AU619728B2 - New N-(1H-indol-4-yl)benzamide derivatives and also their salts, their application by way of medicinal products and the compositions containing them - Google Patents
New N-(1H-indol-4-yl)benzamide derivatives and also their salts, their application by way of medicinal products and the compositions containing them Download PDFInfo
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- C—CHEMISTRY; METALLURGY
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- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
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Abstract
Products of formula (I): <IMAGE> in which one of the substituents X and Y denotes alkyl (C1-C5), alkoxy (C1-C3), chlorine, bromine, iodine, nitro or amino optionally substituted by an aliphatic acyl (C2-C5) or 2 alkyls (C1-C5) and the other substituent denotes a hydrogen, it being understood that Y does not denote methoxy and X chlorine, and their addition salts with acids. The products (I) are endowed with antiarrhythmic properties and some have anticalcic properties.
Description
Australia 619728 Form PATENTS ACT 1952 COMPLETE SPECIFICATION
(ORIGINAL)
FOR OFFICE USE Short Title: Int. CI: Application Number: Lodged: Complete Specification-Lodged: Accepted: Lapsed: Published: Priority: Related Art: TO BE COMPLETED BY APPLICANT Name of Applicant: ROUSSEL-UCLAF Address of Applicant: 35, Boulevard des Invalides, 75007 Paris, France.
Actual Inventor: FRANCOIS CLEMENCE, JACQUES GUILLAUME and GILLES HAMON.
Address for Service: CALLINANS Patent Attorneys, of 48-50 Bridge Road, Richmond, State of Victoria, Australia.
"NEW N-(1H-INDOL-4-YL)BENZAMIDE DERIVATIVES AND ALSO THEIR SALTS, THEIR APPLICATION BY Complete Specification for the invention entitled: AND ALO EI AL EIN B WAY OF MEDICINAL PRODUCTS AND THE COMPOSITIONS CONTAINING THEM" The following statement is a full description of this invention, including the best method of performing it known to me:-' Note: The description is to be typed in double spacing, pica type face, in an area not exceeding 250 mm in depth and 160 rim in width, on tough white paper of good quality and it is to be inserted inside this form.
K,
la The invention relates to new N-(IH-indol-4-yl)benzamide derivatives and also their salts, their application by way of medicinal products and the compositions containing them.
N-(1H-Indol-4-yl)benzamide derivatives are described in European Patent Application No.86/401,528.4.
These derivatives correspond to the following general II formula: S. R 3
O-A-N
b B c R2 in which R and R 1 denote, independently of one another, a hydrogen atom, a linear alkyl radical containing from 1 to 5 carbon atoms, a branched alkyl radical containing Sfrom 3 to 5 carbon atoms, a cycoaky ra ica containing from 3 to 7 carbon atoms, a cycloalkylky radical containing from 3 to 7 carbon atoms, a cycloalkylalkyl radical containing from 4 to 7 carbon atoms or an aralkyl radical containing from 7 to 12 carbon atoms, optionally substituted with 1, 2 or 3 radicals chosen from the group consisting of halogen and methyl, ethyl, methoxy, ethoxy, trifluoromethyl, methylthio, amino and nitro radicals, or R and R- together form a saturated or unsaturated heterocycle which can contain a second hetero atom chosen from oxygen, sulphur and nitrogen atoms, this nitrogen atom optionally being substituted with an alkyl radical containing from 1 to 5 carbon atoms, with a phenyl, siubstituted phenyl or naphthyl radical or with an aralkyl 1
I
.11
I
radical containing from 7 to 12 carbon atoms, R 3 denotes a hydrogen atom, an alkyl radical containing from 1 to carbon atoms, an alkoxy radical containing from 1 to 3 carbon atoms, a chlorine, bromine or iodine atom, a nitro radical or an amino radical optionally substituted with an aliphatic acyl group containing from 2 to 5 carbon atoms or an^alkyl radical contaiinng from to 5 .arbon atoms, a together with b denotes an oxo group, or together with c denotes a carbon-carbon bond, b denotes a hydrogen atom, or together with a an oxo group, c denotes a hydrogen atom, or together with a denotes a carbon-carbon bond, A denotes a chain -(CH2)n- in which n can assume the values 2, 3, 4 or 5, or a chain -(CH 2 )m-CH-CH 2 in which m can
OH
assume the values 1, 2 or 3, B denotes a -CO-NH- or -NH-CO- 15 chain, and R 2 denotes a hydrogen atom, a linear alkyl radical containing from 1 to 5 carbon atoms or a branched alkyl radical containing from 3 to 5 carbon atoms.
