IL44320A - Derivatives of 2-aminoindane their preparation and pharmaceutical compositions containing them - Google Patents

Derivatives of 2-aminoindane their preparation and pharmaceutical compositions containing them

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IL44320A
IL44320A IL44320A IL4432074A IL44320A IL 44320 A IL44320 A IL 44320A IL 44320 A IL44320 A IL 44320A IL 4432074 A IL4432074 A IL 4432074A IL 44320 A IL44320 A IL 44320A
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formula
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aminoindane
phenyl
equal
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IL44320A
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Christiaens Sa A
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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • 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

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  • Organic Chemistry (AREA)
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  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Veterinary Medicine (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pyridine Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

o* »aon ninpn »n*cani jnaan New derivatives of 2-aminoindane, their preparation and pharmaceutical compositions containing them CHRISTIAEKS SOCIETE ANONYMS This invention relates to new derivatives of 2-aminoindane, as well as to the preparation and the use of these new derivatives.
From French Patent No. 2,081,383 there are known 2- (N-phenyl-N-dialkylaminoethyl) -aminoindanes and 2-(N-phenyl-N-dialkylaminopropyl) -aminoindanes, of general formula: in which m is 2 or 3 and the R radicals each represent the same lower alkyl group.
The new derivatives of 2-aminoindane according to this invention may be represented by the general in which n is 2, 3 or 4, the (CH2)n has a straight or branched chain, and represent each a lower alkyl or hydroxyalkyl radical containing 1 to 3 carbon atoms or a lower alkenyl or alkynyl radical containing 2 or 3 carbon atoms or form together with the attached nitrogen atom a saturated nitrogenous heterocyclic ring and A represents a 2-pyridyl radical or a phenyl radical, with the proviso that (1) when n is equal to 2 or 3, R^ and are different from each other or represent the same hydroxyalkyl, alkenyl or alkynyl radicals, (2) when n is equal to 4, and R2 may be identical or different from each other and (3) when A represents a 2-pyridyl radical, n is equal to 2, 3 or 4, R^ and R2 may be identical or different or form a saturated nitrogenous heterocyclic ring with the attached nitrogen atom, as well as the acid addition salts of said derivatives of formula (I). ··'.·' 44320/2 When R1 and R2 form together with the attached nitrogen atom a saturated nitrogenous heterocyclic ring, t ring may be selected among the piperidino, pyrrolidine, morpholino, piperazino and methylpiperazino rings.
The acid addition salts of the compounds of formula (I) may be the hydrochlorides, furaarates, malea-tes and oxalates thereof.
A few compounds according to this invention are listed hereafter : - N-phenyl-N-diethylaminobutyl-2-aminoindane (n = ; R,j = R2 = ; A = phenyl) ; - N-phenyl-N-piperidinobutyl-2-aminoindane (n = 4 ; NvΊ = piperidino ; A = phenyl) ; - N-phenyl-N- ( Y-dihydroxyethylaminopropyl )-2-aminoindane (formula I : A = phenyl ; R1 = R2 = CH2CH20H ; n = 3) - N-phenyl-N- (Y-diallylaminopropyl)-2-aminoindane (formula I : A = phenyl ; R1 = R2 = allyl ; n = 3) ; - N-phenyl-N-dipropargylaminopropyl-2-aminoindane (n = 3 ; 1 = R2 = CH2-CH=CH2 ; A = phenyl) ; - N-phenyl-N-methylethylaminopropyl-2-aminoindane (n = 3 ; 1 = CH3 ; R2 = C2H5 ; A = phenyl) ; - N-phenyl-N-ethylpropylaminopropyl-2-aminoindane (n = 3 ; R1 = C2H5 ; R2 = C3H? ; A = phenyl) ; - N-phenyl-N-ethylhydroxyethylaminopropyl-2-aminoindane (n = 3 ; R1 = C2H5 ; R2 = CH2CH20H ; A = phenyl) ; - N-( Y-dimethylaminopropyl)-N-(2-pyridyl)-2-aminoindane hydrochloride (formula I : A = pyridyl ; = R2 = CH n = 3) ; - N- ( β-diethylaminoethyl)-N- ( 2-pyridyl )-2-aminoindane oxalate (formula I : A = pyridyl ; = R2 = ^2Η5 5 n = 2) ; - N- ( β-piperidinoethyl)-N- (2-pyridyl )-2-aminoindane (formula I : A = pyridyl ; } = piperidino ; n = 2) ; - N-phenyl-N- "( Y- 1 -methyl-N '-propyl)-aminopropyl_7-2- aminoindane (formula I : A = phenyl ; R^ = CH^ ; R2 = C3H? ; n = 3) ; - N-phenyl-N- ( Y-N 1 -ethyl- ' -isopropylaminopropyl)-2- aminoindane monohydrochloride (formula I : A = phenyl R. = CpH,- ; R9 = -CH. ^ ; n = 3). 1 CH, 3 This invention relates also to processes for preparing the new compounds of formula (I).
