Claims
- 1. A compound of the formula ##STR8## wherein each of Ph and Ph' is phenyl, unsubstituted or monosubstituted by lower alkyl, halogeno or trifluoromethyl; each of R.sub.1 and R.sub.2 are hydrogen, alkyl with up to 3 carbon atoms, or both (R.sub.1 +R.sub.2) together represent alkylene with up to 3 carbon atoms; each of m and n is an integer from 1 to 3; p is an integer from 2 to 7, whereby C.sub.p H.sub.2p separates the adjacent nitrogen atoms by at least 2 carbon atoms; and A is alkylene or alkenylene with 2-7 carbon atoms, 4 to 7 ring-membered mono- or bicyclo-alkylene or -alkenylene, or 4 to 7 ring-membered 2-spiro-cycloalkane- (ethylene or 1,3-propylene) unsubstituted or ring-substituted by up to three lower alkyls, or a therapeutically acceptable acid addition salt thereof.
- 2. A compound as claimed in claim 1, in which formula each of Ph and Ph' is phenyl, (lower alkyl)-phenyl, (halogen)-phenyl or (trifluoromethyl)-phenyl, each of R.sub.1 and R.sub.2 are hydrogen, alkyl with up to 3 carbon atoms, or both (R.sub.1 +R.sub.2) together represent alkylene with up to 3 carbon atoms; each of m and n is an integer from 1 to 3; p is an integer from 2 to 7, whereby C.sub.p H.sub.2p separates the adjacent nitrogen atoms by at least 2 carbon atoms; and A is alkylene or alkenylene with 2-7 carbon atoms, 4 to 7 ring-membered mono- or bicyclic 1,2- or 1,3-cycloalkylene or -cyclo-alkenylene, or 4 to 7 ring-membered 2-spirocycloalkane-1,3-propylene, or a therapeutically acceptable acid addition salt thereof.
- 3. A compound as claimed in claim 1, in which formula each of Ph and Ph' is phenyl, (lower alkyl)-phenyl, (halogeno)-phenyl or (trifluoromethyl)-phenyl; each of R.sub.1 and R.sub.2 is hydrogen or both (R.sub.1 +R.sub.2) together are alkylene with 2 or 3 carbon atoms; each of m and n is the integer 2 or 3; p is an integer from 2 to 4, whereby C.sub.p H.sub.2p separates the adjacent nitrogen atoms by at least 2 carbon atoms; and A is straight or branched alkylene or alkenylene with 2-7 carbon atoms, 4 to 7 ring-membered mono- or bicyclic 1,2- or 1,3-cycloalkylene or -chcloalkeneylene, or 4 to 7 ring-membered 2-spirocycloalkane-1,3-propylene, or a therapeutically acceptable acid addition salt thereof.
- 4. A compound as claimed in claim 1 and corresponding to the formula ##STR9## wherein each of R and R' is hydrogen, alkyl with 1-4 carbon atoms, halogeno or trifluoromethyl; each of R" is hydrogen or both R" together represent ethylene; q is 2 to 4, r is 0 or 1 and each of R"', is alkyl with 1-4 carbon atoms, or both R"' together stand for alkylene with 3-5 carbon atoms, or a therapeutically acceptable acid addition salt thereof.
- 5. A compound as claimed in claim 4, in which formula each of R and R' is hydrogen, methyl or chlorine, each of R" is hydrogen or both R" together are ethylene forming with the bridge heads and the nitrogen atom a 5-membered ring; q is 2 or 3 r is one and both R"' stand for 1,3-propylene or 1,4-butylene; or a therapeutically acceptable acid addition salt thereof.
- 6. A compound as claimed in claim 4 and being the N-[2-(4-diphenylmethoxy-piperidino)-ethyl]-.beta.,.beta.-tetramethylene-glutarimide, or a therapeutically acceptable acid addition salt thereof.
- 7. An antiallergic and antiasthmatic pharmaceutical composition consisting essentially of a correspondingly effective amount of a compound claimed in claim 1, together with a pharmaceutical excipient.
- 8. A method of treating allergic and asthmatic conditions in mammals, which consists in administering to said mammals enterally or parenterally a composition as claimed in claim 7.
CROSS-REFERENCE TO RELATED APPLICATION
This is a continuation-in-part of application Ser. No. 899,149, filed Apr. 24, 1978, (now abandoned).
