Abstract:
Compounds having the formula ##STR1## wherein A is a straight or branched chain alkylene group; R is hydrogen, halogen, alkyl, alkoxy, alkylthio, trifluoromethyl, nitro, amino, or cyano; and m is 2, 3 or 4; are useful in the treatment of allergic conditions in mammals.

Description:
SUMMARY OF THE INVENTION 
     Useful pharmaceutical activity is exhibited by compounds having the formula ##STR2## In formula I, and throughout the specification, the symbols are as defined below. 
     R can be hydrogen, halogen, alkyl, alkoxy, alkylthio, trifluoromethyl, nitro, amino, or cyano; 
     A can be a straight or branched chain alkylene group having 2 to 8 carbon atoms; and 
     M CAN BE 2, 3, OR 4. 
     The broken line in the piperidine nucleus represents the optional presence of ethylenic unsaturation. 
     The term &#34;alkyl,&#34; as used throughout the specification, refers to alkyl groups having 1 to 4 carbon atoms. 
     The term &#34;alkoxy,&#34; as used throughout the specification, refers to groups having the formula Y-O- wherein Y is alkyl as defined above. 
     The term &#34;alkylthio,&#34; as used throughout the specification, refers to groups having the formula Y-S- wherein Y is alkyl as defined above. 
     The term &#34;halogen,&#34; as used throughout the specification, refers to fluorine, chlorine, bromine, and iodine; fluorine, chlorine, and bromine are the preferred halogens. 
     DETAILED DESCRIPTION OF THE INVENTION 
     The compounds of formula I, and their pharmaceutically acceptable salts, are useful in treating various allergic conditions in mammalian species such as mice, cats, dogs, etc., when administered in amounts ranging from about 1 milligram to about 500 milligrams per kilogram of body weight per day. The compounds can be used prophylactically or therapeutically to treat various allergic and immunological disorders and in particular to treat certain types of asthma, hay-fever, and rhinitis. A preferred dosage regimen would be from about 3 milligrams to about 200 milligrams per kilogram of body weight per day administered in a single dose or plurality of divided doses. 
     The compounds of formula I, and the pharmaceutically acceptable salts thereof, are anti-allergics which inhibit the effects of certain antigen-antibody reactions and in particular inhibit the release of mediators such as histamine. The antiallergy activity of these compounds is determined by the reaginic antibody induced passive cutaneous anaphylaxis (PCA) reaction in rats. (See Bach, Immediate Hypersensitivity: Laboratory Models and Experimental Findings, Ann. Rep. Med. Chem., 7: 238-248 (1972), for a discussion of the pedictability of clinical efficacy of compounds active in the PCA). 
     A compound of formula I, or a salt thereof, can be administered by the inhalation of an aerosol or powder as described in U.S. Pat. No. 3,772,336 (i.e., breathing finely divided particles of the active ingredient into the lungs), orally, or parenterally. Powders can be prepared by comminuting the active ingredient with a similarly comminuted diluent such as starch or lactose. Suitable forms for oral administration include capsules, tablets, and syrups, and a suitable form for parenteral administration is a sterile injectable. Such unit dosage forms are prepared by compounding with a conventional vehicles, excipients, binders, preservatives, stabilizers, flavoring agents or the like as called for by acceptable pharmaceutical practice. Also, the compounds of this invention can be formulated with other pharmaceutically active compounds such as bronchodilators, steroids, antihistamines, etc. 
     The products of formula I can be prepared using as starting materials compounds having the formulas ##STR3## 
     
         X&#39; -- A -- X                                               IV. In formula IV, and throughout the specification, the symbols X and X&#39; can be the same or different and can be halogen (preferably chlorine or bromine), alkylsulfonate (e.g., methanesulfonate), or arylsulfonate (e.g., toluenesulfonate). 
    
     Reaction of a compound of formula II with a compound of formula IV yields an intermediate having the formula ##STR4## The reaction can be run in a polar organic solvent, e.g., dimethylsulfoxide or dimethylformamide, in the presence of alkali. 
