US3051622A - Analgesic cyclobutanes - Google Patents
Analgesic cyclobutanes Download PDFInfo
- Publication number
- US3051622A US3051622A US855285A US85528559A US3051622A US 3051622 A US3051622 A US 3051622A US 855285 A US855285 A US 855285A US 85528559 A US85528559 A US 85528559A US 3051622 A US3051622 A US 3051622A
- Authority
- US
- United States
- Prior art keywords
- analgesic
- dimethyl
- radical
- animal
- cyclobutane
- 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
- 230000000202 analgesic effect Effects 0.000 title claims description 67
- 150000001930 cyclobutanes Chemical class 0.000 title description 32
- 239000000203 mixture Substances 0.000 claims description 31
- 150000003839 salts Chemical class 0.000 claims description 29
- 239000002253 acid Substances 0.000 claims description 27
- 231100000252 nontoxic Toxicity 0.000 claims description 22
- 230000003000 nontoxic effect Effects 0.000 claims description 22
- 239000003937 drug carrier Substances 0.000 claims description 10
- 239000002552 dosage form Substances 0.000 claims description 9
- PMPVIKIVABFJJI-UHFFFAOYSA-N Cyclobutane Chemical class C1CCC1 PMPVIKIVABFJJI-UHFFFAOYSA-N 0.000 claims description 6
- -1 alkyl radicals Chemical class 0.000 description 82
- 241001465754 Metazoa Species 0.000 description 63
- 238000000034 method Methods 0.000 description 34
- 150000001875 compounds Chemical class 0.000 description 26
- 241000700159 Rattus Species 0.000 description 25
- 125000004432 carbon atom Chemical group C* 0.000 description 22
- 230000036592 analgesia Effects 0.000 description 19
- 241000282414 Homo sapiens Species 0.000 description 18
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 18
- 239000000730 antalgic agent Substances 0.000 description 18
- 229940035676 analgesics Drugs 0.000 description 17
- 150000003254 radicals Chemical class 0.000 description 17
- 238000006243 chemical reaction Methods 0.000 description 16
- 239000001257 hydrogen Substances 0.000 description 16
- 229910052739 hydrogen Inorganic materials 0.000 description 16
- 230000001939 inductive effect Effects 0.000 description 16
- 125000000217 alkyl group Chemical group 0.000 description 15
- OROGSEYTTFOCAN-DNJOTXNNSA-N codeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC OROGSEYTTFOCAN-DNJOTXNNSA-N 0.000 description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 13
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 11
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 10
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical group CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 10
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 9
- 229960001138 acetylsalicylic acid Drugs 0.000 description 9
- 125000003118 aryl group Chemical group 0.000 description 9
- 239000000376 reactant Substances 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 8
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 8
- 229910052799 carbon Inorganic materials 0.000 description 8
- WZCOQWVIQBLQKQ-UHFFFAOYSA-N diethyl 4-(dimethylamino)-3,3-dimethylcyclobutane-1,2-dicarboxylate Chemical compound CCOC(=O)C1C(N(C)C)C(C)(C)C1C(=O)OCC WZCOQWVIQBLQKQ-UHFFFAOYSA-N 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 229960004715 morphine sulfate Drugs 0.000 description 8
- GRVOTVYEFDAHCL-RTSZDRIGSA-N morphine sulfate pentahydrate Chemical compound O.O.O.O.O.OS(O)(=O)=O.O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O.O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O GRVOTVYEFDAHCL-RTSZDRIGSA-N 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- UIQMVEYFGZJHCZ-SSTWWWIQSA-N Nalorphine Chemical compound C([C@@H](N(CC1)CC=C)[C@@H]2C=C[C@@H]3O)C4=CC=C(O)C5=C4[C@@]21[C@H]3O5 UIQMVEYFGZJHCZ-SSTWWWIQSA-N 0.000 description 7
- 239000007795 chemical reaction product Substances 0.000 description 7
- 229960004126 codeine Drugs 0.000 description 7
- OROGSEYTTFOCAN-UHFFFAOYSA-N hydrocodone Natural products C1C(N(CCC234)C)C2C=CC(O)C3OC2=C4C1=CC=C2OC OROGSEYTTFOCAN-UHFFFAOYSA-N 0.000 description 7
- 150000002431 hydrogen Chemical group 0.000 description 7
- AMIMRNSIRUDHCM-UHFFFAOYSA-N Isopropylaldehyde Chemical compound CC(C)C=O AMIMRNSIRUDHCM-UHFFFAOYSA-N 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 6
- 229920002472 Starch Polymers 0.000 description 6
- 150000001336 alkenes Chemical class 0.000 description 6
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- DKSZLDSPXIWGFO-BLOJGBSASA-N (4r,4ar,7s,7ar,12bs)-9-methoxy-3-methyl-2,4,4a,7,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7-ol;phosphoric acid;hydrate Chemical compound O.OP(O)(O)=O.OP(O)(O)=O.C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC.C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC DKSZLDSPXIWGFO-BLOJGBSASA-N 0.000 description 5
- ZQZUJFQBFGFJMM-UHFFFAOYSA-N 1-(2-methylprop-1-enyl)piperidine Chemical compound CC(C)=CN1CCCCC1 ZQZUJFQBFGFJMM-UHFFFAOYSA-N 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 5
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical class OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 5
- 229960004415 codeine phosphate Drugs 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 239000008101 lactose Substances 0.000 description 5
- 235000019359 magnesium stearate Nutrition 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 230000004044 response Effects 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- 231100000419 toxicity Toxicity 0.000 description 5
- 230000001988 toxicity Effects 0.000 description 5
- 241000282472 Canis lupus familiaris Species 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 208000004756 Respiratory Insufficiency Diseases 0.000 description 4
- 206010038678 Respiratory depression Diseases 0.000 description 4
- 230000001154 acute effect Effects 0.000 description 4
- 125000003545 alkoxy group Chemical group 0.000 description 4
- 125000005907 alkyl ester group Chemical group 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 238000007796 conventional method Methods 0.000 description 4
- 230000002939 deleterious effect Effects 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- 230000002349 favourable effect Effects 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 4
- 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 4
- IHSJXWLJYTXOCL-UHFFFAOYSA-N n,n,2-trimethylprop-1-en-1-amine Chemical compound CN(C)C=C(C)C IHSJXWLJYTXOCL-UHFFFAOYSA-N 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- 231100001274 therapeutic index Toxicity 0.000 description 4
- YNGSZDZAESJMEY-UHFFFAOYSA-N 1,4-bis(2-methylprop-1-enyl)piperazine Chemical compound CC(C)=CN1CCN(C=C(C)C)CC1 YNGSZDZAESJMEY-UHFFFAOYSA-N 0.000 description 3
- NLHHRLWOUZZQLW-UHFFFAOYSA-N Acrylonitrile Chemical compound C=CC#N NLHHRLWOUZZQLW-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 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
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 3
- 150000001721 carbon Chemical group 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 125000004093 cyano group Chemical group *C#N 0.000 description 3
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000004081 narcotic agent Substances 0.000 description 3
- 230000003533 narcotic effect Effects 0.000 description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 230000002195 synergetic effect Effects 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- 150000003512 tertiary amines Chemical class 0.000 description 3
- SYZVQXIUVGKCBJ-UHFFFAOYSA-N 1-ethenyl-3-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC(C=C)=C1 SYZVQXIUVGKCBJ-UHFFFAOYSA-N 0.000 description 2
- UWNADWZGEHDQAB-UHFFFAOYSA-N 2,5-dimethylhexane Chemical group CC(C)CCC(C)C UWNADWZGEHDQAB-UHFFFAOYSA-N 0.000 description 2
- VNPLFTXNVIADTR-UHFFFAOYSA-N 2-methyl-n-(2-methylprop-1-enyl)-n-(2-methylpropyl)propan-1-amine Chemical compound CC(C)CN(CC(C)C)C=C(C)C VNPLFTXNVIADTR-UHFFFAOYSA-N 0.000 description 2
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
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- 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 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
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- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
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- 125000004850 cyclobutylmethyl group Chemical group C1(CCC1)C* 0.000 description 2
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- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
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- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 2
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- GCBDWULRISFGNH-UHFFFAOYSA-N methyl 3,3-dimethyl-2-morpholin-4-ylcyclobutane-1-carboxylate Chemical compound COC(=O)C1CC(C)(C)C1N1CCOCC1 GCBDWULRISFGNH-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/225—Polycarboxylic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
Definitions
- analgesic In the past a large number of substances have been used to produce analgesic action. All of the prior art analgesics have suffered from one or more serious disadvantages. Some of the substances employed are strong narcotic or toxic agents and give rise to addiction or deleterious side efifects such as respiratory depression, pruritis, constipation, nausea, sphincter constriction, sedation and euphoria. Others are only slightly effective and give no relief against deep-seated and pronounced pain. Still others are absorbed only slowly from the alimentary canal and require a prolonged period and large dosages before their action is eifective. Still other substances require an aryl substituent in the molecule and give irritation on parenteral injection or have a low therapeutic ratio.
- the cyclobutane derivatives of this invention possess many advantageous properties when used as analgesics.
- the advantageous analgesic properties include: greater therapeutic efiect than known non-prescriptive types of analgesics such as aspirin, phenacetin or salicylamide; absence of deleterious side effects, e.g., respiratory depression, vomiting, constipation, sedation, euphoria and pruritis as are produced by narcotic types of analgesics; good tolerance and less toxicity than many other analgesics presently available; a more favorable therapeutic ratio than codeine; absence of imitation on parenteral injection; the attainment of a maximum analgesic potency value with relatively small quantities of the analgesic wherein the potency value is not significantly increased by the administration of larger quantities; good analgesic effect even when the molecule of the active compounds does not contain the usual aromatic constituents; no physical dependency upon withdrawal
- diethyl 3,3-dimethyl-4-dimethylaminocyclobutane-1,2-dicarboxylate-HCl is relatively non-toxic (e.g. LD 50 of oral dosages of about 3000 mg./kg. of animal weight in mice, greater than 12,000 mg/kg. of animal weight in rats and greater than 3000 mgjkg.
- This mono-ester compound gives very much of a straight line dose response, providing increased analgesic activity on increased dosage levels, particularly dosage levels above mg./kg., whereas the diester compound reaches a peak of activity at a dosage level of about 100 mg./kg. and the activity is not significantly increased by larger dosage levels above that amount.
- analgesicly active cyclobutane derivatives can be represented by the following generic formula:
- A is a lower alkyl radical; A is a lower alkyl radical; R is hydrogen, an electronegative radical as hereinafter disclosed or a lower alkyl radical; R is hydrogen, a lower alkyl radical or an electronegative radical as hereinafter disclosed; R is hydrogen, an electronegative radical as hereinafter disclosed or a lower alkyl radical; R is hydrogen, a lower alkyl radical or an electronegative radical as hereinafter disclosed; provided that at least one of R, R R or R is an electronegative radical as hereinafter disclosed; X is a tertiary amine radical and R is hydrogen or a lower alltyl radical.
- lower alkyl radical or lower alkyl group we mean an alkyl radical containing from 1 to 6 carbon atoms, e.g., methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, etc.
