US3822267A - 1 substituted 4 piperazino cycloalkylthiazoles - Google Patents

1 substituted 4 piperazino cycloalkylthiazoles Download PDF

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Publication number
US3822267A
US3822267A US00276260A US27626072A US3822267A US 3822267 A US3822267 A US 3822267A US 00276260 A US00276260 A US 00276260A US 27626072 A US27626072 A US 27626072A US 3822267 A US3822267 A US 3822267A
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piperazinyl
formula
tetrahydro
cycloheptathiazole
compounds
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US00276260A
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D Sorg
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Wander AG
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Wander AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems

Definitions

  • n is an integer of l to 4 and R is hydrogen, alkyl, alkenyl, hydroxyalkyl, alkoxyalkyl, alkoxycarbonyl, alkanoyl, alkanoyloxyalkyl or benzyl.
  • the compounds exhibit a stimulating effect on mental alertness.
  • the present invention relates to heterocyclic compounds and more specifically to cycloalkylthiazole compounds.
  • the present invention provides compounds of formula I, C
  • n is one of the integers 1, 2,3 or 4 and R is hydrogen, alkyl of 1 to 4 carbon atoms, alkenyl of 2 to 4 carbon atoms, hydroxyalkyl of l to 4 carbon atoms, alkoxyalkyl of 2 to 6 carbon atoms, alkoxycarbonyl of 2 to 6 carbon atoms, alkanoyl of 1 to 4 carbon atoms, alkanoyloxyalkyl of 2 to 6 carbon atoms or benzyl.
  • the present invention also provides a process for the production of a compound of formula I, which comprises (a) Reacting a reactive ester of an alcohol of formula II,
  • R is as defined above, or
  • compounds of formula I may also be produced by interconversion from one compound of formula I to another.
  • the compounds of formula I may exist either in free base or acid addition salt form.
  • Acid addition salt forms may be produced from free base forms in manner known per se, e.g. by reaction with inorganic or organic acids, and vice versa.
  • acids for acid addition salt formation are inorganic acids such as hydrohalic acids, sulphuric acid, nitric acid and phosphoric acid, and organic acids such as toluenesulphonic acid, acetic acid, malonic acid, succinic acid, maleic acid, malic acid and tartaric acid.
  • Process (a) of the invention may be effected as follows:
  • a compound of formula II may be reacted with a. compound of formula III either in an inert solvent or without solvent.
  • a solvent it is preferable to use an alcohol, conveniently in aqueous form, such as methanol, ethanol or isopropanol, a ketone such as acetone, an ether such as dioxane, an aromatic solvent such as benzene, toluene or xylene, an amide such as dimethyl formamide'or dimethyl sulphoxide.
  • the reaction may conveniently be effected at a temperature between room temperature and 140 C., preferably between 70 and 120 C., or, in the absence of a solvent, at a temperature between 70 and 120 C.
  • the compounds of formula III may be reacted either in free base or acid addition salt form.
  • Suitable reactive esters of alcohols of formula II for the above reaction are, for example, a hydrohalic acid ester, especially hydrobromic or hydrochloric acid ester, or toluene sulphonic acid ester.
  • a hydrohalic acid ester especially hydrobromic or hydrochloric acid ester, or toluene sulphonic acid ester.
  • the use of these esters directly yields the corresponding acid addition salts of the compounds of formula I.
  • an acid-binding agent e.g. triethylamine, may be added to the reaction mixture.
  • Process (b) of the invention may be effected as follows:
  • the alcohol of formula II may be employed in the form of the thiocyanate thereof, or when employed in any other reactive ester form, a thiocyanate source should be employed.
  • the thiocyanate source may be provided by effecting the reaction in the presence of thiocyanic acid or in the presence of a thiocyanate salt, e.g. an alkali metal thiocyanate, such as potassium thiocyanate, or ammonium thiocyanate.
  • a thiocyanate source is by employing the compound of formula IV in thiocyanate acid addition salt form.
  • the compound of formula II or formula IV may be reacted with thiocyanate acid or a thiocyanate, e.g. an alkali metal thiocyanate such as potassium thiocyanate or ammonium thiocyanate, in an inert solvent, e.g. ethanol, aqueous ethanol or dioxane, at a temperature between room temperature and 120 C., preferably between 70 and C.
  • thiocyanate acid or a thiocyanate e.g. an alkali metal thiocyanate such as potassium thiocyanate or ammonium thiocyanate
  • an inert solvent e.g. ethanol, aqueous ethanol or dioxane
