US3673205A - 6-(m-AMINO AND SUBSTITUTED-AMINO PHENYL)-2,3,5,6-TETRAHYDRO{8 2,1-b{9 THIAZOLES AND METHOD OF USE - Google Patents

6-(m-AMINO AND SUBSTITUTED-AMINO PHENYL)-2,3,5,6-TETRAHYDRO{8 2,1-b{9 THIAZOLES AND METHOD OF USE Download PDF

Info

Publication number
US3673205A
US3673205A US22701A US3673205DA US3673205A US 3673205 A US3673205 A US 3673205A US 22701 A US22701 A US 22701A US 3673205D A US3673205D A US 3673205DA US 3673205 A US3673205 A US 3673205A
Authority
US
United States
Prior art keywords
amino
mole
thiazole
compounds
tetrahydroimidazo
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
Application number
US22701A
Other languages
English (en)
Inventor
Larry Dean Spicer
John James Hand
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Wyeth Holdings LLC
Original Assignee
American Cyanamid Co
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by American Cyanamid Co filed Critical American Cyanamid Co
Application granted granted Critical
Publication of US3673205A publication Critical patent/US3673205A/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the invention also relates to a novel method for the preparation of these compounds and to the use of said compounds for treating helminthiasis in warm-blooded animals.
  • salts can be the hydrochloride, hydrobromide, sulfate, nitrate, phosphate and the like.
  • an appropriate anilide such as 3-acetylacetanilide, 3-acetylformanilide, 3'- acetylpropionanilide is dissolved in an inert solvent such as methylene chloride, chloroform, carbon tetrachloride or the like, and treated with bromine, chlorine, or the like, to form the corresponding 3-chloro or 3'-bromoacetylacetanilide, formanilide or propionanilide shown as formula (I) on the flow diagram hereinafter.
  • an inert solvent such as methylene chloride, chloroform, carbon tetrachloride or the like
  • T of the formula (1) anilide with an equimolor amount of 2- aminothiazole or 2-amino-2-thiazoline in an solvent such as methylene chloride, chloroform, acetone, ethyl acetate or the like, at a temperature between about C. and 75 C., yields the 3 2-imino-4-thiazolin-3-yl )acetyl acetanilide, formanilide, or propionanilide, hydrochloride or hydrobromide salt of formula (ll).
  • an solvent such as methylene chloride, chloroform, acetone, ethyl acetate or the like
  • This salt is treated with at least the theoretical amount of an alkali metal borohydride in the presence of a lower alcohol such as methanol, ethanol, butanol, isopropanol, water-lower alcohol or the like and then acidified with an organic or hydrohalide mineral acid to form the hydroxyethyl acetanilide hydrohalide or formula (IVB).
  • a lower alcohol such as methanol, ethanol, butanol, isopropanol, water-lower alcohol or the like
  • an organic or hydrohalide mineral acid to form the hydroxyethyl acetanilide hydrohalide or formula (IVB).
  • formula (II) imino-thiazolinyl anilide hydrohalide can be treated with acetic anhydride in the presence of an inert solvent such as acetic acid and an alkali metal acetate at a temperature between about 50 and 120 C.
  • Cyclization of the formula (IV) compounds can also be achieved by reaction with concentrated sulfuric acid followed by treatment of the reaction product with strong base such as formula (V) with hydrochloric or hydrobromic acid at refluxing temperature yields the aminophenyl imidazo thiazole dihydrohalide of formula (Vll).
  • the formula (VII) compound can also be prepared from 2,3,5,6-tetrahydro-6-(m-nitrophenyl)imidazo[ 2,l-b]-thiazole hydrochloride (V1) by reacting such compound with stannous chloride and hydrochloric acid at higher temperature, for example, between about 60 and C. The resulting product is then neutralized with an alkali metal hydroxide and the mixture treated with an alcohol hydrohalide.
  • l-6-(maminophenyl )-2,3 ,5 ,6-tetrahydroimidazo[ 2, l -b]thiazole dihydrochloride is obtained by resolution of racemic dl2,3 ,5 ,6-tetrahydro-6-(m-nitrophenyl )imidazo[ 2, l b]thiazole with d-tartaric acid to give the l-base, d-tartarate salt which is converted to the free base and then to the lisomer, l-6-(m-nitrophenyl )-2,3 ,5 ,6-tetrahydroimidazo[2,1- b]thiazole hydrochloride.
  • the compounds of the present invention are useful as anthelmintic agents effective for treating helminthiasis in warm-blooded animals.
  • They are highly effective at very low dosage levels, for example, at from 1 to about mg./kg. of body weight and preferably are utilized at dose levels from 1.5 to 5.0 mg./kg. of body weight of warm-blooded animal.
