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Publication numberUS2979511 A
Publication typeGrant
Publication dateApr 11, 1961
Filing dateMar 25, 1959
Priority dateMar 25, 1959
Publication numberUS 2979511 A, US 2979511A, US-A-2979511, US2979511 A, US2979511A
InventorsKrapcho John, William A Lott
Original AssigneeOlin Mathieson
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Certain 1, 4-benzodioxanyl imidazolines and corresponding pyrimidines and process
US 2979511 A
Abstract  available in
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Description  (OCR text may contain errors)

United States Patent f This invention relates to. new.-liet er ocyclic derivatives of benzodioxane and more p'arti'cularly to compounds .of the general formula III and acid-addition salts of those compounds which contain a basic nitrogen atom, wherein R and R are the same or different and represent hydrogen, hydroxy, halogen, trifiuoromethyl, nitro, lower alkyl, lower alkenyl or lower alkoxy; R", R'" and R"" are the s'ameor different andrepresent hydrogen or lower alkyl; x is zero or one, y is zero or one, and Z is -NH, or --N( lower alkyl). Particularly preferred are compounds wherein R, R, R",

Rf and'R"" are hydrogen, y is zero, and Z is -NH 'The compounds of this invention are physiologically active substances which are useful as peripheral vasodilators. Thus, they may be used instead of known peripheral vasodilators, such as Priscoline,'in the treatment of peripheral vascular diseases, for which purpose they are administered perorally or parenterally'with concentration and dosage adjusted for the activity of the particular compound. Furthermore, the compounds of this invention also possess adrenergic blocking and hypotensive action, and thus may be used instead of known agents such as Dibenamine in the treatment of hypertension.

The compounds of this invention are prepared by the process of this invention which comprises heating a compound of the general formula CHi I bmomncooa wherein R, R, and x are as hereinbefore defined, and

A is hydrogen or lower alkyl (preferably methyl), wit a compound of the general formula:

wherein R", R', R",' y and Z are as hereinbefore defined.

Suitable benzodioxane reactants include the following carboxylic acids, as well as the lower alkanol esters thereof: 1 ,4-benzodioxane-Z-carboxylic acid; hydroxy-1,4-benzodioxane-Z-carboxylic acids, suchas 6-hydroxy-l,4-benzodioxane-Z-carboxylic acid and 8-hydroxy-l,4-benzodioxane-Z-carboxylic acid; dihydroxy-1,4-benzodioxane-2 carboxylic acid, 8-ethyl-1,4-benzodioxane-2-carboxylic acid, and 7-n-propyl-1,4-benzodioxane-Zcarboxylic acid; di-(lower alkyl)-1,4-benz0dioxane 2 carboxylic acids, such as 6,8-dimethyl-1,4-benzodioxane-Z-carboxylic acid and 7,8-diethyl-1,4 benzodioxane-Z-carboxylic acid; lower alkoxy-l,4-benzodioxane-2-carboxylic acids, such as 6- methoxy-1,4-benzodioxane-2-carboxylic. acid and 8-ethoxy-1,4-benzodioxane-Z-carboxylic acid; di(lower a1koxy)- l,4-benzodioxane-Z-carboxylic acids; lower alkyl-lower alkoxy-1,4-benzodioxane-Z-carbdxylic acids, such as 6- methyl- 8-ethoxyl,4 benzodioxane 2 carboxylic acid;

'- (lower alkenyl)-1,4-benzodioxane-2carboxylic acid, such as 6-allyl-1,4-benzodioxane-Z-carboxylic acid; 1,4-benzo-" dioxane-Z-acetic acid;fand-, the'hydroxy, halo, trifluor'omethyl, nitro, lower alkyl, loweralkenyl, and lower alkoxy derivatives of the last. 7 V

In those cases where the l,4-benzodioxane-2-carboxylic acids (and the corresponding lower alkyl esters) are new compounds, they can be prepared by reacting a pyrocatechol of the formula wherein R and R' are as hereinbefore defined, with a dibromoalkanoic acid ester of the formula:

wherein x is as hereinbefore defined, and if desired hy-. drolyzing the resultant ester to the corresponding acid. Those compounds wherein x is one can also be obtained from the corresponding l,4-benzodioxane-2-carboxylic acid derivative by a series of steps including: (1) treating the acid with lithium aluminum hydride to yield the corresponding carbinol derivative; (2) reacting the carbinol with thionyl chloride in pyridine to yield the corresponding methyl chloride derivative; (3) reacting the methyl chloride derivative with sodium cyanide to yield the cor-f responding methyl nitrile derivative; and (4) hydrolyzing the nitrile to a carboxyl radical, thereby covering the original carboxylic acid radical to an acetic acid radical. (The pyrocatechols can be obtained by reduction ofv the correspondingly substituted o-nitrophenol to the o-aminophenol, followed by diazotization to the pyrocatechols.)

