US3163653A - -nhsoz-r - Google Patents
-nhsoz-r Download PDFInfo
- Publication number
- US3163653A US3163653A US3163653DA US3163653A US 3163653 A US3163653 A US 3163653A US 3163653D A US3163653D A US 3163653DA US 3163653 A US3163653 A US 3163653A
- Authority
- US
- United States
- Prior art keywords
- compound
- edema
- quinuclidine
- compounds
- test
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 150000001875 compounds Chemical class 0.000 description 19
- 206010030113 Oedema Diseases 0.000 description 18
- 229940125890 compound Ia Drugs 0.000 description 12
- WHTVZRBIWZFKQO-UHFFFAOYSA-N chloroquine Natural products ClC1=CC=C2C(NC(C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-UHFFFAOYSA-N 0.000 description 11
- 229960003677 chloroquine Drugs 0.000 description 11
- 230000003110 anti-inflammatory effect Effects 0.000 description 9
- 150000008584 quinuclidines Chemical class 0.000 description 9
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 8
- 241000700159 Rattus Species 0.000 description 7
- 229940121363 anti-inflammatory agent Drugs 0.000 description 7
- 239000002260 anti-inflammatory agent Substances 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 230000005764 inhibitory process Effects 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 6
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- WHTVZRBIWZFKQO-AWEZNQCLSA-N (S)-chloroquine Chemical compound ClC1=CC=C2C(N[C@@H](C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-AWEZNQCLSA-N 0.000 description 5
- FDJKLIVKKYFLSA-UHFFFAOYSA-N 1-oxido-1-azoniabicyclo[2.2.2]octane Chemical class C1CC2CC[N+]1([O-])CC2 FDJKLIVKKYFLSA-UHFFFAOYSA-N 0.000 description 5
- 230000001780 adrenocortical effect Effects 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 235000013350 formula milk Nutrition 0.000 description 5
- -1 hydroccrtisone Chemical compound 0.000 description 5
- 150000003839 salts Chemical class 0.000 description 5
- RMMXTBMQSGEXHJ-UHFFFAOYSA-N Aminophenazone Chemical compound O=C1C(N(C)C)=C(C)N(C)N1C1=CC=CC=C1 RMMXTBMQSGEXHJ-UHFFFAOYSA-N 0.000 description 4
- 241000157855 Cinchona Species 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 229960000212 aminophenazone Drugs 0.000 description 4
- 235000001258 Cinchona calisaya Nutrition 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000005469 granulation Methods 0.000 description 3
- 230000003179 granulation Effects 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 229960000948 quinine Drugs 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- WXTMDXOMEHJXQO-UHFFFAOYSA-N 2,5-dihydroxybenzoic acid Chemical compound OC(=O)C1=CC(O)=CC=C1O WXTMDXOMEHJXQO-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 150000001204 N-oxides Chemical class 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 244000309464 bull Species 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 229940099112 cornstarch Drugs 0.000 description 2
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 231100001231 less toxic Toxicity 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 229960005205 prednisolone Drugs 0.000 description 2
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 1
- FUFLCEKSBBHCMO-UHFFFAOYSA-N 11-dehydrocorticosterone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)C(=O)CO)C4C3CCC2=C1 FUFLCEKSBBHCMO-UHFFFAOYSA-N 0.000 description 1
- BSYNRYMUTXBXSQ-FOQJRBATSA-N 59096-14-9 Chemical compound CC(=O)OC1=CC=CC=C1[14C](O)=O BSYNRYMUTXBXSQ-FOQJRBATSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- OVCDSSHSILBFBN-UHFFFAOYSA-N Amodiaquine Chemical compound C1=C(O)C(CN(CC)CC)=CC(NC=2C3=CC=C(Cl)C=C3N=CC=2)=C1 OVCDSSHSILBFBN-UHFFFAOYSA-N 0.000 description 1
- 235000019890 Amylum Nutrition 0.000 description 1
- 235000021513 Cinchona Nutrition 0.000 description 1
- MFYSYFVPBJMHGN-ZPOLXVRWSA-N Cortisone Chemical compound O=C1CC[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 MFYSYFVPBJMHGN-ZPOLXVRWSA-N 0.000 description 1
- MFYSYFVPBJMHGN-UHFFFAOYSA-N Cortisone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)(O)C(=O)CO)C4C3CCC2=C1 MFYSYFVPBJMHGN-UHFFFAOYSA-N 0.000 description 1
