US3085935A - Method for the elimination of nematode infestations - Google Patents
Method for the elimination of nematode infestations Download PDFInfo
- Publication number
- US3085935A US3085935A US104798A US10479861A US3085935A US 3085935 A US3085935 A US 3085935A US 104798 A US104798 A US 104798A US 10479861 A US10479861 A US 10479861A US 3085935 A US3085935 A US 3085935A
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- US
- United States
- Prior art keywords
- infestations
- elimination
- host
- worms
- intestinal tract
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- Expired - Lifetime
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
Definitions
- the present invention relates to the discovery that the following novel group of di-stilbazoles, expressed in Formula I, have marked activity against nematode infestations of the intestinal tract
- R is selected from the class consisting of methyl, ethyl, n-propyl, n-butyl and benzyl radicals
- R is selected from the class consisting of the methyl and ethyl radicals
- NR may also be pyrrolidino or piperidino
- X-* is the anion of a non-toxic pharmaceutically acceptable acid.
- the parasites of particular concern are pin-worms (Enterobius vermicularis, Syphacia obvelata and Aspicul'uris tetraptera of mice) and hook-worms (Ancylostoma duodenale and Necator americanus and Ancylostoma caninum of dogs).
- the pin-worms of mice are primarily of interest as test-organisms, Syphacia especially having been found to be a reliable indicator of the elfectiveness of drugs against human pin-worm.
- the hook-worms of dogs are both test-organisms and parasites of some importance in their own right since severe infestations by canine hook-worm are common among dogs in the South of the United States, and light infestations are fairly frequent in the North.
- R cannot be a branched group and its size is pretty well limited at four carbons.
- iodide ion is sufliciently nontoxic. Bromide or chloride or methyl sulfate and ptoluene sulfonate are other convenient values for X cates the critical character of the structure-activity relationships. All of these results were obtained with single doses administered orally. It will be observed (cf. cpds. I-V) that substitution by a [dialkylamino group in the benzenoid rings is essential for high activity and that this substitution must be in the para position (compare III and V). Auxiliary substitution is undesirable (compare IV and V).
- NR has an acceptable value, R may vary considerably. It will be seen from the table that all variations of R Within the definition give active compounds. Of these, however, the methiodides and ethiodides are very much the most accessible.
- 2,-6-bz's (p-pyrrolidinostyryl) pyridine ethiodide compound XII of the table.
- a mixture containing 2.6 g. of 2,6-lutidine ethiodide, 100 cc. of methanol, 4.2 g. of p-pyrrolidinobenzaldehyde and 1 cc. of piperidine was refluxed on a steam bath. Insoluble solid precipitated and heavy bumping started in less than one hour. After 2 hours this product was collected (2 g.) and the filtrates were refluxed for 20 hours longer. A second crop of 2.5 g. was obtained and on standing another day or so the filtrates gave a third crop of one g. The total yield was 5.5 g.
- a method of eradicating infestations of parasitic nematodes inhabiting the intestinal tract which comprises administering orally to the host of the infested locus a compound represented by the formula nematodes inhabiting the intestinal tract which comprises administering orally to the host of the infested locus 2,6- bis (p-dimcthylaminostyryl) pyridine methiodide.
- a method of eradicating infestations of parasitic nematodes inhabiting the intestinal tract which comprises administering orally to the host of the infested locus 2,6-bis (p-dimethylaminostyryl)pyridine benzyl iodide.
- a method of eradicating infestations of parasitic nematodes inhabiting the intestinal tract which comprises administering orally to the host of the infested locus 2,6-bis (p-pyrrolidinostyryl) pyridine ethiodide.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
United States Patent York No Drawing. Filed Apr. 24, 1961, Ser. No. 104,798 6 (Ilaims. (Ql. 167-53) The present invention relates to the discovery that the following novel group of di-stilbazoles, expressed in Formula I, have marked activity against nematode infestations of the intestinal tract In the above formula R is selected from the class consisting of methyl, ethyl, n-propyl, n-butyl and benzyl radicals, R is selected from the class consisting of the methyl and ethyl radicals, and NR may also be pyrrolidino or piperidino and X-* is the anion of a non-toxic pharmaceutically acceptable acid.