These compounds are described as possessing advantageous pharmacological properties and, in particular, 20 exceptional antiarrhythmic properties. The present invention relates to new compounds comprised within the general formula of this European patent application, these new compounds being endowed with especially advantageous antiarrhythmic properties.
The subject of the present invention is hence compounds of formula i S S 5* 0 6@ S 5
I
4
S.
*r S
S.
*4 Sr
I
CH 3 1 <CH OH -I CU 3 in which one or other of the substituents X or Y denotes an alkyL radical containing from 1 to 5 carbon atoms, an 1 1 r i :I II ij_- ;j il_ -3alkoxy radical containing from 1 to 3 carbon atoms, a chlorine, bromine or iodine atom, a nitro radical or an amino radical optionally substituted with an aliphatic, acyl group containing from 2 to 5 carbon atoms or one or two alkyl radicals containing from 1 to 5 carbon atoms, and the other substituent denotes a hydrogen atom, with the proviso, that Y does not denote a methoxy group and X..
a chlorine atom, and also their addition salts with acids.
When X or Y denotes an alkyl radical, the latter is preferably a methyl or ethyl radical, but they can also denote an n-propyl, isopropyl, n-butyl, isobutyl, tertbutyl or n-pentyl radical.
When X or Y denotes an alkoxy radical, it is preferably a methoxy, ethoxy, n-propoxy or isopropoxy radi- 5 cal 0 When X or Y denotes an amino radical substituted with an aliphatic acyl group containing from 2 to 5 carbon atoms, it is preferably an amino radical preferably substituted with an acetyl or propionyl radical.
20 When X or Y denotes an amino radical substituted with one or two alkyl radicals, the latter are preferably methyl or ethyl radicals.
The addition salts with inorganic or organic acids can be, for example, the salts formed with hydrochloric, hydrobromic, nitric, sulphuric, phosphoric, acetic, for- *e mic, propionic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic and aspartic acids, alkanesulphonic acids such as methane- and. ethanesulphonic acids, arylsulphonic acids such as benzene- and para- I 30 toluenesulphonic acids, and arylcarboxylic acids.
SThe invention relates, in particular, to the comp.aunds of formula which are characterized in that X denotes a methoxy, nitro, amino or acetylamino radical and Y denotes a hydrogen atom, or alternatively Y denotes a chlorine atom, a nitro, amino or acetylamino radical and X denotes a hydrogen atom, and also their addition salts with acids, and more especially 2-{3-C(1,1-dimethylethyl)amino3-2-hydroxypropo)xy}-N-(1H-indol-4-yl)-5-nitrobenzamide and also its addition salts with acids.
;ru~rr sr~w -n
I
4 The compounds of formula of the present invention may be prepared by a process similar to that described in European Patent Application No. 86/401,528.4.
The process for preparing the products of the present application is characterized in that:a compound-,of formula (II):
(II)
S
S. S 0
*SSS
C
C
S.
in which X and Y have the above meanings, is reacted with a halide of formula (III): HtiLCHC- HCH2 V d
(III)
to obtain a compound of formula
-O-CH
2
-C-CH
0
(IV)
which is reacted with tert-butylamine to obtain a compound of formula which, if desired, is subjected to the action of an inorganic or organic acid to obtain a salt.
When X or Y denotes an alkyl or alkoxy group or a chlorine, bromine or iodine atom in the compound of formula Hal is preferably a chlorine atom in the compound of formula (III).
