Heterocyclic compounds
This is a division of copending application Ser. No. 443,912, filed Nov. 23, 1982, now U.S. Pat. No. 4,581,367, which in turn is a division of application Ser. No. 285,713, filed July 22, 1981, now U.S. Pat. No. 4,378,361, issued Mar. 29, 1983; which which in turn is a continuation of application Ser. No. 156,928, filed June 6, 1980, now abandoned; which in turn is a continuation of application Ser. No. 060,389, filed July 25, 1979, now abandoned. 
    
    
     This invention relates to novel heterocyclic compounds and salts thereof, to various methods of preparing these compounds, to pharmaceutical compositions containing them as active ingredients, and to methods of using them as broncholytics, uterus relaxants, antiallergics and hypotensives. 
     More particularly, the present invention relates to a novel class of heterocyclic compounds represented by the formula ##STR5## wherein Het is ##STR6## n is an integer from 1 to 4, inclusive, preferably 2 or 3, R 1  is H or acyl, 
     R 2  is H, R 1  O, --NHSO 2  R 7 , --NHCOR 8 , --NHCONHR 8 , --NH--CH 2  --C 6  H 4  --R 9 , --CH 2  OH, --CH 2  SO 2  R 7 , --CONHR 8 , halogen or --CN, 
     R 3  is H, halogen, R 7  or --OR 7 , 
     R 2  and R 3 , together with each other are ##STR7## R 4  is H, --CH 3  or --C 2  H 5 , R 5  and R 6  are each H or --CH 3 , 
     R 7  is C 1  -C 4  alkyl, 
     R 8  is H or C 1  -C 4  alkyl, 
     R 9  is H, C 1  -C 4  alkyl or C 1  -C 4  alkoxy optionally interrupted by oxygen, 
     R 10  is H, C 1  -C 4  alkyl, phenyl or pyridyl 
     R 11  and R 12  are each H, CH 3 , Cl or OCH 3 , or together methylenedioxy, 
     X is ##STR8##  or N, and Z is --CH 2  or --CO; 
     in the form of racemates, enantiomers, diastereoisomeric antipode pairs, as well as non-toxic, pharmacologically acceptable acid addition salts thereof. 
     A preferred sub-genus thereunder is constituted by compounds of the formula I 
     wherein 
     R 1  is H, 
     R 2  is H, --OH, --NHSO 2  CH 3 , --NHCOR 8 , --NHCONHR 8 , --NH--CH 2  --C 6  H 4  --R 9 , --CH 2  OH, CH 2  SO 2  CH 3 , --CONHR 8 , Cl or F, 
     R 3  is H, Cl, --CH 3  or --OCH 3 , 
     R 2  and R 3 , together with each other are, ##STR9## R 4  is H, R 5 , R 6 , R 8  and R 10 , which may be the same or different, are each H or --CH 3 , 
     R 9  is H or 4--OCH 3 , 
     Het is ##STR10## X is --CH═ or --N═, and n is an integer from 1 to 4, inclusive, preferably 2 or 3. 
     The compounds embraced by formula I may be prepared by the following methods: 
     METHOD A 
     By reducing an amino-ketone of the formula ##STR11## wherein R 1  through R 6 , Het and n have the above-mentioned meanings, and wherein the central nitrogen atom and/or phenolic OH groups present, if any, may be protected by protective groups, separable by hydrogenation, in a suitable solvent with hydrogen and a hydrogenation catalyst or with hydrides having a reducing action, and protective groups still present are optionally removed after the reduction by hydrogenation. 
     METHOD B 
     For the preparation of those compounds of the formula I wherein R 4  is H, by reacting an amine of the formula ##STR12## wherein R 5 , R 6 , Het and n have the above-mentioned meanings, under the conditions of reductive amination with a phenyl-glyoxal of the formula ##STR13## wherein R 1 , R 2  and R 3  have the above-mentioned meanings, and in which phenolic OH groups present, if any, may be protected by protective groups separable by hydrogenation, optionally in the form of a hemi-acetal, and optionally separating protective groups present by hydrogenation. 
     METHOD C 
     By removing the protective group or groups from a compound of the formula ##STR14## wherein R 3  to R 6 , n and Het have the above-mentioned meanings and R&#39; is H or a protective group separable by hydrogenation, R 1  &#39; is R 1  or a protective group separable by hydrogenation, R 2  &#39; is R 2 , but in the definition thereof of R 1  is to be replaced by R 1  &#39;, and wherein at least one of the radicals R 1  &#39; and R 2  &#39; is a protective group to be removed. 
     The end products obtained by methods A, B and C may, if desired, be separated into their enantiomers, optionally also into their diastereoisomeric antipode pairs, if desired, bases obtained may be converted into acid addition salts, and acid addition salts obtained may be converted into the free bases or into salts with other acids. 
