MXPA06010036A - Ion channel modulators - Google Patents
Ion channel modulatorsInfo
- Publication number
- MXPA06010036A MXPA06010036A MXPA/A/2006/010036A MXPA06010036A MXPA06010036A MX PA06010036 A MXPA06010036 A MX PA06010036A MX PA06010036 A MXPA06010036 A MX PA06010036A MX PA06010036 A MXPA06010036 A MX PA06010036A
- Authority
- MX
- Mexico
- Prior art keywords
- independently selected
- cycloalkyl
- optionally substituted
- halogen
- substituents
- Prior art date
Links
- 108090000862 Ion Channels Proteins 0.000 title claims abstract description 21
- 102000004310 Ion Channels Human genes 0.000 title claims abstract description 21
- 230000000051 modifying Effects 0.000 title claims abstract description 20
- 150000001875 compounds Chemical class 0.000 claims abstract description 107
- 239000000203 mixture Substances 0.000 claims abstract description 55
- 201000010099 disease Diseases 0.000 claims abstract description 39
- 108090000312 Calcium Channels Proteins 0.000 claims abstract description 14
- 102000003922 Calcium Channels Human genes 0.000 claims abstract description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 42
- -1 amino, hydroxy Chemical group 0.000 claims description 42
- 125000001424 substituent group Chemical group 0.000 claims description 41
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 32
- 229910052736 halogen Inorganic materials 0.000 claims description 32
- 150000002367 halogens Chemical class 0.000 claims description 32
- 125000001072 heteroaryl group Chemical group 0.000 claims description 29
- 125000003545 alkoxy group Chemical group 0.000 claims description 28
- 239000003814 drug Substances 0.000 claims description 24
- 125000003118 aryl group Chemical group 0.000 claims description 23
- 229910052739 hydrogen Inorganic materials 0.000 claims description 23
- 239000011780 sodium chloride Substances 0.000 claims description 17
- 208000002193 Pain Diseases 0.000 claims description 16
- 230000000694 effects Effects 0.000 claims description 16
- 125000000623 heterocyclic group Chemical group 0.000 claims description 16
- 125000003342 alkenyl group Chemical group 0.000 claims description 15
- 125000000304 alkynyl group Chemical group 0.000 claims description 14
- 125000001589 carboacyl group Chemical group 0.000 claims description 14
- XNVMFDGFXSZPDU-UHFFFAOYSA-N cyano nitroformate Chemical compound [O-][N+](=O)C(=O)OC#N XNVMFDGFXSZPDU-UHFFFAOYSA-N 0.000 claims description 14
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 14
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 14
- 125000001188 haloalkyl group Chemical group 0.000 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 14
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 13
- 125000003282 alkyl amino group Chemical group 0.000 claims description 13
- 125000005418 aryl aryl group Chemical group 0.000 claims description 13
- 102100004924 CACNA1B Human genes 0.000 claims description 11
- 108060001066 CACNA1B Proteins 0.000 claims description 11
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 10
- 208000006011 Stroke Diseases 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- 101700086511 CAV2 Proteins 0.000 claims description 7
- 206010020772 Hypertension Diseases 0.000 claims description 7
- 101710038725 F2RL2 Proteins 0.000 claims description 6
- 125000004985 dialkyl amino alkyl group Chemical group 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- 206010002383 Angina pectoris Diseases 0.000 claims description 5
- 206010003119 Arrhythmia Diseases 0.000 claims description 5
- 206010007521 Cardiac arrhythmias Diseases 0.000 claims description 5
- 206010012601 Diabetes mellitus Diseases 0.000 claims description 5
- 229920001774 Perfluoroether Polymers 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 125000005010 perfluoroalkyl group Chemical group 0.000 claims description 5
- 206010070976 Craniocerebral injury Diseases 0.000 claims description 4
- 208000003067 Myocardial Ischemia Diseases 0.000 claims description 4
- 208000005765 Traumatic Brain Injury Diseases 0.000 claims description 4
- 206010046543 Urinary incontinence Diseases 0.000 claims description 4
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 4
- 206010007559 Cardiac failure congestive Diseases 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 201000006233 congestive heart failure Diseases 0.000 claims description 3
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 2
- 125000004367 cycloalkylaryl group Chemical group 0.000 claims description 2
- 125000003917 carbamoyl group Chemical class [H]N([H])C(*)=O 0.000 claims 8
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 2
- 230000001225 therapeutic Effects 0.000 abstract description 9
- 230000001404 mediated Effects 0.000 abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- 238000006243 chemical reaction Methods 0.000 description 20
- 210000004027 cells Anatomy 0.000 description 15
- 238000002360 preparation method Methods 0.000 description 15
- 239000000243 solution Substances 0.000 description 15
- 239000003795 chemical substances by application Substances 0.000 description 14
- 235000002639 sodium chloride Nutrition 0.000 description 14
- 239000002253 acid Substances 0.000 description 13
- 239000008194 pharmaceutical composition Substances 0.000 description 13
- OYPRJOBELJOOCE-UHFFFAOYSA-N calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 11
- 239000011575 calcium Substances 0.000 description 11
- 229910052791 calcium Inorganic materials 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 239000000853 adhesive Substances 0.000 description 10
- 230000001070 adhesive Effects 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 125000005842 heteroatoms Chemical group 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 10
- 238000000034 method Methods 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 10
- 239000003153 chemical reaction reagent Substances 0.000 description 9
- 239000000969 carrier Substances 0.000 description 8
- 229940079593 drugs Drugs 0.000 description 8
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 8
- 230000002401 inhibitory effect Effects 0.000 description 8
- 239000003921 oil Substances 0.000 description 8
- 235000019198 oils Nutrition 0.000 description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M buffer Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 7
- UGJMXCAKCUNAIE-UHFFFAOYSA-N Gabapen Chemical compound OC(=O)CC1(CN)CCCCC1 UGJMXCAKCUNAIE-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 210000003491 Skin Anatomy 0.000 description 6
- WVDDGKGOMKODPV-UHFFFAOYSA-N benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 6
- 125000002619 bicyclic group Chemical group 0.000 description 6
- 150000003857 carboxamides Chemical class 0.000 description 6
- 229960002870 gabapentin Drugs 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- 150000002500 ions Chemical class 0.000 description 6
- 125000002950 monocyclic group Chemical group 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 210000003169 Central Nervous System Anatomy 0.000 description 5
- 206010015037 Epilepsy Diseases 0.000 description 5
- 241000700159 Rattus Species 0.000 description 5
- 210000003932 Urinary Bladder Anatomy 0.000 description 5
- 150000001408 amides Chemical class 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 5
- 239000012528 membrane Substances 0.000 description 5
- 210000002569 neurons Anatomy 0.000 description 5
- 239000000651 prodrug Substances 0.000 description 5
- 229940002612 prodrugs Drugs 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- ODIJQIXNOIZUSB-UHFFFAOYSA-N 1-(4-chlorophenyl)-2-[(4-fluorophenyl)methyl]imidazole-4-carboxylic acid Chemical compound N=1C(C(=O)O)=CN(C=2C=CC(Cl)=CC=2)C=1CC1=CC=C(F)C=C1 ODIJQIXNOIZUSB-UHFFFAOYSA-N 0.000 description 4
- 102100004922 CACNA1A Human genes 0.000 description 4
- 206010027599 Migraine Diseases 0.000 description 4
- 208000008085 Migraine Disorders Diseases 0.000 description 4
- 210000001428 Peripheral Nervous System Anatomy 0.000 description 4
- 206010037211 Psychomotor hyperactivity Diseases 0.000 description 4
- 239000002671 adjuvant Substances 0.000 description 4
- 230000000240 adjuvant Effects 0.000 description 4
- 125000004429 atoms Chemical group 0.000 description 4
- 230000027455 binding Effects 0.000 description 4
- 238000004166 bioassay Methods 0.000 description 4
- 125000004432 carbon atoms Chemical group C* 0.000 description 4
- 229910052681 coesite Inorganic materials 0.000 description 4
- 229910052906 cristobalite Inorganic materials 0.000 description 4
- 239000003085 diluting agent Substances 0.000 description 4
- 239000002270 dispersing agent Substances 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 230000003518 presynaptic Effects 0.000 description 4
- 229910052904 quartz Inorganic materials 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 4
- 229910052682 stishovite Inorganic materials 0.000 description 4
- 201000010874 syndrome Diseases 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- 230000000699 topical Effects 0.000 description 4
- 229910052905 tridymite Inorganic materials 0.000 description 4
- 108010078375 voltage-dependent calcium channel (P-Q type) Proteins 0.000 description 4
- DOCIXOHEHMEIQF-UHFFFAOYSA-N 2-[[1-(4-chlorophenyl)-2-[(4-fluorophenyl)methyl]imidazol-4-yl]methyl]-1H-benzimidazole Chemical compound C1=CC(F)=CC=C1CC1=NC(CC=2NC3=CC=CC=C3N=2)=CN1C1=CC=C(Cl)C=C1 DOCIXOHEHMEIQF-UHFFFAOYSA-N 0.000 description 3
- 230000036912 Bioavailability Effects 0.000 description 3
- 210000004369 Blood Anatomy 0.000 description 3
- 208000008787 Cardiovascular Disease Diseases 0.000 description 3
- 229920000858 Cyclodextrin Polymers 0.000 description 3
- 210000003284 Horns Anatomy 0.000 description 3
- YSZHCUVAEULNTG-UHFFFAOYSA-N N'-(4-chlorophenyl)-2-(4-fluorophenyl)ethanimidamide Chemical compound C1=CC(F)=CC=C1CC(=N)NC1=CC=C(Cl)C=C1 YSZHCUVAEULNTG-UHFFFAOYSA-N 0.000 description 3
- NGPNLBONZFXEFT-UHFFFAOYSA-N N-(2-aminophenyl)-2-[1-(4-chlorophenyl)-2-[(4-fluorophenyl)methyl]imidazol-4-yl]acetamide Chemical compound NC1=CC=CC=C1NC(=O)CC1=CN(C=2C=CC(Cl)=CC=2)C(CC=2C=CC(F)=CC=2)=N1 NGPNLBONZFXEFT-UHFFFAOYSA-N 0.000 description 3
- 208000009025 Nervous System Disease Diseases 0.000 description 3
- 208000004296 Neuralgia Diseases 0.000 description 3
- GEYOCULIXLDCMW-UHFFFAOYSA-N O-Phenylenediamine Chemical compound NC1=CC=CC=C1N GEYOCULIXLDCMW-UHFFFAOYSA-N 0.000 description 3
- 125000002947 alkylene group Chemical group 0.000 description 3
- 150000001409 amidines Chemical class 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 230000003042 antagnostic Effects 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 230000035514 bioavailability Effects 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 210000000548 hind-foot Anatomy 0.000 description 3
- 150000003840 hydrochlorides Chemical class 0.000 description 3
- 125000004435 hydrogen atoms Chemical class [H]* 0.000 description 3
- 230000001965 increased Effects 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
- 230000003000 nontoxic Effects 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 230000005062 synaptic transmission Effects 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- DKPIZHYFSSYXRT-UHFFFAOYSA-N 1-(4-chlorophenyl)-N-(4-fluorophenyl)-2-[(4-fluorophenyl)methyl]-N-methylimidazole-4-carboxamide Chemical compound C=1C=C(F)C=CC=1N(C)C(=O)C(N=1)=CN(C=2C=CC(Cl)=CC=2)C=1CC1=CC=C(F)C=C1 DKPIZHYFSSYXRT-UHFFFAOYSA-N 0.000 description 2
- BVDRUCCQKHGCRX-UHFFFAOYSA-N 2,3-dihydroxypropyl formate Chemical compound OCC(O)COC=O BVDRUCCQKHGCRX-UHFFFAOYSA-N 0.000 description 2
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical class CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 2
- GCSJOZFHZGHGTJ-UHFFFAOYSA-N 2-[2-[3,4-bis(2-hydroxyethoxy)oxolan-2-yl]-2-(2-hydroxyethoxy)ethoxy]ethyl formate Chemical compound O=COCCOCC(OCCO)C1OCC(OCCO)C1OCCO GCSJOZFHZGHGTJ-UHFFFAOYSA-N 0.000 description 2
- VLWRKVBQUANIGI-UHFFFAOYSA-N 4-fluoro-N-methylaniline Chemical compound CNC1=CC=C(F)C=C1 VLWRKVBQUANIGI-UHFFFAOYSA-N 0.000 description 2
- 125000004176 4-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1F)C([H])([H])* 0.000 description 2
- 239000005541 ACE inhibitor Substances 0.000 description 2
- 206010001497 Agitation Diseases 0.000 description 2
- 208000006673 Asthma Diseases 0.000 description 2
- FFGPTBGBLSHEPO-UHFFFAOYSA-N Carbamazepine Chemical compound C1=CC2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 FFGPTBGBLSHEPO-UHFFFAOYSA-N 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- 230000035695 Efflux Effects 0.000 description 2
- 241000283073 Equus caballus Species 0.000 description 2
- 230000036826 Excretion Effects 0.000 description 2
- 241000282326 Felis catus Species 0.000 description 2
- 108090000045 G-protein coupled receptors Proteins 0.000 description 2
- 102000003688 G-protein coupled receptors Human genes 0.000 description 2
- BTCSSZJGUNDROE-UHFFFAOYSA-N GABA Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 2
- 210000004392 Genitalia Anatomy 0.000 description 2
- 241000282414 Homo sapiens Species 0.000 description 2
- RAXXELZNTBOGNW-UHFFFAOYSA-N Imidazole Chemical compound C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 2
- 206010021639 Incontinence Diseases 0.000 description 2
- GUBGYTABKSRVRQ-UUNJERMWSA-N Lactose Natural products O([C@@H]1[C@H](O)[C@H](O)[C@H](O)O[C@@H]1CO)[C@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1 GUBGYTABKSRVRQ-UUNJERMWSA-N 0.000 description 2
