US2472496A - L-carbethoxy-x-methylpiperazlisfe - Google Patents
L-carbethoxy-x-methylpiperazlisfe Download PDFInfo
- Publication number
- US2472496A US2472496A US2472496DA US2472496A US 2472496 A US2472496 A US 2472496A US 2472496D A US2472496D A US 2472496DA US 2472496 A US2472496 A US 2472496A
- Authority
- US
- United States
- Prior art keywords
- carbethoxy
- methylpiperazine
- compounds
- methylpiperazlisfe
- parts
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 150000001875 compounds Chemical class 0.000 description 26
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- USYYUUDWGLOMDJ-UHFFFAOYSA-N ethyl 4-methylpiperazine-1-carboxylate Chemical compound CCOC(=O)N1CCN(C)CC1 USYYUUDWGLOMDJ-UHFFFAOYSA-N 0.000 description 12
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 12
- 230000000694 effects Effects 0.000 description 8
- 201000006353 filariasis Diseases 0.000 description 8
- 150000003839 salts Chemical class 0.000 description 8
- 239000011780 sodium chloride Substances 0.000 description 8
- HCHKCACWOHOZIP-UHFFFAOYSA-N zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 8
- 238000001816 cooling Methods 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 229910052725 zinc Inorganic materials 0.000 description 6
- 239000011701 zinc Substances 0.000 description 6
- 239000002253 acid Substances 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 229910001385 heavy metal Inorganic materials 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-M 3-carboxy-2-(carboxymethyl)-2-hydroxypropanoate Chemical compound OC(=O)CC(O)(C(O)=O)CC([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-M 0.000 description 2
- 241000144290 Sigmodon hispidus Species 0.000 description 2
- UGZADUVQMDAIAO-UHFFFAOYSA-L Zinc hydroxide Chemical compound [OH-].[OH-].[Zn+2] UGZADUVQMDAIAO-UHFFFAOYSA-L 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- CWPSTZCYESJGPF-UHFFFAOYSA-N ethyl 2-methylpiperazine-1-carboxylate Chemical compound CCOC(=O)N1CCNCC1C CWPSTZCYESJGPF-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 231100000086 high toxicity Toxicity 0.000 description 2
- 150000003840 hydrochlorides Chemical class 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L na2so4 Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 150000002894 organic compounds Chemical class 0.000 description 2
- 150000002902 organometallic compounds Chemical class 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- 230000001225 therapeutic Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 229940007718 zinc hydroxide Drugs 0.000 description 2
- 229910021511 zinc hydroxide Inorganic materials 0.000 description 2
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
- C07D295/205—Radicals derived from carbonic acid
Definitions
- R is hydrogen or an alkyl radical.
- the relative activity of a number of these compounds is shown in the following table:
- B of the General formula is: filariae in the tonrat MgJKg. 25.0 (I. P.) 6.25 (LP) 50.0 (I. P.) 25.0 (1.1.) 25.0 (I.P.) 50.0 (1.1 100.0 oral inactive 200.0 oral inactive slightly above that of the compound shown in the reference.
- the compound 1-carbethoxy-4- methylpiperazine is approximately eight times as efiective as that of l-carbe-thoxyl-ethylpiperazine and at least four times more effective than any of the other compounds mentioned above. This high order of activity of the compounds of the present invention permits the obtaining of a therapeutic efiect at a much lower dosage level, which in turn lessens the possibility of toxicity.
- the new 1-carbethoxy-4-methylpiperazine may be prepared by reacting l-carbethoxypiperazine or one of its salts with formaldehyde in a minera1 acid such as hydrochloric acid and in the resence of zinc.
- the reaction is generally carried out in water or aqueous solutions of solvents such as dioxane, ethanol, and the like.
- hydrochloride salt The preparation and description of the hydrochloride salt is given hereinafter.
- Other salts of 1-carbethoxyl-methylpiperazine such as the hydrochloride, sulfate, dihydrogen citrate and the like, can be prepared in a similar manner.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Patented June 7, 1949 1-CARBETHOXY-4-METHYLPIPERAZINE,lTs
SALTS, AND METHOD or rnarnnnvq I,
SAME
Hugh W. Stewart, Plainfield, N.
1., assignor to American Cyanamid Company, New York, N. Y.,
a corporation of Maine I No Drawing. Application February 26, 1948, Serial No. 11,337
5 Claims.
This invention relates to new organic compounds and the methods of preparing the same. More particularly, the invention relates to 1- carbethoxy--methylpiperazine, its salts and methods of preparing said compounds.
In medical science there has long existed a need for compounds effective in the treatment of filariasis. In the past this disease has been treated with heavy metal organic com-pounds which, while being effective to some extent, must be used over a long period of time and have the relatively high toxicity characteristic of heavy metals in general. In a search ior compounds efi'ective in the treatment of filariasis, compounds of the type 1-carbethoxy-4-alkylpiperazine were prepared and tested. The compound l-carbethoxy-4-ethylpiperazine is known, having been described in the literature by Moore et :aL, Journal of the Chemical Society, 39 (1929). This compound, when tested against filariasis in the cotton rat, proved to be only slightly active.