- the lower alkyls having from 1 to 2 carbon atoms are preferred.
- tertiary amine radical we mean a radical of the ammonia molecule wherein the hydrogen atoms have been replaced by three radicals.
- the tertiary amine can be a lower allcyl amine, cycloaliphatic amine, an aryl amine or a saturated cyclic amine wherein the ring contains elements such as sulfur or oxygen in addition to nitrogen and carbon.
- amine radicals there can be mentioned: those of lower alkyls, e.g., dimethyl, diethyl, dipropyl, 'diisopropyl, diisobutyl, methyl ethyl amine, methylisopropylamine, ethyl tertiar butylamine and the like; cyclic including substituted alicyclic amines, e.g., piperazino, piperidino, morpholino, thiomorpholino and the like.
- the amine be a dialkyl amine having from 1 to 2 carbon atoms in each alkyl radical and that the nitrogen be bound directly to a ring carbon atoms of the cyclobutane.
- the electronegative radicals or groups satisfactory in the compounds of this invention are: phenyl and substituted phenyls, nitro, lower alkyl sulfonyl, cyano, lower alkyl esters, and lower. alkyleneamino radicals.
- the compound is inactive if the group is capable of dissociation into two fragments, one carrying a formal negative charge attached to the cyclobutane ring and a free positive fragment.
- sulfonyl radical (-'SO -R) there can be mentioned: methyl sulfonyl, ethyl sulfonyl, propyl sulfonyl, isopropyl sulfonyl, butyl sulfonyl, isobutyl sulfonyl and the like.
- ester groups there can be mentioned: the .carbomethoxy, carboethoxy, carbopropoxy, carboisopropoxy, carbobutoxy, carboisobutoxy and the like. It is preferred that the alkyl portion of the carbalkoxy radical be one having from 1 to 3 carbon atoms.
- esters formed by the reaction of 'a carboxylic acid of cyclobutane with a lower alkyl alcohol it has been found that the reduction of a cyclo butane carboxylic acid to a cyclobutyl methyl alcohol and subsequent reaction of the alcohol with a lower alkyl acid also produces a therapeutically active and equivalent compound.
- esters formedfrom a cyclobutyl methyl alcohol and a lower alkyl acid there can be mentioned those wherein the following radicals are attached directly to one of the ring carbons:
- A, A, R, R and X are the same radicals as discussed for the preferred generic formula and provided that at least one of R and R is an elcctronegative group as hereinabove disclosed.
- the preferred electronegative group is that of lower alkyl carbalkoxy radicals particularly when the alkyl contains from 1 to 3 carbon atoms. It is also preferred that when only one of R and R is an electronegative group that the remaining R and R be hydrogen.
- Either the cyclobutane derivatives of this inventionor their acid addition salts can be administered by the conventional methods, the conventional types of unit dosages or with the conventional pharmaceutical carriers to produce an analgesic effect in human beings and animals.
- Conventional methods of administration of the analgesics include oral or parenteral administration. Oral administration by the use of tablets or capsules or in liquid form such as suspensions, solutions or emulsions is particularly advantageous since the novel analgesics are rapidly absorbed from the gastrointestinal tract.
- the conventional binding and disintegrating agents used in analgesic unit dosages can be used. illustrative of binding agents there can be mentioned: glucose, gum acacia, gelatin and starch paste.
- the acid addition salts are formed by the conventional techniques of neutralizing the amine portion of a com- ,poundwith either an'organic or inorganic acid.”
- the novel analgesic compounds of this invention can be administered in combination with other analgesics particularly those containing an aromatic nucleus. Such combination of some of the novel analgesic compounds with an aromatic nucleus analgesic can produce a synergistic analgesic effect.
- analgesics containing an aromatic nucleus which produce synergistic effects with the cyclobutane derivatives there can be mentioned: aspirin and its salts such as those of the alkali metal or alkaline earth metal salts, e.g., sodium, potassium, calcium and magnesium; salicylic acid and its salts such as those of the alkali metal or alkaline earth metal salts, e.g., sodium, potassium, calcium and magnesium; D- propoxyphene'HCl, codeine phosphate and morphine sulfate.
- the unit dos-age or analgesicaily effective quantity of the cyclobutane derivatives for human beings can vary over wide limits such as that of about 0.1 of a grain to about 25 grains or more such as 100 grains. The upper limit is limited only by the degree of effect desired and economic considerations.
- oral administration it is preferable to employ from aboutl to about 10 grains per unit dosage.
- Each unit dosage form of the novel therapeutic compounds can contain from about 1% to about 95% and preferably from about 5% to 80% of the novel analgesic agent by weight of the entire composition with the remainder comprising conventional pharmaceutical carriers and option ally other analgesics such as
- pharmaceutical carrier we intend to include non-analgesic materials which are conventionally used with analgesics and includes fillers, diluents, binders, lubricants, disintegrating agents and solvents.
- the quantity of the conventional aromatic analgesic used in combination with the cyclobutane derivative is not critical and can vary from 0.05 to 10 times'the weight of novel analgesic employed depending on the conventional analgesic employed.
- aspirin it is preferable to use between about .25 to about 4 times the weight of the novel analgesic.
- a suitable formulation of tablets consists of:
- hydrochloride Salt of methyl 3,3-dimethy1-2-dimethylammo-cyclobutane-l-carboxylate, mannitol and starch are thoroughly mixed and granulated.
- the magnesium stearate is added, mixed with granules, and the mixture tableted on a rotary press. Use of this procedure produces 100 tablets each containing 250 mg. of the active analgesic salt.
- EXAMPLE C Another suitable formulation of tablets consists of: Grams 1 1,4-bis (4-oarbmethoxy-2,Z-dirnethylcyclobutyl) piperazine 25 (2) b-Lactose 20 (3) Dextrin l (4) Hydrogenated vegetable oil 0.5 (5) Talc 2
- the 1,4 bis(4-carbmethoxy-2,Z-dimethylcyolobutyl)- piperazine, b-lactose, and dextrin are thoroughly mixed and granulated.
- the hydrogenated vegetable oil and talc are added, mixed with the granules, and the mixture tableted on a rotary press. Use of this procedure produces 200 tablets of 125 mg. of active analgesic.
- EXAMPLE D Another suitable formulation of tablets consists of preparing tablets by the conventional techniques wherein each tablet comprises:
- a suitable formulation of oral elixir consists of: (l) The phosphoric acid salt of N,N,2,2-tetramethyl-4-methylsulfonylcyclobutylamine grams" (2) Aromatic elixir base to make "liters-.. Base contains: orange spirits, sugar syrup,
- EXAMPLE F An illustrative example of preparing solutions for injection consists of placing 300 milliliters of distilled water for injection, U.S.P., in a two-liter Pyrex flask, and adding 7.5 grams of the hydrochloride salt of diethyl 3,3 dimethyl-4-dimethylaminocyclobutane-1,2-dicarboxylate With stirring until solution is effected. The pH is then adjusted with N/ sodium hydroxide to a pH of approximately 6.0. Sufficient Water for injection is added to make the volume to 1 liter. The solution is filled into clean, dry l-cc. ampules and the ampules are sealed and sterilized.
- a suitable formulation of tablets consists of:
- EXAMPLE 1 This example shows analgesic eifect on rats by the tail 'flick'test. This test is performed by uniformly blackening the tails of rats, administering an analgesic to the animal and subsequently focusing a beam of light on the animals tail at various intervals after administration of the analgesic. The time required for the animal to flick its tail after the beam of light is applied determines the analgesic efiect of'the material being tested. The longer the interval for the tail flick, after the application of the concentrated beam of light, the more effective is the analgesic.
- Predeterrnined dosages of diethyl 3,3-dimethyl- 4 dimethylaminocyclobutane-1,2-dicarboxylate-HCl, D- propoxyphene-HCI and'the very strong narcotic types of analgesics such as morphine sulfate and codeine phosphate were given to rats.
- Each material was administered orally to sets of fiteen animals except for morphine sulfate which was given subcutaneously to fifteen animals and codeine phosphate which was given orally to twenty-five anirnals.
- the following quantities of each material were used: morphine sulfate, 1.5 milligrams per kilogram weight of each animal; D-propoxyphene-HCI,
- Table 1 shows that an oral dose of 100 mg. of the cyclobutane compound per kg. Weight of the animal is equivalent in analgesic potency to oral doses of either 25 mg./kg. of D-propoxyphene-HCI or 40 mg./kg. of codeine phosphate and to a subcutaneous dose of 1.5 mg./ kg. of morphine surfate.
- EXAMPLE 2 This example shows the analgesic dose response of diethyl 3,3-dimethyl-4-dimethylaminocyclobutane-1,2-dicarboxylate'HCl on rats by the tail flick method as described in Example 1.
- the cyclobutane compound was administered orally to all the animals.
- Four difierent dosages were used wherein 350 milligrams per kilogram weight of animal was administered to five rats; 175 milligrams per kilogram weight of animal was administered to fifteen rats; 100 milligrams per kilogram weight of animal was administered to fifteen rats; and twenty-five additional rats were administered 50 milligrams per kilogram weight of animal.
- the time required for the rats to flick their tails after the concentrated beam of light was focused thereon at various intervals of time is given in Table 2. Average readings for the animals of each dosage group is also given in the table.
- EXAMPLE 3 This example shows potentiation of diethyl 3,3-dimethyl 4 dimethylaminocyclobutane 1,2 dicarboxylate-HCl with Nalline and the antagonistic elfect of Nalline with morphine sulfate.
- the rat tail flick test as described in Example 1 was employed. Two sets of fiive rats in each set were given 175 mg. of diethyl 3,3- dimethyl 4 dimethylaminocyclobutane 1,2 dicarboxylate-HCI per kg. of animal weight. Two sets of five rats in each set were subcutaneously injected with 2 mg. of morphine sulfate per kg. weight of each animal. Tail flick determinations were made for 20 minutes after administration of the two analgesics after which 1 mg.
- Table 3 Time in minutes after administration of an ina it- 1 Immediately prior to administration of analgesic.
- EXAMPLE 4 This example shows that diethyl 3,3-dimethyl-4-dimethylaminocyclobutane-1,2-dicarboxylate hydrochloride is non-irritating on parenteral injection. Intradermal skin irritation tests were conducted on rabbits using the Trypan Blue method. Concentrations of 1.0%, 5.0% and 10.0% of the HCl salt of the diethyl ester were injected intradermally in a volume of 0.3 cc. A different skin area was used for each concentration. A control area was treated with a similar volume of physiological saline.
- EXAMPLE 5 This example shows the quantity of diethyl 3,3-dimethyl 4 dimethylarninocyclobutane 1,2 dicarboxylate-HCI required for an LD 50 in mice by different methods of administration.
- Acute intravenous LD 50 125 mg./kg. of ani mal (5 mice per dose level for a total of 25 animals).
- Acute subcutaneous LD 50 2,000 mg./kg. of animal (10 mice per dose level for a total of 20 animals).
- diethyl 3,3-dimethyl-4-dimethylamin0- cyclobutane-1,2-dicarboxylate-I-IC1 has a relatively low order of toxicity.