- 210000004324 Lymphatic System Anatomy 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 208000008466 Metabolic Disease Diseases 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- WVVWKFGTBVQRLM-UHFFFAOYSA-N N-[[1-(4-chlorophenyl)-2-[(4-fluorophenyl)methyl]imidazol-4-yl]methyl]-4-fluoro-N-methylaniline Chemical compound C=1C=C(F)C=CC=1N(C)CC(N=1)=CN(C=2C=CC(Cl)=CC=2)C=1CC1=CC=C(F)C=C1 WVVWKFGTBVQRLM-UHFFFAOYSA-N 0.000 description 2
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N Oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 206010038683 Respiratory disease Diseases 0.000 description 2
- 229940076279 Serotonin Drugs 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 230000001154 acute Effects 0.000 description 2
- 230000002730 additional Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 239000002333 angiotensin II receptor antagonist Substances 0.000 description 2
- 239000005557 antagonist Substances 0.000 description 2
- 230000002429 anti-coagulation Effects 0.000 description 2
- 230000003092 anti-cytokine Effects 0.000 description 2
- 239000003146 anticoagulant agent Substances 0.000 description 2
- 239000007900 aqueous suspension Substances 0.000 description 2
- 235000019445 benzyl alcohol Nutrition 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 229960000623 carbamazepine Drugs 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 230000000875 corresponding Effects 0.000 description 2
- 229920003013 deoxyribonucleic acid Polymers 0.000 description 2
- 238000003745 diagnosis Methods 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 201000010870 diseases of metabolism Diseases 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 238000009510 drug design Methods 0.000 description 2
- 238000009509 drug development Methods 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- VICYTAYPKBLQFB-UHFFFAOYSA-N ethyl 3-bromo-2-oxopropanoate Chemical compound CCOC(=O)C(=O)CBr VICYTAYPKBLQFB-UHFFFAOYSA-N 0.000 description 2
- 125000004494 ethyl ester group Chemical group 0.000 description 2
- 230000029142 excretion Effects 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 238000005755 formation reaction Methods 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 239000008079 hexane Substances 0.000 description 2
- 150000002430 hydrocarbons Chemical group 0.000 description 2
- 230000004941 influx Effects 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 230000000968 intestinal Effects 0.000 description 2
- 238000007913 intrathecal administration Methods 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- HPQVWDOOUQVBTO-UHFFFAOYSA-N lithium aluminium hydride Substances [Li+].[Al-] HPQVWDOOUQVBTO-UHFFFAOYSA-N 0.000 description 2
- OCZDCIYGECBNKL-UHFFFAOYSA-N lithium;alumanuide Chemical compound [Li+].[AlH4-] OCZDCIYGECBNKL-UHFFFAOYSA-N 0.000 description 2
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium;hydroxide;hydrate Chemical compound [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000002480 mineral oil Substances 0.000 description 2
- 235000010446 mineral oil Nutrition 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000006011 modification reaction Methods 0.000 description 2
- 210000000653 nervous system Anatomy 0.000 description 2
- 239000004090 neuroprotective agent Substances 0.000 description 2
- 239000002858 neurotransmitter agent Substances 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 229940021182 non-steroidal anti-inflammatory drugs Drugs 0.000 description 2
- 239000000346 nonvolatile oil Substances 0.000 description 2
- 210000000287 oocyte Anatomy 0.000 description 2
- 210000000056 organs Anatomy 0.000 description 2
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 2
- 230000036961 partial Effects 0.000 description 2
- 230000001575 pathological Effects 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 235000021317 phosphate Nutrition 0.000 description 2
- 230000035790 physiological processes and functions Effects 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 229920000136 polysorbate Polymers 0.000 description 2
- 239000011148 porous material Substances 0.000 description 2
- OZAIFHULBGXAKX-UHFFFAOYSA-N precursor Substances N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 2
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 2
- 230000001681 protective Effects 0.000 description 2
- 238000005956 quaternization reaction Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 230000001105 regulatory Effects 0.000 description 2
- 239000000952 serotonin receptor agonist Substances 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 150000003431 steroids Chemical class 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 229940086735 succinate Drugs 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 230000002459 sustained Effects 0.000 description 2
- 230000002889 sympathetic Effects 0.000 description 2
- 230000002194 synthesizing Effects 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- 238000000844 transformation Methods 0.000 description 2
- 230000001131 transforming Effects 0.000 description 2
- 230000032258 transport Effects 0.000 description 2
- 230000002485 urinary Effects 0.000 description 2
- 239000001993 wax Substances 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
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 description 1
- JHQBLYITVCBGTO-UHFFFAOYSA-N 2-(4-fluorophenyl)acetonitrile Chemical compound FC1=CC=C(CC#N)C=C1 JHQBLYITVCBGTO-UHFFFAOYSA-N 0.000 description 1
- 229940080296 2-naphthalenesulfonate Drugs 0.000 description 1
- LEACJMVNYZDSKR-UHFFFAOYSA-N 2-octyldodecan-1-ol Chemical compound CCCCCCCCCCC(CO)CCCCCCCC LEACJMVNYZDSKR-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K 2qpq Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- MGBKJKDRMRAZKC-UHFFFAOYSA-N 3-aminobenzene-1,2-diol Chemical compound NC1=CC=CC(O)=C1O MGBKJKDRMRAZKC-UHFFFAOYSA-N 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-M 3-phenylpropionate Chemical compound [O-]C(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-M 0.000 description 1
- QSNSCYSYFYORTR-UHFFFAOYSA-N 4-Chloroaniline Chemical compound NC1=CC=C(Cl)C=C1 QSNSCYSYFYORTR-UHFFFAOYSA-N 0.000 description 1
- PLMCCOPFYJURPS-UHFFFAOYSA-M 4-bromo-3-oxobutanoate Chemical compound [O-]C(=O)CC(=O)CBr PLMCCOPFYJURPS-UHFFFAOYSA-M 0.000 description 1
- YUXBNNVWBUTOQZ-UHFFFAOYSA-N 4-phenyltriazine Chemical class C1=CC=CC=C1C1=CC=NN=N1 YUXBNNVWBUTOQZ-UHFFFAOYSA-N 0.000 description 1
- UXANBZHWKRDSDP-UHFFFAOYSA-M 5-bromo-2-oxopentanoate Chemical compound [O-]C(=O)C(=O)CCCBr UXANBZHWKRDSDP-UHFFFAOYSA-M 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N AI2O3 Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 229940116904 ANTIINFLAMMATORY THERAPEUTIC RADIOPHARMACEUTICALS Drugs 0.000 description 1
- 108010004463 Abciximab Proteins 0.000 description 1
- 229940022659 Acetaminophen Drugs 0.000 description 1
- 229960000583 Acetic Acid Drugs 0.000 description 1
- 229960004373 Acetylcholine Drugs 0.000 description 1
- 208000005298 Acute Pain Diseases 0.000 description 1
- 229940063655 Aluminum stearate Drugs 0.000 description 1
- 229940006211 Anticholinergic mydriatics and cycloplegics Drugs 0.000 description 1
- 229940065524 Anticholinergics inhalants for obstructive airway diseases Drugs 0.000 description 1
- 206010003402 Arthropod sting Diseases 0.000 description 1
- 229940009098 Aspartate Drugs 0.000 description 1
- 206010003591 Ataxia Diseases 0.000 description 1
- KPYSYYIEGFHWSV-UHFFFAOYSA-N Baclofen Chemical compound OC(=O)CC(CN)C1=CC=C(Cl)C=C1 KPYSYYIEGFHWSV-UHFFFAOYSA-N 0.000 description 1
- 229960000794 Baclofen Drugs 0.000 description 1
- 229940050390 Benzoate Drugs 0.000 description 1
- 210000000133 Brain Stem Anatomy 0.000 description 1
- PRRZDZJYSJLDBS-UHFFFAOYSA-N Bromopyruvic acid Chemical compound OC(=O)C(=O)CBr PRRZDZJYSJLDBS-UHFFFAOYSA-N 0.000 description 1
- 102100017589 CACNA1E Human genes 0.000 description 1
- 108060001069 CACNA1E Proteins 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- YKPUWZUDDOIDPM-SOFGYWHQSA-N Capsaicin Chemical compound COC1=CC(CNC(=O)CCCC\C=C\C(C)C)=CC=C1O YKPUWZUDDOIDPM-SOFGYWHQSA-N 0.000 description 1
- 206010007554 Cardiac failure Diseases 0.000 description 1
- 210000000170 Cell Membrane Anatomy 0.000 description 1
- 206010064012 Central pain syndrome Diseases 0.000 description 1
- 206010008190 Cerebrovascular accident Diseases 0.000 description 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M Copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- 229940097362 Cyclodextrins Drugs 0.000 description 1
- FBPFZTCFMRRESA-KAZBKCHUSA-N D-Mannitol Natural products OC[C@@H](O)[C@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KAZBKCHUSA-N 0.000 description 1
- CKLJMWTZIZZHCS-UHFFFAOYSA-N DL-aspartic acid Chemical compound OC(=O)C(N)CC(O)=O CKLJMWTZIZZHCS-UHFFFAOYSA-N 0.000 description 1
- NIJJYAXOARWZEE-UHFFFAOYSA-N Depacane Chemical compound CCCC(C(O)=O)CCC NIJJYAXOARWZEE-UHFFFAOYSA-N 0.000 description 1
- HCYAFALTSJYZDH-UHFFFAOYSA-N Desimpramine Chemical compound C1CC2=CC=CC=C2N(CCCNC)C2=CC=CC=C21 HCYAFALTSJYZDH-UHFFFAOYSA-N 0.000 description 1
- MKXZASYAUGDDCJ-SZMVWBNQSA-N Dextromethorphan Chemical compound C1CCC[C@H]2[C@@]3([H])N(C)CC[C@]21C1=CC(OC)=CC=C1C3 MKXZASYAUGDDCJ-SZMVWBNQSA-N 0.000 description 1
- 229960001985 Dextromethorphan Drugs 0.000 description 1
- 208000001636 Diabetic Neuropathy Diseases 0.000 description 1
- 206010012680 Diabetic neuropathy Diseases 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L Dipotassium phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- RUZYUOTYCVRMRZ-UHFFFAOYSA-N Doxazosin Chemical compound C1OC2=CC=CC=C2OC1C(=O)N(CC1)CCN1C1=NC(N)=C(C=C(C(OC)=C2)OC)C2=N1 RUZYUOTYCVRMRZ-UHFFFAOYSA-N 0.000 description 1
- 229960001389 Doxazosin Drugs 0.000 description 1
- ODQWQRRAPPTVAG-GZTJUZNOSA-N Doxepin Chemical compound C1OC2=CC=CC=C2C(=C/CCN(C)C)/C2=CC=CC=C21 ODQWQRRAPPTVAG-GZTJUZNOSA-N 0.000 description 1
- 229960005426 Doxepin Drugs 0.000 description 1
- ZEUITGRIYCTCEM-KRWDZBQOSA-N Duloxetine Chemical compound C1([C@@H](OC=2C3=CC=CC=C3C=CC=2)CCNC)=CC=CS1 ZEUITGRIYCTCEM-KRWDZBQOSA-N 0.000 description 1
- 208000005171 Dysmenorrhea Diseases 0.000 description 1
- 206010013935 Dysmenorrhoea Diseases 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 102000002045 Endothelin Human genes 0.000 description 1
- 108050009340 Endothelin Proteins 0.000 description 1
- ZUBDGKVDJUIMQQ-UBFCDGJISA-N Endothelin-1 Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(O)=O)NC(=O)[C@H]1NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@@H](CC=2C=CC(O)=CC=2)NC(=O)[C@H](C(C)C)NC(=O)[C@H]2CSSC[C@@H](C(N[C@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N2)=O)NC(=O)[C@@H](CO)NC(=O)[C@H](N)CSSC1)C1=CNC=N1 ZUBDGKVDJUIMQQ-UBFCDGJISA-N 0.000 description 1
- 229940095399 Enema Drugs 0.000 description 1
- 241000792859 Enema Species 0.000 description 1
- 239000001116 FEMA 4028 Substances 0.000 description 1
- PJMPHNIQZUBGLI-UHFFFAOYSA-N Fentanyl Chemical compound C=1C=CC=CC=1N(C(=O)CC)C(CC1)CCN1CCC1=CC=CC=C1 PJMPHNIQZUBGLI-UHFFFAOYSA-N 0.000 description 1
- 229960002428 Fentanyl Drugs 0.000 description 1
- 208000001640 Fibromyalgia Diseases 0.000 description 1
- OPYFPDBMMYUPME-UHFFFAOYSA-N Flumizole Chemical compound C1=CC(OC)=CC=C1C1=C(C=2C=CC(OC)=CC=2)NC(C(F)(F)F)=N1 OPYFPDBMMYUPME-UHFFFAOYSA-N 0.000 description 1
- 102000005915 GABA Receptors Human genes 0.000 description 1
- 108010005551 GABA Receptors Proteins 0.000 description 1
- 210000003594 Ganglia, Spinal Anatomy 0.000 description 1
- 229940049906 Glutamate Drugs 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 229960002449 Glycine Drugs 0.000 description 1
- 229940093915 Gynecological Organic acids Drugs 0.000 description 1
- 206010019280 Heart failure Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 102000008100 Human Serum Albumin Human genes 0.000 description 1
- 108091006822 Human Serum Albumin Proteins 0.000 description 1
- WJRBRSLFGCUECM-UHFFFAOYSA-N Hydantoin Chemical compound O=C1CNC(=O)N1 WJRBRSLFGCUECM-UHFFFAOYSA-N 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- 206010061216 Infarction Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010065390 Inflammatory pain Diseases 0.000 description 1
- 229940102223 Injectable Solution Drugs 0.000 description 1
- 206010061255 Ischaemia Diseases 0.000 description 1
- 210000003734 Kidney Anatomy 0.000 description 1
- 208000001083 Kidney Disease Diseases 0.000 description 1
- SFLSHLFXELFNJZ-MRVPVSSYSA-N L-Noradrenaline Natural products NC[C@@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-MRVPVSSYSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 241001325354 Lamiinae Species 0.000 description 1
- PYZRQGJRPPTADH-UHFFFAOYSA-N Lamotrigine Chemical compound NC1=NC(N)=NN=C1C1=CC=CC(Cl)=C1Cl PYZRQGJRPPTADH-UHFFFAOYSA-N 0.000 description 1
- 239000004166 Lanolin Substances 0.000 description 1
- 229940039717 Lanolin Drugs 0.000 description 1
- 229940067606 Lecithin Drugs 0.000 description 1
- 208000004731 Long QT Syndrome Diseases 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FEWJPZIEWOKRBE-XIXRPRMCSA-N Mesotartaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-XIXRPRMCSA-N 0.000 description 1
- 230000036740 Metabolism Effects 0.000 description 1
- 229940042472 Mineral Oil Drugs 0.000 description 1
- BQJCRHHNABKAKU-KBQPJGBKSA-N Morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 1
