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Publication numberUS2780577 A
Publication typeGrant
Publication dateFeb 5, 1957
Filing dateMay 26, 1951
Priority dateMay 26, 1951
Publication numberUS 2780577 A, US 2780577A, US-A-2780577, US2780577 A, US2780577A
InventorsArthur P Phillips, Julio C Castillo
Original AssigneeBurroughs Wellcome Co
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Inhibiting polymethylene diquaternary curariform activity by alpha-stilbazoline derivatives
US 2780577 A
Abstract  available in
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Description  (OCR text may contain errors)

United States Patent 4 Claims. (Cl. 167-65) The present invention relates to a new class of derivatives having the property of inhibiting the action of certain curariform drugs. These compounds comprise a family of diquaternary salts having the formula:

wherein R and R are radicals selected from the class consisting of the methyl and ethyl radicals and R is a lower alkyl radical of not over four carbon atoms, and X- is the anion of a non-toxic acid.

The inhibiting action of these compounds which are derived from alpha-stilbazoline is entirely unexpected in view of the very potent curare-like activity of the closely related diquaternary salts of the 'y-stilbazoline system such as While the present derivatives show only very minor curate-like activity, they possess the surprising property of inhibiting the action of their 'y-analogs. This inhibitory action, however, does not extend to natural d-tubocurarine chloride but it does afiect the powerful polymethylene diquaternary salts of which thebest known is decarn'ethylene bis-trimethylammonium bromide (Decamethonium Bromide, Syncurine, Ceeten,. C-lO). Since these latter compounds which are already in clinical use suffer from the disadvantage of having no direct antidote, the protective utility of our a-stilbazoline diquaternary salts in medicine is considerable.

The compounds of the present invention are conveniently prepared by a sequence of reactions parallel to that shown in our co-pending patent application No. 218,279, now Pat. No. 2,655,503, on the -y-stilbazoline diquaternary salts.

2,780,577 A, Patented Feb. 5, 1957 base Steps land 11 have already been described (Phillips, J. Org. Chem, 12, 333 (1947), and J. Amer. Chem. Soc., 72, 1850 (1950) wherefore the present application discloses only those processes involved in the third step and the preparation of certain intermediates not specifically reported before.

In the general formula of these diquaternary salts the III nature of the alkyl groups (R, R and R appears not 7 to be especially critical; however, the simplest compound in which all are methyl groups is at least as active as any of the others. Further, with increasing size of the alkyl groups the respiration is afiected unfavorably and the synthetic operations become more difficult so that the given limits cover the substances that are believed to be of practical utility. The compounds having R =n-propyl and n-butyl with R=R =methyl were not obtained in crystalline form though analytically pure. In part this may be due to the general tendency of larger alkyl groups to lower melting points; however, other influences may be at work. When all-alkyl groups are the same these substances have one asymmetric atom and exist as racemic mixtures, but when R and R are ditferent a second point of asymmetry is created at the piperidine nitrogen. Such substances can exist in four stereo-isomeric forms or as two different racemic modifications. It is very likely that the lower and unsharp melting points correspond to the presence of such isomeric mixtures. Further separation of isomers will doubtless reveal variations in physiological activity, but it is not believed that such separation will be of commercial value.

According to the given scheme of synthesis X- is 1'. However, other anions can be present. such as Br, SO4= etc. through the use of other alkylating agents in place of methyl or ethyl iodide. Furthermore, the iodides can readily be converted into other salts by conventional methods. In the doses to be used in practice the nature of the anion is of no consequence and therefore we consider all anions of acids possessing low inherent toxicity to be equivalent and comprehended in our invention.

EXAMPLE 1 1 methyl 2 (4' dimethylaminophenethyl) piperidine bis methiodide (compound 49-204) The base obtained from 12.5 g. (0.033 mole) of 1 methyl 2 (4 dimethylaminophenethyl) piperidine hydroiodide (or 1 methyl 4 dimethylamino a stilbazoline hydroiodide) was taken up in ether and dried over potassium carbonate. The solution was filtered from the desiccant and evaporated. The residual base (8.3 g.) was dissolved in methanol, 8 cc. of methyliodide was added, and the solution was refluxed 8 hours on the steam bath. The solvent and excess methyliodide were then evaporated and the diquaternary salt was crystallized from a methanol ethyl acetate mixture, M. P., 188- 189 C. Conversion to the chloride was accomplished by shaking with silver chloride in aqueous solution.

