CH634050A5 - 3-Aminopropoxyindoles - Google Patents

Abstract

The compounds of formula I, <IMAGE> in which the substituents have the meaning given in patent claim 1, are novel. They exhibit alpha - and beta -adrenoceptor-blocking and antihypertensive effects and can therefore be used as drugs. They are obtained by reacting compounds of the formula II, <IMAGE> in which Rx represents a radical which yields a 2-amino-1-hydroxyethyl group on reaction with an amine, with compounds of the formula III, <IMAGE>

Description

       

  
 

** WARNING ** beginning of DESC field could overlap end of CLMS **.

 



   PATENT CLAIMS 1. Compounds of formula I,
EMI1.1
 wherein
A denotes alkylene with 2 to 5 carbon atoms,
X represents oxygen or sulfur,
R3 denotes hydrogen, hydroxy, alkoxy having 1 to 4 carbon atoms, halogen with an atomic number of 9 to 35, cyano, carbamoyl or acetamido, and
R4 is hydrogen and, if R3 is alkoxy with 1 to 4 carbon atoms, also for alkoxy with 1 to 4 carbon atoms or, if R3 is halogen with an atomic number of 9 to 35, also for halogen with an atomic number of 9 to 35 can be either R1 methyl and R2 halogen with an atomic number of 17 or 35 or Rt halogen with an atomic number of 17 or 35 and R2 is hydrogen or methyl, with the proviso

   that
X is removed from the nitrogen atom of the 3-amino-2-hydroxypropoxy chain by at least 2 carbon atoms, in free form or in salt form.



   2. 1- (3-chloro-2-methylindol-4-yloxy) -3- (2-phenoxyethylamino) -2-propanol as a compound according to claim 1, in free form or in salt form.



   3. Remedies, characterized in that they contain compounds of the formula I in free form or in the form of their physiologically tolerable salts.



   The invention relates to the object defined in claims 1 to 3.



   Structurally similar connections are e.g. known from ICI DOS 1493 853, ICI DOS 15 93 901 or Cigy DOS 25 20 910
R2 is preferably hydrogen or methyl. R3 preferably represents hydrogen, hydroxy, alkoxy, cyano or carbamoyl. X preferably represents oxygen.



   Alkoxy preferably contains 1 or 2, in particular 1 carbon atom (s). Halogen in particular means chlorine.



   A is preferably branched, especially branched alkylene in the z-position to the nitrogen atom of the side chain, e.g. 2-butylene, 2-methyl-2-butylene or 2-methyl-2-propylene, or for ethylene.



   The compounds of the formula I are obtained by using compounds of the formula II
EMI1.2
 wherein R1 and R2 have the meaning given in claim 1 and Rx is a radical which, when reacted with an amine, gives a 2-amino-l-hydroxyethyl group with compounds of the formula III,
EMI1.3
 wherein A, X, R3 and R4 have the meaning given in claim 1.



   If the phenyl ring of the side chain is mono- or disubstituted, the substituents are preferably in 4 or



  3,4 position.



   The compounds of formula I can be in free form or in salt form. Salts can be obtained in a known manner from the compounds of formula I in free form and vice versa. Thus the compounds of formula I according to the invention, e.g. with inorganic acids such as hydrochloric or hydrobromic acid, or with organic acids such as fumaric or maleic acid, acid addition salts.



   The reaction is an amination by a primary amine. It can be carried out using conditions known for the preparation of known 3-amino-2-hydroxy-propoxyarvl compounds. For example, the group Rx is used as the group
EMI1.4
 or a reactive derivative of this group, for example a group of the formula
EMI1.5
 where Y is halogen, preferably chlorine or bromine, or a group RySO2, where Ry is phenyl, tolyl or lower alkyl. Y stands in particular for chlorine.



   The compounds of the formula I can be isolated and purified from the reaction mixture by known methods.



   In the compounds of the formula the carbon atom of the side chain which carries the hydroxyl group is asymmetrical; they can therefore occur in the form of the corresponding enantiomers. The enantiomers of the compounds of formula I can be obtained in a manner known per se, e.g. by executing the implementation based on corresponding, optically active starting products.



   Insofar as the production of the required starting materials is not described, they are known or can be produced by known processes or analogously to processes known per se.