- EXAMPLE 8 This example shows analgesic tests on rats by the tail flick test as described in Example 1. Predetermined dosages of methyl 3,3-dimethy1-4-dimethylaminocyclobutane-l-carboxylate'ficl were administered orally. to rats. IEach dosage level contained five animals and the results are given in Table 6 as the average time in seconds for the pain response of the animals in each dosage level.
- test compound of Example 8 possesses analgesic activity.
- EXAMPLE 9 This example shows analgesic testson rats by the tail flick test as described in Example 1. Predetermined dosages of methyl 2,2-dimethyl-3-(l-piperidyl)cyclobutanel-carboxylate-HCI were administered orally to rats. Five animals were used with each dosage level. The results are given in Table 7 as the average time in seconds for the pain response of the animals in each group.
- EXAMPLE 10 This example shows analgesic tests on rats by the tail flick test as described in Example 1. The tests were performed with the following nine compounds which were administered orally to rats.
- Table 8 shows the increase in analgesic effect over control values for each compound at various time intervals and also at The dosages are expressed in milli grams of the active compound per kilogram weight of the animal.
- the time at which the animals were tested after the administration of the analgesic is given in Table 8. Values are also shown for aspirin and codeine which were run by the same method.
- the control value represents the time required fora tail flick by the rats when tested by the method of Example 1 but when no analgesic is given to .the animal.
- the control value is about 4.3
- Table 8 Increase in analgesic Compound Dose, Time, effect over rug/kg. minutes control values, seconds 1 0.7 sec. at 20 7
- Table 9 Time in minutes after administration of analgesic. 40 60 Time requiredin seconds for pain response of am malstested 4.0 6.9 6.8 6.0 5.7 4.8 4.4
- novel therapeutic compounds of this invention can be produced by a number of methods.
- they can be produced by reacting a suitably substituted ketene, preferably in a polar solvent, with an unsaturated ester.
- the cyclic ketone so produced can be reduced to the alcohol, the alcohol converted into the bromide and the bromide treated with a suitable secondary dialkyl amine.
- a preferred method is by reacting enamines, such as those derived from secondary amines and aldehydes containing one alpha-hydrogen atom, with certain substituted olefins. This reaction can be illustrated by the following equation:
- the molar proportion of the enarnine reactant to the electronegative group-containing olefin reactant can be widely varied as the cyclobutane derivative product can be readily separated from excess or unreacted reactants. However, substantially stoichiometric amounts of the reactants are more generally utilized in accordance with usual chemical practice.
- Enamines such as N,N-dimethylisobutylenylamine react with equal molar proportions of such olefins as methyl acrylate as represented by the following equation:
- reaction of enamines and the substituted olefins to prepare the cyclobutane derivatives proceeds readily in the absence ott added catalyst materials.
- the reaction can be conveniently effected by merely combining the reactants at room temperature.
- the olefinic compound reactants having nitro groups as the electronegative group are particularly reactive at ambient or even depressed ternperat'ures in the present reaction.
- Reaction temperatures up to the decomposition of the reactants or the reaction product can be used, although reaction temperatures in the range of about 0 C. to 200 C. are more usually used, with elevated temperatures in the range of about 50 C. to 190 C. oftentimes utilized to facilitate the reaction.
- Typical reaction times vary from a few minutes to 20 hours depending mainly on the reaction temperature and the reactants employed.
- reaction is conveniently efiected under atmospheric pressure, although higher pressures or even subatmospheric pressures can be utilized.
- subject reaction can be effected in the absence of a solvent although a solvent that is substantially inert to the reactants and the reaction product can be utilized if desired.
- the reaction of the described enamines and olefins containing electronegative groups proceeds in high yields to form the described cyclobutane derivatives.
- the cyclo butane derivative product can be worked-up or purified by conventional purification methods, the preferred method varying with the properties of the pro-duct.
- Particularly effective purification methods include fractional distillation under reduced pressure and fractional crystallization from solvents.
- other purification methods such as solvent extraction, chromatographic adsorption and the like can also be utilized.
- EXAMPLE 12 A mixture of N-isobutenylpiperidine (69.5 g., 0.5 mole) and acrylonitrile (26.5 g., 0.5 mole) was heated in an autoclave for 2 hours at C. Distillation of the reaction mixture gave 3.5 g. of acrylonitrile, 17 g. of N-isoibutenylpiperidine, and 59.5 g. (62% conversion) of 3,3- dimethyl-2-(l-piperidyl)cyclobutanecarbonitrile, B.P. 94- 99 C. at 1.8-2.0 mm., N 1.4780.
- EXAMPLE 16 A mixture of N,N-dimethylisobutenylamine (297 g., 3 moles) and acrylonitrile (159 g., 3 moles) was heated for two hours at 170 C. in an autoclave. Distillation of the reaction mixture gave, after removal of unreacted starting materials, 292 grams (64% yield) of 3,3-dimethyl-2-dimethylaminocyclobutanecarbonitrile, B.P. 44-45 C. at ca. 1 mm., N Q 1.4531.
- EXAMPLE 18 A mixture of N,N-dimethylisobutenylamine (28 g., 0.283 mole) and methyl vinyl sulfone (28 g., 0.264 mole) was heated at atmospheric pressure. When the temperature reached 90 C., the mixture became homogeneous. The temperature was raised over a two-hour period to 160 C., and the reaction mixture was then distilled to give 49 grams (91% yield) of N,N-2,2-tetramethyl-4- methylsulfonylcyclobutylamine, B.P. 100-103 C. at 0.5- 0.6 mm. The product crystallized in the receiver and meltedat 8586 C.
- EXAMPLE 20 A mixture of N-isobutenylpiperidine (208.5 g., 1.5 moles) and diethylmaleate (322.5 g., 1.87 moles) was heated at 150 C. for hours. Distillation of the reaction mixture gave, after removal of unreacted starting materials, 274 g. of the diethyl ester O f 3,3-dimethyl-4-(1- piperidyl)cycbbutane-LZ-dicarboxylic acid, B.P. 113- 1.2-0 C. at 1.0-1.5 mm., N 1.4663.
- EXAMPLE 21 A one mole proportion of N-(2-ethyl-1-butenyl)piperidine was reached with a one mole proportion of methyl acrylate for 2 hours at 170 C. in an autoclave. The resulting reaction product was distilled to separate the cyclobutane derivative, methyl 3,3-diethyl-2-(1-piperidyl)cyclobutanecarboxylate, B.P. l19-121 C. at 2 mm., N "v EXAMPLE 22 A one mole proportion of 1,4-diisobutenylpiperazine and a two mole proportion of methyl acrylate were reacted for 2 hours at 170 C. in an autoclave.
- EXAMPLE 24 A one mole proportion of N,N-di-n-butylisobutenylamine was reacted with a one mole proportion of methyl acrylate for 2 hours at 170 C. in an autoclave. The resulting reaction product was distilled to separate the cyclobutane derivative, methyl 3,3-dimethyl-2-di-n-butylarninocyclobutanecarboxylate, B.P. 98 C. at ca. 1.5 mm., N 1.4543. r A
- EXAMPLE 25 A one mole proportion of N ,N-diisobutylisobutenylamine was reacted with a one mole proportion of methyl acrylate for 2 hours at 170 C. in an autoclave. The resulting reaction product was distilled to separate the cyclobutane derivative, methyl 3,3-dimethyl-2-diisobutylamino cyclobutanecarboxylate, B.P. 93-100 C. at ca. 2 mm., N 1.4510.
- Typical enamines used to prepare the present cyclobutane derivatives by the preferred method can be prepared by the methods described below.
- EXAMPLE 29 EXAMPLE 30 Over a 2-hour period isobutyraldehyde (400 g., 5 moles) was added to piperazine (172 g., 2 moles) at 35- 40 C. The mixture was stirred and refluxed under a Dean-Stark trap for 7 hours, during which time 74 ml.
- An analgesic composition in unit dosage form comprising a significant quantity of a pharmaceutical carrier and from about 0.1 grain to about 25 grains of a member selected from the group consisting of a cyclobutane derivative and a non-toxic acid addition salt of said cyclobutane derivative wherein the cyclobutane derivative can be represented by the following generic formula:
- each of A and A is a lower alkyl radical
- each of'R, R R and R is a member selected from the group consisting of hydrogen, a lower alkyl radical, the phenyl radical, the nitro radical, a lower alkyl sulfonyl radical, the cyano radical, a lower alkyl ester, and a lower 'alkyleneamino radical, provided that at least one of R, R R and R is the phenyl, the nitro, a lower alkyl sulfonyl, the cyano, a lower alkyl ester, and a lower alkyleneamino radical;
- R is a member selected from the group consisting of hydrogen and a lower alkyl radical having from 1 to 2 carbon atoms; and
- X is tertiary amino radical selected from the group consisting of a lower dialkylamino, the piperazino, the piperidino, the
- An analgesic composition in unit dosage form comprising a significant quantity of a pharmaceutical carrier and from about 0.1 grain to about 25 grains of a cyclobutane derivative having the following generic formula:
- An analgesic composition in unit dosage form comprising a significant quantity of a pharmaceutical carrier and from about 1 to about grains of a non-toxic acid addition salt of diethyl 3,3-dimethyl- Ldimethylaminocyclobutane-1,2-dicarboxylate.
- An analgesic composition in unit dosage form comprising a significant quantity of a pharmaceutical carrier and from about 1 to about 10 grains of a non-toxic acid addition salt of methyl 3,3-dimethyl-2-dimethylaminocyclobutane-l-carboxylate.
- An analgesic composition in unit dosage form comprising a significant quantity of a pharmaceutical carrier and from about 1 to about 10 grains of a non-toxic acid addition salt of N,N,2,Z-tetramethyl-4-methylsulfonylcyclobutylamine.
- An analgesic composition in unit dosage form comprising a significant quantity of a pharmaceutical carrier and from about 1 to about 10 grains of a non-toxic acid addition salt of 2,2-dimethyl-3-(1-piperidyl)cyclobutanecarbonitrile.
- An analgesic composition comprising from about 1 to about 10 grains of a member selected from the group 18 v consisting of diethyl 3,3-dimethyl-4-dimethylaminocyclobutane 1,2-dicarboxylate and a non-toxic acid addition salt thereof, and aspirin in a quantity varying from about 0.25 to 4 times the quantity of said cyclobutane derivative.
- a method for inducing analgesia which comprises administering to an animal, including a human, an analge'sically eifective quantity of a member selected from the group consisting of a cyclobutane derivative and a nontoxic acid addition salt of said cyclobutane derivative wherein the cyclobutane derivative can be represented by the following generic formula:
- a R r tina RML R wherein each of A and A is a lower alkyl radical; each of R, R R and R is a member selected from the group consisting of hydrogen, a lower alkyl radical, the phenyl radical, the nitro radical, a lower alkyl sulfonyl radical, the cyano radical, a lower alkyl ester, and a lower alkyleneamino radical, provided that at least one of R, R R and R is the phenyl, the nirto, a lower alkyl sulfonyl, a lower alkyleneamino, the cyano and a lower alkyl ester radical; R is a member selected from the group consisting of hydrogen and a lower alkyl radi cal having from 1 to 2 carbon atoms; and X is a tertiary amino radical selected from the group consisting of a lower dialkylamino, the piperazino, the piperidino, the morpholin
- a method for inducing analgesia which comprises adminstering to an animal, including a human, an analgesically eifective quantity of a cyclobutane derivative having the following generic formula:
- each of A and A is a lower alkyl radical having from 1 to 2 carbon atoms; R and R is a carbalkoxy radical having from 1 to 3 carbon atoms in each alkoxy chain; and X is a dialkylamino radical having from 1 to 2 carbon atoms in each alkyl chain.
