US2742472A - Spasmolytic pipergzjnes - Google Patents
Spasmolytic pipergzjnes Download PDFInfo
- Publication number
- US2742472A US2742472A US2742472DA US2742472A US 2742472 A US2742472 A US 2742472A US 2742472D A US2742472D A US 2742472DA US 2742472 A US2742472 A US 2742472A
- Authority
- US
- United States
- Prior art keywords
- chloride
- pipergzjnes
- spasmolytic
- amide
- acid
- 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
- 230000002048 spasmolytic Effects 0.000 title description 4
- 239000000812 cholinergic antagonist Substances 0.000 title 2
- 150000001875 compounds Chemical class 0.000 claims description 14
- 150000003242 quaternary ammonium salts Chemical class 0.000 claims description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 16
- 239000002585 base Substances 0.000 description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- -1 1- phenylcyclohexyl Chemical group 0.000 description 12
- 239000002253 acid Substances 0.000 description 12
- 150000001408 amides Chemical class 0.000 description 8
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-M chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 238000002844 melting Methods 0.000 description 8
- HVTICUPFWKNHNG-UHFFFAOYSA-N Ethyl iodide Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 4
- VSBFNCXKYIEYIS-UHFFFAOYSA-N 9H-xanthene-9-carboxylic acid Chemical compound C1=CC=C2C(C(=O)O)C3=CC=CC=C3OC2=C1 VSBFNCXKYIEYIS-UHFFFAOYSA-N 0.000 description 4
- FMKOJHQHASLBPH-UHFFFAOYSA-N Isopropyl iodide Chemical compound CC(C)I FMKOJHQHASLBPH-UHFFFAOYSA-N 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N Thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- 150000001450 anions Chemical class 0.000 description 4
- 125000004432 carbon atoms Chemical group C* 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 4
- 230000003000 nontoxic Effects 0.000 description 4
- 231100000252 nontoxic Toxicity 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- WGCYRFWNGRMRJA-UHFFFAOYSA-N 1-ethylpiperazine Chemical compound CCN1CCNCC1 WGCYRFWNGRMRJA-UHFFFAOYSA-N 0.000 description 2
- LBLYYCQCTBFVLH-UHFFFAOYSA-M 2-methylbenzenesulfonate Chemical compound CC1=CC=CC=C1S([O-])(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 2
- JYRSCMLJPXJTLI-UHFFFAOYSA-N 9H-xanthene-9-carbonyl chloride Chemical compound C1=CC=C2C(C(=O)Cl)C3=CC=CC=C3OC2=C1 JYRSCMLJPXJTLI-UHFFFAOYSA-N 0.000 description 2
- 229930006677 A03BA01 - Atropine Natural products 0.000 description 2
- 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 2
- 229960000396 Atropine Drugs 0.000 description 2
- RDHPKYGYEGBMSE-UHFFFAOYSA-N Bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 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
- 235000001188 Peltandra virginica Nutrition 0.000 description 2
- 244000197580 Poria cocos Species 0.000 description 2
- 235000008599 Poria cocos Nutrition 0.000 description 2
- HKZLPVFGJNLROG-UHFFFAOYSA-M Silver chloride Chemical compound [Cl-].[Ag+] HKZLPVFGJNLROG-UHFFFAOYSA-M 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- IJDNQMDRQITEOD-UHFFFAOYSA-N butane Chemical compound CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 150000001768 cations Chemical class 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000005712 crystallization Effects 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 230000004059 degradation Effects 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- PSLIMVZEAPALCD-UHFFFAOYSA-N ethanol;ethoxyethane Chemical compound CCO.CCOCC PSLIMVZEAPALCD-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 229940050411 fumarate Drugs 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N fumaric acid Chemical compound OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-M iodide Chemical compound [I-] XMBWDFGMSWQBCA-UHFFFAOYSA-M 0.000 description 2
- 229940049920 malate Drugs 0.000 description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-L malate(2-) Chemical compound [O-]C(=O)C(O)CC([O-])=O BJEPYKJPYRNKOW-UHFFFAOYSA-L 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate Chemical compound CS([O-])(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000001766 physiological effect Effects 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 231100000486 side effect Toxicity 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 229940086735 succinate Drugs 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 2
- 229940095064 tartrate Drugs 0.000 description 2
- 230000001225 therapeutic Effects 0.000 description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical group CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 2
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D337/00—Heterocyclic compounds containing rings of more than six members having one sulfur atom as the only ring hetero atom
- C07D337/02—Seven-membered rings
- C07D337/06—Seven-membered rings condensed with carbocyclic rings or ring systems
- C07D337/10—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with two six-membered rings
- C07D337/14—[b,f]-condensed
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/62—Quaternary ammonium compounds
- C07C211/63—Quaternary ammonium compounds having quaternised nitrogen atoms bound to acyclic carbon atoms
Definitions
- the present invention relates to a group of quaternary ammonium salts derived from N-acyl-N-alkyl piperazines and a method of preparing them.