   In the following example, all temperatures are in degrees Celsius and are uncorrected.



   example
1- (3-chloro-2-methylindol-4-yloxy) -3- (2-phenoxyethylamino) -2-propanol
5 g of 3-chloro-4 (2,3-epoxypropoxy) -2-methylindole, 4.3 g of 2-phenoxyethylamine and 75 ml of dioxane are heated to 1300 in an autoclave for 15 hours. After cooling, the dioxane is turned on in a water jet vacuum and the excess



  2-phenoxyethylamine distilled off at 80 "in a high vacuum.



  The residue is shaken out between tartaric acid solution and methylene chloride, the acid phase is made up with conc. Ammonia alkaline and extracted with methylene chloride. After evaporation of the solvent, the residue crystallizes with 0.5 mol of malonic acid from methanol (mp. Of the hydrogen malonate 135-137; mp. Of the bis [base] fumarate 1871900).



   The compounds according to the invention, i.e. the compounds of the formula I in free form or in the form of their physiologically tolerable salts are distinguished by interesting pharmacodynamic properties. They can be used as a remedy.



   They show on isolated spiral strips of the femoral vein and coronary artery from dogs to noradrenaline or



  Isoprenaline additive (E. Müller-Schweinitzer and E. Stürmer, Br. J. Pharmac. 119741 51, 441-446; TJ Bücher et aL, Naunyn-Schmiedberg's Arch Pharmacol. 280 [1973] 153-160) a blockade of a -respectively. , 3-adrenoceptors, this antagonistic effect occurring at bath concentrations of approximately 19 to 106 M. In the spontaneously striking, isolated guinea pig atrium (K. Saameli, Helv. Physiol. Acta 25 [1967] CR 219-CR 221) they show an inhibition of the positive inotropic adrenaline effect, this antagonistic effect at bath concentrations of approx. 0.005 to 2.5 mg / l occurs.



   They can therefore be used as a and B receptor blockers, among others. for the prophylaxis and therapy of disease states which are associated with a vasoconstriction and energetic coronary diseases, in particular for the treatment of angina pectoris. They are also suitable for the treatment of conditions associated with paralysis of the intestinal motility, e.g. from the paralytic ileus. Due to their antiarrhythmic effects, they can also be used to treat cardiac arrhythmias.



   For the above applications, the doses to be used naturally vary depending on the type of substance used, the administration and the condition to be treated. In general, however, satisfactory results are achieved with a daily dose of approximately 1 to 100 mg. If necessary, this dose can be administered in 2 to 4 portions or as a slow-release form. For oral applications, the partial doses contain about 0.25 to 50 mg of the new compounds in addition to solid or liquid carriers.



   They also have antihypertensive properties, as can be seen in animal experiments on the hypertonic Grollman rat [method according to A. Grollman, Proc. Soc. Exptl. Biol. And Med.



  57, (1944) 102] at doses of approximately 0.1 to 10 mg / kg s.c.



  and about 10 to 100 mg / kg p.o. and on the normotonic anesthetized rat [D. Chu, A. Hofmann and E. Stürmer, Naunyn-Schmiedberg's Arch. Pharmacol, (1975), Suppl. 287, R 18] at doses of approximately 0.01 to 5 mg / kg iv shows.



   Due to their hypotensive effects, they can be used as antihypertensives e.g. find application in high pressure therapy. The doses to be used naturally vary depending on the type of substance, the administration and the condition to be treated. In general, however, satisfactory results are obtained with a daily dose of approximately 0.1 to 100 mg; if necessary, this dose can be administered in 2 to 4 portions or as a slow-release form. For example, for oral applications, the partial doses of about 0.025 to 50 mg of the compounds of the formula I in addition to solid or liquid carriers.

 

   Of the compounds of formula I in optically active form, those compounds in which the carbon atom in the 2-position of the side chain has the (S) configuration are ss-blocking and antihypertensively more active than the corresponding (R) -enantiomers.



   The compounds of the formula I in free form or in the form of their physiologically tolerable salts can be administered alone or in a suitable dosage form. The dosage forms, e.g. a tablet, can be prepared analogously to known methods.



