IL28047A - Mucous membrane constricting agents for local application containing 2,5-dimethoxy-benzyl-2-imidazoline compounds - Google Patents

Description

C O H E N Z E D E K & S P I S B A C H E6D. PATENT ATTORNEYS 24, LEVONTIN ST ., P. O. B. I 169 T E L - A V I V P A T E N T S & D E S I G N S O R D I N A N C E 16491/6? SPECIFICATION MUCOUS MMBHAME C0KSTRIC3?INQ AGSNTS FOB LOC L PPLICATION CONTAINING 2 , 5-DIMET¾OXY-BENZYL-2-IMIDAZOLINE COMPOUNDS We, E, EHCK AKillN BSSJjLSCBA T, a Gexaaa Aktieagesellschaf » of 250t Pxaakiuxtex Stxaaae, 61 Daxmatadfc, Gaxmar r, DO HEREBY DECLARE ihe nafure of this invention and in what manner the same is to be performed to be particularly described and ascertained in and by the following statement : Muoouo Membrane Conotri-e¾A¾g Age ts- ! , for- Local Application*— : The present invention concerns mucous membrane constricting agents in liquid form, useful for local application. These new agents contain one or more imidazoline compounds of formula I wherein R R2 and R3 signif hydrogen or lower alkyl radicals with 1 to 4 carbon atoms or acid addition salts thereof in a quantity of o.ool-o.l# in addition tcr either at least 98, 5$> of water and a preserving agent or one or several fluorinated chloro-hydrocarbons. The concentration of the preserving agent is .preferably from o.ool to 1C>. : The new agents cause, surprisingly, by local application a quick and long lasting constriction of mucous membranes, especially in the nasal and pharingeal^ area and in the eye.

The new agents shall be used therefore as pharmaceuticals. It could not b^redioted that with these compositions in those special pharmacological preparations such good results could be obtained.

Compounds that are especially effective that may be used in the new agents according to the invention are e.g. 2-(2' ,5'-dimethoxybenzyi)-2-iraidazoline, m.p. 94-95°C, hydrochloride m.p. 165°C; 2-(2' ,5 '-dimethoxy-4* ,6' -dimethyl-benzyl)-2-imidazoline, m.pi 119-X21°C, and 2-(2' 51 -dimethoxy-3' 6' -dimethylbenzyl)-2-imidazoline, m.p. 152°C, and their acid addition salts1.' These compounds oan be used separately or in mixture. As acid addition salts those can be taken into account which are physiologically acceptable. Specially mentioned are the following acids: hydrogenhalides, especially hydrochloric acid} sulfuric acidJ orthophosphoric acid; alkane carboxylic acids like acetic acid, propionic acid etc,, as well as poly-basic acids like. oxalic acid, tartaric acid, succinic acid, maleic acid, ascorbic acid, citric acid etc.; sulfonic acids like methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid,! p-toluenesulfonic acid, aromatic carboxylic acids such as benzdic acid, salicylic acid or pi-aminosalicylic acid.

The compounds used in the new agents according to the invention may be produced by treating of phenylacetic acid which is substituted in the benzene ring according to formula I or tile functional derivatives thereof with ethylene diamine, or with a reactive H-derivative thereof, or with ammonia or ammonia-yielding agents and a compound which can be converted ixroi ethylene diamine by a treatment with ammonia.

If desired, the .imidazolines obtained may be treated with acids.

As functional acid derivatives e.g. esters, ortho- esters, acid halogenides - preferably acid chlorides, amides, thioamides, amidines, imino-ethers, iminohalogenides, or the nitriles of these carboxylic acids, can be used. For this purpose, the reaction conditions can be selected so that the functional acid derivatives are formed only during the reaction. ! 1 Besides ethylene diamine itself, reactive N-deri- vatives of ethylene diamine can be used as well. Those ethylene diamine derivatives are particularly suited which when treated with^ carboxylic acids or their functional derivatives yield imidazolines not substituted on the nitrogen atom. Compounds of this type ai?e e.g. N-acyl ethylenediamines and like ethylene urea (2-oxoimidazo- * lidine).

' Compounds that can be transformed into ethylene diamine by treatment with ammonia* are, e.g., aminoj¾thanol and its esters* β-halogen-ethylamines like β-chloroethylamine, ethylene dihal6genides like 1, 2-dichloroethane, or ethylene chloro hydrine. Ethylene diamine or its derivatives may be used either as free bases Or in the form of their mono- or disalts. Thus, the Ethylene diamine may be used, for example, as mono-p-toluene-eulfonic acid salt.

If as starting material a nitrile of a substituted phenylacetio acid is used and treated with ethylene diamine or its derivatives it is advantageous to perform the transformation in presence of hydrogen sulfide or hydrogen sulfide producing agents, such as carbon .disulfide. i Thus, compounds of formula I are obtained either directly or gradually while forming various intermediate products.

:· As preserving agents al those substances may be used which usually are used for aqueous preparations to be applied .· locally. In the first place bacteriostatic agents are suitable. Of tfehe numerous substances to be considered the following are speftifically mentioned: boric acid, sorbic acid and its salts, particularly potassium sorbate, phenylmercuric nitrate, alcohols, benzalkonium chloride, methyl and* propyl p-hydroxybenzoate as well as various antibiotics. <·> The new agents according to the invention may contain besides o. oolite o.l$ Of the active substance and o.ool to 1% of 'a preserving agent further carrier and additional substances. As iagents fo the constriction of the mucous membranes in the node such aqeious preparations are mainly used thait contain besides the active compound and the preserving agent at least 98, $ of water as well as additional agents that are conventionally used to prepare physiological acceptable " buffer solutions, particularly isotonic solutions:; Such additional agents for the preparation of physiologically buffered solutions are besides sodium chlcri.de especially other sodium salts, for example sodium phosphates, the acetate, borates, citrates. Normall the concentrations of the salts are o.oo5- 6,2%. The pH value of the so obtained solutions is to be between about 6.5 and 7.8.

