Search Images Maps Play YouTube News Gmail Drive More »
Sign in
Screen reader users: click this link for accessible mode. Accessible mode has the same essential features but works better with your reader.

Patents

  1. Advanced Patent Search
Publication numberUS3585193 A
Publication typeGrant
Publication dateJun 15, 1971
Filing dateNov 8, 1968
Priority dateNov 15, 1967
Also published asDE1809225A1
Publication numberUS 3585193 A, US 3585193A, US-A-3585193, US3585193 A, US3585193A
InventorsRoger Canevari, Michel Laubie, Gilbert Regnier
Original AssigneeEn Nom Collectif Science Union
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Heterocyclic compounds
US 3585193 A
Images(3)
Previous page
Next page
Description  (OCR text may contain errors)

United States Patent 015cc 3,585,193 HETEROCYCLIC COMPOUNDS Gilbert Regnier, Sceaux, Roger Canevari, LHay les Roses, and Michel Lauhie, Vaucresson, France, assignors to Societe en nom collectif Science Union et Cie, Societe Francaise de Recherche Medicale, Suresnes, France N Drawing. Filed Nov. 8, 1968, Ser. No. 774,478 Claims priority, application Great Britain, Nov. 15, 1967, 57,999/67 Int. Cl. C0711 99/04 US. Cl. 260256.4 4 Claims ABSTRACT OF THE DISCLOSURE 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 The condensation is carried out in 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. in the presence of an acceptor for the hydrohalic acid formed during the reaction. The latter 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. As 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.

If desired or required, 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.

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.

An intravenous perfusion of the new compounds at a level of 5 mg./kg. in the rabbit increases the blood flow of the paw from 20 to 225%, demonstrating an important vasodilator activity.

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%.

These properties enable the use of the new compounds in therapy, and especially in the treatment of peripheral circulatory disorders such, for example, as arteritis or phlebitis, chronic or acute respiratory insufficiency, and particularly bronchial asthma.

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 pharmaceutical preparations 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.

The following examples illustrate the manufacture of the new compounds. The melting points were determined on a Kofler heater under a microscope, unless otherwise indicated.

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.

The following derivatives may be prepared as described above, using the appropriate starting materials:

(a) 1-(4'-carbethoxy-methoxy-pyrimidin 2' yl) 4- (3,4 methylenedioxybenzyl)-piperazine, starting from 2-chloro-4-carbethoxy-methoxy-pyrimidine. Its dihydrochloride melts at 195-200 C.

In the same manner other 4' carbalkoxy-methoxypyrimidin-2'-yl compounds are prepared, starting only from the appropriate starting material, wherein alkoxy has 1 to 4 carbon atoms inclusive, for example, the corresponding carbomethoxy, carbopropoxy, carboisopropoxy and carbobutoxy compounds.

(b) 1- 5 -carbethoxy-pyrimidin-2'-yl -4-( 3 ",4"-methylenedioxybenzyl)-piperazine, starting from 2 chloro-S- carbethoxy-pyrimidine. The free base melts at 104 C.

In the same manner other 5-carbalkoxy-pyrimidin-2'- yl compounds are prepared, starting only from the appropriate starting material, wherein alkoxy has 1 to 4 carbon atoms inclusive, for example, the corresponding carbomethoxy, carbopropoxy, carboisopropoxy and carbobutoxy compounds.

(c) 1 (4 ethoxy-S-carbethoxy-pyrimidin-2-yl)-4- (3,4"-methylenedioxybenzyl)piperazine, starting from 2- chloro-4-ethoxy-5-carbethoxy-pyrimidine. Its hydrochloride melts at 260 C.

In the same manner other 4-alkoxy-5-carbethoxy-pyrimidin-2-yl compounds are prepared starting only from the appropriate starting material, wherein alkoxy has 1 to 4 carbon atoms inclusive, for example the corresponding methoxy, propoxy, isopropoxy and butoxy compounds.

(d) 1-(4'-ethoxy-5-carboxy-pyrimidin-2'-y1)-4-(3 ",4"- methylenedioxybenzyl)-piperazine, starting from 2-chloro- 4-ethoxy-S-carboxy-pyrimidine. Its hydrochloride melts at 196-200 C.

