US3313688A - Method of producing central nervous system stimulation and anorexia - Google Patents
Method of producing central nervous system stimulation and anorexia Download PDFInfo
- Publication number
- US3313688A US3313688A US353590A US35359064A US3313688A US 3313688 A US3313688 A US 3313688A US 353590 A US353590 A US 353590A US 35359064 A US35359064 A US 35359064A US 3313688 A US3313688 A US 3313688A
- Authority
- US
- United States
- Prior art keywords
- phenyl
- oxazolin
- central nervous
- nervous system
- compositions
- 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
- 238000000034 method Methods 0.000 title claims description 19
- 230000000638 stimulation Effects 0.000 title claims description 5
- 210000003169 central nervous system Anatomy 0.000 title description 6
- 208000022531 anorexia Diseases 0.000 title 1
- 206010061428 decreased appetite Diseases 0.000 title 1
- 239000000203 mixture Substances 0.000 claims description 28
- 150000001875 compounds Chemical class 0.000 claims description 20
- 230000008569 process Effects 0.000 claims description 13
- 241000124008 Mammalia Species 0.000 claims description 9
- 230000000694 effects Effects 0.000 claims description 5
- 239000002253 acid Substances 0.000 description 15
- 150000003839 salts Chemical class 0.000 description 15
- 231100000252 nontoxic Toxicity 0.000 description 14
- 230000003000 nontoxic effect Effects 0.000 description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 229920002261 Corn starch Polymers 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 239000008120 corn starch Substances 0.000 description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 239000008187 granular material Substances 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 5
- NLLUMJUXYNCDIS-UHFFFAOYSA-N 2-(diethylamino)-5-phenyl-1,3-oxazol-4-one Chemical compound O1C(N(CC)CC)=NC(=O)C1C1=CC=CC=C1 NLLUMJUXYNCDIS-UHFFFAOYSA-N 0.000 description 4
- 235000019359 magnesium stearate Nutrition 0.000 description 4
- 239000000155 melt Substances 0.000 description 4
- NRNCYVBFPDDJNE-UHFFFAOYSA-N pemoline Chemical compound O1C(N)=NC(=O)C1C1=CC=CC=C1 NRNCYVBFPDDJNE-UHFFFAOYSA-N 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- KCOPAESEGCGTKM-UHFFFAOYSA-N 1,3-oxazol-4-one Chemical compound O=C1COC=N1 KCOPAESEGCGTKM-UHFFFAOYSA-N 0.000 description 3
- 208000020401 Depressive disease Diseases 0.000 description 3
- 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 3
- 230000009471 action Effects 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 230000000578 anorexic effect Effects 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 150000003335 secondary amines Chemical class 0.000 description 3
- 238000010998 test method Methods 0.000 description 3
- 229940124597 therapeutic agent Drugs 0.000 description 3
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 206010010904 Convulsion Diseases 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- -1 Quinones Quinones Chemical class 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 239000000783 alginic acid Substances 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 229960001126 alginic acid Drugs 0.000 description 2
- 150000004781 alginic acids Chemical class 0.000 description 2
- 230000001430 anti-depressive effect Effects 0.000 description 2
- 239000003576 central nervous system agent Substances 0.000 description 2
- 229940125693 central nervous system agent Drugs 0.000 description 2
- 230000036461 convulsion Effects 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 239000011812 mixed powder Substances 0.000 description 2
- XSWHNYGMWWVAIE-UHFFFAOYSA-N pipradrol Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(O)C1CCCCN1 XSWHNYGMWWVAIE-UHFFFAOYSA-N 0.000 description 2
- 229960000753 pipradrol Drugs 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- MKJIEFSOBYUXJB-HOCLYGCPSA-N (3S,11bS)-9,10-dimethoxy-3-isobutyl-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one Chemical compound C1CN2C[C@H](CC(C)C)C(=O)C[C@H]2C2=C1C=C(OC)C(OC)=C2 MKJIEFSOBYUXJB-HOCLYGCPSA-N 0.000 description 1
- KWTSXDURSIMDCE-QMMMGPOBSA-N (S)-amphetamine Chemical compound C[C@H](N)CC1=CC=CC=C1 KWTSXDURSIMDCE-QMMMGPOBSA-N 0.000 description 1
- TUSDEZXZIZRFGC-UHFFFAOYSA-N 1-O-galloyl-3,6-(R)-HHDP-beta-D-glucose Chemical class OC1C(O2)COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC1C(O)C2OC(=O)C1=CC(O)=C(O)C(O)=C1 TUSDEZXZIZRFGC-UHFFFAOYSA-N 0.000 description 1
- LEWYGHTWFCXHSW-UHFFFAOYSA-N 2-ethyl-5-(methylamino)-5-phenyl-1,3-oxazol-4-one Chemical compound C(C)C=1OC(C(N1)=O)(C1=CC=CC=C1)NC LEWYGHTWFCXHSW-UHFFFAOYSA-N 0.000 description 1
- NJBCRXCAPCODGX-UHFFFAOYSA-N 2-methyl-n-(2-methylpropyl)propan-1-amine Chemical compound CC(C)CNCC(C)C NJBCRXCAPCODGX-UHFFFAOYSA-N 0.000 description 1
- 241000272189 Accipiter gentilis Species 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 241000167854 Bourreria succulenta Species 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 description 1
