chemical compound C12=CC=CC=C2C(OCCCN(C)C)=NN1CC1=CC=CC=C1 CNBGNNVCVSKAQZ-UHFFFAOYSA-N 0.000 description 6
- 239000002775 capsule Substances 0.000 description 6
- CPJSUEIXXCENMM-UHFFFAOYSA-N phenacetin Chemical compound CCOC1=CC=C(NC(C)=O)C=C1 CPJSUEIXXCENMM-UHFFFAOYSA-N 0.000 description 6
- 230000035479 physiological effects, processes and functions Effects 0.000 description 6
- 229960000371 rofecoxib Drugs 0.000 description 6
- 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 6
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 6
- 208000024891 symptom Diseases 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 208000004454 Hyperalgesia Diseases 0.000 description 5
- 206010065952 Hyperpathia Diseases 0.000 description 5
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 5
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 description 5
- 229960000590 celecoxib Drugs 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 230000009133 cooperative interaction Effects 0.000 description 5
- 229920000159 gelatin Polymers 0.000 description 5
- 235000019322 gelatine Nutrition 0.000 description 5
- 229960001680 ibuprofen Drugs 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 208000004296 neuralgia Diseases 0.000 description 5
- 208000021722 neuropathic pain Diseases 0.000 description 5
- 229960004662 parecoxib Drugs 0.000 description 5
- TZRHLKRLEZJVIJ-UHFFFAOYSA-N parecoxib Chemical compound C1=CC(S(=O)(=O)NC(=O)CC)=CC=C1C1=C(C)ON=C1C1=CC=CC=C1 TZRHLKRLEZJVIJ-UHFFFAOYSA-N 0.000 description 5
- 241000894007 species Species 0.000 description 5
- 230000002195 synergetic effect Effects 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- LNPDTQAFDNKSHK-UHFFFAOYSA-N valdecoxib Chemical compound CC=1ON=C(C=2C=CC=CC=2)C=1C1=CC=C(S(N)(=O)=O)C=C1 LNPDTQAFDNKSHK-UHFFFAOYSA-N 0.000 description 5
- 229960002004 valdecoxib Drugs 0.000 description 5
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 4
- 206010020751 Hypersensitivity Diseases 0.000 description 4
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 4
- 235000010489 acacia gum Nutrition 0.000 description 4
- 239000001785 acacia senegal l. willd gum Substances 0.000 description 4
- 230000003213 activating effect Effects 0.000 description 4
- 239000003513 alkali Substances 0.000 description 4
- 208000026935 allergic disease Diseases 0.000 description 4
- 230000007815 allergy Effects 0.000 description 4
- WEUCPZFPBXPCQU-UHFFFAOYSA-K aluminum;2-acetyloxybenzoate;dihydroxide Chemical compound O[Al+]O.CC(=O)OC1=CC=CC=C1C([O-])=O WEUCPZFPBXPCQU-UHFFFAOYSA-K 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
- 201000011510 cancer Diseases 0.000 description 4
- 229960002504 capsaicin Drugs 0.000 description 4
- 235000017663 capsaicin Nutrition 0.000 description 4
- 125000004093 cyano group Chemical group *C#N 0.000 description 4
- 230000006378 damage Effects 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 239000000839 emulsion Substances 0.000 description 4
- 210000001035 gastrointestinal tract Anatomy 0.000 description 4
- 125000001475 halogen functional group Chemical group 0.000 description 4
- 229960000905 indomethacin Drugs 0.000 description 4
- 229960002009 naproxen Drugs 0.000 description 4
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 4
- 230000008058 pain sensation Effects 0.000 description 4
- 230000002265 prevention Effects 0.000 description 4
- 238000011552 rat model Methods 0.000 description 4
- 239000002464 receptor antagonist Substances 0.000 description 4
- 229940044551 receptor antagonist Drugs 0.000 description 4
- 238000004088 simulation Methods 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- 239000000829 suppository Substances 0.000 description 4
- 208000011580 syndromic disease Diseases 0.000 description 4
- ZZMSHBOVYPIYOB-UHFFFAOYSA-N 1,4-diphenylpyrazolidine-3,5-dione Chemical compound O=C1NN(C=2C=CC=CC=2)C(=O)C1C1=CC=CC=C1 ZZMSHBOVYPIYOB-UHFFFAOYSA-N 0.000 description 3
- XOZLRRYPUKAKMU-UHFFFAOYSA-N 1,5-dimethyl-2-phenyl-4-(propan-2-ylamino)-3-pyrazolone Chemical compound O=C1C(NC(C)C)=C(C)N(C)N1C1=CC=CC=C1 XOZLRRYPUKAKMU-UHFFFAOYSA-N 0.000 description 3
- FMBVHKPWDJQLNO-UHFFFAOYSA-N 1-[(3-fluorophenyl)methyl]-5-nitroindazole Chemical compound N1=CC2=CC([N+](=O)[O-])=CC=C2N1CC1=CC=CC(F)=C1 FMBVHKPWDJQLNO-UHFFFAOYSA-N 0.000 description 3
- NYIZXMGNIUSNKL-UHFFFAOYSA-N 2,3-diacetyloxybenzoic acid Chemical group CC(=O)OC1=CC=CC(C(O)=O)=C1OC(C)=O NYIZXMGNIUSNKL-UHFFFAOYSA-N 0.000 description 3
- JJBCTCGUOQYZHK-UHFFFAOYSA-N 2-acetyloxybenzoate;(5-amino-1-carboxypentyl)azanium Chemical compound OC(=O)C(N)CCCC[NH3+].CC(=O)OC1=CC=CC=C1C([O-])=O JJBCTCGUOQYZHK-UHFFFAOYSA-N 0.000 description 3
- XCHHJFVNQPPLJK-UHFFFAOYSA-N 2-carboxyphenolate;1h-imidazol-1-ium Chemical compound C1=CNC=N1.OC(=O)C1=CC=CC=C1O XCHHJFVNQPPLJK-UHFFFAOYSA-N 0.000 description 3
- PCYLDXMXEPSXFW-UHFFFAOYSA-N 6-amino-2-(2-chloroethyl)-2,3-dihydro-1,3-benzoxazin-4-one Chemical compound O1C(CCCl)NC(=O)C2=CC(N)=CC=C21 PCYLDXMXEPSXFW-UHFFFAOYSA-N 0.000 description 3
- RLFWWDJHLFCNIJ-UHFFFAOYSA-N Aminoantipyrine Natural products CN1C(C)=C(N)C(=O)N1C1=CC=CC=C1 RLFWWDJHLFCNIJ-UHFFFAOYSA-N 0.000 description 3
- RMMXTBMQSGEXHJ-UHFFFAOYSA-N Aminophenazone Chemical compound O=C1C(N(C)C)=C(C)N(C)N1C1=CC=CC=C1 RMMXTBMQSGEXHJ-UHFFFAOYSA-N 0.000 description 3
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 108010078791 Carrier Proteins Proteins 0.000 description 3
- 208000000094 Chronic Pain Diseases 0.000 description 3
- 108010005939 Ciliary Neurotrophic Factor Proteins 0.000 description 3
- 102100031614 Ciliary neurotrophic factor Human genes 0.000 description 3
- OIRAEJWYWSAQNG-UHFFFAOYSA-N Clidanac Chemical compound ClC=1C=C2C(C(=O)O)CCC2=CC=1C1CCCCC1 OIRAEJWYWSAQNG-UHFFFAOYSA-N 0.000 description 3
- RHAXSHUQNIEUEY-UHFFFAOYSA-N Epirizole Chemical compound COC1=CC(C)=NN1C1=NC(C)=CC(OC)=N1 RHAXSHUQNIEUEY-UHFFFAOYSA-N 0.000 description 3
- 108010010803 Gelatin Proteins 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- SBDNJUWAMKYJOX-UHFFFAOYSA-N Meclofenamic Acid Chemical compound CC1=CC=C(Cl)C(NC=2C(=CC=CC=2)C(O)=O)=C1Cl SBDNJUWAMKYJOX-UHFFFAOYSA-N 0.000 description 3
- 208000019695 Migraine disease Diseases 0.000 description 3
- 101800003845 Neuropeptide Y Proteins 0.000 description 3
- 102400000064 Neuropeptide Y Human genes 0.000 description 3
- BRZANEXCSZCZCI-UHFFFAOYSA-N Nifenazone Chemical compound O=C1N(C=2C=CC=CC=2)N(C)C(C)=C1NC(=O)C1=CC=CN=C1 BRZANEXCSZCZCI-UHFFFAOYSA-N 0.000 description 3
- 208000008589 Obesity Diseases 0.000 description 3
- AVKHCKXGKPAGEI-UHFFFAOYSA-N Phenicarbazide Chemical compound NC(=O)NNC1=CC=CC=C1 AVKHCKXGKPAGEI-UHFFFAOYSA-N 0.000 description 3
- 206010036376 Postherpetic Neuralgia Diseases 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 208000027418 Wounds and injury Diseases 0.000 description 3
- TWIIVLKQFJBFPW-UHFFFAOYSA-N acetaminosalol Chemical compound C1=CC(NC(=O)C)=CC=C1OC(=O)C1=CC=CC=C1O TWIIVLKQFJBFPW-UHFFFAOYSA-N 0.000 description 3
- 229950007008 acetaminosalol Drugs 0.000 description 3
- 229960001138 acetylsalicylic acid Drugs 0.000 description 3
- 229960005142 alclofenac Drugs 0.000 description 3
- ARHWPKZXBHOEEE-UHFFFAOYSA-N alclofenac Chemical compound OC(=O)CC1=CC=C(OCC=C)C(Cl)=C1 ARHWPKZXBHOEEE-UHFFFAOYSA-N 0.000 description 3
- MANKSFVECICGLK-UHFFFAOYSA-K aloxiprin Chemical compound [OH-].[Al+3].CC(=O)OC1=CC=CC=C1C([O-])=O.CC(=O)OC1=CC=CC=C1C([O-])=O MANKSFVECICGLK-UHFFFAOYSA-K 0.000 description 3
- 229960000212 aminophenazone Drugs 0.000 description 3
- 238000013459 approach Methods 0.000 description 3
- 208000010668 atopic eczema Diseases 0.000 description 3
- 229960004277 benorilate Drugs 0.000 description 3
- FEJKLNWAOXSSNR-UHFFFAOYSA-N benorilate Chemical compound C1=CC(NC(=O)C)=CC=C1OC(=O)C1=CC=CC=C1OC(C)=O FEJKLNWAOXSSNR-UHFFFAOYSA-N 0.000 description 3
- 229960000333 benzydamine Drugs 0.000 description 3
- REHLODZXMGOGQP-UHFFFAOYSA-N bermoprofen Chemical compound C1C(=O)C2=CC(C(C(O)=O)C)=CC=C2OC2=CC=C(C)C=C21 REHLODZXMGOGQP-UHFFFAOYSA-N 0.000 description 3
- 229950007517 bermoprofen Drugs 0.000 description 3
- 229960000962 bufexamac Drugs 0.000 description 3
- MXJWRABVEGLYDG-UHFFFAOYSA-N bufexamac Chemical compound CCCCOC1=CC=C(CC(=O)NO)C=C1 MXJWRABVEGLYDG-UHFFFAOYSA-N 0.000 description 3
- 229960003354 bumadizone Drugs 0.000 description 3
- FLWFHHFTIRLFPV-UHFFFAOYSA-N bumadizone Chemical compound C=1C=CC=CC=1N(C(=O)C(C(O)=O)CCCC)NC1=CC=CC=C1 FLWFHHFTIRLFPV-UHFFFAOYSA-N 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- YEKMWXFHPZBZLR-UHFFFAOYSA-N chlorthenoxazine Chemical compound C1=CC=C2OC(CCCl)NC(=O)C2=C1 YEKMWXFHPZBZLR-UHFFFAOYSA-N 0.000 description 3
- 229950007438 chlorthenoxazine Drugs 0.000 description 3
- 229950010886 clidanac Drugs 0.000 description 3
- 229960000842 dipyrocetyl Drugs 0.000 description 3
- 229940120889 dipyrone Drugs 0.000 description 3
- 230000000857 drug effect Effects 0.000 description 3
- 201000006549 dyspepsia Diseases 0.000 description 3
- 229950003801 epirizole Drugs 0.000 description 3
- PXBFSRVXEKCBFP-UHFFFAOYSA-N etersalate Chemical compound C1=CC(NC(=O)C)=CC=C1OCCOC(=O)C1=CC=CC=C1OC(C)=O PXBFSRVXEKCBFP-UHFFFAOYSA-N 0.000 description 3
- 229950006159 etersalate Drugs 0.000 description 3
- 235000019197 fats Nutrition 0.000 description 3
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 3
- 239000008273 gelatin Substances 0.000 description 3
- 235000011852 gelatine desserts Nutrition 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 229960004769 imidazole salicylate Drugs 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 208000002551 irritable bowel syndrome Diseases 0.000 description 3
- LZRDDINFIHUVCX-UHFFFAOYSA-N isofezolac Chemical compound OC(=O)CC1=C(C=2C=CC=CC=2)C(C=2C=CC=CC=2)=NN1C1=CC=CC=C1 LZRDDINFIHUVCX-UHFFFAOYSA-N 0.000 description 3