- These compounds can be represented by the formula n-o 0--N' N wherein R is selected from the class consisting of the 1- phenylcyclohexyl and 9-xanthenyl radicals, R and R" are lower alkyl radicals having between them at least three and not more than four carbon atoms and X" is the anion of a nontoxic acid.
- the compounds of the above class have atropine-like activities as spasmolytics and the potency of the members varies from about a third that of atropine to somewhat more than equipotency. It will be realized that since the therapeutic utility of such compounds depends not only on inherent activity but also upon ease of absorption, resistance to degradation and absence of side effects, it does not always follow that the most active member of a series is the most useful.
- the ethiodide was converted by the action of silver chloride .to the etho-chloride.
- the acid chloride from 8.4 g. of acid was added to 7 g. of methylpiperazine in 20 cc. of benzene.
- the reaction mixture was warmed on the steam bath for hour and then cooled and partitioned between water and ether.
- the ethereal layer was then extracted with dilute hydrochloric acid to remove the amide base which precipitated as a low-melting solid "on basification. This base forms a hydrochloride melting at 266.
- a method of preparing compounds of the formula the mid of a nontoxic acid which comprises reacting a compoundof the fo mula RCON' H N X- RCON/ H U with a quaternizing reagent of the formula R" X wherein R, R, R" and X have the above indicated values and recovering the product.
- R is a radical selected from the class consistingof the 9-xanthenyl and l-phenylcyclohexyl radicals, R and R are lower alkyl radicals having together at least threetand not more than four carbon atoms and X is v a Noreferences cited.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
come & Co. (U. S. A.) Inc., Tuckahoe, N. Y., a corporation of New York No Drawing. Application December 28, 1954, Serial No. 478,211
Claims. (Cl. 260-468) The present invention relates to a group of quaternary ammonium salts derived from N-acyl-N-alkyl piperazines and a method of preparing them. These compounds can be represented by the formula n-o 0--N' N wherein R is selected from the class consisting of the 1- phenylcyclohexyl and 9-xanthenyl radicals, R and R" are lower alkyl radicals having between them at least three and not more than four carbon atoms and X" is the anion of a nontoxic acid.
The compounds of the above class have atropine-like activities as spasmolytics and the potency of the members varies from about a third that of atropine to somewhat more than equipotency. It will be realized that since the therapeutic utility of such compounds depends not only on inherent activity but also upon ease of absorption, resistance to degradation and absence of side effects, it does not always follow that the most active member of a series is the most useful.
These compounds are advantageously prepared by the following reaction sequence RI! wherein R, R and R" and X- have the above-mentioned values. The anion X is 'of little consequence in such active compounds since the physiological activity resides in the cation. As prepared, X- may be chloride, bromide, iodide, methanesulfonate, ethanesulfonate, toluenesulfonate or the like. By exchange reactions of the conventional sort one of .the original variants of X might be replaced by malate, succinate, fumarate, tartrate or oleatc. The salts obtained through these variations of X may in some cases have special advantages due to solubility, ease of crystallization, lack of objectionable taste, etc., but these are all subsidiary to the main physiological action which is independent of the character of X. Hence, all variants of X" are considered equivalents.
EXAMPLE I The N-methylpiperazine amide of I-phenylcyclohexane carboxylic acid l-phenylcyclohexane carboxylic acid was converted to the acid chloride (B. P., 127 at 2-3 mm.) by treatment with thionyl chloride. In a little dry benzene 7.4 g. (0.033 mole) of this acid chloride was mixed with 6.6 g. (0.066 mole) of methylpiperazine. The reaction mixture was held under gentle reflux for hours, then cooled and partitioned between water and ether. The ethereal United st o 4, 2,742,412 Patented Apr. .11, .1956
1 layer was then extracted with dilute hydrochloric acid from :which 9.2 g. of water-insoluble base precipitated addition-of alkali. The base Was a solid melting at 96.- 98"... Whendissolved in absolute e-thanol and neutralized with hydrogen chloride it forms a hydrochloride melting at 268.