- 239000001263 FEMA 3042 Chemical class 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 244000246386 Mentha pulegium Species 0.000 description 1
- 235000016257 Mentha pulegium Nutrition 0.000 description 1
- 235000004357 Mentha x piperita Nutrition 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- LRBQNJMCXXYXIU-PPKXGCFTSA-N Penta-digallate-beta-D-glucose Chemical class OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@@H]2[C@H]([C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-PPKXGCFTSA-N 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000001800 adrenalinergic effect Effects 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 229940025084 amphetamine Drugs 0.000 description 1
- 239000002269 analeptic agent Substances 0.000 description 1
- 230000001539 anorectic effect Effects 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 230000036528 appetite Effects 0.000 description 1
- 235000019789 appetite Nutrition 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 235000019693 cherries Nutrition 0.000 description 1
- 235000019219 chocolate Nutrition 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000010908 decantation Methods 0.000 description 1
- DENRZWYUOJLTMF-UHFFFAOYSA-N diethyl sulfate Chemical compound CCOS(=O)(=O)OCC DENRZWYUOJLTMF-UHFFFAOYSA-N 0.000 description 1
- 229940008406 diethyl sulfate Drugs 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 235000012631 food intake Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- LRBQNJMCXXYXIU-QWKBTXIPSA-N gallotannic acid Chemical class OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@H]2[C@@H]([C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-QWKBTXIPSA-N 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 235000001050 hortel pimenta Nutrition 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 231100000636 lethal dose Toxicity 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 208000024714 major depressive disease Diseases 0.000 description 1
- 201000003995 melancholia Diseases 0.000 description 1
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 1
- 229960001252 methamphetamine Drugs 0.000 description 1
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 230000037023 motor activity Effects 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical class C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 238000004088 simulation Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 235000015523 tannic acid Nutrition 0.000 description 1
- 229920002258 tannic acid Chemical class 0.000 description 1
- 229940033123 tannic acid Drugs 0.000 description 1
- 229960005333 tetrabenazine Drugs 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 231100000816 toxic dose Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000009637 wintergreen oil Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D263/48—Nitrogen atoms not forming part of a nitro radical
Definitions
- This invention rel-ates to novel pharmaceutical compositions having a therapeutic effect on the central nervous system and to methods of treatment involving such compositions.
- the present invention comprises a pharmaceutical composition containing as a principal active central nervous system agent a S-phenyl-Z-dialkylamino-2-oxazolin-4-one of the following formula:
- NR Rg wherein R and R are the same or different lower alkyl radicals having from 1 to 4 carbon atoms.
- compositions containing one or more of the above compounds have been found to be highly useful central nervous system agents.
- the new compositions of this invention show a mild stimulant action and excellent anoretic action over a wide range of doses and possess distinct advantages over other stimulant drugs such as amphetamines and pipradrol.
- the new compositions of this invention are valuable centrally acting therapeutic agents for the management of depression.
- Amphetamine and closely related compounds such as methamphetamine have been used as central nervous system stimulants for many years, but numerous undesirable side reactions accompany their administration. For instance, they cause more or less pronounced rise in blood pressure and there is a tendency toward developing tolerance upon continual use.
- the compositions of the present invention do not have these serious side-effects and thus are markedly superior to the amphetamines.
- the compositions of this invention also, even at high doses, are freeof the undesirable adrenergic and cardiovascular actions characteristic of the amphetamines. As increasing doses of the amphetamines are given, convulsions are usually observed. The compositions of this invention do not cause convulsions as the doses are increased.
- compositions containing the active drugs are considerably more active than S-phenyl-Z- imino-4-oxo oxazolidine disclosed in United States Patent No. 2,892,753.