According to this invention, the compounds of formula (I) may be prepared by the following processes : First process : . -' This process involves the reaction of a N-phenyl (or N-2-pyridyl)-2-aminoindane of the formula in which A has the above meanings, with sodium amide (NaNH2) and with a halogenated amine of the formula : Hal - (CH2)n - N (III) X R,2^- in which Hal represents a halogen atom, preferably a chlorine atom, whereas n, and FL, have the above meanings. · Second process : This process involves the acylation of a compound of formula (II) with an acid chloride of the formula : (CH2)n, C0C1 (IV) in which n1 = 1, 2 or 3, so as to obtain an acylated compound of the formula : and the subsequent reduction of the acylated compound of formula (V) by means of lithium aluminum hydride into a compound of the following formula : the obtained compound of formula (VI) being finally reacted with an amine of the formula : R1\ H - N (VII) in which and R2 have the above meanings.
Third process : This process involves the acylation of a compound of formula (II) with an acid chloride of the formula : Cl(CH2)n,C0Cl (IV) wherein n' = 1, 2 or 3, so as to obtain an acylated compound of the formula : the acylated compound of formula (V) being reacted with a · secondary amine of the formula : so as to obtain a compound of the formula the latter compound being finally reduced into a com- pound of formula (I) by means of lithium aluminum hydride . i This process involves the reaction of a pound of formula (V) with a primary amine of the fo mula : /R1 H - N (XIII) wherein R1 has the above meanings to give a compound of the formula : and the acylation of the latter compound by means of a compound of the formula : X C0(CH2)x H (XV) wherein X is a halogen atom and x is equal to 1, 2 or 3 to give a compound of the formula : which latter compound is then reduced to give the desir< ed compound of formula (I).
Fifth process; This process involves the reaction of a coiri- of fornula XIII to ftive a compound pound of formula (XII with a primary amine/oi' the i'or-mu and the acylation of the latter compound by means of a compound of formula (XV) to give a compound of the fo (CH2)xH (XVIII) which latter compound is then reduced to give the desired compound of formula (I).
The compound of formula (II) used as starting material in the first, second and third above described processes may be prepared by various methods : First method : This method comprises the two following y steps : 1°) reaction of 2-keto-3-cyanoindane of the formula : with aniline, a substituted aniline or 2-aminopyri-7 dine (as described in J.C.S., 1961, page 178) so as to obtain a,2-phenyl (or 2-pyridyi)-amino-3-cyano~ ! indene of the formula : 2°) reduction of the 2-phenyl (or 2-pyridyl)-amino-3- cyanoindene (XX) into the compound of formula (II) by the Bouveault-Blanc method.
Second' method : This method involves the reaction of the ester of methane sulfonic acid and 2-indanol of the following formula : with aniline, a substituted aniline or 2-pyridine.
Third method : This method comprises the two following steps : 1°) reaction of 2-indanone of the following formula : with aniline, a substituted aniline or 2-pyridine so as to obtain a N-phenyl (or 2-pyridyl)-2-iminoindane of the following formula : (XXIII) 2°) reduction of .the N-phenyl (or 2-pyridyl)-2-imino- indane by means of sodium borohydride.
The compounds of formula (I) according to this invention have an interesting pharmacological activity. They are active against heart arrhythmia.
Said compounds can be used for the treatment of various heart diseases such as premature heart contractions, ventricular and supraventricular tachycardias either idiopathic or subsequent to a cardiopathia or to a coronary disease, cardiac arrhythmias due to digitalin intoxication, as well as atrial fibrillation and flutter particularly in the early stage .
It is known (see Koch-Weser, J. Arch. Int. Med. 129; 763, 1972) that none of the presently available antiarrhythmic agents are satisfactory for the prophylaxis of tachycardias and fibrillation of ventricular origin.
The oral activity of the known antiarrhythmic agents, such as procainamide or lidocaine,- is either too short leading to multiple day and night administra- / tion (for example with procainamide) or too low to be of some practical utility (for example with lidocaine) or their therapeutic activity is conjugated with frequent and dangerous side effects, such as hypotension (with procainamide), sudden death, agranulocytosis or idiosyncrasy.
The compounds of general formula (I) according to this invention are very active when orally administered, although they may also be administered paren-terally. They have also a long activity duration and are not depressant for the myocardial function.
Applicants do not know any orally active anti' arrhythmic agent which does not act at the same time as a depressant of the myocardial function.
The oral antiarrhythmic activity of the compounds of formula (I) has been proved by tests on rats using aconitine which is a compound causing premature heart contractions and death of the animals.
The method used for these tests is described hereafter : Animals : ^ ■ Male or female rats with a body-weight ranging from 380 to 450 g.
Aconitine solution : 3.12 μg aconitine nitrate/1 ml physiological saline.
Solution of the compound to be tested : 0.75 % in distilled water.
Method : Six randoms selected animals are required for each compound to be tested. The compound is administered by oral I --* - route at the dose of 75 mg/kg (1 ml of the 0.75 % solution/100 g of body-weight) 75 minutes before the intravenous perfusion of the aconitine solution is initiated..'' Control groups of animals are treated only with distilled water (1 ml/100 g) .