- 241001448862 Croton Species 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 229910010084 LiAlH4 Inorganic materials 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- GLNADSQYFUSGOU-GPTZEZBUSA-J Trypan blue Chemical compound [Na+].[Na+].[Na+].[Na+].C1=C(S([O-])(=O)=O)C=C2C=C(S([O-])(=O)=O)C(/N=N/C3=CC=C(C=C3C)C=3C=C(C(=CC=3)\N=N\C=3C(=CC4=CC(=CC(N)=C4C=3O)S([O-])(=O)=O)S([O-])(=O)=O)C)=C(O)C2=C1N GLNADSQYFUSGOU-GPTZEZBUSA-J 0.000 description 1
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical class [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 125000005037 alkyl phenyl group Chemical group 0.000 description 1
- 229960001444 amodiaquine Drugs 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940125810 compound 20 Drugs 0.000 description 1
- ALEXXDVDDISNDU-JZYPGELDSA-N cortisol 21-acetate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)C)(O)[C@@]1(C)C[C@@H]2O ALEXXDVDDISNDU-JZYPGELDSA-N 0.000 description 1
- 229960004544 cortisone Drugs 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000001177 diphosphate Substances 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-N diphosphoric acid Chemical compound OP(O)(=O)OP(O)(O)=O XPPKVPWEQAFLFU-UHFFFAOYSA-N 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 229960005219 gentisic acid Drugs 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 229940083577 gold sodium thiosulfate Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- 229960001067 hydrocortisone acetate Drugs 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- XXSMGPRMXLTPCZ-UHFFFAOYSA-N hydroxychloroquine Chemical compound ClC1=CC=C2C(NC(C)CCCN(CCO)CC)=CC=NC2=C1 XXSMGPRMXLTPCZ-UHFFFAOYSA-N 0.000 description 1
- 229960004171 hydroxychloroquine Drugs 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 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
- 230000008018 melting Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 229960000901 mepacrine Drugs 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229960002895 phenylbutazone Drugs 0.000 description 1
- VYMDGNCVAMGZFE-UHFFFAOYSA-N phenylbutazonum Chemical compound O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 VYMDGNCVAMGZFE-UHFFFAOYSA-N 0.000 description 1
- 229960004618 prednisone Drugs 0.000 description 1
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
- 238000002203 pretreatment Methods 0.000 description 1
- GPKJTRJOBQGKQK-UHFFFAOYSA-N quinacrine Chemical compound C1=C(OC)C=C2C(NC(C)CCCN(CC)CC)=C(C=CC(Cl)=C3)C3=NC2=C1 GPKJTRJOBQGKQK-UHFFFAOYSA-N 0.000 description 1
- SBYHFKPVCBCYGV-UHFFFAOYSA-N quinuclidine Chemical compound C1CC2CCN1CC2 SBYHFKPVCBCYGV-UHFFFAOYSA-N 0.000 description 1
- 229910001426 radium ion Inorganic materials 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- MBGGBVCUIVRRBF-UHFFFAOYSA-N sulfinpyrazone Chemical compound O=C1N(C=2C=CC=CC=2)N(C=2C=CC=CC=2)C(=O)C1CCS(=O)C1=CC=CC=C1 MBGGBVCUIVRRBF-UHFFFAOYSA-N 0.000 description 1
- 229960003329 sulfinpyrazone Drugs 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- KZNBHWLDPGWJMM-UHFFFAOYSA-J trisodium;dioxido-oxo-sulfanylidene-$l^{6}-sulfane;gold(1+);dihydrate Chemical compound O.O.[Na+].[Na+].[Na+].[Au+].[O-]S([O-])(=O)=S.[O-]S([O-])(=O)=S KZNBHWLDPGWJMM-UHFFFAOYSA-J 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
- C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
Definitions
- adrenocorticoids such as cortisone, hydroccrtisone, prednisone and prednisolone.
- cortisone As anti-inflammatory agents, there have been mostly used adrenocorticoids such as cortisone, hydroccrtisone, prednisone and prednisolone.
- these adrenocorticoids generally exhibit undesirable side actions, when continuously administered for a long time.
- non-adrenocortical anti-inflammatory agents such as acetylsalicylic acid, gentisic acid, 2 (fi-chloroethyl) 2,3-dihydro-4-oxo-,1,3- benzoxazine, salicylarnide, aminopyrine, phenylbutazone, sulfinpyrazone; quinacrine, chloroquine, hydroxychloroquine, amodiaquin, gold sodium thiosulfate and e-amiuocaproic acid.