- 2-dimethylamino-S-phenyl- 2 oxazolin 4-one and 2-ethylmethylamino-5-phenyl-2- oxazolin-4-one are approximately nine times as effective in causing a 50% increase in motor activity at a non-toxic dose.
- This type of test is well recognized as a useful method for the determination of stimulant activity and is "ice described by P. B. Dews, British Journal of Phat-macology, vol. 8, page 46 (1953), and by G. Chen et al., Journal of Pharmacology and Experimental Therapeutics, vol. 127, page 241 (1959).
- the valuable pharmaceutical properties of the new compositions of this invention are demonstrated in a variety of test procedures.
- the anoretic activity of these compositions is readily demonstrated by measuring the marked reduction in food consumption following the administration of the active agents. This indicates a therapeutically desirable method of treating obese conditions.
- Another test procedure which demonstrates the valuable central nervous system actions of these compositions consists of measuring their ability to counteract a depression induced in mammals by the administration of tetrabenazine hexamate. This test procedure indicates these new compositions show useful antidepressant activity at dose levels which produce little or no untoward reactions or toxic manifestations. These compositions may, therefore, be considered as valuable therapeutic agents for the treatment of depressive states and melancholia.
- the above compounds are in general, white crystalline solids, only slightly soluble in water. They are insoluble in alkaline solutions. They are basic substances soluble in aqueous mineral acids at room temperature, and in some cases form isolable acid addition salts.
- the active compounds incorporated in a pharmaceutically acceptable carrier therefor may be used in the form of their free bases or as the non-toxic acid addition salts such as the hydrochloride, sulfate, phosphate, citrate, etc.
- the new compositions may be administered orally or parenterally and when so administered have been found to be useful therapeutic agents at individual doses ranging from about 25 to 150 milligrams of active ingredient.
- the dosage regimen can be adjusted to provide the optimum therapeutic response. For example, several doses may be administered daily, or the dose may be proportionately reduced as indicated by the exigencies of the therapeutic situation.
- compositions and preparations should contain at least 0.25% of the active ingredient.
- the percentage in the compositions and preparations may, of course, be varied and may conveniently be between 2% and about 60% or more of the weight of the unit.
- the amount of active ingredient in such therapeutically useful compositions or preparations is such that a suitable dosage will be obtained.
- Preferred compositions or preparations according to the present invention are prepared in such a manner that a dosage unit form contains between about 25 milligrams and about milligrams of the active compound.
- Tablets, pills, drages, and the like usually contain the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; 3. disintegrating agent such as corn starch, potato starch, alginic acid, or the like; a lubricant such as stearic acid, magnesium stearate, talc, or the like; and a sweetening agent such as sucrose or saccharin may be added, as Well as a flavoring such as peppermint, oil of Wintergreen, or cherry flavoring.
- a binder such as gum tragacanth, acacia, corn starch or gelatin
- disintegrating agent such as corn starch, potato starch, alginic acid, or the like
- a lubricant such as stearic acid, magnesium stearate, talc, or the like
- a sweetening agent such as sucrose or saccharin may be added, as Well as a flavoring such as peppermint, oil of Wintergreen, or
- the active 2-oxazolin-4-ones may be made up into one of the various sustained release forms known to the pharmaceutical art.
- the therapeuticaly active oxazolin-4-ones may be prepared by several ditferent routes.
- Z-imino- 5-phenyl-4-oxazolidinone may be readily converted to 3 the active compounds by reaction with secondary amines as illustrated below:
- This reaction is generally carried out in a solvent such as a lower alkanol, methyl Cellosolve and the like.
- the temperature range is generally from about 50 to 200 C. It is usually desirable to use an excess of secondary amine to insure a reasonably complete reaction. It is also sometimes desirable to carry out the reaction in an autoclave or other pressure vessel to prevent loss of the secondary amine at the reaction temperature.
- EXAMPLE 1 Z-dimethylamino-S-phenyl-2-0xaz0lin-4-one A mixture of 8.8 grams of 5-phenyl-2-imino-4-oxazolidino, 9 grams of dimethylamine and 50 milliliters of ethanol is heated in an autoclave at 125 C. for two hours. After cooling, the ethanol is removed by distillation and the residual product is recrystallized from 50 milliliters of ethyl acetate and then from water. 2-dimethylamino 5-pheny1 2 oxazolinl one, MP. 137- 139 C., is thereby obtained.
- the hydrochloride (prepared with ethanolic hydrogen chloride) melts at 167171 C. (with decomposition).