     Reaction of an intermediate of formula V with a pyridine derivative of formula III yields an intermediate having the formula ##STR5## The reaction can be run in an organic solvent, e.g., benzene, toluene, etc., preferably in the presence of an organic or inorganic base, e.g., a tertiary amine such as ethyldiisopropylamine or an alkali metal carbonate such as sodium carbonate. While reaction conditions are not critical, the reaction will most conveniently be run at the reflux temperature of the solvent. 
     An intermediate of formula VI can be converted to the corresponding product of formula I via acid hydrolysis. This is most conveniently carried out by extracting the reaction product of an intermediate of formula V and a pyridine derivative of formula III with a mineral acid (hydrochloric acid is preferred) and allowing the acid solution to stand for about 1 week. The hydrolysis can be accelerated by heating. 
     Other procedures for preparing the compounds of formula I are available. For example, an intermediate of formula VI can be prepared by first reacting a compound of formula II with an appropriate base, e.g., potassium hydroxide or thallous ethoxide. The resultant salt is reacted with a compound having the formula ##STR6## to yield an intermediate of formula VI. The compounds of formula I can then be prepared by acid hydrolysis as described above. 
     In still another method for preparing the compounds of formula I, a compound having the formula ##STR7## is reacted with a compound having the formula ##STR8## to yield the products of formula I directly. 
     The compounds of formula I can be converted into their pharmaceutically acceptable salts using procedures well known in the art. Acid addition salts such as the hydrohalides, nitrate, phosphate, sulfate, tartrate, maleate, fumarate, citrate, succinate, methanesulfonate, benzenesulfonate, toluenesulfonate, and the like, are specifically contemplated. Basic salts are also specifically contemplated. The compounds of formula I form salts with bases such as alkali metal hydroxides, sodium hydroxide, potassium hydroxide, etc.), alkaline earth metal hydroxides (e.g., calcium hydroxide, magnesium hydroxide, etc.), alkali metal carbonates (e.g., sodium carbonate, etc.) and alkali metal bicarbonates (e.g., potassium bicarbonate, etc.). 
     The following examples are specific embodiments of this invention. 
    
    
     EXAMPLE 1 
     5-[[4-(3,6-Dihydro-4-Phenyl-1(2H)-Pyridinyl)Butyl]Amino]-5-Oxopentanoic Acid, Hydrochloride (1:1) 
     A. n-(4-bromobutyl)glutarimide 
     Sodium (5g) is dissolved in 100 ml of absolute ethanol and the sodium ethoxide solution is added to a solution of 23 g of glutarimide in 160 ml of warm absolute ethanol. The mixture is allowed to cool to 25° C with stirring and the solvent is removed under vacuum. To the residue is added 70 ml of dimethylformamide and 60 ml of 1,4-dibromobutane and the mixture is refluxed for 10 minutes. The solvent is removed under vacuum and the residue is shaken with hexane to remove excess 1,4-dibromobutane. The hexane layer is decanted off, the residue is taken up in ether and the insoluble material is filtered off. The ethereal filtrate is washed with 10% sodium hydroxide, 10% hydrochloric acid, water, and dried over sodium sulfate. The solvent is removed under vacuum to yield 26 g of N-(4-bromobutyl)glutarimide. 
     B. 5-[[4-(3,6-dihydro-4-phenyl-1(2H)-pyridinyl)butyl]amino]-5-oxopentanoic acid, hydrochloride (1:1) 
     4-Phenyl-1,2,3,6-tetrahydropyridine hydrochloride (10 g) is converted to its free base and combined with 11.0 g of N-(4-bromobutyl)glutarimide and 18 g of sodium carbonate in 200 ml of toluene. The mixture is refluxed for 5 hours, cooled to 25°C and 50 ml of water is added. After stirring for 15 minutes, the layers are separated and the organic layer is filtered through fritted glass to remove insoluble material and then extracted with 10% hydrochloric acid. The acid solution is allowed to stand in an open beaker for 1 week during which time the product precipitates out. It is filtered off and dried at 70° C, 0.1 mm of Hg, for 12 hours to yield 6.3 g of the title compound, melting point 163°-165°C. 