- Chloroquine diphosphate ggg i 2 can be prepared in conventional manners [F eidelberger 100 1g 12 13 et al.: J. Am. Chem. Soc., 41, 819 (1919; Ochiai et al.: J. P1181111; J p 101 Ochlal et L hNorE.'Ihe rats1 wee orally petrcatcil witl lilthe teat coilnpgund and "o s i t en subcu ancousy a ministere orrna in.
- epro uce c eina was i 33 g 5 2 gig: gi 52 measured and compared with that produced without pretreatment.
- the quinuclidine compounds I possess a high anti-inwhen Orally admmlstered 10 rats" fiarnmatory activity.
- the compound 20 3 Ia is at least 100 times as effective as aminopyrine in the D tr n com and M 5 48 edema inhibiting action, when subcutaneously admina 1 32 50 istered to rats. Adding to this, it can be also said that 12 they exhibit a total activity, when administered together.
- the anti-inflammatory efiect of the compound Ia is approximately times that of chloroquine diphosphate, when subcutaneously administered to mice.
- the compound Ia is more toxic than the commercially available anti-inflammatory agent, e.g. ch-loroquine diphosphate, but the former is remarkably more effective than the latter.
- the quinuclidine compounds I are the non-adrenocortical anti-inflammatory agents which can be used safely, compared with the heretofore known non adrenocortical anti inflammatory agents.
- the quinculidine compounds I have a relatively high toxicity. However, according to this invention, the toxicity can be decreased by their conversion into the corresponding N-oxides.
- the quinuclidine-N-oxide compounds II are .novel and can be produced'by subjecting the quinuclidine compounds I to oxidation according to aper se conventional manner. For instance, the quinuclidine compound I is treated with hydrogen peroxide in acetic acidat room temperature to C.) whereby the quinuclidine-N-oxide compound II is prepared.
- the quinuclidine N-oxide compounds II are less toxic than the quinuclidine compounds I, the former being parallelly less potent than the latter in anti-inflammatory activity.
- the animal test data of the quinuclidine-N-oxide compound corresponding to the following formula:
- the quinuclidine-N-oxide compounds II are less toxic and less potent than the quinuclidine compounds I. But, they are still remarkably active, compared with the heretofore known anti-inflammatory agents. Therefore, they are useful as non-adrenocottical anti-inflammatory agents which can be employed safely, too.
- the quinuclidine-N-oxide compounds II may also be employed in the form of their salts with non-toxic acids.
- the salts there may be exampled those with hydrochloric, hydrobromic, sulfuric, acetic, lactic, succinic, tartaric, citric, ascorbic, cinnamic, salicylic or 4-arninosalicylic acid.
- the salicylic acid addition salt is particularly preferred in easy crystallizability.
- the active medicaments e.g. the quinuclidine compounds II or their salts with non-toxic acids
- the preparation is orally administered, although they are just as effective whenotherwise administered. They may be administered in various dosages such as 3, 5, 10, 15, 20, 25 or 30 milligrams, although the unit dosage range may vary more broadly from about 1 toabout milligrams and preferably from about 5 to about 30 milligrams. They may be added to or otherwise used with various pharmaceutical carriers.
- various solid carriers may be employed such as lactose, mannitol, cornstarch, talc and magnesium stearate as well as other tableting aids and fillers.
- some other ingredients such as hydrocortisone, prednisolone, aminopyrine, chloroquine and the like may be mixed with the said active medicaments.
- the medicinal mixture may then be tableted or encapsulated in a hard gelatine' capsule, depending on the commercial unit form desired. Ordinarily tableting is preferred.
- the amount of carrier or diluent may vary, according to tablet size desired or Whether the dosage is made up in encapsulated form, from 7 zero amount to the maximum amount consistent with the practical limits of bulk for a dosage unit. Normally the carrier with which the medicament is mixed does not exceed about 300 to about 500 milligrams.
