US3585193A - Heterocyclic compounds - Google Patents

Heterocyclic compounds Download PDF

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Publication number
US3585193A
US3585193A US774478A US3585193DA US3585193A US 3585193 A US3585193 A US 3585193A US 774478 A US774478 A US 774478A US 3585193D A US3585193D A US 3585193DA US 3585193 A US3585193 A US 3585193A
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United States
Prior art keywords
compounds
starting
piperazine
methylenedioxybenzyl
pyrimidin
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Expired - Lifetime
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US774478A
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English (en)
Inventor
Gilbert Regnier
Roger Canevari
Michel Laubie
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EN NOM COLLECTIF SCIENCE UNION
SOC EN NOM COLLECTIF SCIENCE UNION ET CIE SOC FRANCAISE DE RECHERCHE MEDIC AL
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EN NOM COLLECTIF SCIENCE UNION
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/14—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom
    • C07D251/22—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to two ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention provides new heterocyclic compounds of the general formula -OH2N N-Het in which Het represents a pyrimidinyl radical attached in the 4- position, or a prazinyl, s-triazinyl, or quinazolinyl radical which may be unsubstituted or substituted by one two lower alkyl radicals containing 1 to 4 carbon atoms, by lower alkoxy radicals containing 1 to 4 carbon atoms, or by an amino group, or a pyrimidinyl radical attached in the 2-position which is mono-substituted by a halogen atom or by a carboxy, carbalkoxy or carbalkoxymethoxy group, or disubstituted by an alkoxy radical and a carboxy or carbalkoxy radical, wherein the alkoxy have from 1 to 4 carbon atoms inclusive.
  • the new compounds of this invention are obtained by condensing a halogenated derivative of the general formula HetZ II) where Z represents a chlorine or bromine atom and Het has the meaning given above with 1-(3,4-methylenedioxybenzy1)-piperazine of the formula
  • a polar solvent such, for example, as a high-boiling alcohol, for example butanol or pentanol, or in an aromatic amide such, for example, as dimehtylformamide, in a non-polar sol vent such, for example, as an aromatic hydrocarbon, for example benzene, toluene or xylene.
  • the condensation is advantageously carried out at a temperature ranging from 80 to 140 C.
  • an acceptor for the hydrohalic acid formed during the reaction may be an alkali or alkaline earth metal salt of carbonic acid such, for example, as the bicarbonate or carbonate of sodium or potassium, or calcium carbonate, or a tertiary organic base, for example, dimethylaniline, pyridine or 3,585,193 Patented June 15, 1971 triethylamine. If desired, these salts or tertiary bases may be replaced by an excess of the monosubstituted piperazine.
  • the new heterocyclic compounds obtained in this manner are weak bases and can be converted into acid addition salts which are likewise included in this invention.
  • These acid addition salts are obtained by reacting the new derivatives with acids in suitable solvents, for example in water or water-miscible alcohols.
  • acids capable of forming such acid addition salts there may be mentioned mineral acids such, for example, as hydrochloric, hydrobromic, methanesulphonic, sulphuric and phosphoric acids, and organic acids such as acetic, propionic, maleic, fumaric, tartaric, citric, oxalic, benzoic acid and the like.
  • the new compounds may be purified by physical operations such as distillation, crystallization or chromatography, or by chemical operations such as decomposition of the acid addition salts by reaction with alkaline agents.
  • the compounds of the invention possess interesting pharmacological and therapeutic properties and may be used especially as peripheral vasodilators and bronchodilators.