Sixty minutes after the administration of the compound to be tested, the animals are anesthesized by an intraperitoneal injection of Pentobarbital (50 mg/kg) and the jugular vein is dissected.
A catheter is introduced in the vein and fixed by a ligature .
The ECG (D II derivation) is then continuously recorded. The perfusion of the aconitine solution is started 75 minutes after the administration of the compound to be tested.
The volume delivered by the injection device being 0.2S7 ml/minute, the dose of aconitine nitrate administered is 0.895 g/minute (0.20-0.24 μg/100 g/minute according tc the minimal and maximal weight of the animals).
The experience is stopped as soon as the first extra-systoles are appearing and the time elapsed from the beginning of the perfusion is noted.
The results are expressed as the mean total dose of aconitine injected in a group of animals.
The relative activity between a tested compound and a reference substance (lidocaine, procainamide) is computed in the following way : X - "C A (x) = x 100 K - U where : A (x) = activity of tested compound X (in %) * Aconitine test by rat With respect to the known compounds of French Patent Ho. 2,081,383, the new compbunds according to the present invention show surprisingly better activities as appears from the following data of comparative tests : The compounds of the formula (I) may be administered orally or parenterally.
Oral preparations may be administered under =; the form of capsules, tablets, pills and the like. Each capsule, tablet or pill may contain from 10 to 200 mg of a compound of formula (I) as active ingredient, together with pharmaceutically acceptable excipients or carriers.
Parenteral preparations may consist in a solution for perfusion or for intravenous or intramuscular injection. Such a solution may contain from 0.2 per thousand to 2 per thousand of a compound of formula (I).
The parenteral preparation may be either a solution which may be directly used for the perfusion and contains a proportion of the active ingredient within the above limits, or a concentrated solution containing 1 to 10 % of the active ingredient, said concentrated solution being diluted when administered to a patient.
The initial dose of active ingredient may be of 200 to 800 mg per day during 2 or 3 days, the maintenance dose being of about 25 mg to 300 mg per day.
If a single dose is sufficient for obtaining the therapeutic effect, this dose is generally comprised between 50 and 300 mg.
The active ingredient may be administered at the same time by the parenteral route (for example by perfusion) and by the oral route.
This invention relates therefore also to pharmaceutical compositions which are particularly suitable for the treatment of heart arrhythmia, said compositions containing a compound of formula (I) or an acid \ addition salt thereof as active ingredient, together v/ith a suitable pharmaceutical excipient or carrier.
The following examples illustrate the preparation of new compounds of formula (I).
EXAMPLE 1 Preparation of N-phenyl-N-(£ -diethylaminobutyl)-2-amino-indane (formula I : A = phenyl ; n = 4 ; = R2 = C2H^).
A.- Preparation of N-phenyl-(N-Y-chlorobutyroyl)-2-amino- indane . 53 ml (0.4 mole) of the chloride of Y-chloro-butyric acid are added drop by drop, at a temperature of 20°C, to a solution of 41.86 g of 2-phenylaminoindane in 270 ml of benzene. The mixture is refluxed during 2 hours and then concentrated to dryness. The oily residue is washed with petroleum ether (B.P. : 40-60°C) and the insoluble oil is crystallized from cyclohexane . M.P. : 76-77°C Analysis : Calculated % : C 72.71 ; H 6.42 ; N 4.46 ; CI 11.30 Found % : C 72.73 ; H 6.37 ; N 4.64 ; CI 10.30 B.~ Preparation of N-phenyl-N-( Y-diethylaminobutyroyl)-2- aminoindane . 19 g (0.062 mole) of N-phenyl-N- (Y-chloro- · butyroyl)-2-aminoindane, 28 ml of diethylamine and 70 ml of ethanol are. heated in an autoclave at 100°C during 24 hours. After cooling and evaporation, the residue is treated with a 1N caustic soda solution and extracted with benzene.
The obtained product is purified by converting it into oxalate. The pure recovered base is crystal- - - lized from a mixture of methylethylketone and methanol. M.P . : 121 -122°C .
Analysis : Calculated % : C 68. 16 ; H 7.32 ; N 6.36 ; CI 18. 16 Found % : C 68.03 ; H 7.04 ; N 6 .53 C .- Preparation of N-phenyl-N-( -diethylaminobutyl) -2- aminoindane .
A solution of 13.5 g of N-phenyl-N-(Y-diethyl-aminobutyroyl) -2-aminoindane in 200 ml of ether is added to 300 ml of ether containing 3 .25 g of AlLiH^. The mixture is refluxed during 4 hours, and, after cooling, 50 ml of water are added thereto. The separated ether phase is washed with water, dried and evaporated. 10.79 g of an oil are obtained. This oil is treated with 50 ml of water and 32 ml of 1N hydrochloric acid. The acid phase is extracted with petroleum ether and with dichloromethane. The oil ( 12.5 g) obtained after evaporation of the dichloromethane is crystallized from ethyl acetate. M.P. 124-124 o 5°C (hydrochloride).
