US2561385A - Aranoalkyl-z-tmenyl-cycloalkenyl - Google Patents
Aranoalkyl-z-tmenyl-cycloalkenyl Download PDFInfo
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- US2561385A US2561385A US2561385DA US2561385A US 2561385 A US2561385 A US 2561385A US 2561385D A US2561385D A US 2561385DA US 2561385 A US2561385 A US 2561385A
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- Prior art keywords
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- thienyl
- neurotropic
- musculotropic
- cyclopentenyl
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- 150000001875 compounds Chemical class 0.000 claims description 62
- 230000003170 musculotropic Effects 0.000 claims description 26
- 230000002276 neurotropic Effects 0.000 claims description 26
- 230000002921 anti-spasmodic Effects 0.000 claims description 24
- 239000004480 active ingredient Substances 0.000 claims description 10
- 238000002360 preparation method Methods 0.000 claims description 8
- -1 atropine Chemical class 0.000 description 30
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 28
- 125000004432 carbon atoms Chemical group C* 0.000 description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 8
- 208000005392 Spasm Diseases 0.000 description 6
- 235000011054 acetic acid Nutrition 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- 125000003710 aryl alkyl group Chemical group 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
- 229910052736 halogen Inorganic materials 0.000 description 6
- 150000002367 halogens Chemical class 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 231100000419 toxicity Toxicity 0.000 description 6
- 230000001988 toxicity Effects 0.000 description 6
- FKLJPTJMIBLJAV-UHFFFAOYSA-N 5-(7-(4-(4,5-DIHYDRO-2-OXAZOLYL)PHENOXY)HEPTYL)-3-METHYL ISOXAZOLE Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 4
- 229930008281 A03AD01 - Papaverine Natural products 0.000 description 4
- 229930006677 A03BA01 - Atropine Natural products 0.000 description 4
- 208000006673 Asthma Diseases 0.000 description 4
- RKUNBYITZUJHSG-SPUOUPEWSA-N Atropine Chemical compound O([C@H]1C[C@H]2CC[C@@H](C1)N2C)C(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-SPUOUPEWSA-N 0.000 description 4
- 229960000396 Atropine Drugs 0.000 description 4
- GZUXJHMPEANEGY-UHFFFAOYSA-N Bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 description 4
- WWXJABGQHQSNCU-UHFFFAOYSA-N Cl.C(C)(=O)OC1=CCCCC1 Chemical compound Cl.C(C)(=O)OC1=CCCCC1 WWXJABGQHQSNCU-UHFFFAOYSA-N 0.000 description 4
- 210000003205 Muscles Anatomy 0.000 description 4
- XQYZDYMELSJDRZ-UHFFFAOYSA-N Papaverine Chemical compound C1=C(OC)C(OC)=CC=C1CC1=NC=CC2=CC(OC)=C(OC)C=C12 XQYZDYMELSJDRZ-UHFFFAOYSA-N 0.000 description 4
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 238000007792 addition Methods 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 238000009835 boiling Methods 0.000 description 4
- 230000001713 cholinergic Effects 0.000 description 4
- DRJNNZMCOCQJGI-UHFFFAOYSA-N cyclohexen-1-yl acetate Chemical compound CC(=O)OC1=CCCCC1 DRJNNZMCOCQJGI-UHFFFAOYSA-N 0.000 description 4
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 229940079593 drugs Drugs 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 150000004820 halides Chemical class 0.000 description 4
- 150000002431 hydrogen Chemical class 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 231100000636 lethal dose Toxicity 0.000 description 4
- 231100000053 low toxicity Toxicity 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- 229960001789 papaverine Drugs 0.000 description 4
- 230000000638 stimulation Effects 0.000 description 4
- 238000007920 subcutaneous administration Methods 0.000 description 4
- 238000005292 vacuum distillation Methods 0.000 description 4
- 229960004373 Acetylcholine Drugs 0.000 description 2
- WDIHJSXYQDMJHN-UHFFFAOYSA-L Barium chloride Chemical compound [Cl-].[Cl-].[Ba+2] WDIHJSXYQDMJHN-UHFFFAOYSA-L 0.000 description 2
- AGEZXYOZHKGVCM-UHFFFAOYSA-N Benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 2
- GCLAUHZHMZEYCR-UHFFFAOYSA-M C(CC(=O)[O-])(=O)OC=1SC=C(C=1CC)CC Chemical compound C(CC(=O)[O-])(=O)OC=1SC=C(C=1CC)CC GCLAUHZHMZEYCR-UHFFFAOYSA-M 0.000 description 2
- 241000700198 Cavia Species 0.000 description 2
- 241000700199 Cavia porcellus Species 0.000 description 2
- NEHMKBQYUWJMIP-UHFFFAOYSA-N Chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 2
- QKKHTZPWKOWHDL-UHFFFAOYSA-N Cl.C(C)(=O)OC1=CCCC1 Chemical compound Cl.C(C)(=O)OC1=CCCC1 QKKHTZPWKOWHDL-UHFFFAOYSA-N 0.000 description 2
