CH601244A5 - Carbostyryl and 3,4-dihydro carbostyryl derivs. - Google Patents

Abstract

Carbostyryl and 3,4-dihydro carbostyryl derivs. bronchodilators, vasodilators and antihypertensives, esp. useful against bronchial asthma

Description

  

  
 



   The present invention relates to a process for the preparation of 5- (1-hydroxy-2-arninosubstituted) alkyl-8-substituted carbostyril and 3,4-dihydrocarbostyril derivatives represented by the respective formulas (ira) and (in):

  :
EMI1. 1
 wherein R1, R4 and Rs each represent an H atom or an alkyl group of I to 4C, at least one of R4 and R5 being an H atom, and R2 and R3, which are the same or different, each represent a H atom, an alkyl group of 1 to 4 C, an aralkyl group, containing a straight or branched chain alkyl group of 1 to 4 C, or a cycloalkyl group of 4 to 6 C, or alternatively R2 and R3, taken together with the nitrogen atom to which they are attached, form a 5 to 6 membered heterocycle substituted or unsubstituted and containing as heteroatoms 1 or 2 N, or atoms of O or S; this invention also relates to the novel compounds of formulas (Ia) and (Ib) obtained, as well as their pharmaceutically acceptable acid addition salts. 



   It is well known that certain carbostyril derivatives exhibit useful pharmaceutical activities.  Representative compounds of this type have been disclosed in the Journal of Medical Chemistry, vol.  15, N "3, pp.  260-266 (1972), in Japanese Patent Publication No. 38789/71 and in Chemical Abstracts 62, 16212 e (1965), etc.  However, these prior art references do not indicate that compounds having a (1-hydroxy-2-aminosubstituted) alkyl group in the 5-position of a carbostyril or 3,4-dihydrocarbostyril have a excellent stimulating activity of p-adrenoreceptors.    



   The object of this invention therefore consists of a process for the preparation of a derivative of carbostyril or 3,4-dihydrocarbostyril of general formula (Ia) or (Ib), characterized in that it comprises the following steps: 1) reaction of a carbostyril or 3,4dihydrocarbostyril compound of formula (VI)
EMI1. 2
 where R4 and Rs are as defined above, with an α-alkanoic acid halide of the formula
EMI1. 3
 where X and X ', which are the same or different, each represent a halogen atom, in the presence or absence of a solvent and in the presence of a Lewis acid catalyst,

   2) reaction of the 5-haloalkanoylcarbostyril or 5-haloalkanoyl-3,4-dihydrocarbostyril derivative obtained in step 1) and represented by the formula OV)
EMI1. 4
 or Rl, R4 and Rs are as defined above, and X is a halogen atom, with an amine of formula (III),
EMI1. 5

 where R2 and R3 are as defined above, in the presence or in
The absence of a solvent,
 3) reduction of the 5-alkylaminoalkanoylcarbostyril derivative or 5
   3,4-alkylaminoalkanoyl-dihydrocarbostyril obtained in
 step 2) and represented by formula (II)
EMI1. 6

 where R1, R2, R3, R4 and Rs are as defined above, in
 presence of a catalyst or by means of a reducing agent. 



   The inventors have found that the derivatives of carbostyril or
 3,4-dihydrocarbostyril having a 5- (1-hydroxy-2-amino- group
 substituted) alkyl in position 5 and being substituted in position 1
 or 8, as well as the acceptable acid addition salts thereof
 from a pharmaceutical point of view, have a stimulated activity
 of P-adrenoreceptors and, therefore, that they are useful
 as therapeutic agents as a bronchodilator,
 peripheral vasodilator, antihypertensive agent and the like,
 particularly for the treatment of bronchial asthma. 



   The term alkyl, as used for R1, R2 and R3, means a
 straight or branched chain alkyl group having 1 to 4 C, and
 includes, for example, methyl, ethyl, propyl,
 isopropyl, butyl, sec-butyl, tert-butyl and the like. 



   The term aralkyl, as used herein, means an aralkyl group.
 containing a straight or branched chain alkyl group having
 I to 4 C in the alkyl ring, for example a benzyl group, a-
 methylbenzyl, α, α-dimethylbenzyl, phenethyl and the like. 



   The term cycloalkyl, as used herein, means a group
N cycloalkyl having 4 to 6 C atoms, for example a group
 cyclobutyl, cyclopentyl, cyclohexyl and the like. 



   The term 5- or 6-membered heterocyclic ring substituted or
 unsubstituted, as used herein, represents heterocy groups
 cliques containing 1 or 2 nitrogen atoms, or oxygen atoms
 or sulfur, as heteroatoms, such as for example
 pyrrolidino, pyrrolidinyl, piperidino, piperidinyl groups,
 morpholino, morpholinyl, piperazino, piperazinyl or the simi
 milks, which may be substituted with an alkyl group having
 1 to 4 C, such as methyl, ethyl, isopropyl, tert-butyl and
 similar, for example a 2-methylpiperidino, 3-methylpiperi
 dino, N-methylpiperazino and the like. 



   The term halogen, as used in this specification, com
 take fluorine, chlorine, bromine and iodine, preferably
 chlorine and bromine. 



   The compounds of formulas (Ia) and (lb) are therefore prepared at
 from a carbostyril compound of formula (VI) according to the sche
 mas following reactions:
Reaction scheme I
EMI2. 1
   Reaction scheme II
EMI2. 2
   Reaction scheme III
EMI2. 3
  
Reaction scheme III (continued)
EMI3. 1

Reaction scheme IV
EMI3. 2
  
Reaction scheme V
EMI4. 1

 [A] represents catalytic reduction where [B] represents reduction with a reducing agent. 



   Reaction scheme VI
EMI4. 2
  where R4 and Rs each represent an H atom or an alkyl group, and Y represents an H atom, a group
EMI5. 1
 or a group
EMI5. 2

 In the chemical structures shown in Schemes I and II above, as well as in the description and claims, the dotted line at positions -3 and -4 of the carbostyril ring indicates either an additional single bond between these two positions, or two. atoms of H bonded to these two positions. 

  Thus, the chemical structure
EMI5. 3
 denotes a carbostyril nucleus or a 3,4-dihydrocarbostyril nucleus having respectively the structures:
EMI5. 4

 As illustrated in Reaction Scheme I, the 1-substituted-5 haloacetyl-8-substituted-carbostyril or -3,4-dihydrocarbostyril represented by the formula (IV), which is an intermediate in the process according to the invention, can be prepared in a single step by reacting 1-substituted-8-substituted-carbostyril or -3,4-dihydrocarbostyril (VI) with a haloacetyl halide in the absence or presence of a solvent and in the presence of a acid catalyst
Lewis known (lane A). 



   The compound of formula (IV), where R4 is H, can also be prepared by one of the other routes (B) + (B ') and (C) + (C') starting from 8-hydroxycarbostyril or 8-hydroxy -3,4-dihydrocarbbstyril of formula (VI), where R4 is H.  In route (B) + (B '), the reaction between 8-hydroxycarbostyril or 8-hydroxy-3,4 dihydroxycarbostyril (VI) and the α-haloalkynoic acid halide of formula (V) results to the production of a new 8haloalkanoylcarbostyril or -3,4-dihydrocarbostyril of formula (ira)
EMI5. 5
 wherein X is a halogen atom, which is then subjected to the rearrangement of the haloacetyl group to form the term (IV).     In lane (C) + (C '),

   the reaction between the starting material (VI) and the α-alkanolque acid halide results in the production of a new 5-haloalkanoyl-8-haloalkanoyloxycarbostyril or 3,4-dihydrocarbostyril of formula (IVb). 
EMI5. 6




  wherein X is as defined above, which is then subjected to the hydrolysis of the 8-haloalkanoyl group to form intermediate (IV).    



   In practice, the reaction between 8-hydroxy-3,4-dihydroxycarbostyril and α-alkanoic acid halide occurs via a combination of the 3 reaction pathways described above, namely (A), (B) + (B ') and (C) + (C').  This is why the reaction product is obtained in the form of a mixture of the compounds (IV), (IVa) and (IVb).  Generally, when the reaction is carried out at relatively low temperatures, the product obtained will be a mixture of the compounds (IV) and (IVa), with a small amount of the compound (IVb), whereas, if the reaction takes place at temperatures relatively high, the product obtained will be a mixture of compounds ('v) and (IVb) with a small amount of compound (IVa).    



   The isolation of compounds (IV), (IVa) and (IVb) from the reaction product can advantageously be carried out by a well known technique, for example by fractional crystallization. 



   In a preferred variant for isolation, after completion of the reaction, the solvent used is removed by distillation to obtain a residue, or the reaction mixture is poured into crushed ice to precipitate the crystals.  The residue or crystals are washed with hot water or cold methanol. 

  Insoluble substances are recrystallized from methanol to give 5-haloalkanoyl-8-substituted-carbostyril or 3,4-dihydrocarbostyril (in).     The residual methanolic mother liquor is concentrated to dryness under reduced pressure, and the residue is recrystallized from acetone to give 8-haloalkanoylcarbostyril or -3,4-dihydrocarbostyril (IVa).     The acetone mother liquor is then concentrated to dryness under reduced pressure, and the residue is recrystallized from acetone or ethyl acetate, to obtain 5-haloalkanoyl-8haloalkanoyloxycarbostyril or 3,4dihydrocarbostyril (IVb).    



   Compounds of formula (Ia) and (Ib) can be prepared from 5-haloalkanoyl-8-substituted-carbostyril or 3,4-dihydrocarbostyril (IV) thus obtained by reaction of 5- (a-haloalkanoyl) - 8- hydroxycarbostyril or 3, 4-dihydrocarbostyril of formula (IV) with an amine of formula (III)
EMI5. 7
 where R2 and R3 are as defined above, the new carbostyril or -3,4-dihydrocarbostyril derivative having the formula (II),
EMI5. 8
 in which Rl, R2, R3, R4 and Rs are as defined above; this reaction is shown in Reaction Scheme II.    

 

   The 1- or 8-substituted-3,4-dihydrocarbostyril (VI) used as starting product of the process according to the invention is a known compound, and can easily be prepared, for example by the method described by G.  R.  Pettit et al. , in J.  Org.  Chem.  , 33, 1089 (1968). 



   The α-haloalkanoic acid halide (V), which can be used in the process according to the invention, comprises α-chloropropionyl, ss-bromopropionyl, α-chlorobutyryl, bromobutyryl, bromide d α-bromobutyryl, α-chlorovaleryl chloride and the like. 



   In reaction route (A), the catalyst which can be used is a conventional Lewis acid, for example aluminum bromide or chloride, zinc chloride, ferric chlorides, stannic chloride, boron trifluoride and the like, sodium chloride. Al preferably being used.  These catalysts are used in an amount of about 2 to about 10 moles, preferably 3 to 6 moles, per mole of the starting carbostyril compound (VI).    



   This reaction can be carried out in the absence of a solvent, but the reaction proceeds more easily in an inert organic solvent.  Suitable examples of the solvent which can be used in this reaction are C disulfide, nitrobenzene, ether, dioxane and the like, preferably C.  These solvents are usually used in a volume of 0.5 to 20 times the volume of the reagents, preferably 2 to 10 times. 



   Reaction (A) is generally carried out using an amount equimolar to a large excess of the halide - haloalkanoic acid, preferably about 2 to 20 moles, preferably 2 to 10 moles, of the halide of acid per mole of starting carbostyril compound (VI).     The reaction takes place from room temperature up to about 150 C, preferably between room temperature and 80 C.  The reaction time varies according to the temperature of the reaction, but it is usually between 1 and 20 h approximately, preferably between 1 and 10 h. 



   Reaction (B) can be carried out using the same amount of the same catalyst as in reaction (A), and in the same solvent or without a solvent.  This reaction can be carried out using an amount ranging from an equimolar amount to a large excess of the α-haloalkanoic acid halide, preferably between about 2 and 20 moles, more particularly from 2 to 10 moles, per mole of the. starting carbostyril compound, at a temperature between room temperature and approximately 150 ° C., preferably from room temperature to 80 ° C., and for approximately 1 to 20 h, preferably from 1 to 10 h. 



   Reaction (B ') to obtain a 5-haloalkanoyl-8-substituted (3,4-dihydro) carbostyril, from 8-haloalkanoyloxy (-3,4dihydro) carbostyril obtained in reaction (B) as described above, is generally known as a rearrangement of
 Fries, and can be carried out using the same amount of the same catalyst as in reaction (A), and in the same solvent as in reaction (A) or without a solvent.  The temperature range is between room temperature and approximately 150 ° C., preferably between room temperature and 80 ° C., and the reaction time is between approximately 1 and 20 h, preferably between 1 and 10 h.  This reaction can take place in the presence of any x-haloalkanoic acid halide which remains unreacted in the previous reaction system (B). 

  In this case, it was found that the presence of the α-haloal kanoic acid halide increases the yield of the product, 5-haloalkanoyl-8
 substituted- (3,4-dihydro) carbostyril (IV).    



   Reaction (C) can be carried out using the same amount of the same catalyst as in reaction (A), and in the same solvent or without a solvent.  The α-haloalkanol acid halide is used in an equimolar amount up to a large excess, but preferably about 2 to 20 moles, more preferably 3 to 6 moles, per mole of the 8-substituted- (3, 4-dihydro) carbostyril (VI).    



   The reaction temperature varies from room temperature to
   150 "C approximately, preferably from room temperature to 80" C, and the reaction time is approximately 1 to 20 h, preferably 1 to 10 h. 



   Reaction (C ') to obtain compound (IV), from 5 (a-haloalkanoyl) -8-haloalkanoyloxy- (-3,4-dihydro) carbostyril
 obtained above, can be carried out using a catalyst, for example
 example a basic substance such as a hydroxide or carbonates of an alkali metal, such as sodium hydroxide,
 potassium hydroxide, sodium carbonate, potassium carbonate and the like, or an inorganic acid, such as hydrochloric, sulfuric, phosphoric, and the like,
 in the presence of a solvent, for example water, a lower alcohol such as ethanol, methanol, isopropanol and the like.  The
 amount of catalyst varies depending on the type thereof. 

  For example,
 Hydrochloric acid or sodium hydroxide and the like are used in an amount of 1 to 5 moles of 5- (α-haloalkanoyl-8-haloalkanoyloxy) - (- 3,4-dihydro) carbostyril.     The reaction generally takes place at a temperature of about 0 C to 150 "C, for about 0.5 to 5 h, but it is advantageous to carry out this reaction at a temperature of 0 C to 40" C when a basic substance is used as a catalyst and at a temperature of 70 "C to 100" C when inorganic acid is used as a catalyst. 



   Amines which can be used in the reaction with the 5 (α-haloalkanoyl) - 1 - and / or -8-substituted- (3,4-dihydro) carbostyril (IV) obtained above include the alkylamines, for example methylamine , ethylamine, n-propylamine, isopropylamine, nbutylamine, sec-butylamine, tert-butylamine; cycloalkylamines, for example cyclobutylamine, cylopentylamine, cyclohexylamine; aralkylamines, for example benzylamine, z-methylbenzylamine, α, α-dimethylbenzylamine, phenethylamine,, α-dimethylphenetylamine and the like;

   and substituted or unsubstituted heterocyclic amines, for example pyrrolidine, piperidine, morpholine, piperazine, 2-methylpiperidine, 3methylpiperidine, N-methylpiperazine and the like. 



   This reaction between the amine (III) and 5- (-haloalkanoyl) -1- and / or -8-substituted- (3,4-dihydro) carbostyril (IV) can be carried out using the amine in an amount equimolar to a large excess, at a temperature between room temperature and the reflux temperature of the reaction system,

   preferably at a temperature of 40 "C to 100" C in a suitable solvent or using the amine per se as a solvent at a pressure between atmospheric pressure and 10 atmospheres to obtain a 5- (a-substituted-aminoalkanoyl) -8-substituted- (3,4-dihydro) carbostyril (II), a 5- (a-substituted-aminoalkanoyl> 8-hydroxy- (3,4-dihydro) carbostyril (IIa), or a 5- (a- substituted aminoalkanoyl) -8-alkoxy- (3,4-dihydro) carbostyril (IIb).    



   Alternatively, the carbostyril or 3,4-dihydrocarbostyril compound, where R4 is an alkyl group (IIa), can be subjected to dealkylation with an H halide before reduction, to obtain the compound of formula (IIb), or else the A carbostyril or 3,4-dihydrocarbostyril compound, where R4 is a hydroxy group, can be alkylated prior to reduction, to obtain the compound of formula (IIa), as shown in Reaction Scheme III. 