     EXAMPLES 2-55 
     Following the procedure of Example 1, but substituting the compound listed in Column I for glutarimide, the compound listed in Column II for 1,4-dibromobutane and the compound listed in Column III for 4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride, yields the compound listed in Column IV. 
     
         __________________________________________________________________________ExampleColumn I      Column II Column III    Column IV__________________________________________________________________________ 2   glutarimide      1,2-dibromoethane                4-(4-chlorophenyl)1,2,3,                              5-[[2-[3,6-dihydro-4-(4-                6-tetrahydropyridine                              chlorophenyl)-1(2 -H)-pyri-                              dinyl]ethyl]amino]-5-oxo-                              pentanoic acid, hydro-                              chloride 3   glutarimide      1,3-dibromopropane                4-(4-bromophenyl)-1,2,3,                              5-[[3-[3,6-dihydro-4-(4-                6-tetrahydropyridine                              bromophenyl)-1(2 -H)-pyri-                              dinyl]propyl]amino]-5-                              oxopentanoic acid, hydro-                              chloride 4   glutarimide      1,5-dibromopentane                4-(2-methylphenyl)-1,2,                              5-[[5-[3,6-dihydro-4-(2-                3,6-tetrahydropyridine                              methylphenyl)-1(2 -H)-py-                              ridinyl]pentyl]amino]-5-                              oxopentanoic acid, hydro-                              chloride 5   glutarimide      1,5-dibromohexane                4-(3-methoxyphenyl)-                              5-[[6-[3,6-dihydro-4-(3-                1,2,3,6-tetrahydropyri-                              methoxyphenyl)-1(2 -H)-py-                dine          ridinyl]hexyl]amino]-5-                              oxopentanoic acid, hydro-                              chloride 6   glutarimide      1,7-dibromoheptane                4-(4-methylthiophenyl)-                              5-[[7-[3,6-dihydro-4-(4-                1,2,3,6-tetrahydropyri-                              methylthiophenyl)-1(2 -H)-py-                dine          ridinyl]heptyl]amino]-                              5-oxopentanoic acid, hy-                              drochloride 7   glutarimide      1,8-dibromooctane                4-(4-trifluoromethylphen-                              5-[[8-[3,6-dihydro-4-(4-                yl)-1,2,3,6-tetrahydro-                              trifluoromethylphenyl)-                pyridine      1(2 -H)-pyridinyl]octyl]-                              amino]-5-oxopentanoic                              acid, hydrochloride 8   glutarimide      1,3-dibromo-2-                4-(3-nitrophenyl)-1,2,3,-                              5-[[3-[3,6-dihydro-4-(3-      methylpropane                6-tetrahydropyridine                              nitrophenyl)-1(2 -H)-py-                              ridinyl]-2-methylpropyl]-                              amino]-5-oxopentanoic                              acid, hydrochloride 9   glutarimide      1,2-dibromoethane                4-(2-aminophenyl)-1,2,3,-                              5-[[2-[3,6-dihydro-4-(2-                6-tetrahydropyridine                              aminophenyl)-1(2 -H)-pyri-                              dinyl]ethyl]amino]-5-                              oxopentanoic acid, hydro-                              chloride10   glutarimide      1,3-dibromopropane                4-(2-cyanophenyl)-1,2,3,-                              5-[[3-[3,6-dihydro-4-(2-                6-tetrahydropyridine                              cyanophenyl)-1(2 -H)-pyri-                              dinyl]propyl]amino]-5-                              oxopentanoic acid, hydro-                              chloride11   succinimide      1,2-dibromoethane                4-phenyl-1,2,3,6-tetra-                              4-[[2-(3,6-dihydro-4-                hydropyridine phenyl-1(2 -H)-pyridinyl)-                              ethyl]amino]-4-oxobutan-                              oic acid, hydrochloride12   succinimide      1,8-dibromooctane                4-(2-chlorophenyl)-1,2,3,                              4-[[8-[3,6-dihydro-4-(2-                6-tetrahydropyridine                              chlorophenyl)-1(2 -H)-pyri-                              dinyl]octyl]amino]-4-oxo-                              butanoic