- BFSVOASYOCHEOV-UHFFFAOYSA-N Diethylethanolamine Chemical compound CCN(CC)CCO BFSVOASYOCHEOV-UHFFFAOYSA-N 0.000 description 2
- 210000000936 Intestines Anatomy 0.000 description 2
- FEWJPZIEWOKRBE-XIXRPRMCSA-N Mesotartaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-XIXRPRMCSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 229940050176 Methyl Chloride Drugs 0.000 description 2
- 229960002362 Neostigmine Drugs 0.000 description 2
- ALWKGYPQUAPLQC-UHFFFAOYSA-N Neostigmine Chemical compound CN(C)C(=O)OC1=CC=CC([N+](C)(C)C)=C1 ALWKGYPQUAPLQC-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 150000001266 acyl halides Chemical class 0.000 description 2
- 150000001447 alkali salts Chemical class 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 150000001350 alkyl halides Chemical class 0.000 description 2
- 230000001387 anti-histamine Effects 0.000 description 2
- 239000000739 antihistaminic agent Substances 0.000 description 2
- 229910001626 barium chloride Inorganic materials 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 230000036760 body temperature Effects 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 239000001569 carbon dioxide Substances 0.000 description 2
- 229910002092 carbon dioxide Inorganic materials 0.000 description 2
- 239000000812 cholinergic antagonist Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 230000000875 corresponding Effects 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000005712 crystallization Effects 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- MBVZEDIBUZMQOR-UHFFFAOYSA-N cyclopenten-1-yl acetate Chemical compound CC(=O)OC1=CCCC1 MBVZEDIBUZMQOR-UHFFFAOYSA-N 0.000 description 2
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 description 2
- 150000005382 diphenylacetic acid esters Chemical class 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 150000002168 ethanoic acid esters Chemical class 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 125000001841 imino group Chemical group [H]N=* 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 238000009114 investigational therapy Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 210000004914 menses Anatomy 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 229940102396 methyl bromide Drugs 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 210000000663 muscle cells Anatomy 0.000 description 2
- 210000002569 neurons Anatomy 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-L propanedioate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 230000001148 spastic Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000001384 succinic acid Substances 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- 125000004354 sulfur functional group Chemical group 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 229960001367 tartaric acid Drugs 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- 230000002588 toxic Effects 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
- C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
Definitions
- This invention relates to new compounds of pharmaceutical value, particularly as antispasmodics.
- the first type manifested by compounds such as atropine
- neurotropic action in that stimulation of the muscle is inhibited by action on the nerve cells.
- papaverine is known as musculotropic action in that stimulation of the muscle is inhibited by direct action on the muscle cells. While both papaverine and atropine have been employed clinically on a wide scale, there are many spastic conditions which are not relieved by either substance. Further, there is a considerable demand for products possessing both neurotropic and musculotropic activity.
- R denotes a cyclohexenyl or cyclopentenyl radical
- R and R which may be the same or different, denote alkyl radicals containing not over 4 carbon atoms, or together denote a polymethylene radical containing not over 5 carbon atoms, and which may be interrupted by an oxygen, sulfur or imino group
- R denotes hydrogen, a short chain alkyl radical or halogen, which members may be the same or different;
- R, R and Alk are a above defined and Hal denotes halogen, with a compound of the formula (RWMU CHCOOH in which R and 1'1, are as above defined, or with an alkali salt thereof; this reaction may be carried out readily under reflux in a suitablesolvent such as isopropanol.
- My compounds may also be prepared by reacting under reflux and in a suitable solvent a compound of the formula NAlkOH 61 with an acyl halide of the thienyl acetic acids above illustrated.