  • they are effective for removing all of the important gastrointestinal nematodes, namely, ascarids, hookworms, whipworms and tapeworms. They have the advantage over their known relatives of being highly effective against whipworms, a helminth heretofore extremely difficult to control. They may be used for treatment of helminthiasis in laboratory, farm and domestic animals as well as wild animals held in captivity and are particularly useful in the treatment of helminthiasis in Canidae.
  • the active compounds may be administered orally or parenterally. They may be administered orally in the form of a tablet, pill, capsule, bolus, drench, liquid formulation or in the feed.
  • a pharmaceutically acceptable carrier such as distilled water, polyethyleneglycol or the like and adjusted to a pH between 3.5 to 6.5 and given by subcutaneous or intramuscular injection.
  • EXANIPLE 1 Preparation of 3'-Bromoacetylacetanilide (1A) To a stirred solution of 110.0 g. (0.62 mole) of 3'- acetylacetanilide in 2,400 m1. of chloroform is added dropwise a solution of 33.0 ml. 102.9 g; 0.644 mole) of bromine in 240 ml. of chloroform. The solution is stirred one hour and the resultant precipitate is then filtered, washed with ether and dried. The solid is stirred in a large volume of water to give an oily precipitate which crystallizes on further stirring. The solid is filtered, washed with water and then 2-propanol.
  • the dried product weighs 148.34 g., and is recrystallized from 2- propanol to give the product, melting point 108.5l 10 C.
  • EXAMPLE 8 Preparation of 3-(2,3,5,6-Tetrahydroirnidazo[2,1-b]thiazol- 6-yl)-acetanilide (VB) Addition of 5.00 g. (0.0158 mole) of 3'-[1-hydroxy-2-(2- imino-3-thiazolidinyl)ethyl]acetanilide hydrochloride (Example 6) to 15 ml. of concentrated sulfuric acid is carried out in small increments over 0.5 hour. The orange solution is stirred an additional 1 hour, poured onto ice and made basic with concentrated ammonium hydroxide.
  • the precipitated salt is filtered, washed with ethanol and dried to give 15.4 g. (77 percent) of the l-base, dacid salt, melting point 181l82 C., dec., [ah-58. 1 (C 7.7, H Two recrystallizations from 90 percent ethanol give the analytical sample, melting point 182 C., dec. [04],, 603 (c 7.5, H 0).
  • mice are each inoculated with about 20 infectious larvae of Nematospiroides dubius.
  • This nematode is a representative of the economically important trichostrongylid worms of ruminants and other hosts, and of nematodes in general.
  • Twenty-two days after inoculation groups'of four randomly selected mice containing adult N. dubius are given single oral doses or test compounds dissolved or suspended in 0.4 ml. of water per 20 gram mouse.
  • treated mice and in each test four randomly selected groups of untreated mice are necropsied. The number of worms in the small intestine of each mouse are determined by microscopic examination. Average worm numbers for each treated group and for the untreated controls are computed and the percent efficacy determined by the customary formula:
  • EXAMPLE l9 EXAMPLE 20 Using procedures of Example 16, the approximate single dose oral ED values against N. dubius in mice were determined for tetramisole and analogs with various substituents on its phenyl ring (Table 4 hereinafter). The unexpected high activity of dl-m-amino tetramisole is attributable to its laevo component; and not only amino, but also various substituted Dogs infected with mature adult whipworms Trichuris vulpis were treated with various single or double doses of unsubstituted or substituted tetramisole analogs by the oral or subcutaneous route (Table 5 hereinafter).
  • whipworms passed in the feces were collected for several days, and the whipworms still present determined at necropsy. Percent efficacy was amino groups in the meta position increased activity over determined in these critical" tests.
  • the meta-amino analogs tetramisole. identical substituents in the para or ortho posihad surprisinglgchigher activity than unsubstituted tetramisole tions were less active than tetramisole; as were other types of E Pmneous doses whlch were nontoxlc for the substituents in the meta position.
  • QE Tnchurfs a type Pfflematode refacmry to treatment higher quantitative activity than for the meta-nitro analogs.
  • most P anthelnumlcs at well tolerated dosesonomically allied nematodes e.g., Trichinella and Capillaria TABLE 4 are also refractory to most anthelmintics.
  • tctrahyrlro is a hydrochloride salt.
  • N o'rE. Indicates inactive at dose shown. I 7 W i a t 3* TABLE 5 Comparative Oral or Subcutaneous (SC) Activity vs. Mature Trichuris vulpis in Dogs Maximum non-lethal dose for Percent eflicaey orally at Meta dog, mg./kg. mgJkg. of- Percent etficaey SC at mgJkg. Stereo substituent isomer on phenyl Oral SC 5 2. 5 1. 25 20 15 10 5 2. 5 1. 25