The reaction of the compound of formula with the compound of formula (III) is then preferably carried" out in the presence of a base such as potassium carbonate or sodium carbonate, sodium hydroxide or potassium hydroxide.
When X or Y denotes a nitro group in the compound of formula Hal is preferably a bromine atom in the compound of formula (III). The reaction is then carried out by heating the compound of formula (IV) under reflux.
The reaction of the derivative of formula (IV) with tert-butylamine is carried out using a solvent such •15 as an aliphatic alcohol,,,for example methanol or ethanol.
When it is desired to prepare a compound of for- S mula in which X or Y denotes an optionally substituted amino radical, it is possible to reduce the compound of formula in which X or Y denotes a nitro radical and, where appropriate, the amino derivative is reacted with a derivative of the substituent which it is desired to obtain.
The corresponding working conditions are known to those versed in the art.
The starting substance of formula (II) may be S. prepared by reaction of 4-aminoindole with a hydroxybenzoic-.acid substituted with X or Y.
The derivatives which are the subject of the present invention possess very advant:geous pharmacological properties; they are endowed, in particular, with exceptional antiarrhythmic properties and some of the products possess calcium-antagonistic properties.
These properties are illustrated later in the experimental part.
These properties justify the use of the N-(1Hindol-4-yl)benzamide derivatives of formula and also their salts, by way of medicinal products.
The subject of the present patent application is thus also the application, by way of medicinal products, @00.
0 0 0 00060 0 0000 0000 -6of the N-(1H-indol-4-yl 0enzamide derivatives as defined by the formula and also of their addition salts with pharmaceutically acceptable acids.
Among the medicinal products which are the subject of the invention, the medicinal products preferably selected are characterized in that they consist of the new N-(1H-indol-4-yl)benzamide derivatives corresponding to the formula characterized in that X denotes a methoxy, nitro, amino or acetylamino radical and Y denotes a hydrogen atom, or alternatively Y denotes a chlorine atom or a nitro, amino, acetylamino radical and X denotes a hydrogen atom, and also their addition salts with acids.
Among these products, 2-f3-C(1,1-dimethylethyl)amino-2-hydroxypropoxy}-N-(1H-indol-4-yl)-5-nitrobenz- .15 amide, and also its addition salts with acids, are most especially selected.
The medicinal products according to the invention find their application, for example, in the treatment of arrhythmias.
20 The usual dose, which varies according to the derivative used, the subject and the condition in question, can be, for example, from 50 mg to 1 g per day. Orally in man, the derivative of Example 1 can be administered at a daily dose of 200 mg to 800 mg, for example for the 25 treatment of ventricular, supraventricular and junctional arrhythmias, equivalent to approximately 3 mg to 12 mg per kilogram of body weight.
The subject of the invention is also the pharmaceutical compositions which contain at least one of the abovementioned derivatives or one of its addition salts with pharmaceutically acceptable acids, by way of active pr inciple.
By way of medicinal products, the derivatives corresponding to the formula and their addition salts with pharmaceutically acceptable acids can be incorporated into pharmaceutical compositions intended for enteral or parenteral administration.
These pharmaceutical compositions can be, for example, solid or liquid, and can be presented in the 00 00 00 0S
SO
50 0@SS0 0 @0r 7 pharmaceutical forms commonly used in.human. medicine, such as, for example, simple or sugar-coated tablets,, gelatin capsules, granules, suppositories or injectable preparations; they are prepared according to the usual methods. The active principle or principles can be incorporated therein with excipients customar ily employed in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fats of animal or vegetable origin, paraffin derivatives, glycols, various wetting, dispersant or emulsifying agents and preservatives.
"The examples which follow illustrate the present invention without, however, limiting it.
15 Example 1: 2-{3-E(1,1-dimethylethyl)amino3-2-hydroxyl propoxyj-N-(IH-indol-4-yl)-5-nitrobenzamide and its hydrochloride.