- the chloroform layer is washed with water and dried over anhydrous sodium sulfate. Removing the solvent from the chloroform layer, the residue is crystallized from a mixture of acetone and ether to give 4-(3- ethylquinuclidin-8-yl) 4 hydroxy '3 (Z-toluenes-ulfonamido-S-methoxyphenyl) butanol-N-oxide mg.) as white pillars melting at 228 C.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
=4 a nrnrromnncrmm a YL)-4HYDROXY- 3 TQLUENESULFONAMIDQ PHENYL)-EUTANOL-N-0XIDE Eiji ()chiai, '72 Myogaelani-cho, Bnnlryo-ku, Tokyo, Japan, and Ryonosulre Kido, 1679 Karnikeda-cho, lkeda-shi, Osaka Prefecture, Japan v No Drawing. Original application Sept. 21, 1962, Ser. No. 225,386. Divided and" this appiication July 29, 1963, Ser. No.301,692
1 Claim. (Cl. 260-2934) This invention relates to compounds useful in preparations for anti-inflammatory administration and in meth- 0d of producing anti-inflammatory activity in living bodies.
As anti-inflammatory agents, there have been mostly used adrenocorticoids such as cortisone, hydroccrtisone, prednisone and prednisolone. However, these adrenocorticoids generally exhibit undesirable side actions, when continuously administered for a long time. Because of the drawback present in adrenocorticoids, there have been proposed and made available some non-adrenocortical anti-inflammatory agents such as acetylsalicylic acid, gentisic acid, 2 (fi-chloroethyl) 2,3-dihydro-4-oxo-,1,3- benzoxazine, salicylarnide, aminopyrine, phenylbutazone, sulfinpyrazone; quinacrine, chloroquine, hydroxychloroquine, amodiaquin, gold sodium thiosulfate and e-amiuocaproic acid. However, these non-adrenocortical compounds are generally inferior to the said adrenocorticoids in anti-inflammatory activity. Therefore, it has been desired to realize any other non-adrenocortical compounds possessing a high anti-inflammatory activity as Well as the adrenocorticoids. I
- METHOXY- As the results of the pharmacological investigation on a variety of heretofore known or novel quinuclidine compounds derived from a naturally existing cinchona alkaloid, quinine, it has been now discovered that the quinuclidine compounds, corresponding to the following for mula:
CHzCHzOH wherein R is lower alkyl, phenyl or lower alkylphenyl, possesses a high anti-inflammatory activity. [In this connection, it should be understood that there are actually 0 OHzCHzOH T NHSO R C2H5 wherein R has the same significance as designated above. The present invention is primarily concerned with the particular N-oxide of formula Ila, infra.
The production of the quinuclidine compounds I from 3,163,653 Patented Dec. 29, 1964 quinine can be illustrativcly shown by the following scheme:
Quinine CHr-CO d of chloroquine diphosphate, when subcutaneously administered to rats.
N TABLE 11 LiAlH4 5 Edema Inhzbltzon ACflVlly Test NHSO2R #32115 Average edema D inhibition (percent) ose ZII CHzOH N T t d (magi/15g. of T ft d L v es compoun o y imea era minis ra ion CHaO H weight) of formalin (hour) -N HS 0 z-R 0 2H 5 1-3 443 74) Compound Ia 40 39 20 18 it a at 2 wherein R has the same significance as designated above. All the compounds in the above scheme are known and Chloroquine diphosphate ggg i 2 can be prepared in conventional manners [F eidelberger 100 1g 12 13 et al.: J. Am. Chem. Soc., 41, 819 (1919; Ochiai et al.: J. P1181111; J p 101 Ochlal et L hNorE.'Ihe rats1 wee orally petrcatcil witl lilthe teat coilnpgund and "o s i t en subcu ancousy a ministere orrna in. epro uce c eina was i 33 g 5 2 gig: gi 52 measured and compared with that produced without pretreatment.