In the same manner other 4'-alkoxy-5'-carboxy-pyrimidin-2-yl compounds are prepared, starting only from the appropriate starting material, wherein alkoxy has 1 to 4 carbon atoms inclusive, for example, the corresponding methoxy, propoxy, isopropoxy and butoxy compounds.

(e) 1-(5-carboxy pyrimidin 2'-yl)-4-(3,4-methylenedioxybenzyl)-piperazine, starting from 2-chloro-5- carboxy-pyrimidine. The free base melts at 234 C.

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.

In the same manner as described in this example the following compound was obtained:

1-(2' amino pyrimidin-4'-yl)-4-(3",4"-methylene dioxybenzyl)-piperazine, starting from 2-amino-4-chl0ropyrimidine. The free base melts at 171 C.

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.

1- (quinazolin-4'-yl)-4-(3",4"-methylenedioxybenzyl)- piperazine This compound is obtained by working according to the method given in Example 1 in dimethylforrnamide in the presence of potassium carbonate and starting from 4- chloroquinazoline. The corresponding dihydrochloride melts as 230233 C.

The following compounds were obtained as described in this example:

(a) l-(quinazolin 2 yl)-4-(3,4-methylenedioxybenzyl)-piperazine, starting from 2-chloro quinazoline. The free base melts at 141 C.

(b) 1-(2-methyl-quinazolin 4 yl)-4-(3",4"-methylenedioxybenzyl)-piperazine, starting from 2-methyl-4- chloro-quinazoline. The dihydrochloride melts at 210- 218 C.

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).

The following compounds were also obtained by the method described in this example:

(a) 1-(2,5'-dimethyl-pyrazin 3' yl)-4-(3",4-methylenedioxybenzyl)-piperazine, starting from 2,5-dimethyl- 3-chloropyrazine. The dihydrochloride melts at 273- 275 C.

(b) l-(5'-methyl-pyrazin 3' yl)-4-(3,4", methylenedioxybenzyl)-piperazine, starting from 3-chloro-5- methyl-pyrazine. The dihydrochloride melts at 254-255 C (c) 1-(2-amino-pyrazin 3 yl)-4-(3,4-methylenedioxybenzyl)-piperazine, starting from 2-amino-3-chloropyrazine. The dihydrochloride melts at 225228 C.

Various modifications and equivalents will be apparent to one skilled in the art and may be made in the compounds, compositions, and methods of the present invention without departing from the spirit or scope thereof, and it is therefore to be understood that the invention is to be limited only by the scope of the appended claims.

What we claim is:

1. A compound selected from the group consisting of (A) heterocyclic compounds of the Formula I CH2N N-Het wherein Het is selected from the group consisting of:

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.

3 l (quinazoline Y1)-4-(3"a4mmethylenedioxy R. GALLAGHER, Asslstant Examlner benzy1)-p1peraz1ne. US Cl.

4. 1-(2'-methyl-quinazo1in-4-yl) 4 (3,4"-methylenedioxybenzyl)-pipe1azine 10 260-2495, 249.8, 256.5, 268; 424-200, 249, 250, 251

Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US3859438 *Nov 21, 1973Jan 7, 1975Boehringer Sohn IngelheimPharmaceutical compositions containing an n-(1-bicyclic aryl-propyl-2)-n-bicyclic aryl-piperazine and method of use
US4010267 *Mar 26, 1975Mar 1, 1977Science Union Et Cie, Societe Francaise De Recherche MedicalVasodilators, cns stimulants
US4166852 *Feb 28, 1977Sep 4, 1979Produits Chimiques Ugine KuhlmannPiperazino-pyrimidines and their use as spasmolytic agents
US4260610 *Nov 3, 1978Apr 7, 1981Science Union Et CieDisubstituted piperazines
US4588725 *Nov 10, 1983May 13, 1986Sandoz Ltd.Neuroleptic agents; hypotensive agents
Classifications
U.S. Classification544/283, 544/212, 544/295, 544/292, 544/293, 544/357
International ClassificationC07D405/14, C07D251/00, C07D239/00, C07D405/06, C07D251/22, C07D239/24, C07D405/00
Cooperative ClassificationC07D405/06, C07D239/24, C07D251/22, C07D405/14
European ClassificationC07D405/14, C07D239/24, C07D405/06, C07D251/22