   The H halides used in the above dealkylation include, for example, HBr, HCl, HI and the like, preferably HBr.  These H halides can be advantageously employed in a suitable solvent such as methanol, ethanol, isopropanol, preferably water, in the form of an aqueous solution at 10 to 50%, preferably 47%, d 'a halide of H. 



   This dealkylation reaction can generally be carried out using the H halide in an equimolar amount, preferably in a large excess relative to the compound (IIa), by heating at a temperature of about 100 ° C to about 1500 C, preferably at reflux temperature, for about 5 to 20 hours, preferably 5 to 10 hours. 



   Alkylation of compounds of formula (IIb) can be effected by reaction with an alkylating agent, well known in the art, in the presence of a basic compound.  Suitable examples of alkylating agents are alkyl halides, such as iodides, chlorides, alkyl bromides, dialkylsulphates, such as dimethyl, diethyl sulphate, etc.  Suitable examples of basic compounds are the alkali metals such as sodium, potassium, and the hydroxides, carbonates, bicarbonates and alcoholates thereof, aromatic amines such as pyridine, piperidine and the like. 

 

   The alkylation advantageously takes place in a solvent such as water, lower alcohols, such as methanol, ethanol, isopropanol, n-butanol, etc. , and ketones such as acetone, methyl ethyl ketone and the like, using the alkylating agent in an amount ranging from an equimolar amount and a large excess thereof, preferably 5 to 10 moles per mole of the compound (IIb ).     Alkylation generally takes place at room temperature. 



   The reduction of S (ar-substituted-aminoalkanoyl) carbostyril of formula (li), (IIa) or (IIb) to compounds according to the invention of formula (I), (Ia) or (Ib), respectively, can be carried out in a usual way using a reducing agent such as lithium aluminum hydride, Na borohydride and the like, or usual catalytic reduction in the presence of a catalyst such as Pd black, Pd on C , Ni Raney, Pt black, Pt oxide and the like, and H. 



   The above reducing agents can be used in an amount of about 2 to 10 moles, preferably 2 to 5 moles, per mole of carbostyril compound (IIa) in a solvent, cooling at atmospheric pressure, and at a temperature of 0 C to 1000 C, preferably 20 "C to 50" C: When Na borohydride is used as a reducing agent, the solvent is preferably water or alcohols, such as methanol, ethanol and the like. , and, when Li-Al hydride is used as a reducing agent, the solvent is preferably a non-aqueous solvent such as anhydrous diethyl ether, ethyl acetate, tetrahydrofuran and the like. 



   Catalytic reduction can be carried out using the above catalyst in an amount of about 0.05 to 1 mole, preferably 0.1 to 0.5 mole, per mole of the carbostyril compound (IIa) in a solvent, for example example water, or an alcohol such as methanol, ethanol, isopropanol, under an atmosphere of H at a pressure between atmospheric pressure and about 100 atmospheres, preferably between atmospheric pressure and 50 atmospheres, at a temperature between room temperature and about 1500 C, preferably between room temperature and 1200 C and, advantageously, with agitation of the reduction system.  The above catalytic reduction is advantageously carried out at a temperature below 50 ° C., at atmospheric pressure or at a temperature higher than ambient temperature and under pressure. 



   The catalytic reduction and the reduction with a reducing agent which are applicable to the process according to the invention are illustrated in detail in reaction scheme V.  These reductions can be carried out in the same manner as that described above for the reduction of compounds (in), (IIa) and (IIb).    



   Catalytic reduction of the compound of formula (II), (IIa) or (IIb) having a double bond between the 3- and 4-positions generally produces the corresponding 3,4-dihydrocarbostyriles of formula (I), (Ia) or (Ib), respectively , which is saturated in the 3,4- position, but it should be noted that catalytic reduction can also be used for the reduction only in the 5- position of the carbostyril compound of formula (II), (IIa) or (IIb), for produce the corresponding carbostyril compound of formula (Ia) or (Ib) maintaining the double bond between the 3- and 4- positions, if the reducing conditions are carefully controlled. 

  However, it is preferred to use the reduction with the reducing agent described above for the reduction of the only 5-position carbostyril compounds. 



   Conversion of the compound of formula (Ia) to compound of formula (Ib) or vice versa, i.e. alkylation or dealkylation, can be carried out in the same manner as described for
The alkylation or dealkylation of the compound of formula (IIa) or (IIb).    



   As shown in Reaction Scheme VI, the 3,4-dihydrocarbostyril compound can be converted into a corresponding carbostyril compound at any stage of the process according to the invention. 



   The conversion of the compound of formula (Ib) to the compound of formula (Ia), namely dehydrogenation, can be carried out by a known procedure, capable of removing one H from each of the 3- and 4- positions of the carbostyril ring, to form a double bond between these positions.  This dehydrogenation can be achieved by: 1) a technique using a dehydrogenating agent, for example chloranil (tetrachloro-1,4-benzoquinone), dichlorodicyano-1,4-benzoquinone and the like, 2) a technique using a dehydrogenating agent such as sulfide, selenium dioxide and the like. 

  The dehydrogenation can be carried out in a solvent such as aromatic hydrocarbons, for example benzene, toluene, xylene, phenetol, chlorobenzene and the like; lower alcohols, for example methanol, ethanol, isopropanol, tert-butanol and the like; ethers, for example dioxane; ketones, for example acetone and the like; Water; Acetic acid, etc.  The dehydrogenation can be advantageously carried out at a temperature between room temperature and the reflux temperature of the system, preferably at or near this reflux temperature. 



   The compounds of formula m and formula (I) as obtained above are basic substances, and can form acid addition salts with various organic or inorganic acids. 



  Particularly useful are the pharmaceutically acceptable salts formed with inorganic acids such as hydrochloric, sulfuric, phosphoric, hydrobromic, etc. , or organic acids such as oxalic, maleic, fumaric, malic, tartaric, citric, ascorbic, etc. 



  These acid addition salts can be easily prepared by well known techniques; for example by adding an equimolar amount or in excess of the acid to a solution of the compound dissolved in a suitable organic solvent such as methanol,
Ethanol, isopropanol, acetone and the like. 



   The free bases of the compounds of formula (I) and their acid addition salts exhibit ss-adrenoreceptor stimulating activity and, therefore, are very useful as pharmaceuticals for the treatment of disorders such as bronchial asthma. . 



   The compounds of the present invention contain two asymmetric centers and, therefore, can be present in 4 optically active forms. 



   This invention will now be illustrated in detail with reference to the following examples.  Unless otherwise indicated, all parts, percentages, ratios and the like are by weight. 



  Example 1:
 27 g of 8-hydroxycarbostyril and 37 ml of chloroacetyl chloride were dissolved in 250 ml of nitrobenzene, and 85 g of aluminum chloride were added to the resulting solution, the mixture being stirred at 700 C for 20 h.  500 ml of 10% aqueous HCl was added to the reaction mixture and the nitrobenzene was removed by steam stripping.  After cooling, the precipitated crystals were collected by filtration and were then washed with 300 ml of hot water.  Recrystallization from methanol gave 14.0 g of 5-chloroacetyl-8-hydroxycarbostyril having a melting point of 285-287 C (with decomposition), as pale yellow crystals. 



  Example 2:
 20 g of Al chloride was added to 5.0 g of 8-hydroxycarbostyril, and the resulting mixture was thoroughly mixed.  10 g of chloroacetyl chloride was gradually added to the mixture while ice-cooling.  The mixture was reacted by heating at 40-45 ° C for 2 h to form 8-chloroacetoxycarbostyril, then stirred at 700 C for 3 h.  After cooling, the precipitated crystals were collected by filtration, and the crystals were washed with 300 ml of water, then recrystallized from methanol to obtain 2.6 g of 5-chloroacetyl-8-hydroxycarbostyril having a melting point of 285-287 "C (with decomposition) as pale yellow crystals. 

 

   On the other hand, part of the 8-chloroacetoxycarbostyril which was formed in this example was separated and recrystallized from acetone to give pale yellow crystals having a melting point of 248-250 C (with decomposition).   



  Example 3:
 1.5 g of chloroacetyl chloride and 20 ml of C disulfide were added to 0.5 g of 8-hydroxycarbostyril, and 2 g of Al chloride was gradually added to the solution obtained by cooling with ice.  After vigorous stirring, the mixture was gradually heated and maintained at reflux for 30 min. 



  After cooling, the unreacted chloroacetyl chloride and C disulfide were removed, and crushed ice was added to the residue to crystallize the product.  The crystals thus obtained were washed with water, then recrystallized from acetone to give 0.45 g of 8-chloroacetyoxycarbostyril having a melting point of 248-251 C (with decomposition), as pale yellow crystals. . 



  Example 4:
 20 g of Al chloride and 10 g of chloroacetyl chloride were added to 10 g of the 8-chloroacetoxycarbostyril obtained in Example 3, and the resulting mixture was heated at 75-85 C for
 1 hr.  The mixture was poured hot onto crushed ice and the precipitated crystals were filtered off, washed with water and recrystallized.
 Sés in methanol to obtain 3.7 g of 5-chloroacetyl-8hydroxycarbostyril having a melting point of 285-287 C (with decomposition) in the form of pale yellow crystals. 



  Example 5:
 7.3 g of 8-hydroxycarbostyril and 12.5 g of chlo chloride
 roacetyl was added to 70 ml of nitrobenzene, and 30 g of Al chloride was gradually added to the resulting solution with stirring and ice-cooling.  The mixture was stirred at 50-55 C for 6 h, then poured into a water-ice mixture.  The precipitated crystals were filtered, washed with methanol and recrystallized from acetone to obtain 3.5 g of 5-chloroacetyl-8chloroacetoxycarbostyril having a melting point of 239-241 C (with decomposition), as pale yellow crystals. . 



  Example 6:
 1.7 g of the 5-chloroacetyl-8-chloroacetoxycarbostyril obtained in Example 5 was added to 50 ml of 10% aqueous HCl, then the mixture was stirred at 95-1000 C for 2 h.  After cooling, the precipitated crystals were filtered, washed with water, then recrystallized from ethanol to obtain 1.1 g of 5-chloroacetyl-8hydroxycarbostyril having a melting point of 285-286 ° C (with decomposition ) as pale yellow crystals. 



  Example 7:
 2.5 g of the 5-chloroacetyl-8-chloroacetoxycarbostyril obtained in Example 5 were added to 30 ml of a 5% aqueous solution of potassium hydroxide, then the mixture was stirred at 20 25 C for 30 min. .  The resulting solution was adjusted to pH 2-3 with dilute HCl while cooling.  The precipitated crystals were filtered off, washed with water and recrystallized from methanol to obtain 1.7 g. of 5-chloroacetyl-8-hydroxycarbostyril having a melting point of 285-287 C (with decomposition) as pale yellow crystals. 



  Example 8:
 20 g of Al chloride was gradually added to a mixture of 4.5 g of 8-hydroxycarbostyril and 10 g of chioroacetyl chloride with stirring and ice-cooling.  The resulting mixture was stirred at 55-60 ° C for 8 h to form 5-chloroacetyl-8-chloroacetoxycarbostyril.  40 ml of 5% KOH were then added to the reaction mixture, then the latter was stirred for 30 min.  A 10% aqueous solution of HCl was added to the mixture to make it acidic and form crystals.  The precipitated crystals were filtered off, washed with water and then recrystallized from methanol to obtain 2.3 g of 5-chloroacetyl-8hydroxycarbostyril having a melting point of 285-286 C (with decomposition) as yellow crystals. blade. 



   On the other hand, a part of the above reaction mixture before the addition of the 5% aqueous KOH as described above was separated and poured into a water-ice mixture.  The precipitated crystals were filtered off, washed with methanol and recrystallized from ethyl acetate to obtain 5-chloroacetyl-8-chloroacetoxycarbostyril having a melting point of 238-241 C (with decomposition) as yellow crystals. 



  Example 9:
 12.6 g of the 5-chloroacetyl-8-hydroxycarbostyril obtained in Example 4 or 8 were suspended in 130 ml of isopropanol, and 2515 g of isopropylamine were added dropwise to the suspension obtained with stirring.  The reaction mixture was then stirred at 55-60 ° C for 3 h.  After cooling, concentrated HCl was added to the mixture to adjust its pH to 2-3, and the precipitated crystals were filtered, washed with acetone and recrystallized from methanol-dimethylformamide (1: 1 by volume) to obtain 6.5 g of 5-isopropylaminoacetyl-8-hydroxycarbostyril hydrochloride having a melting point of 286,288 C (with decomposition) in the form of pale yellow crystals. 



  Example 10:
 8.0 g of the 5-chloroacetyl-8-hydroxycarbostyril obtained in Example 4 or 8 were suspended in 100 ml of ethanol, and 10 g of tert-butylamine was added dropwise to the suspension obtained with stirring, then maintaining stirring at 55-60 ° C for 5 h.  After the mixture was concentrated to half the volume, concentrated HCl was added thereto, to adjust the pH to 2-3.  The precipitated crystals were filtered, washed with acetone and recrystallized from ethanol, to obtain 4.1 g of 5-tert-butylaminoacetyl-8-hydroxycarbostyril having a melting point of 291-293 C (with decomposition) in the form of yellow crystals. 



  Example 11:
 4.3 g of the 5-chloroacetyl-8-hydroxycarbostyril obtained in Example 4 or 8 were suspended in 50 ml of ethanol, and 5 g of sec-butylamine were added dropwise to the suspension obtained with stirring, Agitation then being maintained at 60-65 ° C for 5 h.  After cooling, the resulting mixture was adjusted to pH 3 with concentrated HCl.  The precipitated crystals were filtered off, washed with acetone and recrystallized from methanol-ethanol (1: 1 by volume) to obtain 2.9 g of 5-sec-butylaminoacetyl-8-hydroxycarbostyril hydrochloride having a point of Melting 289-291 C (with decomposition) as pale yellow crystals. 



  Example 12:
 10 g of the 5-chloroacetyl-8-hydroxycarbostyril prepared in Example 4 or 8 was suspended in 50 ml of benzene, and 10 ml of piperidine was added to the suspension, then the mixture was reacted with heating at reflux and with stirring for 6 h.  The reaction mixture was filtered to recover the reaction product, which was then washed with benzene, then with 50 ml of isopropanol.  The insoluble product obtained was dissolved in 150 ml of 2% aqueous HCl.  The solution was concentrated to dryness under reduced pressure and the residue was recrystallized from ethanol to obtain 7.5 g of 5-piperidinoacetyl-8-hydroxycarbostyril hydrochloride 1/2 hydrate, amorphous white, having a melting point. of 239-241 C (with decomposition). 

 

  Example 13:
 10 g of the 5-chloroacetyl-8-carbostyril prepared in Example 4 or 8 was suspended in 60 ml of benzene, and 9 ml of morpholine was added to the suspension, followed by reacting the mixture in heating to reflux and stirring for 4 h.  The reaction mixture was cooled and the resulting precipitate was filtered; then it was dissolved in 60 ml of isopropanol, and the solution was adjusted to pH 2-3 with conc. HCl.  The resulting acidic solution was cooled with ice and the precipitate formed was filtered off, then recrystallized from ethanol.  The precipitate was dissolved in 20 ml of water, and the solution was adjusted to pH 7.5-8.0 with sodium bicarbonate, and cooled with ice. 



  The precipitate formed on cooling was filtered and recrystallized from ethanol to obtain 4.2 g of 5-morpholinoacetyl-8hydroxycarbostyril, amorphous white, having a melting point of 232-239.5 ° C (with decomposition).  The product thus obtained was confirmed by analysis of IR and NMR spectra and by elemental analysis. 



  Example 14:
 120 ml of benzylamine was added to 15 g of 5-chloroacetyl-8-hydroxycarbostyril prepared in Example 4 or 8, and the mixture was stirred for 1 h at room temperature.  The precipitate which was formed by adding petroleum ether to the reaction mixture was dissolved by adding dilute HCl, and the solution was filtered to remove any remaining insoluble product. 



  The HCl phase was then concentrated to dryness, and the residue was recrystallized from methanol to obtain 16.4 g of product having a melting point of 274-279 C (with coloring and decomposition).  The product thus obtained was confirmed by analysis of IR and NMR spectra and by elemental analysis as being 5-benzylaminoacetyl-8-hydroxycarbostyril hydrochloride monohydrate. 