- a method for inducing analgesia which comprises administering to an animal, including a human, from about 1 to about 10 grains of a non-toxic acid addition salt of diethyl 3,3-dimethyl-4-dimethylaminocyclobutane- 1,2-dicarboxylate.
- a method for inducing analgesia which comprises administering to an animal, including a human, from about 1 to about 10 grains of a non-toxic acid addition salt of methyl 3,3-dimethyl-2-dimethylaminocyclobutanel-carboxylate.
- a method for inducing analgesia which comprises administering to an animal, including a human, from about 1 to about 10 grains of a non-toxic acid addition salt of N,N,2,2-tetramethyl-4 methylsulfonylcyclobutylamine.
- a method for inducing analgesia which comprises administering to an animal, including a human, from about 1 to about 10 grains of a non-toxic acid addition salt of 2,2-dimethyl-3-(1-piperidyl)cyclobutanecarbonitrile.
- a method for inducing analgesia which comprises administering to an animal, including a human, from about 1 to about 10 grains of a cyclobutane derivative selected from the group consisting of diethyl 3,3-dimethyl- 4-dimethylaminocyclobutane 1,2-dicarboxylate and a non-toxic acid addition salt thereof and aspirin, the quantity of aspirin being about 0.25 to 4 times that of the cyclobutane derivative.
- a method for inducing analgesia which comprises 19 administering to an animal, including a human, an analgesically eifective quantity of a cyclobutane derivative selected from the group consisting of diethyl 3,3-dimethyl- 4-dimethylaminocyclobutane 1,2-dicarboxy1ate and a nontoxic acid addition salt thereof and codeine.
- a method for inducing analgesia which comprises administering to an animal, including a human, an analgesically effective quantity of a non-toxic acid addition salt of 1-(2,2-dimethyl-4-nitro-3-phenylcyclobuty1)piperidine.
- a method for inducing analgesia which comprises administering to an animal, including a human, an analgesically efiective quantity of a non-toxic acid addition salt of 2,2 dimethyl-3-( l-piperidyl)-cyclobutylmethylamine.
- a method for inducing analgesia which comprises administering to an animal, including a human, an analgesically effective quantity of a non-toxic acid addition salt of 2-dimethylarr1ino-3,3-dimethylcyclobutanecarbonitrile.
- a method for inducing analgesia which comprises administering to an animal, including a human, an analgesically effective quantity of a member selected from the group consisting of bis(4-methoxycarbonyl-2,2-dimethylcyclobutyl)-piperazine and a non-toxic acid addition salt thereof.
- a method for inducing analgesia which comprises administering to an animal, including a human, an analgesically eifective quantity of a non-toxic acid addition salt of methyl 3,3-dimethyl-2-morpholinocyclobutane-1- carboxylate.
- a method of inducing analgesia which comprises administering to an animal, including a human, an analgesically eifective quantity of a member selected from the group consisting of Z-(thiomorpholino)-2-ethyl-3- wherein each of A and A is' an alkyl having from 1 to 2 carbon atoms; R is a carbalkoxy radical having from '1 to 3 carbon atoms in the alkoxy portion; and X is a dialkylamino radical having from 1 to 2 carbon atoms in each alkyl chain.
- a method for inducing analgesia which comprises administering to an animal, including a human, an analgesically effective quantity of a cyclobutane derivative of the formula:
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Description
United States Patent 3,051,622 ANALGESIC CYCLOBUTANES Samuel Kuna, Westfield, and Anthony W. Pircio, East Brunswick, N.J., assignors to Bristol-Myers Company, New York, N.Y., a corporation of Delaware No Drawing. Filed Nov. 25, 1959, Ser. No. 855,285 26 (Ilaims. (Cl. 16765) This invention relates to therapeutic compositions. More specifically, this invention relates to compositions which possess analgesic activity and which show indications of antihalucinatory and anticonvulsive activity.
In the past a large number of substances have been used to produce analgesic action. All of the prior art analgesics have suffered from one or more serious disadvantages. Some of the substances employed are strong narcotic or toxic agents and give rise to addiction or deleterious side efifects such as respiratory depression, pruritis, constipation, nausea, sphincter constriction, sedation and euphoria. Others are only slightly effective and give no relief against deep-seated and pronounced pain. Still others are absorbed only slowly from the alimentary canal and require a prolonged period and large dosages before their action is eifective. Still other substances require an aryl substituent in the molecule and give irritation on parenteral injection or have a low therapeutic ratio.
It has now been found that excellent analgesic activity is obtained by the administration of cyclobutane derivatives wherein one carbon atom of the cyclobutane ring is substituted by two lower alkyl radicals, a second ring carbon atom has one of its valences satisfied by a tertiary amine and the remaining valence of the second carbon atom is satisfied by hydrogen or a lower alkyl radical and wherein at least one of the third and fourth carbon atoms of the cyclobutane ring contains at least one electronegative group as hereinafter disclosed with the remaining valences of the third and fourth ring carbon atoms being satisfied by hydrogen or lower alkyl radicals.
The cyclobutane derivatives of this invention possess many advantageous properties when used as analgesics. Although some of the advantageous analgesic properties of the active ingredients are dependent on the particular compound selected, the advantageous analgesic properties include: greater therapeutic efiect than known non-prescriptive types of analgesics such as aspirin, phenacetin or salicylamide; absence of deleterious side effects, e.g., respiratory depression, vomiting, constipation, sedation, euphoria and pruritis as are produced by narcotic types of analgesics; good tolerance and less toxicity than many other analgesics presently available; a more favorable therapeutic ratio than codeine; absence of imitation on parenteral injection; the attainment of a maximum analgesic potency value with relatively small quantities of the analgesic wherein the potency value is not significantly increased by the administration of larger quantities; good analgesic effect even when the molecule of the active compounds does not contain the usual aromatic constituents; no physical dependency upon withdrawal; rapid absorption from the alimentary canal and a rapid analgesic effect. Illusti'atively, diethyl 3,3-dimethyl-4-dimethylaminocyclobutane-1,2-dicarboxylate-HCl; one of the compounds of this invention is relatively non-toxic (e.g. LD 50 of oral dosages of about 3000 mg./kg. of animal weight in mice, greater than 12,000 mg/kg. of animal weight in rats and greater than 3000 mgjkg. of animal weight in rabbits, cats and dogs); has a very favorable therapeutic ratio, e.g., better than that of codeine; exhibits synergistic analgesic efiects with conventional analgesics containing an aromatic ring, e.g., aspirin, morphine etc.; not antagonized by Nalline (N allynormorphine) but gives an increased analgesic efiect with Nalline; gives no physical dependence upon withdrawal; shows ice no deleterious side effects; shows no apparent cumulative toxicity; produces analgesia in the range of the less potent narcotics such as codeine and 2-propionoXy-4-dimethylamino-1,2-diphenyl-3-methylbutane hydrochloride; shows an absence of respiratory depression and in fact this compound stimulates respiration; permits the attainment of a level of analgesia which is not significantly increased by the administration of larger dosages and the animals treated with the compound show very rapid recovery from toxic signs exhibited following administration of large dosages. Illustrative of specific advantageous properties for methyl 3,3-dimethyl-Q-dimethylaminocyclobutane-lcarboxylate, another active compound of this invention, there can be mentioned; low toxicity (even more favorable than that of the above discussed diester compound); a very favorable therapeutic ratio (e.g. better than that of codeine); an absence of antagonism by Nalline; no apparent cumulative toxicity; analgesia in the potency range of the less active narcotics such as codeine and 2- propionoxy 4 dimethylamino 1,2 diphenyl-S-methylbutane hydrochloride; no deleterious side eifects; an absence of physical dependence upon withdrawal; an absence of respiratory depression and in fact an increase in respiration; and the animals treated with this compound show a very rapid recovery from toxic signs exhibited following administration of large dosages. This mono-ester compound gives very much of a straight line dose response, providing increased analgesic activity on increased dosage levels, particularly dosage levels above mg./kg., whereas the diester compound reaches a peak of activity at a dosage level of about 100 mg./kg. and the activity is not significantly increased by larger dosage levels above that amount.
A preferred class of the analgesicly active cyclobutane derivatives can be represented by the following generic formula:
A R ii -him R4- -('JR i la wherein A is a lower alkyl radical; A is a lower alkyl radical; R is hydrogen, an electronegative radical as hereinafter disclosed or a lower alkyl radical; R is hydrogen, a lower alkyl radical or an electronegative radical as hereinafter disclosed; R is hydrogen, an electronegative radical as hereinafter disclosed or a lower alkyl radical; R is hydrogen, a lower alkyl radical or an electronegative radical as hereinafter disclosed; provided that at least one of R, R R or R is an electronegative radical as hereinafter disclosed; X is a tertiary amine radical and R is hydrogen or a lower alltyl radical. By the terms lower alkyl radical or lower alkyl group we mean an alkyl radical containing from 1 to 6 carbon atoms, e.g., methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, etc. The lower alkyls having from 1 to 2 carbon atoms are preferred. By the term tertiary amine radical we mean a radical of the ammonia molecule wherein the hydrogen atoms have been replaced by three radicals. The tertiary amine can be a lower allcyl amine, cycloaliphatic amine, an aryl amine or a saturated cyclic amine wherein the ring contains elements such as sulfur or oxygen in addition to nitrogen and carbon. Illustrative of amine radicals there can be mentioned: those of lower alkyls, e.g., dimethyl, diethyl, dipropyl, 'diisopropyl, diisobutyl, methyl ethyl amine, methylisopropylamine, ethyl tertiar butylamine and the like; cyclic including substituted alicyclic amines, e.g., piperazino, piperidino, morpholino, thiomorpholino and the like. It is preferred that the amine be a dialkyl amine having from 1 to 2 carbon atoms in each alkyl radical and that the nitrogen be bound directly to a ring carbon atoms of the cyclobutane. The electronegative radicals or groups satisfactory in the compounds of this invention are: phenyl and substituted phenyls, nitro, lower alkyl sulfonyl, cyano, lower alkyl esters, and lower. alkyleneamino radicals. However, the compound is inactive if the group is capable of dissociation into two fragments, one carrying a formal negative charge attached to the cyclobutane ring and a free positive fragment. Illustrative of the sulfonyl radical (-'SO -R) there can be mentioned: methyl sulfonyl, ethyl sulfonyl, propyl sulfonyl, isopropyl sulfonyl, butyl sulfonyl, isobutyl sulfonyl and the like. Illustrative of ester groups there can be mentioned: the .carbomethoxy, carboethoxy, carbopropoxy, carboisopropoxy, carbobutoxy, carboisobutoxy and the like. It is preferred that the alkyl portion of the carbalkoxy radical be one having from 1 to 3 carbon atoms. In addition to the esters formed by the reaction of 'a carboxylic acid of cyclobutane with a lower alkyl alcohol it has been found that the reduction of a cyclo butane carboxylic acid to a cyclobutyl methyl alcohol and subsequent reaction of the alcohol with a lower alkyl acid also produces a therapeutically active and equivalent compound. Illustrative of such esters formedfrom a cyclobutyl methyl alcohol and a lower alkyl acid there can be mentioned those wherein the following radicals are attached directly to one of the ring carbons:
' The more preferred analgesicly active compounds of this invention can be represented by the following generic formula:
wherein A, A, R, R and X are the same radicals as discussed for the preferred generic formula and provided that at least one of R and R is an elcctronegative group as hereinabove disclosed. The preferred electronegative group is that of lower alkyl carbalkoxy radicals particularly when the alkyl contains from 1 to 3 carbon atoms. It is also preferred that when only one of R and R is an electronegative group that the remaining R and R be hydrogen.