     In method A, solvents which are sufficiently inert under the reaction conditions, for example alcohols such as methanol or ethanol, and conventional hydrogenation catalysts, for example palladium, platinum or Raney nickel are used. Hydrides which may be used as reducing agents are sodium borohydride and other complex hydrides, or diborane. The reaction temperature lies between about 0° C. and the boiling point of the reaction mixture. If the central amino group (contained in the side chain) or the substituents R 1  O and/or R 2  in the starting starting material have a protecting group separable by hydrogenation, for example an optionally substituted benzyl group, attached thereto, this protective group is removed during, or, if necessary, after the reduction of the --CO-- group. 
     The starting materials of the formula II are obtained, for example, by reaction of amines of the formula III with bromo-ketones of the formula IV in solvents, such as acetonitrile or ethyl acetate, in the presence of an acid-binding agent, such as sodium carbonate, or an excess of the amine: ##STR15## wherein R 1  &#39; is R 1  or a radical separable by hydrogenation, such as benzyl, R&#39; is H or a radical separable by hydrogenation, such as benzyl, and the remaining substituents are as defined above. 
     In method B it is possible to use compound VI also in the form of a hemi-acetal, that is, in the form of a compound of the formula ##STR16## wherein R 1 , R 2  and R 3  have the above-mentioned meanings and alkyl represents an optionally substituted, preferably C 1  -C 6  alkyl radical. 
     The Schiff&#39;s bases of the formula VIII possibly occurring as intermediate compounds ##STR17## wherein the individual substituents are as defined above, may also be isolated and then subjected to reduction. 
     Complex hydrides, preferably sodium borohydride or hydrogen in the presence of hydrogenation catalysts, such as platinum, palladium or Raney nickel, are used as reducing agents. If R 1  O and/or R 2  are phenolic OH groups which are protected by a group separable by hydrogenation, such as benzyl, these groups are, if necessary, removed in the conventional way after reduction. 
     The amines of the formula are accessible, for example, by alkylating a heterocycle Het-H on the amino group with a compound of the formula ##STR18## wherein R 5  and R 6  have the meanings previously defined, 
     X is chlorine, bromine, methylsulfonic or tolylsulfonic acid radical, and 
     B is a functional group, such as NO 2 , dibenzylamino or benzalamino, which may be converted into the amino group by catalytic hydrogenation or hydrolysis in the presence of sodium hydride in solvents such as hexamethyl phosphoric acid triamide, and by converting thereafter the functional radical B into the amino group. 
     The phenyl glyoxals of the formula VI or the corresponding hemi-acetals of the formula VII may be obtained, for example, by oxidation of an acetophenone of the formula ##STR19## wherein R 1 , R 2  and R 3  are as defined above, with selenium dioxide in aqueous dioxane and crystallization from water or alcohols. 
     In mehod C separation of the protective groups is effected with hydrogen and hydrogenation catalysts, such as palladium, platinum or Raney nickel, at temperatures between 0° C. and the boiling point of the reaction mixture. Lower alkanols, primarily methanol, serve preferably as solvents. 
     The starting materials of the formula XI may be prepared according to method A or B. Another possibility consists of converting precursors of R 2  &#39; in formula XI into R 2  &#39; in compounds of the formula ##STR20## in which n, Het, R&#39;, R 1  &#39; and R 3  to R 6  have the above-mentioned meanings and R&#34; 2  is a precursor of NH--CONH--R 8 , NHCOR 8 , NHSO 2  R or NH--CH 2  --C 6  H 4  --R 9  (e.g. NH 2 ), or of CH 2  OH or CONHR 8  (e.g. COOC 2  H 5 ), by conventional methods. 
     Thus, from compounds of the formula XII where R 2  &#34; is NH 2 , compounds of the formula XI wherein R 2  &#39; is NHCONH 2  may be obtained with potassium cyanate, or the compounds of the formula XI where R 2  &#39; is NH--COR 8  may be obtained with compounds of the formula (R 8  CO) 2  O. Compounds of the formula XII where R 2  &#34; is COOC 2  H 5  yield by reduction with lithium aluminum hydride compounds of the formula XI where R 2  &#39; is CH 2  OH and by reaction with amines of the formula H 2  NR 8  compounds of the formula XI where R 2  &#39; is CONHR 8  may be obtained. 
     The following examples illustrate the present invention and will enable others skilled in the art to understand it more completely. It should be understood, however, that the invention is not limited solely to the particular examples given below. 
     The compounds embraced by formula I are organic bases and therefore form acid addition salts with inorganic or organic acids. Examples of non-toxic, pharmacologically acceptable acid addition salts are those formed with hydrochloric acid, cyclamic acid, maleic acid, sulfuric acid, formic acid, succinic acid, methanesulfonic acid, cyclohexanesulfamic acid, fumaric acid, benzoic acid or the like. 