Analysis : · Calculated % : C 74.06 ; H 8.92 ; N 7.51. CI 9.51 Found % : C 74.69 ; H 8.48 ; N 7.72 ; CI 9.47 EXAMPLE 2 Preparation of N-phenyl-N-piperidinobutyl-2-aminoindane (formula I : A = phenyl ; piperidino ; n = 4) . 2.24 g of N-phenyl-N-(£-chlorobutyl) -2-amino-indane, 4.54 g ( 5 .3 ml) of piperidine and 50 ml of anhydrous ethanol are heated at 100°C in an autoclave during 24 hours. After cooling and evaporation, the residue is. treated with water and made alkaline (pH : 11). After extraction with benzene, washing, drying and evaporation of the benzene, an oily residue is obtained. This residue is treated with 1N hydrochloric acid and extracted by means of dichloromethane 0 The acid aqueous phase is brought to a pH of 6 and extracted by means of dichloromethane. The obtained monohydrochloride is recrystalliz-ed of' a mixture of methylethylketone and methanol0 M.P. 170°C.
Analysis : Calculated % : C 74.87 ; H 8.64 ; N 7.28 ; Cl 9.21 Found % : C 74.75 ; H 8.55 ; N 7.34 ; Cl 9.29 EXAMPLE 3 Preparation of N-phenyl-N-( Y-dihydroxyethylaminopropyl)-2-aminoindane (formula I : A = phenyl ; = FL, = CH2CH20H ; n = 3).
A.- Preparation of N-phenyl- -( -dihydroxyethylamino- propionyl)-2-amino.indane » 6.93 g of N-phenyl-N- ( -chloropropionyl)-2-aminoindane and 14 ml of dihydroxyethylamine are heated on a water-bath during 30 minutes. After dilution by water, the reaction mixture is made acid.
The obtained solution is treated with charcoal and filtered. The filtrate is concentrated to dryness and the residue is recrystallized from isopro-panol. M.P. : 130-131°C.
Analysis : Calculated % : C 65.2 ; H 7.22 ; N 6.92 ; Cl 8.76 Found % : C 65.26 ; H 7.17 ; N 7.10 ; Cl 8.9 B.- Preparation of N-phenyl-N-(Y-dihydroxyethylamino- propyl)-2-aminoindane fumarate. ' 5.2 g of N-phenyl-N-(β-dihydroxyethylamino-propionyl)-2-aminoindane are reduced by means of lithium aluminum hydride in ether by refluxing the mixture during 3 hours. The separated product is converted into the corresponding fumarate which is recrystallized from ethanol. M.P. : 137-138°C.
Analysis : Calculated % : C 65.36 ; H 7.28 ; N 5.95 Found % : C 66.28 ; H 7.23 ; N 6.00 EXAMPLE 4 Preparation of N-phenyl-N- (Y-diallylaminopropyl)-2-aminoindane monohydrochloride (formula I : A = phenyl ; R1 = R2 = allyl ; n = 3). 6.44 g of N-phenyl-N-(Y-chloropropyl)-2-aminoindane, 15.54 g of diallylamine and 50 ml of ethanol are heated at 100°C in an autoclave during 24 hours.
The reaction mixture is treated in the usual way, so as to obtain the monohydrochloride which melts at 138- 39°C after recrystallization from jnethylethyl-ketone.
Analysis : Calculated % : C 75.26 ; H 8.16 ; N 7.31 ; CI 9.26 Found % : C 75.22 ; H 7.97 ; N 7.24 ; CI 9.09 EXAMPLE 5 Preparation of N-phenyl-N- ( Y - ' -methyl- 1 -ethylamino-propyl)-2-aminoindane monohydrochloride (formula I : A = phenyl ; R1 = CH^ ; R2 = Ο,Η^ ; n = 3). 6,44 g (0.02 mole) of N-phenyl-N-(Y-chloro- - - propyl)-2-aminoindane hydrochloride, 9.44 g (0.16 mole) of methylethylamine and 50 ml of ethanol are heated at 100°C in an autoclave during 24 hours. After evaporation to dryness, the mixture is treated with a 0.1 sodium hydroxide solution. The obtained mixture is extracted with dichloromethane, washed and dried. By evaporation of the dichloromethane , 6.3 g of a residual oil are obtained.
The monohydrochloride prepared from this oil and recrystallized in ethyl acetate melts at 26-127°C Analysis : Calculated % : C 73.12 ; H 8.48 ; N 8.12 ; CI 10.28 Found % : C 73.01 ; H 8.35 ; N 8.21 ; CI 10.57 "EXAMPLE 6 Preparation of N-phenyl-N-( Y-N ' -ethyl-N ' -propylamino-propyl)-2-aminoindane monohydrochloride (formula I : A = phenyl ; R1 = C^ ; R2 = C^ ; n = 3).