Either the cyclobutane derivatives of this inventionor their acid addition salts can be administered by the conventional methods, the conventional types of unit dosages or with the conventional pharmaceutical carriers to produce an analgesic effect in human beings and animals. Conventional methods of administration of the analgesics include oral or parenteral administration. Oral administration by the use of tablets or capsules or in liquid form such as suspensions, solutions or emulsions is particularly advantageous since the novel analgesics are rapidly absorbed from the gastrointestinal tract. When formed into tablets, the conventional binding and disintegrating agents used in analgesic unit dosages can be used. illustrative of binding agents there can be mentioned: glucose, gum acacia, gelatin and starch paste. Illustrative of disintegrating agents there can be mentioned: corn starch, keratin and potato starch. When administered as liquids the conventional liquid carriers can be used.
' The acid addition salts are formed by the conventional techniques of neutralizing the amine portion of a com- ,poundwith either an'organic or inorganic acid." Illustrative of the acids there can be mentioned: hydrochloric, sulfuric, citric, acetic, malonic, maleic and phosphoric acids. The novel analgesic compounds of this invention can be administered in combination with other analgesics particularly those containing an aromatic nucleus. Such combination of some of the novel analgesic compounds with an aromatic nucleus analgesic can produce a synergistic analgesic effect. Illustrative of analgesics containing an aromatic nucleus which produce synergistic effects with the cyclobutane derivatives there can be mentioned: aspirin and its salts such as those of the alkali metal or alkaline earth metal salts, e.g., sodium, potassium, calcium and magnesium; salicylic acid and its salts such as those of the alkali metal or alkaline earth metal salts, e.g., sodium, potassium, calcium and magnesium; D- propoxyphene'HCl, codeine phosphate and morphine sulfate.
The unit dos-age or analgesicaily effective quantity of the cyclobutane derivatives for human beings can vary over wide limits such as that of about 0.1 of a grain to about 25 grains or more such as 100 grains. The upper limit is limited only by the degree of effect desired and economic considerations. For oral administration it is preferable to employ from aboutl to about 10 grains per unit dosage. When administered parenterally, it is preferable to employ about 0.10 to about 2 grains. Each unit dosage form of the novel therapeutic compounds can contain from about 1% to about 95% and preferably from about 5% to 80% of the novel analgesic agent by weight of the entire composition with the remainder comprising conventional pharmaceutical carriers and option ally other analgesics such as By the term pharmaceutical carrier we intend to include non-analgesic materials which are conventionally used with analgesics and includes fillers, diluents, binders, lubricants, disintegrating agents and solvents. When it is desired to use the novel analgesics in combination with a conventional analgesic containing an aromatic nucleus, the quantity of the conventional aromatic analgesic used in combination with the cyclobutane derivative is not critical and can vary from 0.05 to 10 times'the weight of novel analgesic employed depending on the conventional analgesic employed. Thus with aspirin it is preferable to use between about .25 to about 4 times the weight of the novel analgesic. Of course, it is possible to administer the novel analgesics, e.g., the pure compounds or their acid addition salts, without the use of a pharmaceutical carrier.
EXAMPLE A A suitable formulation of tablets consists of:
' Grams (1) The citric acid salt of diethyl 3,3dimethyl-4-digmethylaminocyclobutane-1,2-dicarboxylate 12.5 (2) Lactose 1 30 (3) Starch 5 (4) Magnesium stearate 2 The citric acid salt of diethyl 3,3-dimethyl-4-dimethylamino-cyclobutane1,2-dicarboxylate, lactose, and starch are thoroughly mixed and granulated. For tableting, the magnesium stearate is added, mixed with the granules, and the mixture tableted on a rotary press. Use of this procedure produces tablets each containing mg. of the active analgesic. salt.
The hydrochloride Salt of methyl 3,3-dimethy1-2-dimethylammo-cyclobutane-l-carboxylate, mannitol and starch are thoroughly mixed and granulated. For-tableting, the magnesium stearate is added, mixed with granules, and the mixture tableted on a rotary press. Use of this procedure produces 100 tablets each containing 250 mg. of the active analgesic salt.
EXAMPLE C Another suitable formulation of tablets consists of: Grams 1 1,4-bis (4-oarbmethoxy-2,Z-dirnethylcyclobutyl) piperazine 25 (2) b-Lactose 20 (3) Dextrin l (4) Hydrogenated vegetable oil 0.5 (5) Talc 2 The 1,4 bis(4-carbmethoxy-2,Z-dimethylcyolobutyl)- piperazine, b-lactose, and dextrin are thoroughly mixed and granulated. For tableting, the hydrogenated vegetable oil and talc are added, mixed with the granules, and the mixture tableted on a rotary press. Use of this procedure produces 200 tablets of 125 mg. of active analgesic.
EXAMPLE D Another suitable formulation of tablets consists of preparing tablets by the conventional techniques wherein each tablet comprises:
Grams (l) The citric acid salt of diethyl 3,3-dimethyl-4- dimethylaminocyclobutaned,2-dicarb0Xy1ate 0.550 (2) Starch corn (U.S.P.) 0.065 (3) Talc (U.S.P.) 0.015 (4) Micronized Mico-Cal-C 0.015 (5) Magnesium stearate 0.005
Total EXAMPLE E A suitable formulation of oral elixir consists of: (l) The phosphoric acid salt of N,N,2,2-tetramethyl-4-methylsulfonylcyclobutylamine grams" (2) Aromatic elixir base to make "liters-.. Base contains: orange spirits, sugar syrup,
ethyl alcohol, and distilled water.
Use of the above formula Will make 100-pint bottles of oral elixir. Each bottle contains approximately 100 one-teaspoon doses. Each dose contains 50 mg. of active analgesic salt.
EXAMPLE F An illustrative example of preparing solutions for injection consists of placing 300 milliliters of distilled water for injection, U.S.P., in a two-liter Pyrex flask, and adding 7.5 grams of the hydrochloride salt of diethyl 3,3 dimethyl-4-dimethylaminocyclobutane-1,2-dicarboxylate With stirring until solution is effected. The pH is then adjusted with N/ sodium hydroxide to a pH of approximately 6.0. Sufficient Water for injection is added to make the volume to 1 liter. The solution is filled into clean, dry l-cc. ampules and the ampules are sealed and sterilized.
EXAMPLE G A suitable formulation of tablets consists of:
Grams (l) The citric acid salt of diethyl 3,3-dimethy1-4- dimethylaminocyclobutane-l,Z-dicarboxylate 50 (2) Aspirin 50 (3) Lactose 16 (4) Starch 10 (5) Magnesium stearate 4 The citric acid salt of diethyl 3,3-dimethyl-4-dimethyl- CH H Methyl 3,3-dimethyl-2-dimethylaminocyclobutane-1- carboxylate Methyl 2,2-dimethyl-3-dimethy1aminocyelobutane-lcarboxylate Diethyl 3,3-dimethyl4-dimethylaminocyc1obutane-1,% dicarboxylate has it Dlmethyl 3-3-dimethy1-4-dimethylamlnocyclobutane-LZ- dicarboxylate Methyl 2,2-dlmethyl-3- (l-piperidyl) -cyclobutane-1- dicarboxylate I H H3 H3 1,4-bis (4-carbmethoxy-2,2rdimethylcyclobutyl) -piperazine Jamil H N,N-2,2-tetramethy1-4-methy1sn1fony1cyclobutylamine 2,2-dimethyl-3- (l-pip eridyl) -cyc1obuty1methy1amine 1- (2,2-dimethyl-4-nitro-3-phenylcyclobutyl) -piperidine raz- Methyl 3,3-diethy1-2- (l-piperidyl) -cyc1obutane-1-carb0xylate 2,2-dimethy1-3- (l-piperidyl) cyclobutanecarbonitrile C2H5 'H CHa--CH: r I
3 1 3 3 Z-(N-ethyl N-propyl amino)-2-methyl-3-methyl-3ethyl-4- methyl-1-methy1-1-carbmethoxycyclobutane C H (IN 0 2-d1methylamino-2-isopropy1-3-methy1-3-bntyL4-cyano-4- carbmethoxy-1-carbeth0xy-l-methylsulfonylcyclobutane ll C-O-CH:
lit
2- (4-methylpiperazino) -3,3-dimethy1-4,4-d1carbmethoxy-1- 1 carbpropoxy cyclobutane a 2-carbethoxy-3,3-dimethyl--cyano-l-dimethylaminocyclobutane I C H3 0 H3 2,2,4,4-tetramethyl-3-dimethy1amino-1-methyl-1- carbmethoxycyclobutane In addition to 'the above illustrated compounds the following can also be mentioned:
Z-dimthylamino-lS-dimethyl l-methyl-lcarbmethoxycyclobutane;
2-dipropylamino-3,3-dimethyl-4-methyl-4-carbethoxy-1- methyl-l-carbethoxycyclobutane;
2,2-diethyl-3-piperidinocyclobutylmethylamine;
Z-dimethylamino-3,3-dimethyl-4-ethyleneamino1-1 carbethoxycyclobutane;
tetramethyl-4,4-dimethyl-3-dimethylaminocyclobutane- 1,1,2,2-tetracarboxylate;
and the like.
EXAMPLE 1 This example shows analgesic eifect on rats by the tail 'flick'test. This test is performed by uniformly blackening the tails of rats, administering an analgesic to the animal and subsequently focusing a beam of light on the animals tail at various intervals after administration of the analgesic. The time required for the animal to flick its tail after the beam of light is applied determines the analgesic efiect of'the material being tested. The longer the interval for the tail flick, after the application of the concentrated beam of light, the more effective is the analgesic. Predeterrnined dosages of diethyl 3,3-dimethyl- 4 dimethylaminocyclobutane-1,2-dicarboxylate-HCl, D- propoxyphene-HCI and'the very strong narcotic types of analgesics such as morphine sulfate and codeine phosphate were given to rats. Each material was administered orally to sets of fiteen animals except for morphine sulfate which was given subcutaneously to fifteen animals and codeine phosphate which was given orally to twenty-five anirnals. The following quantities of each material were used: morphine sulfate, 1.5 milligrams per kilogram weight of each animal; D-propoxyphene-HCI,
25 milligrams per kilogram weight of each animal; codeine phosphate, 40 milligrams per kilogram weight of each animal; and diethyl 3,3-dimethyl-4-dimethylaminocyclobutane-1,2-dicarboxylate-HCl, 100 milligrams per kilogram weight of each animal. The time in seconds during which the animals could tolerate the concentrated beam of light at various intervals after administration of the analgesics is given in Table 1. The values in the table are averages for the animals in each set.