The present invention concerns and has for its objects the provision of new N-(diphenylmethoxy-mono or bicyclic-alkyleneimino-alkyl)-dicarboximides, more particularly of those of Formula I ##STR2## wherein each of Ph and Ph' is phenyl, unsubstituted or monosubstituted by lower alkyl, halogeno or trifluoromethyl; each of R.sub.1 and R.sub.2 are hydrogen, alkyl with up to 3 carbon atoms, or both (R.sub.1 +R.sub.2) together represent alkylene with up to 3 carbon atoms; each of m and n is an integer from 1 to 3; p is an integer from 2 to 7, whereby C.sub.p H.sub.2p separates the adjacent nitrogen atoms by at least 2 carbon atoms; and A is lower alkylene, lower alkenylene, lower mono- or bicyclo-alkylene, or -alkenylene, or lower spirocycloalkane-alkylene, unsubstituted or ring-substituted by up to three lower alkyls; or a therapeutically acceptable acid addition salt thereof; of corresponding pharmaceutical compositions and of methods for the preparation and application of these products, which are useful antiasthmatic, antiallergic and antihistaminic agents.
Of the radicals Ph and Ph' one is preferably phenyl and the other phenyl, (lower alkyl)-phenyl, (halogeno)-phenyl or (trifluoromethyl)-phenyl, wherein alkyl preferably represents methyl, but also ethyl, n- or i-propyl or -butyl; and halogeno is preferably chloro, but also fluoro or bromo.
Each of R.sub.1 and R.sub.2 is preferably hydrogen, but may also stand for methyl, ethyl or n-propyl; or both (R.sub.1 +R.sub.2) are preferably ethylene, but also methylene, 1,2- or 1,3-propylene.
Each of H--C.sub.m H.sub.2m-1 and H--C.sub.n H.sub.2n-1 is preferably ethylene, but also, for example, methylene, 1,2- or 1,3-propylene.
The group C.sub.p H.sub.2p also represents preferably ethylene, 1,2- or 1,3-propylene or -butylene or 1,4-butylene. The term "lower" referred to above and hereinafter in connection with organic radicals, or compounds, respectively, defines such with up to 7, preferably up to 4, especially with 1 or 2 carbon atoms.
A lower alkylene or alkenylene radical A is preferably ethylene, 1,3-propylene, 2,2-di-(methyl, ethyl, n-propyl or n-butyl)-1,3-propylene, 1,4-butylene or 1,4-but-2-enylene.
A mono- or bicycloalkylene or -alkenylene radical A is preferably 4 to 7 ring-membered and unsubstituted, or ring-substituted by up to 3 lower alkyls, preferably methyls, such as 1,2- or 1,3-cyclopentylene or -cyclohexylene, 1,2,2-trimethyl-1,3-cyclopentylene, 2-methyl-1,3-cyclohexylene, 3,6-ethano-1,2-cyclohexylene or -cyclo-4-hexenylene.
A spirocycloalkane-alkylene radical A is preferably a 4 to 7 ring-membered unsubstituted 2-spirocycloalkane- (ethylene or 1,3-propylene) group, e.g. 2-(spirocylobutane, pentane or hexane)- (ethylene or 1,3-propylene), or such radicals alkylated, preferably methylated, as shown above.
The acid addition salts of the compounds of Formula I are preferably derived from the therapeutically acceptable acids listed below.
The compounds of the invention exhibit valuable pharmacological properties, for example antiasthmatic, antiallergic and antihistaminic effects. This can be demonstrated either in vitro or in vivo tests, using advantageously mammals, such as mice, rats, guinea pigs or dogs as test objects, or isolated organs thereof. The in vitro tests are performed either with human leukocytes of volunteers who are allergic to ragweed pollen, or with the guinea pig ileum in a standard organ bath, e.g. physiological saline. In the former test, as described by Lichtenstein et al., J. Exp. Med. 120, 507 (1964), the aqueous leukocyte suspension, when treated with a purified ragweed pollen extract (antigen E), releases histamine, which can be estimated fluorometrically. The compounds of the invention, especially the N-[2-(4-diphenylmethoxy-piperidino)-ethyl]-.beta.,.beta.-tetramethylene-glutarimide hydrochloride, being illustrative thereof, when added to said ileum bath, in an amount to reach concentrations down to about 10.sup.-5 molar, inhibit the histamine-induced ileum-contraction respectively, thus indicating antiallergic and antihistaminic effects, which latter are also confirmed by the classical in vivo tests in mice, rats and guinea pigs. With enteral or parenteral, e.g. oral or intravenous, doses of said components, for example in the range between 0.1 and 200 mg/kg/day, preferably between about 1 and 100 mg/kg/day; especially with about 5 or 10 mg/kg/day i.v., or with about 50 or 100 mg/kg/day p.o. doses of said hydrochloride, significant protection against egg-albumin anaphylaxis, or passive cutaneous anaphylaxis is achieved (J. Carr, J. Path. 108, 1, 1972).