- 229950004425 isofezolac Drugs 0.000 description 3
- RBLKLJDYAHZCFW-UHFFFAOYSA-L magnesium;2-acetyloxybenzoate Chemical compound [Mg+2].CC(=O)OC1=CC=CC=C1C([O-])=O.CC(=O)OC1=CC=CC=C1C([O-])=O RBLKLJDYAHZCFW-UHFFFAOYSA-L 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 229960003803 meclofenamic acid Drugs 0.000 description 3
- 230000004060 metabolic process Effects 0.000 description 3
- DJGAAPFSPWAYTJ-UHFFFAOYSA-M metamizole sodium Chemical compound [Na+].O=C1C(N(CS([O-])(=O)=O)C)=C(C)N(C)N1C1=CC=CC=C1 DJGAAPFSPWAYTJ-UHFFFAOYSA-M 0.000 description 3
- 206010027599 migraine Diseases 0.000 description 3
- OOGNFQMTGRZRAB-UHFFFAOYSA-N morazone Chemical compound CC1C(C=2C=CC=CC=2)OCCN1CC(C1=O)=C(C)N(C)N1C1=CC=CC=C1 OOGNFQMTGRZRAB-UHFFFAOYSA-N 0.000 description 3
- 229960004610 morazone Drugs 0.000 description 3
- 230000007823 neuropathy Effects 0.000 description 3
- 229960002187 nifenazone Drugs 0.000 description 3
- 235000020824 obesity Nutrition 0.000 description 3
- 201000008482 osteoarthritis Diseases 0.000 description 3
- GHZNWXGYWUBLLI-UHFFFAOYSA-N p-Lactophenetide Chemical compound CCOC1=CC=C(NC(=O)C(C)O)C=C1 GHZNWXGYWUBLLI-UHFFFAOYSA-N 0.000 description 3
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 3
- 229960005489 paracetamol Drugs 0.000 description 3
- 229960003893 phenacetin Drugs 0.000 description 3
- LQJARUQXWJSDFL-UHFFFAOYSA-N phenamine Chemical compound CCOC1=CC=C(NC(=O)CN)C=C1 LQJARUQXWJSDFL-UHFFFAOYSA-N 0.000 description 3
- 229950010879 phenamine Drugs 0.000 description 3
- 229960001206 phenicarbazide Drugs 0.000 description 3
- PSBAIJVSCTZDDB-UHFFFAOYSA-N phenyl acetylsalicylate Chemical compound CC(=O)OC1=CC=CC=C1C(=O)OC1=CC=CC=C1 PSBAIJVSCTZDDB-UHFFFAOYSA-N 0.000 description 3
- 229950009058 phenyl acetylsalicylate Drugs 0.000 description 3
- XGNKHIPCARGLGS-UHFFFAOYSA-N pipebuzone Chemical compound O=C1N(C=2C=CC=CC=2)N(C=2C=CC=CC=2)C(=O)C1(CCCC)CN1CCN(C)CC1 XGNKHIPCARGLGS-UHFFFAOYSA-N 0.000 description 3
- 229950004769 pipebuzone Drugs 0.000 description 3
- 229960003192 propacetamol Drugs 0.000 description 3
- QTGAJCQTLIRCFL-UHFFFAOYSA-N propacetamol Chemical compound CCN(CC)CC(=O)OC1=CC=C(NC(C)=O)C=C1 QTGAJCQTLIRCFL-UHFFFAOYSA-N 0.000 description 3
- 229960002189 propyphenazone Drugs 0.000 description 3
- PXWLVJLKJGVOKE-UHFFFAOYSA-N propyphenazone Chemical compound O=C1C(C(C)C)=C(C)N(C)N1C1=CC=CC=C1 PXWLVJLKJGVOKE-UHFFFAOYSA-N 0.000 description 3
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 3
- WVTKBKWTSCPRNU-UHFFFAOYSA-N rac-Tetrandrin Natural products O1C(C(=CC=2CCN3C)OC)=CC=2C3CC(C=C2)=CC=C2OC(=C2)C(OC)=CC=C2CC2N(C)CCC3=CC(OC)=C(OC)C1=C23 WVTKBKWTSCPRNU-UHFFFAOYSA-N 0.000 description 3
- 229950000385 ramifenazone Drugs 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- 206010039073 rheumatoid arthritis Diseases 0.000 description 3
- JZWFDVDETGFGFC-UHFFFAOYSA-N salacetamide Chemical compound CC(=O)NC(=O)C1=CC=CC=C1O JZWFDVDETGFGFC-UHFFFAOYSA-N 0.000 description 3
- 229950009280 salacetamide Drugs 0.000 description 3
- RLISWLLILOTWGG-UHFFFAOYSA-N salamidacetic acid Chemical compound NC(=O)C1=CC=CC=C1OCC(O)=O RLISWLLILOTWGG-UHFFFAOYSA-N 0.000 description 3
- 229950000417 salamidacetic acid Drugs 0.000 description 3
- 229960004889 salicylic acid Drugs 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 235000010356 sorbitol Nutrition 0.000 description 3
- 239000007921 spray Substances 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- PFENFDGYVLAFBR-UHFFFAOYSA-N tinoridine Chemical compound C1CC=2C(C(=O)OCC)=C(N)SC=2CN1CC1=CC=CC=C1 PFENFDGYVLAFBR-UHFFFAOYSA-N 0.000 description 3
- 229950010298 tinoridine Drugs 0.000 description 3
- 210000001835 viscera Anatomy 0.000 description 3
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 description 2
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 2
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 2
- HYSLHVMRVBBRIG-UHFFFAOYSA-N 6-chloro-2-methyl-1h-pyrido[3,2-d]pyrimidin-4-one Chemical compound C1=C(Cl)N=C2C(=O)NC(C)=NC2=C1 HYSLHVMRVBBRIG-UHFFFAOYSA-N 0.000 description 2
- 206010000087 Abdominal pain upper Diseases 0.000 description 2
- 102100021641 Acetyl-CoA carboxylase 2 Human genes 0.000 description 2
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 description 2
- 102100022089 Acyl-[acyl-carrier-protein] hydrolase Human genes 0.000 description 2
- 241000416162 Astragalus gummifer Species 0.000 description 2
- 208000008035 Back Pain Diseases 0.000 description 2
- 108010018763 Biotin carboxylase Proteins 0.000 description 2
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 208000006561 Cluster Headache Diseases 0.000 description 2
- 206010009900 Colitis ulcerative Diseases 0.000 description 2
- 206010009944 Colon cancer Diseases 0.000 description 2
- 206010011224 Cough Diseases 0.000 description 2
- 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 2
- 206010013710 Drug interaction Diseases 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- 208000004232 Enteritis Diseases 0.000 description 2
- 108010039731 Fatty Acid Synthases Proteins 0.000 description 2
- 208000001640 Fibromyalgia Diseases 0.000 description 2
- 208000018522 Gastrointestinal disease Diseases 0.000 description 2
- 239000001828 Gelatine Substances 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- 206010065390 Inflammatory pain Diseases 0.000 description 2
- 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 2
- 102000016267 Leptin Human genes 0.000 description 2
- 108010092277 Leptin Proteins 0.000 description 2
- 102400001132 Melanin-concentrating hormone Human genes 0.000 description 2
- 101800002739 Melanin-concentrating hormone Proteins 0.000 description 2
- 102000015494 Mitochondrial Uncoupling Proteins Human genes 0.000 description 2
- 108010050258 Mitochondrial Uncoupling Proteins Proteins 0.000 description 2
- 206010028391 Musculoskeletal Pain Diseases 0.000 description 2
- 208000028389 Nerve injury Diseases 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 2
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 2
- 206010036049 Polycystic ovaries Diseases 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 208000004550 Postoperative Pain Diseases 0.000 description 2
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 2
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 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
- 206010043269 Tension headache Diseases 0.000 description 2
- 208000008548 Tension-Type Headache Diseases 0.000 description 2
- 229920001615 Tragacanth Polymers 0.000 description 2
- 201000006704 Ulcerative Colitis Diseases 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 206010047700 Vomiting Diseases 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 208000038016 acute inflammation Diseases 0.000 description 2
- 230000006022 acute inflammation Effects 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 208000011341 adult acute respiratory distress syndrome Diseases 0.000 description 2
- 201000000028 adult respiratory distress syndrome Diseases 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 125000000304 alkynyl group Chemical group 0.000 description 2
- 230000000172 allergic effect Effects 0.000 description 2
- 230000000202 analgesic effect Effects 0.000 description 2
- 239000000883 anti-obesity agent Substances 0.000 description 2
- 229940125710 antiobesity agent Drugs 0.000 description 2
- 208000006673 asthma Diseases 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 208000018912 cluster headache syndrome Diseases 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 229940110456 cocoa butter Drugs 0.000 description 2
- 235000019868 cocoa butter Nutrition 0.000 description 2
- 230000002079 cooperative effect Effects 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 239000008298 dragée Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 229950005722 flosulide Drugs 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 229940031574 hydroxymethyl cellulose Drugs 0.000 description 2
- 230000000917 hyperalgesic effect Effects 0.000 description 2
- 208000027866 inflammatory disease Diseases 0.000 description 2
- 208000014674 injury Diseases 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 229940039781 leptin Drugs 0.000 description 2
- NRYBAZVQPHGZNS-ZSOCWYAHSA-N leptin Chemical compound O=C([C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CC(C)C)CCSC)N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](CS)C(O)=O NRYBAZVQPHGZNS-ZSOCWYAHSA-N 0.000 description 2
- 239000007937 lozenge Substances 0.000 description 2
- KHPKQFYUPIUARC-UHFFFAOYSA-N lumiracoxib Chemical compound OC(=O)CC1=CC(C)=CC=C1NC1=C(F)C=CC=C1Cl KHPKQFYUPIUARC-UHFFFAOYSA-N 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
- ORRDHOMWDPJSNL-UHFFFAOYSA-N melanin concentrating hormone Chemical compound N1C(=O)C(C(C)C)NC(=O)C(CCCNC(N)=N)NC(=O)CNC(=O)C(C(C)C)NC(=O)C(CCSC)NC(=O)C(NC(=O)C(CCCNC(N)=N)NC(=O)C(NC(=O)C(NC(=O)C(N)CC(O)=O)C(C)O)CCSC)CSSCC(C(=O)NC(CC=2C3=CC=CC=C3NC=2)C(=O)NC(CCC(O)=O)C(=O)NC(C(C)C)C(O)=O)NC(=O)C2CCCN2C(=O)C(CCCNC(N)=N)NC(=O)C1CC1=CC=C(O)C=C1 ORRDHOMWDPJSNL-UHFFFAOYSA-N 0.000 description 2
- 230000027939 micturition Effects 0.000 description 2
- MSLICLMCQYQNPK-UHFFFAOYSA-N n-(4-bromophenyl)acetamide Chemical compound CC(=O)NC1=CC=C(Br)C=C1 MSLICLMCQYQNPK-UHFFFAOYSA-N 0.000 description 2
- CXJONBHNIJFARE-UHFFFAOYSA-N n-[6-(2,4-difluorophenoxy)-1-oxo-2,3-dihydroinden-5-yl]methanesulfonamide Chemical compound CS(=O)(=O)NC1=CC=2CCC(=O)C=2C=C1OC1=CC=C(F)C=C1F CXJONBHNIJFARE-UHFFFAOYSA-N 0.000 description 2
- 210000005036 nerve Anatomy 0.000 description 2
- 230000008764 nerve damage Effects 0.000 description 2
- 201000001119 neuropathy Diseases 0.000 description 2
- 229960000965 nimesulide Drugs 0.000 description 2