The new agents according to the invention may also be formulated in such a manner that they can be sprayed as aerosols with the aid of the usual driving gases.

!! In these cases, the agents contain the conven- ■' tionally used fluorinated chlorohydrocarbons besides the active compounds, for example monofluorotrichloromethane, dichlorodifluoromethane, trifluoromonochloromethane , mone- fluorodichloromethane, difluoromonochloiomethane , l',l, 2- trifluorotrichloroethane, l, l , 2 , 2¾-tetrafluorodichloroethane. Frequently it is of advantage to use mixtures of these driving gases'. In addition it is' often advantageous to add solubilizers to those preparations, preferably physiologically compatible alcohols. Flavorings, buffer substances or other usual additives conventionally used in such formulations may be used as well.

''■ Of course, if desired, additional active compounds may be includediin the new preparations according to the in-vention, especially additional further niucous membrane constricting compounds such as f.e. xylcJmetazoline hydrochloride, tetrahydroaoline or oxymetazoline. n »· ) Substances inhibiting inflammation such as anti-phlogistically active steroids and also ^antibiotics can suitably be added to the new agents. If any of the "additional active agents are not well soluble in wa*ter, the agents according to the invention may be "used in the form of suspensions;! The possibly added antibiotics can simultanedusly serve as preserving agents so that they "may be applied instead of or in combination with one of the conventional preserving agents.

: The new liquid agents according to the invention are used either as drops or in form of a. spray. Spray formulations are either applied as" aerosols with the help of conventional pressurized gases, or also without such driving gases, f.e. from the usual plastic bottles with suitable nozzles.

The therapeutic broadness of the active compounds contained in the new agents is extremely advantageous. The local "compatibility of the agents according to the invention is likewise excellent. On the human nasal mucosa a clear astririgeney was obtained in cases of a nasal cold. Side reactions were riot observed. For children very low concentrations are needed, e.g. dilutions of l:4ooo. In cases of nasal colds '^and affections of the nasal cavities and illnesses of the e e 2-4 drops are applied 1-3 times daily to each nostril or to the eyes. Accordingly the corresponding amount of spray is applied. The 'new agents can be used generally foi the reduction in swelling of mucous membranes for diagnostic purposes. Particularly they can be used, however, in cases of (acut-ef, allergic or vasomotoric) rhinitis, sinusitis, nasopharingitiSjconiunctivitis, and1 keratitis excematosa.

In addition, the new agents are useful in' all those instances where vasoconstricting effects 'are to be (Obtained.

Example 1 2- ( 2 ',5 ' -dimethoxy-4 *»6 » -dimethylbehzyl)-2-imidazoline 0.025 g + 1.01 ml 0.1 N hydrochloric acid bori acid 0.152 g borax 0.053 g phenylmercurie nitrate 0.001 g water ad 100.0 ml (pH '-value: 7,65) Example 2 - 2-( 2 *, ' -dimethoxybenzyl)-2-imidazoline 0.050 g + 2.'27 ml 0.1 N hydrochloric acid sodium acetate ; 0.190 g boric acid 0.009 g β-phenylethyl alcohol o.ioo g distilled water ad 100.0 ml (pH value: 7.4) benzalkonium chloride 0.002 g i distilled water ad 100.0 ml (pH value: 6.85) Example 4 benzalkoni m chloride 0.010 g distilled water ad 100.0 " ml (pii value: 6,85) Example 5 2- (2', '-dimethoxybenzyl)-2-imidazoline 0.050 g + 2.27 ml 0.1 N hydrochloric acid boric acid 0.171 borax (Na2B407.10H20) 0.0265 g poiymyxinsuliate 100000 Units benzalkoniumchloride 0.010 g distilled water ad 100.0 ml (pH value: 7.2) Example 2- ( 2f» 1 -dime;thoxybenzyl)-2-imidazoline Q.6 g absulute ethanol 50 g peppermint oil i 0.5 g 1j!l, 2-trifluorotrichlbroethane 199 g dichlorodifluoromethane / 1,1,2,2-tetrafluoro- 750 g dichloroe hane 40:60 Example 7 2- (2 5 ' -dimethoxy-4 ',6 · dimethylbenzyl)-2-imidazoline absolute ethanol 1 ,1 , 2-trifluorotrichlor0ethane " dichlorodifluoromethane / 1,1, 2, 2-tetra fluorodichloroethane 40:60

Claims (1)

1. HAVING described tained the nature of our said invention and in what the same is to be pe we declare What we claim membrane constricting agent for local application liquid consisting of to of at least one compound of the formula wherein and are hydrogen atoms or lower radicals containing 1 to 4 carbon atoms or one of its acid addition salts in at least of water besides a preserving agent or in at least one fluorinated Agent according to claim 1 wherein the content of preserving agent is from to Agent according to claims 1 2 wherein the aqueous solution isotonic by the addition of physiologically acceptable 1 Agent according to claims 1 to 3 wherein the aqueous solution has a pH value of between nd according to claim 1 wherein a mixture of chlorohydrocarbons is Agent according to claims 1 to 5 wherein the active ingredient is or its acid addition Agent according to claims 1 to 6 wherein the active ingredient ist Agent according to claims 1 to 7 wherein the active ingredient is or its acid addition salt Agent according to claims 1 to 4 and 6 to 8 characterized by the form of Agent according to claims 1 tb 9 characterized by the form DATED THIS insufficientOCRQuality