USRE30577E - Ether of n-propanol amine - Google Patents

Ether of n-propanol amine Download PDF

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Publication number
USRE30577E
USRE30577E US06/015,752 US1575279A USRE30577E US RE30577 E USRE30577 E US RE30577E US 1575279 A US1575279 A US 1575279A US RE30577 E USRE30577 E US RE30577E
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iaddend
iadd
ether
phenyl
compound
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US06/015,752
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Norbert Busch
Jacques Simond
Andre Monteil
Jacques Moleyre
Roland Y. Mauvernay
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Centre Europeen de Recherches Mauvernay CERM
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain

Definitions

  • a stimulating electrode was placed in position on the right stellar ganglion of dogs anaesthetised as described above and for which there were recorded:

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pyrrole Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

.[.Ethers.]. .Iadd.An ether .Iaddend.of n-propanolamine, preparation thereof and .[.their.]. .Iadd.its .Iaddend.use in treatment of cardiovascular conditions.

Description

This invention relates to .[.ethers.]. .Iadd.an ether .Iaddend.of n-propanolamine, to the preparation thereof and to the use thereof.
The present invention provides an ether of an n-propanolamine having the .[.general.]. formula: ##STR1## .[.in which A is a tertiary aliphatic, cycloaliphatic or heterocyclic amino group, R is a straight or branched chain lower alkyl group or an aralkyl group, Ar is an aromatic group and Ar1 is an aromatic or heterocyclic group,.]. and addition salts thereof with pharmacologically acceptable acids.
.[.When Ar and Ar1 are both aromatic groups they may be like or unlike. Ar and Ar1 may both be monocyclic aromatic groups and Ar1 may be a heteromonocyclic group which may contain a nuclear nitrogen atom with or without an additional nuclear hetero atom..].
The .[.compounds.]. .Iadd.compound .Iaddend.of the present invention .[.are.]. .Iadd.is .Iaddend.useful as .[.medicaments.]. .Iadd.a medicament .Iaddend.especially in the treatment of cardiovascular conditions.
In earlier patent applications we have described compounds having the general formula: ##STR2## in which A .Iadd.is substantially a tertiary aliphatic, cycloaliphatic or heterocyclo amino group .Iaddend.and R .[.have substantially the same meanings as in formula I above,.]. .Iadd.is substantially a straight or branched chain lower alkyl group, .Iaddend.and X respectively represents the following groupings in the various cases: ##STR3## .Iadd.wherein Ar is an aromatic group and Ar1 is an aromatic or heterocyclic group. .Iaddend.
Moreover, compounds having the following general formula are already known for their properties as antihistamines: ##STR4## in which A has the same meaning as .[.in the general formulae I and II.]. .Iadd.indicated .Iaddend.above, whilst Ar and Ar1 are aromatic groups. (Ehrhart/Ruschig Arzneimittel I, pages 208-210).
The .[.compounds.]. .Iadd.compound .Iaddend.according to the present invention having the .[.general.]. formula I, .[.are.]. .Iadd.is .Iaddend.manifestly different from any of these groups of compounds.
The .[.compounds.]. .Iadd.compound .Iaddend.of the present invention may be prepared from .Iadd.an .Iaddend.amino .[.alcohols.]. .Iadd.alcohol .Iaddend.having the .[.general.]. formula: ##STR5## .[.in which A and R are as defined above in connection with formula I..].
In the first step of such preparation, the amino .[.alcohols.]. .Iadd.alcohol .Iaddend.(IV), which .[.are.]. .Iadd.is a .Iaddend.known .[.materials.]. .Iadd.material.Iaddend., and .[.are.]. .Iadd.is .Iaddend.described inter alia in Belgium Pat. No. 718 425, .[.are.]. .Iadd.is .Iaddend.treated with thionyl chloride dissolved in a suitable solvent such as chloroform in order to obtain the corresponding chloro .[.compounds.]. .Iadd.compound .Iaddend.having the .[.general.]. formula: ##STR6## The latter .[.compounds are.]. .Iadd.compound is .Iaddend.then condensed with .[.amines.]. .Iadd.an amine .Iaddend.having the .[.general.]. formula ##STR7## which .[.have.]. .Iadd.has .Iaddend.previously been converted to .[.their.]. .Iadd.its .Iaddend.sodium .[.derivatives.]. .Iadd.derivative .Iaddend.by reaction with sodium amide, to obtain the .[.compounds.]. .Iadd.compound .Iaddend.of the present invention.
The invention also includes the addition salts of the .[.compounds.]. .Iadd.compound .Iaddend.having the .[.general.]. formula I with pharmaceutically acceptable organic and inorganic acids such as hydrochloric acid and fumaric acid.
.[.As an.]. .Iadd.An .Iaddend.example of the process of the invention .[.there.]. will now be described .Iadd.for .Iaddend.the synthesis of .[.1-(3-isobutoxy-2-(phenylbenzyl)-amino)-propyl-pyrrolidino-hydrochloride (Compound No. 1)..]. .Iadd.1-iso-butoxy-2-pyrrolidino-3-N-benzylanilino propane hydrochloride (Compound 1). .Iaddend. ##STR8## First step
Preparation of 1-(3-isobutoxy-2-chloro)propyl pyrrolidine ##STR9## 345 ml of thionyl chloride dissolved in 345 ml of chloroform are added, drop by drop, to 275 g of 1(3-isobutoxy-2-hydroxy)-propyl-pyrrolidine dissolved in 350 ml of chloroform, while maintaining the temperature at approximately 45° C. The reaction mixture is heated to reflux until gas is no longer evolved. The chloroform and the excess of thionyl chloride are removed under reduced pressure. The residue is poured on to 400 g of crushed ice. The reaction mixture is rendered alkaline with soda and the resulting mixture is extracted twice with 250 ml of diethyl ether. The combined ethereal extracts are dried over anhydrous sodium sulphate. After evaporation of the solvent the residue is distilled under reduced pressure: 220 g of product are obtained having the following properties:
Boiling point=96° C./3 mm, nD 24° C. =1,4575,
Second step
Main product
23.4 g of sodium amide is added little by little to a solution of 92 g of N-benzylaniline in 500 ml of anhydrous xylene. The reaction mixture is then heated at 130° to 135° C. for 6 hours.
Whilst maintaining the temperature at 110° C., 110 g of the product of the first step dissolved in 150 ml of xylene is added and the product heated for 6 hours at 120° C.
The product having been allowed to cool to ambient temperature, 200 ml of cold water are added. The organic phase is separated and extracted with an aqueous solution of hydrochloric acid.
After twice washing with 100 ml of diethyl ether, the aqueous phase is made alkaline with 50% caustic soda solution. The liberated base is twice extracted with 150 ml of diethyl ether. After the ether has been evaporated, the residue is distilled under reduced pressure and has Bpt=184° C./0.1 mm, nD 20 =1.5538.
77 g of the pure base in the form of a viscous liquid is thus obtained.
The hydrochloride, which is prepared in conventional manner, has a melting point of 128° C.
______________________________________                                    
Analysis  C%         H%         N%                                        
______________________________________                                    
Calculated:                                                               