- HYWYRSMBCFDLJT-UHFFFAOYSA-N nimesulide Chemical compound CS(=O)(=O)NC1=CC=C([N+]([O-])=O)C=C1OC1=CC=CC=C1 HYWYRSMBCFDLJT-UHFFFAOYSA-N 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 208000033808 peripheral neuropathy Diseases 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 206010035653 pneumoconiosis Diseases 0.000 description 2
- 201000010065 polycystic ovary syndrome Diseases 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 239000003380 propellant Substances 0.000 description 2
- 239000012268 protein inhibitor Substances 0.000 description 2
- 229940121649 protein inhibitor Drugs 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 210000000664 rectum Anatomy 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 208000023504 respiratory system disease Diseases 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- 239000008279 sol Substances 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 235000010487 tragacanth Nutrition 0.000 description 2
- 239000000196 tragacanth Substances 0.000 description 2
- 229940116362 tragacanth Drugs 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- DCXXMTOCNZCJGO-UHFFFAOYSA-N tristearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCC DCXXMTOCNZCJGO-UHFFFAOYSA-N 0.000 description 2
- 230000008673 vomiting Effects 0.000 description 2
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 1
- RDJGLLICXDHJDY-NSHDSACASA-N (2s)-2-(3-phenoxyphenyl)propanoic acid Chemical compound OC(=O)[C@@H](C)C1=CC=CC(OC=2C=CC=CC=2)=C1 RDJGLLICXDHJDY-NSHDSACASA-N 0.000 description 1
- GUHPRPJDBZHYCJ-SECBINFHSA-N (2s)-2-(5-benzoylthiophen-2-yl)propanoic acid Chemical compound S1C([C@H](C(O)=O)C)=CC=C1C(=O)C1=CC=CC=C1 GUHPRPJDBZHYCJ-SECBINFHSA-N 0.000 description 1
- AKTXOQVMWSFEBQ-LCYFTJDESA-N (5z)-2-amino-5-[(3,5-ditert-butyl-4-hydroxyphenyl)methylidene]-1,3-thiazol-4-one Chemical compound CC(C)(C)C1=C(O)C(C(C)(C)C)=CC(\C=C/2C(N=C(N)S\2)=O)=C1 AKTXOQVMWSFEBQ-LCYFTJDESA-N 0.000 description 1
- YFMFNYKEUDLDTL-UHFFFAOYSA-N 1,1,1,2,3,3,3-heptafluoropropane Chemical compound FC(F)(F)C(F)C(F)(F)F YFMFNYKEUDLDTL-UHFFFAOYSA-N 0.000 description 1
- LVGUZGTVOIAKKC-UHFFFAOYSA-N 1,1,1,2-tetrafluoroethane Chemical compound FCC(F)(F)F LVGUZGTVOIAKKC-UHFFFAOYSA-N 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 102000004277 11-beta-hydroxysteroid dehydrogenases Human genes 0.000 description 1
- 108090000874 11-beta-hydroxysteroid dehydrogenases Proteins 0.000 description 1
- DNCYBUMDUBHIJZ-UHFFFAOYSA-N 1h-pyrimidin-6-one Chemical compound O=C1C=CN=CN1 DNCYBUMDUBHIJZ-UHFFFAOYSA-N 0.000 description 1
- MVZNVBXATDCMMJ-UHFFFAOYSA-N 2-(hydroxymethyl)-4-[5-(4-methoxyphenyl)-3-(trifluoromethyl)pyrazol-1-yl]benzenesulfonamide Chemical compound C1=CC(OC)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C(CO)=C1 MVZNVBXATDCMMJ-UHFFFAOYSA-N 0.000 description 1
- 102100024959 5-hydroxytryptamine receptor 2C Human genes 0.000 description 1
- 101710138093 5-hydroxytryptamine receptor 2C Proteins 0.000 description 1
- 208000004998 Abdominal Pain Diseases 0.000 description 1
- 206010000060 Abdominal distension Diseases 0.000 description 1
- 208000000187 Abnormal Reflex Diseases 0.000 description 1
- 235000019489 Almond oil Nutrition 0.000 description 1
- 201000004384 Alopecia Diseases 0.000 description 1
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 208000006820 Arthralgia Diseases 0.000 description 1
- 208000033116 Asbestos intoxication Diseases 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 description 1
- MNIPYSSQXLZQLJ-UHFFFAOYSA-N Biofenac Chemical compound OC(=O)COC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl MNIPYSSQXLZQLJ-UHFFFAOYSA-N 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- 108010073466 Bombesin Receptors Proteins 0.000 description 1
- 206010048962 Brain oedema Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 206010006458 Bronchitis chronic Diseases 0.000 description 1
- 208000007596 Byssinosis Diseases 0.000 description 1
- IJKMJYAZHSXHHL-UHFFFAOYSA-N C(C)(=O)C1=CC=C(N)C=C1.[Br] Chemical compound C(C)(=O)C1=CC=C(N)C=C1.[Br] IJKMJYAZHSXHHL-UHFFFAOYSA-N 0.000 description 1
- 206010058019 Cancer Pain Diseases 0.000 description 1
- 235000002566 Capsicum Nutrition 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 208000017897 Carcinoma of esophagus Diseases 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- 101710150887 Cholecystokinin A Proteins 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 208000013586 Complex regional pain syndrome type 1 Diseases 0.000 description 1
- 206010010774 Constipation Diseases 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 102000034534 Cotransporters Human genes 0.000 description 1
- 108020003264 Cotransporters Proteins 0.000 description 1
- 201000003883 Cystic fibrosis Diseases 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
- 201000004624 Dermatitis Diseases 0.000 description 1
- 206010012442 Dermatitis contact Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 208000032131 Diabetic Neuropathies Diseases 0.000 description 1
- 206010051153 Diabetic gastroparesis Diseases 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 206010013654 Drug abuse Diseases 0.000 description 1
- 208000005171 Dysmenorrhea Diseases 0.000 description 1
- 206010013935 Dysmenorrhoea Diseases 0.000 description 1
- 206010014020 Ear pain Diseases 0.000 description 1
- 206010014759 Endometrial neoplasm Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 208000010228 Erectile Dysfunction Diseases 0.000 description 1
- 206010015958 Eye pain Diseases 0.000 description 1
- 102000018711 Facilitative Glucose Transport Proteins Human genes 0.000 description 1
- 102000000476 Fatty Acid Transport Proteins Human genes 0.000 description 1
- 108010055870 Fatty Acid Transport Proteins Proteins 0.000 description 1
- 206010016275 Fear Diseases 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 208000014540 Functional gastrointestinal disease Diseases 0.000 description 1
- 206010017865 Gastritis erosive Diseases 0.000 description 1
- 206010052105 Gastrointestinal hypomotility Diseases 0.000 description 1
- 208000005922 Glossalgia Diseases 0.000 description 1
- 229940123037 Glucocorticoid antagonist Drugs 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 108091052347 Glucose transporter family Proteins 0.000 description 1
- 201000005569 Gout Diseases 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 206010020741 Hyperpyrexia Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 206010020853 Hypertonic bladder Diseases 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- 206010021137 Hypovolaemia Diseases 0.000 description 1
- 206010021518 Impaired gastric emptying Diseases 0.000 description 1
- 206010021639 Incontinence Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 208000006877 Insect Bites and Stings Diseases 0.000 description 1
- 208000005615 Interstitial Cystitis Diseases 0.000 description 1
- 201000005081 Intestinal Pseudo-Obstruction Diseases 0.000 description 1
- 208000007914 Labor Pain Diseases 0.000 description 1
- 208000035945 Labour pain Diseases 0.000 description 1
- 206010024453 Ligament sprain Diseases 0.000 description 1
- 229940086609 Lipase inhibitor Drugs 0.000 description 1
- 208000008930 Low Back Pain Diseases 0.000 description 1
- 101150051050 MC3R gene Proteins 0.000 description 1
- 101150110867 MC4R gene Proteins 0.000 description 1
- 102000017351 Melanocortin 3 receptors Human genes 0.000 description 1
- 108050005365 Melanocortin 3 receptors Proteins 0.000 description 1
- 102000001796 Melanocortin 4 receptors Human genes 0.000 description 1
- 108050009019 Melanocortin 4 receptors Proteins 0.000 description 1
- ZRVUJXDFFKFLMG-UHFFFAOYSA-N Meloxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=NC=C(C)S1 ZRVUJXDFFKFLMG-UHFFFAOYSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 241000867725 Mucilago Species 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- 208000007101 Muscle Cramp Diseases 0.000 description 1
- 208000000112 Myalgia Diseases 0.000 description 1
- 208000030858 Myofascial Pain Syndromes Diseases 0.000 description 1
- BLXXJMDCKKHMKV-UHFFFAOYSA-N Nabumetone Chemical compound C1=C(CCC(C)=O)C=CC2=CC(OC)=CC=C21 BLXXJMDCKKHMKV-UHFFFAOYSA-N 0.000 description 1
- 208000018526 Narcotic-Related disease Diseases 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 206010062501 Non-cardiac chest pain Diseases 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
- 206010030216 Oesophagitis Diseases 0.000 description 1
- 102000002512 Orexin Human genes 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 208000009722 Overactive Urinary Bladder Diseases 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 206010033645 Pancreatitis Diseases 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 239000006002 Pepper Substances 0.000 description 1
- 208000004983 Phantom Limb Diseases 0.000 description 1
- 206010056238 Phantom pain Diseases 0.000 description 1
- 235000016761 Piper aduncum Nutrition 0.000 description 1
- 235000017804 Piper guineense Nutrition 0.000 description 1
- 244000203593 Piper nigrum Species 0.000 description 1
- 235000008184 Piper nigrum Nutrition 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 206010054048 Postoperative ileus Diseases 0.000 description 1
- 229920003110 Primojel Polymers 0.000 description 1
- ZGUGWUXLJSTTMA-UHFFFAOYSA-N Promazinum Chemical compound C1=CC=C2N(CCCN(C)C)C3=CC=CC=C3SC2=C1 ZGUGWUXLJSTTMA-UHFFFAOYSA-N 0.000 description 1
- QOSMNYMQXIVWKY-UHFFFAOYSA-N Propyl levulinate Chemical compound CCCOC(=O)CCC(C)=O QOSMNYMQXIVWKY-UHFFFAOYSA-N 0.000 description 1
- 102100038280 Prostaglandin G/H synthase 2 Human genes 0.000 description 1