  • mice The acute toxicity was determined in mice and it was found that the DL varies from 50 to 1500 mg./'kg. LP. and from 1200 to 3000 mg./kg. P.O. according to the compound tested.
  • the bronchodilator activity was demonstrated by the method of Konzett and Rossler [Arch. Exptl. Pathol. U. Pharmak. 195, 71 (1940)]. It was found that the new compounds inhibit the bronchospasm in the guinea-pig provoked by histamine, serotonine or acetylcholine. The doses from 1 to 5 mg./kg. administered intravenously inhibit these spasms from 30 to 100%.
  • the doses used may vary from 10 to 200 mg., and the dosage regimen may be 2 to 4 times per day.
  • the compounds can be administered per oral, rectal or parenteral route, and the active principle may be mixed or associated with the usual pharmaceutical carriers such as: distilled water, starch, talc, lactose, ethyl cellulose, cocoa butter, according to the desired pharmaceutical form, which can be: tablet, drage, capsule suppository, injectable or drinkable solution.
  • the active principle may be mixed or associated with the usual pharmaceutical carriers such as: distilled water, starch, talc, lactose, ethyl cellulose, cocoa butter, according to the desired pharmaceutical form, which can be: tablet, drage, capsule suppository, injectable or drinkable solution.
  • compositions containing a compound of the general Formula I, or one of its salts in admixture or conjunction with a pharmaceutically suitable carrier are also a part of this invention.
  • EXAMPLE 1 1- 5 -chloro-pyrimidin-2-yl) -4- (3 ,4' methylendioxyb enzyl -pip er azine 28 grams of potassium carbonate are added to a solution of 21 g. of 1 (3',4-methylenedioxybenzyl)-piperazine and 14.9 g. of 2,5-dichloropyrimidine in 150 cc. of dimethylformamide (DMF) and the mixture is heated for 8 hours at C. After this time the salt formed is filtered 01f, the DMF is distilled 01f under reduced pressure and the hot residue is poured into 100 cc. of boiling water. The whole is vigorously agitated while being cooled, whereupon the oil crystallizes; it is suctioned off and recrystallized from ethanol, to yield 25 g. of cream colored crystals melting at 99-101 C.
  • DMF dimethylformamide
  • EXAMPLE 2 1-(pyrimidin-4-yl)-4- 3,4"-methylenedioxybenzyl)- piperazine This compound is obtained by working according to the method given in Example 1 in toluene under reflux in the presence of potassium carbonate and starting from 4-chloropyrimidine. The corresponding dihydrochloride melts at 192-198 C. with decomposition.
  • EXAMPLE 3 l-(4',6'-dimethoxy-s-triazin-2'-yl)-4-(3",4-methylenedioxybenzyl -piperazine This compound is obtained by Working according to the method given in Example 1 in benzene under reflux in the presence of potassium carbonate and starting from 2-chloro-4,6-dimethoxy-s-triazine.
  • the free base melts on a Kofler heater at 102 C.
  • the corresponding hydrochloride melts at 250 C. with decomposition.
  • EXAMPLE 5 1- pyrazin-3 '-yl -4- 3 ',4"-methylenedioxybenzyl piperazine This compound is obtained by working according to the method given in Example 1 in dimethylformamide in the presence of potassium carbonate and starting from 3- chloropyrazine. The dihydrochloride melts at 228-234 C. (capillary).
  • quinazolinyl optionally substituted by a substituent selected from the group consisting of lower-alkyl of up 6 to 4 carbon atoms inclusive, lower-alkoxy of up to References Cited incltusge 33 39 i f UNITED STATES PATENTS P glca y amp a e a sa S 3,119,826 1/1964 Regnier et a1. 260-268 organic and mineral acids. 2. l-(quinazolin 4' yl)-4-(3",4"-methylenedioxy- 5 ALEX M AZEL Primary Examiner benzyl)-piperazine.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
US774478A 1967-11-15 1968-11-08 Heterocyclic compounds Expired - Lifetime US3585193A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB51999/67A GB1187680A (en) 1967-11-15 1967-11-15 New Heterocyclic Substituted Piperazines
GB5799967 1967-11-15