- Another suitable method involves reacting a lower alkyl, e. g. methyl or ethyl, ester of the thienyl acetic acids above illustrated with an aikanol of the formula above given under conditions accomplishing ester interchange and volatilization of the lower alcohol, e. g. by heating tained by reacting diethyl-2-thienyl malonate with a cyclohexem'l or cyclopentenyl halide in a menses suitable solvent and at temperatures varying between and 78 C.
- the free bases of my invention are water-insoluble solids.
- Water-soluble salts may be formed by treating the free bases with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, tartaric acid, citric acid or succinic acid, or with suitable organic halides, e. g. alkyl halides such as methyl chloride or methyl bromide, aralkyl halides such as benzyl cloride 0r benzyl bromide, or other organic halides such as thienylmethyl chloride.
- acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, tartaric acid, citric acid or succinic acid
- suitable organic halides e. g. alkyl halides such as methyl chloride or methyl bromide, aralkyl halides such as benzyl cloride 0r benzyl bromide, or other organic halides such as thienylmethyl chloride.
- the products of my invention have been found to be highly eifective antispasmodics. They may be administered orally in the form of tablets containin 50 to 75 mg. of the active ingredient, or parenterally in the form of aqueous solutions containing about of one of the water soluble salts herein described.
- Musculotropic activity was determined in the same manner, except that barium chloride in a concentration of one part per five thousand was used to induce spasm.
- intravenous 'and subcutaneous toxicity in mice 01' the compounds tested was determined, expressed in terms of LD50 (lethal dose against 50% of test animals). The results of these tests are given below, together with comparative data obtained with the diphenyl acetic acid ester of diethylaminoethanol of the prior art.
- the compounds tested were as follows, each being in the form of its hydrochloride:
- Examples 4.9 g. of sodium were dissolved in 150 cc. absolute ethanol, the solution cooled to 50 C. and 38.7 g. of ethyl-,2-thienyl malonate added; the mixture was then heated to reflux and cooled to 0 C. 39.7 g. 01 a toluene solution containremoved by vacuum distillation, 50 cc. of water were added and the organic layer separated; the aqueous layer was washed with toluene and the washings combined with the organic layer. The combined organic layers were washed with water, the toluene removed by vacuum distillation and the residual oil fractionated. The compound diethyl 2 thienyl A -cyclopenteny1 malonate, boiling at 175-185 C. at 5.5 mm., was recovered.
- R denotes a member selected from the 0 group consisting of cyclohexenyl and cyclopentenyl radicals
- R" and R denote radicals selected from the group consisting of alkyl radicals containing not over 4 carbon atoms or together denote a radical selected from the group consisting of polymethylene radicals containing not over 5 carbon atoms and polymethylene radicals containing not over 4 carbon atoms interrupted by a member selected from the group consisting of oxygen, sulfur and imino substituents
- R denotes a member selected from the group consisting of hydrogen, short chain alkyl radicals and halogens
- Alk denotes an alkylene radical containing not over 6 carbon atoms, and their salts.
- a preparation having high neurotropic and musculotropic antispasmodic activity containing as its essential active ingredient the compound 5 diethylaminoethyl 2 thienyl A cyclopentenyl acetate hydrochloride.
- a preparation having high neurotropic and musculotropic antispasmodic activity containing as its essential active ingredient the compound 3 diethylaminoethyl 2 thienyl A cyclohexenyl acetate hydrochloride.
- a preparation having high neurotropic and musculotropic antispasmodic activity containing as its essential active ingredient the compound 5 piperidinoethyl 2 thienyl A cyclohexenyl acetate hydrochloride.
- Huttrer Enzymologia, 12, 308 (1948).
Description
Patented July 24, 1951 AMINOALKYL-Z-THIENYL-CYCLOALKENYL ACETATE Frederick Leonard, Brooklyn, N. Y., assignor to Warner-Hudnut, Inc., New York, N. Y., a. corporation of Delaware No Drawing. Application October 1, 1949,
Serial No. 119,197
6 Claims. (01. zoo-294.3}
This invention relates to new compounds of pharmaceutical value, particularly as antispasmodics.
Two principal types of antispasmodic action are recognized. The first type, manifested by compounds such as atropine, is known as neurotropic action in that stimulation of the muscle is inhibited by action on the nerve cells. The other type, manifested by compounds such as papaverine, is known as musculotropic action in that stimulation of the muscle is inhibited by direct action on the muscle cells. While both papaverine and atropine have been employed clinically on a wide scale, there are many spastic conditions which are not relieved by either substance. Further, there is a considerable demand for products possessing both neurotropic and musculotropic activity.