- 108050003267 Prostaglandin G/H synthase 2 Proteins 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 208000015634 Rectal Neoplasms Diseases 0.000 description 1
- 201000001947 Reflex Sympathetic Dystrophy Diseases 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- 206010039085 Rhinitis allergic Diseases 0.000 description 1
- 206010039094 Rhinitis perennial Diseases 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 208000008765 Sciatica Diseases 0.000 description 1
- 206010040070 Septic Shock Diseases 0.000 description 1
- 201000010001 Silicosis Diseases 0.000 description 1
- 206010040744 Sinus headache Diseases 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 239000004141 Sodium laurylsulphate Substances 0.000 description 1
- NWGKJDSIEKMTRX-AAZCQSIUSA-N Sorbitan monooleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O NWGKJDSIEKMTRX-AAZCQSIUSA-N 0.000 description 1
- 208000005392 Spasm Diseases 0.000 description 1
- 208000010040 Sprains and Strains Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 102000003566 TRPV1 Human genes 0.000 description 1
- 208000033781 Thyroid carcinoma Diseases 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- KJADKKWYZYXHBB-XBWDGYHZSA-N Topiramic acid Chemical compound C1O[C@@]2(COS(N)(=O)=O)OC(C)(C)O[C@H]2[C@@H]2OC(C)(C)O[C@@H]21 KJADKKWYZYXHBB-XBWDGYHZSA-N 0.000 description 1
- 102100029613 Transient receptor potential cation channel subfamily V member 1 Human genes 0.000 description 1
- 101150016206 Trpv1 gene Proteins 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 206010046543 Urinary incontinence Diseases 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 206010046851 Uveitis Diseases 0.000 description 1
- 241000792914 Valeriana Species 0.000 description 1
- 206010053510 Venomous sting Diseases 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 208000003728 Vulvodynia Diseases 0.000 description 1
- 206010069055 Vulvovaginal pain Diseases 0.000 description 1
- 206010053692 Wound complication Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 229960004420 aceclofenac Drugs 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 208000005298 acute pain Diseases 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- 206010053552 allodynia Diseases 0.000 description 1
- ZOJBYZNEUISWFT-UHFFFAOYSA-N allyl isothiocyanate Chemical compound C=CCN=C=S ZOJBYZNEUISWFT-UHFFFAOYSA-N 0.000 description 1
- 239000008168 almond oil Substances 0.000 description 1
- 231100000360 alopecia Toxicity 0.000 description 1
- CEGOLXSVJUTHNZ-UHFFFAOYSA-K aluminium tristearate Chemical compound [Al+3].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CEGOLXSVJUTHNZ-UHFFFAOYSA-K 0.000 description 1
- 208000028462 aluminosis Diseases 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 238000002266 amputation Methods 0.000 description 1
- 208000010123 anthracosis Diseases 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000002421 anti-septic effect Effects 0.000 description 1
- 229940125681 anticonvulsant agent Drugs 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 206010003441 asbestosis Diseases 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 229960001671 azapropazone Drugs 0.000 description 1
- WOIIIUDZSOLAIW-NSHDSACASA-N azapropazone Chemical compound C1=C(C)C=C2N3C(=O)[C@H](CC=C)C(=O)N3C(N(C)C)=NC2=C1 WOIIIUDZSOLAIW-NSHDSACASA-N 0.000 description 1
- 150000008331 benzenesulfonamides Chemical class 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 210000003461 brachial plexus Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 208000006752 brain edema Diseases 0.000 description 1
- 210000000133 brain stem Anatomy 0.000 description 1
- 201000008275 breast carcinoma Diseases 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 229940105329 carboxymethylcellulose Drugs 0.000 description 1
- 235000010418 carrageenan Nutrition 0.000 description 1
- 229920001525 carrageenan Polymers 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 239000007910 chewable tablet Substances 0.000 description 1
- 229940068682 chewable tablet Drugs 0.000 description 1
- 208000007451 chronic bronchitis Diseases 0.000 description 1
- 208000037976 chronic inflammation Diseases 0.000 description 1
- 208000037893 chronic inflammatory disorder Diseases 0.000 description 1
- 210000000589 cicatrix Anatomy 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 230000019771 cognition Effects 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 229940127113 compound 57 Drugs 0.000 description 1
- 239000007891 compressed tablet Substances 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 208000010247 contact dermatitis Diseases 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 239000012050 conventional carrier Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 201000003146 cystitis Diseases 0.000 description 1
- 229950000393 darbufelone Drugs 0.000 description 1
- 230000013872 defecation Effects 0.000 description 1
- 229960002783 dexketoprofen Drugs 0.000 description 1
- DKYWVDODHFEZIM-NSHDSACASA-N dexketoprofen Chemical compound OC(=O)[C@@H](C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-NSHDSACASA-N 0.000 description 1
- 150000001991 dicarboxylic acids Chemical class 0.000 description 1
- 229960000616 diflunisal Drugs 0.000 description 1
- HUPFGZXOMWLGNK-UHFFFAOYSA-N diflunisal Chemical compound C1=C(O)C(C(=O)O)=CC(C=2C(=CC(F)=CC=2)F)=C1 HUPFGZXOMWLGNK-UHFFFAOYSA-N 0.000 description 1
- MUCZHBLJLSDCSD-UHFFFAOYSA-N diisopropyl fluorophosphate Chemical compound CC(C)OP(F)(=O)OC(C)C MUCZHBLJLSDCSD-UHFFFAOYSA-N 0.000 description 1
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 1
- 238000007907 direct compression Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 208000007176 earache Diseases 0.000 description 1
- 239000008157 edible vegetable oil Substances 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 230000007831 electrophysiology Effects 0.000 description 1
- 238000002001 electrophysiology Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 201000003914 endometrial carcinoma Diseases 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- 201000005619 esophageal carcinoma Diseases 0.000 description 1
- 208000006881 esophagitis Diseases 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 229940011871 estrogen Drugs 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 229960005293 etodolac Drugs 0.000 description 1
- XFBVBWWRPKNWHW-UHFFFAOYSA-N etodolac Chemical compound C1COC(CC)(CC(O)=O)C2=N[C]3C(CC)=CC=CC3=C21 XFBVBWWRPKNWHW-UHFFFAOYSA-N 0.000 description 1
- 229960004945 etoricoxib Drugs 0.000 description 1
- MNJVRJDLRVPLFE-UHFFFAOYSA-N etoricoxib Chemical compound C1=NC(C)=CC=C1C1=NC=C(Cl)C=C1C1=CC=C(S(C)(=O)=O)C=C1 MNJVRJDLRVPLFE-UHFFFAOYSA-N 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- ZPAKPRAICRBAOD-UHFFFAOYSA-N fenbufen Chemical compound C1=CC(C(=O)CCC(=O)O)=CC=C1C1=CC=CC=C1 ZPAKPRAICRBAOD-UHFFFAOYSA-N 0.000 description 1
- 229960001395 fenbufen Drugs 0.000 description 1
- 229960001419 fenoprofen Drugs 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 206010016766 flatulence Diseases 0.000 description 1
- 229960002390 flurbiprofen Drugs 0.000 description 1
- SYTBZMRGLBWNTM-UHFFFAOYSA-N flurbiprofen Chemical compound FC1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-UHFFFAOYSA-N 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 238000002599 functional magnetic resonance imaging Methods 0.000 description 1
- 201000010175 gallbladder cancer Diseases 0.000 description 1
- 201000007487 gallbladder carcinoma Diseases 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 208000015589 gastric non-hodgkin lymphoma Diseases 0.000 description 1
- 208000001288 gastroparesis Diseases 0.000 description 1
- 229940014259 gelatin Drugs 0.000 description 1
- 238000001879 gelation Methods 0.000 description 1
- 206010018388 glossodynia Diseases 0.000 description 1
- 239000003635 glucocorticoid antagonist Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 208000024798 heartburn Diseases 0.000 description 1
- 208000014617 hemorrhoid Diseases 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 229940071826 hydroxyethyl cellulose Drugs 0.000 description 1
- 206010020745 hyperreflexia Diseases 0.000 description 1
- 230000035859 hyperreflexia Effects 0.000 description 1
- 230000036543 hypotension Effects 0.000 description 1
- 201000001881 impotence Diseases 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000007373 indentation Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 208000021267 infertility disease Diseases 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 229940125425 inverse agonist Drugs 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 229960004752 ketorolac Drugs 0.000 description 1
- OZWKMVRBQXNZKK-UHFFFAOYSA-N ketorolac Chemical compound OC(=O)C1CCN2C1=CC=C2C(=O)C1=CC=CC=C1 OZWKMVRBQXNZKK-UHFFFAOYSA-N 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- GOTYRUGSSMKFNF-UHFFFAOYSA-N lenalidomide Chemical compound C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O GOTYRUGSSMKFNF-UHFFFAOYSA-N 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229960000994 lumiracoxib Drugs 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 210000004086 maxillary sinus Anatomy 0.000 description 1
- 231100000682 maximum tolerated dose Toxicity 0.000 description 1
- 238000011177 media preparation Methods 0.000 description 1
- 229960003464 mefenamic acid Drugs 0.000 description 1
- HYYBABOKPJLUIN-UHFFFAOYSA-N mefenamic acid Chemical compound CC1=CC=CC(NC=2C(=CC=CC=2)C(O)=O)=C1C HYYBABOKPJLUIN-UHFFFAOYSA-N 0.000 description 1
- 229960001929 meloxicam Drugs 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- FJQXCDYVZAHXNS-UHFFFAOYSA-N methadone hydrochloride Chemical compound Cl.C=1C=CC=CC=1C(CC(C)N(C)C)(C(=O)CC)C1=CC=CC=C1 FJQXCDYVZAHXNS-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 230000000407 monoamine reuptake Effects 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 239000008164 mustard oil Substances 0.000 description 1