    
    
     EXAMPLE 1 
     1-(4-Hydroxy-phenyl)-2-[3-(1-benzimidazolyl)-propyl-amino]ethanol and its dihydrochloride by method A 
     30.5 gm of 2-bromo-p-benzyloxyacetophenone and 35 gm of 1-aminopropyl-benzimidazole were stirred for 1 hour at 30°-40° C. in 150 ml of acetonitrile. After separation of the hydrobromide, the mother liquor was acidified with 12 gm of maleic acid, and the precipitated α-[3-(1-benzimidazolyl)propylamino]-4-benzyloxyacetophenone maleate (m.p. 145°-148° C.) was collected by suction of filtiation. Aqueous ammonia was used to prepare the base, which was reduced in 200 ml of alcohol with sodium borohydride to form 1-(4-benzyloxyphenyl)-2-[3-(1-benzimidazolyl)-propylamino]-ethanol (m.p. 83°-85° C.). 
     Catalytic hydrogenation of 7 gm of this compound in 100 ml of methanol with 1 gm of palladium charcoal as the catalyst yielded 4.5 gm of 1-(4-hydroxyphenyl)-2-[3-(1-benzimidazolyl)-propylamino]-ethanol (m.p.146°-148° C., 83% of theory), whose dihydrochloride of the formula ##STR21## had a melting point of 184°-185° C. 
     EXAMPLE 2 
     1-[3-(3-Carbamoyl-4,β-dihydroxy-phenethylamino)-propyl]-1-H-benzotriazole and its cyclamate by method A 
     A mixture of 17.5 gm of 2-benzyloxy-5-bromoacetyl salicylamide, 17.6 gm of 1-(3-aminopropyl)-1H-benzotriazole, 6 gm of sodium carbonate and 150 ml of ethyl acetate was refluxed for 1.5 hours. After separation of the inorganic constituents, the mother liquor was evaporated, the residue was dissolved in a 100 ml of acetonitrile, and the solution was acidified with 5 gm of oxalic acid. The precipitated 1-[3-(3-carbamoyl-4-benzyloxy-β-oxophenethylamino)-propyl]-1-H-benzotriazole oxalate was collected by suction of filtration converted with aqueous ammonia into the base (m.p. 186°-188° C.) and reduced in 100 ml of ethanol with sodium borohydride to form 1-(3-carbamoyl-4-benzyloxy-β-hydroxyphenethylamino)propyl]-1-H-benzotriazole. 
     Hydrogenation of 6 gm of this compound in 100 ml of methanol at a pressure of 6 bars and 40° C. in the presence of palladium charcoal yielded 3 gm of 1-[3-(3-carbamoyl-4,β-dihydroxy-phenethylamino)-propyl]-1-H-benzotriazole (m.p. 154°-155° C.), 77.5% of theory) whose cyclamate of the formula ##STR22## had a melting point of 165° C. 
     EXAMPLE 3 
     1-[3-Carbamoyl-4-β-dihydroxy-phenethylamino)-propyl]-3-methylquinazoline-2,4-dione dihydrochloride by method A 
     A mixture of 12.9 gm of 5-bromoacetyl salicylamide, 15.45 gm of 1-(3-benzylaminopropyl)-3-methyl-quinazoline-2,4-dione, 6 gm of sodium carbonate and 300 ml of acetonitrile was refluxed for 1.5 hours. After suction-filtering off the inorganic constituents, the mother liquor was evaporated, the residue was dissolved in 500 ml of methanol, and the solution was hydrogenated, after addition of 12 ml of benzyl chloride, at 6 bars and 60° C. with palladium charcoal as the catalyst. After 2 mols of hydrogen had been taken up, the hydrogenation was complete, and the resulting 1-[3-(3-carbamoyl-β-oxo-4-hydroxyphenethylamino)-phenyl]-3-methyl-quinazoline-2,4-dione hydrochloride (m.p.=253° C. with decomposition) was isolated. 
     Catalytic hydrogenation of 13 gm of this compound in 250 ml of a methanol/water mixture 1:1 at 6 bars pressure and 50° C. with palladium as the catalyst yielded 8 gm of 1-[3-(3-carbamoyl-4-β-dihydroxy-phenethylamino)-propyl]-3-methylquinazoline-2,4-dion hydrochloride of the formula ##STR23## which had a melting point of 220°-221° C. The yield was 61.5% of theory. 
     Using procedures analogous to those described in Examples 1 to 3, the following compounds of the formula I was also prepared: 
     
                                           TABLE I                                 
__________________________________________________________________________
                                        Yield          Melting point      
Formula                                 (%)  Salt with in                 
__________________________________________________________________________
                                                       °C.         