- EXAMPLE 2 Z-diethylamino-S-phenyl-2-0xaz0line-4-0ne The procedure of Example 1 is repeated using 4.4 grams of 5-phenyl-Z-imino-4-oxazolidinone and 7.3 grams of diet-hylamine in 25 milliliters of ethanol. The crude product is obtained as an oily syrup and is partially purified by dissolving it in about 25 milliliters of methylene chloride, washing the organic layer with dilute sodium hydroxide solution and recovering the product by distillation of the organic solvent.
- the hydrochloride (prepared with ethanolic hydrogen chloride) melts at 149-154 C. (with decomposition).
- EXAMPLE 3 5 -pheny l-2-di-is0-butyIamirz0-2-0xazolin-4-0ne
- a mixture of 4.4 grams of 5-phenyl-2-imino-4-oxazolidinone and 14 milliliters of di-iso-butylamine in about 13 milliliters of 2 methoxyethanol is "heated at the reflux temperature for 22 hours.
- the solvent is removed by distillation and the residual oil is Washed ('by decantation) with 50 milliliters of petroleum-ether and then suspended in 25 milliliters of diethyl ether.
- the solid obtained is unreacted 5-phenyl-2-imino-4-oxazolidinone.
- EXAMPLE 4 Z-ethylmethylamin0-5-phenyl-2-oxaz0lin-4-0ne
- a solution of sodium ethoxide prepared by dissolving 0.5 gram of sodium in 20 milliliters of ethanol is treated with 3.8 grams of 5-phenyl-2-methylimino-4-oxo-oxazolidinone ifollowed by 2 milliliters of diethyl sulfate.
- the solution is refiuxed for about one-half hour and concentrated.
- the residue is treated with 40 milliliters of water and the product is extracted with methylene chloride.
- EXAMPLE 5 PREPARATION or PHARMACEUTICAL TABLETS
- the active ingredient, lactose and corn starch (for mix) are blended together.
- the corn starch (for paste) is suspended in about 800 milliliters of Water and heated, with stirring, to form a paste. This paste is then used to granulate the mixed powders. Additional water is used, if necessary.
- the wet granules are passed through a No. 8 hand screen and .dried at 120 F.
- the dry granules are then passed through a No. 16 screen.
- the mixture is lubricated with 1% magnesium stearate and compressed into tablets in a suitable tableting machine.
- the active ingredient, lactose and corn starch (for mix) are blended together.
- the corn starch (for paste) is suspended in 800 milliliters of water and heated with stirring, to form a paste. This paste is then used to 'granulate the mixed powders. Additional water is used, if necessary.
- the wet granules are passed through a No. 8 hand screen and dried at F.
- the dry granules are then passed through a No. 16 screen.
- the mixture is lubricated with 1% magnesium stearate and compressed into tablets in a suitable tableting machine.
- R and R are lower alkyl and the non-toxic acid addition salts thereof and a pharmaceutically acceptable carrier therefor.
- R and R are lower alkyl and the non-toxic acid addition salts thereof and a pharmaceutically acceptable carrier therefor.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Description
United States Patent 3,313,688 METHOD OF PRODUCING CENTRAL NERVOUS SYSTEM SIMULATION AND AN OREXIA Robert Allis Hardy, Jr., Ridgewood, N.J., and Charles Frederick Howell, New City, and Nicanor Quinones Quinones, New York, N.Y., assignors to American Cyanamid Company, Stamford, Conn., a corporation of Maine No Drawing. Filed Mar. 20, 1964, Ser. No. 353,590 12 Claims. (Cl. 167-55) This application is a continuation-in-part of our copending application Ser. No. 35,115 filed June 10, 1960, now abandoned.
This invention rel-ates to novel pharmaceutical compositions having a therapeutic effect on the central nervous system and to methods of treatment involving such compositions.
The present invention comprises a pharmaceutical composition containing as a principal active central nervous system agent a S-phenyl-Z-dialkylamino-2-oxazolin-4-one of the following formula:
| NR Rg wherein R and R are the same or different lower alkyl radicals having from 1 to 4 carbon atoms.
Pharmaceutical compositions containing one or more of the above compounds have been found to be highly useful central nervous system agents. The new compositions of this invention show a mild stimulant action and excellent anoretic action over a wide range of doses and possess distinct advantages over other stimulant drugs such as amphetamines and pipradrol. In addition, the new compositions of this invention are valuable centrally acting therapeutic agents for the management of depression.