In the search for more satisfactory and effective antispasmodics, aryl and cycloalkyl monoand disubstituted acetic acid esters of dialkylaminoalkanols have been developed. While these compounds have been found to possess both neurotropic and musculotropic activity and have attained a degree of clinical acceptance, their efficacy and toxicity is such that considerable improvement is desired.
It is an object of this invention to provide new compounds having the desirable combination of high musculotropic and neurotropic activity with low toxicity.
As a result of extensive investigation, I have found that a certain limited class of compounds, identified below, possess in an optimum degree the combination of both musculotropic and neurotropic antispasmodic action with low toxicity, so that they are definitely superior to the aryl or cycloalkyl acetic acid esters heretofore available. The compounds of my invention are characterized by the structural formula:
wy-E R" S CH 0 OAIkN in which R denotes a cyclohexenyl or cyclopentenyl radical; R and R which may be the same or different, denote alkyl radicals containing not over 4 carbon atoms, or together denote a polymethylene radical containing not over 5 carbon atoms, and which may be interrupted by an oxygen, sulfur or imino group; R denotes hydrogen, a short chain alkyl radical or halogen, which members may be the same or different; and All:
2 denotes an alkylene radical containing not over 6 carbon atoms and which may be straight chain or branched. These compounds have been found to possess excellent antispasmodic activity of both neurotropic and musculotropic nature, being more eflective than the aryl or cycloalkyl acetic acid esters above described. Furthermore, the toxicity of the compounds of this invention is considerably in which R, R and Alk are a above defined and Hal denotes halogen, with a compound of the formula (RWMU CHCOOH in which R and 1'1, are as above defined, or with an alkali salt thereof; this reaction may be carried out readily under reflux in a suitablesolvent such as isopropanol. My compounds may also be prepared by reacting under reflux and in a suitable solvent a compound of the formula NAlkOH 61 with an acyl halide of the thienyl acetic acids above illustrated. Another suitable method involves reacting a lower alkyl, e. g. methyl or ethyl, ester of the thienyl acetic acids above illustrated with an aikanol of the formula above given under conditions accomplishing ester interchange and volatilization of the lower alcohol, e. g. by heating tained by reacting diethyl-2-thienyl malonate with a cyclohexem'l or cyclopentenyl halide in a menses suitable solvent and at temperatures varying between and 78 C.
The free bases of my invention are water-insoluble solids. Water-soluble salts may be formed by treating the free bases with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, tartaric acid, citric acid or succinic acid, or with suitable organic halides, e. g. alkyl halides such as methyl chloride or methyl bromide, aralkyl halides such as benzyl cloride 0r benzyl bromide, or other organic halides such as thienylmethyl chloride.
The products of my invention have been found to be highly eifective antispasmodics. They may be administered orally in the form of tablets containin 50 to 75 mg. of the active ingredient, or parenterally in the form of aqueous solutions containing about of one of the water soluble salts herein described.
Extensive tests have established my compounds to have both neurotropic and musculotropic activity. In these tests, the results of which are set forth below, antispasmodic neurotropic activity was determined by suspending a strip of guinea pig intestine in a bath of oxygenated Locke's solution maintained at body temperature and inducing spasm by addition of an aqueous solution of acetyl choline in a concentration of one part per million; the quantity of compound being tested required to prevent development of spasm induced in this manner was then determined.
Musculotropic activity was determined in the same manner, except that barium chloride in a concentration of one part per five thousand was used to induce spasm. In addition, intravenous 'and subcutaneous toxicity in mice 01' the compounds tested was determined, expressed in terms of LD50 (lethal dose against 50% of test animals). The results of these tests are given below, together with comparative data obtained with the diphenyl acetic acid ester of diethylaminoethanol of the prior art. The compounds tested were as follows, each being in the form of its hydrochloride:
.It will be evident from the table that compounds I, II and III, compounds of this invention, are
more active antispasmodics in both their neurotropic and musculotropic activity than compound IV, and further that the compounds of my in'- vention are less toxic than compound IV.