          71.52      8.75       6.95                                      
Found:    71.20      9.01       6.93                                      
______________________________________
.[.Table I which follows sets out a series of products according to the present invention which were obtained using the foregoing method but substituting the appropriate intermediates containing the desired groups R and A and Ar and Ar1 respectively..].
.[.TABLE I                                                                
__________________________________________________________________________
COM-                              Melting                                 
                                       ANALYSIS                           
POUND                             Points of                               
                                       C%      H%      N%                 
No.  Ar    Ar.sup.1                                                       
                 R        A       Salts °C.                        
                                       Theory                             
                                           Found                          
                                               Theory                     
                                                   Found                  
                                                       Theory             
                                                           Found          
__________________________________________________________________________
      ##STR10##                                                           
            ##STR11##                                                     
                  ##STR12##                                               
                           ##STR13##                                      
                                  Hydro- chloride 128°             
                                       71.52                              
                                           71.20                          
                                               8.75                       
                                                   9.01                   
                                                       6.95               
                                                           6.93           
2                                                                         
      ##STR14##                                                           
            ##STR15##                                                     
                  ##STR16##                                               
                           ##STR17##                                      
                                  Fumarate 150°                    
                                       67.08                              
                                           66.90                          
                                               7.66                       
                                                   7.20                   
                                                       8.69               
                                                           8.75           
3                                                                         
      ##STR18##                                                           
            ##STR19##                                                     
                  ##STR20##                                               
                           ##STR21##                                      
                                  Fumarate 98°                     
                                       69.39                              
                                           69.46                          
                                               8.31                       
                                                   8.34                   
                                                       5.77               
                                                           5.72           
4                                                                         
      ##STR22##                                                           
            ##STR23##                                                     
                 CH.sub.3                                                 
                           ##STR24##                                      
                                  Fumarate 155°                    
                                       68.16                              
                                           68.42                          
                                               7.32                       
                                                   7.30                   
                                                       6.35               
                                                           6.31           
5                                                                         
      ##STR25##                                                           
            ##STR26##                                                     
                  ##STR27##                                               
                           ##STR28##                                      
                                  Fumarate 195°                    
                                       67.44                              
                                           67.90                          
                                               7.68                       
                                                   7.76                   
                                                       5.61               
                                                           5.64           
6                                                                         
      ##STR29##                                                           
            ##STR30##                                                     
                  ##STR31##                                               
                           ##STR32##                                      
                                  Hydro- chloride 133°             
                                       74.55                              
                                           74.05                          
                                               7.82                       
                                                   7.40                   
                                                       6.21               
                                                           6.14 .].       
__________________________________________________________________________
The pharmacological activity of the .[.compounds.]. .Iadd.compound .Iaddend.of the invention in the cardiovascular field was determined on the dog in the manner described below:
An incision is made in the right-hand chest wall of an animal, which has been anaesthetised with chloralose and given artificial respiration, to enable the blood from the venus sinus to be drawn off and the apparatus required to record the following parameters to be inserted in position:
a. Output of the coronary sinus;
b. Pv O2 of the blood from the coronary sinus; and
c. Amplitude of the contractions of the right ventricule.
At the same .Iadd.time .Iaddend.there were also measured:
d. Arterial pressure in a main carotid artery; and
e. The rate of heart-beat determined cardiotachometrically.
Table II which follows records the determinations made of the various parameters, the results being expressed as a maximum percentage variation relative to the pre-treatment values.
                                  TABLE II                                
__________________________________________________________________________
     DOSE                                                                 
COM- mg/kg                                                                
         NUMBER        RATE OF       ARTERIAL                             
                                            AMPLITUDE OF                  
POUND                                                                     
     (intra-                                                              
         OF    CORONARY                                                   
                       HEART-BEAT                                         
                               P.sub.V O.sub.2                            
                                     PRESSURE                             
                                            VENTRICULAR                   
No.  venous)                                                              
         ANIMALS                                                          
               OUTPUT %                                                   
                       %       %     %      CONTRACTION                   
__________________________________________________________________________
                                            %                             
 1   2.5 7     +51.2   -28.6   +119.2                                     
                                     -39.8  -0.7                          
     5   7     +36.9   -31.8   +120.8                                     
                                     -40.2  -22.3                         
.[.2 5   3     +55     -28     +71   -43    -25.5.].                      
.[.3 5   4     +117.8  -19.2   +158  -30.5  -3.].                         
.[.4 5   4     +110.5  -14.5   -56   -26    +17.5.].                      
.[.5 5   3     +24     -3.5    +11.6 -15    +1.5.].                       
__________________________________________________________________________
These results show that, taken as a whole, the .[.products.]. .Iadd.product .Iaddend.under examination .[.have.]. .Iadd.has .Iaddend.the ability to increase the output of cornary blood, to reduce the rate of heart beat and especially.[., with the exception of compound No. 4,.]. to increase the oxygen content of the venous cardiac blood. The latter action is demonstrated by an excess in the supply of oxygen relative to the requirements of the myocardium. The arterial pressure is also lowered for a short time. .[.In most cases there.]. .Iadd.There .Iaddend.is little alteration in the ventricular inotropism.
Particular note should be taken.[., in the case of compound No. 1,.]. of the very considerable increase in the oxygen content of the venous cardiac blood in relation to the increase in coronary output, which may be simply attributed to the improved circulation of the blood. The extremely slow rate of heart-beat brought about by the products certainly plays an important role in this respect.
It then seemed interesting.[., using compound No. 1,.]. to seek the existence of an action on the β-adrenergic receptors in the manner outlined below:
A stimulating electrode was placed in position on the right stellar ganglion of dogs anaesthetised as described above and for which there were recorded:
a. The arterial pressure,
b. Ventricular inotropism (the amplitude of contraction of the right ventricle), and
c. The rate of heart-beat.
The chest of the animals were not open and they were breathing freely.
The β-adrenergic receptors, both cardiac and vascular, were stimulated by electrical stimulation of the right stellar ganglion or by intravenous injection with isoprenaline (5 μg/kg). The measurements were taken both before and after administration of compound No. 1 by the intravenous route in a dose of 5 mg/kg bodyweight.
The following Table III gives the average percentage inhibition of the cardiovascular effects of isoprenaline and of the cardiac effects of the stimulation of the right stellar ganglion.
              TABLE III                                                   
______________________________________                                    
           Number                   Positive                              
           of     Hypo-   Rate of   inotropic                             
           Animals                                                        
                  tension Heart-beat                                      
                                    effect                                
______________________________________                                    
ISOPRENALINE 4        -54%    -32.7%  -46.5%                              
.[.(5 ug/kg.]..Iadd.(5 μg/kg.Iaddend.                                  
intravenous)                                                              
STIMULATION OF                                                            
THE RIGHT                                                                 
STELLAR                                                                   
GANGLION     3                -30%    -21.3%                              
______________________________________
These results show that a partial inhibiting effect is achieved as regards the β-adrenergic receptors at the cardiovascular level of treatment.
In conclusion, it is apparent that the .[.members of the series of compounds possess.]. .Iadd.compound possesses .Iaddend.a distinct cardio-vascular activity which is manifested by an improvement in circulation by the enhanced oxygenation of the myocardium in consequence of a slow rate of heart-beat.
In addition to the general properties .[.of the compounds of the present invention,.]. compound No. 1 is also of interest in that it also possesses inhibiting effects with respect to the stimulation of the β-adrenergic receptors.
The pharmacological activities of .[.the compounds having the general formula.]. .Iadd.compound .Iaddend.I thus .[.enable their.]. .Iadd.enables its .Iaddend.application in human therapy to be anticipated, as .[.medicaments.]. .Iadd.a medicament .Iaddend.intended for treating particularly:
Myocardiac anoxaemia,
Coronary deficiencies, angina pectoris,
Infarction of the myocardium, and
Cardiac deficiencies associated with coronary circulatory trouble.
When admixed with the usual excipients, .[.they.]. .Iadd.it .Iaddend.may be administered orally or rectally, in daily doses of between 100 and 800 mg.