- 210000002464 Muscle, Smooth, Vascular Anatomy 0.000 description 1
- 210000003205 Muscles Anatomy 0.000 description 1
- 208000003627 Muscular Dystrophy Diseases 0.000 description 1
- 150000001204 N-oxides Chemical class 0.000 description 1
- 229940097496 Nasal Spray Drugs 0.000 description 1
- 206010029164 Nephrotic syndrome Diseases 0.000 description 1
- 108009000551 Nephrotic syndrome Proteins 0.000 description 1
- 210000004412 Neuroendocrine Cells Anatomy 0.000 description 1
- 206010029446 Nocturia Diseases 0.000 description 1
- 229960002748 Norepinephrine Drugs 0.000 description 1
- 101700048704 O17A Proteins 0.000 description 1
- 229940074726 OPHTHALMOLOGIC ANTIINFLAMMATORY AGENTS Drugs 0.000 description 1
- 229940005483 OPIOID ANALGESICS Drugs 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- BRUQQQPBMZOVGD-XFKAJCMBSA-N Oxycontin Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(OC)C2=C5[C@@]13CCN4C BRUQQQPBMZOVGD-XFKAJCMBSA-N 0.000 description 1
- 210000000578 Peripheral Nerves Anatomy 0.000 description 1
- 229950010765 Pivalate Drugs 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N Pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 210000002381 Plasma Anatomy 0.000 description 1
- 239000004698 Polyethylene (PE) Substances 0.000 description 1
- 229940113116 Polyethylene Glycol 1000 Drugs 0.000 description 1
- 229920001451 Polypropylene glycol Polymers 0.000 description 1
- 229920001214 Polysorbate 60 Polymers 0.000 description 1
- 206010036376 Post herpetic neuralgia Diseases 0.000 description 1
- 229940069338 Potassium Sorbate Drugs 0.000 description 1
- CHHHXKFHOYLYRE-STWYSWDKSA-M Potassium sorbate Chemical compound [K+].C\C=C\C=C\C([O-])=O CHHHXKFHOYLYRE-STWYSWDKSA-M 0.000 description 1
- 210000001774 Pressoreceptors Anatomy 0.000 description 1
- 229950008679 Protamine sulfate Drugs 0.000 description 1
- 206010061920 Psychotic disease Diseases 0.000 description 1
- 208000002815 Pulmonary Hypertension Diseases 0.000 description 1
- 210000000664 Rectum Anatomy 0.000 description 1
- 206010039911 Seizure Diseases 0.000 description 1
- 210000002966 Serum Anatomy 0.000 description 1
- 229940075582 Sorbic Acid Drugs 0.000 description 1
- HVUMOYIDDBPOLL-XWVZOOPGSA-N Sorbitan monostearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O HVUMOYIDDBPOLL-XWVZOOPGSA-N 0.000 description 1
- 208000009415 Spinocerebellar Ataxias Diseases 0.000 description 1
- KZNICNPSHKQLFF-UHFFFAOYSA-N Succinimide Chemical class O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 1
- GKZARTFJSANTLY-UHFFFAOYSA-N Sumatriptan Chemical compound [CH]1C(CS(=O)(=O)NC)=CC=C2N=CC(CCN(C)C)=C21 GKZARTFJSANTLY-UHFFFAOYSA-N 0.000 description 1
- 229960003708 Sumatriptan Drugs 0.000 description 1
- 108060008443 TPPP Proteins 0.000 description 1
- 208000001871 Tachycardia Diseases 0.000 description 1
- FKHIFSZMMVMEQY-UHFFFAOYSA-N Talc Chemical compound [Mg+2].[O-][Si]([O-])=O FKHIFSZMMVMEQY-UHFFFAOYSA-N 0.000 description 1
- DQHNAVOVODVIMG-UHFFFAOYSA-M Tiotropium bromide Chemical compound [Br-].C1C(C2C3O2)[N+](C)(C)C3CC1OC(=O)C(O)(C=1SC=CC=1)C1=CC=CS1 DQHNAVOVODVIMG-UHFFFAOYSA-M 0.000 description 1
- 102000003978 Tissue plasminogen activator Human genes 0.000 description 1
- 108090000373 Tissue plasminogen activator Proteins 0.000 description 1
- TVYLLZQTGLZFBW-ZBFHGGJFSA-N Tramadol Chemical compound COC1=CC=CC([C@]2(O)[C@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-ZBFHGGJFSA-N 0.000 description 1
- 229960004380 Tramadol Drugs 0.000 description 1
- 206010052779 Transplant rejections Diseases 0.000 description 1
- 206010044652 Trigeminal neuralgia Diseases 0.000 description 1
- JLTRXTDYQLMHGR-UHFFFAOYSA-N Trimethylaluminium Chemical compound C[Al](C)C JLTRXTDYQLMHGR-UHFFFAOYSA-N 0.000 description 1
- 210000003741 Urothelium Anatomy 0.000 description 1
- 241000269370 Xenopus <genus> Species 0.000 description 1
- BPKIMPVREBSLAJ-QTBYCLKRSA-N Ziconotide Chemical compound C([C@H]1C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]2C(=O)N[C@@H]3C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@H](C(N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CSSC2)C(N)=O)=O)CSSC[C@H](NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)CNC(=O)[C@H](CCCCN)NC(=O)CNC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CSSC3)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(N1)=O)CCSC)[C@@H](C)O)C1=CC=C(O)C=C1 BPKIMPVREBSLAJ-QTBYCLKRSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K [O-]P([O-])([O-])=O Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 229960000446 abciximab Drugs 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 1
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 230000002378 acidificating Effects 0.000 description 1
- 230000036982 action potential Effects 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 238000007792 addition Methods 0.000 description 1
- WNLRTRBMVRJNCN-UHFFFAOYSA-L adipate(2-) Chemical compound [O-]C(=O)CCCCC([O-])=O WNLRTRBMVRJNCN-UHFFFAOYSA-L 0.000 description 1
- 230000001919 adrenal Effects 0.000 description 1
- 239000000674 adrenergic antagonist Substances 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 125000002877 alkyl aryl group Chemical group 0.000 description 1
- 201000004384 alopecia Diseases 0.000 description 1
- 231100000360 alopecia Toxicity 0.000 description 1
- 229960003318 alteplase Drugs 0.000 description 1
- 230000004075 alteration Effects 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
- 229960003692 aminobutyric acid Drugs 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 230000003288 anthiarrhythmic Effects 0.000 description 1
- 230000001078 anti-cholinergic Effects 0.000 description 1
- 230000003110 anti-inflammatory Effects 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000001022 anti-muscarinic Effects 0.000 description 1
- 230000000111 anti-oxidant Effects 0.000 description 1
- 239000003416 antiarrhythmic agent Substances 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 125000005129 aryl carbonyl group Chemical group 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 108091008020 baroreceptors Proteins 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- 230000003542 behavioural Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- 150000001556 benzimidazoles Chemical class 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-M benzoate Chemical compound [O-]C(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-M 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 235000011175 beta-cyclodextrine Nutrition 0.000 description 1
- 229960004853 betadex Drugs 0.000 description 1
- 239000000560 biocompatible material Substances 0.000 description 1
- 230000000903 blocking Effects 0.000 description 1
- 229940090129 blood glucose lowering drugs Thiazolidinediones Drugs 0.000 description 1
- MCQRPQCQMGVWIQ-UHFFFAOYSA-N boron;methylsulfanylmethane Chemical compound [B].CSC MCQRPQCQMGVWIQ-UHFFFAOYSA-N 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 235000019437 butane-1,3-diol Nutrition 0.000 description 1
- PUPZLCDOIYMWBV-UHFFFAOYSA-N butylene glycol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-M butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 1
- MIOPJNTWMNEORI-UHFFFAOYSA-M camphorsulfonate anion Chemical compound C1CC2(CS([O-])(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-M 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-M caproate Chemical compound CCCCCC([O-])=O FUZZWVXGSFPDMH-UHFFFAOYSA-M 0.000 description 1
- 235000017663 capsaicin Nutrition 0.000 description 1
- 229960002504 capsaicin Drugs 0.000 description 1
- 229930003833 capsaicin Natural products 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 230000003197 catalytic Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 229940081733 cetearyl alcohol Drugs 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 230000000973 chemotherapeutic Effects 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 125000000068 chlorophenyl group Chemical group 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- 230000001684 chronic Effects 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 239000008119 colloidal silica Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000001808 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 201000003883 cystic fibrosis Diseases 0.000 description 1
- 230000001419 dependent Effects 0.000 description 1
- 230000002999 depolarising Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 229960003914 desipramine Drugs 0.000 description 1
- DMJZZSLVPSMWCS-UHFFFAOYSA-N diborane Chemical compound B1[H]B[H]1 DMJZZSLVPSMWCS-UHFFFAOYSA-N 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 229910000396 dipotassium phosphate Inorganic materials 0.000 description 1
- 235000019797 dipotassium phosphate Nutrition 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-M dodecyl sulfate Chemical compound CCCCCCCCCCCCOS([O-])(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-M 0.000 description 1
- 229940043264 dodecyl sulfate Drugs 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 229960002866 duloxetine Drugs 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 230000001804 emulsifying Effects 0.000 description 1
- 239000008387 emulsifying waxe Substances 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 239000007920 enema Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002708 enhancing Effects 0.000 description 1
- 201000004403 episodic ataxia Diseases 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- QJTGOEZLCSWVIE-UHFFFAOYSA-N ethyl 1-(4-chlorophenyl)-2-[(4-fluorophenyl)methyl]imidazole-4-carboxylate Chemical compound N=1C(C(=O)OCC)=CN(C=2C=CC(Cl)=CC=2)C=1CC1=CC=C(F)C=C1 QJTGOEZLCSWVIE-UHFFFAOYSA-N 0.000 description 1
- RZZFZPXUSOFOCC-UHFFFAOYSA-N ethyl 3-(4-chlorophenyl)-2-[(4-fluorophenyl)methyl]-5-hydroxy-4H-imidazole-5-carboxylate Chemical compound N=1C(C(=O)OCC)(O)CN(C=2C=CC(Cl)=CC=2)C=1CC1=CC=C(F)C=C1 RZZFZPXUSOFOCC-UHFFFAOYSA-N 0.000 description 1
- MGDWUTQKXCZNAJ-UHFFFAOYSA-N ethyl 4-bromo-3-oxobutanoate Chemical compound CCOC(=O)CC(=O)CBr MGDWUTQKXCZNAJ-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 230000003176 fibrotic Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N fumaric acid Chemical compound OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000002496 gastric Effects 0.000 description 1
- 230000002068 genetic Effects 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 230000001434 glomerular Effects 0.000 description 1
- AEMRFAOFKBGASW-UHFFFAOYSA-M glycolate Chemical compound OCC([O-])=O AEMRFAOFKBGASW-UHFFFAOYSA-M 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 235000015220 hamburgers Nutrition 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 230000003862 health status Effects 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-M heptanoate Chemical compound CCCCCCC([O-])=O MNWFXJYAOYHMED-UHFFFAOYSA-M 0.000 description 1
- 125000005223 heteroarylcarbonyl group Chemical group 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 125000006517 heterocyclyl carbonyl group Chemical group 0.000 description 1
- UBHWBODXJBSFLH-UHFFFAOYSA-N hexadecan-1-ol;octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO.CCCCCCCCCCCCCCCCCCO UBHWBODXJBSFLH-UHFFFAOYSA-N 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000003284 homeostatic Effects 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 1
- 230000036543 hypotension Effects 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000002757 inflammatory Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 229910001410 inorganic ion Inorganic materials 0.000 description 1
- 230000002452 interceptive Effects 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 230000003834 intracellular Effects 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000007919 intrasynovial administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-M isethionate Chemical compound OCCS([O-])(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-M 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M isothiocyanate Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 229960001848 lamotrigine Drugs 0.000 description 1
- 235000019388 lanolin Nutrition 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 230000000670 limiting Effects 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 239000000391 magnesium silicate Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229910000386 magnesium trisilicate Inorganic materials 0.000 description 1
- 229940099273 magnesium trisilicate Drugs 0.000 description 1
- 235000019793 magnesium trisilicate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-L maleate(2-) Chemical compound [O-]C(=O)\C=C/C([O-])=O VZCYOOQTPOCHFL-UPHRSURJSA-L 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000035786 metabolism Effects 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate Chemical compound CS([O-])(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M methanoate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000002297 mitogenic Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229960005181 morphine Drugs 0.000 description 1
- 229930014694 morphine Natural products 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 201000006938 muscular dystrophy Diseases 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-M naphthalene-2-sulfonate Chemical compound C1=CC=CC2=CC(S(=O)(=O)[O-])=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-M 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 201000003631 narcolepsy Diseases 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 201000008383 nephritis Diseases 0.000 description 1