acid, hydrochlo-                              ride13   succinimide      1,3-dibromopropane                4-(2-ethylphenyl)-1,2,3,-                              4-[[3-[3,6-dihydro-4-(2-                6-tetrahydropyridine                              ethylphenyl-1(2 -H)-pyri-                              dinyl]propyl]amino]-4-                              oxobutanoic acid, hydro-                              chloride14   succinimide      1,4-dibromobutane                4-(2-ethoxyphenyl)-1,2,-                              4-[[4-[3,6-dihydro-4-(2-                3,6-tetrahydropyridine                              ethoxyphenyl)-1(2 -H)-pyri-                              dinyl]butyl]amino]-4-oxo-                              butanoic acid, hydrochlo-                              ride15   succinimide      1,5-dibromopentane                4-(2-ethylthiophenyl)-1,-                              4-[[5-[3,6-dihydro-4-(2-                2,3,6-tetrahydropyridine                              ethylthiophenyl)-1(2 -H)-                              pyridinyl]pentyl]amino]-                              4-oxobutanoic acid, hydro-                              chloride16   succinimide      1,6-dibromohexane                4-(3-trifluoromethyl-                              4-[[6-[3,6-dihydro-4-(3-                phenyl)-1,2,3,6-tetra-                              trifluoromethylphenyl)-                hydropyridine 1(2 -H)-pyridinyl]hexyl]-                              amino]-4-oxobutanoic acid,                              hydrochloride17   succinimide      1,7-dibromoheptane                4-(4-nitrophenyl)-1,2,3,-                              4-[[7-[3,6-dihydro-4-                6-tetrahydropyridine                              (4-nitrophenyl)-1(2 -H)-                              pyridinyl]heptyl]amino]-                              4-oxobutanoic acid, hydro-                              chloride18   succinimide      1,2-dibromoethane                4-(4-aminophenyl)-1,2,3,-                              4-[[2-[3,6-dihydro-4-(4-                6-tetrahydropyridine                              aminophenyl)-1(2 -H)-pyri-                              dinyl]ethyl]amino]-4-                              oxobutanoic acid, hydro-                              chloride19   succinimide      1,5-dibromo-3-                4-(4-cyanophenyl)-1,2,3,-                              4-[[5-[3,6-dihydro-4-(4-      methylpentane                6-tetrahydropyridine                              cyanophenyl)-1(2 -H)-pyri-                              dinyl]3-methylpentyl]-                              amino]-4-oxobutanoic                              acid, hydrochloride20   adipimide      1,2-dibromoethane                4-phenyl-1,2,3,6-tetra-                              6-[[2-(3,6-dihydro-4-                hydropyridine phenyl-1(2 -H)-pyridinyl)-                              ethyl]amino]-6-oxohexa-                              noic acid, hydrochloride21   adipimide      1,3-dibromopropane                4-(3-fluorophenyl)-1,2,-                              6-[[3-[3,6-dihydro-4-                3,6-tetrahydropyridine                              (3-fluorophenyl)-1(2 -H)-                              pyridinyl]propyl]amino]-                              6-oxohexanoic acid, hydro-                              chloride22   adipimide      1,3-dibromopropane                4-(3-t-butylphenyl)-1,2,-                              6-[[3-[3,6-dihydro-4-(3-                3,6-tetrahydropyridine                              t-butylphenyl)-1(2 -H)-py-                              ridinyl]propyl]amino]-                              6-oxohexanoic acid, hydro-                              chloride23   adipimide      1,4-dibromobutane                4-(2-ethoxyphenyl)-1,2-                              6-[[4-[3,6-dihydro-4-(2-                3,6-tetrahydropyridine                              ethoxyphenyl)-1(2 -H)-pyri-                              dinyl]butyl]amino]-6-oxo-                              4-oxohexanoic acid, hydrochlo-                              ride24   adipimide      1,5-dibromopentane                4-(4-ethylthiophenyl)-1,-                              6-[[5-[3,6-dihydro-4-(4-                2,3,6-tetrahydropyridine                              ethylthiophenyl)-1(2 -H)-                              pyridinyl]pentyl]amino]-                              4-oxohexanoic acid, hy-                              drochloride25   adipimide      1,6-dibromohexane                4-(3-trifluoromethyl-                              