The parasites of particular concern are pin-worms (Enterobius vermicularis, Syphacia obvelata and Aspicul'uris tetraptera of mice) and hook-worms (Ancylostoma duodenale and Necator americanus and Ancylostoma caninum of dogs). The pin-worms of mice are primarily of interest as test-organisms, Syphacia especially having been found to be a reliable indicator of the elfectiveness of drugs against human pin-worm. The hook-worms of dogs are both test-organisms and parasites of some importance in their own right since severe infestations by canine hook-worm are common among dogs in the South of the United States, and light infestations are fairly frequent in the North.
Some of the compounds of Formula I have been described previously but none have ever been examined as anthelmintics. The doses required vary somewhat with the parasite and with the host, and rather less with the individual compounds. Against mouse pin-worms oral doses of 5-20 mg./kg. eliminate all or virtually all the worms in one treatment. With dogs hook-worms are well eliminated by compound V (Table I) in a single dose of 25 trig/kg. The whip-worm, Trz'curis vulpis, requires the same sized dose but repeated twice a day for three days. The common round-worm of dogs (Toxocara canz's) is also vulnerable to this compound.
These compounds are conveniently prepared by condensation or" two equivalents of an aldehyde:
with a quarternary salt of 2,6-lutidine The condensation is conveniently run in a lower alcohol with a secondary amine, such as piperidine, as catalyst. When X- in the above formula is iodide ion (correspond- 3,085,935, Patented Apr. 16, 1963 ing to an .alkiodide of lutidine) the condensation product, I, is relatively insoluble and precipitates in the course of the reaction. The yields of I, so obtained, are nearly quantitative.
Of the p-dialkylaminobenzaldehydes required for this synthesis, padimethylamino and p-diethylaminobenzaldehydes are known. The preparation of p-pyrrolidino and p-piperidinobenzaldehydes is described in a companion application. The nature of R, beyond being a lower alkyl.
group, is pretty well determined by the chemistry of the situation. The normal diminution in the reactivity of alkyl halides with the increasing size of the alkyl group is here accentuated by the hindrance of the 2,6-lutidine.
As a result R cannot be a branched group and its size is pretty well limited at four carbons. The more reactive benzyl is, however, usable.
In the doses employed iodide ion is sufliciently nontoxic. Bromide or chloride or methyl sulfate and ptoluene sulfonate are other convenient values for X cates the critical character of the structure-activity relationships. All of these results were obtained with single doses administered orally. It will be observed (cf. cpds. I-V) that substitution by a [dialkylamino group in the benzenoid rings is essential for high activity and that this substitution must be in the para position (compare III and V). Auxiliary substitution is undesirable (compare IV and V). Taking p-dialkylamino substitution as essential it will be seen that high activity ceases above diethylamino (VIII-X) but that pyrollidino and piperidino are satisfactory values for NR Morpholino and N'-alkyl piperazino substitutions give relatively inactive compounds (XVI-XVII).
Provided NR has an acceptable value, R may vary considerably. It will be seen from the table that all variations of R Within the definition give active compounds. Of these, however, the methiodides and ethiodides are very much the most accessible.
PREPARATION OF THE DI-STILBAZOLES All of the di-stilbazoles were prepared by essentially thesame method. Compounds V and VI of Table I were reported by Crippa and Verdi (Ann. chim. applioata, 26, 418 (1936) (Chem. Abs. 31, 2214" (1937).
2,-6-bz's (p-pyrrolidinostyryl) pyridine ethiodide (compound XII of the table).A mixture containing 2.6 g. of 2,6-lutidine ethiodide, 100 cc. of methanol, 4.2 g. of p-pyrrolidinobenzaldehyde and 1 cc. of piperidine was refluxed on a steam bath. Insoluble solid precipitated and heavy bumping started in less than one hour. After 2 hours this product was collected (2 g.) and the filtrates were refluxed for 20 hours longer. A second crop of 2.5 g. was obtained and on standing another day or so the filtrates gave a third crop of one g. The total yield was 5.5 g. (-85%) in three crops, M.P. 282-283 C. The product was nearly insoluble in hot methanol and was purified by washing several times With ether and then digesting one or two times with 10-20 times its weight of hot methanol. Because it is difficult to recrystallize it is desirable that nearly all insoluble impurities (dust, boiling stones, etc.) be removed from the easily purified reactants before the final condensation step and be kept out as much as possible thereafter.
Table I Substitution in benzene rings Percent worms removed Dose. nag/Kg.
4-CH3O 2-N(CH3) z--CH3 VII-..
VIII
XVII.