- 230000001537 neural Effects 0.000 description 1
- 230000004112 neuroprotection Effects 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N nicotinic acid Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 231100000344 non-irritating Toxicity 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 230000003364 opioid Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 125000004043 oxo group Chemical group O=* 0.000 description 1
- 229960002085 oxycodone Drugs 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 125000004430 oxygen atoms Chemical group O* 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N p-acetaminophenol Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- 102000002574 p38 Mitogen-Activated Protein Kinases Human genes 0.000 description 1
- 108010068338 p38 Mitogen-Activated Protein Kinases Proteins 0.000 description 1
- 229960005489 paracetamol Drugs 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- JRKICGRDRMAZLK-UHFFFAOYSA-L peroxydisulfate Chemical compound [O-]S(=O)(=O)OOS([O-])(=O)=O JRKICGRDRMAZLK-UHFFFAOYSA-L 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000000275 pharmacokinetic Effects 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 230000000865 phosphorylative Effects 0.000 description 1
- 229920000406 phosphotungstic acid polymer Polymers 0.000 description 1
- 229940075930 picrate Drugs 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical compound [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229940096700 plain lipid modifying drugs Fibrates Drugs 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 description 1
- 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 description 1
- 229920002503 polyoxyethylene-polyoxypropylene Polymers 0.000 description 1
- 229940113124 polysorbate 60 Drugs 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229920000346 polystyrene-polyisoprene block-polystyrene 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
- 229910001414 potassium ion Inorganic materials 0.000 description 1
- 239000004302 potassium sorbate Substances 0.000 description 1
- 235000010241 potassium sorbate Nutrition 0.000 description 1
- 230000002335 preservative Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 230000002035 prolonged Effects 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L propanedioate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 239000011241 protective layer Substances 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 235000021251 pulses Nutrition 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 230000002829 reduced Effects 0.000 description 1
- 239000003638 reducing agent Substances 0.000 description 1
- 230000011514 reflex Effects 0.000 description 1
- 230000025160 regulation of secretion Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 230000001953 sensory Effects 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- BZKBCQXYZZXSCO-UHFFFAOYSA-N sodium hydride Inorganic materials [H-].[Na+] BZKBCQXYZZXSCO-UHFFFAOYSA-N 0.000 description 1
- 229910001415 sodium ion Inorganic materials 0.000 description 1
- WSWCOQWTEOXDQX-UHFFFAOYSA-N sorbic acid Chemical compound CC=CC=CC(O)=O WSWCOQWTEOXDQX-UHFFFAOYSA-N 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000001587 sorbitan monostearate Substances 0.000 description 1
- 235000011076 sorbitan monostearate Nutrition 0.000 description 1
- 229940035048 sorbitan monostearate Drugs 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 238000009168 stem cell therapy Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 150000003457 sulfones Chemical group 0.000 description 1
- YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical compound OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 description 1
- 150000003462 sulfoxides Chemical group 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000003956 synaptic plasticity Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 150000001467 thiazolidinediones Chemical class 0.000 description 1
- 229940110309 tiotropium Drugs 0.000 description 1
- 210000001519 tissues Anatomy 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- OOGJQPCLVADCPB-HXUWFJFHSA-N tolterodine Chemical compound C1([C@@H](CCN(C(C)C)C(C)C)C=2C(=CC=C(C)C=2)O)=CC=CC=C1 OOGJQPCLVADCPB-HXUWFJFHSA-N 0.000 description 1
- 229960004045 tolterodine Drugs 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 230000001256 tonic Effects 0.000 description 1
- 231100000224 toxic side effect Toxicity 0.000 description 1
- 239000012096 transfection reagent Substances 0.000 description 1
- 230000001052 transient Effects 0.000 description 1
- 239000003029 tricyclic antidepressant agent Substances 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 230000001960 triggered Effects 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-M undecanoate Chemical compound CCCCCCCCCCC([O-])=O ZDPHROOEEOARMN-UHFFFAOYSA-M 0.000 description 1
- 229960000604 valproic acid Drugs 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 235000021119 whey protein Nutrition 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
- WHGYBXFWUBPSRW-FOUAGVGXSA-N β-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 1
Abstract
The invention relates to compounds, compositions comprising the compounds, and methods of using the compounds and compound compositions. The compounds, compositions, and methods described herein can be used for the therapeutic modulation of ion channel function, and treatment of disease and disease symptoms, particularly those mediated by certain calcium channel subtype targets.
Description
ION CHANNEL MODULATORS
Background of the Invention All cells depend on the regulated movement of inorganic ions through cell membranes to perform essential physiological functions. Electrical excitability, synaptic plasticity, and signal transduction are examples of processes in which changes in ion concentration play a critical role. In general, the ion channels that allow these changes are protein pores consisting of one or multiple subunits, each containing two or more membrane coverage domains. Most ion channels have selectivity for specific ions, mainly Na +, K +, Ca2 +, or Cl-, by virtue of physical preferences for size and charge. The electrochemical forces, instead of the active transport, lead to the ions through the membranes, in this way a single channel can allow the passage of millions of ions per second. The channel opening, or "gate", is closely controlled by changes in voltage or ligand binding, depending on the subclass of the channel. Ion channels are attractive therapeutic targets because they are involved in many physiological processes, although the generation of drugs with
REF: 175186 specificity for particular channels in particular tissue types maintains a greater challenge. Voltage gate ion channels open in response to changes in membrane potential. For example, the depolarization of excitable cells such as neurons results in a transient influx of Na + ions, which propagate nerve impulses. This change in Na + concentration is sensitive by the voltage gate K + channels, which then allow an efflux of + ions. The efflux of K + ions repolarizes the membrane. Other cell types depend on the voltage gate Ca2 + channels to generate action potentials. Voltage gate ion channels also perform important functions in non-excitable cells, such as the regulation of secretion, homeostatic, and mitogenic processes. The ligand gate ion channels can be opened by extracellular stimuli such as neurotransmitters (eg, glutamate, serotonin, acetylcholine), or intracellular stimuli (eg, cAMP, Ca2 +, and phosphorylation). The Cav2 family of voltage gate calcium channels consists of 3 major subtypes Cav2.1 (calcium currents of type P or Q), Cav2.2 (calcium currents of type N), and Cav2.3 (calcium currents of type R). These currents are found at least exclusively in the central nervous system (CNS), peripheral nervous system (PNS) and neuroendocrine cells and constitute the predominant forms of presynaptic voltage gate calcium current. Presynaptic calcium entry is modulated by many types of G-protein coupled receptors (GPCR) and modulation of Cav2 channels is an extensive and highly effective means of regulating neurotransmission. The subunit composition of the Cav2 channels are defined by their subunit ai, which forms the pore and contains the voltage sensitive gates (a2.1, a.?2.2, and ot? 2.3, also known as a1A, 1B, and a1E respectively) and subunits ß, a2d and?. Genetic or pharmacological disturbances in the function of the ion channel can have dramatic clinical consequences. Long QT syndrome, epilepsy, cystic fibrosis, and episodic ataxia are some examples of inherited diseases that result from mutations in the ion channel subunits. Toxic side effects such as arrhythmia and stroke that are triggered by certain drugs are due to interference with the function of the ion channel (Sirois, JE and, Atchison, .D., Neurotoxicology 1996; 17 (1): 63-84; Keating, MT, Science 1996 272: 681-685). The drugs are useful for the therapeutic modulation of ion channel activity, and have applications in the treatment of many pathological conditions, including hypertension, angina pectoris, myocardial ischemia, asthma, overactivity of the bladder, alopecia, pain, heart failure , dysmenorrhea, type II diabetes, arrhythmia, graft rejection, stroke, seizures, epilepsy, infarction, gastric hypermobility, psychosis, cancer, muscular dystrophy, and narcolepsy (Coghlan, MJ, et al., J. Med. Chem. 2001 , 44: 1627-1653; Ackerman. M.J., and Clapham, D.E. N. Eng. J. Med. 1997, 336: 1575-1586). The increasing number of ion channels identified and the understanding of their complexity help in future therapy efforts, which modify the function of the ion channel. The therapeutic modulation of Cav2 channel activity has applications in the treatment of many pathological conditions. All the primary sensory afferents provide input to neurons in the dorsal horns of the spine and in the dorsal root ganglion neurons in the dorsal horn and influx of calcium through the channels of Cav2.'2 triggering the release of neurotransmitters from terminals of the presynaptic nerve in the spine. Therefore, blockade of Cav2.2 channels is expected to be broadly effective because these channels are on a common downward trajectory of the wide variety of receptors that mediate pain (Julius, D. and Basbaum, Al. Nature 2001, 413: 203-216). In fact, intrathecal injection of Cav2.2 selective conopeptide ziconitide (SNX-111) has been shown to be widely effective against both neuropathic and inflammatory pain in animals and humans (Bowersox, SS et al, J Pharmacol Exp Ther 1996, 279: 1243-1249). Ziconitide has also been shown to be highly effective as a neuroprotective agent in rat models of global or focal ischemia (Colburne, F. et al, Stroke 1999, 30: 662-668). Thus, it is reasonable to conclude that the modulation of Cav2.2 has implications in the neuroprotection / apoplexy treatment. The Cav2.2 channels are located in the periphery and mediate the release of catecholamine from sympathetic neurons and adrenal chuffin cells. Some forms of hypertension result from elevated sympathetic tone and Cav2.2 modulators may be particularly effective in the treatment of this disorder. Although complete blockade of Cav2.2 can cause hypotension or deteriorated baroreceptor reflexes, partial inhibition by Cav2.2 modulators can reduce hypertension with minimal reflex tachycardia (Uneyama, OD Int. J. Mol. Med. 1999 3: 455-466). Overactivity of the bladder (OAJ3) is characterized by storage symptoms such as urgency, frequency and nocturia with or without stimulation of incontinence, which results from overactivity of the muscle in the bladder. OAB can lead to incontinence stimulation. The etiology of OAB and painful bladder syndrome is unknown, although alterations in nerves, smooth muscle and urothelium can cause OAB (Steers, W. Rev Urol, 4: S7-S18). There is evidence to suggest that the reduction of bladder overactivity can be indirectly effected by the inhibition of Cav2.2 and / or Cavl channels. The location of Cav2.1 channels in the superficial laminae of the dorsal horn of the spine suggests that these channels are involved in the perception and maintenance of certain forms of pain (Vanegas, H. and Schaible, H. Pain 2000, 85: 9-18). The complete elimination of Cav2.1 calcium currents alters the synaptic transmission resulting in severe ataxia. Gabapentin has been used clinically for many years as an aid therapy for the treatment of epilepsy. In recent years, it has emerged as a leading treatment for neuropathic pain. Clinical trials have shown that gabapentin is effective for the treatment of post-herpetic neuralgia, diabetic neuropathy, trigeminal neuralgia, migraine and fibromyalgia (Mellegers, P. G. et al. Clin J Pain 2001, 17: 284-295). Gabapentin was designed as a metabolically stable GABA imitator, but most studies have no effect on GABA receptors. The x2d subunit of the Cav2.1 channel has been identified as a high affinity binding site for gabapentin in the CNS. There is evidence to suggest that gabapentin could inhibit neurotransmission in the spine by interfering with the function of the a2d subunits, thereby inhibiting presynaptic calcium currents.