- BEIZIEZPGSIQGR-UHFFFAOYSA-N n-[5-(4-fluorophenoxy)thiophen-2-yl]methanesulfonamide Chemical compound S1C(NS(=O)(=O)C)=CC=C1OC1=CC=C(F)C=C1 BEIZIEZPGSIQGR-UHFFFAOYSA-N 0.000 description 1
- 229960004270 nabumetone Drugs 0.000 description 1
- 239000003887 narcotic antagonist Substances 0.000 description 1
- 239000006199 nebulizer Substances 0.000 description 1
- 201000008383 nephritis Diseases 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 206010029446 nocturia Diseases 0.000 description 1
- 208000037916 non-allergic rhinitis Diseases 0.000 description 1
- 229960002748 norepinephrine Drugs 0.000 description 1
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 1
- 230000001473 noxious effect Effects 0.000 description 1
- 230000000414 obstructive effect Effects 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
- 235000019198 oils Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 108060005714 orexin Proteins 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 208000020629 overactive bladder Diseases 0.000 description 1
- 238000002638 palliative care Methods 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- IMACFCSSMIZSPP-UHFFFAOYSA-N phenacyl chloride Chemical compound ClCC(=O)C1=CC=CC=C1 IMACFCSSMIZSPP-UHFFFAOYSA-N 0.000 description 1
- 229960002895 phenylbutazone Drugs 0.000 description 1
- VYMDGNCVAMGZFE-UHFFFAOYSA-N phenylbutazonum Chemical compound O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 VYMDGNCVAMGZFE-UHFFFAOYSA-N 0.000 description 1
- IVXQBCUBSIPQGU-UHFFFAOYSA-N piperazine-1-carboxamide Chemical compound NC(=O)N1CCNCC1 IVXQBCUBSIPQGU-UHFFFAOYSA-N 0.000 description 1
- 229960002702 piroxicam Drugs 0.000 description 1
- QYSPLQLAKJAUJT-UHFFFAOYSA-N piroxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 QYSPLQLAKJAUJT-UHFFFAOYSA-N 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 229960003598 promazine Drugs 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 201000001514 prostate carcinoma Diseases 0.000 description 1
- 125000004353 pyrazol-1-yl group Chemical group [H]C1=NN(*)C([H])=C1[H] 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 206010038038 rectal cancer Diseases 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 201000010174 renal carcinoma Diseases 0.000 description 1
- 210000004994 reproductive system Anatomy 0.000 description 1
- 206010039083 rhinitis Diseases 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 238000006748 scratching Methods 0.000 description 1
- 230000002393 scratching effect Effects 0.000 description 1
- 230000000580 secretagogue effect Effects 0.000 description 1
- 230000036303 septic shock Effects 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 239000003772 serotonin uptake inhibitor Substances 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 230000008591 skin barrier function Effects 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000003238 somatosensory effect Effects 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 210000005070 sphincter Anatomy 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 230000035882 stress Effects 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 229960000894 sulindac Drugs 0.000 description 1
- MLKXDPUZXIRXEP-MFOYZWKCSA-N sulindac Chemical compound CC1=C(CC(O)=O)C2=CC(F)=CC=C2\C1=C/C1=CC=C(S(C)=O)C=C1 MLKXDPUZXIRXEP-MFOYZWKCSA-N 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002889 sympathetic effect Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 239000003491 tear gas Substances 0.000 description 1
- 210000001738 temporomandibular joint Anatomy 0.000 description 1
- 229960002871 tenoxicam Drugs 0.000 description 1
- WZWYJBNHTWCXIM-UHFFFAOYSA-N tenoxicam Chemical compound O=C1C=2SC=CC=2S(=O)(=O)N(C)C1=C(O)NC1=CC=CC=N1 WZWYJBNHTWCXIM-UHFFFAOYSA-N 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 210000004357 third molar Anatomy 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 208000013077 thyroid gland carcinoma Diseases 0.000 description 1
- 229960001312 tiaprofenic acid Drugs 0.000 description 1
- 229960002905 tolfenamic acid Drugs 0.000 description 1
- YEZNLOUZAIOMLT-UHFFFAOYSA-N tolfenamic acid Chemical compound CC1=C(Cl)C=CC=C1NC1=CC=CC=C1C(O)=O YEZNLOUZAIOMLT-UHFFFAOYSA-N 0.000 description 1
- 208000004371 toothache Diseases 0.000 description 1
- 229960004394 topiramate Drugs 0.000 description 1
- 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 1
- 208000020049 trigeminal nerve disease Diseases 0.000 description 1
- 206010044652 trigeminal neuralgia Diseases 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 210000003708 urethra Anatomy 0.000 description 1
- 208000012991 uterine carcinoma Diseases 0.000 description 1
- 235000017468 valeriana Nutrition 0.000 description 1
- 230000009278 visceral effect Effects 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/06—Antimigraine agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- G—PHYSICS
- G11—INFORMATION STORAGE
- G11B—INFORMATION STORAGE BASED ON RELATIVE MOVEMENT BETWEEN RECORD CARRIER AND TRANSDUCER
- G11B33/00—Constructional parts, details or accessories not provided for in the other groups of this subclass
- G11B33/02—Cabinets; Cases; Stands; Disposition of apparatus therein or thereon
- G11B33/04—Cabinets; Cases; Stands; Disposition of apparatus therein or thereon modified to store record carriers
- G11B33/0405—Cabinets; Cases; Stands; Disposition of apparatus therein or thereon modified to store record carriers for storing discs
- G11B33/0411—Single disc boxes
- G11B33/0422—Single disc boxes for discs without cartridge
- G11B33/0427—Single disc boxes for discs without cartridge comprising centre hole locking means
Landscapes
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Endocrinology (AREA)
- Diabetes (AREA)
- Reproductive Health (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pain & Pain Management (AREA)
- Biomedical Technology (AREA)
- Gynecology & Obstetrics (AREA)
- Obesity (AREA)
- Heart & Thoracic Surgery (AREA)
- Hematology (AREA)
- Cardiology (AREA)
- Emergency Medicine (AREA)
- Rheumatology (AREA)
- Child & Adolescent Psychology (AREA)
- Pregnancy & Childbirth (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
本发明涉及香草素受体VR-1拮抗剂与NSAID或这两种化合物中一种或两种的可药用盐或溶剂化物的协同组合。
Description
本发明涉及用于治疗由VR-1所介导的障碍的香草素受体(VR-1、TRPV1或辣椒素受体)拮抗剂和非甾体抗炎药(NSAID)如COX-2抑制剂的组合。
WO2004056394描述了VR-1拮抗剂和NSAID如COX-2抑制剂的组合。该申请公开了在组合中VR-1拮抗剂减少NSAID的所需治疗剂量的能力和由此减少任何副作用的倾向的能力。该申请没有公开其中在两种组分之间达到协同或超过加合的效应的任何组合。因而,需要能以减少的剂量提供有效治疗而具有最小副作用的改善的治疗剂。
本发明人发现了香草素VR-1拮抗剂与NSAID如COX-2抑制剂以一定比率组合,会令人惊奇地以协同方式相互作用,从而在治疗VR-1所介导的障碍如疼痛和缓解与此相关的症状中提供特别有益的作用。所述活性剂可同时、依次或分别施用。协同效应使得各化合物的所需的预期剂量减少,从而使副作用降低并增强化合物的临床效用。
非甾体抗炎药(NSAID)已用于治疗疼痛相关病症和缓解与此相关的症状。然而,显著的副作用如尤其是肠胃侵蚀和肾损伤限制了它们的应用。因为所述组合使得与障碍如疼痛相关的病症及其相关症状的缓解增强而不损害治疗利益,所以认为本发明的组合特别有益。
本发明的组合还可通过将较低剂量的NSAID与VR-1受体拮抗剂联合使用而使得易于达到单独施用较高剂量的NSAID所能达到的缓解疼痛相关病症及其相关症状的相同水平,并由此降低与NSAID的使用有关的显著的副作用的风险。
本发明的组合可适当地包括次于最大量的香草素受体VR-1拮抗剂或NSAID如COX-2抑制剂。显示该组合对疼痛及其相关病症提供了有益的作用。
当在本文使用时,术语“次于最大”量的香草素受体VR-1拮抗剂或NSAID如COX-2抑制剂是指低于所述活性剂的适当的非组合剂量的量,如以下参考文本中所描述或提及:如British National Formulary(英国国家药品集)(BNF)、英国和美国药典、Remington′s Pharmaceutical Sciences(雷明登氏药学)(Mack Publishing Co.)、Martindale The ExtraPharmacopoeia(马西德尔外药典)(伦敦,The Pharmaceutical Press)。适合的次于最大的剂量低于所述活性剂的适当的非组合剂量的100%,且通常在5-95%范围内,例如所述活性剂的适当的非组合剂量的75%、80%、90%或95%。
特别是,在足量的香草素受体VR-1拮抗剂的存在下,通过使用次于最大的剂量而降低NSAID如COX-2抑制剂的剂量还具有减少与使用NSAID相关的副作用的益处。
相似地,通过将次于最大剂量的VR-1拮抗剂与协同剂量的NSAID如COX-2抑制剂联合使用可减少与VR-1拮抗剂相关的潜在的副作用,例如,高热(Gavva等人,J Neurosci.第27卷,第13期,第3366-3374页,2007)。
可使用各种临床前急性或慢性躯体痛模型评价药效,如但不限于用于急性炎性痛的角叉菜胶模型(Guilbaud G.&Kayser V.Pain 28(1987)99-107)、用于急性或慢性炎性痛的FCA模型(弗氏完全佐剂)(Hay等人,Neuroscience第78卷,第3期,第843-850页,1997)或用于神经病性疼痛的CCI模型(慢性压迫性损伤)(Bennett,G.J.&Xie.Y.K.(1988)Pain,33:87-107)。对内脏痛的效果可以使用临床前模型评价,如芥子油模型(Laird等人,Pain第92卷,第3期,第335-342页)、化学或机械诱导的炎性内脏痛觉过敏模型(Burton和Gebhart Brain Res第672卷,第1-2期,第77-82页)或应激诱导的内脏痛觉过敏模型(Schwetz等人,第286页,第4期,第G683-691页)。
因而,作为第一个方面,本发明提供了香草素受体VR-1拮抗剂与NSAID如COX-2抑制剂或这两种化合物中一种或两种的可药用盐或溶剂化物的协同组合。
应理解提及治疗意指包括预防以及缓解所述的症状。
依据本发明的另一个方面提供了香草素受体VR-1拮抗剂或其可药用衍生物与NSAID如COX-2抑制剂或其可药用衍生物的协同组合在制备用于治疗VR-1介导的障碍如疼痛和缓解其相关症状的药物中的应用。
本发明另一个或作为选择的方面提供了NSAID如COX-2抑制剂或其可药用衍生物与香草素受体VR-1拮抗剂或其可药用衍生物的协同组合在制备用于治疗VR-1介导的障碍如疼痛和缓解其相关症状的药物中的应用。
作为VR-1拮抗剂的具有生物活性的化合物显示可用于治疗和/或预防VR-1介导的障碍,特别是治疗或预防具有炎性成分的慢性疼痛如类风湿性关节炎;骨与关节疼痛(骨性关节炎);手术后或创伤疼痛,包括牙痛例如第三磨牙拔除后的疼痛,乳房切除术后疼痛和与扭伤或骨折相关疼痛;肌肉骨骼痛如纤维肌痛;肌筋膜痛综合征;头痛,包括偏头痛,急性或慢性紧张性头痛,丛集性头痛,颞下颌疼痛和上颌窦疼痛;耳痛;外阴切开术疼痛;灼伤,以及尤其是与其相关的原发性痛觉过敏;深部或内脏痛如心脏痛,肌肉痛,眼痛,口面疼痛,腹痛,妇科痛如痛经和分娩阵痛;痔;泌尿生殖道相关疼痛如膀胱炎和外阴痛;与神经损伤和/或影响神经系统的疾病有关的慢性疼痛,如与疱疹后神经痛、糖尿病性神经病、化学疗法诱发的神经病、切断术(“幻肢痛”)、神经卡压和臂丛撕脱伤有关的神经病性疼痛、腰痛、坐骨神经痛和强直性脊椎炎、反射交感性营养不良和其它慢性神经损伤;复合性局部疼痛综合征;舌痛或口灼伤综合征;中枢神经系统疼痛如由于脊髓或脑干损伤、多发性硬化或中风引起的疼痛;痛风;疤痕疼痛;癌相关疼痛,经常是指癌症疼痛;与病毒(例如HIV)-诱导的神经病、酒精和麻醉品滥用相关的疼痛;与阳光或UV灼伤、暴露于VR1激动剂(例如辣椒素、酸、催泪性毒气、伤害性热辐射(noxious heat)或胡椒喷雾)、蛇、蜘蛛或昆虫咬伤和海蜇螯相关的疼痛和其它症状。
根据本发明使用的VR-1拮抗剂可用于治疗胃肠道病症,包括与胃肠道超敏反应、内脏痛和/或运动反应改变(包括电解质/水分泌)相关的那些胃肠道障碍,如功能性肠紊乱和功能性胃肠病,包括肠易激综合征(IBS)、功能性消化不良、胃灼热、非侵蚀性反流病、假性肠梗阻、功能性腹部气胀和功能性腹痛;其它与内脏超敏反应相关的病症,包括胃食管反流病和呕吐、食道炎、术后内脏痛、术后肠梗阻、内脏平滑肌痉挛、溃疡性结肠炎、局限性回肠炎、溃疡、慢性便秘、腹泻、早饱、心口痛、恶心、呕吐、胃肠胀气综合征、肛门失禁、排便紧迫和直肠超敏、胃轻瘫、例如糖尿病性胃轻瘫、胰腺炎和赫希施普龙病。
依据本发明,使用VR-1拮抗剂治疗的尿失禁(“UI”)或膀胱过度活动症为覆盖一系列障碍和症状的广义术语,包括紧迫性UI、压力性UI、混合型紧迫性/压力性UI、神经原性UI、膀胱逼尿肌反射亢进(神经原性逼肌活动过度)、逼肌不稳定(自发性逼肌活动过度)、膀胱顺应性下降、尿道括约肌虚弱、排尿口阻塞、间质性膀胱炎、肾炎、眼色素层炎、感觉性尿急、运动性尿急、夜尿和与膀胱相关的内脏痛。
VR-1拮抗剂还可用作高反应性、炎性或阻塞性气道疾病的治疗剂,包括哮喘、炎性气道疾病例如慢性阻塞性肺病或气道疾病(COPD或COAD)、成人呼吸窘迫综合征(ARDS)、慢性支气管炎、尘肺例如矾土肺、炭肺、石棉肺、石末肺、驼鸟毛尘肺、铁尘肺、硅肺、烟尘肺、棉尘肺;鼻炎,包括过敏性鼻炎如季节性和常年性鼻炎,以及非过敏性鼻炎;咳嗽,自发性或与呼吸系统疾病如COPD、哮喘、囊性纤维化、癌症或胃肠道紊乱如胃食管反流相关的咳嗽。
VR-1拮抗剂还可在以下病症中具有治疗利益:炎性皮肤障碍、例如银屑病和湿疹,或非特定原因的搔痒;接触性皮炎和超敏反应;自身免疫或炎性疾病,包括局限性回肠炎、溃疡性结肠炎和Gullian Barre综合征;多化学品过敏、神经学疾病如焦虑、惊恐症、抑郁、精神分裂症、认知、帕金森病和阿尔茨海默病;脱发;糖尿病;肥胖和肥胖相关疾病;作为抗痉挛剂,例如用于治疗胃肠道或子宫痉挛;用于治疗脓毒性休克,例如作为抗低血容量和/或抗低血压剂;和脑水肿。