4-N(CH CH2CH:)2
4-N(CH:C5H5)2 C H5CH2 11-C4Hn M \I HM HHN} r-u- N: i-nm HM t- Nn- M HMP-M' l-u- 00 010010 0010 momo 01cc ooooovoooouvmcuocovcncuv oncom amazes 10:08 soccer: in! umzocow woocomscnzozo sm M coo ours wooco oo cnqacr ONO: vm wficcoworocawqoww-q owitmmuomw These substances can be presented in capsules or as compressed tablets or can be administered in a chewing wafer.
What we claim is: 1. A method of eradicating infestations of parasitic nematodes inhabiting the intestinal tract which comprises administering orally to the host of the infested locus a compound represented by the formula nematodes inhabiting the intestinal tract which comprises administering orally to the host of the infested locus 2,6- bis (p-dimcthylaminostyryl) pyridine methiodide.
3. A method of eradicating infestations of parasitic nematodes inhabiting the intestinal tract which comprises administering orally to the host of the infested locus 2,6 bis (p-diethylaminostyryl) methiodide.
4. A method of eradicating infestations of parasitic nematodes inhabiting the intestinal tract which comprises administering orally to the host of the infested locus 2,6-bis (p-dimethylaminostyryl) pyridine ethiodide.
5. A method of eradicating infestations of parasitic nematodes inhabiting the intestinal tract which comprises administering orally to the host of the infested locus 2,6-bis (p-dimethylaminostyryl)pyridine benzyl iodide.
6. A method of eradicating infestations of parasitic nematodes inhabiting the intestinal tract which comprises administering orally to the host of the infested locus 2,6-bis (p-pyrrolidinostyryl) pyridine ethiodide.
No references cited.
Claims (1)
1. A METHOD OF ERADICATING INFESTATIONS OF PARASITIC NEMATODES INHABITING THE INTESTINAL TRACT WHICH COMPRISES ADMINISTERING ORALLY TO THE HOST OF THE INFESTED LOCUS A COMPOUND REPRESENTED BY FORMULA
Priority Applications (16)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
NL277327D NL277327A (en) | 1961-04-24 | ||
US104798A US3085935A (en) | 1961-04-24 | 1961-04-24 | Method for the elimination of nematode infestations |
US115996A US3075975A (en) | 1961-04-24 | 1961-06-07 | Anthelmintic distilbazoles and method |
GB22626/61A GB1009301A (en) | 1961-04-24 | 1961-12-22 | Styryl-pyridinium compounds, the preparation thereof, and pharmaceutical compositions thereof |
DE19621470413 DE1470413A1 (en) | 1961-04-24 | 1962-04-16 | Quaternary ammonium compounds, their manufacture and pharmaceutical preparations |
ES276612A ES276612A1 (en) | 1961-04-24 | 1962-04-18 | A method for the preparation of diestilizabol compounds (Machine-translation by Google Translate, not legally binding) |
DK179562AA DK104234C (en) | 1961-04-24 | 1962-04-18 | Process for the preparation of distilbazole compounds. |
CH480662A CH413836A (en) | 1961-04-24 | 1962-04-18 | Process for the preparation of distilbazoles |
AT945364A AT248792B (en) | 1961-04-24 | 1962-04-20 | Method for the treatment of nematode worm infections in animals |
AT328762A AT239218B (en) | 1961-04-24 | 1962-04-20 | Process for the preparation of new quaternary ammonium compounds of distilbazole |
LU41596D LU41596A1 (en) | 1961-04-24 | 1962-04-21 | |
BR138334/62A BR6238334D0 (en) | 1961-04-24 | 1962-04-23 | A PROCESS FOR THE PREPARATION OF CATION DISTILBAZOL COMPOUNDS |
FR895386A FR1841M (en) | 1961-04-24 | 1962-04-24 | Medicinal product based on a quaternary salt derived from distilbazole. |
FR895385A FR1320520A (en) | 1961-04-24 | 1962-04-24 | Quaternary salts of distilbazole derivatives |
OA52810A OA02352A (en) | 1961-04-24 | 1967-03-11 | Quaternary salts of distibazole derivatives. |
MY196793A MY6700093A (en) | 1961-04-24 | 1967-12-31 | Styryl-pyridium compounds, the preparation thereof, and pharmaceutical compositions thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US104798A US3085935A (en) | 1961-04-24 | 1961-04-24 | Method for the elimination of nematode infestations |
Publications (1)