a w a m V. (1953); Ochiai et al.: Pharm. Bull., 2, 128 (1954); Ishi- {b115, vhe edema lnhlbltwn activity of the cornpound kawa. pharm Bull 6, 71 (1958)] la 18 at least 10 times that of chloroquine diphosphate,
The quinuclidine compounds I possess a high anti-inwhen Orally admmlstered 10 rats" fiarnmatory activity. For instance, the animal test data TABLE In of the quinuclidine compound corresponding to the followin" formula Edema lnlzzbrtzon Actzvlty Test n Avera c edema inhibition CH CHQOI-I N g (percent) CH O -CH- Dose Edema Test compound (m1g)./l5g.of Tiirficdalter adnliinistration producing E o y o c ema pro ucing agent agen NHS 0 z C Ha 0 2 weight) (hour) 1 3 4-0 are shown in Tables I, II, III, IV, V and VI in contrast with some commercially available anti-inflammatory Aminopyrme 50 16 7 n age ts Compound Ia 0.5
Formalin. TABLE I Ammopyrinenh 5 l I Con1poundIo 0..) 8 5 Edema Inhzbztzon Activity Test Aminopyrine. 50
22 10 Compound 1a-... 0.5 D 45 extran. Edema Dose (m'n/ Average 5 producing Test compound kg. of edema Ammopynne 0 9 2 agent body inhibition Compound m (L 5 12 5 weight) (percent) Norm-The rats were subcutaneously pretreated with the test coin- Compound Ia 5 43 pound and then subcutaneously administered the edema producing 1 00 agent. The produced edema was measured and compared with that 5 3 produced without pretreatment. Chloroquine diphosphate--. 128 12 From the above table, it can be said that the compound 20 3 Ia is at least 100 times as effective as aminopyrine in the D tr n com and M 5 48 edema inhibiting action, when subcutaneously admina 1 32 50 istered to rats. Adding to this, it can be also said that 12 they exhibit a total activity, when administered together.
' h 2 Chloroquine diphosp ate 80 22 TABLE IV 20 0 Anti-Inflammatory Effect Histamine Compound Ia g (it) 1 2g Edema producing Formalin Croton agent Chloro nine di hos hate 100 9 q p p T t R /ff /i? t0 C u 11 "0 (35 g- E. III 3. Sem Hm Omp n a 3 3 M compound oibody of l JOdY 1 28 6o weight) weight) 1 5 Ch Omqume dlphosphate 100 1 Chloroquine diphosphatc 97. 5 97. 5
Nora-The rats were subcutaneously pretreated with the test com- Compound 2 pound and then subcutaneously administered the edema producing In the above table, it is shown that the edema inhibition activity of the compound Ia is more than 100 times that No'rE.The test compound was subcutaneously administered to mice. For the comparison of the efiect, there was employed Trypan Blue test.
Thus, the anti-inflammatory efiect of the compound Ia is approximately times that of chloroquine diphosphate, when subcutaneously administered to mice.
TABLE V Granulation Inhibition Activity Test compound was subcutaneously a istered once daily for 6 days. Twenty-four hours after the last administration, the animals were killed and the granulations weighed.
It is clear that the potency of the compound Ia is approximately 8 times that of hydrocortisone acetate in the granulation inhibiting action.
TABLE VI Toxicity in Rats so (mg/kg. of bodyweight) Test compound Subcuta- Orally neously Chloroquine diphosphate 187. 2 v 884 Compound Ia .Q. 34.8 103 From the above table, it can be said that the compound Ia is much more toxic than chloroquine diphosphate, i.e. 5.5 times at the subcutaneous administration and 8 times at the oral administration.
Summarizing the above animal test data, it is concluded that the compound Ia is more toxic than the commercially available anti-inflammatory agent, e.g. ch-loroquine diphosphate, but the former is remarkably more effective than the latter. Thus, the quinuclidine compounds I are the non-adrenocortical anti-inflammatory agents which can be used safely, compared with the heretofore known non adrenocortical anti inflammatory agents.
As disclosed above, the quinculidine compounds I have a relatively high toxicity. However, according to this invention, the toxicity can be decreased by their conversion into the corresponding N-oxides. The quinuclidine-N-oxide compounds II are .novel and can be produced'by subjecting the quinuclidine compounds I to oxidation according to aper se conventional manner. For instance, the quinuclidine compound I is treated with hydrogen peroxide in acetic acidat room temperature to C.) whereby the quinuclidine-N-oxide compound II is prepared. The quinuclidine N-oxide compounds II are less toxic than the quinuclidine compounds I, the former being parallelly less potent than the latter in anti-inflammatory activity. For instance, the animal test data of the quinuclidine-N-oxide compound, corresponding to the following formula:
are compared with that of the in Tables VII and VIII.
quinuclidine compound Ia TABLE VII Edema Inhibition Activity Test Average edema inhibition (percent) Dose (mg./ 7 Test compound kg. of body Time after administration of weight) formalin (hour) Compound la 5.0 43 10 1 Compound Ila 50.0 26 18 12 NOTE.-The rats were subcutaneously pretreated with the test compound and then subcutaneously administered the edema producing agent. The produced edema was measured and compared with that produced without -pre treatment.