  • reaction between the thiocyanate ester of the alcohol of formula II and the compound of formula IV, or between a reactive ester of the alcohol of formula I I andthe thiocyanic acid addition salt of the compound of formula IV, as the case may be, or alternatively, the reaction between a reactive ester of an alcohol of formula II and the compound of formula IV in the presence of thiocyanic acid or a thiocyanate salt, may be effected under similar conditions to those hereinbefore described for the reaction in accordance with process (a).
  • reaction may be effected in the presence of an inert solvent such as an alcohol, e.g. ethanol, benzene, toluene, dioxane or pyridine, or alternatively in the absence of a solvent, at a temperature between room temperature and 120 C., preferably between 50 and 80 C.
  • an acid-binding agent e.g. 1,8-bis- (dimethylamino)naphthalene, in this reaction is convenient.
  • the group R may be introduced into a compound of formula I, wherein R is hydrogen by reactive alkylation, i.e. by reaction with the aldehyde analogue of the compound of formula V, either with simultaneous reduction with hydrogen in the presence of a catalyst, e.g. platinum oxide, at room temperature, or in the presence of a reducing agent such as formic acid.
  • a catalyst e.g. platinum oxide
  • the latter reaction is conveniently effected by dissolving the unsubstituted compound in 90% formic acid and heating to a temperature between 50 and 150 C., preferably at the boil, with the corresponding aldehyde for 5 to 20 hours.
  • the introduction of a hydroxyalkyl group may be effected by reacting the unsubstituted compound with an alkylene oxide, the reaction conveniently being effected in an organic solvent, e.g. an alcohol such as methanol, at a temperature of 0 C. to room temperature.
  • an organic solvent e.g. an alcohol such as methanol
  • the removal of a benzyl group may, for example, be effected by hydrogenolysis.
  • Hydrogenolysis is preferably effected by dissolving the starting material in an alcohol, e.g. ethanol, or in ethyl acetate, and hydrogenating with hydrogen, at normal pressure, in the presence of a noble metal catalyst, preferably platinum oxide or palladium charcoal, at a temperature between room temperature and 50 C.
  • a noble metal catalyst preferably platinum oxide or palladium charcoal
  • the reaction of the starting material with cyanogen bromide is preferably effected by heating the reaction components in an inert solvent, such as benzene, toluene or dioxane, to a temperature between 80 and 120 C., preferably to the boil.
  • the reaction of the starting material with the chloroformic acid ester may be effected either in the absence of an inert solvent or in an inert solvent such as benzene, at a temperature between 70 and 120 0, preferably at the boil. This reaction yields compounds containing a cyano or a carbalkoxy group. These groups may subsequently be removed hydrolytically or hydrogenolytically.
  • Hydrolysis to the secondary amine is effected under the conditions indicated above. Hydrolysis may, for example, be effected by heating the reaction product with an aqueous mineral acid, preferably hydrochloric acid, preferably to the boil.
  • an aqueous mineral acid preferably hydrochloric acid
  • hydrohalic acid esters of alcohols of formula II used as starting materials in processes (a) and (b), are
  • halogen or a halogenation agent such as N-bromosuccinimide or sulphuryl chloride. It is not essential that the hydrohalic acid esters of an alcohol of formula II be isolated before the subsequent reaction with the thiourea derivative of formula III.
  • esters e.g. toluenesulphonic acid esters, of an alcohol of formula II may, for example, be obtained by reacting the corresponding hydrohalic acid ester with a salt, preferably the sodium salt, of the corresponding acid.
  • the thiourea derivatives of formula III, required as starting materials in process (a), are known or may be produced in known manner, e.g. by heating piperazine or a piperazine derivative of formula IV with ammonium thiocyanate in concentrated aqueous solution, to a temperature between and C., for several hours.
  • the piperazine derivatives of formula IV are known or may be produced in known manner.
  • the compounds of formula I obtained in accordance with the processes described above may be isolated in known manner, e.g. by extraction, precipitation or acid addition salt formation, and may be subsequently purified in known manner, e.g. by recrystallization.
  • the compounds of formula I are useful because they possess pharmacological activity in animals.
  • the compounds are useful as psychostimulating agents, especially for increasing mental alertness or awareness as indicated by a stimulating eflfect on the mental alertness of mice when administered orally at a dose of from 0.5 to 20 mg./kg. animal body weight.