  Example 15:
 10 g of 5-chloroacetyl-8-hydroxycarbostvril was dissolved in 50 ml of ethanol, and 25 g of 1-phenethylamine was added dropwise to the solution, then the mixture was stirred at SOC C for 4 hrs.  The ethanol was then removed by distillation and the precipitate was washed with diethyl ether and dissolved in isopropanol to remove any insoluble product.  The isopropanol phase was concentrated to a volume equivalent to about 1/3 of the original volume, and adjusted to pH 4 with concentrated HCl.  The precipitate formed was recrystallized from a mixture of ethanol and acetone to obtain 9.8 g of a product having a melting point of 246-249 ° C. 

  The product thus obtained was confirmed by analysis of IR and NMR spectra and by elemental analysis such as 5- (1-phenethylaminoacetyl) -8-hydroxycarbostyril hydrochloride. 



  Example 16:
 40 ml of 1,1-dimethylphenethylamine was added to 5 g of 5-chloroacetyl-8-hydroxycarbostyril, and the mixture was stirred at room temperature in the dark for 5 h.  The precipitate which was formed by adding petroleum ether to the reaction mixture was washed with diethyl ether and dissolved in methanolic HCl solution to remove any insoluble product.  The methanol was then removed by distillation, and the residue was recrystallized from methanol to obtain 6.1 g of a product having a melting point of 246-247 C (with coloring and decomposition). 

  The product thus obtained was confirmed by analysis of IR and NMR spectra such as 5 (1,1 -dimethylphenethylaminoacetyl) hydrochloride. 8. 1/2 hydrated hydroxycarbostyril. 



  Example 17:
 24.3 g of 8-hydroxy-3,4-dihydrocarbostyril and 68 g of chloroacetyl chloride were added to 130 ml of C disulfide, and 200 g of Al chloride was added slowly to the mixture with stirring and cooling. with a water-ice mixture.  The mixture was stirred for 6h at a temperature of 60-70 C and the C disulfide was removed by distillation.  The residue obtained was poured into 500 ml of ice-water mixture. 

  The precipitated crystals were filtered off, washed with water and recrystallized twice from methanol to give 8.0 g of 5-chloroacetyl-8-hydroxy-3,4-dihydrocarbostyril as light yellow crystals having a point of. fusion of 189-191 "C.    



   Example 18:
 13 g of 8-hydroxy-3,4-dihydrocarbostyril and 20 g of chloride
 of chloroacetyl were dissolved in 100 ml of nitrobenzene, and
 40 g of Al chloride was slowly added to the mixture, then
 this was stirred for 15 h at a temperature of 70-75 ° C. 



   Then the mixture was steamed to remove the nitro benzene.     After allowing the mixture to cool, the crystals
 precipitates were filtered off, washed with hot water and recrystallized
 in methanol to give 7.2 g of 5-chloroacetyl-8-hydroxy
 3,4-dihydrocarbostyril in the form of light yellow crystals having
 a melting point of 189-190 C.    



   Example 19:
 66 g of chloroacetyl chloride and 30 ml of nitrobenzene have
 was added to 17 g of 8-methoxy-3,4-dihydrocarbostyril, and 100 g
 of Al chloride were slowly added to the reaction mixture
 nel by cooling with ice, then stirring for
 30 minutes at room temperature.  After leaving the mixture at
 standing for 30 minutes, it was poured into 700 ml of mixture
 ice-water. 

  The precipitate thus formed was filtered off, washed with etha
 nol and recrystallized from methanol to give 20 g of crystals
 white in needles, having a melting point of 187-188 ° C.     The
 crystals thus obtained were confirmed by analysis of
 IR and NMR spectra and by elemental analysis such as 5-chloroacetyl-8-methoxy-3,4-dihydrocarbostyril.    



   Example 20:
 33 g of chloroacetyl chloride and 80 ml of C disulfide
 were added to 8.5 g of 8-methoxy-3,4-dihydrocarbostyril, and
 50 g of Al chloride was slowly added to the mixture
 obtained by cooling with ice, then stirring for
   2 hours at room temperature.  The disulfide phase of C has been removed
 born by decantation, and crushed ice was added to the solution
 remaining to crystallize the product.  The crystals thus precipitated
 obtained were filtered, washed with methanol and recrystallized from
 methanol to give 11 g of white needle crystals having
 a melting point of 187-188 "C. 

  The product thus obtained was
 confirmed by IR and NMR spectra and by elemental analysis
 such as 5-chloroacetyl-8-methoxy-3 4-dihydrocarbostyril.    



   Example 21:
 24.3 g of 8-hydroxy-3,4-dihydrocarbostyril and 68 g of chlo
 Chloroacetyl ride was added to 130 ml of C disulfide, and
 200 g of Al chloride was slowly added to the mixture while
 stirring and cooling with a water-ice mixture.  The mixture
 obtained was then reacted for 4 h while cooling to
 ice to give 8-chloroacetoxy-3,4-dihydrocarbostyril. 



   The reaction mixture was stirred for 2h at a temperature
 60-70 ° C and the C disulfide was removed by distillation.  The
 residue obtained was poured into 500 ml of water-ice mixture and the
 precipitated crystals were filtered off, washed with water and recrystallized
 sintered twice in methanol to give 8.0 g of 5-chloroaceous
   tyl-8-hydroxy-3,4dihydrocarbostyril as light yellow crystals having a melting point of 189-191 "C.    

 

   The 8-chloroacetoxy-3,4-dihydrocarbostyril produced as an intermediate in the procedure below was isolated from the aliquot.
 of the reaction mixture and found to have a melting point
 183-186 ° C after recrystallization from acetone;
Example 22:
 40 g of Al chloride was added to 11.5 g of 8-hydroxy
 3,4dihydrocarbostyril, and the mixture was stirred vigorously. 



  21 g of chloroacetyl chloride was then added slowly to the mixture while cooling with a water-ice mixture, and the resulting mixture was stirred at a temperature of 35-40 "C for 2 h, then the excess of chloroacetyl chloride was removed by distillation.  The residue thus obtained was poured into crushed ice and the precipitated crystals were filtered off, washed with water and recrystallized from potter's acetone to give 5.6 g of 8-chloroacetoxy3,4-dihydrocarbostyril as crystals. light yellow having a melting point of 182-184 "C.    



  Example 23:
 13 g of 8-hydroxy-3,4-dihydrocarbostyril and 20 g of chloroacetyl chloride were dissolved in 100 ml of nitrobenzene, and 40 g of Al chloride was slowly added to the mixture, and the mixture was stirred at 70-75 "C for 15 hrs.  Nitrobenzene has been
 then steam entrained.  After allowing the mixture to cool,
 the precipitated crystals were filtered off, washed with hot water and
 recrystallized from methanol to give 7.2 g of 5-chloroaceous
 tyl-8-hydroxy-3,4-dihydrocarbostyril as light yellow crystals with a melting point of 189-190 C.    



   Example 24:
 30 g of Al chloride was added slowly as it cooled
 with stirring and 6.0 g of 8-hydroxy-3,4-dihydrocarbostyril,
 as well as 15.0 g of chloroacetyl chloride, then the mixture was
 stirred at 55-60 "C for 6h to produce 5-chloroacetyl-8
   Chloroacetoxy-3,4-dihydrocarbostyril.     50 ml of 10% aqueous HCl was added to the reaction mixture which was then stirred for 3 h at 95-100 ° C.     After allowing the mixture to cool, the precipitated crystals were filtered off,

   washed with water and recrystallized from methanol to give 2.7 g of 5-chloroacetyl-8-hydroxy-3,4-dihydrocarbostyril as light yellow crystals having a melting point of 189-190 ° C.    



   In the above procedure, an aliquot of the reaction mixture was taken from the reaction system prior to hydrolysis with HCl and poured into an ice-water mixture.  The precipitated crystals were filtered off, washed with hot water and recrystallized from dimethylformamide-methanol (1: 1 by volume) to give 5-chloroacetyl-8-chloroacetoxy-3,4-dihydrocarbostyril as yellow crystals. having a melting point of 206-207 "C. 



  Example 25:
 4 g of 5-chloroacetyl-8-hydroxy-3,4-dihydrocarbostyril prepared as described in example 24 was dissolved in 50 ml of isopropanol, and 20 g of isopropylamine was added to the solution, then the mixture was stirred at a temperature of 60 C for 3 h.  The reaction mixture was concentrated to a volume of 1/3 to 1/4 of the original volume and saturated with dry HCl gas. 



  After cooling the mixture, the precipitate thus formed was filtered and recrystallized from ethanol to give 3.5 g of a colorless amorphous product having a melting point of 274-275 ° C.  The product thus obtained was confirmed by IR and NMR spectra and by elemental analysis such as 5-isopropyla minoacetyl-8-hydroxy-3,4-dihydrocarbostyril hydrochloride.    



  Example 26:
 3 g of 5-chloroacetyl-8-hydroxy-3,4-dihydrocarbostyril prepared as described in Example 24 was dissolved in 40 ml of isopropanol, and 3 g of methylamine was added dropwise to the solution with stirring at a temperature of 60 C, over a period of 30 min.  After the addition was complete, the mixture was stirred with heating at this temperature for a further 1 h.  The reaction mixture was then concentrated to a volume of 1/3 the original volume and adjusted to pH 1 to 2 with concentrated HCl.  The precipitate thus formed was filtered and recrystallized from ethanol to give 1.5 g of an amorphous and colorless product, having a melting point of 254-256 ° C. 

  The product thus obtained was confirmed by IR and NMR spectra, and by elemental analysis such as 5-methylaminoacetyl-8 hydroxy-3,4-dihydrocarbostyril hydrochloride.    



   Example 27:
 2.54 g of 5-chloroacetyl-8-hydroxy-3,4-dihydrocarbostyril
 prepared as described in Example 24 were dissolved in
 30 ml of isopropanol, and 2.7 g of ethylamine were added dropwise.
 drop to the solution with stirring and at a temperature of 60 C,
 over a period of 20 minutes.  After the addition is complete, the mixture has
 was stirred by heating at this temperature for a further 40 min. 



   The reaction mixture was then concentrated to a volume of 1/3
 from the initial volume, and adjusted to pH 1 to 2 with concentrated HCl. 



   The precipitate thus obtained was filtered off and recrystallized from methanol.
 to give 1.9 g of colorless amorphous product having a
 fusion of 258-260 "C.  The product thus obtained was confirmed by
 IR and NMR spectra and by elemental analysis such as
 5-Ethylaminoacetyl-8-hydroxy-3,4-dihydrocarbos- hydrochloride
 tyrile. 



   Example 28:
 4 g of 5-chloroacetyl-8-hydroxy-3,4-dihydrocarbostyril
 prepared as described in Example 24 were dissolved in 60 ml of isopropanol, and 20 g of tert-butylamine was added
 drop by drop with stirring at a temperature of 60 C on a
 period of 20 minutes.  After the addition was complete, the mixture was stirred
 by heating at this temperature for a further 40 minutes.  The
 reaction mixture was then concentrated to a volume of 1/2 of the
 initial volume and adjusted to pH 1 to 2 with concentrated HCl.  The
 precipitate thus formed was filtered and recrystallized repeatedly
 in an ethanol-acetone mixture (1: 2 by volume) to give
 2.0 g of a colorless amorphous product having a melting point of
   253 C to 255 C. 

  The product thus obtained was confirmed by
 IR and NMR spectra and by elemental analysis such as
 5-tert-butylaminoacetyl-8-hydroxy-3,4-dihydro- hydrochloride
 carbostyril. 



   Example 29:
 3 g of 5-chloroacetyl-8-hydroxy-3,4-dihydrocarbostyril
 prepared as described in Example 24 were dissolved in
 40 ml of isopropanol, and 10 g of sec-butylamine were added
 drip to solution with stirring at a temperature of 60 C
 over a period of 20 minutes.  After the addition is complete, the mixture has
 was stirred with heating at this temperature for an additional 2.5 h. 



   The reaction mixture was then concentrated to a volume of 1/3
 of the initial volume and saturated with dry gaseous HCl.  The precipitate thus
 formed was filtered and recrystallized from ethanol to give
 1.8 g of a colorless amorphous product having a melting point of
 269 to 271 "C.     The product thus obtained was confirmed by
 IR and NMR spectra and by elemental analysis as 5-sec-butylaminoacetyl-8-hydroxy-3, 4-dihydrocarbos- hydrochloride
 tyrile. 



   Example 30:
 4 g of 5-chloroacetyl-8-methoxy-3,4-dihydrocarbostyril prepared as described in Examples 19 and 20 was dissolved
 in 50 ml of isopropanol, and 20 g of isopropylamine were added
 to the solution, and the mixture was stirred at 60 ° C for 3 h.  The
 reaction mixture was then concentrated to a volume of 1/3 to
 1/4 of the initial volume and saturated with dry HCl gas.  After cooling
 When the mixture dissolved, the precipitate formed was filtered off and recrystallized
 in ethanol to give 3.5 g of a colorless product in
 needles having a melting point of 208-209 C.     The product as well
 obtained was confirmed by IR and NMR spectra and by analysis
 elemental such as 5-isopropylaminoacetyl-8 hydrochloride
 methoxy-3,4-dihydrocarbostyril. 

 

   Example 31:
 3 g of 5-chloroacetyl-8-methoxy-3,4-dihydrocarbostyril,
 prepared as described in Examples 19 and 20, were dissolved
 in 40 ml of isopropanol, and 3 g of methylamine were added dropwise to the solution with stirring at a temperature of 60 ° C over a period of 30 min.  After the addition was complete, the mixture was stirred with heating at this temperature for an additional 1 h.  The reaction mixture was then concentrated to a volume of 1/3 the original volume and adjusted to pH 1 to 2 with concentrated HCl.  The precipitate thus formed was filtered and recrystallized from ethanol to give 1.5 g of a colorless crystalline needle product, having a melting point of 232-234 ° C. 

  The product thus obtained was confirmed by IR and NMR spectra and by elemental analysis such as 5-methylaminoacetyl-8-methoxy-3,4-dihydrocarbostyril hydrochloride.    



  Example 32:
 2.54 g of 5-chloroacetyl-8-methoxy-3,4-dihydrocarbostyril prepared as described in Examples 19 and 20 was dissolved in 30 ml of isopropanol, and 2.7 g of ethylamine was added dropwise. drop to the solution with stirring at a temperature of 60 ° C. over a period of 20 min.  After the addition was complete, the mixture was stirred with heating at this temperature for a further 40 min. 



  The reaction mixture was then concentrated to a volume of 1/3 of the original volume, and adjusted to a pH of I to 2 with concentrated hydrochloric acid.  The precipitate thus formed was filtered and recrystallized from ethanol to give 1.9 g of a colorless needle product having a melting point of 224-227 ° C.     The product thus obtained was confirmed by IR and NMR spectra and by elemental analysis such as 5-ethylaminoacetyl-8-methoxy-3,4-dihydrocarbostyril hydrochloride. 



  Example 33:
 4 g of S-chloroacetyl-8-methoxy-3,4-dihydrocarbostyril prepared as described in Examples 19 and 20 was dissolved in 60 ml of isopropanol, and 20 g of tert-butylamine was added to the solution with stirring. at a temperature of 60 C for 20 min.  After the addition was complete, the mixture was stirred with heating at this temperature for a further 40 min.  The reaction mixture was then concentrated to a volume of 1/2 of the original volume, and adjusted to pH 1 to 2 with concentrated hydrochloric acid. 

  The precipitate thus formed was filtered and recrystallized from a mixture of ethanol and acetone (1: 2 by volume) to give 2.0 g of a colorless amorphous product having a melting point of 208-210 C.     The product thus obtained was confirmed by IR and NMR spectrum and by elemental analysis such as hydrochloride.
S-tert-butylaminoacetyl-8-methoxy-3,4-dihydrocarbostyril. 



  Example 34:
 3 g of 5-chloroacetyl-8-methoxy-3,4-dihydrocarbostyril prepared as described in Examples 19 and 20 was dissolved in 40 ml of isopropanol, and 10 g of sec-butylamine was added dropwise to the mixture. solution by stirring at a temperature of 60 ° C over a period of 20 min.  The reaction mixture was then concentrated to a volume of 1/3 of the initial volume, and saturated with dry hydrochloric acid gas.  The precipitate thus formed was filtered and recrystallized from ethanol to give 1.8 g of colorless needle crystals having a melting point of 212 C to 214 C.    



  The product thus obtained was confirmed by IR and NMR spectra and by elemental analysis such as S-sec-butylaminoacetyl-8-methoxy-3,4-dihydrocarbostyril hydrochloride.    