Brief Description of the Invention The invention relates to heterocyclic compounds, compositions comprising the compounds, and methods of using the compounds and compositions of the compound. The compounds and compositions comprising them are useful for treating diseases or symptoms of diseases, including those mediated by or associated with ion channels. In one aspect it is a compound of the formula (I) or a pharmaceutical salt thereof
wherein, Ar 1 is cycloalkyl, aryl, heterocyclyl or heteroaryl, each may be optionally substituted with one or more substituents selected from the group consisting of H, halogen, amino, hydroxy, cyano, nitro, carboxylate, alkyl, alkenyl, alkynyl, cycloalkyl, cyclohexyl, alkoxy, mono and di-alkyl amino, phenyl, carboxamide, haloalkyl, haloalkoxy, and alkanoyl; R1 is Ar2 or lower alkyl optionally substituted with Ar2; Ar2 is independently selected from cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of H, halogen, amino, hydroxy, cyano, nitro, carboxylate, alkenyl, alkenyl, alkynyl, cycloalkyl, cyclohexyl, alkoxy, mono and di-alkyl amino, phenyl, carboxamide, haloalkyl, haloalkoxy, and alkanoyl; each R2 is independently selected from C02R3, COAr ?, CONR3R4, (CH2) mAr3, (CH2) nNR3R4 or CH2OR4; each R3 is independently selected from H, or lower alkyl; each R 4 is independently selected from H, lower alkyl, C (0) OR 5, C (0) NR 5 R 6, S (0) 2 NR 5 R 6, C (0) R 7 S (0) 2 R 7 or (CH 2) p Ar 3; each Ar3 is cycloalkyl, aryl, heterocyclyl, or heteroaryl, each optionally substituted with one or more substituents, each m is independently 0 or 1, each n is independently 1 or 2, each p is independently 0 or 1, each substituted by Ar3 is independently selected from halogen, CN, N02, OR5, SR5, S (0) 2OR5, NR5Re, cycloalkyl, perfluoroalkyl C? -C2, perfluoroalkoxy C? -C2 / 1,2-methylenedioxy, C (0) 0R5, C (0) NR5R6, 0C (0) NR5Re, NR5C (0) NR5R6, C (NR5) NR5R6, NR5C (NR6) NR5R6, S (0) 2NR5R6, R7, C (0) R7, NRsC (0) R7, S (0) R7, or S (0) 2R7;
each R5 is independently selected from hydrogen or optionally substituted lower alkyl with one or more substituents independently selected from halogen,
OH, C 1 -C 4 alkoxy, NH 2, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino or C 3 -C 3 cycloalkyl; each R6 is independently selected from hydrogen, (CH2) qAr4, or lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, C?-C4 alkoxy, NH2, C?-C4 alkylamino, C dial-C4 dialkylamino or cycloalkyl C3-C6; each R7 is independently selected from (CH2) qAr4 or lower alkyl optionally substituted with one or more substituents independently selected from halogen,
OH, alkoxy Q1.-C4, NH2, C1-C4 alkylamino, dialkylamino Ca-C4 or cycloalkyl C3-C6; and each, Ar 4 is independently selected from C 3 -C 6 cycloalkyl, aryl or heteroaryl, each optionally substituted with one to three substituents independently selected from halogen, OH, C 4 -C 4 alkoxy, NH 2, C 1 -C 4 alkylamino, dialkylamino C 1 C4 or 1,2-methylenedioxy; and each q is independently 0 or 1. In other aspects, the compounds are those of any of the formulas herein (including any combination thereof): wherein, Ar1 is aryl or heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of H, halogen, amino, hydroxy, cyano, nitro, carboxylate, alkyl, alkenyl, alkynyl, cycloalkyl, cyclohexyl, alkoxy, mono and di-alkyl amino, phenyl, carboxamide, haloalkyl , haloalkoxy, and alkanoyl; R1 is Ar2; Ar2 is independently selected from aryl or heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of H, halogen, amino, hydroxy, cyano, nitro, carboxylate, alkyl, alkenyl, alkynyl, cycloalkyl, cyclohexyl, alkoxy, mono and di-alkyl amino, phenyl, carboxamide, haloalkyl, haloalkoxy, and alkanoyl; and each R2 is independently selected from COAr3, C0NR3R4, (CH2) mAr3, or (CH2) nNR3R4; wherein, Ar 1 is aryl, which may be optionally substituted with one or more substituents selected from the group consisting of H, halogen, amino, hydroxy, cyano, nitro, carboxylate, alkyl, alkenyl, alkynyl, cycloalkyl, cyclohexyl, alkoxy, mono and di-alkyl amino, phenyl, carboxamide, haloalkyl, haloalkoxy, and alkanoyl;
Ar2 is independently aryl which may be optionally substituted with one or more substituents selected from the group consisting of H, halogen, amino, hydroxy, cyano, nitro, carboxylate, alkyl, alkenyl, alkynyl, cycloalkyl, cyclohexyl, alkoxy, mono and di -alkylamino, phenyl, carboxamide, haloalkyl, haloalkoxy, and alkanoyl; and each R2 is independently selected from (CH ^^ Ar3, O (CH2) nNR3R4; wherein, each Ar3 is independently aryl or heteroaryl, each optionally substituted with one or more substituents, wherein each R4 is (CH2) PAr3 and each Ar3 is independently aryl or heteroaryl, each substituted with one or more substituents, wherein each R2 is independently selected from (CH2) nNR3R4, and each R4 is (CH2) pAr3; wherein, R1 is para-chlorophenyl Wherein, Ar 1 is para-fluorophenyl, wherein the compound of formula I is a compound delineated in any of the tables herein or a pharmaceutical salt thereof In other aspects, the invention relates to a composition that it comprises a compound of any of the formulas herein, an additional therapeutic agent, and a pharmaceutically acceptable carrier The additional therapeutic agent can be a cardiovascular disease agent and / or a disease agent of the system A disease agent of the nervous system refers to an agent of peripheral nervous system (PNS) and / or central nervous system (CNS) disease agent. Yet another aspect of this invention relates to a method of treating a subject (e.g., mammal, human, horse, dog, cat) having a disease or symptom of the disease (including, but not limited to, angina, hypertension). , congestive heart failure, myocardial ischemia, arrhythmia, diabetes, urinary incontinence, stroke, pain, traumatic brain injury, or a nervous system disorder). The method includes administering to the subject (which includes a subject identified as needing such treatment) an effective amount of a compound described herein, or a composition described herein to produce such an effect. A subject who needs such treatment may be in the judgment of a subject or a health care professional and may be subjective (for example, opinion) or objective (for example, measured by a method of testing or diagnosis). ). Yet another aspect of this invention relates to a method of treating a subject (e.g., mammalian, human, horse, dog, cat) having a disease mediated by the ion channel or symptom of the disease (including, but not is limited to angina, hypertension, congestive heart failure, myocardial ischemia, arrhythmia, diabetes, urinary incontinence, stroke, pain, traumatic brain injury, or a nervous system disorder). The method includes administering to the subject (including a subject identified as in need of such treatment) an effective amount of a compound described herein, or a composition described herein to produce such an effect. Identifying a subject who needs such treatment may be in the judgment of a subject or a health care professional and may be subjective (for example, opinion) or objective (for example, measured by a method of testing or diagnosis). ). The invention also relates to a method for making a compound described herein, the method includes any of the reactions or reagents as outlined in the reaction schemes or examples herein. Alternatively, the method includes taking any of the intermediate compounds described herein and reacting this with one or more chemical reagents in one or more steps to produce a compound described herein. Another aspect is a method for modulating (eg, inhibiting, agonizing, antagonizing) channel activity of calcium comprising contacting a calcium channel with a compound (or composition thereof) of any of the formulas herein. Other aspects are a method for modulating the activity of the calcium channel Cav2 in a subject in need thereof which includes administering to the subject a therapeutically effective amount of a compound (or composition thereof) of any of the present formulas. Also within the scope of this invention is a packaged product. The packaged product includes a container, one of the above compounds in the container, and a legend (e.g., a label or an insert) associated with the container and indicating administration of the compound to treat a disorder associated with modulation in the ion channel. In other embodiments, the compounds, compositions, and methods delineated herein are any of the compounds of the tables herein or methods included therein.
The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from the description and from the claims.
Detailed Description of the Description As used herein, the term "halo" refers to any radical of fluorine, chlorine, bromine or iodine. The term "alkyl" refers to a hydrocarbon chain which may be a straight chain or branched chain, which contains the indicated number of carbon atoms. For example, C-C5 indicates that the group can have from 1 to 5
(inclusive) "carbon atoms in this.The term" lower alkyl "refers to a C? -C6 alkyl chain.
"Arylalkyl" refers to a portion in which an alkyl hydrogen atom is replaced by an aryl group. The term "alkoxy" refers to an -O-alkyl radical.
The term "alkylene" refers to an alkyl divalent
(that is, -R-). The term "alkylene dioxo" refers to a divalent species of the structure -O-R-O-, in which R represents an alkylene. The term "cycloalkyl" as used herein includes partially saturated and unsaturated cyclic hydrocarbon groups having 3 to 12 carbons, preferably 3 to 8 carbons, and more preferably 3 to 6 carbons. The term "aryl" refers to a 6-membered monocyclic hydrocarbon ring or multicyclic aromatic ring system of 10 to 14 members wherein 0, 1, 2, 3, or 4 atoms of each ring may be substituted by a substituent. Examples of the aryl groups include phenyl, naphthyl and the like. The term "heterocyclyl" refers to a non-aromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having 1-3 heteroatoms if it is monocyclic, 1-6 heteroatoms if is bicyclic, or 1-9 heteroatoms if tricyclic, heteroatoms selected from 0, N, or S (eg, carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, 0, or S if it is monocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2 or 3 atoms of each ring can be replaced by a substituent. The term "heteroaryl" refers to a 5-8 membered aromatic monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having 1-3 heteroatoms if it is monocyclic, 1-6 heteroatoms if it is bicyclic, or 1-9 heteroatoms if it is tricyclic, heteroatoms selected from 0, N, or S (for example, carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, or S if is monocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2, 3, or 4 atoms of each ring can be substituted by a substituent. The term "oxo" refers to an oxygen atom, which forms a carbonyl when bonded to a carbon, an N-oxide when bound to nitrogen, and a sulfoxide or sulfone when bonded to sulfur. The term "acyl" refers to a substituent alkylcarbonyl, cycloalguylcarbonyl, arylcarbonyl, heterocyclylcarbonyl, or heteroarylcarbonyl, any of which may be further substituted by substituents. The term "substituents" refers to a group "substituted" on an alkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl group at any atom of that group. Suitable substituents include, without halogen limitation, CN, N02, OR5, SR5, S (0) 20R5, NR5R6, perfluoroalkyl C? -C2, perfluoroalkoxy C? -C2, 1,2-methylenedioxy, C (0) 0R5, C (0) NR5Rs, OC (0) NR5R6, NR5C (0) NR5R6, C (NR6) NR5R6, NR5C (NR6) NR5R6, S (0) 2NR5RS, R7, C (0) R7, NR5C (0) R7, S (0) R7, or S (0) 2R7. Each R 5 is independently hydrogen, C 1 -C 4 alkyl or C 3 -C 6 cycloalkyl. Each Rs is independently hydrogen, C3-C6 cycloalkyl, aryl, heterocyclyl, heteroaryl, C? -C4 alkyl or C? -C4 alkyl substituted with C3-C6 cycloalkyl, aryl, heterocyclyl or heteroaryl. Each R7 is independently C3-C6 cycloalkyl, aryl, heterocyclyl, heteroaryl, C 1 -C 4 alkyl or C 1 -C 4 alkyl substituted with C 3 -C 6 cycloalkyl, aryl, heterocyclyl or heteroaryl. Each C3-C6 cycloalkyl, aryl, heterocyclyl, heteroaryl and C? -C4 alkyl in each R5, R6 and R7 can optionally be substituted with halogen, CN, C? -C4 alkyl, OH, C? -C4 alkoxy / NH2, alkylamino C? -C4, dialkylamino C? -C4, perfluoroalkyl C? -C2, perfluoroalkoxy C? -C2, or 1,2-methylenedioxy. In one aspect, the substituents in a group are independently hydrogen, hydroxyl, halogen, nitro, S03H, trifluoromethyl, trifluoromethoxy, straight or branched C-C6 alkyl, straight or branched C6-C6 alkoxy, O-benzyl , 0-phenyl, phenyl, 1,2-methylenedioxy, carboxyl, morpholinyl, piperidinyl, amino or OC (0) NR5R6. Each R5 and R6 are as described above. The term "treat" or "treatise" refers to administering a compound described herein to a subject for the purpose of curing, healing, alleviating, alleviating, altering, remedying, ameliorating, ameliorating or affecting a disease, the symptoms of the disease or predisposition towards the disease. "An effective amount" refers to an amount of a compound, which confers a therapeutic effect on the treated subject. The therapeutic effect may be objective (that is, measured by some test or marker) or subjective (that is, the subject gives an indication of or feels an effect). An effective amount of the compound described above may be in the range from about 0.1 mg / Kg to about 500 mg / Kg. The effective dose also varies depending on the route of administration, as well as the possibility of co-use with other reagents. Representative compounds useful in the compositions and methods are delineated herein:
TABLE IT
TABLE IB
TABLE 1C
Ion channel modulator compounds can be identified through both in vitro (e.g., cell-based and cell-free) and in vivo methods. Representative examples of these methods are described in the examples herein. The combinations of the substituents and variables descried by this invention are only those that result in the formation of the stable compounds. The term "stable", as used herein, refers to compounds in which sufficient stability is possessed to allow manufactures and which maintain the integrity of the compound for a sufficient period of time to be useful for the purpose detailed in the present (for example, therapeutic or prophylactic administration to a sutto). The compounds delineated herein can be synthesized using conventional methods, as illustrated in the reaction schemes herein. In the reaction schemes herein, unless stated otherwise, the variables in the chemical formulas are as defined in other formulas herein. For example, Ar1, Ar3, R1, R2, R3 and R4 in the reaction schemes are defined as in any of the formulas herein, except where otherwise defined in the reaction schemes. Reaction scheme 1
Treatment of aryl nitrile with alcohol under acidic conditions provided the alkoxy imidate intermediate, which is treated with the appropriate substituted amine under catalytic conditions (eg, ethanolic HCl, CuCl, Ln (III) ions) to provide the substituted amidine (I ). The treatment of amidine (I) with a bromopyruvate or a
4-bromo-3-oxo-butyrate or a 5-bromo-oxo-pentanoate under basic conditions provided the imdiazole ester (lia), which is hydrolyzed to provide the corresponding acid derivative (Ilb).