A.- Preparation of N-phenyl-N- f~ (Y-N' -ethyl- '-propionyl)- aminopropyl 7-2-aminoindane . 8.6 g of N-phenyl-N- (ethylaminopropyl)-2-aminoindane, 2.3 ml of the chloride of the propionic acid, 3.7 ml of anhydrous triethylamine and 200 ml of benzene are stirred during 1 hour at room temperature.
After addition of 50 ml of water, the benzene phase is decanted by means of 100 ml of water, dried and evaporated. An oily residue (9 g) is obtained. By recrystallization from petroleum ether (B.P. 40-60°C) a solid melting at 47-49°C is obtained.
Analysis : •Calculated % : C 78.81 ; H 8.63 ; N 7.99 Found % : C 78.75 ; H 8.65 ; N 8.00 1 - - B.- Preparation of N-phenyl-N-/~(Y-N'-ethyl-N'-propyl)- aminopropyl 7-2-aminoindane monohydrochloride „ v 1,5 g of N-phenyl-N-zf Y-N'-ethyl-N'-propion- yl)-aminopropylJ7-2-aminoindane dissolved in 70 ml of ether are added drop by drop to a suspension to 0.35 g of lithium aluminum hydride in 120 ml of ether. The obtained cooled mixture is refluxed during 3 hours.
The desired monohydrochloride is obtained by the. usual extraction method. The oily residue obtain- ed by extraction from the aqueous phase at a pH of 6, by means of dichloromethane, is recrystallized from ethyl acetate. M.P. : · 107-108°C.
Analysis : Calculated % : C 74.06 ; H 8.92 ; N 7.51 ; CI 9.51 Found % : C 74.01 ; H 8.85 ; N 7.25 ; CI 9.64 EXAMPLE 7 Preparation of N-phenyl-N-(Y-hydroxyethyl-ethylaminopro~ pyl)-2-aminoindane monohydrochloride (formula I : A = "■' phenyl ; = C^ ; R2 = CgH^OH ; n = 3).
A.- Preparation of N-phenyl-K-( -hydroxyethyl-ethylamino- propionyl)-2-aminoindane monohydrochloride . 20 g of N-phenyl-N-( -chloropropionyl)-2- aminoindane, 17.83 g (19.6 ml - 0.2 mole) of ethylethan- olamine and 100 ml of ethanol are refluxed during 24 hours. After evaporation of the volatile materials, 150 ml of a 0.1N sodium hydroxide solution are added and the mixture is extracted with benzene. The residue of the benzene solution is dissolved in ether, a stream of gaseous hydrochloric acid being then passed through the ether solution. After recrystallization from methylethyl- ketone, the desired hydrochloride melts at 90-95°C.
Analysis : Calculated % : C 67.93 ; H 7.52 ; N 7.20 ; CI 9.11 Found % : C 68.12 ; H 7.64 ; N 7.50 ; CI 9.17 B„- Preparation of N-phenyl- -( Y-hydroxyethyl-ethylamino)- propyl-2-aminoindane monohydrochloride .
The N-phenyl-N-( -hydroxyethyl-ethylamino)-pro-pionyl-2-aminoindane monohydrochloride is reduced by means of lithium aluminum hydride. The desired product recrystallized from ethylraethylketone melts at 98-100°C. Analysis : Calculated % : C 70.47 ; H 8.53 ; N 7.47 ; CI 9.45 Found % : C 70.55 ; H 8.10 ; N 7.52 ; CI 9.42 EXAMPLE' 8 Preparation of N-phenyl-N-(^-methyl-propylaminobutyl)-2--aminoindane oxalate (formula I : A = phenyl ; = CH^ ; R2 = C3H7 5 n = )· 6 g (0.02 ml) of N-phenyl-N-(£-chlorobutyl)- 2-aminoindane, 3.75 g (0.05 mole) of methylpropylamine and 50 ml of anhydrous methanol are refluxed under nitrogen during 24 hours. After cooling and evaporation of the volatile materials, 100 ml of a 0.1N solution of sodium hydroxide are added and the obtained mixture is extracted with dichloromethane . The extract is dried and evaporated. The residue is treated with 40 ml of 1N hydrochloric acid and the mixture is extracted with dichloromethane. The obtained extract is evaporated, brought to a pH of 6 and again extracted with dichloromethane. After evaporation, a residual oil is obtained which is converted into an oxalate. The oxalate recrys- tallized from a mixture of ethyl acetate and methanol melts at 154-157°C Analysis : Calculated % : C 70.39 ; H 8.13 ; N 6.57 Found % : C 70.67 ; H 8.02 ; N 6.70 EXAMPLE 9 Preparation of N-( Y-dimethylarninopropyl)-N-(2-pyridyl)-2-aminoindane hydrochloride (formula I : A = pyridyl ; R1 = R2 = CH3 ;. n = 3).