 ##STR24##                              88   2 × maleic             
                                                       178-180            
 ##STR25##                              61   Sulphuric acid ×       
                                             2H.sub.2 O                   
                                                       199-202            
 ##STR26##                              65   Sulphuric acid × 0.5   
                                             H.sub.2 O 174-176 163        
                                                       (Base)             
 ##STR27##                              80   Formic acid                  
                                                       158-160            
 ##STR28##                              60   1.5 × succinic         
                                                       154-156            
 ##STR29##                              83   2 × maleic acid        
                                                       137-140            
 ##STR30##                              60   Methanesulphonic acid        
                                                       178-180            
 ##STR31##                              80   Formic acid                  
                                                       163-166            
 ##STR32##                              65   Cyclohexane sulphaminic      
                                                       174-176            
__________________________________________________________________________
 
    
     EXAMPLE 4 
     1-(2,5-Dichloro-4-hydroxy-phenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]-ethanol dihydrochloride by method B 
     A mixture of 9.3 gm of 2,5-dichloro-4-hydroxyphenylglyoxal hydrate, 7.25 gm of 1-(3-amino-3-methylbutyl)-benzimidazole and 100 ml of alcohol was stirred for 3 hours at 40°-45° C. The resulting solution was subsequently cooled, admixed in portions with 8 gm of sodium borohydride, and the mixture was stirred for 3 hours at room temperature. After the addition of 100 ml of methanol for decomposition of the sodium borohydride, the mixture was allowed to stand for 10 hours, the solvent was distilled off under reduced pressure, the residue was dissolved in 200 ml of water, and the solution was acidified with concentrated hydrochloric acid. 9.5 gm of 1-(2,5-dichloro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]-ethanol dihydrochloride×1H 2  O, m.p. 180°-183° C., of the formula ##STR33## were obtained. The yield was 50.4% of theory. 
     EXAMPLE 5 
     2&#39;-Hydroxy-5&#39;-[1-hydroxy-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]-ethyl]-methanesulfonanilide and its formate by method B 
     A mixture of 14.4 gm of 2&#39;-benzyloxy-5&#39;-(1-oxo-2-hydroxy-2-ethoxy-ethyl)-methanesulfonanilide, 7 gm of 1-(3-amino-3-methylbutyl)-benzimidazole and 150 ml of alcohol was heated for 3 hours at 50° C. and then admixed in portions with 9.2 gm of sodium borohydride. The resulting solution is kept for 12 hours at room temperature, the alcohol is then removed under reduced pressure on a Rotavapor, and the residue is dissolved with 200 ml of water and 500 ml of ethyl acetate. After decomposition of the sodium borohydride by stirring with concentrated hydrochloric acid and ice cooling, the mixture was made alkaline with aqueous ammonia, and the ethyl acetate phase was separated, dried with sodium sulfate and evaporated on a Rotavapor. The residue was dissolved in 200 ml of alcohol, the solution was acidified with 6.3 gm of oxalic acid, and the precipitated 2&#39;-benzyloxy-5&#39;-[1-hydroxy-2-[4-(1-benzimiazolyl)-2-methyl-2-butylamino]-ethyl]methane sulfonanilide dioxalate (m.p. 185°-187° C.) is extracted. The base (m.p. 65°-70° C.) was liberated from this compound with aqueous ammonia. Catalytic hydrogenation of this compound (m.p. 65°-70° C.) in 250 ml of methanol under standard conditions with palladium charcoal as a catalyst yielded 8 gm of 2&#39;-hydrox-5&#39;-[1-hydroxy-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]-ethyl]-methanesulfonanilide (m.p. 170°-173° C.; 81% of theory) whose formates of the formula ##STR34## had a melting point of 161°-164° C. 
     EXAMPLE 6 
     1-(2-Fluoro-4-hydroxy-phenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]-ethanol and its formate by method B 
     A solution of 15.2 gm of 1-(2-fluoro-4-benzyloxyphenyl)-1-oxo-2-hydroxy-2-ethoxy-ethane in 200 ml of alcohol was admixed with 8.2 gm of 1-(3-amino-3-methylbutyl)-benzimidazole, and the mixture was stirred for 3 hours at 50° C. The resulting solution was subsequently cooled, admixed with 4 gm of sodium borohydride and stirred for 6 hours at room temperature. The mixture was then worked up as described in Example 3. The residue was dissolved in 200 ml of alcohol, the solution was acidified with 7.2 gm of oxalic acid, and the precipitated 1-(2-fluoro-4-benzyloxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]-ethanol dioxalate (m.p. 184°-188° C.) was suction filtered off. The base (m.p. 85°-88° C.) was liberated from the dioxalate with aqueous ammonia. 