Publications (1)

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US3585193A true US3585193A (en) 1971-06-15

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US774478A Expired - Lifetime US3585193A (en) 1967-11-15 1968-11-08 Heterocyclic compounds

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US (1) US3585193A (enrdf_load_stackoverflow)
CH (1) CH498862A (enrdf_load_stackoverflow)
DE (1) DE1809225A1 (enrdf_load_stackoverflow)
FR (2) FR1591665A (enrdf_load_stackoverflow)
GB (1) GB1187680A (enrdf_load_stackoverflow)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3859438A (en) * 1971-07-08 1975-01-07 Boehringer Sohn Ingelheim Pharmaceutical compositions containing an n-(1-bicyclic aryl-propyl-2)-n-bicyclic aryl-piperazine and method of use
US4010267A (en) * 1972-04-07 1977-03-01 Science Union Et Cie, Societe Francaise De Recherche Medical Benzodioxole compounds
US4166852A (en) * 1974-08-09 1979-09-04 Produits Chimiques Ugine Kuhlmann Piperazino-pyrimidines and their use as spasmolytic agents
US4260610A (en) * 1977-11-09 1981-04-07 Science Union Et Cie Disubstituted piperazines
US4588725A (en) * 1982-11-12 1986-05-13 Sandoz Ltd. 2-piperazinyl-quinazoline derivatives and pharmaceutical compositions containing them
US20070219213A1 (en) * 2004-05-20 2007-09-20 Soares Romeiro Luiz A Use of Adrenergic N-Phenylpiperazine Antagonists, Pahrmaceutical Compositions Containning Them, and Methods of Preparing Them
CN107108569A (zh) * 2014-12-17 2017-08-29 方济各安吉利克化学联合股份有限公司 具有广谱活性的抗菌化合物

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2519986A1 (fr) * 1982-01-21 1983-07-22 Adir Nouveaux derives de benzodioxine, leurs procedes de preparation et les compositions pharmaceutiques les renfermant
ES2062940B1 (es) * 1993-03-11 1995-06-16 Vita Invest Sa Agente gastrocinetico, proceso para su preparacion y composiciones farmaceuticas que lo contengan.
ES2063700B1 (es) * 1993-04-28 1995-07-16 Vita Invest Sa Agente activo sobre el sistema nervioso central, proceso para su preparacion y composiciones farmaceuticas que lo contengan.

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3859438A (en) * 1971-07-08 1975-01-07 Boehringer Sohn Ingelheim Pharmaceutical compositions containing an n-(1-bicyclic aryl-propyl-2)-n-bicyclic aryl-piperazine and method of use
US4010267A (en) * 1972-04-07 1977-03-01 Science Union Et Cie, Societe Francaise De Recherche Medical Benzodioxole compounds
US4166852A (en) * 1974-08-09 1979-09-04 Produits Chimiques Ugine Kuhlmann Piperazino-pyrimidines and their use as spasmolytic agents
US4260610A (en) * 1977-11-09 1981-04-07 Science Union Et Cie Disubstituted piperazines
US4588725A (en) * 1982-11-12 1986-05-13 Sandoz Ltd. 2-piperazinyl-quinazoline derivatives and pharmaceutical compositions containing them
US20070219213A1 (en) * 2004-05-20 2007-09-20 Soares Romeiro Luiz A Use of Adrenergic N-Phenylpiperazine Antagonists, Pahrmaceutical Compositions Containning Them, and Methods of Preparing Them
CN107108569A (zh) * 2014-12-17 2017-08-29 方济各安吉利克化学联合股份有限公司 具有广谱活性的抗菌化合物
US10221144B2 (en) * 2014-12-17 2019-03-05 Aziende Chimiche Riunite Angelini Francesco A.C.R.A.F. S.P.A. Antibacterial compounds having broad spectrum of activity
AU2015366469B2 (en) * 2014-12-17 2019-06-27 Aziende Chimiche Riunite Angelini Francesco A.C.R.A.F. S.P.A. Antibacterial compounds having broad spectrum of activity

Also Published As

Publication number Publication date
FR1591665A (enrdf_load_stackoverflow) 1970-05-04
DE1809225A1 (de) 1971-04-22
CH498862A (fr) 1970-11-15
GB1187680A (en) 1970-04-15
FR8193M (enrdf_load_stackoverflow) 1970-09-07

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