Pharmacological tests have also indicated that the products of my invention are extremely etfective in protecting against bronchial asthma which may be induced by cholinergic drugs. Thus it has been established that subcutaneous doses of from 10 to 20 mg. per kg. of the compounds of this invention completely protected guinea pigs against bronchial asthma or other untoward effects following lethal doses of the cholinergic drug neostigmine. The compounds of my invention are also effective anti-histaminics.
The following examples are illustrative of my invention:
Examples 4.9 g. of sodium were dissolved in 150 cc. absolute ethanol, the solution cooled to 50 C. and 38.7 g. of ethyl-,2-thienyl malonate added; the mixture was then heated to reflux and cooled to 0 C. 39.7 g. 01 a toluene solution containremoved by vacuum distillation, 50 cc. of water were added and the organic layer separated; the aqueous layer was washed with toluene and the washings combined with the organic layer. The combined organic layers were washed with water, the toluene removed by vacuum distillation and the residual oil fractionated. The compound diethyl 2 thienyl A -cyclopenteny1 malonate, boiling at 175-185 C. at 5.5 mm., was recovered.
37.5 g. of the above compound, 27.4 g. potassium hydroxide, 27.4 cc. water and cc. 95% ethanol were then mixed and refluxed for 20 hours. At the end of this time the alcohol was removed by distillation and the residual oil dissolved in water and extracted with ether. The alkaline aqueous solution was then covered with ether and acidified by the addition of concentrated hydrochloric acid, during which time vigorous evolution of carbon dioxide occurred. The organic layer was then separated and the aqueous layer extracted with ether, washed and dried. Ether was then removed by evaporation and the residue distilled under vacuum, whereby 2-thienyl-A -cyclopentenyl acetic acid was obtained, boiling at 161-166 C. at 3 mm; Upon standing, the material crystallized to form a product melting at 60-65 C.
6.305 g. of the above product and 4.11 g. of' fi-diethylaminoethyl chloride were mixed with 80 cc. absolute isopropanol and refluxed for 48 hours. At the end of this time, the reaction mixture was cooled, filtered and solvent removed by evaporation. Ether was then added to the resultant oil, whereupon crystallization soon commenced. The crystals obtained were recovered by filtration, washed with ether and dried. The desired product, after recrystallization from a' mixture of isopropanol and ether, melted at 128- 130 C. and was identified as the hydrochloride of B diethylamino ethyl 2 thienyl A cyclopentenyl acetate.
By substituting for the n -cyclopentenyl chloride employed in the above example an equivalent amount of n -cyclohexenyl chloride, the compound 5 diethylaminoethyl 2 thienyl- A -cyclohexenyl acetate hydrochloride was obtained. Likewise. by substitutin for the p-diethylaminoethyl chloride in either of the above examples an equivalent amount of p-piperidinoethyl chloride, corresponding esters of p-piperidinoethanol may be obtained. In addition to the compounds above mentioned, the following additional compounds may be obtained by substituting suitable reactants in accordance with the foregoing disclosure in the procedure described in the above example: fl-diethylaminoethyl-3-methyl-2-thienyl-A -cyclopentenyl tate; p-diethylaminoethyl-i-chloro-2-thienyl-A=*- cyclohexenyl acetate; fi-dimethylaminoethyl-2- thienyl-A -cyclopentenyl acetate; B-di-isopropylaminoethyl-ii-thienyl-A cyclohexenyl acetate; 7 diethylamino B -methy1propyl 2 thienyl- A -cyclopentenyl acetate; fl-morpholinoetlwl-2- thienyl-M-cyclopentenyl acetate; p-thiomorph-' lin0methyl-2-thienyl-A cyclohexenyl acetate;
- p piperazl'noethyl 2 thienyl-A -cyclopentenyl ing the structural formula.
S CH0 0 olun/ in which R denotes a member selected from the 0 group consisting of cyclohexenyl and cyclopentenyl radicals; R" and R denote radicals selected from the group consisting of alkyl radicals containing not over 4 carbon atoms or together denote a radical selected from the group consisting of polymethylene radicals containing not over 5 carbon atoms and polymethylene radicals containing not over 4 carbon atoms interrupted by a member selected from the group consisting of oxygen, sulfur and imino substituents; R denotes a member selected from the group consisting of hydrogen, short chain alkyl radicals and halogens; and Alk denotes an alkylene radical containing not over 6 carbon atoms, and their salts.