   The invention therefore also relates to medicaments which contain the compounds according to the invention. The auxiliaries and carriers customary in pharmacy can be used for their production.


    

Claims (3)

 PATENT CLAIMS 1. Compounds of formula I, EMI1.1  wherein A denotes alkylene with 2 to 5 carbon atoms, X represents oxygen or sulfur, R3 denotes hydrogen, hydroxy, alkoxy having 1 to 4 carbon atoms, halogen with an atomic number of 9 to 35, cyano, carbamoyl or acetamido, and R4 is hydrogen and, if R3 is alkoxy with 1 to 4 carbon atoms, also for alkoxy with 1 to 4 carbon atoms or, if R3 is halogen with an atomic number of 9 to 35, also for halogen with an atomic number of 9 to 35 can be either R1 methyl and R2 halogen with an atomic number of 17 or 35 or Rt halogen with an atomic number of 17 or 35 and R2 is hydrogen or methyl, with the proviso  that X is removed from the nitrogen atom of the 3-amino-2-hydroxypropoxy chain by at least 2 carbon atoms, in free form or in salt form.  2. 1- (3-chloro-2-methylindol-4-yloxy) -3- (2-phenoxyethylamino) -2-propanol as a compound according to claim 1, in free form or in salt form.  3. Remedies, characterized in that they contain compounds of the formula I in free form or in the form of their physiologically tolerable salts.  The invention relates to the object defined in claims 1 to 3.  Structurally similar connections are e.g. known from ICI DOS 1493 853, ICI DOS 15 93 901 or Cigy DOS 25 20 910 R2 is preferably hydrogen or methyl. R3 preferably represents hydrogen, hydroxy, alkoxy, cyano or carbamoyl. X preferably represents oxygen.  Alkoxy preferably contains 1 or 2, in particular 1 carbon atom (s). Halogen in particular means chlorine.  A is preferably branched, especially branched alkylene in the z-position to the nitrogen atom of the side chain, e.g. 2-butylene, 2-methyl-2-butylene or 2-methyl-2-propylene, or for ethylene.  The compounds of the formula I are obtained by using compounds of the formula II EMI1.2  wherein R1 and R2 have the meaning given in claim 1 and Rx is a radical which, when reacted with an amine, gives a 2-amino-l-hydroxyethyl group with compounds of the formula III, EMI1.3  wherein A, X, R3 and R4 have the meaning given in claim 1.  If the phenyl ring of the side chain is mono- or disubstituted, the substituents are preferably in 4 or 3,4 position.  The compounds of formula I can be in free form or in salt form. Salts can be obtained in a known manner from the compounds of formula I in free form and vice versa. Thus the compounds of formula I according to the invention, e.g. with inorganic acids such as hydrochloric or hydrobromic acid, or with organic acids such as fumaric or maleic acid, acid addition salts.  The reaction is an amination by a primary amine. It can be carried out using conditions known for the preparation of known 3-amino-2-hydroxy-propoxyarvl compounds. For example, the group Rx is used as the group EMI1.4  or a reactive derivative of this group, for example a group of the formula EMI1.5  where Y is halogen, preferably chlorine or bromine, or a group RySO2, where Ry is phenyl, tolyl or lower alkyl. Y stands in particular for chlorine.  The compounds of the formula I can be isolated and purified from the reaction mixture by known methods.  In the compounds of the formula the carbon atom of the side chain which carries the hydroxyl group is asymmetrical; they can therefore occur in the form of the corresponding enantiomers. The enantiomers of the compounds of formula I can be obtained in a manner known per se, e.g. by executing the implementation based on corresponding, optically active starting products.    Insofar as the production of the required starting materials is not described, they are known or can be produced by known processes or analogously to processes known per se.  In the following example, all temperatures are in degrees Celsius and are uncorrected.  example 1- (3-chloro-2-methylindol-4-yloxy) -3- (2-phenoxyethylamino) -2-propanol 5 g of 3-chloro-4 (2,3-epoxypropoxy) -2-methylindole, 4.3 g of 2-phenoxyethylamine and 75 ml of dioxane are heated to 1300 in an autoclave for 15 hours. After cooling, the dioxane is turned on in a water jet vacuum and the excess ** WARNING ** End of CLMS field could overlap beginning of DESC **.