1 Immediately prior to administration of analgesic.
Table 1 shows that an oral dose of 100 mg. of the cyclobutane compound per kg. Weight of the animal is equivalent in analgesic potency to oral doses of either 25 mg./kg. of D-propoxyphene-HCI or 40 mg./kg. of codeine phosphate and to a subcutaneous dose of 1.5 mg./ kg. of morphine surfate.
EXAMPLE 2 This example shows the analgesic dose response of diethyl 3,3-dimethyl-4-dimethylaminocyclobutane-1,2-dicarboxylate'HCl on rats by the tail flick method as described in Example 1. The cyclobutane compound Was administered orally to all the animals. Four difierent dosages were used wherein 350 milligrams per kilogram weight of animal was administered to five rats; 175 milligrams per kilogram weight of animal was administered to fifteen rats; 100 milligrams per kilogram weight of animal was administered to fifteen rats; and twenty-five additional rats were administered 50 milligrams per kilogram weight of animal. The time required for the rats to flick their tails after the concentrated beam of light was focused thereon at various intervals of time is given in Table 2. Average readings for the animals of each dosage group is also given in the table.
1 Immediately prior to administration of analgesic.
It can be seen from Table 2 that large quantities of the cyclobutane compound do not give a proportionally high analgesic eifect and that above certain quantities the increase in analgesic effect is not significant but the duration of activity is somewhat increased.
EXAMPLE 3 This example shows potentiation of diethyl 3,3-dimethyl 4 dimethylaminocyclobutane 1,2 dicarboxylate-HCl with Nalline and the antagonistic elfect of Nalline with morphine sulfate. The rat tail flick test as described in Example 1 was employed. Two sets of fiive rats in each set were given 175 mg. of diethyl 3,3- dimethyl 4 dimethylaminocyclobutane 1,2 dicarboxylate-HCI per kg. of animal weight. Two sets of five rats in each set were subcutaneously injected with 2 mg. of morphine sulfate per kg. weight of each animal. Tail flick determinations were made for 20 minutes after administration of the two analgesics after which 1 mg.
of Nalline per kg. weight of each animal was subcutaneously administered to the rats of one set which had been treated with morphine sulfate and one set which had been treated with diethyl 3,3-dimethyl-4-dirnethylaminocyclobutane-1,2-dicarboxylate-HC1. The results of this test are shown in Table 3 wherein the average time for a tail flick is reported in seconds for each group.
Table 3 Time in minutes after administration of an ina it- 1 Immediately prior to administration of analgesic.
It can be seen from the Table 3 that the addition of Nalline caused a potentiation of diethyl 3,3-dimethyl-4- dimethylaminocyclobutane-1,2-dicarboxylate HCl whereas it antagonized the morphine sulfate.
EXAMPLE 4 This example shows that diethyl 3,3-dimethyl-4-dimethylaminocyclobutane-1,2-dicarboxylate hydrochloride is non-irritating on parenteral injection. Intradermal skin irritation tests were conducted on rabbits using the Trypan Blue method. Concentrations of 1.0%, 5.0% and 10.0% of the HCl salt of the diethyl ester were injected intradermally in a volume of 0.3 cc. A different skin area was used for each concentration. A control area was treated with a similar volume of physiological saline.
Immediately following the injection of the test drug, 1.0 cc. of a 1.0% solution of Trypan Blue per kilogram was administered intraveneously. Observations were made for the degree of localization of the dye at 3, 24, 48 and hours after drug treatment. No signs of accumulation of dye were evident in those areas treated with 1.0% of the drug or saline. Definite localization of dye was noted at the areas treated with 5.0% and 10.0% of diethyl 3,3-dimethyl-4-dimethylaminocyclobutane-1,2-dicarboxylate-HC1. The dye had practically disappeared within 48 hours from the area treated with the 5.0% concentration, while some dye was still evident in the area treated with the 10.0% concentration. No signs of erythema, edema or other gross evidence of irritation were noted during the 160 hour treatment period.
EXAMPLE 5 This example shows the quantity of diethyl 3,3-dimethyl 4 dimethylarninocyclobutane 1,2 dicarboxylate-HCI required for an LD 50 in mice by different methods of administration.
Acute intravenous LD 50=125 mg./kg. of ani mal (5 mice per dose level for a total of 25 animals).
Acute intraperitoneal LD 50==700 mg./kg. of animal (10 mice per dose level for a total of 60 animals).
Acute subcutaneous LD 50= 2,000 mg./kg. of animal (10 mice per dose level for a total of 20 animals).
Acute oral LD 50:3,000 mg./kg. of animal (10 mice per dose level for a total of 50 animals).
It can be seen that diethyl 3,3-dimethyl-4-dimethylamin0- cyclobutane-1,2-dicarboxylate-I-IC1 has a relatively low order of toxicity.
'EXAMPLE6 This example shows subacute administration of diethyl 3,3 dimethyl 4 dimethylaminocyclobutane l,2 dicarboxylate-HCI to rats for a period of three weeks. Daily oral administrations ('6 times weekly) of the cyclobutane compound at dosage levels of 100, 300 and 500 mg./kg. were given to young rats for .a period of three weeks. Since a limited amount of material was available for these tests, only males received the 500 mglevel. Five animals of each sex were used on each dose level tested. No untoward effects orsigns of toxicity Were evident during this treatment period. On the basis of appetite, body weight, appearance and behavior, the treatment was well tolerated by all animals. Average body weights of males and females at each dose level during the conduction of the test are given in Table 4. All of the animals including the controls were of about the same age.
' 4 Table 4 SUBACUTE TOXICITY [Rat weights in grams] Similar to the studies in rats, daily doses of 100 and 300 mg. of diethyl 3,3-dimethyl-4-dimethylarninocyclobutane-1,2-dicarboxylate-HCl were administered orally per kilogram (6 times weekly) to mature male dogs for a period of three weeks. Two animals were used to test each dose level. No untoward side eflects such as vomiting or anorexia were evident in this study. Individual body weights of the experimental animals at each dose level are shown in Table 5.
Table 7 [Body weight of dogs in kg.]
Dog No. Dose Original First Second Third mg./kg weight week week week EXAMPLE 8 This example shows analgesic tests on rats by the tail flick test as described in Example 1. Predetermined dosages of methyl 3,3-dimethy1-4-dimethylaminocyclobutane-l-carboxylate'ficl were administered orally. to rats. IEach dosage level contained five animals and the results are given in Table 6 as the average time in seconds for the pain response of the animals in each dosage level.
Table 6 .Time in minutes after administration of analgesic 20 40 -Time required in seconds for pain response of animals tested with the following quantities of methyl 3,3'din1ethyl-2-dimethylaminocyclobutane-l-carboxylate H01:
100 mg. per kg 175 mg. per kg 1 Immediately prior to administration of analgesic.
It can be seen from Table 6 that the test compound of Example 8 possesses analgesic activity.
various dosages.
12 EXAMPLE 9 This example shows analgesic testson rats by the tail flick test as described in Example 1. Predetermined dosages of methyl 2,2-dimethyl-3-(l-piperidyl)cyclobutanel-carboxylate-HCI were administered orally to rats. Five animals were used with each dosage level. The results are given in Table 7 as the average time in seconds for the pain response of the animals in each group.
Table 7 Time in minutes after administration of analgesic. 20 40 Time required in seconds for pain response:
mg. per kg l 4.4 5.0 4. 3 200 mg. per kg 1 4. 4 5.0 4. 7
1 Immediately prior to administration of analgesic.
It can be seen from Table 7 that the test compound of Example 9 possesses analgesic activity.
EXAMPLE 10 This example shows analgesic tests on rats by the tail flick test as described in Example 1. The tests were performed with the following nine compounds which were administered orally to rats.
The results of the test are given in Table 8 which shows the increase in analgesic effect over control values for each compound at various time intervals and also at The dosages are expressed in milli grams of the active compound per kilogram weight of the animal. The time at which the animals were tested after the administration of the analgesic is given in Table 8. Values are also shown for aspirin and codeine which were run by the same method. The control value represents the time required fora tail flick by the rats when tested by the method of Example 1 but when no analgesic is given to .the animal. The control value is about 4.3
seconds.
Table 8 Increase in analgesic Compound Dose, Time, effect over rug/kg. minutes control values, seconds 1 0.7 sec. at 20 7 Table 9 Time in minutes after administration of analgesic. 40 60 Time requiredin seconds for pain response of am malstested 4.0 6.9 6.8 6.0 5.7 4.8 4.4
1 Immediately prior to administration of analgesic.
It can be seen from Table 9 that the test compound of Example 11 possesses rapid analgesic activity.
The novel therapeutic compounds of this invention can be produced by a number of methods. Thus they can be produced by reacting a suitably substituted ketene, preferably in a polar solvent, with an unsaturated ester. The cyclic ketone so produced can be reduced to the alcohol, the alcohol converted into the bromide and the bromide treated with a suitable secondary dialkyl amine. A preferred method is by reacting enamines, such as those derived from secondary amines and aldehydes containing one alpha-hydrogen atom, with certain substituted olefins. This reaction can be illustrated by the following equation:
wherein X is a tertiary amine group having the nitrogen bonded directly to the unsaturated starting material, R and R are lower alkyl groups, R is an electronegative group and R is an electronegative group or hydrogen atom.
The molar proportion of the enarnine reactant to the electronegative group-containing olefin reactant can be widely varied as the cyclobutane derivative product can be readily separated from excess or unreacted reactants. However, substantially stoichiometric amounts of the reactants are more generally utilized in accordance with usual chemical practice. Enamines such as N,N-dimethylisobutylenylamine react with equal molar proportions of such olefins as methyl acrylate as represented by the following equation:
CH One molar porportion of such enamines as 1,4-diisobutenylpiperazine react in the present process with 2 molar proportions of such olefins as methyl acrylate as repre- CH GE -CH; l
The reaction of enamines and the substituted olefins to prepare the cyclobutane derivatives proceeds readily in the absence ott added catalyst materials. The reaction can be conveniently effected by merely combining the reactants at room temperature. The olefinic compound reactants having nitro groups as the electronegative group are particularly reactive at ambient or even depressed ternperat'ures in the present reaction. Reaction temperatures up to the decomposition of the reactants or the reaction product can be used, although reaction temperatures in the range of about 0 C. to 200 C. are more usually used, with elevated temperatures in the range of about 50 C. to 190 C. oftentimes utilized to facilitate the reaction. Typical reaction times vary from a few minutes to 20 hours depending mainly on the reaction temperature and the reactants employed. However, longer or shorter reaction periods can be utilized. The reaction is conveniently efiected under atmospheric pressure, although higher pressures or even subatmospheric pressures can be utilized. The subject reaction can be effected in the absence of a solvent although a solvent that is substantially inert to the reactants and the reaction product can be utilized if desired.