I have found, unexpectedly, that the compound 1-carbethoxy-4-methylpiperazine shows a high degree of effectiveness against filariasis. This activity is unusual because the activity of adjacent homologues such as l-carbethoxyl-ethylpiperazine shown in the reference above, was of a very low order. I
The compounds of this general group may be illustrated by the following formula:
in which R is hydrogen or an alkyl radical. The relative activity of a number of these compounds is shown in the following table:
Minimum eiiective dose against micro- When B of the General formula is: filariae in the tonrat MgJKg. 25.0 (I. P.) 6.25 (LP) 50.0 (I. P.) 25.0 (1.1.) 25.0 (I.P.) 50.0 (1.1 100.0 oral inactive 200.0 oral inactive slightly above that of the compound shown in the reference. The compound 1-carbethoxy-4- methylpiperazine is approximately eight times as efiective as that of l-carbe-thoxyl-ethylpiperazine and at least four times more effective than any of the other compounds mentioned above. This high order of activity of the compounds of the present invention permits the obtaining of a therapeutic efiect at a much lower dosage level, which in turn lessens the possibility of toxicity.
The new 1-carbethoxy-4-methylpiperazine may be prepared by reacting l-carbethoxypiperazine or one of its salts with formaldehyde in a minera1 acid such as hydrochloric acid and in the resence of zinc. The reaction is generally carried out in water or aqueous solutions of solvents such as dioxane, ethanol, and the like.
It is preferred that the reaction be carried out at a temperature below 0., preferably from about 0 to 25 C.
The preparation and description of the hydrochloride salt is given hereinafter. Other salts of 1-carbethoxyl-methylpiperazine such as the hydrochloride, sulfate, dihydrogen citrate and the like, can be prepared in a similar manner.
To illustrate the invention with greater exactness the following description is given in which the new product is prepared from known intermediates. It will be understood, of course, that variations in the details may be made without departing from the initial features of the process.
To a solution of 106 parts of I-carbethoxypiperazine hydrochloride in 200 parts of water is added '72 parts of zinc dust. With cooling and stirring, 63.5 parts of 36% aqueous formaldehyde is slowly added, keeping the temperature at 15 C. Then, while maintaining a temperature of 15 C. by cooling, slowly add with stirring 240 parts of 38% aqueous hydrochloric acid. The reaction is then stirred overnight at room temperature. The small amount of zinc present is removed by filtration and to the filtrate slowly add, while stirring and cooling, 50% aqueous sodium hydroxide solution at 20 C. until the first precipitate of zinc hydroxide re-dissolves, giving a turbid solution. The oil which separates is extracted with ether and dried over sodium sulfate. On distillation at 7 mm., the yield is parts (96%) of 1-carbethoxy-4-methylpiperazine which distills at 9697 C. and is soluble in water.
By dissolving the 1-carbethoxy-4-methylpiperazine' in absolute ethanol and passing in dry hydrogen chloride, 1-carbethoxy-4-methylpipera 5. A method of preparing 1-carbethoxy-4-methylpiperazine which comprises mixing under reactive conditions a member of the group consisting of l-carbethoxypiperazine and salts thereof with formaldehyde in the presence of a mineral acid and zinc.
HUGH W. STEWART.
No references cited.
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US2472496A true US2472496A (en) | 1949-06-07 |
Family
ID=3436430
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US2472496D Expired - Lifetime US2472496A (en) | L-carbethoxy-x-methylpiperazlisfe |
Country Status (1)
| Country | Link |
|---|---|
| US (1) | US2472496A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2535971A (en) * | 1948-10-15 | 1950-12-26 | American Cyanamid Co | 1-carbalkoxy-4-substituted piperazines |
| US2617803A (en) * | 1949-10-21 | 1952-11-11 | American Cyanamid Co | Dialkylaminoalkyl esters of piperazine carboxylic acids |
| US2780625A (en) * | 1954-08-17 | 1957-02-05 | American Cyanamid Co | Piperazine derivatives and method of preparing the same |
| US4977156A (en) * | 1988-07-26 | 1990-12-11 | The Dow Chemical Company | Amino piperazine esters showing biocidal activity |
-
0
- US US2472496D patent/US2472496A/en not_active Expired - Lifetime
Non-Patent Citations (1)
| Title |
|---|
| None * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2535971A (en) * | 1948-10-15 | 1950-12-26 | American Cyanamid Co | 1-carbalkoxy-4-substituted piperazines |
| US2617803A (en) * | 1949-10-21 | 1952-11-11 | American Cyanamid Co | Dialkylaminoalkyl esters of piperazine carboxylic acids |
| US2780625A (en) * | 1954-08-17 | 1957-02-05 | American Cyanamid Co | Piperazine derivatives and method of preparing the same |
| US4977156A (en) * | 1988-07-26 | 1990-12-11 | The Dow Chemical Company | Amino piperazine esters showing biocidal activity |
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