A.- Preparation of (2-pyridyl)-2-aminoindane . 92 g of 2-aminopyridine are heated at 125 °C and stirred under nitrogen. Indane mesylate is then added gradually, so as to maintain the temperature at 125-130°C. After the addition, the reaction mixture is still stirred during 15 minutes at 125°C. The reaction mixture is then cooled. 200 ml of ether, 200 ml of water and caustic soda are then added so as to obtain a pH of 11. After decantation, the ether phase is washed with water and dried on potassium carbonate. By filtration of the dried product, 67 g of an oil are obtained. This oil is distilled, under reduced pressure (0.5 mm). After removal of indene and 2-aminopyridine, 24 g of a liquid distilling at 175-178°C are obtained. This liquid becomes solid.
M.P. 97-98°C.
Analysis : Calculated % : C 79.96 ; H 6.71 ; N 13.32 Found % : C 80.13 ; H 7.2' ; .13.3 B.- Preparation of N-(T-dimethylaminopropyl)-M-(2-pyrid- yl)-2-aminoindane hydrochloride . 0.034 mole of (2-pyridyl)-2-aminoindane and - - 0.051 mole of sodium amide are stirred at room temperature in 100 ml of benzene, under nitrogen. 0.0374 mole of Y-chloropropyl-dimethylamine are then added and the mixture is stirred during 1 hour at room temperature.
After refluxing during 11 hours, the reaction mixture is cooled and 100 ml of water are added thereto. The mixture is then decanted and the "benzene phase is concentrated to dryness. The residue is treated with 75 ml of 2N hydrochloric acid and extracted by means of dichloromethane .
The pH of the aqueous phase is adjusted at 6.5 and this phase is extracted by means of chloroform. The chloroform solution is concentrated to dryness, the obtained residue is treated with 25 ml of acetone and the desired product is recrystallized from a mixture of acetone and methanol. M.P. 169-170.5°C Analysis : Calculated % : C 68.76 ; H 7.89 ; N 12.66 ; CI 10.68 Found % : C 68.5 ; H 7.75 ; N 12.4 ; CI 10.5 EXAMPLE 10 Preparation of N-(p-diethylamiiioethyl)-N-(2-pyridyl)-2-aminoindane oxalate (formula I : A = pyridyl ; = = C2H5 ; n = 2).
This compound is prepared in the manner described in Example 9, using diethylamino- -chloroethyl-amine instead of Y-chloropropyldimethylamine .
The obtained oxalate recrystallized from acetone melts at 111-114°C.
Analysis : Calculated % : C 66.14 ; H 7.32 ; N 10.5 Found % : C 65.8 ; H 7.2 ; N 10.3 EXAMPLE 11 Preparation of N-^-piperidinoe¾iyl)-N-(2-pyridyl)-2--aminoindane (formula I : A = pyridyl ; N-" ; = piperidino ; n = 2).
This compound is prepared by treating (2-pyridyl)-2-aminoindane with chloroethylpiperidine .
After refluxing the reaction mixture in benzene during 12 hours and cooling, water is added thereto and the organic phase is decanted and extracted by means of 1N hydrochloric acid. The pH is then adjusted to 5.5-6 and the obtained monohydrochloride is extract ed with chloroform. After recrystallization from a mixture of acetone and methanol, said monohydrochloride melts at 204-206°C.
Analysis : Calculated % : C 70.46 ; H 7.88 ; N 11.74 ; CI 9.91 Found 96 : C 70.1 ; H 7.68 ; N 11.5 ; CI 9.82 EXAMPLE 12 Preparation of N-phenyl- -/~(Y-N ' -methyl-N 1 -propyl )-aminopropyl 7-2-aminoindane monohydrochloride (formula I A = phenyl ; R1 3) .
A.- Preparation of N-phenyl-N-( -methylaminopropionyl)- 2-arninoindane . 30 g of N-phenyl-N-0-chloropropionyl)-2-aminoindane and 37 ml of a 33 % solution of methylamine in ethanol are heated in an autoclave at 100°C during 24 hours. After said heating, the solvent is evaporated, retaken up with water and alkalinized by means of 1N NaOH. The base is extracted with benzene and, after the solvent has been expelled, the residue is taken up with anhydrous ether in which a flow of HC1 is caused to pass. The hydrochloride thus obtained is recrystaliiz-ed from a mixture of methanol and raethylethylketone and melts at 202-20 °C.
Analysis : Calculated % : C 69.97 ; H 7.01 ; N 8.47 ; CI 10.71 Found % : C 68.95 ; H 6.94 ; N 8.36 ; CI 10.98 B.- Preparation of N-phenyl- -/~(Y- '-methyl- '-propyl)- aminopropyl 7-2-aminoindane . 3.3 g of N-phenyl--( -methylaminopropionyl)-2-arninoindane, 0.70 ml of the chloride of propionic acid, 1.3 ml of anhydrous triethylamine and 75 cc of benzene are stirred during 1 hour at room temperature. After addition of water, the benzene phase is decanted, dried and evaporated. The residue comprising 3.5 g (0.01 mole) is dissolved in 70 ml of ether and added drop by drop to a suspension of 1.14 g (0.03 mole) of lithium aluminum hydride in 50 ml of ether. The obtained cooled mixture is refluxed during 3 hours.