Claims (2)

    What we claim is: .[.1. An ether of n-propanolamine having the formula.]. ##STR33## .[.wherein A is morpholino, pyrrolidino, piperidyl, and di-lower-alkyl amino, R is a straight or branched chain lower alkyl, or benzyl, Ar is aryl and Ar1 is aryl or pyridyl, and pharmacologically acceptable
  1. salts thereof..]. .[.2. The ether of claim 1 in which A is pyrrolidino, R is isobutyl and Ar and Ar1 are both phenyl, and the hydrochloride thereof..]. .[.3. The ether of claim 1 in which A is pyrrolidino, R is isobutyl, Ar is phenyl and Ar1 is 2-pyridyl, and the acid fumarate thereof..]. .[.4. The ether of claim 1 in which A is diethylamino, R is an isobutyl and Ar and Ar1 are both phenyl, and the acid fumarate thereof..]. .[.5. The ether of claim 1 in which A is morpholino, R is isobutyl and Ar and Ar1 are both phenyl and the acid fumarate thereof..]. .[.6. The ether of claim 1 in which A is piperidyl, R is benzyl and Ar and Ar1 are both phenyl and the hydrochloride thereof..]..Iadd. 7. An ether having the formula .Iaddend. ##STR34## .Iadd.and pharmaceutically acceptable acid addition salts thereof.
  2. .Iaddend. .Iadd. 8. An ether according to claim 7 wherein the acid addition salt is the hydrochloride or the acid fumarate. .Iaddend.
US06/015,752 1972-03-06 1979-02-27 Ether of n-propanol amine Expired - Lifetime USRE30577E (en)