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
US22701A 1970-03-25 1970-03-25 6-(m-AMINO AND SUBSTITUTED-AMINO PHENYL)-2,3,5,6-TETRAHYDRO{8 2,1-b{9 THIAZOLES AND METHOD OF USE Expired - Lifetime US3673205A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US2270170A 1970-03-25 1970-03-25

Publications (1)

Publication Number Publication Date
US3673205A true US3673205A (en) 1972-06-27

Family

ID=21810982

Family Applications (1)

Application Number Title Priority Date Filing Date
US22701A Expired - Lifetime US3673205A (en) 1970-03-25 1970-03-25 6-(m-AMINO AND SUBSTITUTED-AMINO PHENYL)-2,3,5,6-TETRAHYDRO{8 2,1-b{9 THIAZOLES AND METHOD OF USE

Country Status (10)

Country Link
US (1) US3673205A (it)
AU (1) AU2571671A (it)
BE (1) BE764755A (it)
DE (1) DE2114563A1 (it)
ES (3) ES389573A1 (it)
FR (1) FR2085742B1 (it)
IT (1) IT1008517B (it)
NL (1) NL7104032A (it)
PH (1) PH10140A (it)
ZA (1) ZA71969B (it)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4014892A (en) * 1972-09-14 1977-03-29 American Cyanamid Company 6-Substituted amino phenyl-2,3,5,6-tetrahydro[2,1-b]thiazoles
US4112102A (en) * 1976-05-01 1978-09-05 Pfizer Inc. Halopyridyl derivatives of m-aminotetramisole as anthelmintics
US4389406A (en) * 1980-05-30 1983-06-21 Beecham Group Limited Meta-pyrazolylaminotetramisole analogs and their use in pharmaceutical compositions
US6884412B1 (en) * 1996-08-01 2005-04-26 Dale Wallis Dectection of and methods and composition for prevention and/or treatment of papillomatous digital dermatitis

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3274209A (en) * 1964-05-11 1966-09-20 Janssen Pharmaceutica Nv Certain 6-substituted-imidazo[2, 1-b] thiazole compounds
US3547996A (en) * 1965-10-05 1970-12-15 American Cyanamid Co Di 2 - (2 - ((beta - hydroxyphenethyl)amino)ethyl) - 2 - thiopseudourea and hydrochloride salt thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3274209A (en) * 1964-05-11 1966-09-20 Janssen Pharmaceutica Nv Certain 6-substituted-imidazo[2, 1-b] thiazole compounds
US3547996A (en) * 1965-10-05 1970-12-15 American Cyanamid Co Di 2 - (2 - ((beta - hydroxyphenethyl)amino)ethyl) - 2 - thiopseudourea and hydrochloride salt thereof