Amphetamine and closely related compounds such as methamphetamine have been used as central nervous system stimulants for many years, but numerous undesirable side reactions accompany their administration. For instance, they cause more or less pronounced rise in blood pressure and there is a tendency toward developing tolerance upon continual use. The compositions of the present invention do not have these serious side-effects and thus are markedly superior to the amphetamines. The compositions of this invention also, even at high doses, are freeof the undesirable adrenergic and cardiovascular actions characteristic of the amphetamines. As increasing doses of the amphetamines are given, convulsions are usually observed. The compositions of this invention do not cause convulsions as the doses are increased. They possess a low order of toxicity and a desirably large spread between effective and lethal doses, i.e., a high therapeutic index. They also have a much greater margin of safety than pipradrol which shows a rather narrow range between effective and toxic doses.
Furthermore, the new compositions containing the active drugs are considerably more active than S-phenyl-Z- imino-4-oxo oxazolidine disclosed in United States Patent No. 2,892,753. For example, 2-dimethylamino-S-phenyl- 2 oxazolin 4-one and 2-ethylmethylamino-5-phenyl-2- oxazolin-4-one are approximately nine times as effective in causing a 50% increase in motor activity at a non-toxic dose. This type of test is well recognized as a useful method for the determination of stimulant activity and is "ice described by P. B. Dews, British Journal of Phat-macology, vol. 8, page 46 (1953), and by G. Chen et al., Journal of Pharmacology and Experimental Therapeutics, vol. 127, page 241 (1959).
Additionally, the valuable pharmaceutical properties of the new compositions of this invention are demonstrated in a variety of test procedures. For example the anoretic activity of these compositions is readily demonstrated by measuring the marked reduction in food consumption following the administration of the active agents. This indicates a therapeutically desirable method of treating obese conditions. Another test procedure which demonstrates the valuable central nervous system actions of these compositions consists of measuring their ability to counteract a depression induced in mammals by the administration of tetrabenazine hexamate. This test procedure indicates these new compositions show useful antidepressant activity at dose levels which produce little or no untoward reactions or toxic manifestations. These compositions may, therefore, be considered as valuable therapeutic agents for the treatment of depressive states and melancholia.
The above compounds are in general, white crystalline solids, only slightly soluble in water. They are insoluble in alkaline solutions. They are basic substances soluble in aqueous mineral acids at room temperature, and in some cases form isolable acid addition salts.
The active compounds incorporated in a pharmaceutically acceptable carrier therefor may be used in the form of their free bases or as the non-toxic acid addition salts such as the hydrochloride, sulfate, phosphate, citrate, etc. The new compositions may be administered orally or parenterally and when so administered have been found to be useful therapeutic agents at individual doses ranging from about 25 to 150 milligrams of active ingredient. The dosage regimen can be adjusted to provide the optimum therapeutic response. For example, several doses may be administered daily, or the dose may be proportionately reduced as indicated by the exigencies of the therapeutic situation.
For therapeutic administration the compounds may be incorporated with pharmaceutical excipients and used, for instance, in the form of tablet, drages, capsules, suppositories, liquids to be administered in drops, emulsions, suspensions, syrups, chocolate, candy, and the like. Such compositions and preparations should contain at least 0.25% of the active ingredient. The percentage in the compositions and preparations may, of course, be varied and may conveniently be between 2% and about 60% or more of the weight of the unit. The amount of active ingredient in such therapeutically useful compositions or preparations is such that a suitable dosage will be obtained. Preferred compositions or preparations according to the present invention are prepared in such a manner that a dosage unit form contains between about 25 milligrams and about milligrams of the active compound.
Tablets, pills, drages, and the like usually contain the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; 3. disintegrating agent such as corn starch, potato starch, alginic acid, or the like; a lubricant such as stearic acid, magnesium stearate, talc, or the like; and a sweetening agent such as sucrose or saccharin may be added, as Well as a flavoring such as peppermint, oil of Wintergreen, or cherry flavoring.
In the form of a pamoic acid, alginic acid, tannic acid or other insoluble salt, the active 2-oxazolin-4-ones may be made up into one of the various sustained release forms known to the pharmaceutical art.
The therapeuticaly active oxazolin-4-ones may be prepared by several ditferent routes. For example, Z-imino- 5-phenyl-4-oxazolidinone may be readily converted to 3 the active compounds by reaction with secondary amines as illustrated below:
NH 0 NH 0 IQIH 1 :11.12, where R and R are lower alkyl radicals.