  • the effect is observed by a mode of behaviour such as a continuous shaking of the head, characteristic of compounds with a strong psychoactive effect. Every five minutes, each animal is under observation over a period of two minutes to ascertain whether shaking of the head occurs.
  • the dose to be administered will naturally vary depending on the compound used, the mode of administration and the condition to be treated. However, in general, satisfactory results are obtained when administered at a daily dose of from 0.15 to 20 mg./kg. animal body weight, which may be administered in divided doses 2 to 5 times a day, or in retard form.
  • the total daily dosage is in the range of from about 10 mg. to about 200 mg.
  • dosage forms suitable for oral administration comprise from about 2 mg. to about 200 mg. of the compound admixed with a solid or liquid pharmaceutical carrier or diluent.
  • Examples of pharmaceutical carriers and diluents are lactose, maize, starch, talc and magnesium stearate.
  • the preferred class of compounds of formula I are those wheerin R is alkyl of 1 to 4 carbon atoms or hydroxyalkyl of 1 to 4 carbon atoms.
  • Free base and pharmaceutically acceptable acid addition salt forms of the compounds of formtla I have the same type of activity.
  • Examples of forms of pharmaceutical compositions for oral administration are tablets, granulates, capsules or dragees, and an example for parenteral administration is an injectable solution.
  • An example of a tablet composition is as follows:
  • magnesium stearate 0.1 mg. of magnesium stearate.
  • EXAMPLE 4 (4-Benbyl-l-piperazinyl -5,6,7,8-tetrahydro-4H- cycloheptathiazole [Process (a) 1 Proceeding in a manner analogous to that described in Example 1, but using an equivalent amount of 4- benzyl-l-piperazinyl-thiocarboxamide in place of 4-methyl-l-piperazinyl-thiocarboxamide, 2 (4-'benzyl-lpiperazinyl) 5,'6,7,8 tetrahydro-4H-cycloheptathiazole is obtained as base having a M.P. of 98-99 (recrystallized from ether/petroleum ether). The dihydrochloride has an indefinite M.P. from 215 (recrystallized from ethanol/ethyl acetate.
  • EXAMPLE 7 2-[4-(2-Hydroethyl)-1-piperazinyl]-5,6,7,8-tetrahydro- 4H-cycloheptathiazole [Process (b)] 3.04 g. of ammonium thiocyanate are added to 5.2 g. of 1-(2-hydr0xyethyl)piperazine in 20 cc. of ethanol, and the mixture is heated to the boil on a water bath (bath temperature until ammonia evolution stops (approx. half an hour). After the addition of 9.55 g. of 2-bromocycloheptanone, the reaction mixture is diluted with 10 cc. of ethanol and is heated at the same bath temperature for a further 12 hours.
  • the mixture is subsequently concentrated by evaporation in a vacuum and the residue is dissolved in a small amount of dilute hydrochloric acid.
  • the resulting mixture is extracted twice with ether.
  • the aqueous phase is rendered alkaline with a concentrated caustic soda solution and is exhaustively extracted with ether.
  • EXAMPLE 8 2-(4-Methyl-l-piperazinyl)-5,6,7,8tetrahydro4H- cycloheptathiazole [Process (b)] Proceeding in a manner analogous to that described in Example 7, but using an equivalent amount of lmethylpiperazine in place of 1-(2-hydroxyethyl)-piperazine, 2 (4-methyl-l-piperazinyl)-5,6,7,8-tetrahydro-4H- cycloheptathiazole, having a M.P. of 73, is obtained.
  • the residue After concentrating by evaporation in a vacuum, the residue is taken up in a small amount of Water and is extracted twice with ether. After drying the ether solution, the dihydrochloride of 2-[4-(2-methoxyethyl)-1-piperazinyl]-5,6,7,8-tetrahydro 4H cycloheptathiazole is precipitated in crystalline form by passing hydrogen chloride gas through the solution. After recrystallization from absolute ethanol, the dihydrochloride has a M.P. of 203-205.
  • the aqueous solution is heated in an oil bath (120-l40) for 26 hours. After concentrating in a vacuum to k, of the original volume, the reaction mixture is made alkaline with a concentrated aqueous sodium hydroxide solution and is extracted with ether. After concentrating the ethereal solution, 2-(l-piperazinyl)-5,6,7,8-tetrahydro-4H cycloheptathiazole, having a M.P. of 70-73 crystallizes. Treatment with hydrochloric acid in ethanol yields the dihydrochloride, having a M.P. of 185 (indefinite) (recrystallized from ethanol/ ethyl acetate).
  • n is one of the integers l, 2, 3 or 4 and R is hydrogen, alkyl of 1 to 4 carbon atoms, alkenyl of 2 to 4 carbon atoms, hydroxyalkyl of 1 to 4 carbon atoms, alkoxyalkyl of 2 to 6 carbon atoms, alkoxycarbonyl of 2 to 6 carbon atoms, alkanoyl of 1 to 4 carbon atoms, alkanoyloxyalkyl of 2 to 6 carbon atoms or benzyl,

