Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
2000-03-23
2001-11-20
Vollano, Jean F. (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
Reexamination Certificate
active
06320079
ABSTRACT:
FIELD OF INVENTION
This invention relates to a process for preparation of S-(&ohgr;-aminoalkylamino) alkyl aryl sulfide dihydrochlorides particularly S-2 (2-aminoethylamino) ethyl phenyl sulfide dihydrochloride, and to a process for the preparation thereof. Without implying any limitation on the scope of invention, the compound of the present invention has application as a new and effective antidote against highly toxic sulfur mustard (SM).
PRIOR ART
Sulfur mustard (SM) is a highly toxic chemical and a well known chemical warfare agent. This chemical attacks not only skin but all epithelial tissues with which it comes into contact including those of eyes and airways. Exposure to higher doses of sulfur mustard causes systemic toxicity with little or no involvement of the eyes, respiratory tract or skin. The signs and symptoms of systemic poisoning are similar to those caused by nuclear radiation.
One type of antidote known in the art is a SM scavenger, which is comprised of compounds that prevent alkylation of critical targets. Representative members of this class that have been tested are sodium thiosulfate, N-acetyl-L-cysteine, and several other sulfur compounds such as thiophosphonates, thiophosphates and thiocarbamates. These classes of compounds have several disadvantages that would preclude their practical use as antidotes for the systemic toxicity of sulfur mustard. One such disadvantage is that such compounds can only be administered intraveneously thereby making them unsuitable for self-administration. Another disadvantage is that such compounds are suitable only for pretreatment. A further disadvantage for use as antidotes against SM is that these compounds are excreted rapidly by the kidney after which their efficacy as an SM scavenger is lost.
Another type of compound known in the art is a NAD level stabilizer. Nicotinamide and nicotinic acids have been tested as representatives of this class. Although some of these compounds under certain circumstances have been found effective in preventing SM toxicity, these also suffer from certain drawbacks. One such drawback is that they are effective in lymphocytes but not in cultured keratinocytes. Another disadvantage is that, if these compounds are administered 24 hours after SM exposure, they fail to provide any protection against SM toxicity. Still another disadvantage is that these compounds fail to prevent SM-induced adenosine triphosphate (ATP) loss in the cells and thus these compounds provide only short term cytoprotection. A further disadvantage is that these compounds can only be administered parenterally.
OBJECTS OF PRESENT INVENTION
A primary object of this invention is to propose S-(&ohgr;-aminoalkylanino) alkyl aryl sulfide dihydrochlorides, particularly S-2(2-aminoethylamino) ethyl phenyl sulfide dihydrochloride, and a process for the preparation thereof for use as a new and effective antidote against sulfur mustard, which is a highly toxic and known chemical warfare agent.
Another object of this invention is to propose a process which provides S-(&ohgr;-aminoalkylamino) alkyl aryl sulfide dihydrochlorides, particularly S-2(2-aminoethylamino) ethyl phenyl sulfide dihydrochloride, which can be administered both orally as well as parenterally as an antidote against sulfur mustard, thereby making the compound suitable for self-administration.
Still another object of this invention is to propose a process for preparation of S-(&ohgr;-aminoalkylamino) alkyl aryl sulfide dihydrochlorides particularly S-2(2-aminoethylamino) ethyl phenyl sulfide dihydrochloride which is effective antidote as a pretreatment and also as a therapeutic agent.
A further object of the present invention is to propose a process for preparation of S-(&ohgr;-aminoalkylamino) alkyl aryl sulfide dihydrochlorides, particularly S-2(2-aminoethylamino) ethyl phenyl sulfide dihydrochloride, which provides cytoprotection.
DESCRIPTION OF THE INVENTION
According to this invention there is provided S-(&ohgr;-aminoalkylamino) alkyl aryl sulfide dihydrochlorides.