Antiasthmatic activity is estimated in dogs, which are naturally sensitive to ascaris antigens, causing asthma-like syndromes after inhalation of said nebulized antigens. The compounds of the invention are administered orally or intraveneously in about the same dosage ranges mentioned above, about 30-60 minutes after antigen-challenge, and efficacy is observed by the change in the dogs' respiratory-rate and airway-resistance.
Accordingly, the compounds of the invention can be applied enterally or parenterally, e.g. by inhalation of a nebulized aqueous solution, or by peroral, subcutaneous, intramuscular or intraveneous administration, in about the dosage range shown above. According to the test results obtained, they are useful antiasthmatic, antiallergic and antihistaminic agents. They are also valuable intermediates of other preparations, preferably of pharmacologically useful products.
Particularly useful are compounds of Formula I, wherein each of Ph and Ph' is phenyl, (lower alkyl)-phenyl, (halogen)-phenyl or (trifluoromethyl)-phenyl, each of R.sub.1 and R.sub.2 are hydrogen, alkyl with up to 3 carbon atoms, or both (R.sub.1 +R.sub.2) together represent alkylene with up to 3 carbon atoms; each of m and n is an integer from 1 to 3; p is an integer from 2 to 7, whereby C.sub.p H.sub.2p separates the adjacent nitrogen atoms by at least 2 carbon atoms; and A is lower alkylene, lower alkenylene, 4 to 7 ring-membered mono- or bicyclic 1,2- or 1,3-cycloalkylene or -cycloalkenylene, or 4 to 7 ring-membered 2-spirocycloalkane-1,3-propylene, or a therapeutically acceptable acid addition salt thereof.
Preferred compounds of the invention are those of Formula I, wherein each of Ph and Ph' is phenyl, (lower alkyl)-phenyl, (halogeno)-phenyl or (trifluoromethyl)-phenyl; each of R.sub.1 and R.sub.2 is hydrogen or both (R.sub.1 +R.sub.2) together are alkylene with 2 or 3 carbon atoms; each of m and n is the integer 2 or 3; p is an integer from 2 to 4, whereby C.sub.p H.sub.2p separates the adjacent nitrogen atoms by at least 2 carbon atoms; and A is straight or branched alkylene or alkenylene with 2-7 carbon atoms, 5 to 7 ring-membered mono- or bicyclic 1,2- or 1,3-cycloalkylene or -cycloalkenylene, or 4 or 7 ring-membered 2-spirocycloalkane-1,3-propylene, or a therapeutically acceptable acid addition salt thereof.
Outstanding on account of their usefulness are the compounds of Formula II ##STR3## wherein each of R and R' is hydrogen, alkyl with 1-4 carbon atoms, halogeno or trifluromethyl; each of R" is hydrogen or both R" together represent ethylene; q is 2 to 4, r is 0 or 1 and each of R"' is alkyl with 1-4 carbon atoms, or both R"' together stand for alkylene with 3-5 carbon atoms, or a therapeutically acceptable acid addition salt thereof.
The most preferred compounds are those of Formula II, wherein each of R and R' is hydrogen, methyl or chlorine, each of R" is hydrogen or both R" together are ethylene forming with the bridge heads and the nitrogen atom a 5-membered ring; q is 2 or 3, r is one, and both R"' stand for 1,3-propylene or 1,4-butylene; or a therapeutically acceptable acid addition salt thereof.
The compound of this invention are prepared according to conventional methods, for example, by condensing compounds of formulae III and IV ##STR4## wherein X is amino or reactively esterified hydroxy and Y is oxygen or imino, or alkali metal salts thereof, provided that (X+Y) contain one nitrogen atom only and, if desired, converting any resulting compound of Formula I into another compound of the invention.
A reactively esterified hydroxy group X is preferably a halogen atom, advantageously chloro or bromo, or an aliphatic or aromatic sulfonyloxy group, such as alkane- or Ph-sulfonyloxy, e.g. mesyloxy, besyloxy, tosyloxy, closyloxy or brosyloxy; and an alkali metal salt is preferably the sodium or potassium salt of the compounds with Y=NH.