本发明所描述的VR-1拮抗剂与NSAID的协同组合尤其可用作治疗或预防疼痛的止痛药。它们可用于改善患有疼痛的宿主、通常是人的病症。它们可用来缓解宿主的疼痛。因而,本发明的组合可用作止痛药以治疗急性疼痛如肌肉骨骼痛、术后疼痛和外科疼痛,慢性疼痛如慢性炎性痛(例如类风湿性关节炎(RA)和骨关节炎(OA),神经病性疼痛(例如疱疹后神经痛(PHN)、三叉神经痛、与糖尿病相关的神经病和交感神经维持性疼痛)和与癌症和纤维肌痛相关的疼痛。本发明的组合还可用于治疗或预防偏头痛和/或与偏头痛相关的疼痛、紧张性头痛和丛集性头痛及与功能性肠紊乱(例如肠易激综合征)相关的疼痛、非心脏性胸痛和非溃疡性消化不良。VR-1拮抗剂和NSAID如COX-2抑制剂的协同组合还可特别用于治疗UI和涉及炎症的疾病,例如炎性气道障碍和胃食管反流病。
本发明的适合的生理学可接受的盐包括与无机酸形成的酸加成盐如盐酸盐、氢溴酸盐、磷酸盐和硫酸盐,及与有机酸形成的酸加成盐例如酒石酸盐、马来酸盐、富马酸盐、琥珀酸盐和磺酸盐。
适合的香草素受体(VR-1)拮抗剂包括但不限于在下列公开物中的实例和一般描述,据此其被全部引入作为参考;共未决GB专利申请GB0303464.2、GB 0305291.7、GB 0305290.9、GB 0305165.3、GB 0305426.9、GB 0305285.9、GB 0305163.8和GB 0316554.5;US 20030158188;US20030158198;US 20040157845;US 20040157849;US 20040209884;US20050009841;US 20050080095;US 20050085512;WO 02008221;WO02030956;WO 02072536;WO 02076946;WO 02090326;WO 03006019;WO 03014064;WO 03022809;WO 03029199;WO 03049702;WO03053945;WO03055484;WO03055484;WO 03055848;WO 03062209;WO 03066595;WO 03068749;WO 03070247;WO 03074520;WO03080578;WO 03093236;WO 03095420;WO 03097586;WO 03097670;WO 03099284;WO 04002983;WO 04007459;WO 04007495;WO04011441;WO 04014871;WO 04024710;WO 04028440;WO 04029031;WO 04029044;WO 04033435;WO 04035533;WO 04035549;WO04046133;WO 04052845;WO 04052846;WO 04054582;WO 04055003;WO 04055004;WO 04056774;WO 04058754;WO 04072020;WO04072069;WO 04074290;WO 04078101;WO 04078744;WO 04078749;WO 04089877;WO 04089881;WO 04096784;WO 04099177;WO04100865;WO 04103281;WO 04108133;WO 04110986;WO 04111009;WO 05003084;WO 05004866;WO 05007646;WO 05007648;WO05007652;WO 05009977;WO 05009980;WO 05009982;WO 05009987;WO 05009988;WO 05012287;WO 05014580;WO 05016915;WO05016922;WO 05030753;WO 05030766;WO 05032493;WO 05033105;WO 05035471;WO 05028445;WO 05033105;US 2005080095;WO05040121;WO 05051390;US 20050277643;US-7015233;WO 06031852;WO 06033620;WO 06033620;WO 06038041;WO 06047279;WO06038041;WO 06038871;WO 06038871;WO 06042289;WO 06044527;WO 06047492;WO 06045498;US-7037927;US 20060100460;US20060100245;US 20060111337;WO 2006058338;WO 2006062981;US20060128689;WO 2006063178;US 20060128704;US 20060128755;US20060135505;US 20060128704;WO 2006065872;WO 2006065646;US7067553(B2);WO 2006068593;WO 2006068592;WO 2006068618;US7071335;US 20060148814(A1);WO 2006071538;WO 2006072736;WO2006076646(A2);WO 2006078907(A1);WO 2006078992(A2);WO2006081388(A2);WO 2006080821;US 2006089311(A1);US 2006183745;WO 2006093832(A2);US 20060194805(A1);US 2006205773(A1);WO2006095263(A1);WO 2006094627(A2);WO 2006097817(A1);WO2006098554;WO 2006101318;WO 2006101321;WO 2006102645;WO2006100520;WO 2006103503;WO 2006105971;US 20060235036;WO2006111346;US 20060240097;US 20060241296;WO 2006115168;WO2006122250;US 2006120481(A2);US 2006122200(A1);WO 2006122769;WO 2006122770;WO 2006122771(A2);WO 2006122772(A2);WO2006122773(A1);WO 2006122776(A1);WO 2006122777(A2);WO2006122799(A1);WO 2006124753(A2);US 20060270682(A1);US20060270682(A1);WO 2006125276(A1);WO 2006136245(A1);WO2007009798(A2);WO 2007010383(A1);WO 2007010138(A2)。
示例性的VR1拮抗剂包括在国际专利申请--公开号WO 02/076946(Novartis AG)中一般和具体公开的那些化合物,其公开了游离碱或酸加成盐形式的式(I)化合物:
其中:
R1和R2一起是-NH-C(SR6)=N-C(O)-、
-NR7-C(R8)=N-C(O)-、-N=C(SR9)-NR10-C(O)-、-NR11-X-NR12C(O)-、
-NH-X-NH-、-NH-X-N=C(R13)-、-NH-X-NH-CH2-、-N=Z-NH-、
-N=Z-NH-CH2-、-N=Z-NH-C(O)-和-N=Z-N=C(R14)-,其中X是C(O)、C(S)或C(O)-C(O);Z是N或CR15,R6是C1-C4烷基;R7和R8各自独立地是氢、C1-C4烷基、C3-C8环烷基或与相邻的原子一起形成5或6元杂环;R9和R10一起是C1-C4亚烷基;R11是氢;C1-C4烷基;被C(O)OC1-C4烷基取代的C1-C4烷基;或被C1-C4烷基取代的苯基;R12是氢、NH2;C1-C4烷基;或被C1-C4烷基取代的苯基;R13是氢、卤素、NH2或C1-C4烷氧基;R14是氢、羟基、卤素、NH2、C1-C4烷基或C1-C4烷氧基;且R15是氢、卤素、C1-C4烷基、C1-C4烷氧基或SCH2C(O)OC(CH3)3;
R3是氢;OH;CN;C1-C6烷基;苯基;或C(O)OC1-C4烷基;
R4是氢;卤素;NH2;CN;C1-C6烷基;被OH取代的C1-C6烷基;苯基;被OH、卤素、C1-C6烷基、C1-C6卤代烷基或C1-C6烷氧基取代的苯基;苄基;被OH取代的苯甲酰基;或C(O)OC1-C6烷基;5或6元的芳族或脂肪族杂环;
R5是氢;OH;NH2;卤素;C1-C6烷基;被卤代苄基取代的C1-C6烷基;C3-C6环烷基;苯基;吡啶基;NHC1-C4烷基;或N=CHN(C1-C4烷基)2;
条件是式I化合物不是吡啶并[3,2-d]嘧啶-2,4(1H,3H)-二酮和6-氯-2-甲基-4-氧代-吡啶并[3,2-d]嘧啶。
优选的化合物涉及实施例1、2、1.1-1.5、2.1-2.16和3.1-3.6,特别是实施例2。
另外的示例性的VR1拮抗剂包括在国际专利申请--公开号WO2005120510中一般和具体公开的那些化合物,其公开了作为香草素拮抗剂的游离形式或盐形式的以及当可能时酸加成盐形式的式(II)化合物:
其中:
R1是C1-C6烷基、(C1-C6烷基)C1-C6烷基、二-(C1-C6烷基)C1-C6烷基、C3-C6环烷基、(C1-C6烷基)氨基或二-(C1-C6烷基)氨基;
各R2独立地是卤素、C1-C6烷基、卤代C1-C6烷基、羟基C1-C6烷基、氰基或-C(=O)-R2a,其中R2a是C1-C6烷基;
R3是氢、卤素、C1-C6烷基、C2-C6链烯基、C2-C6炔基、羟基、羟基取代的C1-C6烷基、C1-C6烷氧基、C3-C6环烷基、氰基、-C(=O)H、苯基、(C3-C6环烷基)C1-C6烷氧基、(C1-C6烷氧基羰基氨基)C1-C6烷氧基或(C1-C6烷基羰基氨基)C1-C6烷氧基;
R4是羟基、酯化的羟基、醚化的羟基、氨基、(C1-C6烷基)氨基、
或
其中R4a是C1-C6烷基或卤代C1-C6烷基,或
其中R4b是苄基或苯乙基;
R5是氢或羟基;且
m是1或2。
优选的化合物涉及1至28和实施例29.1至29.54,特别是实施例29.31。
另外的适合的香草素受体(VR-1)拮抗剂是(2R)-4-(3-氯吡啶-2-基)-2-甲基-N-[4-三氟甲基)苯基]哌嗪-1-甲酰胺(实施例20,WO 02/08221)和N-(2-溴苯基)-N′-[((R)-1-(5-三氟甲基-2-吡啶基)吡咯烷-3-基)]脲(实施例1,WO03/022809)。
本发明优选的方面中,提供了选自7-叔丁基-6-(4-氯苯基)-2-硫代-2,3-二氢-1H-吡啶并[2,3-d]嘧啶-4-酮和4-(7-羟基-2-异丙基-4-氧代-4H-喹唑啉-3-基)-苄腈的化合物或其可药用盐或溶剂化物与NSAID如COX-2抑制剂或其可药用衍生物的协同组合。
上述专利申请描述了有关它们所公开的香草素VR-1拮抗剂的用于其制备的适合的方法和用于其施用的剂量。
依据本发明使用的适合的NSAID包括:萘普生、芬布芬、非诺洛芬、氟比洛芬、酮基布洛芬、右酮洛芬、噻洛芬酸、阿扎丙宗、双氯芬酸、醋氯芬酸、二氟尼柳、吲哚美辛、酮咯酸、甲芬那酸、萘丁美酮、保泰松、吡罗昔康、舒林酸、替诺昔康、托芬那酸、噁丙嗪、布洛芬和COX-2选择性抑制化合物(本文称为“COX-2抑制剂”)。
应理解本发明涉及具有本领域已知的香草素受体VR-1拮抗剂活性的任何化合物特别与具有本领域已知的COX-2抑制剂活性的任何化合物的协同组合的应用。
本领域中已描述了各种COX-2抑制剂,例如以下专利申请中所述提及的那些:
AU9719132CA2164559CA2180624EP-799823EP-846689
EP-863134FR2751966GB2283745GB2319772GB2320715
JP08157361US5510368US5681842US5686460US5776967
US5783597US5824699US5830911US5859036US5869524WO94/13635
WO94/20480WO94/26731WO95/00501WO952/1817
WO96/03385WO96/03387WO96/06840WO96/09293WO96/09304
WO96/13483WO96/16934WO96/19462WO96/19463WO96/19469
WO96/21667WO96/23786WO96/24584WO96/24585WO96/25405
WO96/26921WO96/31509WO96/36617WO96/36623WO96/37467
WO96/37469WO96/38418WO96/38442WO96/40143WO97/03953
WO97/09977WO97/13755WO97/13767WO97/14691WO97/16435
WO97/25045WO97/25046WO97/25047WO97/25048WO97/27181
WO97/28120WO97/28121WO97/30030WO97/34882WO97/36863
WO97/37984WO97/38986WO97/40012WO97/46524WO97/46532
WO98/03484WO98/O4527WO98/06708WO98/06715WO98/07425
WO98/11080WO98/15528WO98/21195WO98/22442WO98/28292
WO98/29382WO98/41511WO98/41516WO98/43966WO98/45294
WO98/46594WO98/46611WO98/47890WO98/51667WO98/57924
WO99/01455WO99/05104WO99/10331WO99/10332WO99/11605
WO99/12930WO99/14194WO99/14195WO99/14205WO99/15505
ZA9704806ZA9802828,全部都被引入本文作用参考,就像在本文进行详述一样。以上申请还描述了有关它们所公开的COX-2抑制剂的用于其制备的适合的方法和用于其施用的剂量。
依据本发明使用的适合的COX-2抑制剂包括:2-[(2-氯-6-氟-苯基)氨基]-5-甲基苯基(芦米考昔)、2-(4-乙氧基-苯基)-3-(4-甲磺酰基-苯基)-吡唑并[1,5-b]哒嗪、CDC-501、塞来考昔、COX-189、4-(2-氧代-3-苯基-2,3-二氢噁唑-4-基)苯磺酰胺、CS-179、CS-502、D-1367、达布非酮、DFP、DRF-4367、依托度酸、氟舒胺、JTE-522(4-(4-环己基-2-甲基-5-噁唑基)-2-氟苯磺酰胺)、L-745337、L-768277、L-776967、L-783003、L-791456、L-804600、美洛昔康、MK663(艾托考昔)、尼美舒利、NS-398、帕瑞考昔、1-甲基磺酰基-4-(1,1-二甲基-4-(4-氟苯基)环戊-2,4-二烯-3-基)苯、4-(1,5-二氢-6-氟-7-甲氧基-3-(三氟甲基)-(2)-苯并噻喃并(4,3-c)吡唑-1-基)苯磺酰胺、4,4-二甲基-2-苯基-3-(4-甲基磺酰基)苯基)环丁烯酮、4-氨基-N-(4-(2-氟-5-三氟甲基)-噻唑-2-基)-苯磺酰胺、1-(7-叔丁基-2,3-二氢-3,3-二甲基-5-苯并-呋喃基)-4-环丙基丁-1-酮、Pharmaprojects号6089(Kotobuki Pharmaceutical)、罗非考昔、RS-113472、RWJ-63556、S-2474、S-33516、SC-299、SC-5755、伐地考昔、UR-8877、UR-8813、UR-8880。
依据本发明使用的优选的COX-2抑制剂包括:芦米考昔、塞来考昔、罗非考昔、伐地考昔、帕瑞考昔、4-(4-环己基-2-甲基-5-噁唑基)-2-氟苯磺酰胺(JTE-522)、MK663、尼美舒利、氟舒胺、DFP和2-(4-乙氧基-苯基)-3-(4-甲磺酰基-苯基)-吡唑并[1,5-b]哒嗪,及它们的生理学可接受的盐或溶剂化物。
依据本发明使用的更优选的COX-2抑制剂是芦米考昔、塞来考昔、罗非考昔、伐地考昔、帕瑞考昔、4-(4-环己基-2-甲基-5-噁唑基)-2-氟苯磺酰胺(JTE-522)和2-(4-乙氧基-苯基)-3-(4-甲磺酰基-苯基)-吡唑并[1,5-b]哒嗪,及它们的生理学可接受的盐或溶剂化物。
依据本发明使用的特别优选的COX-2抑制剂是芦米考昔(Prexige)及其生理学可接受的盐或溶剂化物。
依据本发明使用的另外特别优选的COX-2抑制剂是2-(4-乙氧基-苯基)-3-(4-甲磺酰基-苯基)-吡唑并[1,5-b]哒嗪及其生理学可接受的盐或溶剂化物。特别感兴趣的可药用衍生物是在其苯磺酰胺官能团进行修饰以提供代谢不稳定的苯磺酰胺类。尤其感兴趣的是酰化的苯磺酰胺衍生物。
依据本发明使用的另外特别优选的COX-2抑制剂是罗非考昔及其生理学可接受的盐或溶剂化物。
依据本发明另一个方面,提供了选自芦米考昔、塞来考昔、罗非考昔、伐地考昔、帕瑞考昔、4-(4-环己基-2-甲基-5-噁唑基)-2-氟苯磺酰胺(JTE-522)和2-(4-乙氧基-苯基)-3-(4-甲磺酰基-苯基)-吡唑并[1,5-b]哒嗪的化合物或其可药用盐或溶剂化物与香草素受体VR-1拮抗剂或其可药用盐或溶剂化物的协同组合。
依据本发明另一个方面,提供了选自7-叔丁基-6-(4-氯苯基)-2-硫代-2,3-二氢-1H-吡啶并[2,3-d]嘧啶-4-酮和4-(7-羟基-2-异丙基-4-氧代-4H-喹唑啉-3-基)-苄腈的化合物或其可药用盐或溶剂化物与选自芦米考昔、塞来考昔、罗非考昔、伐地考昔、帕瑞考昔、4-(4-环己基-2-甲基-5-噁唑基)-2-氟苯磺酰胺(JTE-522)和2-(4-乙氧基-苯基)-3-(4-甲磺酰基-苯基)-吡唑并[1,5-b]哒嗪或其可药用盐或溶剂化物的化合物或其可药用盐或溶剂化物的协同组合。
依据本发明使用的化合物可同时或依次施用,且当依次施用时,香草素受体VR-1拮抗剂或NSAID如COX-2抑制剂均可首先施用。
当同时施用时,所述组合可在相同或不同药物组合物中施用。
依据本发明使用的化合物可作为原料被施用,但是活性成分优选地以药物制剂的形式提供。
活性成分可作为单独的制剂或作为单一的组合制剂来使用。当两种化合物组合于同一制剂中时,应理解这两个化合物必须稳定且彼此相容且与制剂中其他组分相容。因此,包含如上文定义的组合和可药用稀释剂或载体的药物制剂构成本发明的另一个方面。当分别配制时,它们可以以任何方便的制剂以本领域中对所述化合物而言已知的方式方便地提供。
因此,在本发明的另一个方面提供了为通过任何方便的途径施用而配制的药物组合物,其包含香草素受体VR-1拮抗剂或其可药用衍生物与NSAID如COX-2抑制剂或其可药用衍生物的协同组合以及适合的载体或赋形剂。
以上提及的包括专利申请书和专利的出版的文献,被引入本文作为参考,就像在本文专门地并充分地阐述了各个公开物一样。
制剂包括那些适合口服、胃肠外(包括皮下例如通过注射或通过贮库片剂(depot tablet),皮内,鞘内,肌内例如通过储库制剂和静脉注射)、直肠和局部(包括皮肤、颊和舌下)施用的制剂,或以适于通过吸入或吹入施用而施用的形式的制剂,尽管最适合的途径可能依赖于例如接受者的病症和障碍。制剂可方便地以单位剂型存在,且可通过配药学领域公知的任何方法制备。所有的方法包括将化合物(“活性成分”)与构成一种或多种辅助成分的载体混合的步骤。通常制剂通过以下步骤制备:均匀地并密切地将活性成分与液体载体或细粉碎的固体载体或与这两者混合,然后如果需要的话,使得到的产物成形,得到所需要的制剂。优选地将所述组合物配制为口服施用制剂。
应理解当两种活性成分独立地施用时,其各自可通过不同的方式施用。
适于口服施用的制剂可作为散在单元存在,如胶囊剂、扁囊剂或片剂(例如特别用于儿科施用的咀嚼片剂),其各自包含预设量的活性成分;作为散剂或颗粒剂存在;作为在水性液体或非水性液体中的溶液剂或混悬剂存在;或作为水包油液体乳剂或油包水液体乳剂存在。
活性成分还可作为大丸剂、药糖剂或糊剂存在。
片剂可通过任选地与一种或多种辅助成分压缩或模制制备。压制片可通过在适合的机器中将自由流动形式的活性成分如粉末或颗粒任选地与以下的其它的常规赋形剂压缩而制备:如粘合剂(例如,糖浆剂、阿拉伯胶、明胶、山梨醇、黄蓍胶、淀粉胶浆、聚乙烯吡咯烷酮)或羟基甲基纤维素或羟基甲基纤维素填充剂(例如,乳糖、糖、微晶纤维素、玉米淀粉、磷酸钙或山梨醇)、润滑剂(例如,硬脂酸镁、硬脂酸、滑石粉、聚乙二醇或二氧化硅)、崩解剂(例如,马铃薯淀粉或淀粉羟乙酸钠)或湿润剂如十二烷基硫酸钠。模印片可通过在适合的机器中模制用惰性液体稀释剂湿润的粉末状的化合物的混合物而制备。所述片剂可任选地被包衣或刻痕且可为了提供活性成分的缓慢或受控释放而配制。所述片剂可依据本领域公知的方法进行包衣。
或者,可将本发明的化合物掺入口服液体制剂中,例如水性或油性混悬剂、溶液剂、乳剂、糖浆剂或酏剂。此外,包含这些化合物的制剂可作为干的产品存在,其在使用前用水或其它适合的介质配制。所述液体制剂可包含常规添加剂如助悬剂如山梨醇糖浆、甲基纤维素、葡萄糖/糖糖浆、明胶、羟基乙基纤维素、羧基甲基纤维素、硬脂酸铝凝胶或氢化食用脂;乳化剂如卵磷脂、脱水山梨醇单油酸酯或阿拉伯胶;非水的介质(其可包括食用油)如杏仁油、分馏椰子油、油性酯、丙二醇或乙醇;和防腐剂如对-羟基苯甲酸甲酯或丙酯或山梨酸。这些制剂还可配制为栓剂,例如,包含栓剂常规基质如可可豆脂或其它甘油酯的栓剂。
用于胃肠外施用的制剂包括含水和非水无菌注射溶液剂,其可包含抗氧化剂、缓冲剂、抑菌剂和使得所述制剂与预期的接受者的血液等渗的溶质;以及含水和非水无菌混悬剂,其可包含助悬剂和增稠剂。
制剂可以存在于单位剂量或多剂量容器中,例如密封安瓿和小瓶,且可在冻干状态下储存,在临用前只需要加入无菌液体载体,例如注射用水。临时注射溶液和混悬液可由前述种类的无菌粉末、颗粒和片剂制备。
用于直肠给药的制剂可作为栓剂存在,其具有常规的载体如可可豆脂、硬脂或聚乙二醇。
用于在嘴中局部施用的制剂,例如向颊施用或舌下施用,包括糖锭剂,所述糖锭剂包含在矫味基质(如蔗糖和阿拉伯胶或黄蓍胶)中的活性成分;和锭剂,所述锭剂包含在基质(如明胶和甘油或蔗糖和阿拉伯胶)中的活性成分。
对表皮局部施用而言,化合物可配制为霜剂、凝胶剂、软膏剂或洗剂或配制为透皮贴剂。
还可将化合物配制为贮库制剂。此类长效制剂可通过植入(例如皮下或肌内)或通过肌内注射施用。因而,例如,化合物可用适合的聚合物或疏水物质(例如作为在可接受的油中的乳液)或离子交换树脂来配制,或配制为微溶的衍生物,例如微溶的盐。