Reaction Scheme 2
(ii) (iii) íiv)
Reaction of the acid (Ilb) with the appropriately substituted amine under standard coupling procedures provided the desired amide (III). Reduction of the amide with common reducing agents such as diborane or lithium aluminum hydride provided the corresponding amine (IV). Alternatively the treatment of the acid (Ilb) with Weinreb reagent provided amide (V). Treatment of the amide under standard condition with an organometallic reagent (eg, aryl lithium or magnesium aryl halide) provided the ketone (VI). The reduction of the ketone under a variety of conditions provided the desired product (VII)
Reaction Scheme 3
Í% I s Ar 3 is aryl or heteroaryl p is 0, 1, 2 or 3
Alternatively the treatment of amidine (I) with (X) provided the desired imidazole (VII).
Reaction Scheme 4
An alternative route to obtain heteroaryl derivatives is to react the activated acid of (Ilb) with the appropriate substrate followed by cyclization to provide the desired product. For example as described in Reaction Scheme 4, the reaction of the activated acid of (Ilb) with benzene-1,2-diamine gave the intermediate amide (VIII), which is cyclized to provide the benzimidazole derivative (IX) .
Reaction Scheme 5
nte
The treatment of carboxylic acid (Ilb) under standard reduction conditions (eg, lithium aluminum hydride) gave (XI). Treatment of (XI) under standard ether formation conditions (e.g., NaH, halo-R4) gave (XII). The synthesized compounds can be separated from the reaction mixture and then purified by a method such as column chromatography, high pressure liquid chromatography, or recrystallization. As can be appreciated by the skilled artisan, additional methods for synthesizing the compounds of the formulas herein will be apparent to those of ordinary skill in the art. Additionally, the various synthetic steps can be performed in an alternating sequence in order to give the desired compounds. Synthetic chemistry transformations and protective group methodologies (protection and deprotection) useful in the synthesis of the compounds described herein are known in the art and include, for example, those such as those described in R. Larock, Comprehensive Organic Transformations , 2nd. Ed., Wiley-VCH Publishers (1999); T. W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd. Ed., John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1999); and L. Paquette, ed. , Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), and subsequent editions thereof. The compounds of this invention may contain one or more asymmetric centers and thus be presented as racemates and racemic mixtures, single enantiomers, individual diastereomers and diastereomeric mixtures. All of these isomeric forms of these compounds are expressly included in the present invention. The compounds of this invention may also be represented in multiple tautomeric forms, in such cases, the invention expressly includes all tautomeric forms of the compounds described herein (for example, alkylation of a ring system may result in alkylation in multiple sites, the invention expressly includes all these reaction products). Such isomeric forms of such compounds are expressly included in the present invention. All crystal forms of the compounds described herein are expressly included in the present invention.
As used herein, the compounds of this invention, including the compounds of the formulas described herein, are defined to include pharmaceutically acceptable derivatives or prodrugs thereof. A "pharmaceutically acceptable derivative or prodrug" means any salt, ester, salt of an ester, or other pharmaceutically acceptable derivative of a compound of this invention which, during administration to a recipient, is capable of providing (directly or indirectly) the compound of this invention. Particularly favored derivatives and prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a mammal (e.g., by allowing an orally administered compound to be more rapidly absorbed in the blood) or that increase the release from the precursor compound to the biological compartment (for example, the brain or lymphatic system) in relation to the precursor species. Preferred prodrugs include derivatives wherein a group that increases aqueous solubility or active transport through the intestinal membrane is added to the structure of the formulas described herein. See, for example, Alexander, J. et al. Journal of Medicinal Chemistry 1988, 31, 318-322; Bundgaard, H. Design of Prodrugs; Elsevier: Amsterdam, 1985; pp 1-92; Bundgaard, H.; Nielsen, N.M. Journal of Medicinal Chemistry 1987, 30, 451-454;
Bundgaard, H. A Textbook of Drug Design and Development; Har ood Academic Publ .: Switzerland, 1991; pp 113-191; Digenis, G. A. et al. Handbook of Experimental Pharmacology 1975, 28, 86-112; Friis, G. J., - Bundgaard, H. A Textbook of Drug Design and Development; 2 ed.; Overseas Publ .: Amsterdam, 1996; pp 351-385; Pit an, I.H. Medicinal Research Reviews 1981, 1, 189-214; Sinkula, A. A .; Yalkowsky Journal of Pharmaceutical Sciences 1975, 64, 181-210; Verbiscar, A. J.; Abood, L. G Journal óf Medicinal Chemistry 1970, 13, 1176-1179; Stella, V. J.; Himmelstein, K. J. Journal of Medicinal Chemistry 1980, 23, 1275-1282; Bodor, N.; Kaminski, J. J. Annual Reports in Medicinal Chemistry 1987, 22, SOS-SIS. The compounds of this invention can be modified by appropriate functionalities added to increase the selective biological properties. Such modifications are known in the art and include those that increase biological penetration in a given biological compartment
(eg, blood, lymphatic system, nervous system), increased oral availability, increased solubility to allow administration by injection, altered metabolism and altered excretion ratio. The pharmaceutically acceptable salts of the compounds of this invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases.
Examples of suitable acid salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorrate, camphorsulfonate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride , bromohydrate, iodohydrate, 2-hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate , thiocyanate, tosylate and undecanoate. Other acids, such as oxalic, although not by themselves pharmaceutically acceptable, can be employed in the preparation of salts useful as intermediates for obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts. Suitable base salt derivatives include alkali metal (eg, sodium), alkaline earth metal (eg, magnesium), ammonium and N- (alkyl) 4+ salts. This invention also divides the quaternization of any of the nitrogen-containing groups of the compounds described herein. The soluble or dispersible products in water or oil can be obtained by such quaternization. The compounds of the formulas described herein can, for example, be administered by injection, intravenously, intraarterially, subdermally, intraperitonally, intramuscularly, or subcutaneously.; or orally, buccally, nasally, transmucosally, topically, in an ophthalmic preparation, or by inhalation, with a dose in the range from about 0.5 to about 100 mg / kg of body weight, alternatively doses between 1 mg and 1000 mg / dose, every 4 to 120 hours, or in accordance with the requirements of the particular drug. The methods herein contemplate the administration of an effective amount of the compound or composition of compound to achieve the desired or established effect. Typically, the pharmaceutical compositions of this invention will be administered from about 1 to about 6 times a day or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy. The amount of active ingredient that can be combined with the carrier materials to produce a single dose form will vary depending on the host treated and the particular mode of administration. A typical preparation will contain from about 5% to about 95% active compound (w / w). Alternatively, such preparations contain from about 20% to about 80% active compound. Lower or higher doses than those recited above may be required. The specific dose and treatment regimens for any particular patient will depend on a variety of factors, including the activity of the specific compound employed, age, body weight, general health status, sex, diet, time of administration, rate of excretion, combination of the drug, the severity and course of the disease, condition or symptoms, the patient's disposition to the disease, condition or symptoms, and the judgment of the treating physician. During the improvement of the patient's condition, a maintenance dose of a compound, composition or combination of this invention can be administered, if necessary. Subsequently, the dose or frequency of administration, or both, can be reduced, as a function of the symptoms, to a level at which the improved condition is maintained when the symptoms have been alleviated to the desired level, the treatment would be stopped. Patients may, however, require intermittent treatment on a long-term basis on any recurrence of the symptoms of the disease. The compositions delineated herein include the compounds of the formulas delineated herein, as well as additional therapeutic agents present, in amounts effective to achieve a modulation of disease or symptoms of the disease, including disorders mediated by the ion channel or symptoms. of the same.
References that include examples of additional therapeutic agents are: 1) Burger's Medicinal Chemistry & Drug Discovery 6th edition, by Alfred Burger, Donald J. Abraham, ed., Volumes 1 through 6, Wiley Interscience Publication, NY, 2003; 2) Ion Channels and Disease by Francis M. Ashcroft, Academic Press, NY, 2000; and 3) Calcium Antagonists in Clinical Medicine 3rd edition, Murray Epstein, MD, FACP, ed. , Hanley & Belfus, Inc., Philadelphia, PA, 2002. Additional therapeutic agents include but are not limited to agents for the treatment of cardiovascular disease (e.g., hypertension, angina, etc.), metabolic disease.
(eg syndrome X, diabetes, obesity), pain (eg, acute pain, pain from inflammation, neuropathic pain, migraine, etc.), kidney disease or urinary genital (eg, glomerular nephritis, urinary incontinence, nephrotic syndrome) , abnormal growth of the cell (eg, oncology, fibrotic diseases), nervous system disease (eg, epilepsy, stroke, migraine, traumatic brain injury or neuronal disorders, etc.), respiratory disease (eg, asthma, COPD, pulmonary hypertension) and its symptoms of the disease. Examples of additional therapeutic agents for the treatment of cardiovascular disease and symptoms of the disease including but not limited to antihypertensive agents, ACE inhibitors, angiotensin II receptor antagonists, statins, β-blockers, antioxidants, anti-inflammatory drugs, anti -trombotic, anti-coagulants or antiarrhythmics. Examples of additional therapeutic agents for the treatment of metabolic disease and symptoms of the disease include but are not limited to ACE inhibitors, angiotensin II antagonists, fibrates, thiazolidinediones or antidiabetic drugs of sulfonylurea. Examples of additional therapeutic agents for the treatment of pain and its symptoms include but are not limited to non-steroidal anti-inflammatory drugs
("NSAIDS", eg, aspirin, ibuprofen, flumizol, acetaminophen, etc.), opioids (eg, morphine, fentanyl, oxycodone), and agents such as gabapentin, ziconitide, tramadol, dextromethorphan, carbamazepine, lamotrigine, baclofen or capsaicin Examples of additional therapeutic agents for the treatment of urinary kidney and / or genital syndromes and their symptoms include but are not limited to alpha-1 adrenergic antagonists (eg, doxazosin), anti-muscarinic (eg, tolterodine), reuptake inhibitors, norepinephrine / serotonin (eg, duloxetine), tricyclic antidepressants (eg, doxepin, desipramine) or steroids. Examples of additional therapeutic agents for the treatment of cell growth syndromes and their symptoms include but are not limited to anti-cytokine therapies (eg, biological anti-TNF and anti-IL-1, p38 MAPK inhibitors), endothelin antagonists 1 or stem cell therapies (e.g., progenitor cells). Examples of additional therapeutic agents for the treatment of stroke and symptoms of the disease include but are not limited to neuroprotective agents and anticoagulants (eg, alteplase (TPA), abciximab). Examples of additional therapeutic agents for the treatment of epilepsy and its symptoms include but are not limited to GABA analogs, hydantoins, barbiturates, phenyl triazines, succinimides, valproic acid, carbamazepine, falbamate, and leveracetam. Examples of additional therapeutic agents for the treatment of migraine include but are not limited to serotonin / 5-HT receptor agonist (e.g., sumatriptan, etc.). Examples of additional therapeutic agents for the treatment of respiratory diseases and their symptoms include but are not limited to anticholinergics (e.g., tiotropium), steroids, anti-inflammatory agents, anti-cytokine agents or inhibitors. The term "pharmaceutically acceptable carrier or adjuvant" refers to a carrier or adjuvant that can be administered to a patient, together with a compound of this invention, and which does not destroy the pharmacological activity thereof and is non-toxic when administered in sufficient doses to administer a therapeutic amount of the compound. Carriers, adjuvants and pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchange, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) as -tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens or other similar polymeric release matrices, whey proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, mixtures of partial glyceride of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium acid phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, substances based on cellulose, polyethylene glycol, carboxymethylcellulose of s hatred, polyacrylates, waxes, polyethylene polyoxypropylene blocking polymers, polyethylene glycol and lanolin. Cyclodextrins such as a ~ rβ- / and β-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-β-cyclodextrins, or other soluble derivatives may also be advantageously used to increase the administration of compounds of the formulas described herein. The pharmaceutical compositions of this invention can be administered orally, parenterally, by spray inhalation, topically, rectally, nasally, buccally, vaginally or by means of an implanted reservoir, preferably by oral administration or administration by injection. The pharmaceutical compositions of this invention may contain any of conventional non-toxic pharmaceutically acceptable carriers, adjuvants or vehicles. In some cases, the pH of the formulation can be adjusted with pharmaceutically acceptable acids, bases or buffer solutions to increase the stability of the formulated compound or its administration form. The term "parenteral" as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques. The pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleagenous suspension. This suspension can be formulated in accordance with techniques known in the art using suitable wetting or dispersing agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation can also be a suspension or sterile injectable solution in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the vehicles and acceptable solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspension medium. For this purpose, any soft fixed oil can be employed including synthetic mono or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms such as emulsions and or suspensions. Other commonly used surfactants such as Tweens or Spans and / or other similar emulsifying or bioavailability enhancing agents that are commonly used in the manufacture of liquid, pharmaceutically acceptable solid or other dosage forms may also be used for the purposes of the formulation. The pharmaceutical compositions of this invention can be administered orally in any orally acceptable dosage form including, but not limited to, capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions. In the case of tablets for oral use, carriers that are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When the aqueous suspensions and / or emulsions are administered orally, the active ingredient can be suspended or dissolved in an oily phase is combined with emulsifiers and / or suspending agents. If desired, certain sweeteners and / or flavorings and / or coloring agents may be added. The pharmaceutical compositions of this invention can also be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing a compound of this invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and will therefore melt in the rectum to release the active components.
Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols. Topical administration of the pharmaceutical compositions of this invention is useful when the desired treatment involves areas or organs readily accessible by topical application. For topical application to the skin, the pharmaceutical composition may be formulated with an appropriate ointment containing the active components suspended or dissolved in a carrier. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petroleum, white gasoline, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical composition can be formulated with an appropriate cream or lotion containing the active compound suspended or dissolved in a carrier with appropriate emulsifying agents. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. The pharmaceutical compositions of this invention can also be applied topically in the lower intestinal tract by the rectal formulation of the suppository or in an appropriate enema formulation. Topically transdermal patches are also included in this invention.
The pharmaceutical compositions of this invention can be administered by nasal spray or inhalation. Such compositions are prepared in accordance with techniques well known in the art of pharmaceutical formulation and can be prepared as solutions in saline, benzyl alcohol employed or other appropriate preservatives, absorption promoters to increase bioavailability, fluorocarbons, and / or other solubilizing or dispersing agents known in the art. A composition having the compound of the present formulas and an additional agent (e.g., a therapeutic agent) can be administered using an implantable device. Implantable devices and related technologies are known in the art and are useful as delivery systems where a continuum, or prolonged release of compounds or compositions delineated herein, is desired. Additionally, the implantable device administration system is useful for specific points of compound or composition release direction (eg, localized sites, organs). Negrin et al., Biomaterials, 22 (6): 563 (2001). The extended release technology involves alternative release methods that can also be used in this invention. For example, sustained release formulations based on polymer technologies, sustained release techniques and encapsulation techniques (eg, polymeric, liposomal) can also be used for administration of the compounds and compositions delineated herein. Also within the invention is a patch for administering active chemotherapeutic combinations herein. The patch includes a layer of material (eg, polymeric, cloth, gauze, bandage) and the compound of the formulas herein as set forth herein. One side of the material layer may have a protective layer adhering to it to resist the passage of the compounds or compositions. The patch may additionally include an adhesive to hold the patch in place in a subject. The adhesive is a composition, including that of either natural or synthetic origin, which, when in contact with the subject's skin, temporarily adheres to the skin. It can be water resistant. The adhesive can be placed on the patch to keep it in contact with the subject's skin for an extended period of time. The adhesive can be made of a tack, or adhesive strength, such that it holds the device in place of the subject for incidental contact, however, during an affirmative act (eg, tearing, peeling, or other intentional removal) the adhesive gives a path to the external pressure placed on the device or the adhesive by itself, and allows the adhesion contact to be broken. The adhesive may be pressure sensitive, that is, it may allow the adhesive (and the device to adhere to the skin) to be placed against the skin by the application of pressure (e.g., pressing, rubbing) on the adhesive or device. When the compositions of this invention comprise a combination of a compound of the formulas described herein and one or more additional therapeutic or prophylactic agents, both the additional compound and agent should be present at dose levels of between about 1 to 100% , and more preferably between about 5 to 95% of the dose normally administered in a monotherapy regimen. The additional agents can be administered separately, as part of a multiple dose regimen, from the compounds of this invention. Alternatively, those agents can be part of a single dose form, mixed together with the compounds of this invention in a simple composition. The invention will be further described in the following examples. It will be understood that these examples are for illustrative purposes only and are not construed as limiting this invention in any way.
Example 1 Oocyte Assay Compounds representative of the formulas herein are separated by exclusion for activity against calcium channel targets in an assay essentially as described in Neuron, January 1997, 18 (11): 153-166, Lin. et. to the; J. Neurosci, July 1, 2000, 20 (13): 4768-75, J. Pan and D. Lipsombe; and J. Neurosci., August 15, 2001, 21 (16): 5944-5951, W. Xu and D. Lipscombe, using a heterologous expression system of Xenopus oocyte. The assay is carried out in several calcium channels (for example, subfamily Cav2.2) so the modulation of the calcium channel is measured for each compound.
Table 2
Example 2 HEK assay HEK-293T / 17 cells were transiently transfected in a similar manner as described in FuGENE 6 Package Insert Version 1, April 2002, Roche Applied Science, Indianapolis, IN. Cells are seeded at 2.5 x 10 5 cells in a 6 mL 2-well plate in an incubator overnight and reach a confluence of 30 ~ 40%. In a small sterile tube, sufficient serum-free medium is added as a diluent for the FuGENE transfection reagent (Roche Applied Science, Indianapolis, IN), to a total volume of 100 μL. 3 μL of FuGENE 6 reagent was added directly in this medium. The medium is gently covered to mix. 2 μg of DNA solution (0.8-2.0 μg / μL) is added to the previously diluted FuGENE 6 reagent. The DNA / Fugene 6 mixture is pipetted gently to mix the contents and incubate for about 15 minutes at room temperature. The complex mixture is then added to the HEK-293T / 17 cells, distributed around the well, and stirred to ensure uniform dispersion. The cells are returned to the incubator for 24 hrs. Transfected cells are plated at a density of 2.5X105 in a 35mm dish with 5 glass slides and grown in low serum (1%) medium for 24 hrs. The slides with isolated cells are then transferred into the chamber current and the calcium channel (eg type L, type N, etc.) or other currents to exclude by exclusion the counter are recorded from HEK-293T cells / 17 transiently transfected. The full-cell voltage clamp configuration of the patch clamp technique is employed to evaluate voltage-dependent calcium currents essentially as described by Thompson and Wong (1991) J. Physiol, 439: 671-689. To record the currents of the calcium channel (for example, type L, type N, etc.) for evaluation of the inhibitory potency of compounds (analysis of response to the study state concentration), five pulses of 20-30 ms of voltage are carried in stages up to about +10 V (the peak of the current voltage ratio) are administered at five Hz every 30 seconds from a holding potential at -100mV.The evaluations of the compound are carried out essentially as described by Sah DW and Bean BP (1994) Mol Pharmacol 45 (1): 84-92 Table 3 contains IC50 for representative compounds.
Table 3
Example 3 Formalin Test Compounds representative of the formulas herein are separated by exclusion for activity in the formalin test. The formalin test is widely used as a model of acute inflammatory and tonic pain (Dubuisson &Dennis, 1977 Pain 4: 161-174, Wheeler-Aceto et al, 1990, Pain 40: 229-238, Coderre et al, 1993 , Pain 52: 259-285). The test involves administration to the hind paw of the rat of dilute formalin solution followed by monitored behavioral signals (ie, kickback, stings and licks) during the "late phase" (11 to 60 minutes after injection) of the response to formalin that reflects both peripheral nerve activity and central sensitization. Sprague-Dawley rats, males (Harían, Indianapolis, IN) are used weighing approximately 225-300 g with n = 6 ~ 8 for each treatment group. Depending on the pharmacokinetic profile and the route of administration, the vehicle or dose of the test compound is administered to each rat by an intraperitoneal or oral route 30-120 minutes before formalin. Each animal is acclimated to a chamber for 60 minutes before the administration of formalin, which is 50μL of a 5% solution injected subcutaneously on the surface of the plant of a hind paw using a 300μL microsyringe and a measuring needle 29. A mirror is placed at an angle behind the cameras to increase the views of the legs of the animals. The number of kickbacks (legs raised with or without agitation of the fast leg) and the time consumed from the bite or licking of the injured hind foot are recorded for each rat for 2 continuous minutes every 5 minutes for a total of 60 minutes after the administration of formalin. A sample of terminal blood is harvested for analysis of compound concentrations in the plasma. Between the group comparisons of the total number of recums or the time consumed of pitting and / or licking during the early or late phase, they are conducted using a one-way analysis of variation (ANOVA).
Example 4 Compounds representative of the formulas herein were evaluated for activity against calcium channel targets.
Compound 1 [1- (4-Chloro-phenyl) -2- (4-fluoro-benzyl) -lH-imidazol-4-ylmethyl] - (4-fluoro-phenyl) -methyl-amine Reaction Scheme 6
Part 1. Preparation of N- (4-chloro-phenyl) -2- (4-fluoro-phenyl) -acetamidine A 4-chloroaniline (54.0 g, 424 mmol) in toluene (1000 mL) at 0 ° C was added , dropwise, trimethylaluminum (2.0 M in toluene, 200 mL, 400 mmol) and the reaction was warmed at room temperature for 3 hours under nitrogen. A solution of 4-fluorophenylacetonitrile (31.8 g, 235 mmol) in toluene (20 mL) was added and the mixture was heated at 80 ° C overnight. The mixture was cooled to room temperature, treated with chloroform (200 ml) and SiO2, the thick mixture was stirred for 1 hour and emptied into a plug of Si02. The elution with 5:10:85 ammonium hydroxide: methanol: methylene chloride gave a light brown solid during the concentration in vacuo. Recrystallization from ethyl acetate / hexanes gave N- (4-chlorophenyl) -2- (4-fluoro-phenyl) -acetamidine (54.5 g, 207 mmol) as a white solid.
Part 2. Preparation of 1- (4-chloro-phenyl) -2- (4-fluoro-benzyl) -4-hydroxy-4,5-dihydro-lH-imidazole-4-carboxylic acid ethyl ester A solution of N- (4-chloro-phenyl) -2- (4-fluoro-phenyl) -acetamidine (6.2 g, 24 mmol), ethyl bromopyruvate (10.1 g, 52 mmol), and sodium hydrogen carbonate (8.9 g, 106 g) mmol) in THF (100 mL) and water (100 mL) was refluxed 4 hours. The mixture was cooled to room temperature and extracted with diethyl ether. The organics were dried and concentrated in vacuo to give a dark brown oil. Recrystallization from ethyl acetate / hexanes gave 1- (4-chloro-phenyl) -2- (4-fluoro-benzyl) -4-hydroxy-4,5-dihydro-lH-imidazole-4-ethyl ester carboxylic acid (1.8 g, 4.7 mmol) as a light brown solid.
Part 3. Preparation of 1- (4-chloro-phenyl) -2- (4-fluoro-benzyl) -lH-imidazole-4-carboxylic acid ethyl ester A solution of ethyl ester of 1- (4-) acid chloro-phenyl) -2- (4-fluoro-benzyl) -4-hydroxy-4,5-dihydro-1H-imidazole-4-carboxylic acid (1.8 g, 4.7 mmol) and p-toluenesulfonic acid monohydrate (0.2 g, 0.9 mmol) in toluene (20 mL) was refluxed 2 hours. The mixture was cooled to room temperature, the solvent was removed in vacuo, and the residue was partitioned between water and ethyl acetate. The organics were dried and concentrated in vacuo to give a dark red oil which was purified by chromatography (Si0, 3% methanol in methylene chloride) to give ethyl ester of 1- (4-chloro-phenyl) -2- ( 4-fluoro-benzyl) -lH-imidazole-4-carboxylic acid (1.6 g, 4.4 mmol).