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
US00276260A 1971-08-03 1972-07-28 1 substituted 4 piperazino cycloalkylthiazoles Expired - Lifetime US3822267A (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
CH1691773A CH556872A (de) 1971-08-03 1971-08-03 Verfahren zur herstellung von neuen piperazinderivaten.
CH1137371A CH556870A (de) 1971-08-03 1971-08-03 Verfahren zur herstellung von neuen piperazinderivaten.
CH897572A CH570999A5 (enrdf_load_stackoverflow) 1971-08-03 1972-06-15

Publications (1)

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US3822267A true US3822267A (en) 1974-07-02

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US (1) US3822267A (enrdf_load_stackoverflow)
AT (1) AT336620B (enrdf_load_stackoverflow)
BE (1) BE787059A (enrdf_load_stackoverflow)
CH (3) CH556870A (enrdf_load_stackoverflow)
DE (1) DE2237502A1 (enrdf_load_stackoverflow)
FR (1) FR2150715B1 (enrdf_load_stackoverflow)
GB (1) GB1392007A (enrdf_load_stackoverflow)
NL (1) NL7210425A (enrdf_load_stackoverflow)
SE (1) SE387949B (enrdf_load_stackoverflow)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4093726A (en) * 1976-12-02 1978-06-06 Abbott Laboratories N-(2-benzimidazolyl)-piperazines
FR2587342A1 (fr) * 1985-06-22 1987-03-20 Sandoz Sa Nouveaux derives du thiazole, leur preparation et leur utilisation en therapeutique
US5173490A (en) * 1991-01-08 1992-12-22 Adir Et Compagnie Benzisoxazole and benzisothiazole compounds
US20020064131A1 (en) * 2000-11-07 2002-05-30 Marcus Boesinger Method for operating a data network

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4093726A (en) * 1976-12-02 1978-06-06 Abbott Laboratories N-(2-benzimidazolyl)-piperazines
FR2587342A1 (fr) * 1985-06-22 1987-03-20 Sandoz Sa Nouveaux derives du thiazole, leur preparation et leur utilisation en therapeutique
US4737500A (en) * 1985-06-22 1988-04-12 Sandoz Pharm. Corp. 1-substituted-4-(thiazolyl-2-)-piperazines, -piperidines and -tetrahydropyridines useful as anxiolytic, psychogeriatric, antidepressant and antischizophrenic agents
US4892879A (en) * 1985-06-22 1990-01-09 Sandoz Pharm. Corp. 1-substituted-4-(thiazolyl-2-)-piperazines, -piperidines and tetrahydro-pyridines useful as anxioltic, psychogeriatric, antisepressant and antischiziphrenic agents
US5173490A (en) * 1991-01-08 1992-12-22 Adir Et Compagnie Benzisoxazole and benzisothiazole compounds
US20020064131A1 (en) * 2000-11-07 2002-05-30 Marcus Boesinger Method for operating a data network
US7020088B2 (en) * 2000-11-07 2006-03-28 Daimlerchrysler Ag Method for operating a data network

Also Published As

Publication number Publication date
CH570999A5 (enrdf_load_stackoverflow) 1975-12-31
CH556870A (de) 1974-12-13
AT336620B (de) 1977-05-10
FR2150715A1 (enrdf_load_stackoverflow) 1973-04-13
ATA667672A (de) 1976-09-15
DE2237502A1 (de) 1973-03-01
SE387949B (sv) 1976-09-20
NL7210425A (enrdf_load_stackoverflow) 1973-02-06
CH556872A (de) 1974-12-13
FR2150715B1 (enrdf_load_stackoverflow) 1976-04-16
BE787059A (fr) 1973-02-01
GB1392007A (en) 1975-04-23

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