TABLE VIH Toxicity in Mice LDsn (mg/kg. of
venously Compound Ia 2.0
Compound Ila 42. 3
Thus, the quinuclidine-N-oxide compounds II are less toxic and less potent than the quinuclidine compounds I. But, they are still remarkably active, compared with the heretofore known anti-inflammatory agents. Therefore, they are useful as non-adrenocottical anti-inflammatory agents which can be employed safely, too.
The quinuclidine-N-oxide compounds II may also be employed in the form of their salts with non-toxic acids. As the salts, there may be exampled those with hydrochloric, hydrobromic, sulfuric, acetic, lactic, succinic, tartaric, citric, ascorbic, cinnamic, salicylic or 4-arninosalicylic acid. Of these salts, the salicylic acid addition salt is particularly preferred in easy crystallizability.
The active medicaments, e.g. the quinuclidine compounds II or their salts with non-toxic acids, are administered in dosage unit form, as carried by a suitable pharmaceutical carrier, to living bodies particularly for the relief of rheumatism. Normally, the preparation is orally administered, although they are just as effective whenotherwise administered. They may be administered in various dosages such as 3, 5, 10, 15, 20, 25 or 30 milligrams, although the unit dosage range may vary more broadly from about 1 toabout milligrams and preferably from about 5 to about 30 milligrams. They may be added to or otherwise used with various pharmaceutical carriers. By way of exemplification, various solid carriers may be employed such as lactose, mannitol, cornstarch, talc and magnesium stearate as well as other tableting aids and fillers. If desired, some other ingredients such as hydrocortisone, prednisolone, aminopyrine, chloroquine and the like may be mixed with the said active medicaments. The medicinal mixture may then be tableted or encapsulated in a hard gelatine' capsule, depending on the commercial unit form desired. Ordinarily tableting is preferred. The amount of carrier or diluent may vary, according to tablet size desired or Whether the dosage is made up in encapsulated form, from 7 zero amount to the maximum amount consistent with the practical limits of bulk for a dosage unit. Normally the carrier with which the medicament is mixed does not exceed about 300 to about 500 milligrams.
The following are typical examples of preparations embodying the present invention.
EXAMPLE 1 Kilograms 4 (3-ethylquinuelidin-8-yl) 4 hydroxy 3 (2- toluenesulfonamido-S-methoxyphenyl-butanol 1.00 Lactose 8.47 Cornstarch 3.48 Magnesium stearate 2.60
The foregoing are mixed and granulated with a acacia solution and dried. The granule is forced through a 16 mesh screen, and thereafter is mixed with the following:
Kilograms Sodium lauryl sulfate 0.20 Magnesium stearate 1.00
Amylum solani, q.v. to 37.50
This mixture is tableted in the usual way to give 100,000 tablets. Each tablet weighing 37.5 milligrams contains 12.73 milligrams of the active ingredient (equal to 10 milligrams of the free base).
EXAMPLE 3 To a solution of 4-(3-ethylquinuclidin-8-yl)-4-hydroxy- 3- 2-toluenesulfonamido-5 -methoxyphenyl -butano1 (300 mg.) in glacial acetic acid (2.5 ml.), there is added 30% hydrogen peroxide (0.3 ml.-), and the resultant solution is allowed to stand for 24 hours at room temperature. Then, 30% hydrogen peroxide (0.3 ml.) is further added to the solution and allowed to stand for 48 hours at room temperature. The reaction mixture is adjusted with 10% aqueous sodium hydroxide to alkalinity and shaken with chloroform. The chloroform layer is washed with water and dried over anhydrous sodium sulfate. Removing the solvent from the chloroform layer, the residue is crystallized from a mixture of acetone and ether to give 4-(3- ethylquinuclidin-8-yl) 4 hydroxy '3 (Z-toluenes-ulfonamido-S-methoxyphenyl) butanol-N-oxide mg.) as white pillars melting at 228 C.
AIZGIYSI S-Cfllcd. for C H O N St C, H, N, 5.41. Found: C, 63.05; H, 7.64; N, 5.44.
The present application is a division of copending application, Serial No. 225,386, filed September 21, 1962.
What is claimed is:
The compound of the formula:
orr cmo H 'r No references cited.