对于鼻内施用而言,本发明的化合物可例如作为液体喷雾、粉末或以滴剂的形式使用。
对于通过吸入施用而言,将本发明的化合物以气雾喷雾剂(aerosolspray)形式使用适合的抛射剂由耐压的包装或雾化吸入器方便地递送,所述适合的抛射剂为例如1,1,1,2-三氟乙烷(HFA 134A)和1,1,1,2,3,3,3,-七丙烷(HFA 227)、二氧化碳或其他适合的气体。在加压气雾剂的情况下,可通过提供阀门以递送测定的量而确定剂量。可以配制用于吸入器或吹入器中的胶囊和药筒例如明胶胶囊和药筒,其包含本发明化合物和适合的粉末基质如乳糖或淀粉的粉末混合物。
除以上特别提及的成分外,考虑到所述制剂的类型,其可包含本领域常规的其他物质,例如那些适于口服使用的制剂可包含矫味剂。
本领域技术人员应理解本文提及的治疗涵盖预防以及治疗所述的疾病或症状。
依据本发明的药物组合物可通过常规技术制备。例如当组合于同一制剂中时,可将香草素VR-1拮抗剂或其可药用盐或溶剂化物与NSAID如COX-2抑制剂或其可药用盐或溶剂化物混合在一起,如需要时还与适合的赋形剂混合。片剂可通过例如将该混合物直接压片制备。胶囊可通过例如使用适合的填充机将混合物与适合的赋形剂一起填充到明胶胶囊中来制备。
如需要,依据本发明使用的组合物可存在于可包含一个或多个包含活性成分的单位剂型的包装中或分配装置中。所述包装可例如包括金属或塑料箔如泡罩。当化合物计划作为两个单独的组合物施用时,其可例如以成对包装的形式存在。
药物组合物还可以以“患者包装”处方给患者,其在单一的包装中包括了整个的疗程,通常是泡罩包装。
患者包装相对于传统处方具有优势,其中药剂师从药物成批供应中分出患者供应,优势在于患者总能得到包含在患者包装中的药品说明书,而这通常在传统处方中是缺少的。已显示包含药品说明书改善患者对医师指示的依从性。
应理解通过包含指导患者正确应用本发明的药品说明书的单一的患者包装或各组合物的患者包装的方式施用本发明组合是本发明的合乎需要的附加特征。
依据本发明的另一个方面,提供了包含本发明组合的至少一种活性成分及包含本发明组合的使用指导的信息说明的患者包装。
依据本发明的另一个方面,提供了以联合的形式包含香草素受体VR-1拮抗剂或其可药用衍生物与NSAID如COX-2抑制剂或其可药用衍生物的用于单独施用的成对包装。
应理解本发明化合物用于治疗所需的量会根据待治疗的病症和患者的年龄和病症而变化,且最终由专责医生或兽医判定。然而,通常,成人治疗所使用剂量一般在每天0.02-5000mg,优选地在每天1-1500mg。所需剂量可方便地以单一剂量或以适当间隔施用的分开的剂量存在,例如以每天两次、三次、四次或更多的亚剂量施用。本发明的制剂可包含0.1-99%的活性成分,对于片剂和胶囊方便地从30至95%且对于液体制剂为3-50%。
单个剂型的本发明的组合适合施用于任何哺乳动物个体,优选人类。施用可为每日一次(o.d.)、每日两次(b.i.d.)或每日三次(t.i.d.),适合地为每日两次或每日三次,更适合为每日两次,最适合为每日一次。
因而,本发明的另一个方面提供了治愈性、预防性或姑息治疗哺乳动物个体的疼痛的方法,所述方法包括施用香草素受体VR-1拮抗剂与NSAID、适合地为COX-2抑制剂或这两种化合物中一种或两种的可药用盐或溶剂化物的协同组合,所述施用为每日一次、两次或三次,适合地为两次或三次,更适合为两次,最适合为一次。
在测定一个或多个组分之间协同相互作用时,对效应而言的最适范围和各组分的绝对剂量范围可通过将各组分以不同的w/w比率范围和剂量向需要治疗的患者施用而最终测定。对于人类,在患者中进行临床研究的复杂性和费用使得将这种形式的测试用作对测定协同作用而言的主要模型不切实际。然而,如本文所述,在一个物种中观察到的协同作用可以用来预测在其他物种和动物模型中的协同作用,据此可测定协同作用,且通过药物动力学/药效学方法的应用该研究的结果还能用来预测有效剂量和血浆浓度的比率范围,以及在其它的物种所需的绝对剂量和血浆浓度。动物模型与在人类中所见的作用之间确定的相互关系提示动物中的协同作用可以使用急性或慢性炎症诱导的痛觉过敏或异常性疼痛(例如,在大鼠中脚掌内注射CFA-诱导的机械性痛觉过敏)的测定来证明。因为所述模型中的平顶曲线效应,它们的值以协同作用的角度得到最好评价,其在神经病性疼痛患者中将转变为剂量节约优势。其它的模型(其中现有的用于治疗神经病性疼痛的药物只给出部分反应)更适于预测协同性地作用的组合在两个组分的最大耐受剂量产生增加的最大效能的可能性。
因而,本发明的另一个方面,提供了用于人类施用的包含一定w/w组合范围的香草素受体VR-1拮抗剂与NSAID、适合地为Cox-2抑制剂或其可药用盐或溶剂化物的协同组合,所述组合的范围相应于在非人动物模型、优选大鼠模型中所观测到绝对范围,所述模型主要用于鉴定协同相互作用。在人类中的比率范围适合地对应于选自以下的非人类的比率范围:1∶50至50∶1,1∶50至20∶1,1∶50至10∶1,1∶50至1∶1,1∶20至50∶1,1∶20至20∶1,1∶20至10∶1,1∶20至1∶1,1∶10至50∶1,1∶10至20∶1,1∶10至10∶1,1∶10至1∶1,1∶1至50∶1,1.1至20∶1和1∶1至10∶1(以重量计的份数比)。人类范围更适合地相应于1∶10至20∶1(以重量计的份数比)的协同作用的非人类的范围。优选地,人类的范围相应于1∶1至10∶1(以重量计的份数比)的非人类的范围。
对于人类,几种实验性疼痛模型可用于人以证明在动物中证实有协同作用的药物对人也具有一致的协同效应。可适用于该目的的人类模型的实例包括暴露于UVB后的潮红(flare)和炎性痛觉过敏(Wilgus TA等人(2002)Adv Exp Med Biol.507,第85-92页)、热/辣椒素模型(Petersen,K.L.&Rowbotham,M.C.(1999)NeuroReport 10,1511-1516)、皮内注射辣椒素模型(Andersen,O.L.,Felsby,S.,Nicolaisen,L.,Bjerring,P.,Jsesn,T.S.&Arendt-Nielsen,L.(1996)Pain 66,51-62),其包括使用反复的辣椒素创伤(Witting,N.,Svesson,P.,ArendtNielsen,L.&Jensen,T.S.(2000)Somatosensory Motor Res.17,5-12)以及累加或卷曲反应(Curatolo,M.等人(2000)Anesthesiology 93,1517-1530)。使用这些模型,痛觉强度的主观评定或痛觉过敏的区域可被用作终点,或可采用依赖电生理学技术或影像技术(如功能性磁共振成像)的更客观的终点(Bornhovd,K.,Quante,M.,Glauche,V.,Bromm,B.,Weiller,C.&Buchel,C.(2002)Brain125,1326-1336)。所有此类模型都需要客观的确认有效的证据,之后可做出它们提供了在人类中支持已在动物研究中观察到的组合的协同作用的证据的结论。
对于本发明,在人类中香草素受体VR-1拮抗剂:NSAID(适合地为Cox-2抑制剂)的比率范围选自1∶50至50∶1(以重量计的份数比),1∶50至20∶1,1∶50至10∶1,1∶50至1∶1,1∶20至50∶1,1∶20至20∶1,1∶20至10∶1,1∶20至1∶1,1∶10至50∶1,1∶10至20∶1,1∶10至10∶1,1∶10至1∶1,1∶1至50∶1,1∶1至20∶1和1∶1至10∶1,更适合地为1∶10至20∶1,优选1∶1至10∶1。
对协同作用而言,各组分的最佳剂量能依据已公布的动物模型中方法确定。然而,在人(甚至在实验性的疼痛模型)中,在组合中各组分的所有治疗相关剂量进行研究以测定整个的暴露反应关系的费用会非常高。至少在开始可能需要评价是否可以观测到与在由动物中给出最佳协同作用的那些剂量所推断出的剂量下的协同作用相一致的效应。在由动物至人的剂量比率的确定中,需要考虑因素如相对体重/体表面积、各组分的相对吸收、分布、代谢和排泄及相对的血浆蛋白结合,并且由于这些原因,对人(也对患者)所推测的最佳剂量比率不太可能与动物中所显示的最佳剂量比率相同。然而,动物和人的药物动力学领域的技术人员可以理解和计算这两者的关系。在动物和人效应之间建立桥梁的要点是所获得的在动物研究中使用的各组分的血浆浓度,因为这些与预期在人类中提供效应的各组分的血浆浓度相关。药物动力学/药效的建模(包括方法如等效线图解法、相互作用指标和响应面建模)和模拟可帮助预测人的协同剂量比率,特别是当已经在人类中对这些组分中一种或两者均进行了研究。
确定在动物或人中所观测到任何推断的协同作用是否只由于药物动力学相互作用引起是非常重要的。例如,一种化合物对另一种化合物的代谢的抑制可得出有药效协同作用的假象。在使用香草素受体VR-1拮抗剂与NSAID的动物研究中,提取重复的血液样品,表明依据所述物质已知的药物动力学性质,当施用诱导协同疼痛相互作用的剂量的各化合物时,没有任何药物动力学相互作用的证据。这表明与疼痛相关的协同作用是有药效的,其在各个物质与它们各自的受体和/或酶靶点相互作用之后接着发生。
因而,依据本发明的另一个方面,提供了用于施用于人类的协同组合,其包含香草素受体VR-1拮抗剂与NSAID、适合地为Cox-2抑制剂或其可药用盐或溶剂化物,其中各组分的剂量范围相应于在非人类的动物模型、优选大鼠模型中所观测到的绝对协同范围,所述模型主要用于鉴定协同相互作用。适合地,在人类中香草素受体VR-1拮抗剂的剂量范围相应于在大鼠中1-20mg/kg的剂量范围,更适合为1-10mg/kg,且对于香草素受体VR-1拮抗剂与NSAID、适合地为Cox-2抑制剂的相应的剂量范围是0.1-10mg/kg,更适合为0.1-1mg/kg。
适合地,用于人类的香草素受体VR-1拮抗剂的剂量是选自以下的范围:1-1200mg、1-500mg、1-100mg、1-50mg、1-25mg、500-1200mg、100-1200mg、100-500mg、50-1200mg、50-500mg或50-100mg,适合地为50-500mg,每日两次或每日三次、适合地为每日三次,且NSAID、适合地为Cox-2抑制剂的剂量为选自以下的范围:1-500mg、1-200mg、1-100mg、1-50mg、1-25mg、10-100mg、10-50mg或10-25mg,适合地为10-100mg,每日两次或每日三次。
对作为技术人员的读者而言显而易见地是,为提供疗效所需要的本发明的组合--香草素受体VR-1拮抗剂与NSAID、适合地为Cox-2抑制剂的血浆浓度范围依赖于待治疗的物种和所使用的组分。使用标准的PK/PD和体形变异测定法(allometric method)由在动物模型中所观测的血浆浓度值推断在不同物种、特别是人的预测的给药方案是可能的。因而,本发明的另一个方面提供了用于施用于人类的协同组合,其包含香草素受体VR-1拮抗剂与NSAID、适合地为Cox-2抑制剂,其中各组分的血浆浓度范围相应于在非人类的动物模型、优选大鼠模型中所观测到的绝对范围,所述模型主要用于鉴定协同相互作用。
对本领域技术人员还显而易见地是达到协同作用所需的绝对剂量依赖于对靶组织的暴露和在靶组织中香草素受体VR-1拮抗剂与NSAID、适合地为Cox-2抑制剂的效应。由于这可能随物种不同而变化,所以在本发明组合之间所观测到的协同浓度可作为选择地以在组合中引起最大疗效的各组分在单独施用时的次于最大:最大的剂量的比率的方式表示。例如,基于啮齿类动物中所获得的数据,在人类中达到的最大疗效的协同给药方案可以被定义为:诱发x%的最大疗效的香草素受体VR-1拮抗剂浓度,和诱发y%的最大疗效的NSAID浓度。
使用标准PK/PD和体形变异测定法推断在动物模型中所观测的血浆浓度值以预测不同物种、特别是人的值是可能的。因而,本发明的另一个方面提供了用于施用于人类的协同组合,其包含香草素受体VR-1拮抗剂与NSAID、适合地为Cox-2抑制剂,其中各组分的血浆浓度范围相应于在非人类的动物模型、优选大鼠模型中所观测到的绝对范围,所述模型主要用于鉴定协同相互作用。
因而在作为选择的方面,本发明提供了包含香草素受体VR-1拮抗剂与NSAID、适合地为Cox-2抑制剂或其可药用盐或溶剂化物的协同组合,其中各组分的血浆浓度范围为:香草素VR-1拮抗剂的Cmax值高至20μg/ml,且NSAID如COX-2抑制剂的Cmax值高至4g/ml,更适合地为0.005g/ml至4g/ml。
应理解香草素受体VR-1拮抗剂和COX-2抑制剂施用的剂量依赖于患者的年龄和病症和施用的频率和途径,且最终由专责医师或兽医判定。活性成分可方便地以单位剂型存在。
用于施用于人(体重大约70kg)的香草素受体VR-1拮抗剂和NSAID如COX-2抑制剂可方便地以所述化合物有疗效的本领域中所教导的正常范围内的剂量施用。
例如,依据本发明使用的香草素受体VR-1拮抗剂的建议的剂量为每单位剂量0.1mg至2g、优选1mg至2g、更优选1mg至500mg,其表示为游离碱的重量。单位剂量可以单个或分开的剂量施用,例如,每天1至4次。
例如,依据本发明使用的NSAID如COX-2抑制剂的建议的剂量为每单位剂量0.001至500mg、优选0.01至100mg、最优选0.05至50mg,例如0.5至25mg,其表示为游离碱的重量。单位剂量可以单个或分开的剂量施用,例如,每天1至4次。
实施例1
适合的VR-1化合物是如式(I)所定义的化合物,且在公开号WO02/076946中具体公开,其中还公开了用于制备它们的合成方案。
实施例2
更适合的VR-1化合物如式(II)所定义的化合物,且在公开号WO2005120510中具体公开,其中还公开了用于制备它们的合成方案。
生物学数据
在雄性Wistar Han大鼠(180-200g)进行实验以测定香草素受体VR-1拮抗剂(4-(7-羟基-2-异丙基-4-氧代-4H-喹唑啉-3-基)-苄腈)与NSAID(双氯芬酸)是否有协同性表现以逆转急性炎性疼痛。
在脚掌内注射弗氏完全佐剂(FCA)后,使用带有楔形探针(面积1.75mm2)且断开阈值为180g的痛觉仪(analgesymeter)(Ugo-Basile)对足施加递增的压力刺激,通过测量对所述递增的压力刺激的缩足阈值来测定机械性痛觉过敏。取终点作为疼痛反应(挣扎、嘶叫或缩足)的首个标志。在口服施用溶媒或测试化合物之前,在空白动物测定缩足阈值。痛觉过敏的抑制依据下式计算:
在施用25μl FCA后4小时,测定在大鼠中口服施用4-(7-羟基-2-异丙基-4-氧代-4H-喹唑啉-3-基)-苄腈和双氯芬酸(在痛觉过敏评价前1小时给药)的剂量反应曲线(图1),由这两个曲线得到对4-(7-羟基-2-异丙基-4-氧代-4H-喹唑啉-3-基)-苄腈和双氯芬酸的组合剂量模拟的剂量反应曲线(根据Tallarida等人(Life Sci 61:417-425;参见图2)所述的方法)。然后进行实验来确定由在模拟中所使用的组合剂量得到的剂量反应曲线。当观察到剂量反应曲线相对于模拟的曲线向左位移时,则阳性协同作用是明显的。
检验的组合为(4-(7-羟基-2-异丙基-4-氧代-4H-喹唑啉-3-基)-苄腈比双氯芬酸)1∶1、1∶10、10∶1、1∶20;20∶1&5∶1。剂量组合为10∶1和5∶1时,观测到阳性协同作用(参见针对5∶1实验的图3),在这两种情况中,通过ANCOVA p=<0.05确证有协同作用。所有其它的组合测试没有发生协同作用。
图1:通过单独口服施用香草素受体VR-1拮抗剂或双氯芬酸对由脚掌内注射FCA诱导的急性机械性痛觉过敏的逆转,其中VR-1测试化合物指VR-1拮抗剂4-(7-羟基-2-异丙基-4-氧代-4H-喹唑啉-3-基)-苄腈。
图2:4-(7-羟基-2-异丙基-4-氧代-4H-喹唑啉-3-基)-苄腈(VR-1测试化合物)和双氯芬酸的组合对大鼠急性机械性痛觉过敏的理论效应。
图3:各图显示比率为1∶1、10∶1和5∶1的4-(7-羟基-2-异丙基-4-氧代-4H-喹唑啉-3-基)-苄腈与双氯芬酸的组合剂量对大鼠急性炎性痛觉过敏抑制的效应。还显示了由4-(7-羟基-2-异丙基-4-氧代-4H-喹唑啉-3-基)-苄腈与双氯芬酸单独给药时的实验的剂量反应曲线所得出的理论曲线。
本发明还涉及选自游离碱或酸加成盐形式的式(I):
其中:
R1和R2一起是-NH-C(SR6)=N-C(O)-、
-NR7-C(R8)=N-C(O)-、-N=C(SR9)-NR10-C(O)-、-NR11-X-NR12C(O)-、
-NH-X-NH-、-NH-X-N=C(R13)-、-NH-X-NH-CH2-、-N=Z-NH-、
-N=Z-NH-CH2-、-N=Z-NH-C(O)-和-N=Z-N=C(R14)-,其中X是C(O)、C(S)或C(O)-C(O);Z是N或CR15,R6是C1-C4烷基;R7和R8各自独立地是氢、C1-C4烷基、C3-C8环烷基或与相邻的原子一起形成5或6元杂环;R9和R10一起是C1-C4亚烷基;R11是氢;C1-C4烷基;被C(O)OC1-C4烷基取代的C1-C4烷基;或被C1-C4烷基取代的苯基;R12是氢、NH2;C1-C4烷基;或被C1-C4烷基取代的苯基;R13是氢、卤素、NH2或C1-C4烷氧基;R14是氢、羟基、卤素、NH2、C1-C4烷基或C1-C4烷氧基;且R15是氢、卤素、C1-C4烷基、C1-C4烷氧基或SCH2C(O)OC(CH3)3;
R3是氢;OH;CN;C1-C6烷基;苯基;或C(O)OC1-C4烷基;
R4是氢;卤素;NH2;CN;C1-C6烷基;被OH取代的C1-C6烷基;苯基;被OH、卤素、C1-C6烷基、C1-C6卤代烷基或C1-C6烷氧基取代的苯基;苄基;被OH取代的苯甲酰基;或C(O)OC1-C6烷基;5或6元的芳族或脂肪族杂环;
R5是氢;OH;NH2;卤素;C1-C6烷基;被卤代苄基取代的C1-C6烷基;C3-C6环烷基;苯基;吡啶基;NHC1-C4烷基;或N=CHN(C1-C4烷基)2;
条件是式I化合物不是吡啶并[3,2-d]嘧啶-2,4(1H,3H)-二酮和6-氯-2-甲基-4-氧代-吡啶并[3,2-d]嘧啶;和
游离形式或盐形式的式(II)的VR-1受体拮抗剂和退热剂的组合:
其中:
R1是C1-C6烷基、(C1-C6烷基)C1-C6烷基、二-(C1-C6烷基)C1-C6烷基、C3-C6环烷基、(C1-C6烷基)氨基或二-(C1-C6烷基)氨基;
各R2独立地是卤素、C1-C6烷基、卤代C1-C6烷基、羟基C1-C6烷基、氰基或-C(=O)-R2a,其中R2a是C1-C6烷基;
R3是氢、卤素、C1-C6烷基、C2-C6链烯基、C2-C6炔基、羟基、羟基取代的C1-C6烷基、C1-C6烷氧基、C3-C6环烷基、氰基、-C(=O)H、苯基、(C3-C6环烷基)C1-C6烷氧基、(C1-C6烷氧基羰基氨基)C1-C6烷氧基或(C1-C6烷基羰基氨基)C1-C6烷氧基;
R4是羟基、酯化的羟基、醚化的羟基、氨基、(C1-C6烷基)氨基、
或
其中R4a是C1-C6烷基或卤代C1-C6烷基,或
其中R4b是苄基或苯乙基;
R5是氢或羟基;且
m是1或2;
所述退热剂选自:对乙酰氨基酚、醋氨沙洛、N-乙酰苯胺、阿氯芬酸、氨基比林、阿司匹林、贝诺酯、苄达明、柏莫洛芬、对溴N-乙酰苯胺、丁苯羟酸、布马地宗、阿司匹林钙、氯西诺嗪、环氯茚酸、地匹乙酯、安乃近、依匹唑、布洛芬、水杨酸咪唑、吲哚美辛、乳酰对乙氧苯胺、赖氨酸乙酰水杨酸、阿司匹林镁、甲氯芬那酸、吗拉宗、萘普生、5’-硝基-2’-丙氧基N-乙酰苯胺、非那西丁、非诺可、乙酰水杨酸苯酯、水杨酸苯酯、哌布宗、丙帕他莫、异丙安替比林、雷米那酮、醋水杨胺、邻氨甲酰基苯氧乙酸、水杨酸、粉防己碱、替诺立定、阿司匹林铝、氨氯苯嗪、二羟基铝乙酰水杨酸(dihydroxyaluminium acetylsalicylate)、依特柳酯、三苯唑酸、尼芬那宗、苯胺脲和非诺吡酮。
在一个实施方案中提供了如上定义的式(I)化合物或其可药用衍生物和选自以下的退热剂的组合:对乙酰氨基酚、醋氨沙洛、N-乙酰苯胺、阿氯芬酸、氨基比林、阿司匹林、贝诺酯、苄达明、柏莫洛芬、对溴乙酰苯胺、丁苯羟酸、布马地宗、阿司匹林钙、氯西诺嗪、环氯茚酸、地匹乙酯、安乃近、依匹唑、布洛芬、水杨酸咪唑、吲哚美辛、乳酰对乙氧苯胺、赖氨酸乙酰水杨酸、阿司匹林镁、甲氯芬那酸、吗拉宗、萘普生、5’-硝基-2’-丙氧基N-乙酰苯胺、非那西丁、非诺可、乙酰水杨酸苯酯、水杨酸苯酯、哌布宗、丙帕他莫、异丙安替比林、雷米那酮、醋水杨胺、邻氨甲酰基苯氧乙酸、水杨酸、粉防己碱、替诺立定、阿司匹林铝、氨氯苯嗪、二羟基铝乙酰水杨酸、依特柳酯、三苯唑酸、尼芬那宗、苯胺脲和非诺吡酮。
在另一个实施方案中提供了如上定义的式(II)化合物或其可药用衍生物和选自以下的退热剂的组合:对乙酰氨基酚、醋氨沙洛、N-乙酰苯胺、阿氯芬酸、氨基比林、阿司匹林、贝诺酯、苄达明、柏莫洛芬、对溴乙酰苯胺、丁苯羟酸、布马地宗、阿司匹林钙、氯西诺嗪、环氯茚酸、地匹乙酯、安乃近、依匹唑、布洛芬、水杨酸咪唑、吲哚美辛、乳酰对乙氧苯胺、赖氨酸乙酰水杨酸、阿司匹林镁、甲氯芬那酸、吗拉宗、萘普生、5’-硝基-2’-丙氧基N-乙酰苯胺、非那西丁、非诺可、乙酰水杨酸苯酯、水杨酸苯酯、哌布宗、丙帕他莫、异丙安替比林、雷米那酮、醋水杨胺、邻氨甲酰基苯氧乙酸、水杨酸、粉防己碱、替诺立定、阿司匹林铝、氨氯苯嗪、二羟基铝乙酰水杨酸、依特柳酯、三苯唑酸、尼芬那宗、苯胺脲和非诺吡酮。
本发明还提供了包含如上文所定义的VR-1受体拮抗剂或其可药用衍生物与退热剂或其可药用衍生物及可药用赋形剂的药物组合物。
依据本发明的另一个方面,提供了如上文所定义的VR-1受体拮抗剂或其可药用衍生物与退热剂或其可药用衍生物在制备用于治疗VR-1介导的障碍如疼痛和缓解其相关症状的药物中的应用。
作为本发明的适合的方面,式(II)的化合物或其可药用衍生物和具体公开于WO2005120510中的优选的化合物可用于治疗肥胖和选自以下的肥胖相关障碍:2型糖尿病;1型糖尿病;心脏血管疾病;高血压;癌症,其包括但不限于结肠癌、直肠癌、结直肠癌、胰腺癌、食管癌、乳腺癌、前列腺癌、子宫癌、肾癌、子宫内膜癌、胆囊癌、甲状腺癌、肝癌、宫颈癌、卵巢癌、胃癌、非霍奇金淋巴瘤和多发性骨髓瘤;及生殖系统障碍,其包括但不限于多囊卵巢综合征(PCO)、不孕和阳萎或勃起功能障碍。香草素拮抗剂在肥胖和相关疾病的治疗中的应用在WO2006007851中有描述。