This reaction is generally carried out in a solvent such as a lower alkanol, methyl Cellosolve and the like. The temperature range is generally from about 50 to 200 C. It is usually desirable to use an excess of secondary amine to insure a reasonably complete reaction. It is also sometimes desirable to carry out the reaction in an autoclave or other pressure vessel to prevent loss of the secondary amine at the reaction temperature.
The invention will be described in greater detail in conjunction with the following specific examples.
EXAMPLE 1 Z-dimethylamino-S-phenyl-2-0xaz0lin-4-one A mixture of 8.8 grams of 5-phenyl-2-imino-4-oxazolidino, 9 grams of dimethylamine and 50 milliliters of ethanol is heated in an autoclave at 125 C. for two hours. After cooling, the ethanol is removed by distillation and the residual product is recrystallized from 50 milliliters of ethyl acetate and then from water. 2-dimethylamino 5-pheny1 2 oxazolinl one, MP. 137- 139 C., is thereby obtained.
The hydrochloride (prepared with ethanolic hydrogen chloride) melts at 167171 C. (with decomposition).
EXAMPLE 2 Z-diethylamino-S-phenyl-2-0xaz0line-4-0ne The procedure of Example 1 is repeated using 4.4 grams of 5-phenyl-Z-imino-4-oxazolidinone and 7.3 grams of diet-hylamine in 25 milliliters of ethanol. The crude product is obtained as an oily syrup and is partially purified by dissolving it in about 25 milliliters of methylene chloride, washing the organic layer with dilute sodium hydroxide solution and recovering the product by distillation of the organic solvent. Recrystallization of the product from ether followed by recrystallization from ethyl acetate or aqueous acetone then gives 5-phenyl-2- diethylamino-2-oxazoline-4-one which melts at 7677 C.
The hydrochloride (prepared with ethanolic hydrogen chloride) melts at 149-154 C. (with decomposition).
EXAMPLE 3 5 -pheny l-2-di-is0-butyIamirz0-2-0xazolin-4-0ne A mixture of 4.4 grams of 5-phenyl-2-imino-4-oxazolidinone and 14 milliliters of di-iso-butylamine in about 13 milliliters of 2 methoxyethanol is "heated at the reflux temperature for 22 hours. The solvent is removed by distillation and the residual oil is Washed ('by decantation) with 50 milliliters of petroleum-ether and then suspended in 25 milliliters of diethyl ether. The solid obtained is unreacted 5-phenyl-2-imino-4-oxazolidinone. Concentration of the ethereal filtrate gives the desired product in a crude state. Treatment with an ether solution of anhydrous hydrogen chloride then gives 5-phenyl- 2-di-iso-butylamino-2-oxazolin-4-one hydrochloride.
EXAMPLE 4 Z-ethylmethylamin0-5-phenyl-2-oxaz0lin-4-0ne A solution of sodium ethoxide prepared by dissolving 0.5 gram of sodium in 20 milliliters of ethanol is treated with 3.8 grams of 5-phenyl-2-methylimino-4-oxo-oxazolidinone ifollowed by 2 milliliters of diethyl sulfate. The solution is refiuxed for about one-half hour and concentrated. The residue is treated with 40 milliliters of water and the product is extracted with methylene chloride.
d This solution is Washed with dilute sodium hydroxide solution, dried and concentrated. '2-ethylmethylamino-5- phenyl-2-oxazolin-4-one, M.P. 97 C. is thereby obtained. After two recrystallizations from ethyl acetate the purified product melts at 104107 C.
EXAMPLE 5 PREPARATION or PHARMACEUTICAL TABLETS The active ingredient, lactose and corn starch (for mix) are blended together. The corn starch (for paste) is suspended in about 800 milliliters of Water and heated, with stirring, to form a paste. This paste is then used to granulate the mixed powders. Additional water is used, if necessary. The wet granules are passed through a No. 8 hand screen and .dried at 120 F. The dry granules are then passed through a No. 16 screen. The mixture is lubricated with 1% magnesium stearate and compressed into tablets in a suitable tableting machine.