2. The compounds of claim 1 in which R denotes hydrogen.
3. The compounds of claim 2 in which R and R denote alkyl radicals containing not over 4 carbon atoms.
4. A preparation having high neurotropic and musculotropic antispasmodic activity containing as its essential active ingredient the compound 5 diethylaminoethyl 2 thienyl A cyclopentenyl acetate hydrochloride.
5. A preparation having high neurotropic and musculotropic antispasmodic activity containing as its essential active ingredient the compound 3 diethylaminoethyl 2 thienyl A cyclohexenyl acetate hydrochloride.
6. A preparation having high neurotropic and musculotropic antispasmodic activity containing as its essential active ingredient the compound 5 piperidinoethyl 2 thienyl A cyclohexenyl acetate hydrochloride.
FREDERICK LEONARD.
REFERENCES CITED The following references are of record in the file of this patent:
Blicke: J. Am. Chem. Soc.. 66, pp. 1645-1648 (1 44).
Powers: Advancing Fronts in Chemistry, vol. 2, pp. 32-33 (1946).
Huttrer: Enzymologia, 12, 308 (1948).
Claims (1)
1. A PREPARATION HAVING NEUROTROPIC AND MUSCULOTROPIC ANTISPASMODIC ACTIVITY CONTAINING AS IT ESSENTIAL ACTIVE INGREDIENT A COMPOUND HAVING THE STRUCTURAL FORMULA
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Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2615894A (en) * | 1951-03-10 | 1952-10-28 | Sterling Drug Inc | N-heterylalkyl-isobutyl-(2-thienyl) acetonitriles and preparation thereof |
US2662887A (en) * | 1951-07-21 | 1953-12-15 | Warner Hudnut Inc | Substituted esters of cyclic alcohols |
US2684370A (en) * | 1951-07-21 | 1954-07-20 | Warner Hudnut Inc | Certain aminoalkyl-2-thienyl-cycloalkenyl thiolacetates |
US2684368A (en) * | 1951-07-21 | 1954-07-20 | Warner Hudnut Inc | Basic esters of substituted thienyl acetic acids |
US2684369A (en) * | 1951-07-21 | 1954-07-20 | Warner Hudnut Inc | Certain thienyl, cycloalkenyl acetamides |
US2685589A (en) * | 1952-02-19 | 1954-08-03 | Wm S Merrell Co | Therapeutic composition |
US2686186A (en) * | 1951-07-21 | 1954-08-10 | Warner Hudnut Inc | Aminopropyl-2-thienyl-cycloalkenyl acetate |
US2688025A (en) * | 1952-02-12 | 1954-08-31 | Olin Mathieson | Basic derivatives of substituted cycloalkanecarboxylic acids and methods of preparing same |
DE955503C (en) * | 1954-09-08 | 1957-01-03 | Thomae Gmbh Dr K | Process for the preparation of amino acid esters of endocyclically substituted carbinols and their salts |
-
0
- US US2561385D patent/US2561385A/en not_active Expired - Lifetime
Non-Patent Citations (1)
Title |
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None * |
Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2615894A (en) * | 1951-03-10 | 1952-10-28 | Sterling Drug Inc | N-heterylalkyl-isobutyl-(2-thienyl) acetonitriles and preparation thereof |
US2662887A (en) * | 1951-07-21 | 1953-12-15 | Warner Hudnut Inc | Substituted esters of cyclic alcohols |
US2684370A (en) * | 1951-07-21 | 1954-07-20 | Warner Hudnut Inc | Certain aminoalkyl-2-thienyl-cycloalkenyl thiolacetates |
US2684368A (en) * | 1951-07-21 | 1954-07-20 | Warner Hudnut Inc | Basic esters of substituted thienyl acetic acids |
US2684369A (en) * | 1951-07-21 | 1954-07-20 | Warner Hudnut Inc | Certain thienyl, cycloalkenyl acetamides |
US2686186A (en) * | 1951-07-21 | 1954-08-10 | Warner Hudnut Inc | Aminopropyl-2-thienyl-cycloalkenyl acetate |
US2688025A (en) * | 1952-02-12 | 1954-08-31 | Olin Mathieson | Basic derivatives of substituted cycloalkanecarboxylic acids and methods of preparing same |
US2685589A (en) * | 1952-02-19 | 1954-08-03 | Wm S Merrell Co | Therapeutic composition |
DE955503C (en) * | 1954-09-08 | 1957-01-03 | Thomae Gmbh Dr K | Process for the preparation of amino acid esters of endocyclically substituted carbinols and their salts |
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