本发明的另一个方面提供了如上文所定义的式(II)化合物或其可药用衍生物与选自以下的抗肥胖剂的组合:5HT(血清素)转运蛋白抑制剂、NE(去甲肾上腺素)转运蛋白抑制剂、脑肠肽抗体、脑肠肽拮抗剂、H3(组胺H3)拮抗剂/反相激动剂、MCH1R(黑色素浓集激素1R)拮抗剂、MCH2R(黑色素浓集激素2R)激动剂/拮抗剂、NPY1(神经肽Y Y1)拮抗剂、NPY2(神经肽Y Y2)激动剂、NPY5(神经肽Y Y5)拮抗剂、瘦蛋白、瘦蛋白衍生物、阿片样物质拮抗剂、食欲肽拮抗剂、BRS3(铃蟾肽受体亚型3)激动剂、CCK-A(缩胆囊素-A)激动剂、CNTF(睫状神经营养因子)、CNTF衍生物、GHS(生长激素促分泌素受体)激动剂、5HT2c(血清素受体2c)激动剂、Mc3r(黑皮质素3受体)激动剂、Mc4r(黑皮质素4受体)激动剂、单胺再摄取抑制剂、血清素再摄取抑制剂、托吡酯、Phytopharm化合物57、ACC2(乙酰辅酶A羧化酶-2)抑制剂、β3(β-肾上腺素能受体3)激动剂、FAS(脂肪酸合酶)抑制剂、PDE(磷酸二酯酶)抑制剂、甲状腺激素,B激动剂、UCP-1(解偶联蛋白1)、2或3活化剂、酰基-雌激素、糖皮质激素拮抗剂、110HSD-1(11β-羟化类固醇脱氢酶1型)抑制剂、脂肪酶抑制剂、脂肪酸转运蛋白抑制剂、二羧酸转运蛋白抑制剂、葡萄糖转运蛋白抑制剂和磷酸盐转运蛋白抑制剂。
在本发明的一个实施方案中提供了具体公开于WO2005120510中的化合物与如上文定义的抗肥胖剂的组合。
Claims (7)
1.4-(7-羟基-2-异丙基-4-氧代-4H-喹唑啉-3-基)-苄腈与双氯芬酸或这两种化合物中一种或两种的可药用盐或溶剂化物的协同组合产品,其中4-(7-羟基-2-异丙基-4-氧代-4H-喹唑啉-3-基)-苄腈与双氯芬酸以5∶1至10∶1的比率存在。
2.依据权利要求1的协同组合产品,其中4-(7-羟基-2-异丙基-4-氧代-4H-喹唑啉-3-基)-苄腈与双氯芬酸以5∶1的比率存在。
3.依据权利要求1的协同组合产品,其中4-(7-羟基-2-异丙基-4-氧代-4H-喹唑啉-3-基)-苄腈与双氯芬酸以10∶1的比率存在。
4.依据权利要求1的协同组合产品,其中所述协同组合产品是药物组合物,所述药物组合物还包含适合的赋形剂。
5.4-(7-羟基-2-异丙基-4-氧代-4H-喹唑啉-3-基)-苄腈或其可药用盐或溶剂化物与双氯芬酸或其可药用盐或溶剂化物的协同组合在制备用于治疗VR-1介导的障碍和缓解其相关症状的药物中的应用,其中4-(7-羟基-2-异丙基-4-氧代-4H-喹唑啉-3-基)-苄腈与双氯芬酸以5∶1至10∶1的比率使用。
6.依据权利要求5的应用,其中4-(7-羟基-2-异丙基-4-氧代-4H-喹唑啉-3-基)-苄腈与双氯芬酸以5∶1的比率使用。
7.依据权利要求5的应用,其中4-(7-羟基-2-异丙基-4-氧代-4H-喹唑啉-3-基)-苄腈与双氯芬酸以10∶1的比率使用。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP07112679 | 2007-07-18 | ||
EP07112679.1 | 2007-07-18 | ||
PCT/EP2008/059296 WO2009010529A1 (en) | 2007-07-18 | 2008-07-16 | Synergistic combinations of vr-1 antagonists and cox-2 inhibitors |
Publications (2)
Publication Number | Publication Date |
---|---|
CN101754774A CN101754774A (zh) | 2010-06-23 |
CN101754774B true CN101754774B (zh) | 2013-08-21 |
Family
ID=38828679
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN2008800249638A Expired - Fee Related CN101754774B (zh) | 2007-07-18 | 2008-07-16 | Vr-1拮抗剂和cox-2抑制剂的协同组合 |
Country Status (22)
Country | Link |
---|---|
US (1) | US8618120B2 (zh) |
EP (1) | EP2178562B1 (zh) |
JP (1) | JP5755879B2 (zh) |
KR (1) | KR20100039410A (zh) |
CN (1) | CN101754774B (zh) |
AR (1) | AR067631A1 (zh) |
AU (1) | AU2008277627B2 (zh) |
BR (1) | BRPI0813825A2 (zh) |
CA (1) | CA2692655A1 (zh) |
CL (1) | CL2008002096A1 (zh) |
CO (1) | CO6270239A2 (zh) |
EA (1) | EA201000103A1 (zh) |
EC (1) | ECSP109883A (zh) |
ES (1) | ES2648225T3 (zh) |
GT (1) | GT201000012A (zh) |
MA (1) | MA31563B1 (zh) |
MY (1) | MY147952A (zh) |
NZ (1) | NZ582496A (zh) |
TN (1) | TN2010000004A1 (zh) |
TW (1) | TW200914022A (zh) |
WO (1) | WO2009010529A1 (zh) |
ZA (1) | ZA201000076B (zh) |
Families Citing this family (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB0412769D0 (en) * | 2004-06-08 | 2004-07-07 | Novartis Ag | Organic compounds |
US9290489B2 (en) | 2012-07-06 | 2016-03-22 | Duke University | Activation of TRPV4 ion channel by physical stimuli and critical role for TRPV4 in organ-specific inflammation and itch |
CA2935914C (en) | 2014-01-09 | 2022-02-08 | Eisai R&D Management Co., Ltd. | Cationic lipid |
US10329265B2 (en) | 2014-08-22 | 2019-06-25 | Duke University | TRPA1 and TRPV4 inhibitors and methods of using the same for organ-specific inflammation and itch |
US11229628B2 (en) | 2015-01-09 | 2022-01-25 | Duke University | TRPA1 and TRPV4 inhibitors and methods of using the same for organ-specific inflammation and itch |
EP3439656A4 (en) | 2016-04-07 | 2020-03-11 | Duke University | SMALL MOLECULAR DUAL INHIBITORS OF TRPV4 AND TRPA1 FOR DISINFECTING AND STUNNING |
JP6994061B2 (ja) | 2019-02-15 | 2022-01-14 | ノバルティス アーゲー | 4-(7-ヒドロキシ-2-イソプロピル-4-オキソ-4h-キナゾリン-3-イル)-ベンゾニトリルの製剤 |
TW202045179A (zh) | 2019-02-15 | 2020-12-16 | 瑞士商諾華公司 | 治療眼表痛之方法 |
CN114605408B (zh) * | 2022-03-30 | 2023-06-16 | 沈阳药科大学 | 5-羟基-1,3-二取代苯基吡啶并[2,3-d]嘧啶类化合物及其制法和应用 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1500089A (zh) * | 2001-03-26 | 2004-05-26 | ��˹��ŵ�� | 作为辣椒素受体拮抗剂用于治疗疼痛的稠合吡啶衍生物 |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB0229808D0 (en) * | 2002-12-20 | 2003-01-29 | Glaxo Group Ltd | Novel compositions |
WO2005066130A1 (en) | 2003-12-30 | 2005-07-21 | Euro-Celtique S.A. | Piperazines useful for treating pain |
GB0412769D0 (en) * | 2004-06-08 | 2004-07-07 | Novartis Ag | Organic compounds |
US7879866B2 (en) * | 2004-07-19 | 2011-02-01 | Dorte Xenia Gram | Inhibition of the activity of the capsaicin receptor in the treatment of obesity or obesity-related diseases and disorders |
WO2006124753A2 (en) * | 2005-05-12 | 2006-11-23 | Amgen Inc. | Antipyretic agents against vr1-antagonist-induced increases in body temperature |
EP1967519B1 (en) * | 2005-12-28 | 2012-09-05 | Japan Tobacco Inc. | 3,4-dihydrobenzoxazine compound and inhibitor of vanilloid receptor type 1 (vr1) activity |
-
2008
- 2008-07-16 AU AU2008277627A patent/AU2008277627B2/en not_active Ceased
- 2008-07-16 EP EP08775119.4A patent/EP2178562B1/en not_active Not-in-force
- 2008-07-16 ES ES08775119.4T patent/ES2648225T3/es active Active
- 2008-07-16 WO PCT/EP2008/059296 patent/WO2009010529A1/en active Application Filing
- 2008-07-16 CA CA 2692655 patent/CA2692655A1/en not_active Abandoned
- 2008-07-16 MY MYPI2010000039A patent/MY147952A/en unknown
- 2008-07-16 CN CN2008800249638A patent/CN101754774B/zh not_active Expired - Fee Related
- 2008-07-16 NZ NZ582496A patent/NZ582496A/xx not_active IP Right Cessation
- 2008-07-16 KR KR1020107003447A patent/KR20100039410A/ko not_active Application Discontinuation
- 2008-07-16 EA EA201000103A patent/EA201000103A1/ru unknown
- 2008-07-16 AR ARP080103053A patent/AR067631A1/es not_active Application Discontinuation
- 2008-07-16 BR BRPI0813825-7A2A patent/BRPI0813825A2/pt not_active IP Right Cessation
- 2008-07-16 JP JP2010516499A patent/JP5755879B2/ja not_active Expired - Fee Related
- 2008-07-16 US US12/452,519 patent/US8618120B2/en not_active Expired - Fee Related
- 2008-07-17 TW TW097127192A patent/TW200914022A/zh unknown
- 2008-07-17 CL CL2008002096A patent/CL2008002096A1/es unknown
-
2010
- 2010-01-05 ZA ZA201000076A patent/ZA201000076B/xx unknown
- 2010-01-06 TN TNP2010000004A patent/TN2010000004A1/fr unknown
- 2010-01-07 MA MA32483A patent/MA31563B1/fr unknown
- 2010-01-12 CO CO10002341A patent/CO6270239A2/es not_active Application Discontinuation
- 2010-01-14 GT GT201000012A patent/GT201000012A/es unknown
- 2010-01-18 EC EC2010009883A patent/ECSP109883A/es unknown
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1500089A (zh) * | 2001-03-26 | 2004-05-26 | ��˹��ŵ�� | 作为辣椒素受体拮抗剂用于治疗疼痛的稠合吡啶衍生物 |
Also Published As
Publication number | Publication date |
---|---|
ZA201000076B (en) | 2010-09-29 |
US8618120B2 (en) | 2013-12-31 |
MY147952A (en) | 2013-02-15 |
CO6270239A2 (es) | 2011-04-20 |
CA2692655A1 (en) | 2009-01-22 |
US20100144740A1 (en) | 2010-06-10 |
ECSP109883A (es) | 2010-02-26 |
EP2178562A1 (en) | 2010-04-28 |
AR067631A1 (es) | 2009-10-21 |
CN101754774A (zh) | 2010-06-23 |
WO2009010529A1 (en) | 2009-01-22 |
KR20100039410A (ko) | 2010-04-15 |
MA31563B1 (fr) | 2010-08-02 |
NZ582496A (en) | 2012-06-29 |
GT201000012A (es) | 2012-03-30 |
ES2648225T3 (es) | 2017-12-29 |
AU2008277627A1 (en) | 2009-01-22 |
JP5755879B2 (ja) | 2015-07-29 |
TN2010000004A1 (en) | 2011-09-26 |
AU2008277627B2 (en) | 2011-10-27 |
JP2010533679A (ja) | 2010-10-28 |
BRPI0813825A2 (pt) | 2015-01-06 |
EP2178562B1 (en) | 2017-08-23 |
TW200914022A (en) | 2009-04-01 |
CL2008002096A1 (es) | 2009-06-05 |
EA201000103A1 (ru) | 2010-06-30 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN101754774B (zh) | Vr-1拮抗剂和cox-2抑制剂的协同组合 | |
ES2878575T3 (es) | Métodos para usar agonistas del FXR | |
KR101611824B1 (ko) | 세포 스트레스 반응 조절을 통한 알츠하이머 질환 및 관련 장애의 치료를 위한 신규 치료학적 접근법 | |
Camu et al. | Pharmacology of systemic analgesics | |
JPH0733331B2 (ja) | ジフェンヒドラミン類を含んで成る鎮痛および抗炎症組成物 | |
JP2007533733A (ja) | 食物摂取管理の方法 | |
US20060293309A1 (en) | Method of treating disorders and conditions using peripherally-restricted antagonists and inhibitors | |
Camilleri | LX‐1031, a tryptophan 5‐hydroxylase inhibitor, and its potential in chronic diarrhea associated with increased serotonin | |
JP2014169343A (ja) | 線維筋痛症及び関連症状の治療におけるフルピルチン | |
JPS61500666A (ja) | キサンチン類を含んでなる鎮痛および抗炎症組成物およびその使用法 | |
CZ20023214A3 (cs) | Farmaceutická kompozice pro léčení akutní, chronické a/nebo neuropatické bolesti a migrén | |
CN101568333A (zh) | 广泛性发育障碍的治疗 | |
US10787675B2 (en) | Purified synthetic marijuana and methods of treatment by administering same | |
US20070004745A1 (en) | Methods of treating benign prostatic hyperplasia or lower urinary tract symptoms by using PDE 5 inhibitors | |
CN109789119A (zh) | 用于治疗或预防纤维化、硬化疾病或障碍的含fxr激动剂的复合组合物 | |
Leslie | Alvimopan for the management of postoperative ileus | |
CN109689105A (zh) | Fxr激动剂的组合 | |
ES2840079T3 (es) | Composición farmacéutica para el tratamiento de la esteatosis hepática no alcohólica | |
CN101568362A (zh) | 治疗抑郁症的方法 | |
JPS59501460A (ja) | カフェインを含んで成る改良された鎮痛及び抗炎症組成物並びにその使用方法 | |
US20050119253A1 (en) | Method of treating mental disorders using of D4 and 5-HT2A antagonists, inverse agonists or partial agonists | |
Bouras et al. | Effect of cyclooxygenase‐2 inhibitors on gastric emptying and small intestinal transit in humans | |
WO2007047282A1 (en) | Treatment of benign prostatic hypertrophy and lower urinary tract symptoms | |
EP1547650A1 (en) | Use of D4 and 5-HT2A antagonists, inverse agonists or partial agonists | |
Ho et al. | Real-world experience with tramadol plus dexketoprofen fixed-dose combination in postoperative pain management: a series of case studies from Asia |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
C56 | Change in the name or address of the patentee |
Owner name: NOVARTIS CO., LTD. Free format text: FORMER NAME: NOVARTIS AG |
|
CP01 | Change in the name or title of a patent holder |
Address after: Basel Patentee after: Novartis Ag Address before: Basel Patentee before: Novartis AG |
|
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20130821 Termination date: 20190716 |
|
CF01 | Termination of patent right due to non-payment of annual fee |