6-[[6-[3,6-dihydro-4-(3-                phenyl)-1,2,3,6-tetra-                              trifluoromethylphenyl)-                hydropyridine 1(2 -H)-pyridinyl]hexyl]-                              amino]-4-oxohexanoic                              acid, hydrochloride26   adipimide      1,7-dibromoheptane                4-(3-nitrophenyl)-1,2,-                              6-[[7-[3,6-dihydro-4-(3-                3,6-tetrahydropyridine                              nitrophenyl)-1(2 -H)-pyri-                              dinyl]heptyl]amino]-4-                              oxohexanoic acid, hydro-                              chloride27   adipimide      1,8-dibromooctane                4-(3-aminophenyl)-1,2,3,-                              6-[[8-[3,6-dihydro-4-(3-                6-tetrahydropyridine                              aminophenyl)-1(2 -H)-pyri-                              dinyl]octyl]amino]-4-                              oxohexanoic acid, hydro-                              chloride28   adipimide      1,2-dibromoethane                4-(3-cyanophenyl)-1,2,3,-                              6-[[2-[3,6-dihydro-4-(3-                6-tetrahydropyridine                              cyanophenyl)-1(2 -H)-pyri-                              dinyl]ethyl]amino]-4-                              oxohexanoic acid, hydro-                              chloride29   glutarimide      1,2-dibromoethane                4-(4-chlorophenyl)piperi-                              5-[[2-[4-(4-chlorophenyl)-                dine          piperidinyl]ethyl]amino]-                              5-oxopentanoic acid, hy-                              drochloride30   glutarimide      1,3-dibromopropane                4-(4-bromophenyl)piperi-                              5-[[3-[4-(4-bromophenyl)-                dine          piperidinyl]propyl]amino]-                              5-oxopentanoic acid, hy-                              drochloride31   glutarimide      1,5-dibromopentane                4-(2-methylphenyl)piperi-                              5-[[5-[4-(2-methylphenyl)-                dine          piperidinyl]pentyl]amino]-                              5-oxopentanoic acid, hy-                              drochloride32   glutarimide      1,6-dibromohexane                4-(3-methoxyphenyl)piper-                              5-[[6-[4-(3-methoxyphenyl)-                idine         piperidinyl]hexyl]amino]-                              5-oxopentanoic acid, hydro-                              chloride33   glutarimide      1,7-dibromoheptane                4-(4-methylthiophenyl)-                              5-[[7-[4-(4-methylthio-                piperidine    phenyl)piperidinyl]heptyl]-                              amino]-5-oxopentanoic acid,                              hydrochloride34   glutarimide      1,8-dibromooctane                4-(3-trifluoromethyl-                              5-[[8-[4-(3-trifluoro-                phenyl)piperidine                              methylphenyl)piperidinyl]-                              octyl]amino]-5-oxopentan-                              oic acid, hydrochloride35   glutarimide      1,3-dibromo-2-                4-(3-nitrophenyl)piper-                              5-[[3-[4-(3-nitrophenyl)-      methylpropane                idine         piperidinyl]-2-methyl-                              propyl]amino]-5-oxopen-                              tanoic acid, hydrochloride36   glutarimide      1,2-dibromoethane                4-(2-aminophenyl)piper-                              5-[[2-[4-(2-aminophenyl)-                idine         piperidinyl]ethyl]amino]-                              5-oxopentanoic acid, hydro-                              chloride37   glutarimide      1,3-dibromopropane                4-(2-cyanophenyl)piper-                              5-[[3-[4-(2-cyanophenyl)-                idine         piperidinyl]propyl]amino]-                              5-oxopentanoic acid, hy-                              drochloride38   succinimide      1,2-dibromoethane                4-phenylpiperidine                              4-[[2-(4-phenylpiperi-                              dinyl)ethyl]amino]-4-oxo-                              butanoic acid, hydrochlo-                              ride39   succinimide      1,8-dibromooctane                4-(2-chlorophenyl)piper-                              4-[[8-[4-(2-chloro-                idine         phenyl)piperidinyl]-                              octyl]amino]-4-oxo-                              butanoic