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EP0146155A1 (en) * 1983-11-11 1985-06-26 Akzo N.V. Ether of N-propanolamine derivative
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US4645778A (en) 1983-09-27 1987-02-24 Riom Laboratoires C.E.R.M. "Rl-Cerm"S.A. 2-(N-pyrrolidino)-3-isobutoxy-n-substituted-phenyl-n-benzyl-propylamines, their preparation and pharmaceutical use
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US4888335A (en) 1988-07-25 1989-12-19 Mcneilab, Inc. 3-alkoxy-2-aminopropyl heterocyclic amines and their use as cardiovascular agents
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WO2009032286A2 (en) 2007-09-06 2009-03-12 Nektar Therapeutics Al, Corporation Oligomer-calcium channel blocker conjugates
WO2014170786A1 (en) 2013-04-17 2014-10-23 Pfizer Inc. N-piperidin-3-ylbenzamide derivatives for treating cardiovascular diseases

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US4645778A (en) 1983-09-27 1987-02-24 Riom Laboratoires C.E.R.M. "Rl-Cerm"S.A. 2-(N-pyrrolidino)-3-isobutoxy-n-substituted-phenyl-n-benzyl-propylamines, their preparation and pharmaceutical use
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US4727072A (en) 1986-02-12 1988-02-23 Mcneilab, Inc. 3-alkoxy-2-aminopropylamines compositions and use as cardiovascular agents
US4758563A (en) 1986-02-12 1988-07-19 Mcneilab, Inc. 3-alkoxy-2-aminopropyamines, cardiovascular compositions and use
US4927834A (en) 1987-08-11 1990-05-22 Boehringer Mannhein Gmbh 1,2-diamino compounds, processes for their preparation and pharmaceutical compositions containing them
US4888335A (en) 1988-07-25 1989-12-19 Mcneilab, Inc. 3-alkoxy-2-aminopropyl heterocyclic amines and their use as cardiovascular agents
US5185362A (en) * 1988-09-14 1993-02-09 Mcneilab, Inc. Diphenylamine cardiovascular agents, compositions and use
US20060111422A1 (en) * 2004-11-23 2006-05-25 Warner-Lambert Company Llc Novel pyrazole-based HMG CoA reductase inhibitors
US7446121B2 (en) 2004-11-23 2008-11-04 Pfizer Inc. Pyrazole-based HMG CoA reductase inhibitors
WO2007062314A2 (en) 2005-11-23 2007-05-31 Bristol-Myers Squibb Company Heterocyclic cetp inhibitors
WO2008070496A2 (en) 2006-12-01 2008-06-12 Bristol-Myers Squibb Company N- ( (3-benzyl) -2, 2- (bis-phenyl) -propan-1-amine derivatives as cetp inhibitors for the treatment of atherosclerosis and cardiovascular diseases
WO2009032286A2 (en) 2007-09-06 2009-03-12 Nektar Therapeutics Al, Corporation Oligomer-calcium channel blocker conjugates
US20110098273A1 (en) * 2007-09-06 2011-04-28 Nektar Therapeutics Oligomer-Calcium Channel Blocker Conjugates
US8748648B2 (en) 2007-09-06 2014-06-10 Nektar Therapeutics Oligomer-calcium channel blocker conjugates
US9132200B2 (en) 2007-09-06 2015-09-15 Nektar Therapeutics Oligomer-calcium channel blocker conjugates
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FR2174655A1 (en) 1973-10-19
DE2310918C3 (en) 1980-07-03
NL153190B (en) 1977-05-16
JPS4899127A (en) 1973-12-15
CA1015360A (en) 1977-08-09
ES412203A1 (en) 1975-12-01
FR2174655B1 (en) 1975-08-01
GB1377327A (en) 1974-12-11
DE2310918A1 (en) 1973-09-20
NL153190C (en) 1980-12-15
US3962238A (en) 1976-06-08
BE795735A (en) 1973-06-18
CH556815A (en) 1974-12-13
NL7303117A (en) 1973-09-10
ZA731411B (en) 1974-04-24
CA1048027A (en) 1979-02-06
DE2310918B2 (en) 1979-10-25
IL41619A0 (en) 1973-04-30
IL41619A (en) 1976-05-31

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