  Example 35:
 1 g of the 5-isopropylaminoacetyl-8-methoxy-3,4-dihydrocarbos- tyril prepared in Example 30 was dissolved in 10 ml of a 47% aqueous solution of hydrobromic acid, and the mixture was heated with reflux at 120 "C to 130" C for 2.5 hrs.  20 ml of water was then added to the mixture which was adjusted to pH 6.5-7.5 with sodium bicarbonate.  The precipitate thus formed was filtered, washed with water and dried.  The obtained product was dissolved in isopropanol and the solution was saturated with dry hydrochloric acid gas.  The precipitate was filtered off and recrystallized from ethanol to give 0.5 g of a colorless amorphous product having a melting point of 274-275 C.    



  The product thus obtained was confirmed by IR and NMR spectra and by elemental analysis such as 5-isopropy laminoacetyl-8-hydroxy-3,4-dihydrocarbostyril hydrochloride.    



  Example 36:
 0.7 g of 5-methylaminoacetyl-8-methoxy-3,4-dihydrocarbostyril hydrochloride prepared as described in Example 31 was dissolved in 10 ml of a 47% aqueous solution of hydrobromic acid, and the mixture was obtained. was heated to reflux at 120-130 ° C for 4h.  The reaction mixture was then worked up in the same manner as described in Example 35 to give 0.5 g of a colorless amorphous product having a melting point of 254-256 C.     The product thus obtained was confirmed by IR and NMR spectra and by elemental analysis such as 5-methylaminoacetyl-8-hydroxy-3,4-dihydrocarbostyril hydrochloride. 



  Example 37:
 0.9 g of 5-tert-butylaminoacetyl-8-methoxy3,4-dihydrocarbostyril hydrochloride was dissolved in 10 ml of a 47% aqueous solution of hydrobromic acid, and the obtained solution was treated in the same way. than that described in Example 35 to give 0.2 g of a light yellow amorphous product having a melting point of 253-255 C.     The product thus obtained was confirmed by IR and NMR spectra and by elemental analysis such as 5-tert-butylaminoacetyl-8-hydroxy3,4-dihydrocarbostyril hydrochloride. 



  Example 38:
 0.5 g of 5-sec-butylaminoacetyl-8-methoxy3,4-dihydrocarbostyril hydrochloride prepared as described in Example 34 was dissolved in 10 ml of a 47% aqueous solution of hydrobromic acid, and the solution obtained was treated in the same manner as described in Example 19 to give 0.24 g of a colorless amorphous product having a melting point of 269 271 ° C.     The product thus obtained was confirmed by IR and NMR spectra and by elemental analysis such as 5-sec-butylaminoacetyl-8-hydroxy-3,4-dihydrocarbostyril hydrochloride.    



  Example 39:
 50 g of α-bromobutyric acid bromide (V), 50 g of anhydrous aluminum chloride and 400 ml of carbon disulfide were added to 20 g of 8-hydroxycarbostyril (VI).     The obtained mixture was heated at a temperature of 50 C for 13 h, and the carbon disulfide phase was removed by decantation.  Crushed ice was added to the residue to crystallize the product, and the crystals thus formed were filtered, washed with water and then recrystallized from methanol to obtain 27 g of S- (x-bromobutyryl) -8. -hydroxycarbostyril (IV) having a melting point of 218,219 "C (with coloring and decomposition). 



  Example 40:
 25 g of α-bromobutyric acid chloride (V) and 25 g of anhydrous aluminum chloride were added to 10 g of 8hydroxycarbostyril (seen), and the obtained mixture was heated at a temperature of 70 C for 4 h in shaking vigorously. 

 

  After adding crushed ice to the mixture to crystallize the product, the crystals formed were filtered, washed with water and then recrystallized from methanol to obtain 12.6 g of 5- (-bromobutyryl) -8-hydroxycarbostyril ( IV) having a melting point of 218-219 C (with coloring and decomposition). 



  Example 41:
 25 g of α-bromotutyric acid bromide (V) and 100 ml of nitrobenzene were added to 10 g of 8-hydroxycarbostyril, and 25 g of anhydrous aluminum chloride were added to the solution obtained by cooling.  The mixture was heated at 70 ° C for 10 h, then poured onto crushed ice.  The precipitated crystals were filtered off, washed with water and recrystallized from methanol to obtain 11.2 g of 5- (a-bromobutyryl) -8-hydroxycarbostyril having a melting point of 217-218.5 ° C. (with coloring and decomposition). 



  Example 42:
 200 ml of sec-butylamine (III) was added to 10 g of 5- (c-bromobutyryl) -8-hydroxycarbostyril (IV) obtained in Examples 39-41, and the resulting mixture was heated to a temperature of 60 C for 20 h, then concentrated to dryness.  The crystals which were formed by adding water were filtered, dissolved in 50 ml of ethanol, and the obtained solution was adjusted to a pH of I with concentrated hydrochloric acid.  The precipitated crystals were filtered off and recrystallized from methanol to obtain 8.3 g of 5- (α-sec-butylaminobutyryl) -8-hydroxy-carbostyril (II) hydrochloride having a melting point of 212-214 C (with coloring and decomposition). 



  Example 43:
 10 ml of isopropylamine (III) and 50 ml of methanol were added to 5 g of 5- (a-bromobutyryl) -8-hydrnxycarbostyriîe (IV) obtained in Examples 39 to 41.  The resulting mixture was heated under reflux for 6 h, then concentrated to dryness.  The reaction product was then treated in the same manner as that described in Example 39 to obtain 4.2 g of a methanolic solution of 5- (α-isopropylaminobutyryl) -8-hydroxycarbostyril (II) having a dot melting point of 136-137 "C (with formation of foam and decomposition). 



  Example 44:
 50 g of -bromobutyric acid bromide (V), 50 g of anhydrous aluminum chloride and 400 ml of carbon disulfide were added to 20 g of 8-hydroxycarbostyril (VI).     The obtained mixture was heated at a temperature of SOC C for 13 h and the carbon disulfide phase was removed by decantation.  Crushed ice was added to the residue, and the precipitated crystals were filtered, washed with water and recrystallized from methanol to obtain 27 g of S- (x-bromobutyrvl) -8-hydroxycarbostyrl (VI) having a melting point 218-219 C (with coloring and decomposition). 

  As g of the 5- (ol-bromobutyryl) -8-hydroxycarbostyril (IV) thus obtained was added 100 ml of isopropylamine (III), and the mixture was heated at a temperature of 50 ° C for 4 h, then concentrated to dryness.  The crystals, which were formed by adding water, were filtered, washed with water, then recrystallized from methanol to obtain 4.6 g of a methanolic solution of 5- (α-isopropylaminobutyryl) -8 -hydroxycarbostyril (II) having a melting point of 136-137 C (with formation of foam and decomposition). 



  Example 45:
 25 g of 2-phenethylamine (III) was added to S g of ("- bromobutyryl) -8-hydroxycarbostyril (IV) prepared in Examples 39, 40 or 41, and the mixture was stirred at a temperature of 30 C for 8 h.  A mixture of diethyl ether and petroleum ether was added to the reaction mixture, and the precipitated product was dissolved in dilute hydrochloric acid to remove any insoluble products.  The hydrochloric acid phase was concentrated, and the precipitate was filtered and recrystallized from ethanol to obtain 5.3 g of a product having a melting point of 200 201 ° C (with coloring and decomposition). 

  The product thus obtained was confirmed by IR and NMR spectra and by elemental analysis as being 5- (-2-phenethylamino) butyryl-8-hydroxycarbostyril (II) hydrochloride (II) dihydrate. 



  Example 46:
 5 ml of morpholine (III) was added to 5 g of 5- (a-bromobutyryl) -8-hydroxycarbostyril (IV) prepared as in Examples 39-41, and the mixture was reacted at a temperature of 40 "C for 4 h, with stirring.  The reaction mixture was then concentrated under reduced pressure, and 100 ml of water was added to the residue.  The mixture was stirred and filtered, then the mother liquor filtrate was concentrated under reduced pressure.  The residue was dissolved in acetone and the solution was filtered to remove any insoluble products. 

  The filtrate was then concentrated under reduced pressure, adjusted to a pH of 2 to 3 with concentrated hydrochloric acid, and the precipitate formed by cooling with ice was recrystallized from ethanol to obtain 2.1 g of hydrochloride. of S- (-morpholinobutyryl) -8-hydroxycarbostyril monohydrate (II), amorphous and white, having a melting point of 179-182 ° C (with decomposition).  The product thus obtained was confirmed by IR and NMR spectral analyzes and by elemental analysis. 



  Example 47:
 17.1 g of α-bromopropionyl chloride, 27 g of anhydrous aluminum chloride and 8 ml of nitrobenzene were added to 8 g of 8-methoxy-3,4-dihydrocarbostyril, and the mixture was heated at a temperature. SOC temperature at Åa 60 C for 1 h with stirring.  The reaction mixture was then poured into 200 ml of an ice-water mixture, and the precipitate formed was filtered and washed with water.  The precipitate was then recrystallized from ethanol to obtain 11.5 g of a product having a melting point of 154-155 ° C.     The product thus obtained was confirmed by IR and NMR spectral analyzes and by elemental analysis as 5- (α-bromopropionyl) -8-methoxy-3,4-dihydrocarbostyril. 



  Example 48:
 26.4 g of α-bromobutyryl bromide, 17.5 g of anhydrous aluminum chloride and 5 ml of nitrobenzene were added to S g of 8-methoxy-3,4-dihydrocarbostyril, and the mixture was heated. at SOC C at 60 C for 1 hour with stirring.  The reaction mixture was then poured into 100 ml of ice-water mixture, and the precipitate formed was filtered and washed with water. 



  This was then recrystallized from ethanol to obtain S g of a product having a melting point of 151 ° C to 152 C.     The product thus obtained was confirmed by IR and NMR spectral analyzes and by elemental analysis as being S- (α-bromobutyryl) -8-methoxy-3,4-dihydrocarbostyril.    



  Example 49:
 2 g of S- (a-bromopropionyl) -8-methoxy-3,4-dihydrocarbosty- ril prepared as described in Example 47 were suspended in 50 ml of isopropanol, and the suspension was stirred for 2 h at a temperature of 60 C.     The solvent was then removed by distillation, and the obtained residue was dissolved in S ml of isopropanol.  The solution was then adjusted to pH 2-3 with concentrated hydrochloric acid.  The precipitate formed was filtered off and a mixture of acetone and diethyl ether was added to the filtrate.  The precipitate formed was filtered and recrystallized from isopropanol to obtain 1.5 g of a white amorphous product having a melting point of 172 ° C to 174 ° C (with decomposition).  

  The product thus obtained was confirmed by IR and NMR spectral analyzes and by elemental analysis such as S (α-isopropylaminopropionyl) -8-methoxy-3,4-dihydrocarbostyril dihydrate hydrochloride. 



  Example 50:
 S g of S- (a-bromopropionyl) -8-methoxy-3,4-dihydrocarbostyr prepared as described in example 47 were suspended in 50 ml of isopropanol, and 10 g of t-butylamine were was added to the suspension, then the mixture was stirred at a temperature of 60 C for 15 h.  The solvent was then removed by distillation, and the residue obtained was dissolved in 10 ml of isopropanol.  The solution was then adjusted to pH 2-3 with concentrated hydrochloric acid.  The precipitate formed was filtered off and acetone was added to the filtrate.  The precipitate formed was filtered off, and diethyl ether was added to the filtrate. 

  The precipitate thus formed was filtered and recrystallized from a mixture of isopropanol and diethyl ether to obtain 2.1 g of colorless amorphous product having a melting point of 207-210 ° C (with decomposition).  The product thus obtained was confirmed by IR and NMR spectral analyzes and by elemental analysis such as 5 (x-t-butylaminopropionyl) -8-methoxy-3,4-dihydrocarbostyril monohydrate hydrochloride. 



  Example 51:
 2 g of 5- (x-bromobutyryl) -8-methoxy-3,4-dihydrocarbostyril prepared as described in Example 48 was suspended in 50 ml of isopropanol, and 5 g of isopropylamine was added to the suspension, then the mixture was stirred at a temperature of 60 ° C for 4 h.  The solvent was then removed by distillation, and the residue obtained was dissolved in 5 ml of isopropanol.  The solution was then adjusted to pH 2-3 with concentrated hydrochloric acid.  The precipitate formed was filtered and recrystallized from a mixture of isopropanol and acetone to obtain 1.7 g of a colorless amorphous product having a melting point of 204206-C (with decomposition). 

  The product thus obtained was confirmed by IR and NMR spectral analyzes and by elemental analysis such as 5- (x-isopropylaminobutyryl) -8-methoxy-3,4-dihydrocarbostyril hydrochloride monohydrate. 



  Example 52:
 3 g of 5- (α-bromobutyryl) -8-methoxy-3,4-dihydrocarbostyril prepared as in Example 48 was suspended in 50 ml of isopropanol, and 9 g of t-butylamine was added to the suspension, and the mixture was stirred at a temperature of 60 ° C for 19 h.  The solvent was then removed by distillation and the residue obtained was dissolved in 5 ml of isopropanol.  Then the solution was adjusted to pH 2-3 with concentrated hydrochloric acid.  The precipitate formed was filtered off, and acetone was added to the filtrate.  The precipitate formed was then filtered off and diethyl ether was added to the filtrate.  The precipitate formed was filtered off and recrystallized from isopropanol to obtain 1.6 g of a colorless amorphous product having a melting point of 160 ° C to 162 C (with decomposition). 

  The product thus obtained was confirmed by IR and NMR spectral analyzes and by elemental analysis such as 5- (α-t-butylaminobutyryl) -8-methoxy-3,4-dihydrocarbostyril hydrochloride monohydrate. 



  Example 53:
 1.5 g of 5- (x-isopropylaminopropionyl) -8-methoxy-3,4-dihy-drocarbostyril prepared as described in Example 50 were dissolved in 15 ml of 47% aqueous hydrobromic acid, and the solution was heated under reflux for 15 h at a temperature of 140 ° C.  The reaction mixture was concentrated, and acetone was added to this mixture to crystallize the product.  The product was then recrystallized from a mixture of ethanol and acetone to obtain 1.1 g of a product having a melting point of 223 226-C (with decomposition).  The product thus obtained was confirmed by IR and NMR spectral analyzes and by elemental analysis such as 5- (α-isopropylaminopropionyl) -8-hydroxy-3,4-dihydrocarbostyril hydrobromide.    



  Example 54:
 1.5 g of 5- (α-isopropylaminobutyryl) -8-methoxy-3,4-dihydro-carbostyril was dissolved in 15 ml of 47% aqueous hydrobromic acid, and the solution was heated under reflux for 15 h at a temperature of 130 "C to 140" C.     The reaction mixture was concentrated, and acetone was added to the reaction mixture to crystallize the product.  This product was then recrystallized from a mixture of ethanol and acetone to obtain 1.0 g of a product having a melting point of 165-168 ° C.     The product thus obtained was confirmed by IR and NMR spectral analyzes and by analysis.
 elemental such as 5- (x-isopropylaminobuty- hydrobromide
 ryl) -8-hydroxy-3,4-dihydrocarbostyril 1/2 hydrate. 



   Example 55:
 1 g of 5- (x-t-butylaminopropionyl) -8-methoxy-3,4-dihydrocar-
 bostyril obtained from hydrochloride monohydrate prepared
 as described in Example 50 was dissolved in 15 ml of acid
 47% aqueous hydrobromic, and the solution was heated to
 reflux for 15 h at 140-150 C.  The reaction mixture was concentrated, and acetone was added to this mixture to crystallize.
 ser the product.  This was then recrystallized from a mixture
 of ethanol and acetone to obtain 0.7 g of a product having a
 melting point 224-227 C (with decomposition). 

  The product thus obtained was confirmed by IR and NMR spectral analyzes.
 and by elemental analysis such as 5- (x-t- hydrobromide)
   butylaminopropionyl). 8-hydroxy. 3,4-dihydrocarbostyril monohydrate. 



   Example 56:
 1.5 g of 5- (x-t-butylaminobutyril) -8-methoxy-3,4-dihydrocar-
 bostyril obtained from the hydrochloride monohydrate prepared as described in Example 52 were dissolved in acid
 47% aqueous hydrobromic, and the solution was heated to
 reflux for 19 h at a temperature of 140 "C to 150" C.     The reaction mixture was concentrated and acetone was added thereto to crystallize the product.  The latter was then recrystallized from a mixture of ethanol and acetone to obtain 1.1 g of a product having a melting point of 144-146 ° C. (with decomposition). 

  The product thus obtained was confirmed by IR and NMR spectral analyzes and by elemental analysis such as 5- (x-t-butylaminobutyryl) -8-hydroxy-3,4-dihy-drocarbostyril dihydrate. . 