Part 4. Preparation of 1- (4-chloro-phenyl) -2- (4-fluoro-benzyl) -lH-imidazole-4-carboxylic acid To a solution of 1- (4-chloro-phenyl) ethyl ester ) -2- (4-fluoro-benzyl) -lH-imidazole-4-carboxylic acid (1.6 g,
4. 4 mmol) in 1,4-dioxane (15 mL) and water (15 mL) was added lithium hydroxide hydrate (0.4 g, 8.7 mmol) and the mixture was stirred at 40 ° C for 1 hour. More than 1,4-dioxane was removed in vacuo, the residue was taken up in ethyl acetate / water, the aqueous was washed with ethyl acetate, acid was made at pH 2 with aqueous 2 N HCl and acid 1- ( 4-chloro-phenyl) -2- (4-fluoro-benzyl) -lH-imidazole-4-carboxylic acid (1 g, 2.7 mmol) was collected by filtration as the white HCl salt.
Part 5. Preparation of 1- (4-chloro-phenyl) -2- (4-fluoro-benzyl) -lH-imidazole-4-carboxylic acid (4-fluoro-phenyl) -methyl-amide A mixture of acid 1 - (4-Chloro-phenyl) -2 - (4-fluorobenzyl) -IH-imidazole-4-carboxylic acid (0.4 g, 1.3 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.3 g, 1.5 mmol) and 4-fluoro-N-methylaniline (0.2 g, 1.4 mmol) in methylene chloride (10 mL) was stirred at room temperature for 4 hours. The solvent was removed in vacuo, the residue was taken up in water and extracted with ethyl acetate. The organics were dried, concentrated in vacuo, and the residue was purified by chromatography (Si02, 3% methanol in methylene chloride) to give 1- (4-chloro-phenyl) (4-fluoro-phenyl) -methyl-amide. ) -2- (4-fluorobenzyl) -lH-imidazole-4-carboxylic acid (0.4 g, 0.9 mmol).
Part 6. Preparation of [1- (4-chloro-phenyl) -2- (4-fluoro-benzyl) -IH-imidazol-4-ylmethyl] - (4-fluoro-phenyl) -methyl-amine To one solution ( 1- (4-chloro-phenyl) -2- (4-fluoro-benzyl) -1H-imidazole-4-carboxylic acid (4-fluoro-phenyl) -methyl-amide (0.3 gm, 0.7 mmol) in THF (10 mL) at 0 ° C borane-dimethylsulfide complex was added
(2M in THF, 1.0 mL, 2.0 mmol) and the reaction was heated to reflux overnight. The mixture was cooled and diluted with methanolic HCl (10 mL), heated to reflux for 1 hour, cooled, and concentrated in vacuo. The residue was diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organics were dried and concentrated under vacuum to give an oil. Purification by chromatography (Si02, 3% methanol in methylene chloride) gave an oil which was taken up in ethanol and treated with HCl in ether to give 1- (4-chloro-phenyl) -2- (4-fluoro-benzyl) ) - 1H-imidazol-4-ylmethyl] - (4-fluoro-phenyl) -methyl-amine (0.1 g, 0.2 mmol) as the opaque white HCl salt.
Compound 2 2- [1- (4-Chloro-phenyl) -2- (4-fluoro-benzyl) -lH-imidazol-4-ylmethyl] -IH-benzoimidazole Reaction Scheme 7
Parts 1-5. Preparation of N- (2-Amino-phenyl) -2- [1- (4-chloro-phenyl) -2- (4-fluoro-benzyl) -lH-imidazol-4-yl] -acetamide The N- (2 -Amino-phenyl) -2- [1- (4-chloro-phenyl) -2- (4-fluoro-benzyl) -lH-imidazol-4-yl] -acetamide was made as in
Reaction Scheme 6 replacing ethyl 4-bromoacetoacetate with ethyl bromopyruvate in Part 2 and 1,2-phenylenediamine with 4-fluoro-N-methylaniline in Part 5.
Part 6. Preparation of 2- [1- (4-Chloro-phenyl) -2- (4-fluorobenzyl) -lH-imidazol-4-ylmethyl] -lH-benzoimidazole A solution of N- (2-amino-phenyl) -2- [1- (4-Chloro-phenyl) -2- (4-fluoro-benzyl) -lH-imidazol-4-yl] -acetamide (3.8 g, 8.7 mmol) in glacial acetic acid (10 mL) is heated at 70 ° C for 0.5 hours. The mixture was cooled, added dropwise to saturated aqueous sodium hydrogen carbonate, the pH was adjusted to ~14 with sodium hydroxide, extracted with ethyl acetate, and the organics were dried and concentrated in vacuo to give an oil . Treatment with HCl in ether followed by recrystallization from methanol / ether gave 2- [1- (4-chloro-phenyl) -2- (4-fluoro-benzyl) -lH-imidazol-4-ylmethyl] -lH-benzoimidazole ( 2.0 g, 4.8 mmol) as the white HCl salt. The compounds in the tables herein are prepared in a similar manner as described above and in the general reaction schemes. All references cited herein, whether in print, electronic, computer readable storage or otherwise, are expressly incorporated for references in their entirety, including but not limited to, abstracts, articles, newspapers, publications, texts , treaties, internet network sites, databases, patents, and patent publications. It will be understood that although the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims. It is noted that with this date, the best method known to the applicant to carry out the practice of said invention, is that which is clear from the present description of the invention.
Claims (17)
- OH, C 1 -C 4 alkoxy, NH 2, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino or C 3 -C 6 cycloalkyl; each Ar 4 is independently selected from C 3 -C 3 cycloalkyl, aryl or heteroaryl, each optionally substituted with one to three substituents independently selected from halogen, OH, Ci-C alkoxy, NH 2, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino or , 2-methylenedioxy; and each q is independently 0 or 1.
- 2. The compound according to claim 1, characterized in that Ar1 is aryl or heteroaryl, each may be optionally substituted with one or more substituents selected from the group consisting of H, halogen, amino, hydroxy, cyano, nitro, carboxylate, alkyl, alkenyl, alkynyl, cycloalkyl, cyclohexyl, alkoxy, mono and dialkyl amino, phenyl, carboxamide, haloalkyl, haloalkoxy, and alkanoyl; R1 is Ar2; Ar2 is independently selected from aryl or heteroaryl, each of which may be optionally substituted with one or more substituents selected from the group consisting of H, halogen, amino, hydroxy, cyano, nitro, carboxylate, alkyl, alkenyl, alkynyl, cycloalkyl , cyclohexyl, alkoxy, mono and di-alkyl amino, phenyl, carboxamide, haloalkyl, haloalkoxy, and alkanoyl; and each R2 is independently selected from COAr3, CONR3R4, (CH2) mAr3, or (CH2) nNR3R4.
- 3. The compound according to claim 2, characterized in that Ar1 is aryl, which may be optionally substituted with one or more substituents selected from the group consisting of H, halogen, amino, hydroxy, cyano, nitro, carboxylate, alkyl, alkenyl, alkynyl , cycloalkyl, cyclohexyl, alkoxy, mono and di-alkyl amino, phenyl, carboxamide, haloalkyl, haloalkoxy, and alkanoyl; Ar2 is independently aryl, which may be optionally substituted with one or more substituents selected from the group consisting of H, halogen, amino, hydroxy, cyano, nitro, carboxylate, alkyl, alkenyl, alkynyl, cycloalkyl, cyclohexyl, alkoxy, mono and dialkyl amino, phenyl, carboxamide, haloalkyl, haloalkoxy, and alkanoyl; each R2 is independently selected from (CH ^^ Ar3, or (CH2) nNR3R4.
- 4. The compound according to any of claims 1-3, characterized in that: each Ar3 is independently aryl or heteroaryl, each optionally substituted with one or more substituents.
- 5. The compound according to any of claims 1-3, characterized in that: each R4 is (CH2) pAr3; and each Ar3 is independently aryl or heteroaryl, each optionally substituted with one or more substituents.
- 6. The compound according to claim 1, characterized in that: each R2 is independently selected from (CH2) nNR3R4; and each R4 is (CH2) pAr3.
- 7. The compound according to claim 1, characterized in that R1 is para-chlorophenyl.
- 8. The compound according to claim 1, characterized in that Ar1 is para-fluorophenyl.
- 9. The compound according to claim 1, characterized in that it is any of those delineated in Table 1.
- 10. A method for treating a disease or symptom of the disease in a subject in need of such treatment, characterized in that it comprises administering an effective amount of a compound of the formula (I) or pharmaceutical salt thereof: wherein, Ar 1 is cycloalkyl, aryl, heterocyclyl or heteroaryl, each may be optionally substituted with one or more substituents selected from the group consisting of H, halogen, amino, hydroxy, cyano, nitro, carboxylate, alkyl, alkenyl, alkynyl, cycloalkyl, cyclohexyl, alkoxy, mono and di-alkyl amino, phenyl, carboxamide, haloalkyl, haloalkoxy, and alkanoyl; R1 is Ar2 or lower alkyl substituted with Ar2; Ar2 is independently selected from cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is optionally substituted with one or more substituents selected from the group consisting of H, halogen, amino, hydroxy, cyano, nitro, carboxylate, alkyl, alkenyl, alkynyl, cycloalkyl, cyclohexyl, alkoxy, mono and di-alkyl amino, phenyl, carboxamide, haloalkyl, haloalkoxy, and alkanoyl; each R2 is independently selected from C02R3, COAr3, CONR3R4, (CH2) mAr3, (CH2) nNR3R4 or CH2OR4; each R3 is independently selected from H, or lower alkyl; each R4 is independently selected from H, lower alkyl, C (0) 0R5, C (0) NR5R6, S (0) 2NR5R6, C (0) R7, S (0) 2R7 or (CH2) pAr3; each Ar3 is independently cycloalkyl, aryl, heterocyclyl, or heteroaryl, each optionally substituted with one or more substituents, each m is independently 0 or 1 each n is independently 1 or 2 each p is independently 0 or 1 each substituted by Ar3 is independently selected from halogen, CN, N02, OR5, SR5, S (0) 2OR5, NR5R6, cycloalkyl, perfluoroalkyl Cx-C2, perfluoroalkoxy Cx-C2, 1,2-methylenedioxy, C (0) OR5, C (0) NR5R6 , OC (0) NR5R6, NR5C (0) NR5Rs, C (NR5) NR5R6, NR5C (NR6) NR5Rd, S (0) 2NR5Rs, R7, C (0) R7, NR6C (0) R7, S (0) R7 , or S (0) 2R7; each R 5 is independently selected from hydrogen or lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, C 1 -C 4 alkoxy, NH 2, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino or C 3 -C 6 cycloalkyl; each R6 is independently selected from hydrogen, (CH2) gAr4, or lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, C 1 -C 4 alkoxy, NH 2, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino or C 3 -C 6 cycloalkyl; each R7 is independently selected from (CH2) gAr4 or lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, C1-C4 alkoxy, NH, C? -C4 alkylamino, dialkylamino 1.-C4 or C3-C6 cycloalkyl; each Ar4 is independently selected from C3-C6 cycloalkyl, aryl or heteroaryl, each optionally substituted with one to three substituents independently selected from halogen, OH, C-C4 alkoxy, NH2, C1-C4 alkylamino, C1-C4 dialkylamino or 1, 2- methylenedioxy; and each q is independently 0 or 1.
- 11. The method according to claim 10, characterized in that the disease or symptom of the disease is angina, hypertension, congestive heart failure, myocardial ischemia, arrhythmia, diabetes, urinary incontinence, stroke, pain, traumatic brain injury, or a system disorder. nervous.
- 12. The method according to claim 10, characterized in that the disease or symptom of the disease is modulated by the calcium channel Cav2.
- 13. The method according to claim 12, characterized in that the disease or symptom of the disease is modulated by the calcium channel Cav2.2.
- 1 . A method for modulating calcium channel activity, characterized in that it comprises contacting a calcium channel with a compound of formula I according to claim 1.
- 15. A composition, characterized in that it comprises a compound of formula I, or pharmaceutically acceptable salt thereof, according to any of claims 1-9, and a pharmaceutically acceptable carrier.
- 16. The composition according to claim 15, further characterized in that it comprises an additional therapeutic agent.
- 17. A method for modulating the activity of the ion channel in a subject in need of such treatment, characterized in that it comprises administering an effective amount of a compound of the formula I according to claim 1.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US60/551,447 | 2004-03-08 |
Publications (1)
Publication Number | Publication Date |
---|---|
MXPA06010036A true MXPA06010036A (en) | 2007-04-10 |
Family
ID=
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20070191448A1 (en) | Ion channel modulators | |
US20080090891A1 (en) | Ion channel modulators | |
WO2005087750A1 (en) | Ion channel modulators | |
US20080139560A1 (en) | Ion Channel Modulators | |
US20070197619A1 (en) | Ion Channel Modulators | |
US20080242716A1 (en) | Ion Channel Modulators | |
US20070197513A1 (en) | Ion channel modulators | |
EP1722784A2 (en) | Ion channel modulators | |
US20070208064A1 (en) | Ion channel modulators | |
MXPA06010036A (en) | Ion channel modulators | |
MXPA06010033A (en) | Ion channel modulators | |
MXPA06010034A (en) | Ion channel modulators | |
MXPA06010022A (en) | Ion channel modulators | |
MXPA06010037A (en) | Ion channel modulators | |
MXPA06010040A (en) | Ion channel modulators | |
MXPA06010038A (en) | Ion channel modulators | |
MXPA06010035A (en) | Ion channel modulators | |
MXPA06010029A (en) | Ion channel modulators |