EXAMPLE 6 PREPARATION or PHARMACEUTICAL TABLETS Per For Tablet 10,000
(g.) Tablets Active ingredient; Z-dimethylamino-5-phenyl'2- oxazolin4-one. 0. 0200 200 Lactose 0. 0800 800 Corn Starch (for mix) 0.0150 150 Corn Starch (for paste) 0.0100 0. 1250 l, 250 Magnesium Stearate (1%) 0. 0013 12. 5 0.1263 1, 262. 5
The active ingredient, lactose and corn starch (for mix) are blended together. The corn starch (for paste) is suspended in 800 milliliters of water and heated with stirring, to form a paste. This paste is then used to 'granulate the mixed powders. Additional water is used, if necessary. The wet granules are passed through a No. 8 hand screen and dried at F. The dry granules are then passed through a No. 16 screen. The mixture is lubricated with 1% magnesium stearate and compressed into tablets in a suitable tableting machine.
We claim:
1. The process of producing therapeutically desirable stimulation of the central nervous system of mammals which comprises administering internally to a mammal in whom a stimulation eflect is desired a composition containing between about 25 and milligrams per dosage unit of a compound selected from the group consisting of 5-pheny1-2-dialkylamino-2-oxazolin-4-ones of the formula:
wherein R and R are lower alkyl and the non-toxic acid addition salts thereof and a pharmaceutically acceptable carrier therefor.
2. The process according to claim 1 in which the compound is selected from the group consisting of Z-dimethylamino-5-phenyl-2-oxazolin-4-one and the non-toxic acid addition salts thereof.
3. The process according to claim 1 in which the compound is selected from the group consisting of Z-ethylmethylamino-5-phenyl-2-oXazolin-4-one and the non-toxic acid addition salts thereof.
4. The process according to claim 1 in which the compound is selected from the group consisting of 2- diethylamino-5phenyl-2-oXazolin-4-one and the non-toxic acid addition salts thereof.
5. The process of producing therapeutically desirable anorexic effects in mammals for control of appetite and treatment of obesity which comprises administering internally to a mammal in whom an anorectic effect is desired a composition containing between about 25 and 150 milligrams per dosage unit of a compound selected from the group consisting of 5-phenyl-2-dialkylamino-Z- oXazolin-4-ones of the formula:
I NR R wherein R and R are lower alkyl and the non-toxic acid addition salts thereof and a pharmaceutically acceptable carrier therefor.
6. The process according to claim 5 in which the compound is selected from the group consisting of Z-dimethylamino-5-phenyl 2-oxazolin-4-one and the non-toxic acid addition salts thereof.
7. The process according to claim 5 in which the compound is selected from the group consisting of Z-ethylmethylamino-5-phenyl-2-oxazolin-4-one and the non-toxic acid addition salts thereof.
8. The process according to claim 5 in which the compound is selected from the group consisting of 2-diethylamino-5-phenyl-2-oxazolin-4-one and the non-toxic acid addition salts thereof.
9. The process of producing a therapeutically desirable effect on the central nervous system of mammals for therapeutic treatment of depression which comprises administering internally to mammals in whom an antidepressant effect is desired a composition containing between about 25 and milligrams per dosage unit of a compound selected from the group consisting of S-phenyl- 2-dialkylamino-2-oXazolin-4-ones of the formula:
CH-C=O i) N 0 IL R1RQ wherein R and R are lower alkyl and the non-toxic acid addition salts thereof and a pharmaceutic-ally acceptable carner therefor.
19. The process according to claim 9 in which the compound is selected from the group consisting of 2- dimethylamino-5+phenyl-2-oxazolin-4-one and the nontoxic acid addition salts thereof.
11. The process according to claim 9 in which the compound is selected from the group consisting of 2- ethylmethylamino-5-phenyl-2-oXazolin-4-0ne and the nontoxic acid addition salts thereof.
12. The process according to claim 9 in which the compound is selected from the group consisting of 2- diethylamino-5-phenyl-2-oXazolin-4-one and the non-toxic acid addition salts thereof.
References Cited by the Examiner UNITED STATES PATENTS 2,687,414 8/1954 Cusic 260243 2,892,753 6/1959 Schmidt 16765 3,029,189 4/1962 Hardy 16765 3,038,896 6/1962 Habicht 260-239 OTHER REFERENCES Aspelund, Chem. A'bstracts 41, 2416 (1947). Lienert, Chem. Abstracts 51, 15805 (1957).
ALBERT T. MEYERS, Primary Examiner. SAM ROSEN, Examiner. STANLEY J. FRIEDMAN, Assistant Examiner.