     Catalytic hydrogenation of this compound in 250 ml of methanol at 6 bars pressure with palladium charcoal as the catalyst at about 30° C. yielded 1-(2-fluoro-4-hydroxyphenyl)2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]-ethanol, m.p. 151°-153° C., whose formate of the formula ##STR35## had a melting point of 157°-159° C. 
     By addition of the calculated quantity of methanesulfonic acid to the solution of the base in ethanol and the methanesulfonate, m.p. 178°-179° C. was obtained. The hydrochloride was prepared correspondingly, m.p. 205° C. The dihydrochloride tetrahydrate, m.p. 177° C., was obtained from the base in aqueous acetonitrile was the calculated quantity of concentrated hydrochloric acid. The sulfhate hydrate, m.p. 207°-208° C. was obtained analogously in aqueous ethanol. 
     Using procedures analogous to those described in Examples 4 to 6, the following compounds of the formula I were also prepared. 
     
                                           TABLE II                                
__________________________________________________________________________
                                         Yield        Melting point       
Formula                                  (%) Salt with                    
                                                      °C.          
__________________________________________________________________________
 ##STR36##                               79.5                             
                                             Formic acid                  
                                                      128                 
 ##STR37##                               85  Methanesulphonic acid        
                                                      178-180 123 Base    
 ##STR38##                               54.5                             
                                             Cyclohexane- sulphaminic     
                                             acid     177-179 171 Base    
 ##STR39##                               79  2 × formic acid        
                                             × 1 H.sub.2 O          
                                                      174-176 188-190     
                                                      Base                
 ##STR40##                               83  Formic acid                  
                                                      163-166 193-196     
                                                      Base                
 ##STR41##                               93  0.5 succinic                 
                                                      187-189 168-172     
                                                      Base                
 ##STR42##                               85  Sulphuric acid × 1     
                                             H.sub.2 O                    
                                                      173-175 174-176     
                                                      Base                
 ##STR43##                               93  Maleic acid                  
                                                      190-193 181-183     
                                                      Base                
 ##STR44##                               50  Cyclohexane- sulphaminic     
                                             acid     162-164             
 ##STR45##                               58  Sulphuric acid               
                                                      224-226 decomp.     
 ##STR46##                               48.5                             
                                             hydrochloric                 
                                                      208-210 decomp.     
 ##STR47##                               69  hydrochloric                 
                                                      208-210             
 ##STR48##                               86  Formic acid                  
                                                      158-160 129-132     
                                                      Base                
 ##STR49##                               92  Hydrochloric                 
                                                      203-204 decomp.     
                                                      165-167 Base        
 ##STR50##                               77.5                             
                                             Cyclohexane- sulphaminic     
                                             acid     177-180             
 ##STR51##                               50  1.5 × succinic         
                                                      154-156             
 ##STR52##                               60  Formic acid × 1        
                                             H.sub.2 O                    
                                                      115-119             
 ##STR53##                               87.5                             
                                             2 × maleic             
                                                      137-140 165-168     
                                                      Base                
 ##STR54##                               62  2 × maleic             
                                                      176-179 245 decomp. 
                                                      base                
 ##STR55##                               82  Sulphuric acid               
                                                      287 decomp. 218-220 
                                                      Base                
 ##STR56##                               80  Maleic acid                  
                                                      185-186 175-178     
                                                      Base                
 ##STR57##                               63  Maleic acid                  
                                                      173-174             
 ##STR58##                               75  Maleic acid × 1/2      
                                             Aceton-nitrile               
                                                      161-165 160- 162    
                                                      Base                
 ##STR59##                               72  Cyclohexane- sulphaminic     
                                             acid     174-176 182-184     
                                                      Base                
 ##STR60##                               81  Maleic acid                  
                                                      186-189 155-159     
 ##STR61##                               77.5                             
                                             Fumaric acid                 
                                                      158-160             
 ##STR62##                               78  Formic acid × 1        
                                                      175-178             
 ##STR63##                               73.5                             
                                             Maleic acid × 1/2      
                                             ethanol  167-169             
 ##STR64##                               77.5                             
                                             2 × hydrochloric       
                                                      168-170 186-188     
                                                      Base                
 ##STR65##                               82  Sulphuric acid               
                                                      215-218 decomp.     