Publication Number | Publication Date |
---|---|
US3085935A true US3085935A (en) | 1963-04-16 |
Family
ID=22302443
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US104798A Expired - Lifetime US3085935A (en) | 1961-04-24 | 1961-04-24 | Method for the elimination of nematode infestations |
Country Status (2)
Country | Link |
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US (1) | US3085935A (en) |
AT (2) | AT239218B (en) |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3873312A (en) * | 1973-05-04 | 1975-03-25 | Eastman Kodak Co | Photoconductive composition and elements containing a styryl amino group containing photoconductor |
US3883658A (en) * | 1968-09-19 | 1975-05-13 | Burroughs Wellcome Co | Method of treating nematode infestations |
US4558133A (en) * | 1979-08-08 | 1985-12-10 | Bayer Aktiengesellschaft | p-(Pyridinium-vinyl)-N,N-(disubstituted-aniline salts for dyeing paper and their preparation |
US5360911A (en) * | 1993-06-17 | 1994-11-01 | General Electric Company | Process for the preparation of stilbazolium salts |
US20030138374A1 (en) * | 2000-03-22 | 2003-07-24 | Yukitsuda Kudo | Image diagnosis probe based on substituted azobenzene or analogue thereof for disease attributable to amyloid accumulation and composition for image diagnosis containing the same |
WO2004078136A2 (en) * | 2003-03-03 | 2004-09-16 | Mycosol, Inc. | Pyridinium salts, compounds and methods of use |
-
1961
- 1961-04-24 US US104798A patent/US3085935A/en not_active Expired - Lifetime
-
1962
- 1962-04-20 AT AT328762A patent/AT239218B/en active
- 1962-04-20 AT AT945364A patent/AT248792B/en active
Non-Patent Citations (1)
Title |
---|
None * |
Cited By (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3883658A (en) * | 1968-09-19 | 1975-05-13 | Burroughs Wellcome Co | Method of treating nematode infestations |
US3873312A (en) * | 1973-05-04 | 1975-03-25 | Eastman Kodak Co | Photoconductive composition and elements containing a styryl amino group containing photoconductor |
US4558133A (en) * | 1979-08-08 | 1985-12-10 | Bayer Aktiengesellschaft | p-(Pyridinium-vinyl)-N,N-(disubstituted-aniline salts for dyeing paper and their preparation |
US5360911A (en) * | 1993-06-17 | 1994-11-01 | General Electric Company | Process for the preparation of stilbazolium salts |
WO1996008474A1 (en) * | 1993-06-17 | 1996-03-21 | Molecular Optoelectronics Corporation | Process for the preparation of stilbazolium salts |
US20030138374A1 (en) * | 2000-03-22 | 2003-07-24 | Yukitsuda Kudo | Image diagnosis probe based on substituted azobenzene or analogue thereof for disease attributable to amyloid accumulation and composition for image diagnosis containing the same |
WO2004078136A2 (en) * | 2003-03-03 | 2004-09-16 | Mycosol, Inc. | Pyridinium salts, compounds and methods of use |
US20040224984A1 (en) * | 2003-03-03 | 2004-11-11 | Selph Jeffrey L. | Methods of treating inflammations and infections with pyridinium salts |
WO2004078136A3 (en) * | 2003-03-03 | 2004-12-16 | Mycosol Inc | Pyridinium salts, compounds and methods of use |
US7220761B2 (en) | 2003-03-03 | 2007-05-22 | Mycosol, Inc. | Compounds and methods for controlling fungi, bacteria and insects |
JP2007525441A (en) * | 2003-03-03 | 2007-09-06 | マイコソル,インコーポレイテッド | Pyridinium salts, compounds and methods of use |
US7547444B1 (en) | 2003-03-03 | 2009-06-16 | Mycosol, Inc. | Methods for controlling fungi and bacteria |
US7820696B2 (en) | 2003-03-03 | 2010-10-26 | Mycosol, Inc. | Compounds and methods for controlling fungi, bacteria and insects |
JP4742028B2 (en) * | 2003-03-03 | 2011-08-10 | マイコソル,インコーポレイテッド | Pyridinium salts, compounds and methods of use |
US8124626B2 (en) | 2003-03-03 | 2012-02-28 | Mycosol, Inc. | Methods of treating inflammations and infections with pyridinium salts |
Also Published As
Publication number | Publication date |
---|---|
AT248792B (en) | 1966-08-10 |
AT239218B (en) | 1965-03-25 |
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