3 EXAMPLE 2 N methyl 2 (4 dimethylaminophenethyl) piperidine bis ethiodide (compound 49-241) By the method of Example 1, 1 methyl 2 (4 di methylaminophenethyl) piperidine was converted to its bis-ethiodide which melts at. 205-6.

The corresponding bis n-propiodide and bis n-butiodide were also prepared by the same procedure. Although they could not be obtained crystalline, they were precipitated a number of times as oils which hardened on rubbing with ether to apparent solids. These gave correct analysis for carbon, hydrogen, and iodine and may be regarded as analytically pure. They may be mixtures of stereoisomers. These solids softened over the ranges of 145-l50, and 115-120 C'. respectively EXAMPLE. 3

1' methyl 2 (4 diethylaminophenethyl) piperidine bismethiodide The base was liberated from 6 g. (0.015 mole) of 1 methyl 2 (4 diethylaminophenethyl) piperidine, taken into ether and dried over potassium carbonate. After evaporation of the solvent ether the residue was dissolved in 15 cc. of methanol and the solution was divided into two equal portions. To one of these was added cc. of methyl iodide and the solution was refluxed 18 hours. The solvent was evaporated and the residue was crystallized from ethanol-ether mixtures. The product (3.5 g.) melted with decomposition at 191- 192 C.

The second portion of the solution of the precursor base was converted to the his ethiodide. This, like the bis propiodide and his butiodide of Example 2 could not be crystallized but was obtained as a pseudo solid of correct composition.

omorn-Q-mnnw 2X- N 7 3. A method of checking the curate-like activity of a polymethylene.diquaternary curariform drug which comprises the administration to a human being of a salt of the bivalent cation:

4. emeraQarwmncm.

4. A method of checking the curare-like activity of a polymethylene diquaternary curariform drug which comprises the administration to a human being of a salt of the bivalent cation:

omcmQ-mcnmum References Cited in the file of this patent Phillips. (1): J. Org. Chem., vol. 14, pp. 302-5 (1949).

Phillips (II): J. Am. Chem. Soc., vol. 72, pp. 1850-2, April 1950.

Non-Patent Citations
1 *None
Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US3119824 *Aug 30, 1961Jan 28, 1964 L-substituted-l
US3135659 *May 2, 1962Jun 2, 1964Wallace & Tiernan IncHydroxy and alkoxy aryl quinazolinones
US3161653 *Nov 21, 1961Dec 15, 1964Merck Ag E2-[(2'-methyl-benzo-thienyl-3')-methyl]-delta2-imidazoline and its pharmaceutically aceptable acid addition salts
US3169090 *Jan 23, 1961Feb 9, 1965Upjohn CoThiazoline analgesics
US3209025 *Oct 27, 1961Sep 28, 1965Hoechst AgBis-(beta-carbhydrazido-ethyl)-sulfone
US3222365 *Jan 15, 1962Dec 7, 1965Lilly Co Eli4-halophenyl-2-alkyl-1(2)-phthalazinones
US3235566 *Apr 1, 1963Feb 15, 1966 Benzofuran-j-carboxylic acids and esters
US3238101 *Sep 9, 1964Mar 1, 1966Merck Ag EBlood vessel constricting compositions and methods of using same
US3271398 *Mar 13, 1963Sep 6, 1966Fujisawa Pharmaceutical CoOrotic acid salt of 4-amino-5-imidazolecarboxamide
US3931195 *Jul 31, 1973Jan 6, 1976Mead Johnson & CompanySubstituted piperidines
US4000143 *Oct 8, 1975Dec 28, 1976Mead Johnson & CompanySubstituted piperidines
US4064254 *Oct 21, 1976Dec 20, 1977Mead Johnson & CompanySubstituted piperidines therapeutic process and compositions
US4558133 *Jul 21, 1980Dec 10, 1985Bayer Aktiengesellschaftp-(Pyridinium-vinyl)-N,N-(disubstituted-aniline salts for dyeing paper and their preparation
USRE30811 *Nov 28, 1979Dec 1, 1981Mead Johnson & CompanySubstituted piperidines therapeutic process and compositions
USRE30812 *Nov 28, 1979Dec 1, 1981Mead Johnson & CompanySubstituted piperidines therapeutic process and compositions
U.S. Classification514/331, 546/229, 514/823
Cooperative ClassificationY10S514/823, C07D401/12