                                                      185-186 Base        
 ##STR66##                               77  2 × hydrochloric       
                                                      185-186             
 ##STR67##                               93  2 × hydrochloric       
                                                      189-191 182-184     
                                                      Base                
 ##STR68##                               92.5                             
                                             Formic acid                  
                                                      180-182 125° 
                                                      decomp. Base        
 ##STR69##                               32           148-151 Base        
 ##STR70##                               74  Formic acid                  
                                                      170-172             
 ##STR71##                               93  2 × hydrochloric       
                                                      165-168 163-165     
                                                      Base                
 ##STR72##                               78.5                             
                                             Formic acid                  
                                                      156-159 133-136     
                                                      Base                
 ##STR73##                               87  2 × hydrochloric       
                                                      210-212             
 ##STR74##                               85  Formic acid                  
                                                      160-163 123-125     
__________________________________________________________________________
                                                      Base                
 
    
     EXAMPLE 7 
     1-{3-[2-Hydroxy-2-(4-hydroxy-phenyl)-ethylamino]-propyl}-1,2,3,4-tetrahydro-4-quinazolone and its formate by method C 
     15.5 gm of 1-{-[2-hydroxy-2-(4-benzyloxy-phenyl)benzylethylamino]-propyl}-1,2,3,4-tetrahydro-4-quinazolone (m.p. 119°-121° C.) were dissolved in 250 ml of methanol and debenzylated by hydrogenation at 60° C. and 6 bars pressure in the presence of palladium as the catalyst. After 2 mols of hydrogen had been taken up, the hydrogenation was complete, yielding of 8 gm of 1-{3-[2-hydroxy-2-(4-hydroxyphenyl)ethylamino]-propyl}-1,2,3,4-tetrahydro-4-quinazolone, whose formate of the formula ##STR75## had a melting point of 174°-176° C. The yield was 61.5% of theory. 
     EXAMPLE 8 
     1-{2&#39;-Hydroxy-5&#39;-[1-hydroxy-2-[4-(1-imidazolyl)-2-methyl-2-butylamino]-ethyl]-phenyl}-urea and its sulfate by method C 
     A mixture of 15 gm of 2&#39;-benzyloxy-5&#39;-[1-hydroxy-2-[4-(1-imidazolyl)-2-methyl-2-butylamino]-ethyl]-acetanilide (m.p. of the dioxalate 160°-163° C.), 18.5 gm of KOH, 80 ml of alcohol and 15 ml of water was refluxed for 24 hours, and the resulting 1-(3-amino-4-benzyloxy-phenyl)-2-[4-(1-imidazolyl)-2-methyl-2-butylamino]-ethanol was isolated as the trioxalate (m.p. 95°-100° C.). Aqueous ammonia was used to liberate the base which was reacted with potassium cyanate to form 1-{2&#39;-benzyloxy-5&#39;-[1-hydroxy-2-[4-(1-imidazolyl)-2-methyl-2-butylamino]-ethyl]-phenyl}-urea (m.p. 142°-143° C.). Catalytic hydrogenation of 5.1 gm of this compound in 100 ml of methanol with palladium charcoal as the catalyst yielded 3.5 gm of 1-{2&#39;-hydroxy-5&#39;-[1-hydroxy-2-]-4-(1-imidazolyl)-2-methyl-2-butylamino]-ethyl]-phenyl]-phenyl}-urea, whose sulfate of the formula ##STR76## had a melting point of 243°-244° C. The yield was 70% of theory. 
     EXAMPLE 9 
     5-[1-Hydroxy-2-[4-(1-imidazolyl)-2-methyl-2-butylamino]-ethyl]-N-methyl-salicylamide sulfate by method C 
     8.5 gm of methyl 2&#39;-benzyloxy-5&#39;-[1-hydroxy-2-[4-(1-imidazolyl)-2-methyl-4-butylamino]-ethyl]-benzoate (m.p. of the dioxalate 156°-158° C. were hydrogenated under standard conditions in 100 ml of methanol in the presence of palladium as the catalyst, and after 1 mol of hydrogen had been taken up the catalyst was filtered off, and 15 ml of monomethylamine were added to the filtate. After 2 days of standing the solvent was distilled off, the residue was dissolved in 15 ml of alcohol and 15 ml of water, and the solution was acidified with 2 gm of concentrated sulfuric acid. 
     4.5 gm of 5-[1-hydroxy-2[4-(1-imidazolyl)-2-methyl-2-butylamino]-ethyl]-N-methyl-salicylamide sulfate of the formula ##STR77## having a melting point of 263°-265° C. (decomposition) were obtained. The yield was 52% of theory. 
     EXAMPLE 10 
     1-(3-Hydroxymethyl-4-hydroxy-phenyl)-2-[4-(1-imidazolyl)-2-methyl-2-butylamino]-ethanol and its benzoate by method C 
     13.5 gm of methyl 2&#39;-benzyloxy-5&#39;-[1-hydroxy-2-[4-(1-imidazolyl)-2-methyl-4-butylamino]-ethyl]-benzoate (m.p. of the dioxalate 156°-158° C.) were reduced in 200 ml of tetrahydrofuran with 6 gm of lithium aluminum hydride to form 1-(3-hydroxymethyl-4-benzyloxyphenyl)-2-[4-(1-imidazolyl)-2-methyl-2-butylamino]-ethanol, whose dioxalate melted at 144°-146° C. Aqueous ammonia was used to liberate the base from 10 gm of dioxalate, which was hydrogenated in 100 ml of methanol with palladium as the catalyst. 4.5 gm of 1-(3-hydroxymethyl-4-hydroxyphenyl)-2-[4-(1-imidazolyl)-2-methyl-2-butylamino]-ethanol (m.p. 135°-137° C.) were obtained; the benzoate thereof of the formula ##STR78## had a melting point of 150°-152° C. The yield was 83% of theory. 