  Example 57:
 5 g of 5- (α-bromopropionyl) -8-hydroxy-3,4-dihydrocarbosty- ril was suspended in 30 ml of benzene, and 4.2 ml of morpholine was added to the suspension, followed by mixing. was reacted for 4 h while heating at reflux.  The reaction mixture was filtered and the filtrate was washed with water, then concentrated under reduced pressure to remove the remaining water.  The obtained residue was dissolved in 50 ml of isopropanol and the solution was adjusted to pH 2-3 with concentrated hydrochloric acid.  The viscous precipitate formed by cooling with ice was separated, and dissolved in acetone by heating. 



  After allowing the solution to cool, the precipitate formed was dissolved in 30 ml of water and adjusted to a pH of 7.5-8 with sodium bicarbonate.  The precipitate formed by cooling with ice was filtered and dissolved in 10 ml of 47% aqueous hydrobromic acid, then concentrated under reduced pressure.  The residue thus obtained was washed with 10 ml of ethanol and recrystallized from methanol to obtain 2.6 g of 5- (a-morpholino) - propionyl-8-hydroxy-3,4-dihydrocarbostyr monohydrate, amorphous white, and having a melting point of 235-236 C (with decomposition). 



  Example 58:
 30 ml of nitrobenzene and 70 ml of chloroacetyl chloride were added to 40 g of 1-methyl-8-methoxycarbostyril, and 130 g of aluminum chloride was added slowly to the mixture while cooling with an ice-water mixture, then the mixture was reacted at a temperature of 60 C for 4 h while stirring.  The reaction mixture was then poured into ice-water mixture, to precipitate the product.  

  The precipitate was filtered, washed with diethyl ether and recrystallized from a mixture of chloroform and ethanol (2: 5 by volume) to obtain 32 g of amorphous and white 1-methyl-5chloroacetyl-8-methoxycarbostyril, having a point of fusion of 204-205.5 C.  The product thus obtained was confirmed by elemental analysis and by IR and NMR spectral analyzes. 



  Example 59:
 40 ml of nitrobenzene and 12 ml of monochloroacetyl chloride were added to 7.4 g of 1 -methyl-8-hydroxycarbostyril, and 20 g of aluminum chloride was added slowly to the mixture while cooling with an ice-water mixture. ; then the mixture was reacted at a temperature of 60 ° C for 18 h with stirring.  The reaction mixture was then poured into 500 ml of ice-water mixture, in order to precipitate the product. 

  The precipitate was filtered, washed with diethyl ether and recrystallized from a mixture of ethanol and dimethylformamide (1: 1 by volume) to obtain 2.8 g of amorphous 1-methyl-5-chloroacetyl-8-hydroxycarbostyril and white, having a melting point of 287-289 C (with decomposition).  The product thus obtained was confirmed by elemental analysis and by IR and NMR spectral analyzes. 



  Example 60:
 2.7 g of 1 -methyl-5-chloroacetyl. 8. methoxycarbostyril prepared as described in Example 58 were dissolved in 40 ml of isopropanol, and 9 g of isopropylamine was added to the solution with heating at 55 C to 60 C over a period of 1.5 h .  After completion of the addition, the mixture was reacted for 1 hr with stirring.  The reaction mixture was concentrated under reduced pressure and the residue obtained was dissolved in 40 ml of isopropanol.  The solution was then filtered to remove any insoluble product, and the filtrate was adjusted to pH 2-3 with concentrated hydrochloric acid. 

  The mixture was cooled with ice, and the precipitate formed was filtered and recrystallized from ethanol to obtain 0.4 g of amorphous and white 1-methyl-5-isopropylaminoacetyl-8-methoxycarbostyril hydrochloride.  The product thus obtained was confirmed by elemental analysis and by IR spectral analysis. 



  Example 61:
 10 ml of isopropanolamine was added to 1.6 g of 1-methyl-5-chloroacetyl-8-hydroxycarbostyril prepared as described in Example 59, and the mixture was reacted at a temperature of 35 ° C for 2 hours with stirring.  The reaction mixture was concentrated under reduced pressure, and the residue was azeotroped with ethanol to dryness.  The residue
 obtained was dissolved in 20 ml of ethanol, and the solution was filtered to recover the insoluble product, which was then dissolved in hot ethanol.  The solution was adjusted to pH 2-3 with hydrochloric acid and cooled with ice.  The precipitate formed was filtered off and dissolved in 20 ml of water. 

  The solution was adjusted to pH 6.5-7.5 with sodium bicarbonate.
 sodium, and the precipitate formed was filtered and recrystallized from ethanol to obtain 1.1 g of amorphous and white 1-methyl-5-isopropylaminoacetyl-8-hydroxycarbostyril, having a melting point
 of 136-138 C (with decomposition). 



  Example 62:
 2.0 g of 1-methyl-5-isopropylaminoacetyl-8-methoxycarbostyril hydrochloride prepared as described in Example 60 have
 was dissolved in 30 ml of a 47% aqueous solution of hydrobromic acid and the solution was heated in an oil bath at
 temperature of 120 "C at 1300C for 8 hours at reflux.  10 ml of water
 were then added to the reaction mixture, the latter then being concentrated by distillation.  10 ml of water was again added to the mixture, addition followed by concentration.  After allowing the mixture to cool, the precipitate formed was filtered off and dissolved.
 in 60 ml of water by heating. 

  The resulting solution was adjusted
 at pH 6.5-7.5 with sodium bicarbonate, and the precipitate formed was filtered.  Recrystallization of the precipitate from
 ethanol gave 0.45 g of amorphous and white 1-methyl-5-isopropylaminoacetyl-8hydroxycarbostyril, having a melting point of 136-138 C (with decomposition).  The product thus obtained was confirmed by elemental analysis and by IR and NMR spectral analyzes. 



  Example 63:
 1.0 g of the S-isopropylaminoacetyl-8-hydroxycarbostyril hydrochloride obtained in Example 9 was dissolved in 40 ml of water, and 0.5 g of palladium on carbon was added as a catalyst to the solution obtained.  The resulting mixture was heated to 35 "C to 40" C with stirring, to absorb hydrogen.  After completion of the reduction reaction, the catalyst was filtered off and the filtrate was concentrated to dryness under reduced pressure.  Ethanol was added to the residue, then repeatedly concentrated to dryness in order to completely remove the water. 

  The residue was crystallized from acetone, and recrystallized from ethanol-acetone (1: 1 by volume) to obtain 0.4 g of S- (1-hydroxy-2 isopropylamino) ethyl hydrochloride. 8. Amorphous and pale yellow hydroxycarbostyril having a melting point of 210 "C to 212" C (with decomposition). 



  Example 64:
 2.0 g of the free base of S-sec-butylaminoacetyl-8-hydrocarbostyril obtained in Example 11 was dissolved in 100 ml of methanol, and 0.8 g of sodium borohydride was gradually added to the solution obtained stirring and cooling. 



  The resulting mixture was stirred for 15 min, then stirred again at room temperature for a further 1 h.  Concentrated hydrochloric acid was added to the mixture, in order to adjust it to a pH of 1.5 to 2, and the solvent was distilled off under reduced pressure.  To the residue was added 30 ml of ethanol, then the mixture was concentrated to dryness under reduced pressure, to remove water.  The residue was dissolved in 50 ml of absolute ethanol, and an ethanolic solution of sodium hydroxide was added to the obtained solution, in order to adjust the pH of the solution to 7 to 8.5.  The precipitate thus formed was filtered, and the filtrate was concentrated to dryness under reduced pressure. 

  The residue was then extracted with 50 ml of absolute ethanol, then hydrochloric acid was bubbled through the extract.  The extract was then concentrated to dryness under reduced pressure, and the residue was recrystallized from isopropyl alcohol to obtain 1.3 g of S- (1-hydroxy-2-sec-butylamino) ethyl-8 dihydrochloride. -Hydroxycarbostyril monohydrate, amorphous and pale yellow, having a melting point of 143 "C to 144" C (with decomposition). 



  Example 65:
 1.5 g of 5-tert-butyiaminoacetyi. 8. hydroxycarbostyril obtained in Example 10 were dissolved in 100 ml of methanol and 0.7 g of sodium borohydride was slowly added to the solution obtained with stirring and cooling.  Stirring was then continued at this temperature for 15 min and then at room temperature for an additional 1 h.  The reaction product was treated in the same manner as described in Example 2, then recrystallized from methanol to obtain 0.9 g of S- (1-hydroxy-2-tert-butylamino) ethyl hydrochloride. Amorphous and pale yellow hydroxycarbostyril having a melting point of 242 "C to 244" C (with decomposition). 

 

  Example 66:
 2.0 g of S-piperidinoacètyi-8-hydroxycarbostyril hydrochloride prepared in Example 12 was dissolved in 200 ml of methanol, and 2.0 g of sodium borohydride was added to the solution while cooling with water. ice, then the mixture was stirred for 2 h.  This mixture was then adjusted to pH 2-3 with concentrated hydrochloric acid, then allowed to stand for 1 h at room temperature, and filtered.  The filtered reaction mixture was concentrated under reduced pressure and the residue was dissolved in 30 ml of ethanol.  The solution was filtered to remove any insoluble product, and the filtrate was concentrated under reduced pressure.  These techniques (dissolution in ethanol, filtration and concentration) were repeated three times. 

  The obtained residue was dissolved in acetone by heating, and the precipitate formed by cooling was filtered and recrystallized from isopropanol to obtain 0.6 g of 5- (1-hydroxy2-piperidino) ethyl- hydrochloride. 1 1/2 hydrated 8-hydroxycarbostyril, amorphous and white, having a melting point of 146-148 C (with decomposition).  The product thus obtained was confirmed by IR and NMR spectral analyzes and by elemental analysis. 



  Example 67:
 1.0 g of 5-morpholinoacetyl-8-hydroxycarbostyril, prepared in Example 13 was dissolved in 100 ml of methanol and 1.2 g of sodium borohydride was added to the solution, then it was put in reaction for 2 hours with stirring.  The reaction mixture was adjusted to pH 2-3 with concentrated hydrochloric acid, then the mixture was allowed to stand at room temperature for 1 h.  The reaction mixture was then filtered, and the filtrate was concentrated under reduced pressure.  The residue was dissolved in 20 ml of ethanol, and the solution was filtered to remove any insoluble product, then the filtrate was concentrated under reduced pressure. 

  These procedures (dissolution in ethanol, filtration and concentration) were repeated three times, and the residue thus obtained was crystallized from acetone.  The precipitated crystals were filtered and triturated with 20 ml of an aqueous solution of sodium bicarbonate to remove any insoluble product by filtration and the insoluble product was washed with water and then dissolved in ethanol by heating.  The obtained solution was adjusted to a pH of 2-3 with concentrated hydrochloric acid, and the precipitate formed on cooling was filtered to obtain 0.6 g of S- (1-hydroxy-2-morpholino) hydrochloride. Hydrated, amorphous and white ethyl-8-hydroxycarbostyril I 1/2 having a melting point of 157-158.5 C (with decomposition). 

  The product thus obtained was confirmed by IR and NMR spectral analyzes and by elemental analysis. 



  Example 68:
 50 ml of methanol was added to S g of the free base of S benzylaminoacetyl-8-hydroxycarbostyriy prepared in Example 14, and 3 g of sodium borohydride was added slowly to the solution while cooling in ice, and in stirring, then the mixture was stirred at room temperature for 1 h. 



  The obtained mixture was adjusted to a pH of 1 with concentrated hydrochloric acid, and the precipitate formed was filtered.  The filtrate was concentrated to dryness and crystallized from acetone.  The obtained crystals were adjusted to a pH of 8 with an aqueous solution of sodium hydroxide, and the precipitate formed was filtered off and washed with water.  The precipitate was adjusted to pH 1 with dilute hydrochloric acid and then concentrated to dryness.  The residue thus obtained was recrystallized from a mixture of methanol and acetone to obtain 4.2 g of a white amorphous product having a melting point of 120-121 ° C.  The product thus obtained was confirmed by IR and NMR spectral analyzes and by elemental analysis as S- (1-hydroxy-2-benzylamino) ethyl-8-hydroxycarbostyril hydrochloride dihydrate. 



  Example 69:
 1 g of the S- (1-Phenetylaminoacetyl) -8-hydroxy-carbostyril hydrochloride prepared in Example 15 was dissolved in 50 ml of methanol, and the solution was made weakly alkaline using a methanolic solution of sodium hydroxide.  0.5 g of sodium borohydride was added slowly to the mixture, while cooling, then the mixture was stirred at room temperature for 1 h.  The precipitate which was formed by adding concentrated hydrochloric acid to pH 3 was filtered, and the filtrate was concentrated to dryness.  The obtained residue was dissolved in absolute ethanol, and the solution was adjusted to pH 9 with an ethanolic solution of sodium hydroxide.  The precipitate was filtered off, and the filtrate was concentrated to dryness.  The residue was crystallized from acetone and washed with water. 

  The obtained crystals were dissolved in isopropanol and the solution was saturated with hydrochloric acid, then cooled.  The precipitate formed was filtered off and recrystallized from isopropanol to obtain 0.77 g of a white amorphous product having a melting point of 162 164 C.     The product thus obtained was confirmed by IR and NMR spectral analyzes and by elemental analysis such as 5- [1-hydroxy-2- (1-phenethylamino)] ethyl-8-hydroxy-carbostyril hydrochloride dihydrate. 



     Example 70:
 0.1 g of platinum oxide and 50 ml of water were added to 0.5 g of 5-benzylaminoacetyl-8-hydroxycarbostyril hydrochloride monohydrate prepared in Example 14, and the mixture was reduced to room temperature under atmospheric pressure in a hydrogen atmosphere for 24 h with shaking.  After the reduction was complete, the catalyst was filtered off, and the aqueous phase was concentrated to dryness.  The residue was recrystallized from a mixture of methanol and acetone to obtain 0.25 g of amorphous and white 5- (1-hydroxy-2-amino) ethyl-8-hydroxycarbostyril hydrochloride, having a melting point of 261 -262 C (with decomposition).  The product thus obtained was confirmed by IR and NMR spectral analyzes and by elemental analysis. 



  Example 71:
 1.5 g of S- (1.1. dimethylphenethylaminoacetyl) -8-hydroxycarbostyril were dissolved in 50 ml of methanol, and 1 g of sodium borohydride was slowly added to the solution cooled with ice-water, with stirring; then stirring was continued at room temperature for a further 1 h.  The resulting mixture was then adjusted to pH 1 with concentrated hydrochloric acid, and the mixture was concentrated to dryness.  The residue was dissolved in ethanol, and the insoluble products were removed by filtration.  The ethanolic phase was concentrated to dryness, and the residue was dissolved in isopropanol.  The isopropanol phase was concentrated, and acetone was added to crystallize the product. 

  Recrystallization of the product from methanol-acetone gave 1.4 g of a white amorphous product having a melting point of 167-168 C (with coloring and decomposition).  The product thus obtained was confirmed by IR and NMR spectral analyzes and by elemental analysis as being 5- [2- (1,1-dimethyl-phenetylamino) -1-hydroxy] ethyl-8-hydroxycarbostyril hydrochloride dihydrate. 



  Example 72:
 2.5 g of chloranil and 20 ml of xylene were added to 2.2 g of S- (l. hydroxy-2. amino) ethyl. 8-hydroxy-3,4-dihydrocarbostyril, and the mixture was heated at reflux for 24 h.  The reaction mixture was then concentrated to dryness, and the residue was washed thoroughly with carbon tetrachloride.  The residue was then dissolved in 30 ml of methanol, and the solution was adjusted to pH 1 by introducing gaseous hydrochloric acid into the solution, followed by cooling.  The precipitated crystals were filtered off and recrystallized from methanol to obtain 1.5 g of a product having a melting point of 261 "C to 262" C (with decomposition).  

  The product thus obtained was confirmed by IR and NMR spectral analyzes and by elemental analysis such as 5- (1-hydroxy-2-amino) ethyl-8-hydroxycarbostyril hydrochloride. 



  Example 73:
 200 ml of water, 0.9 g of sodium hydroxide and 4.3 g of nickel
Raney was added to 4.3 g of 5- [2- (1,1-dimethylphenethylamino) -l -hydroxyethyl-8-hydroxy-3,4-dihydrocarbostyril dihydrate, and the mixture was heated. at reflux at 80 C for 15 h.  The reaction mixture was then filtered to remove the catalyst, and the filtrate was concentrated.  The precipitated crystals obtained were recrystallized from water to obtain 2.6 g of a product having a melting point of 167-168 ° C (with decomposition).  The product thus obtained was confirmed by IR and NMR spectra and by elemental analysis as 5- [2- (1,1 -dimethylphenethylamino) - 1 -hydroxy] ethyl-8-hydroxycarbostyril hydrochloride monohydrate. 