When dissolved in acetone the amide base reacted with ethyl iodide to form a solid ethiodide. This ethiodide. after recrystallization from ethanol-ether mixture, melted at 206.
The ethiodide was converted by the action of silver chloride .to the etho-chloride.
The base reacted with ethyl ethane sultonate to form the N '-ethyl ethane sulfonate salt.
When dissolved'in acetone the amide base (2.6 g.) reacted with isopropyl iodide (2 g.) to yield the N'- isopropiodide which was recrystallized from absolute ethanol and then melted at 172.
EXAMPLE H The N-methylpiperazine amide of xanthene-9-carboxylic acid used directly.
The acid chloride from 8.4 g. of acid was added to 7 g. of methylpiperazine in 20 cc. of benzene. The reaction mixture was warmed on the steam bath for hour and then cooled and partitioned between water and ether. The ethereal layer was then extracted with dilute hydrochloric acid to remove the amide base which precipitated as a low-melting solid "on basification. This base forms a hydrochloride melting at 266.
When dissolved in acetone the amide base reacted with excess ethyl iodide to give an ethiodide that melted at 244 with decomposition. methanol. Similarly an etho-bromide was formed by reaction with ethylbromide. With isopropyl iodide the isopropiodide was formed, M. P. 25 6 dec.
EXAMPLE III The N'-ethylpiperazine amide of xanthene-9-carboxylic acid When xanthene-9-carboxylic chloride (Example II) was reacted with ethyl piperazine by the methods of Examples I and H, the N'-ethylpiperazine amide was formed. This substance is an oil. Dissolved in acetone it reacted with ethyl p-toluenesulfona-te to give the quaternary p-toluene sulfona-te. With ethyl iodide it afforded the ethiodide, M. P. 245-246".
We claim:
1. A quaternary ammonium salt represented by the formula R RCON ri It was recrystallized from I 3 te 9' 5. A method of preparing compounds of the formula the mid of a nontoxic acid, which comprises reacting a compoundof the fo mula RCON' H N X- RCON/ H U with a quaternizing reagent of the formula R" X wherein R, R, R" and X have the above indicated values and recovering the product.
wherein R is a radical selected from the class consistingof the 9-xanthenyl and l-phenylcyclohexyl radicals, R and R are lower alkyl radicals having together at least threetand not more than four carbon atoms and X is v a Noreferences cited.
Claims (2)
1. A QUATERNARY AMMONIUM SALT REPRESENTED BY THE FORMULA
5. A METHOD OF PREPARING COMPOUNDS OF THE FORMULA
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US2742472A true US2742472A (en) | 1956-04-17 |
Family
ID=3445685
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US2742472D Expired - Lifetime US2742472A (en) | Spasmolytic pipergzjnes |
Country Status (1)
| Country | Link |
|---|---|
| US (1) | US2742472A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3236881A (en) * | 1960-01-09 | 1966-02-22 | Basf Ag | Organic ammonium salts of vinyl sulfonic acid |
| US3526630A (en) * | 1965-07-02 | 1970-09-01 | Egyt Gyogyszervegyeszeti Gyar | Alkyl dipiperazine derivatives of xanthene-9-carboxylic acid |
| US4492698A (en) * | 1980-06-16 | 1985-01-08 | Bjoerk Anders K | Diphenylbutyl-1-acylpiperazines |
| US11084807B2 (en) | 2016-08-18 | 2021-08-10 | Vidac Pharama Ltd. | Piperazine derivatives, pharmaceutical compositions and methods of use thereof |
-
0
- US US2742472D patent/US2742472A/en not_active Expired - Lifetime
Non-Patent Citations (1)
| Title |
|---|
| None * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3236881A (en) * | 1960-01-09 | 1966-02-22 | Basf Ag | Organic ammonium salts of vinyl sulfonic acid |
| US3526630A (en) * | 1965-07-02 | 1970-09-01 | Egyt Gyogyszervegyeszeti Gyar | Alkyl dipiperazine derivatives of xanthene-9-carboxylic acid |
| US4492698A (en) * | 1980-06-16 | 1985-01-08 | Bjoerk Anders K | Diphenylbutyl-1-acylpiperazines |
| US11084807B2 (en) | 2016-08-18 | 2021-08-10 | Vidac Pharama Ltd. | Piperazine derivatives, pharmaceutical compositions and methods of use thereof |
| US12162868B2 (en) | 2016-08-18 | 2024-12-10 | Vidac Pharma Ltd.. | Piperazine derivatives, pharmaceutical compositions and methods of use thereof |
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