Publications (1)
Publication Number | Publication Date |
---|---|
US3163653A true US3163653A (en) | 1964-12-29 |
Family
ID=3457024
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US3163653D Expired - Lifetime US3163653A (en) | -nhsoz-r |
Country Status (1)
Country | Link |
---|---|
US (1) | US3163653A (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3725410A (en) * | 1970-07-15 | 1973-04-03 | American Home Prod | 3-aminomethyl-3-quinuclidinols |
US3869461A (en) * | 1968-07-02 | 1975-03-04 | Hoffmann La Roche | Intermediates for quinine, quinidine and derivatives thereof |
US3929795A (en) * | 1968-07-02 | 1975-12-30 | Hoffmann La Roche | Processes and intermediates for quinine, quinidine, isomers and derivatives thereof |
US4096146A (en) * | 1968-07-02 | 1978-06-20 | Hoffmann-La Roche Inc. | 4-[5(R)-Alkyl(or alkenyl)-4(S)-quinuclidin-2(S) or 2(R)-ylcarbonyl]-quinolines, antipodes or racemates thereof and processes for their preparation |
-
0
- US US3163653D patent/US3163653A/en not_active Expired - Lifetime
Non-Patent Citations (1)
Title |
---|
None * |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3869461A (en) * | 1968-07-02 | 1975-03-04 | Hoffmann La Roche | Intermediates for quinine, quinidine and derivatives thereof |
US3929795A (en) * | 1968-07-02 | 1975-12-30 | Hoffmann La Roche | Processes and intermediates for quinine, quinidine, isomers and derivatives thereof |
US4096146A (en) * | 1968-07-02 | 1978-06-20 | Hoffmann-La Roche Inc. | 4-[5(R)-Alkyl(or alkenyl)-4(S)-quinuclidin-2(S) or 2(R)-ylcarbonyl]-quinolines, antipodes or racemates thereof and processes for their preparation |
US3725410A (en) * | 1970-07-15 | 1973-04-03 | American Home Prod | 3-aminomethyl-3-quinuclidinols |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US3505337A (en) | N - hydrocarbyl-substituted noratropinium,haloalkylates and o-acyl derivatives thereof | |
US3849561A (en) | Anti-peptic ulcer substance from corydalis tubers | |
PH26157A (en) | 6,11-dihydro-11(4-piperidylidene)-5H-benzo(5,6)cyclohepta(1,2-b)pyridines and compositions and methods of use | |
US3163653A (en) | -nhsoz-r | |
US2917432A (en) | Leukemia treatment | |
US2909524A (en) | Substituted acetylpiperazines | |
US2987442A (en) | Method of treating hypertension with [2-(2, 6-dimethylphenoxy)-propyl]-trimethyl ammonium salts | |
US2918406A (en) | Anti-spasmodics specific for peptic ulcer | |
US3394139A (en) | 3-hydroxy-6-oxo-n-phenethylmorphinan compounds | |
US2918407A (en) | Anti-spasmodics specific for upper gastrointestinal pain and spasm | |
US3245877A (en) | Method of treating inflammation | |
US2943022A (en) | Substituted 1-phenyl-2, 3-dimethyl-4-morpholino methyl pyrazolone-(5) compounds and process of making same | |
US3652567A (en) | Quinazolinone derivative and process for the production thereof | |
US2914532A (en) | Lower alkyl 4-phenyl-1-(3-phenylpropyl) piperidine-4-carboxylates and their preparation | |
US3005818A (en) | 1-phenyl-2, 3-dimethyl-4-morpholino methyl pyrazolone-(5) compounds | |
US3222370A (en) | 4-phenalkyl-1-dialkyl-amino-alkylpiperidines | |
US2838516A (en) | 2-(thienyl methyl) piperidines | |
US3463780A (en) | 4(2'-beta-pyridyl methyloxycarbonyl phenylamino)-chloroquinolines | |
US3436458A (en) | Antispasmodic and gastric antisecretory compositions containing rho-phenylphenacyl derivatives of 1-hyoscyamine and d,1-tropylatropine | |
DE3639466A1 (en) | NEW PYRROLO-BENZIMIDAZOLES, MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS AND METHOD FOR THE PRODUCTION THEREOF | |
US3288679A (en) | Steroidal compositions and method of use | |
US3808216A (en) | 4-amino-quinolines | |
US3181994A (en) | Analgesic biphenyl acetic acid derivatives | |
US3531570A (en) | Method of tranquilizing or anti-depressant treatment with alkaloid derivatives | |
US3856909A (en) | Novel quinolines in the treatment of pain and inflammation |