The desired monohydrochloride is obtained by the usual extraction method. The oily residue obtained by extraction from the aqueous phase at a pH of 6 by means of dichloromethane is recrystallized from ethyl-acetate. M.P. 112.8°C (Mettler).
Analysis : Calculated ¼ : C 73.61 ; H 8.71 ; N 7.81 ; CI 9.88 Found % : C 73.38 ; H 8.55 ; N 8.10 ; CI 10.01 EXAMPLE 13 Preparation of N-phenyl- -(Y-N'-ethyl-N'-isopropylamino- - - propyl)-2-aminoindane monohydrochloride (formula I : A = phenyl ; FL = C9H,- ; R9 = -CH A.- Preparation of N-phenyl-N- (isopropylaminopropyl)-2- 7 g (0.022 mole) of N-phenyl-N- (Ύ-chloro-propyl)-2-aminoindane, 15 ml of isopropylamine and 85 ml of ethanol are heated at 100°C in an autoclave during 24 hours. After evaporation to dryness, the mixture is treated with a 0.1 M sodium hydroxide solution. The obtained mixture is extracted with dichloromethane, washed and dried.
By evaporation of the dichloromethane, an oily residue is obtained. The monohydrochloride prepared from this residue and recrystallized from isopropanol melts at 140-141 °C.
Analysis : Calculated % : C 73.12 ; H 8.47 ; N 8.12 ; CI 10.28 Found % : C 72.91 ; H 8,30 ; N 8.17 ;^ CI 10.40 B.- Preparation of N-phenyl-N-/~"(Ύ-Ν' -isopropyl- ' - acetyl)-aminopropyl 7-2-aminoindane . 2.54 g of N-phenyl-N- (isopropylaminopropyl)-2-aminoindane, 0.6 ml of the chloride of acetic acid, 1.17 ml of anlrydrous triethylamine and 80 ml of benzene are stirred during 3 hours at room temperature. After addition of v/ater, the organic phase is decanted, dried and evaporated.
An oily residue is obtained : 2.86 g.
C- Preparation of N~phenyl-N-(Y-N'~ethyl-N'-isoprop l- aminopropyl)-2--aminoindane dihydrochloride . ' ^ • 2.86 g of N-phenyl-N-^Y-N'-isopropyl-N'-acetyl)-aminopropyl__7-2-aminoindane dissolved in 80 ml of ether are added drop by drop to a suspension of 0.47 g of lithium aluminum hydride in 40 ml of ether. The obtain ed cooled mixture is refluxed during 3 hours.
After decomposition of the cooled mixture by addition of a little amount of water, the ether is evaporated.
^The desired dihydrochloride prepared from the residual oil in water and recrystallized from iso-propanol melts at 196-198°C (crystallized with 1 M.H^O). Analysis : Calculated % : C 64.64 ; H 8.49 ; N 6.55 ; CI 16.59 Found % : C 64.60 ; H 8.60 ; N 6.45 ; CI 16.24 The following examples 14-17 illustrate ' pharmaceutical compositions of this invention for the treatment of heart arrhythn< ia.
EXAMPLE 14 CAPSULE : Active ingredient of formula I . 100 mg Lactose 120 mg Rice starch ' 30 mg Corn starch 30 mg Colloidal silica 1 mg for one capsule EXAMPLE 15 TABLET : Active ingredient of formula I * 200 mg - 20 - Potato starch Lactose Starch sodium glycollate Colloidal silica Magnesium stearate Hydroxy propylcellulose Stearic acid for one tablet EXAMPLE 16 PILLS : Core : Active ingredient of formula I 50.0 mg Lactose 67.5 mg Microcrystalline cellulose 32.0 mg Starch sodium glycollate 8.2 mg Colloidal silica 0.4 mg Magnesium stearate 0.9 mg Coating : Shellac 1.0 mg Sandarac 0.2 mg Castor oil ■· 0.3 mg Gum arabic 7.0 mg Talc 11.2 mg Corn starch' Ϊ.0 rag Titanium oxide 1.3 mg Dyestuff 4.0 mg Sucrose 142.8 rag White wax / carnauba v/ax 0.2 mg for one pill - - EXAMPLE 7 Solution for perfusion : Active ingredient of formula I 200 mg Anhydrous sodium sulfite GO mg Anhydrous sodium metabisulfite 140 mg Sodium chloride .7 mg Water for injection ad 200 ml It should be u rstood that the invention is not exclusively limited to the embodiments described, hereinabove and that many modifications may be brought thereto by the man skilled in the art without departing from the spirit and scope of the invention as defined in the appended claims.