acid, hydro-                              chloride40   succinimide      1,3-dibromopropane                4-(2-ethylphenyl)piper-                              4-[[3-[4-(2-ethylphenyl)-                idine         piperidinyl]propyl]-                              amino]-4-oxobutanoic                              acid41   succinimide      1,4-dibromobutane                4-(2-ethoxyphenyl)-piper-                              4-[[4-[4-(2-ethoxy-                idine         phenyl)piperidinyl]-                              butyl]amino]-4-oxobuta-                              noic acid42   succinimide      1,5-dibromopentane                4-(2-ethylthiophenyl)                              4-[[5-[4-(2-ethylthio-                piperidine    phenyl)piperidinyl]-                              pentyl]amino]-4-oxo-                              butanoic acid43   succinimide      1,6-dibromohexane                4-(3-trifluoromethyl-                              4-[[6-[4-(3-trifluoro-                phenyl)piperidine                              methylphenyl)piperidinyl]-                              hexyl]amino]-4-oxobuta-                              noic acid44   succinimide      1,7-dibromoheptane                4-(4-nitrophenyl)piper-                              4-[( 7-[4-(4-nitrophenyl)-                idine         piperidinyl]heptyl]amino]-                              4-oxobutanoic acid45   succinimide      1,2-dibromoethane                4-(4-aminophenyl)piper-                              4-[[2-[4-(4-aminophenyl)-                idine         piperidinyl]ethyl]amino]-                              4-oxobutanoic acid46   succinimide      1,5-dibromo-3-                4-(4-aminophenyl)piper-                              4-[[5-[4-(4-aminophenyl)-      methylpentane                idine         piperidinyl]-3-methyl-                              pentyl]amino]-4-oxobuta-                              noic acid47   adipimide      1,2-dibromoethane                4-phenylpiperidine                              6-[[2-(4-phenylpiperi-                              dinyl)ethyl]amino]-6-                              oxohexanoic acid, hydro-                              chloride48   adipimide      1,3-dibromopropane                4-(4-fluorophenyl)piper-                              6-[[3-[4-(4-fluorophenyl)-                idine         piperidinyl]propyl]amino]-                              6-oxohexanoic acid, hydro-                              chloride49   adipimide      1,3-dibromopropane                4-(4-t-butylphenyl)                              6-[( 3-[4-(4-t-butylphenyl)-                piperidine    piperidinyl]propyl]amino]-                              6-oxohexanoic acid, hydro-                              chloride50   adipimide      1,4-dibromobutane                4-(3-ethoxyphenyl)piper-                              6-[[4-[4-(3-ethoxyphenyl)-                idine         piperidinyl]butyl]amino]-                              6-oxohexanoic acid, hydro-                              chloride51   adipimide      1,5-dibromopentane                4-(4-ethylthiophenyl)pip-                              6-[[5-[4-(4-ethylthio-                eridine       phenyl)piperidinyl]pen-                              tyl]amino]-6-oxohexanoic                              acid, hydrochloride52   adipimide      1,6-dibromohexane                4-(4-trifluoromethyl-                              6-[[6-[4-(4-trifluoro-                phenyl)piperidine                              methylphenyl)piperidinyl]-                              hexyl]amino]-6-oxohexa-                              noic acid, hydrochloride53   adipimide      1,7-dibromoheptane                4-(3-nitrophenyl)piper-                              6-[[7-[4-(3-nitrophenyl)-                idine         piperidinyl]heptyl]amino]-                              6-oxohexanoic acid, hydro-                              chloride54   adipimide      1,8-dibromooctane                4-(3-aminophenyl)piper-                              6-[[8-[4-(3-aminophenyl)-                idine         piperidinyl]octyl]amino]-                              6-hexanoic acid, hydro-                              chloride55   adipimide      1,2-dibromoethane                4-(3-cyanophenyl)piper-                              6-[[2-[4-(3-cyanophenyl)-                idine         piperidinyl]ethyl]amino]-                              6-oxohexanoic acid, hydro-                              chloride__________________________________________________________________________