Claims (1)
1. THE PROCESS OF PRODUCING THERAPEUTICALLY DESIRABLE STIMULATION OF THE CENTRAL NERVOUS SYTEM OF MAMMALS WHICH COMPRISES ADMINISTERING INTERNALLY TO A MAMMAL IN WHOM A STIMULATION EFFECT IS DESIRED TO COMPOSITION CONTAINING BETWEEN ABOUT 25 AND 150 MILLIGRAMS PER DOSAGE UNIT OF A COMPOUND SELECTED FROM THE GROUP CONSISTING OF 5-PHENYL-2-DIALKYLAMINO-2-OXAZOLIN-4-ONES OF THE FORMULA:
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US353590A US3313688A (en) | 1964-03-20 | 1964-03-20 | Method of producing central nervous system stimulation and anorexia |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US353590A US3313688A (en) | 1964-03-20 | 1964-03-20 | Method of producing central nervous system stimulation and anorexia |
Publications (1)
Publication Number | Publication Date |
---|---|
US3313688A true US3313688A (en) | 1967-04-11 |
Family
ID=23389773
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US353590A Expired - Lifetime US3313688A (en) | 1964-03-20 | 1964-03-20 | Method of producing central nervous system stimulation and anorexia |
Country Status (1)
Country | Link |
---|---|
US (1) | US3313688A (en) |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2687414A (en) * | 1948-11-26 | 1954-08-24 | Searle & Co | Method for producing aromatic aminoalkyl amines |
US2892753A (en) * | 1957-02-26 | 1959-06-30 | Boehringer Sohn Ingelheim | Central nervous system stimulant |
US3029189A (en) * | 1962-04-10 | S-aryl-z-mno-x-qxazolibinones | ||
US3038896A (en) * | 1958-05-30 | 1962-06-12 | Cilag Chemie | 1-(di-lower alkyl amino lower alkyl thio lower alkyl)-aza-[2, 3:5, 6]-dibenzocycloheptadiene compounds |
-
1964
- 1964-03-20 US US353590A patent/US3313688A/en not_active Expired - Lifetime
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3029189A (en) * | 1962-04-10 | S-aryl-z-mno-x-qxazolibinones | ||
US2687414A (en) * | 1948-11-26 | 1954-08-24 | Searle & Co | Method for producing aromatic aminoalkyl amines |
US2892753A (en) * | 1957-02-26 | 1959-06-30 | Boehringer Sohn Ingelheim | Central nervous system stimulant |
US3038896A (en) * | 1958-05-30 | 1962-06-12 | Cilag Chemie | 1-(di-lower alkyl amino lower alkyl thio lower alkyl)-aza-[2, 3:5, 6]-dibenzocycloheptadiene compounds |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US3047461A (en) | Central nervous system stimulant | |
US3029189A (en) | S-aryl-z-mno-x-qxazolibinones | |
US3341584A (en) | Anilides | |
IE901983A1 (en) | Antihyperlipidemic and antiatherosclerotic urea compounds | |
EP0047536B1 (en) | Substituted propylamines | |
DE3411993A1 (en) | SUBSTITUTED BENZOPYRANS, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE IN MEDICINAL PRODUCTS | |
US3253989A (en) | Process for producing anorexia | |
US3621043A (en) | N-substituted octadecadienoic acid amides as cholesterol lowering agents | |
US3483221A (en) | 1 - (isopropylamino)-2-hydroxy-3-(alkenyloxyphenoxy) - propanes and the salts thereof | |
US3689504A (en) | N-substituted -alpha-methyl-3,4-(methylenedioxy) phenethylamines | |
US2879293A (en) | Benzylamine derivatives | |
US3192253A (en) | N-substituted methoxyphenoxy-ethylamines | |
US3445518A (en) | P-acylphenylethylamines | |
US4608391A (en) | Catecholamine derivatives, a process for their preparation and pharmaceutical compositions thereof | |
US3313688A (en) | Method of producing central nervous system stimulation and anorexia | |
US4181738A (en) | Catecholamine derivatives, a process for their preparation and pharmaceutical compositions thereof | |
US3655737A (en) | 1-(3-hydroxy-4-methyl-phenyl)-propylamine (-2) and the salts thereof | |
CY1221A (en) | Secondary amino tetrazolyloxypropanols | |
CH642057A5 (en) | Benzenesulphonamide and benzamide derivatives and their preparation | |
US3313687A (en) | Appetite-suppressing and weight reducing composition | |
US4218477A (en) | Primary aminoacylanilides, methods of making the same and use as antiarrhythmic drugs | |
US3096244A (en) | Substituted butyric acid amide and analgesia | |
US3222395A (en) | Maleamic ackd derivatives | |
US3539642A (en) | 2-phenyl-2-(1-naphthyl)acetamides | |
US3507919A (en) | Triphenylpropyl amines |