In accordance with the present invention, a process is provided for the preparation of S-(&ohgr;-aminoalkylamino) alkyl aryl sulfide dihydrochlorides, particularly S-2(2-aminoethylamino) ethyl phenyl sulfide dihydrochloride, which is a new and effective antidote against sulphur mustard, which is a known chemical warfare agent. The process comprises condensation of S-(&ohgr;-aminoalkylamino) alkyl aryl sulfide dihydrochlorides with aryl mercaptans in the presence of an organic base in an organic solvent. The organic base used is primary or secondary or tertiary alkylamine or arylamine. Particularly for preparation of S-2(2-aminoethylamino) ethyl phenyl sulfide dihydrochloride, the organic base preferably used is triethylamine. The organic solvents used are chloroform or carbon tetrachloride or dimethyl sulfoxide or dimethyl formamide. Particularly for preparation of S-2(2-aminoethylamino) ethyl phenyl sulfide dihydrochloride, the organic solvent preferably used is chloroform. The reaction is carried out at −15 to +15° C. with efficient stirring for 2-5 hours. The residue comprising the free base is converted to its dihydrochloride salt by treatment with concentrated hydrochloric acid. The antidote against SM, prepared by the process of the present invention, can be administered both orally as well as intraperitoneally making it a unique compound which is suitable for self-administration. The compound is effective as a pretreatment as well as a therapeutic agent and provides cytoprotection in cases of systemic toxicity. The process provides 60-65% yield of compound with a very high purity of more than 99%.
Specifically, the process comprises preparation of a suspension of a mixture of (&ohgr;-aminoalkylamino) alkylbromide dihydrobromide and aryl mercaptan taken in 1:1.2 molar ratio in an appropriate quantity of an organic solvent. Specifically for preparation of S-2(2-aminoethylaimino) ethyl phenyl sulfide dihydrochloride, (2-aminoethylamino) ethylbromide dihydrobromide and thiophenol are taken in the above molar ratio. The organic solvent taken is either dry chloroform or carbon tetrachloride or dimethyl sulfoxide or dimethyl formamide preferably dry chloroform.
The suspension is cooled to a temperature of −15 to +15° C., preferably at 0-5° C. and an organic base added with is either primary or secondary or tertiary alkylamine or arylarnine, preferably a tertiary alkylamine or arylamine. Specifically, for preparation of S-2(2-aminoethylamino) ethyl phenyl sulfide dihydrochloride, the organic base preferably taken is triethylamine which is taken in a quantity four times the quantity of bromide salt, with constant stirring, over a period of around 1 hour. Stirring is continued preferably at 0-5° C. for 3-5 hours followed by further stirring at 20 to 40° C. for 3-5 hours and then left at the same temperature for overnight.
The next steps comprises washing with water to remove the triethylamine salt, making the aqueous layer alkaline with sodium hydroxide, and extracting twice with chloroform.
The combined chloroform extracts are dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue is diluted with a mixture of benzene and ethanol taken in 1:1 ratio, and the solvent is removed repeatedly in order to remove traces of triethylamine and moisture.
The residue is dissolved in ethanol and concentrated hydrochloric acid is added until the solution becomes acidic.
The white dihydrochloride salt of the product is precipitated by addition of sufficient quantity of acetone until the completion of precipitation. The contents are kept under refrigeration for 2 hours, filtered and dried at room temperature.
The dried solid is boiled with chloroform for 10 to 30 minutes to remove any triethylamine hydrochloride salt, followed by filtering while hot and drying at room temperature.
The solid obtained by boiling is dissolved in methanol, just sufficient to dissolve the solid, followed by treatment with activated charcoal and addition of acetone until the crystalliz
Jaiswal Devendra Kumar
Joshi Uma
Kumar Pravin
Raza Syed Kalbey
Vijayaraghavan Rajagopalan
Spencer George H.
The Chief Controller, Research & Ministry of Defense, Goverment
Venable
Vollano Jean F.
Wells Ashley J.
LandOfFree
Process for the preparation of S(&ohgr;-aminoalkylamino)... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Process for the preparation of S(&ohgr;-aminoalkylamino)..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Process for the preparation of S(&ohgr;-aminoalkylamino)... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2584948