   In the same manner as in Example 10, the following compound was prepared: 5- (2-isopropylamino-1-hydroxy) ethyl-8-hydroxycarbostyril hydrochloride, having a melting point of 210-212 ° C (with decomposition). 



  Example 74:
 2.0 g of 5-isopropylaminoacetyl-8-hydroxy-3,4-dihydrocarbostyril hydrochloride prepared as described in Example 35 was dissolved in 40 ml of water, and 0.5 g of Pd black was added. as a catalyst to the solution.  The mixture was stirred at 70-75 ° C at atmospheric pressure in the presence of H2.  After the end of the reduction, the catalyst was filtered off, and the filtrate was concentrated to dryness under reduced pressure.  The water remaining in the residue was then completely removed using ethanol, and acetone was added to the residue to crystallize the product. 

  Recrystallization from a mixture of ethanol and acetone (1: 2 by volume) gave 1.1 g of a colorless amorphous product having a melting point of 199-201 ° C.     The product thus obtained was confirmed by IR and NMR spectra and by elemental analysis such as 5- (1-hydroxy-2-isopropylamino) -8hydroxy-3,4-dihydrocarbostyril hydrochloride. 



  Example 75:
 1.5 g of 5-tert-butylaminoacetyl-8-hydroxy3,4-dihydrocarbostyril hydrochloride, prepared as described in Example 31, was dissolved in 35 ml of water, and 1.0 g of Pd on C a was added as a catalyst to the solution.  The mixture was shaken at 5060 C under a pressure of 4-5 atmospheres in the presence of H2. 



  After the end of the reduction, the catalyst was filtered off, and the filtrate was concentrated to dryness under reduced pressure.  Acetone was added to the residue to crystallize the product.  Recrystallization from methanol-acetone (1: 2 by volume) gave 0.8 g of a colorless amorphous product having a melting point of 240,241 ° C.     The product thus obtained was confirmed by IR and NMR spectra and by elemental analysis such as 5- (1 -hydroxy-2-tert-butylamino) ethyl-8-hydroxy-3,4-dihydrocarbostyril hydrochloride. 



  Example 76:
 2.0 g of 5-sec-butylaminoacetyl-8-hydroxy-3,4-dihydrocarbostyril prepared as described in Example 29 was dissolved in 100 ml of methanol, and 0.8 g of sodium borohydride was added slowly to the solution with stirring under ice cooling.  The mixture was then stirred at this temperature for
 15 min, then at room temperature for 1 h.  The mixture was then adjusted to pH 1.5-2 with concentrated HCl, and the solvent was then removed by distillation.  30 ml of ethanol was added to the residue and the mixture was again concentrated to dryness under reduced pressure to remove water.  50 ml of absolute ethanol was added to the obtained residue, and the mixture was adjusted to pH 7 to 8.5.  The precipitate thus formed was filtered off, and the filtrate was concentrated to dryness under reduced pressure. 

  The residue was extracted with 50 ml of absolute ethanol, and HCl gas was passed through the extract.  This was then concentrated to dryness under reduced pressure, and the residue was recrystallized from a mixture of methanol and acetone (1: 2 by volume) to give 1.3 g of a colorless amorphous product having a melting point. from 183-184 "C.     The product thus obtained was confirmed by IR and NMR spectra and by elemental analysis such as 5- (2-sec-butyl amino-1-hydroxy) ethyl-8-hydroxy-3,4-dihydrocarbostyril hydrochloride.    



  Example 77:
 0.7 g of Pd black and 130 ml of water were added to 1.5 g of
 8-hydroxy-S- (x-methylbenzylaminoacetyl) carbos hydrochloride
 tyrile, and the mixture was reacted under a pressure of H2
 of 4 atmospheres, at a temperature of 600 C and shaking. 



   After the end of the reaction, the catalyst was filtered off and the filtrate
 aqueous was concentrated to dryness.  Acetone was added to the residue
 to crystallize the product.  This was then washed with 100 ml.
 ethanol and recrystallized from a mixture of methanol and acetate
 ethyl to obtain 0.8 g of 5 - [(1-hydroxy-2 hydrochloride
   benzylamino) ethyl] -8-hydroxy-3,4-dihydrocarbostyril white
 amorphous.  The product thus obtained was confirmed by IR spectra.
 and NMR and by elemental analysis. 



   Example 78:
 0.1 g of Pd black and 50 ml of water were added to 0.4 g of
 S - [(1-hydroxy-2-benzylamino) ethyl] -8-hydroxy- hydrochloride
 carbostyril dihydrate, and the mixture was reacted with
 ambient temperature and atmospheric pressure in hydro
 gene for 8 h and shaking.  After the reaction has ended, the
 catalyst was filtered off, and the aqueous filtrate was concentrated to dryness.  The residue thus obtained was recrystallized from a mixture of metha
 nol and acetone to obtain 0.2 g of S - [(l-
   hydroxy-2-amino) ethyl-8-hydroxycarbostyril.     The product as well
 obtained was confirmed by IR and NMR spectra and by analysis
 elementary. 



   Example 79:
 0.7 g of Pd black and 100 ml of water were added to 1.4 g of
 5- (a-Benzylaminoacetyl) -8-hydroxy-3,4-dihydro- hydrochloride
 carbostyril, and the mixture was reduced to 600 ° C and a H 2 pressure of 4 atmospheres.  After the end of the reduction, the catalyst
 was filtered and the aqueous filtrate was concentrated to dryness.  Acetone has
 was then added to the residue to crystallize the product.  Crystals
 thus obtained were washed with 10 ml of ethanol and recrystallized
 in a mixture of methanol and ethyl acetate to obtain
 0.7 g of 5 - [(i -hydroxy-2-amino) ethyl] -8-hydroxy- hydrochloride
 Amorphous white 3,4-dihydrocarbostyril. 

  The product thus obtained has
 was confirmed by IR and NMR spectra and by elemental analysis.
 to hush up. 



   Example 80:
 0.05 g of Pd black and 100 ml of water were added to 1 g of
 S - [(1-hydroxy-2-amino) ethyl] -8-hydroxycarbosty- hydrochloride
 rile, and the mixture was reduced under a pressure of H2 of 2 atm.
 spheres for 10 h while shaking.  After the reduction ends, the
 catalyst was filtered off, and the aqueous filtrate was concentrated to dryness.  The
 precipitate thus obtained was recrystallized from a mixture of
 methanol and acetone to obtain 0.9 g of 5 - [(1 hydroxy-2-amino) ethyl] -8-hydroxy-3,4-dihydrocarbostyril hydrochloride
 amorphous white and having a melting point of 270-272 "C.  The
 product thus obtained was confirmed by IR spectral analyzes and
 by NMR and by elemental analysis. 



   Example 81:
 0.5 g of Pd black and 50 ml of water were added to 2 g of 5
   [(1 -hydroxy-2-isopropylamino) ethyl] -8-hydroxycarbostyril and
 mixture was reduced to atmospheric pressure in an atmo
 sphere of H2 at a temperature of 700 C for 8 h while shaking. 

 

   After the end of the reduction, the catalyst was filtered off and the filtrate
 aqueous was concentrated to dryness.  The precipitate thus obtained was
 recrystallized from a mixture of methanol and acetone for
 obtain 1.7 g of 5 - [(1-hydroxy-2-isopropylamine hydrochloride
   no) ethyl] -8-hydroxy-3,4-dihydrocarbostyril.     The product as well
 obtained was confirmed by IR and NMR spectra and by analysis
 elementary. 



   Example 82:
 0.1 g of Pd black and 30 ml of water were added to 1 g of 5
   [(1 -hydroxy-2-sec-butylamino) ethyl] -8-hydroxycarbostyril, and the mixture was reduced under a hydrogen pressure of 3 atmospheres at a temperature of 60; C for 10 h with stirring. 



  After the reduction was complete, the catalyst was filtered off, and the aqueous filtrate was concentrated to dryness.  The precipitate thus obtained was recrystallized from a mixture of methanol and acetone to obtain 0.6 g of 5 - [(1-hydroxy-2-sec-butylamine) ethyl] -8-hydroxy-3 hydrochloride, 4-dihydrocarbostyril.     The product thus obtained was confirmed by IR and NMR spectral analyzes and by elemental analysis. 



  Example 83:
 0.5 g of 10% Pd over C and 50 ml of water was added to 1.5 g of S - [(1 -hydroxy-2-tert-butylamino) ethyl] -8-hydroxycarbostyril hydrochloride, and the mixture was reduced to a pressure of H2 of 5 atmospheres and a temperature of 75 C for
 16 h with stirring.  After the reduction was complete, the catalyst was filtered off and the aqueous filtrate was concentrated to dryness.  The precipitate thus obtained was recrystallized from a mixture of methanol and acetone to obtain 1.1 g of amorphous S - [(1 -hydroxy-2-tert-butylamino) ethyl] 8-hydroxy-3,4-dihydrocarbostyril and white having a melting point of 240-241 ¯ C.  The product thus obtained was confirmed by IR and NMR spectral analyzes and by elemental analysis. 



  Example 84:
 100 mg of Pd black and 50 ml of water were added to 300 mg of 5- [1-hydroxy-2- hydrochloride (l. 1-Dimethylphenethylamine no)] ethyl-8-hydroxycarbostyril monohydrate, and the mixture was reduced at a pressure of H2 of 2.5 atmospheres, and at a temperature of 45-50-C for 8 h.  The catalyst was filtered off, and the filtrate was concentrated to dryness.  The residue was recrystallized from water to obtain 260 mg of an amorphous product having a melting point of.
   120-1 21 C.     The product thus obtained was confirmed by IR and NMR spectral analyzes and by elemental analysis such as S- [1 -hydroxy-2- (1,1 -dimethylphenethylamino) jethyl-8-hydroxy-3,4- hydrochloride. dihydrocarbostyril dihydrate. 



  Example 85:
 0.2 g of Pd oxide and 50 ml of water were added to 1.0 g of 5- (1,1-dimethylphenethylaminoacetyl) -8-hydroxy hydrochloride.    



  1/2 hydrated carbostyril, and the mixture was reduced to a H 2 pressure of 5 atmospheres at a temperature of 80 C for 20 h. 



  The catalyst was filtered off and the filtrate was concentrated to dryness.  The residue obtained was recrystallized from water to obtain 0.8 g of a white amorphous product having a melting point of 120-121 C.     The product thus obtained was confirmed by IR and NMR spectra and by elemental analysis to be 5- [1hydroxy-2- (1,1 -dimethylphenethylamino)] ethyl-3,4dihydrocarbostyril dihydrate. 



  Example 86:
 1.5 g of 5-piperidinoacetyl-8-hydroxycarbostyril hydrochloride was dissolved in 100 ml of water, and 0.5 g of Pd over C and 0.2 g of Pd black were added to the solution, then the mixture obtained was catalytically reduced under atmospheric pressure of hydrogen for 4 days at a temperature of 40 ° C. while shaking.  After the end of the reduction, the reaction mixture was filtered to remove the catalyst by filtration and the filtrate was concentrated to dryness under reduced pressure.  The obtained residue was dissolved in acetone by heating, then the mixture was cooled. 

  The precipitate formed on cooling was recrystallized from isopropanol to obtain 0.8 g of 5- (2-piperidino-1-hydroxyethyl) -8-hydroxy-3,4-dihydrocarbostyril 1/2 hydrate hydrochloride having a melting point 136-139 C (with decomposition).  The product thus obtained was confirmed by IR and NMR spectra and by elemental analysis. 



  Example 87:
 10 ml of 47% aqueous HBr was added to 1 g of 5- (1-hydroxy-2-isopropylamino) ethyl-8-methoxycarbostyril hydrochloride monohydrate, and the mixture was heated under reflux for 15 h, then concentrated to dryness.  Acetone was added to the residue to crystallize the product which was then adjusted to pH 8 with aqueous NaOH solution.     The precipitated crystals were filtered off, washed with water and dissolved in ethanol.  The solution was adjusted to pH 1 with concentrated HCl, then concentrated to dryness.  The residue thus obtained was recrystallized from a mixture of ethanol and diethyl ether to obtain 0.7 g of a product having a melting point of 210-212 C (with decomposition). 

  The product thus obtained was confirmed by IR and NMR spectra and by elemental analysis such as 5- (1-hydroxy-2isopropylamino) ethyl-8-hydroxycarbostyril hydrochloride. 



   In the same manner as described in this Example 87, the following compounds were obtained from the corresponding 8-methoxy compounds:
 5- (1-Hydroxy-2-isopropylamino) ethyl-8-hydroxy-3,4-dihydrocarbostyril hydrochloride having a melting point of 203 204 C (with decomposition). 



   5- (2-hydroxy-tert-butylamino) ethyl-8-hydroxycarbostyril hydrochloride 1/2 hydrate having a melting point of 244,246 C (with decomposition). 



   5- (1-Hydroxy-2-benzylamino) ethyl-8-hydroxycarbostyril hydrochloride dihydrate, amorphous product having a melting point of 120-121 ° C. 



   S- (hydroxy-2- (11-dimethylphenethylamino) ethyl-8-hydroxycarbostyril hydrochloride monohydrate having a melting point of 167-168 C (with decomposition). 



   5- (1 -hydroxy-2-amino) ethyl-8-hydroxy-3, 4-dihydrocarbostyril hydrochloride having a melting point of 270-272.5 C (with decomposition). 



  Example 88:
 40 ml of methanol was added to 2 g of S- (x-isopropylami- nobutyryl) -8-hydroxycarbostyril (II) obtained as in Examples 43 and 44, and 2.5 g of sodium borohydride was added in portions. to the solution obtained by stirring and cooling in ice, then this solution was further stirred for 1 h at room temperature.  Concentrated HCl was added to the reaction mixture to adjust the pH to 1, and the mixture was then concentrated to dryness.  The precipitate was washed with acetone, dissolved in water, then adjusted to pH 8 with aqueous NaOH to precipitate the crystals. 

  These were collected by filtration and recrystallization from ethanol to obtain 1.8 g of 5- [(1 -hydroxy-2-isopropylamino) butyl] -8-hydroxycarbostyrile (I) monohydrate, having a melting point of 141-142 C (with coloring and decomposition). 



  Example 89:
 30 ml of methanol was added to 1.5 g of 5- (x-sec-butyla- minobutyril) -8-hydroxycarbostyril (II) prepared as in Example 42, and 1.5 g of Na borohydride was added in portions to the resulting solution, stirring and cooling in ice.  Stirring was continued at room temperature for 1 hour.  The reaction mixture was then adjusted to pH 1 with concentrated HCl, then concentrated to dryness.  The precipitate was filtered off, washed with acetone, dissolved in water, and adjusted to pH 8 with aqueous NaOH.  The precipitated crystals were filtered, washed with water and again dissolved in dilute HCl.  

  The resulting solution was concentrated to dryness, and the precipitate was recrystallized from ethanol to obtain 1.3 g of 5-M1-hydroxy-2-sec-butylamino) butyl] -8-hydroxycarbostyril (I) hydrochloride monohydrate. having a melting point of 182-183 ° C (with formation of foam and decomposition).   



  Example 90:
 20 ml of tetrahydrofuran was added to 1 g of 5- (α-isopropylaminobutyryl) -8-hydroxycarbostyril (II) hydrochloride obtained as in Example 43 or 44, and the mixture was added dropwise to a suspension of 0.12 g of lithium aluminum hydride in 10 ml of tetrahydrofuran, with stirring at room temperature.  After the addition was complete, a small amount of water was added to the reaction mixture to decompose the excess Li-Al hydride.  The reaction mixture was then poured into 50 ml of water-ice mixture, and the aqueous phase of the obtained solution was separated and concentrated to dryness.  The precipitated crystals were filtered off, washed with acetone and dissolved in water. 

  The solution was adjusted to pH 8 with aqueous NaOH to precipitate the crystals, which were then filtered and recrystallized from ethanol to obtain 0.8 g of 5 - [(1-hydroxy-2-isopropylamine) butyl] -8-hydroxycarbostyril (I) monohydrate having a melting point of 141-142 "C (with coloring and decomposition). 



  Example 91:
 1.5 g of the free base of 5- [a- (2-phenethylamino) butyry-8-hydroxycarbostyril (II) prepared as in Example 45 was dissolved in 150 ml of methanol, and 2 g of sodium borohydride were dissolved in Was slowly added to the solution while cooling with ice-water and stirring, then stirring was continued for a further 1 h at room temperature.  The resulting mixture was then adjusted to a pH of 1 with concentrated HCl and the mixture was filtered to remove the precipitate formed.  The filtrate was concentrated to dryness, and the residue was recrystallized by adding acetone.  An aqueous solution of NaOH was then added to the crystals at pH 8. 