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4014892A (en) * 1972-09-14 1977-03-29 American Cyanamid Company 6-Substituted amino phenyl-2,3,5,6-tetrahydro[2,1-b]thiazoles
US4112102A (en) * 1976-05-01 1978-09-05 Pfizer Inc. Halopyridyl derivatives of m-aminotetramisole as anthelmintics
US4389406A (en) * 1980-05-30 1983-06-21 Beecham Group Limited Meta-pyrazolylaminotetramisole analogs and their use in pharmaceutical compositions
US6884412B1 (en) * 1996-08-01 2005-04-26 Dale Wallis Dectection of and methods and composition for prevention and/or treatment of papillomatous digital dermatitis

Also Published As

Publication number Publication date
AU2571671A (en) 1972-08-24
FR2085742A1 (it) 1971-12-31
IT1008517B (it) 1976-11-30
ZA71969B (en) 1971-12-29
PH10140A (en) 1976-09-06
ES396287A1 (es) 1975-01-01
NL7104032A (it) 1971-09-28
DE2114563A1 (de) 1971-10-14
BE764755A (fr) 1971-09-24
ES389573A1 (es) 1975-05-16
ES396836A1 (es) 1975-03-16
FR2085742B1 (it) 1975-10-31

Similar Documents

Publication Publication Date Title
US3274209A (en) Certain 6-substituted-imidazo[2, 1-b] thiazole compounds
US3586670A (en) Isothiocyanobenzazoles and use thereof as anthelmintics
PL85278B1 (it)
DE3030982A1 (de) 2-phenylimidazo(2,1-b)benzothiazolderivate
CS195280B2 (en) Method of producing substituted chalcones
US4026936A (en) Anthelmintic pyridine and thiazole substituted benzimidazole carbamates
US3673205A (en) 6-(m-AMINO AND SUBSTITUTED-AMINO PHENYL)-2,3,5,6-TETRAHYDRO{8 2,1-b{9 THIAZOLES AND METHOD OF USE
Dunn et al. Antiparasitic Agents. I. 2-(Nitro-heterocyclic) Benzimidazoles, Benzoxazoles, and Benzothiazoles
SU1155158A3 (ru) Способ получени производных дибензимидазоазепина или их солей
US3759938A (en) Thiazolidine derivatives
Kumar et al. Syntheses and anthelmintic activity of alkyl 5 (6)-(substituted carbamoyl)-and 5 (6)-(disubstituted carbamoyl) benzimidazole-2-carbamates and related compounds
SE444314B (sv) Forfarande for framstellning av bensimidazolderivat
US3853872A (en) 2,3,4,5-substituted thiazoles
DE2225071A1 (de) Verfahren zur Herstellung von heterocyclischen Verbindungen und deren Verwendung
US3279988A (en) Process of treating helminthiasis with oxadiazole derivatives
Mohamed et al. An efficient one-pot synthesis and in-vitro anti-microbial study of new thiazolidinones-, imidazolidinones and thiazinanones based amino alcohols
US3929822A (en) 1,5(6)-Disubstituted benzizimidazole-2-carbamate derivatives having anthelmintic activity
US3954784A (en) Imidazo[2,1-b]thiazole and thiazolo[3,2-a]-benzimidazole quaternary salts as hypoglycemic agents and growth promotants
US3989835A (en) Method of using 6-substituted amino phenyl-2,3,5,6-tetra-hydro[2,1-b]thiazoles for controlling gastrointestinal nematodes
CH644384A5 (de) Imidazo(2',1':2,3)thiazolo(5,4-c)pyridine.
Ram et al. Synthesis of potential antifilarial agents. 1. 1-(5-Benzoylbenzimidazol-2-yl)-3-alkyl and aryl ureas
US3801583A (en) Derivatives of 2-mercapto-pyrido(1,2-b)-1,2,4-thiadiazolium salts
US3813360A (en) 7h-thiazolo(3,2-a)pyrimidin-7-ones
US3671534A (en) 6,6-DI-LOWER ALKYL-2,3,5,6-TETRAHYDROIMIDAZO {8 2,1-b{9 {11 THIAZOLES
DE69231244T2 (de) Pyrazolothiazolopyrimidin-derivate