The reaction of the described enamines and olefins containing electronegative groups proceeds in high yields to form the described cyclobutane derivatives. The cyclo butane derivative product can be worked-up or purified by conventional purification methods, the preferred method varying with the properties of the pro-duct. Particularly effective purification methods include fractional distillation under reduced pressure and fractional crystallization from solvents. However, other purification methods such as solvent extraction, chromatographic adsorption and the like can also be utilized.
The above described preferred method for making the compounds of this invention is illustrated by the following examples.
EXAMPLE 12 A mixture of N-isobutenylpiperidine (69.5 g., 0.5 mole) and acrylonitrile (26.5 g., 0.5 mole) was heated in an autoclave for 2 hours at C. Distillation of the reaction mixture gave 3.5 g. of acrylonitrile, 17 g. of N-isoibutenylpiperidine, and 59.5 g. (62% conversion) of 3,3- dimethyl-2-(l-piperidyl)cyclobutanecarbonitrile, B.P. 94- 99 C. at 1.8-2.0 mm., N 1.4780.
EXAMPLE 13 A mixture of N-isobutenylpiperidine (139 g., 1.0 mole) and methyl acrylate (86 g., 1.0 mole) was heated in an autoclave for two hours at C. Distillation of the reaction mixture gave, after removal of the unreacted methyl acrylate and N-isobutenylpiperidine, 157 g. (70% conversion) of the methyl ester of 3,3-dimethyl-2-(lpiperidyl) cyclobutanecarboxylic acid, B.P. 103 C. at 3.7 mm., N 1.4705.
EXAMPLE 14 To b-nitrostyrene (47.5 g., 0.32 mole) was added, N,N- dimethylisobutenylamine (33 g., 0.33 mole). The mixture was stirred manually and the temperature rose to 92 C. over a two-minute period and then began to drop slowly. After about 15 minutes the reaction mixture crystallized. It was triturated with hexane and filtered to give 74.5 g. (94% yield) of crude N,N-dimethyl-2,2- dimethyl 3 phenyl 4 nitrocyclobutyl amine, MP. 86- 91 C. On recrystallization from hexane the product melted at 9092 C. Analysis showed 67.91% carbon, 8.34% hydrogen and 11.49% nitrogen as compared to calculated values of 67.72% carbon, 8.11% hydrogen and 11.28% nitrogen.
EXAMPLE l5 Reacted as described in Example 14, a 0.32 mole portion of b-nitrostyrene and a 0.33 mole portion of N-isobutenylpiperidine gave a substantially quantitative yield of 1-(2,2-
15 dimethyl-4-nitro-3 -phenylcyclobutyl) piperidine, MP. 70- 72 C. Analysis showed 70.57% carbon, 8.52% hydrogen, and 9.67% nitrogen as compared to calculated values of 70.80% carbon, 8.39% hydrogen and 9.71% nitrogen.
EXAMPLE 16 A mixture of N,N-dimethylisobutenylamine (297 g., 3 moles) and acrylonitrile (159 g., 3 moles) was heated for two hours at 170 C. in an autoclave. Distillation of the reaction mixture gave, after removal of unreacted starting materials, 292 grams (64% yield) of 3,3-dimethyl-2-dimethylaminocyclobutanecarbonitrile, B.P. 44-45 C. at ca. 1 mm., N Q 1.4531.
EXAMPLE 18 A mixture of N,N-dimethylisobutenylamine (28 g., 0.283 mole) and methyl vinyl sulfone (28 g., 0.264 mole) was heated at atmospheric pressure. When the temperature reached 90 C., the mixture became homogeneous. The temperature was raised over a two-hour period to 160 C., and the reaction mixture was then distilled to give 49 grams (91% yield) of N,N-2,2-tetramethyl-4- methylsulfonylcyclobutylamine, B.P. 100-103 C. at 0.5- 0.6 mm. The product crystallized in the receiver and meltedat 8586 C. EXAMPLE 19 A mixture of N,N-dinethylisobutenylamine (82 g., 0.83 mole) anddiethylmaleate (172 g., 1 mole) was heated under reflux for 18 hours, during which time the temperature of the mixture rose from 105 C. to 162 C. 'Distillation of the reaction mixture gave, after removal of 'unreacted starting materials, 150.5 g. (67% yield) of diethyl ester of 3,3-dirnethyl-4-dimethylaminocyclobutane- 1,2-dicarboxylic acid (diethyl 3,3-dimethyl-4-dimethylaminocyclobutane-1,2-dicarboxylate), B.P. 93-94 C. at 1.5mm.,N 1.4502."
EXAMPLE 20 A mixture of N-isobutenylpiperidine (208.5 g., 1.5 moles) and diethylmaleate (322.5 g., 1.87 moles) was heated at 150 C. for hours. Distillation of the reaction mixture gave, after removal of unreacted starting materials, 274 g. of the diethyl ester O f 3,3-dimethyl-4-(1- piperidyl)cycbbutane-LZ-dicarboxylic acid, B.P. 113- 1.2-0 C. at 1.0-1.5 mm., N 1.4663.
EXAMPLE 21 A one mole proportion of N-(2-ethyl-1-butenyl)piperidine was reached with a one mole proportion of methyl acrylate for 2 hours at 170 C. in an autoclave. The resulting reaction product was distilled to separate the cyclobutane derivative, methyl 3,3-diethyl-2-(1-piperidyl)cyclobutanecarboxylate, B.P. l19-121 C. at 2 mm., N "v EXAMPLE 22 A one mole proportion of 1,4-diisobutenylpiperazine and a two mole proportion of methyl acrylate were reacted for 2 hours at 170 C. in an autoclave. The resulting reaction product was triturated with hexane and filtered to give the cyclobutane derivative, 1,4-'bis(4-methoxycarbonyl 2,2- dimethylcyclobutyl)-piperazine, M.P. 148 C. 7
16 EXAMPLE 23 A one mole proportion of N-isobutenylmorpholine was reacted with a one mole proportion of'methyl acrylate for 2 hours at 170 C. in" an autoclave. The resulting reaction product Was distilled to separate the cyclobutane derivative, methyl 3,3-dimthyl-Z-morpholinocyclobutanecarboxylate, B.P. 101-102" C. at 2.2 mm., N 1.4711.
EXAMPLE 24 A one mole proportion of N,N-di-n-butylisobutenylamine was reacted with a one mole proportion of methyl acrylate for 2 hours at 170 C. in an autoclave. The resulting reaction product was distilled to separate the cyclobutane derivative, methyl 3,3-dimethyl-2-di-n-butylarninocyclobutanecarboxylate, B.P. 98 C. at ca. 1.5 mm., N 1.4543. r A
EXAMPLE 25 A one mole proportion of N ,N-diisobutylisobutenylamine was reacted with a one mole proportion of methyl acrylate for 2 hours at 170 C. in an autoclave. The resulting reaction product was distilled to separate the cyclobutane derivative, methyl 3,3-dimethyl-2-diisobutylamino cyclobutanecarboxylate, B.P. 93-100 C. at ca. 2 mm., N 1.4510.
, Typical enamines used to prepare the present cyclobutane derivatives by the preferred method can be prepared by the methods described below.
EXAMPLE 26 The preparation of N,N-dibuty1 isobutenyl amine was accomplished as follows. Isobutyraldehyde (180 g., 2.5 moles) was added over a ,-hour period to dibutylamine. The reaction mixture was then refluxed under a Dean- Stark trap for 12 hours during which time 30 ml. of water'was collected. Fractional distillation of the mixture gave, after removal of low boilers, 228 g. (63%) of N,N-dibutylisobutenylamine, B.P. 70.5-72 C. at 4.5- 5.2 mm., 11 1.4409.
EXAMPLE 27 In a manner similar to that described in Example 26, isobutyraldehyde and diisobutylamine gave N,N-diisobutylisobutenylamine, B.P. 64 C. at 5.8 mm., n
EXAMPLE 28 In a manner similar to that described in Example 26, cyclohexanecarboxaldehyde and piperidine gave l-cycloboxylidenemethyl piperidine, B.P. 88 C. at 3 mm., n 1.5042, in 85% yield.
EXAMPLE 29 EXAMPLE 30 Over a 2-hour period isobutyraldehyde (400 g., 5 moles) was added to piperazine (172 g., 2 moles) at 35- 40 C. The mixture was stirred and refluxed under a Dean-Stark trap for 7 hours, during which time 74 ml.
of water was collected, Distillation of the reaction mixture gave, after removal of low boilers, 221 g. (57%) of 1,4-diisobutenyl piperazine, B.P. 70-75 C. at 2 mm.,
M.P. 35-37 C.
EXAMPLE 31 17 the filtrate was distilled to give after removal of unreacted starting materials, 198 g. (50%) of N,N-dimethylisobutenylamine, B.P. 87-89" C., n 1.4219.
This application is a continuation-in-part of our copending application Serial No. 825,648, filed on July 8, 1959, now abandoned.
What is claimed is:
-1. An analgesic composition in unit dosage form comprising a significant quantity of a pharmaceutical carrier and from about 0.1 grain to about 25 grains of a member selected from the group consisting of a cyclobutane derivative and a non-toxic acid addition salt of said cyclobutane derivative wherein the cyclobutane derivative can be represented by the following generic formula:
A' t 1( 3 R til-R2 1% iv wherein each of A and A is a lower alkyl radical; each of'R, R R and R is a member selected from the group consisting of hydrogen, a lower alkyl radical, the phenyl radical, the nitro radical, a lower alkyl sulfonyl radical, the cyano radical, a lower alkyl ester, and a lower 'alkyleneamino radical, provided that at least one of R, R R and R is the phenyl, the nitro, a lower alkyl sulfonyl, the cyano, a lower alkyl ester, and a lower alkyleneamino radical; R is a member selected from the group consisting of hydrogen and a lower alkyl radical having from 1 to 2 carbon atoms; and X is tertiary amino radical selected from the group consisting of a lower dialkylamino, the piperazino, the piperidino, the morpholino, and the thiomorpholino radical.
2. An analgesic composition in unit dosage form comprising a significant quantity of a pharmaceutical carrier and from about 0.1 grain to about 25 grains of a cyclobutane derivative having the following generic formula:
A H A t-AR H(IJ(IJ-R2 X 1% wherein each of A and A is a lower alkyl radical having from 1 to 2 carbon atoms, R and R is a canbalkoxy radical having from 1 to 3 carbon atoms in each alkoxy chain; and X is a dialkylamino radical having from 1 to 2 carbon atoms in each alkyl chain.
. 3. An analgesic composition in unit dosage form comprising a significant quantity of a pharmaceutical carrier and from about 1 to about grains of a non-toxic acid addition salt of diethyl 3,3-dimethyl- Ldimethylaminocyclobutane-1,2-dicarboxylate.