     Using procedures analogous to those described in Example 7 to 10, the following compounds of the formula I were also prepared: 
     
                                           TABLE III                               
__________________________________________________________________________
The following are prepared analogously                                    
Formula                                Yield %                            
                                            Salt with Melting point       
                                                      °C.          
__________________________________________________________________________
 ##STR79##                             62.5 Sulphuric acid × 1      
                                            water     183° C.      
                                                      decomp.             
 ##STR80##                             40   2 × fumaric             
                                                      158-162             
 ##STR81##                             60.8 Sulphuric acid                
                                                      221-223             
 ##STR82##                             52   Cyclohexane- sulphuric        
                                                      126-130             
 ##STR83##                             48   Sulphuric acid                
                                                      192-194 decomp.     
 ##STR84##                             80   2 × hydrochloric        
                                                      157-159 175 Base    
 ##STR85##                             87.5 formic acid                   
                                                      167-169 144-146     
                                                      Base                
 ##STR86##                             71   2 × formic              
                                                      137-138             
 ##STR87##                             87.5 Benzoic acid                  
                                                      165-166             
 ##STR88##                             84   Formic acid                   
                                                      182-184             
 ##STR89##                             79   Hydrochloric                  
                                                      223-225 183-186     
                                                      Base                
 ##STR90##                             76   Methanesulphonic acid         
                                                      193-194             
 ##STR91##                             95   Methanesulphonic acid         
                                                      186-188 127 Base    
 ##STR92##                             83   Hydrochloric                  
                                                      216-271             
 ##STR93##                             45   Maleic acid                   
                                                      186-188             
 ##STR94##                             52   Cyclohexane sulphaminic acid  
                                            × 1 water               
                                                      126-130             
 ##STR95##                             83   Benzoic acid                  
                                                      150-152 137-137     
                                                      Base                
 ##STR96##                             70   Sulphuric acid                
                                                      235-236 142-145     
                                                      Base                
 ##STR97##                             70   Sulphuric acid                
                                                      243-244             
 ##STR98##                             41   Benzoic acid × 1        
                                                      130-133             
 ##STR99##                             85   0,5 × fumaric           
                                                      192d                
 ##STR100##                            63   Maleic acid                   
                                                      155-157             
 ##STR101##                            73.5 Sulphuric acid                
                                                      187-188 decomp.     
 ##STR102##                            76   2 × hydrochloric acid   
                                            × 2 water               
                                                      166-168             
 ##STR103##                            72   Formic acid                   
                                                      172-174             
 ##STR104##                            60   2 × hydrochloric        
                                                      200° C.      
                                                      decomp.             
__________________________________________________________________________
 
    
     The compounds of the present invention, that is, those embraced by formula I above and their non-toxic, pharmaceutically acceptable acid addition salts, have useful pharmaceodynamic porperties. More particularly, they exhibit broncholytic, spasmolytic and anti-allergic activity, and may therefore be used for the treatment of bronchitis, asthma, urticaria, conjunctivitis, hay fever and cold ailments, also as relaxants of the muscles of the uterus, for example in prenatal complaints. Furthermore, the novel compounds are suitable for treatment of cardiovascular disturbances such as high blood pressure, diseases of the peripheral vessels and cardiac arrhythmia. 
     Mention must be made, finally, of their inhibiting activity on gastro-secretion and the primary anti-depressive activity on the central nervous system. 
     To be emphasised is the strong and long-lasting broncholytic activity which is associated with only small secondary effects on the heart and skeleton musculature. 
     The compounds of the formula I where R 2  is CONHR 8  exhibit hypotensive activity, while the remaining compounds exhibit the other activities specified. 
     The therapeutic dose is dependent on the compound used, on the nature of the condition, on the type of administration and also on the body weight, if local application is not adopted. 
     The following are effective daily doses for an adult: For broncholysis: orally 2-20 mg, by inhalation 0.1-1.5 mg, subcutaneously 0.2-1.5 mg. For uterine spasmolysis: orally 10-50 mg, as an infusion solution 0.1-1 mg in ampoules with 10 ml solution. For vasodilation: orally 20-100 mg, in the form of solutions for intramuscular injection 20-40 mg. As a hypotensive agent: orally 200-1800 mg. 