  The precipitate formed was filtered and recrystallized from ethanol to obtain 1.3 g of an amorphous white product having a melting point of 147-148 C (with formation of foam and decomposition).  This product thus obtained was confirmed by IR and NMR spectra and by elemental analysis as 5- [1-hydroxy-2- (2-phenethylamino) butyl] -8-hydroxycarbostyril (I) trihydrate.    



  Example 92:
 2.5 g of chloranil and 20 ml of xylene were added to 2.2 g of 5- (1 -hydroxy-2-isopropylamino) propyî-8-hydroxy-3 4-dihydrocarbostyril (VII), and the mixture was heated at reflux for 24 h. 



  The reaction mixture was concentrated to dryness and the residue was washed thoroughly with 50 ml of C. tetrachloride.  The residue was then dissolved in 30 ml of methanol, and HCl gas was
 introduced into the solution to a pH of 1, then it was
 cooled.  The precipitated crystals were filtered off and recrystallized from methanol to obtain 1.5 g of a product having a melting point of 164-166 ° C (with decomposition).  The product as well
 obtained was confirmed by IR and NMR spectra and by elemental analysis to be 5 - [(1-hydroxy-2-isopropylamino) propyl] -8-hydroxycarbostyril (I) hydrochloride monohydrate. 



   In the same manner as described in this Example 92, the following compounds of formula (I) were also prepared from the corresponding 3,4-dihydrocarbostyril compound of formula (VII):
 5 - [(1-Hydroxy-2-sec-butylamino) butyl] -8-hydroxycarbostyril hydrochloride monohydrate having a melting point of
   182-183 C (with decomposition). 



   5 - [(1-Hydroxy-2-ethylamino) butyl] -8-hydroxy-carbostyril hydrochloride having a melting point of 174-177.5 "C (with
 decomposition). 



  Example 93:
 10 ml of 47% aqueous HBr was added to 1 g of hydrochloride
 drate of S - [(1. hydroxy-2-isopropylamino) propyl] -8-methoxy carbostyril (VIII) monohydrate, and the mixture was heated to
 reflux for 15 h, then concentrated to dryness.  Acetone was
 added to the residue obtained to crystallize the product, which was then adjusted to pH 8 with aqueous NaOH solution.     The precipitated crystals were filtered, washed with water and dissolved in ethanol.  The solution was adjusted to pH 1 with concentrated HCl, then concentrated to dryness.  The residue thus obtained was recrystallized from a mixture of ethanol and diethyl ether to obtain 0.7 g of a product having a melting point of 164-166 ° C (with decomposition). 

  The product thus obtained was confirmed by IR and NMR spectra and by elemental analysis as being 5 - [(1-hydroxy-2-isopropylamino) propyl] -8-hydroxycarbostyril (I) hydrochloride. 



   In the same manner as in this Example 93, the following compound of formula (I) was obtained from the 8-methoxy compound of formula (VIII): 5 - [(1-hydroxy-2-isopropylamino) butyl] -8 hydrochloride -hydroxycarbostyril having a melting point of 213-214 "C (with decomposition). 



  Example 94:
 1.0 g of 5- (a-isopropylaminopropionyl) -8-hydroxy-3,4-dihy-drocarbostyril obtained from hydrated hydrobromide 1/2 prepared as described in Example 54 was dissolved in 50 ml of methanol, and 0.3 g of sodium borohydride was added slowly to the solution while cooling in ice, then the mixture was stirred at room temperature for 1 h.  Methanol, which was saturated with HCl gas, was then added to the mixture to bring the pH thereof to 1-2.  The precipitate formed was filtered off, and the filtrate was concentrated to dryness.  A 1N aqueous solution of NaOH was then added to the residue up to a pH of 7.5-8, and the precipitate formed was filtered, dissolved in methanol, and then HCl gas was bubbled through the solution. 

  The precipitate formed was filtered off and recrystallized from methanol to obtain a product having a melting point of 211-213 C.     The product thus obtained was confirmed by IR and NMR spectra and by elemental analysis as being 5- (hydroxy-2-isopropylamino) propyl-8-hydroxy-3,4-dihydrocarbostyril 1/2 hydrate. 



  Example 95:
 To 1.0 g of 5- (a-isopropylaminobutyryl) -8-hydroxy-3,4-dihydro-carbostyril was added 20 ml of ethanol and 0.05 g of platinum oxide, and the mixture was reduced. under a hydrogen pressure of 2 atmospheres at a temperature of 60 C for 10 h. 



  After the reduction was complete, the catalyst was removed by filtration, and the filtrate was adjusted to pH 1 with concentrated hydrochloric acid, then concentrated to dryness.  The residue obtained was recrystallized from ethanol to obtain 0.9 g of a product having a melting point of 196-198 C.     This product was confirmed by IR and NMR spectra and by elemental analysis to be 5- (1-hydroxy-2-isopropylamino) butyl-8-hydroxy-3, 4-dihydrocarbostyril hydrochloride monohydrate. 



  Example 96:
 To 1.0 g of 5- (α-tert-butylaminopropionyl) -8-hydroxy-3,4-dihydrocarbostyril hydrobromide obtained from the corresponding monohydrate prepared in Example 55, were added 50 ml of water and 0 , 2 g of palladium black, then the mixture was reduced at atmospheric pressure and at a temperature of 60 ° C. for 20 h.  After the reduction was complete, the catalyst was filtered off and the filtrate was concentrated to dryness.  The residue obtained was recrystallized from ethanol to obtain 0.75 g of a product having a melting point of 198-199 C (with decomposition).  

  The product thus obtained was confirmed by IR and NMR spectra and by elemental analysis such as S- (1-hydroxy-2-tert-butylamino) propyl-8-hydroxy-3,4-dihydrocarbostyril monohydrate. 



  Example 97:
 To 1.0 g of 5- (a-tert-butylaminobutyryl) -8hydroxy-3,4-dihydrocarbostyril hydrobromide obtained from the corresponding dihydrate prepared in Example 56 was added 50 ml of water and 0.2 g of palladium black, then the mixture was reduced at atmospheric pressure at a temperature of 80 ° C. for 10 d. 



  After the reduction was complete, the catalyst was filtered off, and the filtrate was concentrated to dryness.  The obtained residue was recrystallized from ethanol to obtain 0.7 g of a product having a melting point of 164166 ° C (with decomposition).  The product thus obtained was confirmed by IR and NMR spectra and by elemental analysis as being 5- (1-hydroxy-2-tert-butylamino) - butyl-8-hydroxy-3,4-dihydrocarbostyril hydrobromide (under the form of a solution in ethanol). 



     Example 98:
 To 2 g of S- (α-isopropylaminobutyryl) -8-hydroxyoerbostyril were added 0.1 g of palladium black and 50 ml of ethanol, and the mixture was reduced to a hydrogen pressure of 35 atmospheres at a temperature of 75 C for 15 h, stirring the mixture.  After the reduction was complete, the catalyst was filtered off, and the filtrate was adjusted to pH 1 with concentrated hydrochloric acid.  The mixture was then concentrated to dryness and the precipitate obtained was recrystallized from ethanol to obtain 1.7 g of S - [(1-hydrnxy-2-isopropylamino) butyfl-8-hydroxy-3,4dihydrocarbostyril monohydrate. having a melting point of 196-198 C. 



  Example 99:
 To 1 g of 5- (x-isopropylaminobutyryl) -8-hydroxycarbostyril hydrochloride were added 0.05 g of platinum black and 100 ml of water, and the mixture was reduced to a hydrogen pressure of 40 atmospheres. at a temperature of 60 ° C for 18 h, shaking the mixture.  After the reduction was complete, the catalyst was filtered off, and the filtrate was concentrated to dryness.  The precipitate formed was then recrystallized from isopropanol to obtain 0.85 g of 5 - [(1-hydroxy-2-isopropylamino) butyl] -8-hydroxy-3,4-dihydrocarbostyril monohydrate having a point of fusion of 196-198 'C. 



     Example 100:
 To 0.5 g of S- (z-sec-butylaminobutyrvi) -8-hydroxycarbostyril were added 0.0025 g of palladium black and 15 ml of ethanol, and the mixture was reduced to a hydrogen pressure of 50 atmospheres at a temperature of 80 ° C for 15 h with shaking the mixture.  After the reduction was complete, the catalyst was filtered off, and the filtrate was adjusted to pH 1 with concentrated hydrochloric acid, then concentrated to dryness.  The precipitate formed was then recrystallized from ethanol to obtain 0.45 g of S - [(1 -hydroxy-2-sec-butylamino) butyl] -8-hydroxy-3,4-dihydrocarbostyril monohydrate having a point 205-207 C.    



  Example 101:
 15 ml of 47% aqueous hydrobromic acid was added to 1.5 g of 5- (1-hydroxy-2-tert-butylamino) propyl-8-methoxy-3,4dihydrocarbostyril, and the mixture was heated under reflux for 3 p.m.  Then, acetone was added to the reaction mixture to crystallize the product, and the obtained crystals were recrystallized from a mixture of ethanol and acetone to obtain 1.4 g of a product having a melting point of 198-199 C (with decomposition).  The product thus obtained was confirmed by IR and NMR spectra and by elemental analysis as being 5- (1-hydroxy-2-tert-butylamino) propyl-8-hydroxy-3,4dihydrocarbostyril monohydrate. 



   In the same manner as that described in Example 101, the following compounds were prepared:
 S- [1-Hydroxy-2- (2-phenetylamino) butyl] -8-hydroxy-3,4-dihydrocarbostyril hydrochloride having a melting point of 127,129 ° C (with decomposition). 



   S- [1-Hydroxy-2-morpholinobutyl] -8-hydroxy hydrobromide.    



  3,4-dihydrocarbostyril having a melting point of 183-185 C (with decomposition). 



  Example 102:
 To 1.0 g of 5- (α-tert-butylaminobutyryl) -8hydroxy-3,4-dihydrocarbostyril hydrobromide were added 50 ml of water and 0.2 g of palladium black, and the mixture was reduced to atmospheric pressure at a temperature of 80 "C for 10 d.  After the reduction was complete, the catalyst was filtered off, and the filtrate was concentrated to dryness.  The residue obtained was recrystallized from ethanol to obtain 0.7 g of a product having a melting point of 164166 ° C (with decomposition).  The product thus obtained was confirmed by IR and NMR spectra and by elemental analysis as being 5- (1-hydroxy-2-tert-butylamino) butyl-8-hydroxy-3,4-dihydrocarbostyril hydrobromide (in the form an ethanolic solution). 



     Example 103:
 1.0 g of 5- (2-morpholinobutyryl) -8-hydroxy- 3,4-dihydrocarbostyril hydrobromide was dissolved in 70 ml of water, and 0.2 g of palladium on carbon and 0.3 g of black Palladium was added to the solution, then it was catalytically reduced under atmospheric pressure of hydrogen for 10 days at a temperature of 70 ° C with shaking.  After the reduction was complete, the reaction mixture was filtered to remove the catalyst, and the filtrate was concentrated to dryness under reduced pressure.  The obtained residue was dissolved in acetone by heating, then the solution was cooled. 

  The precipitate formed on cooling was recrystallized from methanol to obtain 0.7 g of 5- (I -hydroxy-2-morpholino) butyl-8-hydroxy-3,4-dihydrocarbostyril 1/2 hydrate white hydrate and amorphous, having a melting point of 183-185 ° C (with decomposition).  The product thus obtained was confirmed by IR and NMR spectra and by elemental analysis. 



  Example 104:
 0.45 g of the free base of 1-methyl-5-isopropylaminoacetyl-8-hydroxycarbostyril prepared in Example 60 was dissolved in 50 ml of methanol, and 0.2 g of sodium borohydride was slowly added to the mixture. solution by ice-cooling and stirring.  Stirring was further maintained for a further 1 h, and the obtained reaction mixture was adjusted to pH 2 to 3 with concentrated hydrochloric acid.  The precipitate formed was then removed by filtration, and the filtrate was concentrated under reduced pressure, the residue being dissolved in 20 ml of ethanol.  This solution was filtered to remove any insoluble product. 

  The filtrate was concentrated under reduced pressure, and 20 ml of ethanol was added thereto, then the insoluble products were removed by filtration.  The filtrate was concentrated to dryness under reduced pressure, and 40 ml of ethanol was added to the residue to remove any ethanol-soluble products remaining in the residue.  The product
 insoluble in ethanol was washed twice with 20 ml of cold water, and recrystallized from methanol to obtain 0.3 g of 1-methyl-5 - [(1-hydroxy-2-isopropylamino) ethyl] hydrochloride] -
 White and amorphous 8-hydroxycarbostyril, having a melting point
 of 202-203.5 C (with decomposition).  The product thus obtained has
 was confirmed by IR and NMR spectra, and by elemental analysis. 

 

  Example 105:
 1 g of 1-methyl-5-isopropylaminoacetyl-8-hydroxycarbostyril hydrochloride was suspended in 100 ml of water, and 0.1 g of
 palladium black and 0.1 g of palladium on carbon were
 added to the slurry, then the mixture was catalytically reduced
 ment with hydrogen at atmospheric pressure and at a
 temperature of 60 C to 70 C for 25 h.  After the end of the
 reduction, the reaction mixture was filtered and the filtrate was concentrated to dryness under reduced pressure. 

  The residue obtained was crystallized from acetone and then recrystallized from ethanol to obtain 0.3 g of 1-methyl-5 - [(1-hydroxy-2-isopropylamino) ethyl] -8-hydroxy -3,4-dihydrocarbostyril having a melting point of 196-197 C (with decomposition).  The product thus obtained was confirmed by IR and NMR spectra and by elemental analysis. 



  Example 106:
 1.0 g of 5-isopropylaminoacetyl-8-methoxycarbostyril was dissolved in 50 ml of methanol and 0.6 g of sodium borohydride was slowly added to the solution while cooling in ice and stirring, then the mixture was mixed. stirred at room temperature for 1 h.  The reaction mixture was adjusted to pH 2-3 with concentrated hydrochloric acid, and the formed precipitate was filtered.  The filtrate was concentrated to dryness and crystallized from acetone.  Recrystallization of the product from ethanol gave 0.8 g of a product having a melting point of 230-231 ° C (with decomposition). 

  The product thus obtained was confirmed by IR and NMR spectra and by elemental analysis as being S- (1 -hydroxy-2-isopropylamino) ethyl-8-methoxycarbostyril hydrochloride monohydrate. 



  Example 107:
 2 g of 5-isopropylaminoacetyl. 8-methoxy-3,4-dihydrocarbostyril was dissolved in 70 ml of methanol, and 1 g of sodium borohydride was slowly added to the solution while cooling with ice-water, then stirring was continued. at room temperature for a further 1 hour.  The reaction mixture was adjusted to pH 1 with concentrated hydrochloric acid, and the formed precipitate was filtered.  The filtrate was concentrated to dryness and the obtained residue was recrystallized from ethanol to obtain 1.5 g of a product having a melting point of 206-208 C (with decomposition).  The product thus obtained was confirmed by IR and NMR spectra and by elemental analysis such as 5- (1-hydroxy-2-isopropylaminoethyl) -8-methoxy-3,4-dihydrocarbostyril hydrochloride. 



  Example 108:
 3 g of 5- (2-isopropylamino-1-hydroxy) ethyl-8-hydroxycarbostyril hydrochloride was dissolved in 20 ml of water, and 0.9 g of sodium hydroxide was added to the solution.  1.3 g of dimethyl sulfate was then added dropwise to the solution while cooling in ice and stirring over a period of 1 h.  The mixture was stirred for 2 h at a temperature of 400 ° C. at SOC, then the reaction mixture was extracted with chloroform. 

  The chloroform extract was washed with water and dried, then hydrochloric acid gas was introduced into the chloroform extract.     The precipitated crystals were recrystallized from a mixture of ethanol and acetone to obtain 2.3 g of a product having a melting point of 235-237 C (with decomposition).  The product thus obtained was confirmed by IR and NMR spectra and by elemental analysis as being 5- (1hydroxy-2-isopropylamino) ethyl-8-methoxycarbostyril hydrochloride monohydrate. 