Claims (11)

WHAT WE CLAIM IS :
1. New derivatives of 2-aminoindane of the general formula : in which n is 2, 3 or 4, the (CH2)n has a straight or branched chain, and R2 represent, each a lower alkyl or hydroxyalkyl radical containing 1 to 3 carbon atoms or a lower alkenyl or alkynyl radical containing 2 or 3 carbon atoms or form together with the attached nitrogen atom a saturated nitrogenous heterocyclic ring and A represents a 2-pyridyl radical or a phenyl radical, with the proviso that (1) when n is equal to 2 or 3, and are different from each other or represent the same hydroxyalkyl, alkenyl or alkynyl radicals, (2) when n is equal to 4 , and may be identical or different from each, other and (3) when A represents a 2-pyridyl radical, n is equal to 2, 3 or 4, R^ and R2 may be identical or different or form a saturated nitrogenous heterocyclic ring with the attached nitrogen atom, as well as the acid addition salts of said derivatives of formula (I) .
2. New derivatives of 2-aminoindane according to claim 1, wherein and R2 form together with the attached nitrogen atom a saturated nitrogenous heterocyclic ring selected among the piperidino, pyrrolidino, morpholino, piperazino and methylpiperazino rings.
3. ' 3. 'New derivatives of 2-aminoindane according to claim 1, wherein n is equal to 2 or 3, and Rr, which may be equal or different, each represent a methyl, ethyl, propyl or isopropyl group, or form with the attached nitrogen atom a piperidino group and A represents a phenyl or a 2-pyridyl radical.
4. |4. New derivative ¾>f 2-aminoindane according to claim 1, in which n = 3, whereas represents an ./ ethyl group, represents an isopropyl group and A represents a phenyl group, as well as the acid addition salts thereof. '·'
5. New derivatives of 2-aminoindane according to claim 1, in which n = 2 or 3f whereas and R2 represent a methyl or ethyl group and A represents a 2-pyridyl group, as well as the acid addition salts thereof.
6. New derivative of 2-aminoindane according to claim 1, in which n = 3> whereas R^ represents a methyl group and Rg represents an ethyl group , as well as the acid addition salts thereof.
7. ^. Pharmaceutical compositions particularly for the treatment of heart arrhythmia containing, as active ingredient, at least one compound according to : anyone of the preceding claims* together with a pharma-" ceutical carrier or excipient*
8. A process for preparing new derivatives of 2-arninoindane of the general formula : in which n is 2, 3 or 4, the (<¾)η has a straight or branched chain,. and R2 represent each a lower alkyl or hydro yalkyl radical containing 1 to 3 carbon atoins or a lover alkenyl or alkynyl radical containing 2 or 3 carbon atoms or form together with the attached nitrogen atom a saturated nitrogenous heterocyclic ring and A represents a 2-pyridyl radical or a phenyl radical, with the proviso that (1) when n is equal to 2 or 3, and I¾2 are different from each other or represent the same hydroxyalky1 , alkenyl or alkynyl radicals, (2) when n is equal to 4, and may be identical or different from each other and (3) when A represents a 2-pyridyl radical, n is equal to 2 , 3 or 4 , and R2 may be identical or different or form a saturated nitrogenous heterocyclic ring with the attached nitrogen atom, as well as the acid addition salts of said derivatives of formula (I)# said process comprising the reaction of a compound of the formula : - with sodium amide so as to obtain the sodium salt of said compound of formula II, this sodium salt being th reacted with a halogenated amine of the formula : in which Hal represents a halogen atom and n, R^ and have the above-indicated meanings, or with an acid chloride of the formula : CI (CH2)n,-C0Cl (IV) in which n' = 1, 2 or 3, so as to obtain an acylated compound of the formula : 0 said acylated compound being reduced into a compound the formula : in which n! and A have the above meanings, said compound of formula (VI) being then reacted with an amine of the formula : .R„ *v H- ' (VII) R, wherein R^ and R2 have the above meanings, or the acylated compound of formula V may also be reacted with an 44320/2 amine of formula VII 'to give a compound of the formula ': the latter compound being finally reduced into a compound of formula I, · - or a compound of formula V is reacted with a primary amine of the formula : /R1 H-N (XIII) wherein has the above meanings to give a compound the formula : and the latter compound is then acylated by means ^of a compound of the formula : X CO (CH2)X H (XV) wherein X is a halogen atom and x is equal to 1 , 2 or 3 to give a compound of the formula : which latter compound is then reduced to give the desired compound of formula I, - or a compound of formula XII is reacted with a prim amine of formula XIII to obtain a compound of the for 44320/3 and the latter compound is then acylated by moans of a compound of formula XV to give a compound of the formula : (CH2)x H (XYIII) which latter compound is then reduced to give the desired compound of formula I, - whenever necessary, the compound of formula I is transformed into a desired acid addition salt,
9. A process according to claim 8, wherein reduction of a CO group into a CH2 group is effected , . by means of lithium aluminum hydride,
10. A process according to claim 8, substantially described in anyone of the ii araples 1 - ': ;/ .
11. Pharmaceutical compositions substantially, as described in anyone of the Examples 1 —17 · For fhe Applicants DR. REIMH0LD.COHN A
IL44320A 1973-03-02 1974-02-28 Derivatives of 2-aminoindane their preparation and pharmaceutical compositions containing them IL44320A (en)

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