     For administration the conventional galenic preparations, for example capsules, tablets, coated tables, solutions, suspensions, powders, creams, ointments, emulsions and sprays, are prepared from the compounds according to the invention. In pulmonary administration, powders with a particle diameter of 0.5 to 7 μm are preferably introduced into the bronchial region as an aerosol with breathing air, optionally also with additioal propellent gases. 
     Parenteral application is effected preferably in the form of sterile isotonic aqueous solutions, while primarily lotions, creams, ointments, emulsions and sprays serve for local application. 
     The favorable levels of activity of the compounds according to the invention are demonstrated by the following data. 
     1. Bronchospasmolysis 
     The activity was tested on guinea pigs under urethane anaesthesia. Body plethysmography was used to determine the influence on acetylcholine bronchospasm after intravenous and oral application. Furthermore, the heart frequency was monitored. 
     
         ______________________________________                                    
          Broncholysis                                                    
          ED.sub.50 ug/kg                                                 
                      Resorption                                          
            intra-            ratio                                       
Compound    venous    oral    oral/intravenous                            
______________________________________                                    
Table III,  1.2       7.6     6.3                                         
16th compound                                                             
Table II,   1.8       66      37                                          
16th compound                                                             
Table III,  0.9       14      16                                          
15th compound                                                             
Table II,   7.6       190     25                                          
21st compound                                                             
Example 6   3.6        7      1.9                                         
Table III,  0.09      5.4     60                                          
24th compound                                                             
Salbutamol  9.2       1000    109                                         
______________________________________                                    
 
    
     The compounds according to the invention show an outstanding relationship between intravenous and oral activity. The influence on heart rat is simultaneously small. Furthermore, the toxicity is so low that a considerable therapeutic spectrum is obtained; for example, for the compound according to Example 6 the LD 50  in mice is 29 mg/kg i.v and 300 mg/kg p.o. 
     2. Uterine relaxation 
     Uterine relaxation was investigated on anesthetized rats. The intravenous ED 50  of uterine relaxation was determined in ug/kg (50% of the tested animals react) and the (undesirable) increase in heart rate at the ED 50  value was also determined. The comparison compound was fenoterol. 
     
         ______________________________________                                    
          Uterine re-                                                     
                     Increase    Increase                                 
          laxation   in heart rate                                        
                                 in heart rate                            
          ED.sub.50 (g/kg)                                                
                     (beats      in comparison                            
Compound  i.v.       per min.)   with fenoterol                           
______________________________________                                    
Table III 0.82       19          1/2                                      
10th compound                                                             
Table II, 0.76       18          1/2                                      
11th compound                                                             
Table II, 0.44       23          2/3                                      
15th compound                                                             
Table II, 0.5        18          1/2                                      
24th compound                                                             
Fenoterol 0.45       36          1                                        
______________________________________                                    
 
    
     The compounds according to the invention thus bring about upon application of the ED 50  of uterine relaxation a considerably smaller increase of heart rate than the commercial product fenoterol. 
     The following illustrate a few pharmaceutical dosage unit compositions comprising a compound of the present invention as an active ingredient and represent the best modes contemplated of putting the invention into practical use. 
     
         ______________________________________                                    
Tablets                                                                   
Composition of one tablet:                                                
Active substance according to the invention                               
                          20       mg                                     
Colloidal silicic acid    10       mg                                     
Lactose                   118      mg                                     
Potato starch             60       mg                                     
Polyvinyl pyrrolidone     6        mg                                     
Sodium cellulose glycolate                                                
                          4        mg                                     
Magnesium stearate        2        mg                                     
                          220      mg                                     
Ampules                                                                   
Composition of the solution per ampule:                                   
Active substance according to the invention                               
                          10       mg                                     
Sorbitol                  40       mg                                     
Distilled water q.s. ad   10       ml                                     
Suppositories                                                             
Composition per suppository:                                              
Active substance according to the invention                               
                          100      mg                                     
Suppository base (cocoa butter)                                           
                          1600     mg                                     
                          1700     mg                                     
______________________________________                                    
 
    
     Inhalation powder 
     0.5 mg of active substance according to the invention and 19.5 mg of lactose with a particle diameter between 0.5 and 7 μm are used for each hard gelatine capsule. 
     The active substances according to the invention may also be combined with known active substances; for broncholytic application, for example with theophyllines, prasympatholytics (e.g. ipratropium bromide), secretolytics (e.g. bromohexine), musculotropic spasmolytics (e.g. papaverine), corticosteroids, anti-allergic agents. With uterine relaxants among others combinations with corticosteroids are possible. While the present invention has been illustrated with the aid of certain specific embodiments thereof, it will be readily apparent to others skilled in the art that the invention is not limited to these particular embodiments, and that various changes and modifications may be made without departing from the spirit of the invention or the scope of the appended claims.