Suitable amine reactants include lower alkylene di amines, such as ethylene diamine, trimethylene diamine,

isopropylene diamine, 2,3-butylene diamine, 2,4-pentylene diamine, 2,3-hexylene diamine, and 2,4-octylene diamine; and N-(lower alkyl)-lower alkylene diamines, such as N-(lower alkyl)-ethylenediamines (e.g. N-ethyl-ethylenediamine), N-(lower alkyl)-trimethylene diamines (e.g. N-methyl-1,3-propanediamine), and N-(lower alkyl)-isopropylene diamines.

The compound formed, if it contains a basic nitrogen atom, can then be converted to its acid addition salt in the usual manner by treatment with the desired acid. The preferred acids are those which are non-toxic and include inorganic acids, such as the hydrohalic acids (e.g. hydrochloric acid), sulfuric acid, phosphoric acid, and nitric acid; and organic acids, such as tartaric acid, citric acid, oxalic acid, acetic acid, succinic acid, maleic acid and lactic aid. v a

The following examples illustrate the invention (all temperatures being in centigrade):

EXAMPLE 1 2- [2-(1,4-benz0dioxanyl) ]-2-imidaz0line hydrochloride (a) Preparation of 2-[2-(1,4-benzodioxanyl)]-2-imidazoline.-A mixture of 25.0 g. of 1,4-benzodioxane-2-f carboxylic acid and 40 g. of ethylenediamine is refluxed" for sixteen hours. At this point, about 10 ml. of-distils on trituration with aeetonitrile to a crystalline material;

melting at about 235-240 dem). After recrystallization from isopropyl alcohol, the colorless hydrochloride salt melts at about 241-243 (deg),

EXAMPLE 2 Following the procedure of Example 1, step (a) but substituting 27.0 g. of methyl 1,4-benzodioxane-2-carboxylate for the l,4-benzodioxane-Z-carboxylic acid, the same product is obtained.

EXAMPLE 3 2-[2-(8-eth0xy-1,4-benzodioxanyl)]-2-imidaz0line oxalate- Following the procedureof Example 1, step (a) but substituting 25 g. of 8-ethoxy-1,4-benzodioxane-2-carboxylic acid, for the 1,4-benzodioxane-2-carboxylic acid, there is obtained 2-[2 (8-ethoxy l,4-benzodioxanyl)1-2- imidazoline, which upon treatment with an alcoholic solution of oxalic acid by the procedure of Example 1, step (b) yields the oxalate salt.

EXAMPLE 4 2'-['2-(l,4-benzodioxanyl) ]-1-methyl-1,4,5,6-tetra hydropyrimidine hydrochloride Following the procedure of Example 1, but substituting 50 g. of N-rnethyl-1,3-propanediamine for the ethylene diamine in step (a), there is obtained 2-[2-(1,4- benzodioxanyl)]-l-methyl 1,4,5,6-tetrahydropyrimidine hydrochloride.

EXAMPLE 5 2'-[2-(I,4-benzodioxanyl)-methyl]-2-imidazoline hydrochloride Following the procedure of Example 1, but suhstitut-. ing 26 g. of 1,4-benzodioxane-2-acetic acid for the, 1,4-

benzodioxane-2-carboxylic acid, there is obtained 2 -[2 1 ,4-benzodioxanyl methyl] -2-imidazoline hydrochloride.

EXAMPLE 6 2- 2-(7-chl0r0-1,4-benzodioxanyl) ]-2-imidaz0line Interaction of 30 g. of 7-chloro-l,4-benzodi0xane-2- carboxylic acid (prepared by reacting 4-chloropyrocatechol with ethyl u,[3-clibromopropionate) with ethylenediamine in the same manner as Example 1, step (a) gives 2-[Z-(7-ch1oro-1,4-benzodioxanyl) -2-imidazoline.

EXAMPLE 7 2- ['2-(6-trifluor0methyl-1,4-benzodi0xanyl) Z-imidazoline -I r 1 ter action of 28 g. of 6-tr ifl uoromethyl-1,4-benzodioxane-Z-carboxylic acid with ethylenediamine in the same manner as Example 1, step (a) gives 2-[2-(6-trifluoromethyl-l ,4-benzodioxanyl) 1 -2-imidazoline.

EXAMPLE 8 2-[2-(6 allyl-1,4-benz0di0xanyl) ]-2-imidaz0line Interaction of 30 g. of- 6-allyl-1,4-benzodioxane-2 carboxylic acid with ethylenediamine in thesame manner as Example 1, step (a) gives 2-[2 -(6-allyl-1,4-benzodiox-- ant 1 -2-imidazo1ine.

4 EXAMPLE. 9 2-[2-(7-nitro-1,4-benzodioxanyl) ]-2-imidazoline Interaction of 25 g. of 7-nitm-1,4-benzodioxane-2-carboxylic acid, with ethylenediamine, in, the samemanner as Example 1, step. (a) gives 2-[2;('Z-nitro-1,4-benzodioxanyl) ]-2-imidazoline.

I EXAMPLE '10 2-[2.-('l butyl l,4-benzodioxanyl)1-2-imidazoline Interaction of 25 g. of 7-butyl-1,4-benzodioxane-2-carboxylic acid with ethylenediamine in the same manner as Example 1, step (a gives 2-[2- (7-butyl-l,4-benzodioxanyl) ]-2-imidazoline.