4. An analgesic composition in unit dosage form comprising a significant quantity of a pharmaceutical carrier and from about 1 to about 10 grains of a non-toxic acid addition salt of methyl 3,3-dimethyl-2-dimethylaminocyclobutane-l-carboxylate.
5. An analgesic composition in unit dosage form comprising a significant quantity of a pharmaceutical carrier and from about 1 to about 10 grains of a non-toxic acid addition salt of methyl 2,2-dimethyl-3-piperidinocyclobutane-l-carboxylate.
6. An analgesic composition in unit dosage form comprising a significant quantity of a pharmaceutical carrier and from about 1 to about 10 grains of a non-toxic acid addition salt of N,N,2,Z-tetramethyl-4-methylsulfonylcyclobutylamine.
7. An analgesic composition in unit dosage form comprising a significant quantity of a pharmaceutical carrier and from about 1 to about 10 grains of a non-toxic acid addition salt of 2,2-dimethyl-3-(1-piperidyl)cyclobutanecarbonitrile.
8. An analgesic composition comprising from about 1 to about 10 grains of a member selected from the group 18 v consisting of diethyl 3,3-dimethyl-4-dimethylaminocyclobutane 1,2-dicarboxylate and a non-toxic acid addition salt thereof, and aspirin in a quantity varying from about 0.25 to 4 times the quantity of said cyclobutane derivative.
9. A method for inducing analgesia which comprises administering to an animal, including a human, an analge'sically eifective quantity of a member selected from the group consisting of a cyclobutane derivative and a nontoxic acid addition salt of said cyclobutane derivative wherein the cyclobutane derivative can be represented by the following generic formula:
A R r tina RML R= wherein each of A and A is a lower alkyl radical; each of R, R R and R is a member selected from the group consisting of hydrogen, a lower alkyl radical, the phenyl radical, the nitro radical, a lower alkyl sulfonyl radical, the cyano radical, a lower alkyl ester, and a lower alkyleneamino radical, provided that at least one of R, R R and R is the phenyl, the nirto, a lower alkyl sulfonyl, a lower alkyleneamino, the cyano and a lower alkyl ester radical; R is a member selected from the group consisting of hydrogen and a lower alkyl radi cal having from 1 to 2 carbon atoms; and X is a tertiary amino radical selected from the group consisting of a lower dialkylamino, the piperazino, the piperidino, the morpholino, and the thiomorpholino radical.
10. A method for inducing analgesia which comprises adminstering to an animal, including a human, an analgesically eifective quantity of a cyclobutane derivative having the following generic formula:
wherein each of A and A is a lower alkyl radical having from 1 to 2 carbon atoms; R and R is a carbalkoxy radical having from 1 to 3 carbon atoms in each alkoxy chain; and X is a dialkylamino radical having from 1 to 2 carbon atoms in each alkyl chain.
11. A method for inducing analgesia which comprises administering to an animal, including a human, from about 1 to about 10 grains of a non-toxic acid addition salt of diethyl 3,3-dimethyl-4-dimethylaminocyclobutane- 1,2-dicarboxylate.
12. A method for inducing analgesia which comprises administering to an animal, including a human, from about 1 to about 10 grains of a non-toxic acid addition salt of methyl 3,3-dimethyl-2-dimethylaminocyclobutanel-carboxylate.
13. A method for inducing analgesia which comprises administering to an animal, including a human, from about 1 to about 10 grains of a non-toxic acid addition salt of N,N,2,2-tetramethyl-4 methylsulfonylcyclobutylamine.
14. A method for inducing analgesia which comprises administering to an animal, including a human, from about 1 to about 10 grains of a non-toxic acid addition salt of 2,2-dimethyl-3-(1-piperidyl)cyclobutanecarbonitrile.
'15. A method for inducing analgesia which comprises administering to an animal, including a human, from about 1 to about 10 grains of a cyclobutane derivative selected from the group consisting of diethyl 3,3-dimethyl- 4-dimethylaminocyclobutane 1,2-dicarboxylate and a non-toxic acid addition salt thereof and aspirin, the quantity of aspirin being about 0.25 to 4 times that of the cyclobutane derivative.
16. A method for inducing analgesia which comprises 19 administering to an animal, including a human, an analgesically eifective quantity of a cyclobutane derivative selected from the group consisting of diethyl 3,3-dimethyl- 4-dimethylaminocyclobutane 1,2-dicarboxy1ate and a nontoxic acid addition salt thereof and codeine.
17. A method for inducing analgesia which comprises administering to an animal, including a human, an analgesically effective quantity of a non-toxic acid addition salt of methyl 2,2-dimethyl-3-piperidinocyclobutane-l-carboxylate.
' 18. A method for inducing analgesia which comprises administering to an animal, including a human, an analgesically effective quantity of a non-toxic acid addition salt of 1-(2,2-dimethyl-4-nitro-3-phenylcyclobuty1)piperidine.
19. A method for inducing analgesia which comprises administering to an animal, including a human, an analgesically efiective quantity of a non-toxic acid addition salt of 2,2 dimethyl-3-( l-piperidyl)-cyclobutylmethylamine. I
20. A method for inducing analgesia which comprises administering to an animal, including a human, an analgesically effective quantity of a non-toxic acid addition salt of 2-dimethylarr1ino-3,3-dimethylcyclobutanecarbonitrile.
21. A method for inducing analgesia which comprises administering to an animal, including a human, an analgesically effective quantity of a member selected from the group consisting of bis(4-methoxycarbonyl-2,2-dimethylcyclobutyl)-piperazine and a non-toxic acid addition salt thereof.
22. A method for inducing analgesia which comprises administering to an animal, including a human, an analgesically eifective quantity of a non-toxic acid addition salt of methyl 3,3-dimethyl-2-morpholinocyclobutane-1- carboxylate.
23. A method of inducing analgesia which comprises administering to an animal, including a human, an analgesically eifective quantity of a member selected from the group consisting of Z-(thiomorpholino)-2-ethyl-3- wherein each of A and A is' an alkyl having from 1 to 2 carbon atoms; R is a carbalkoxy radical having from '1 to 3 carbon atoms in the alkoxy portion; and X is a dialkylamino radical having from 1 to 2 carbon atoms in each alkyl chain. I
26. A method for inducing analgesia which comprises administering to an animal, including a human, an analgesically effective quantity of a cyclobutane derivative of the formula:
AHLLH H-(iJ-(J-R wherein each of A and A is an alkyl having from 1 to 2 carbon atoms; R is a carbalkoxy radical having from 1 to 3 carbon atoms in the alkoxy portion; and X is a dialkylamino radical having from 1 to 2 carbon atoms in each alkyl chain.
References Cited in the file of this patent Van Itallie: Pulse-0f Pharmacy, vol. 12, No. 2, 1958, pp. 5, 7-8.
1 UNITED STATES swam. oamea fiER'HFiQATE @F QQRREQTWN Patent No.- 3 O5l,622 August 28 1962 Samuel Kuna ei; alo
It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.
Column 9, line 26 for "surfate" read sulfate ---3 column 16 line 38 for "11 read 11 Signed and sealed this 22nd day of January 196,23
(SEAL) fittest:
ERNEST w. SWIDER v DAVID LADD Atiesting Officer Commissioner of Patents
Claims (1)
1. AN ANALGESIC COMPOSITION IN UNIT DOSAGE FORM COMPRISING A SIGNIFICANT QUANTITY OF A PHARMACEUTICAL CARRIER AND FROM ABOUT 0.1 GRAIN TO ABOUT 25 GRAINS OF A MEMBER SELECTED FROM THE GROUP CONSISTING OF A CYCLOBUTANE DERIVATIVE AND A NON-TOXIC ACID ADDITION SALT OF SAID CYCLOBUTANE DERIVATIVE WHEREIN THE CYCLOBUTANE DERIVATIVE CAN BE REPRESENTED BY THE FOLLOWING GENERIC FORMULA:
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US855285A US3051622A (en) | 1959-11-25 | 1959-11-25 | Analgesic cyclobutanes |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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US855285A US3051622A (en) | 1959-11-25 | 1959-11-25 | Analgesic cyclobutanes |
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US3051622A true US3051622A (en) | 1962-08-28 |
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US855285A Expired - Lifetime US3051622A (en) | 1959-11-25 | 1959-11-25 | Analgesic cyclobutanes |
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Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3189608A (en) * | 1960-11-25 | 1965-06-15 | Eastman Kodak Co | Tertiaryaminocyclobutanones and their production |
US3287390A (en) * | 1961-08-21 | 1966-11-22 | Mcneilab Inc | 2, 2, 4, 4-tetramethylcyclobutyl compounds |
US3364114A (en) * | 1962-03-01 | 1968-01-16 | Bristol Myers Co | Therapeutic compositions containing aminocyclobutanols |
US3369024A (en) * | 1961-06-07 | 1968-02-13 | Eastman Kodak Co | Tertiaryaminocyclobutanes with electronegative substituents |
US3481939A (en) * | 1965-03-15 | 1969-12-02 | Eastman Kodak Co | Tertiaryaminocyclobutanes with electronegative substituents |
US3481936A (en) * | 1965-03-15 | 1969-12-02 | Eastman Kodak Co | Tertiaryaminocyclobutanes with electronegative substituents |
EP0246669A2 (en) | 1982-10-07 | 1987-11-25 | Zeneca Inc. | Halopyridones |
US5053516A (en) * | 1984-05-23 | 1991-10-01 | Ici Americas Inc. | Synthesis of 2-substituted-5-methylpyridines from methylcyclobutanecarbonitrile, valeronitrile and pentenonitrile intermediates |
-
1959
- 1959-11-25 US US855285A patent/US3051622A/en not_active Expired - Lifetime
Non-Patent Citations (1)
Title |
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None * |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3189608A (en) * | 1960-11-25 | 1965-06-15 | Eastman Kodak Co | Tertiaryaminocyclobutanones and their production |
US3369024A (en) * | 1961-06-07 | 1968-02-13 | Eastman Kodak Co | Tertiaryaminocyclobutanes with electronegative substituents |
US3287390A (en) * | 1961-08-21 | 1966-11-22 | Mcneilab Inc | 2, 2, 4, 4-tetramethylcyclobutyl compounds |
US3364114A (en) * | 1962-03-01 | 1968-01-16 | Bristol Myers Co | Therapeutic compositions containing aminocyclobutanols |
US3481939A (en) * | 1965-03-15 | 1969-12-02 | Eastman Kodak Co | Tertiaryaminocyclobutanes with electronegative substituents |
US3481936A (en) * | 1965-03-15 | 1969-12-02 | Eastman Kodak Co | Tertiaryaminocyclobutanes with electronegative substituents |
EP0246669A2 (en) | 1982-10-07 | 1987-11-25 | Zeneca Inc. | Halopyridones |
US5053516A (en) * | 1984-05-23 | 1991-10-01 | Ici Americas Inc. | Synthesis of 2-substituted-5-methylpyridines from methylcyclobutanecarbonitrile, valeronitrile and pentenonitrile intermediates |
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