  Example 109:
 2.6 g of 5- (1-hydroxy-2-isopropylamino) ethyl-8-hydroxy-3,4dihydrocarbostyril was dissolved in 30 ml of water, and 0.45 g of sodium hydroxide was added to the solution.  1.3 g of dimethyl sulfate was then added dropwise to the solution with ice cooling and stirring over a period of 1 h.  The reaction mixture was stirred for 2 h at a temperature of 400 ° C. at SOC, then extracted with chloroform.  The chloroform extract was washed with water and dried, then hydrochloric acid gas was introduced into the chioroform extract. 

  The precipitated crystals were recrystallized from ethanol to obtain 2.2 g of a product having a melting point of 206-208 C (with decomposition).  The product thus obtained was confirmed by IR and NMR spectra and by elemental analysis as being 5- (1-hydroxy-2-isopropylamino) ethyl-8-methoxy-3,4-dihydrocarbostyril hydrochloride. 



  Example 110:
 10 ml of 47% aqueous hydrobromic acid was added to 1 g of 1-methyl-5- (1-hydroxy-2-isopropylamino) ethyl-8-methoxy-3,4-dihydrocarbostyril monohydrate, and the mixture was heated at reflux for 15 h, then concentrated to dryness.  Acetone was added to the resulting residue to crystallize the product, which was then adjusted to pH 8 with dilute aqueous sodium hydroxide solution.  The precipitated crystals were filtered off, washed with water and dissolved in ethanol.  The solution was adjusted to a pH of I with concentrated hydrochloric acid, then concentrated to dryness. 

  The residue thus obtained was recrystallized from a mixture of ethanol and diethyl ether to obtain 0.7 g of a product having a melting point of 198-200 C (with decomposition).  The product thus obtained was confirmed by IR and NMR spectra and by elemental analysis as being 1-methyl-5- (1-hydroxy-2-isopropylamino) -ethyl-8-hydroxy-3,4-dihydrocarbostyril hydrochloride. . 



  Example of a reference:
 The stimulating activity of the compounds according to this invention on the ss-adrenoreceptor was determined as follows:
 Adult male hybrid dogs, weighing 10-15 kg, were anesthetized with 30 mg / kg sodium pentobarbital administered intravenously.  Each of the anesthetized dogs was placed on its hindquarters and a cannula was inserted into the trachea.  Artificial respiration was performed using a device according to the Konzett-Rössler method [H.  Konzett and
R.    Rosser, Versuchsanordnung zu Untersuchungen an der
Bronchial Moskolatur, Arch.  Exp.  Path.  , Pharmack, 195, 7174, 27-40 (1940)]. 

  The volume of air rejection at the time of inhalation was measured by a pneumotachometer to determine bronchial resistance and the values obtained were recorded. 



   In the above experiment, histamine was employed as a bronchoconstrictor at a dosage level of 10 mg / kg of body and an aqueous solution containing each of the test and control compounds shown in Table I was then administered. to each of the dogs anesthetized by the femoral vein at different dosage levels as shown in Table I, 1 min before the administration of histamine.  Sodium pentobarbital was infused during the experiment at a dosage level of 4 mg / kg body using an automatic injector in order to spontaneously inhibit respiration and to keep the anesthetic condition constant for the duration of the test.  The results obtained are presented in Table I. 



   In addition, acute toxicity was determined with respect to the test compounds shown in Table II, using 5 or 6 groups each containing 10 male rats (species dd; weight = 18-22 g) which were fasted. for 10 hours before the test.  Salbutamol and isoproterenol were used as controls.  The LD 50 results (50% of the lethal dose) are shown in Table II.    

 

   The compounds according to the present invention can be administered at a dosage level of 100 to 500 mg / kg / day by oral, intravenous, intramuscular or inhalation administration, according to a conventional pharmaceutical dosage, in the form of tablets, powder, granules, capsules, syrup, solution, suspension, inhalation and the like, preferably in combination with pharmaceutically acceptable carriers, and which are well known.  The administrable form containing at least one of the compounds according to this invention can be administered in single or multiple doses. 



   Tables at the end of the patent

 

Claims (1)

CLAIMS I. A process for the preparation of a carbostyril or 3,4-dihydrocarbostyril derivative represented by the general formula (I) EMI21.1 wherein R1, R4 and R5 each represent an H atom or an alkyl group of 1 to 4 C, at least one of R4 and Rs being an H atom, and R2 and R3, which are the same or different, each represent a H atom, an alkyl group of I to 4 C, an aralkyl group, containing a straight or branched chain alkyl group of I to 4 C, or a cycloalkyl group having from 4 to 6 C, or alternatively R2 and R3, taken together with the N atom to which they are attached, form a substituted or unsubstituted 4 to 6 membered heterocyclic ring containing as heteroatoms 1 or 2 nitrogen atoms, or oxygen or sulfur atoms, characterized in that that it includes the following steps: 1) reaction of a carbostyril or 3,4-dihydrocarbostyril compound of formula (VI) EMI21.2 where R4 and Rs are as defined above, with an x-alkanoic acid halide of the formula EMI21.3 where X and X ', which are the same or different, each represent a halogen atom, in the presence or absence of a solvent and in the presence of a Lewis acid catalyst, 2) reaction of the 5-haloalkanoylcarbostyril derivative or 5-haloalka noyl-3,4-dihydrocarbostyril obtained in step 1) and represented by formula (IV) EMI21.4 where Ri, R4 and Rs are as defined above, and X is a halogen atom, with an amine of formula (III), EMI21.5 where R2 and R3 are as defined above, in the presence or absence of a solvent, 3) reduction of the 5-alkylaminoalkanoylcarbostyril or 5alkylaminoalkanoyl-3,4-dihydrocarbostyril derivative obtained in step 2) and represented by formula (II) EMI21.6 where R1, R2, R3, R4 and Rs are as defined above, in the presence of a catalyst or by means of a reducing agent. II. Carbostyril or 3,4-dihydrocarbostyril derivative of formula (I) obtained by the process according to claim I. SUB-CLAIMS 1. Method according to claim I, characterized in that the α-haloalkanoic acid halide is chloromethyl chloride. 2. Method according to claim I, characterized in that the Lewis acid is aluminum chloride. 3. Method according to claim I, characterized in that the solvent of step 1) is carbon disulfide. 4. Method according to claim I, characterized in that the molar ratio of the x-haloalkanoic acid halide to the compound of carbostyril or 3,4-dihydrocarbostyril is equal to or greater than 1. 5. Method according to sub-claim 4, characterized in that said molar ratio is between 2: 1 and 20: 1. 6. Method according to claim I, characterized in that the reaction of step 1) is carried out at a temperature between room temperature and 150 C. 7. Method according to sub-claim 6, characterized in that said temperature is between room temperature and 80 C. 8. Method according to claim I, characterized in that the solvent of step 2) is chosen from methanol, ethanol, Isopropanol, dioxane, diethyl ether, ethyl acetate, benzene, toluene, xylene or acetonitrile. 9. The method of claim I, characterized in that the molar ratio of the amine or 5-haloalkanoylcarbostyril or 5-haloalkanoyl-3,4-dihydrocarbostyril derivative is equal to or greater than 1. 10. Method according to sub-claim 9, characterized in that said molar ratio is between 2: 1 and 10: 1. 11. The method of claim I, characterized in that the reaction of step 2) is carried out at a temperature between room temperature and the reflux temperature of the reaction medium. 12. The method of sub-claim 11, characterized in that the reaction of step 2) is carried out at a temperature of 40 "to 100" C. 13. The method of claim I, characterized in that the reaction of step 2) is carried out at a pressure between 1 and 10 atmospheres. 14. The method of claim I, characterized in that the catalyst used for the reduction 3) of Pd black, Pd on carbon, Raney nickel or Pd oxide, in an amount between 0.05 and 1 mole per mole of the 5alkylaminoalkanoylcarbostyril or 5-alkylaminoalkanoyl-3,4dihydrocarbostyril derivative, at a temperature between room temperature and 150 C, and under an atmosphere of hydrogen at a pressure between atmospheric pressure and 100 atmospheres. 15. The method of claim I, characterized in that as reducing agent for the reduction 3) lithium aluminum hydride or sodium borohydride, in an amount between 2 and 10 moles per mole of the derivative. 5-alkylaminoalkanoylcarbostyril or S-alkylaminoalkanoyl-3,4-dihydrocarbostyril, at a temperature of 0 to 100 ° C and at atmospheric pressure. 16. The method of claim I, characterized in that the reduction 3) is carried out in water, methanol, ethanol or isopropanol. 17. The method of claim I for the preparation of 5- (1 -hydroxy-2-isopropylamino) ethyl-8-hydroxycarbostyril and -3, 4-dihydrocarbostyril. 18. The method of claim I for the preparation of 5- (1 -hydroxy-2-sec-butylamino) ethyl-8-hydroxycarbostyril and -3,4-dihydrocarbostyril. 19. The method of claim I for the preparation of S- (1 -hydroxy-2-tert-butylamino) ethyl-8-hydroxycarbostyril and -3,4-dihydrocarbostyril. 20. The process of claim I for the preparation of 5- [1-hydroxy-2- (α-methylbenzylamino)] ethyl-8-hydroxy. carbostyril and -3,4-dihydrocarbostyril. 21. The process of claim I for the preparation of 5- [1 -hydroxy-2- (a, a-dimethylphenethylamino)] ethyl-8-hydroxy-carbostyril and -3,4-dihydrocarbostyril. 22. The method of claim I for the preparation of 5- (1 -hydroxy-2-piperidino) ethyl-8-hydroxycarbostyril and -3,4-dihydrocarbostyril. 23. The method of claim I for the preparation of 5- (1 -hydroxy-2-morpholino) ethyl-8-hydroxycarbostyril and -3,4-dihydrocarbostyril. 24. The process of claim I for the preparation of 5- (1 -hydroxy-2-benzylamino) ethyl-8-hydrocarbostyril and -3, 4-dihydrocarbostyril. 25. The method of claim I for the preparation of 5- [1 -hydroxy-2- (1-phenethylamino)] ethyl-8-hydroxycarbostyril and -3,4-dihydrocarbostyril. 26. The method of claim I for the preparation of 5- (1 -hydroxy-2-amino) ethyl-8-hydroxycarbostyril and -3, 4-dihydrocarbostyril. 27. The method of claim I for the preparation of 1 -methyl-5- (1 -hydroxy-2-isopropylamino) ethyl-8-hydroxy-carbostyril and -3,4-dihydrocarbostyril. 28. The method of claim I for the preparation of 5- (1-hydroxy-2-isopropylamino) ethyl-8-methoxyvarbostyril and -3,4-dihydrocarbostyril. 29. The method of claim I for the preparation of 5- (1 -hydroxy-2-isopropylamino) propyl-8-hydroxycarbostyril and -3, 4-dihydrocarbostyril. 30. The method of claim I for the preparation of 5- (1 -hydroxy-2-isopropylamino) propyl-8-methoxycarbostyril and -3,4-dihydrocarbostyril. 31. The method of claim I for the preparation of 5- (1 -hydroxy-2-sec-butylamino) propyl-8-hydroxycarbostyril and -3, 4-dihydrocarbostyril. 32. The method of claim I for the preparation of S- (1 -hydroxy-2-tert-butylamino) propyl-8-hydroxycarbostyril and -3,4-dihydrocarbostyril. 33. Process according to claim I for the preparation of 5- (1-hydroxy-2-isopropylamino) butyl-8-hydroxycarbostyril and -3,4-dihydrocarbostyril. 34. The method of claim I for the preparation of 5- (1 -hydroxy-2-sec-butylamino) butyl-8-hydroxycarbostyril and -3,4-dihydrocarbostyril. 35. A process according to claim I for the preparation of 5- [1 -hydroxy-2- (2-phenethylamino)] butyl-8-hydroxycarbostyril and -3,4-dihydrocarbostyril. 36. The method of claim I for the preparation of S- (1 -hydroxy.24ert-butylamino) butyl-8-hydroxycarbostyril and -3,4-dihydrocarbostyril. 37. The method of claim I for the preparation of 5- (1 -hydroxy-2-ethylamino) butyl-8-hydroxycarbostyril and -3,4-dihydrocarbostyril. 38. The method of claim I for the preparation of 5- (1 -hydroxy-2-morpholino) butyl-8-hydroxycarbostyril and -3,4-dihydrocarbostyril. Table I Bronchial resistance (%) Dosage level (llg / kg) Compound 0.01 0.03 0.1 0.3 1.0 3.0 10 30 100 5- (1-Hydroxy-2-isopropylamino) ethyl-8- hydrochloride 5.5 27.7 66.6 83.3 100 - - hydroxycarbostyril 5- (1-Hydroxy-2-tertbutylamino) ethyl-8- hydrochloride 7.3 35.5 78.6 90.4 100 - - - hydroxycarbostyril 5- [1-Hydroxy-2 - (&alpha;, &alpha; hydrochloride) ; -dimethylphenethyl- 3.3 20.0 47.5 87.8 100 - ¯¯ - - amino)] ethyl-8-hydroxycarbostyril 5- (1-Hydroxy-2-isopropyl) ethyl-8- hydrochloride 0 21.4 50.0 85.0 100 ¯¯ - - - hydroxy-3,4-dihydrocarbostyril 5- (1-Hydroxy-2-tertbutylamino) ethyl-8- hydrochloride 4.3 38.7 85.5 100 100 - - - - hydroxy-3,4-dihydrocarbostyril 5- [1-Hydroxy-2 - (&alpha;, &alpha; hydrochloride) ; -dimethylphenethyl- 0 4.7 14.2 45.2 76.4 100 - - amino)] ethyl-8-hydroxy-3,4-dihydrocarbostyril 5 - [(1-Hydroxy-2-isopropylamino) hydrochloride - 0 11.1 30.5 63.3 87.3 100 - - butyl] -8-hydroxycarbostyril 5 - [(1-Hydroxy-2-isopropylamino) hydrochloride - 0 5.5 28.3 65.8 89.4 100 - - propyl] -8-hydroxycarbostyril 5-Ul-hydroxy-2-isopropylamino hydrochloride) - 0 13.5 33.7 73.2 92.3 100 butyl] -8-hydroxy-3,4-dihydrocarbostyril 5 - [(1-Hydroxy-2-tertbutylamino) hydrobromide - 0 5.7 21.4 65.0 81.8 100 - - propyl] -8-hydroxy-3,4-dihydrocarbostyril 1-Methyl-5 - [(1-hydroxy-2-isopropyl- hydrochloride 0 0 0 5.2 16.8 36.5 - - amino) ethyl] -8-hydroxycarbostyril <RTI hydrochloride ID = 23.16> 5 - [(1-hydroxy-2-isopropylamino) - 0 0 0 0 8.2 17.9 - - - ethyl] -8-methoxycarbostyril monohydrate (Control) Isoproterenol 0 16.6 58.3 83.3 100 - - - Saibutamol O 0 16.6 33.3 66.6 100 - - Metaproterenolsulfate (Arotec) O 0 2.7 11.1 27.5 50.0 88.3 100 Quinterenol O 0 0 0 0 0 0 7.6 15.3 Table Il LD50 (mg / kg) Compound i.v. p.o. 5- (1-Hydroxy-2-isopropylamino) ethyl-8-hydroxycarbostyril hydrochloride 90 970 (70-115) (441-2134) 5- [1-Hydroxy-2 - (&alpha;, &alpha; -dimethylphenethylamino) ethyl] -8-hydroxycarbo- hydrochloride 102 2900 styril (84.6-112.8) (2180-3560) 5 - [(1-hydroxy-2- &alpha;, &alpha; hydrochloride) ; -dimethylphenethylamino) ethyl] -8-hydroxy-3,4- 126 1450 dihydrocarbostyril (105.2-105.9) (1179-1784) S. [(1-hydroxy.2.isopropylamino) butyl] .8.hydroxycarbostyril hydrochloride 80 2600 (64-100) (2207-3063) 5 - [(1-Hydroxy-2-isopropylamino) butyl] -8-hydroxy-3,4-dihydrocarbo- hydrochloride 81.5 830 styril (72.4-91.8) (542-1270) 1-Methyl-5 - [(1-hydroxy-2-isopropylamino) ethyl] -8-hydroxycarbostyril hydrochloride 46.5 750 (40.1-51.8) (523-1147) 5- (1-Hydroxy-2-isopropylamino) ethyl-8-methoxycarbostyril hydrochloride 86.3 830 (65.3-103.7) (473-1371) LD50 (mg / kg) (Control) i.v. p.o. Salbutamol 57.1 4620 * (52.7-61.9) (4160-5130) * 660 (412.5-1056) isoproterenol 112.5 2587 * (87.9-144.0) 355 (235.1-536.1) Note: * Literature values.