The invention may be variously otherwise embodied within the scope of the appended claims.

What is claimed is:

1. A compound selected from the group consisting of bases of the general formula and the non-toxic acid addition salts thereof, wherein R and R are each selected .from the group consisting of hydrogen, hyroxy, .halogen, trifluoromethyl, nitro, lower alkyl, lower alkenyl and lower, alkoxy', R", R" and R' are each selectedfrom the group consisting ofhydrogen and; lower alkyl, x is an integer from zero to one, y is, an

integer from zero to one, and Z is selected from the group consisting of NH- and N'(lower alkyl-)--.

2. 2- E 2-( l,4-b enzodioxanyl) -2-imidazoline.

3. A non-toxic acid addition: salts of 2-[2-(1,4-benzodioxanyl) ]'-2-imidazoline.

4. 2[-2-(1,4-benzodioxanyl)] 2-imidazoline hydrochloride.

5. A process for preparing a compound of the general formula wherein R and R' are each selected from the group consisting of hydrogen, hydroxy, halogen, trifluoromethyl, nitro, lower alkyl, lower alkenyl, and lower alkoxy, R, R and R"" are each selected from the group consisting of hydrogen, and lower alkyl, x is an integer from zero to one, y is an integer from zero tome, and Z is. se-

lected from the group consisting of -NH-- and.

--N(lower alkyl)--, which comprises heating a compound of the general formula H(oH, r-o00A wherein R, R and x are asabove defined and A is selected from the group consisting of hydrogen and lower alkyl, with acompound ofthe general formula:

H N-CHR-.-'( CHR" CHR' -ZH whereinR", R', R"", y and Z. are as above defined.

'6'. A process for preparing 2-[2-(l,4-benzodioxanyl)]- Z-imidazoline which comprises heating 1,4-benzodioxane- 2-carboxylic acid with ethylenediamine.

References-Cited in. the file. of this patent- Koo-et aLrJ'. Am. Chem. Soc., vol. 77, pages 5373-4: 619559 v.

Non-Patent Citations
Reference
1 *None
Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US3438995 *Jan 8, 1968Apr 15, 1969Melville SahyunDiazaheterocyclic substituted benz-oxaheterocyclic compounds
US4302469 *Sep 10, 1980Nov 24, 1981Syntex (U.S.A.) Inc.2-(1,4-Benzodioxan-2-ylalkyl)imidazoles useful as antidepressants
US4397860 *Jan 18, 1982Aug 9, 1983Reckitt & Colman Products LimitedBenzodioxanyl imidazoline compounds, compositions and use
US4402967 *Apr 23, 1981Sep 6, 1983Syntex (U.S.A.) Inc.Method for lowering intraocular pressure
US4405622 *Oct 16, 1980Sep 20, 1983Syntex (U.S.A.) Inc.[1-(1,4-Benzodioxan-2-yl)-4-(4-aminopyrimidin-2-yl]piperazines useful as anti-depressants
US4446148 *Mar 29, 1983May 1, 1984Reckitt & Colman Products LimitedBenzodioxanyl imidazoline compounds, compositions and use
US4497818 *Aug 5, 1981Feb 5, 1985Syntex (U.S.A.) Inc.2-(1,4-Benzodioxan-2-ylalkyl)imidazoles useful as antihypertensives and platelet aggregation inhibitors
US4818764 *Feb 2, 1981Apr 4, 1989Reckitt & Colman Products LimitedImidazoline derivative and method of treating depression therewith
EP0033655A2 *Feb 2, 1981Aug 12, 1981Reckitt And Colman Products LimitedImidazoline derivative, its salts, process for preparation and pharmaceutical compositions thereof
EP0058006A1 *Jan 25, 1982Aug 18, 1982Reckitt And Colman Products LimitedImidazoline derivatives, process for the preparation thereof, pharmaceutical compositions containing them and their use
EP0074711A2 *Aug 2, 1982Mar 23, 1983Syntex (U.S.A.) Inc.Benzodioxane-imidazoline compounds, their preparation and use
EP0138358A1 *Aug 31, 1984Apr 24, 1985Farmos-Yhtyma OyThe preparation and use of 2-[2-(1,4-benzodioxanyl)]-2-imidazoline in therapy
EP0838217A2Jan 23, 1997Apr 29, 1998SanofiCosmetic composition containing neuropeptide Y receptor antagonist
WO1983004025A1 *May 18, 1983Nov 24, 1983Inst Nat Sante Rech MedOptical isomers of (benzodioxane-1,4 yl-2)-2delta-2 imidazoline, preparation and therapeutical application thereof
WO1989001774A1 *Sep 1, 1988Mar 9, 1989Saad Al DamlujiPharmaceutical compositions
Classifications
U.S. Classification548/311.7, 544/333
International ClassificationC07D407/06
Cooperative ClassificationC07D407/06
European ClassificationC07D407/06