Said condensation either occurs spontaneously at room temperature or below, or under pyrolytic conditions, for example, at temperatures between room temperature and about 200.degree. and/or in the presence of agents removing the water or acids generated, such as axeotropic solvents, e.g. benzene, toluene or xylene, or alkali metal hydroxides, carbonates or bicarbonates; or tert. amines, e.g. tri-lower alkylamines, pyridine or lower alkylated-pyridines respectively.
In the compounds of Formula I so obtained, any olefinic "A" can be hydrogenated with catalytically activated hydrogen, e.g. hydrogen in the presence of palladium or platinum catalysts.
Any resulting base can be converted into a corresponding acid addition salt, preferably with the use of a therapeutically acceptable acid or anion exchange preparation, or resulting salts can be converted into the corresponding free bases, for example, with the use of a base, such as a metal hydroxide, basic salt, ammonia, amine or cation exchange preparation, e.g. an alkali metal hydroxide or carbonate. Said acid addition salts are preferably such of therapeutically acceptable inorganic or organic acids, such as strong metalloidic acids, for example hydrohalic, e.g. hydrochloric or hydrobromic acid; sulfuric, phosphoric, nitric or perchloric acid; aliphatic or aromatic carboxylic or sulfonic acids, e.g. formic, acetic, propionic, succinic, glycollic, lacetic, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, pyroracemic, phenylacetic, benzoic, 4-aminobenzoic, anthranilic, 4-hydroxybenzoic, salicyclic, 4-aminosalicylic, pamoic, nicotinic; methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, ethylenesulfonic, halogen-benzenesulfonic, toluenesulfonic, naphthalenesulfonic, sulfanilic or cyclohexylsulfamic acid. These or other salts, for example, the picrates, can also be used for purification of the bases obtained; the bases are converted into salts, the salts are separated and the bases are liberated from the salts. In view of the close relationship between the free compounds and the compounds in the form of their salts, whenever a compound is referred to in this context, a corresponding salt is also intended, provided such is possible or appropriate under the circumstances.
The starting material of Formulae III and IV are well known diphenylmethoxy-alkyleneimino-alkylamines or -alkanol esters, or dicarboxanhydrides or - imides respectively, described, together with their precursors, inter alia in J. Org. Chem. 37, 3453 (1972) or British Pat. No. 688,354 or Bull. Soc. Chim. France 10, 2572 (1964).
In case mixtures of geometrical or optical isomers of the compounds of Formulae I to IV are obtained, these can be separated into the single isomers by method in themselves known, e.g. by fractional distillation, crystallization and/or chromatography. Racemic products can likewise be resolved into the optical antipodes, for example, by separation of diastereomeric salts thereof, e.g. by the fractional crystallizaton of d- or 1-tartrates.
The above-mentioned reactions are carried out according to standard methods, in the presence or absence of diluents, preferably such as are inert to the reagents and are solvents thereof, of catalysts, condensing or said other agents respectively and/or inert atmospheres, at low temperatures, room temperature or elevated temperatures, preferably at the boiling point of the solvents used, at atmospheric or superatmospheric pressure.
The invention further includes any variant of the present process, in which an intermediate product obtainable at any stage of the process is used as a starting material and any remaining steps are carried out, or the process is discontinued at any stage thereof, or in which the starting materials are formed under the reaction conditions, or in which the reaction components are used in the form of their salts or optically pure antipodes. Thus, for example, the anhydrides IV may form with the amines III open amides first, which ring-close to the imides I or II by prolonged heating and/or azeotropic water-removal, or the reactive esters III may form intramolecular quaternaries first, e.g. aziridinium salts, which condense in similar fashion. Mainly those starting materials should be used in said reactions that lead to the formation of those compounds indicated above as being especially valuable, e.g. those of Formulae II.
The pharmacologically active compounds of the invention are useful in the manufacture of pharmaceutical compositions comprising an effective amount thereof in conjunction or admixture with excipients suitable for either enteral or parenteral application. Preferred are tablets and gelatin capsules comprising the active ingredient together with (a) diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine, (b) lubricants, e.g. silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol, for tablets also (c) binders, e.g. magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, if desired, (d) disintegrants, e.g. starches, agar, alginic acid or its sodium salt, enzymes of the binders or effervescent mixtures and/or (e) absorbents, colorants, flavors and sweeteners. Injectable or inhalable compositions are preferably aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions. Said compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition they may also contain other therapeutically valuable substances. Said compositions are prepared according to conventional mixing, granulating or coating methods respectively and contain about 0.1 to 75%, preferably about 1 to 50%, of the active ingredient.
US Referenced Citations (5)
Continuation in Parts (1)
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899149 |
Apr 1978 |
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Patent Grant
4261990