•9.8 g of 2-hydroxy-5-nitro-N-(lH-indol-4-yl)-benzamide are heated under reflux for 1 hour with 40 cm 3 of 20 epibromohydrin. The excess epibromohydrin is removed under reduced pressure at 60 0 C, the resin obtained is 3 taken up with 100 cm of ethanol and 40 cm of tert-butylamine and the mixture is heated under reflux for 2 hours.
The excess solvent and reagent is removed under reduced pressure at 60°C and 78 g of crude product are obtained.
Purification is performed by two successive chromatographic. runs on silica (1st: eluant: chloroform/methanol/triethylamine 8 2nd: eluant: chloroform/acetone/triethylamine 4.4 g of product are recovered in the form of the base. M.p. 2080 C Formation of the hydrochloride g of base prepared above are dissolved in one litre of isopropanol and 250 cm 3 of methanol at the reflux, and a saturated solution of hydrochloric acid in ethyl acetate is added until the pH is acid. The mixture is heated for 30 minutes und-r reflux, concentrated to approximately 500 cm 3 chilled, filtered and dried under reduced pressure at 50°C. 2.85 g of expected product are obtained. M.p. 260 0
C.
o f -8 F Analysis: Catlculated: CL% 57.08 H% 5.88 N%_:12.10, CL 7.66 Found 56.8 6.1 12.0 7.4 Preparation of 2-hydroxy-5-nitro-N-(1H-indoL-4-y.)benzamide 6 g of 4-aminoindole, 150 cm 3 of tetrahydrofuran, 8.4 g of 5-nitrosalicylic acid and 12.5 g of dicycLohexyLcarbodiimide are heated under reflux for 3 hours.
The mixture is cooLed and filtered, 200 cm 3 of ethyl acetate are added, the excess unreacted 4-aminoindoe is removed by washing with 1N hydrochloric acid and the mixture is dried, filtered and evaporated to dryness under reduced pressure at 500C. 20 g of resin are obtained, which is made into a paste with a chloroform/methanol (50:50) mixture, filtered and dried under reduced pressure, and 7.5 g of expected prdduct are obtained. M.p. 260 0
C.
t **Example 2: 5-amino-2-{3-C(1,1-dimethyLethyL)amino)-2- *hydroxypropoxy-N-(1H-indo-4-yL)-benzamide.
142 mg of product of Example 1, 5 cm 3 of methanol, 2 0 a pinch of Raney nicke and 0.2 cm 3 of hydrazine hydrate S are heated for 1 hour under reflux. The mixture is filtered, the methanoL is removed under reduced pressure at 50 0 C and 128 mg of expected product are obtained.
*5S565 UV spectrum: ethanoL: 1 SMax. 219 nm E 443 Max. 310 nm E 230 in ethano, N HCL SMax. 299 nm E 208 e 8,200 Inft. 275 and 332 nm Example 3: 5-acetyLamino-2-3-E (1,1-dimethyLethyL )amino3- 2-hydroxypropoxy-N-( 1H-indoL-4-yL )benzamide and its neutra oxaLate.
Stage A: 5-amino-2-hydroxy-N-(1H-indol-4-yL)benzamide.
A suspension comprising 6 g of 5-nitro-2-hydroxy- N-(1H-indoL-4-y)benzamide prepared in Example 1, 600 cm 3 of methanol and 15 cm 3 of 64% strength hydrazine hydrate p F3 -9is heated under reflux for 2 hours in the presence of 6 g of Raney nickel. The solution obtained is ,filtered, the solvent removed under reduced pressure at 50 0 C, the resiTdue taken up with a chloroform/methanol mixture. and the crystallized product filtered off and dried, and 4 g of expected product are collected Mi.p. 2600C.
Stage B: 5-acetylamino-2-acetoxy-N-( H-indol-4-yl)benzamide.
2.6 g of product prepared in the preceding stage, suspended in 70 cm 3 of tetrahydrofuran, are cooled to between 0 and 4.7 cm 3 of acetic anhydride are then added and the mixture is then maintained at room temperae*se ture for 3 hours. The solvent is removed under reduced pressure at 50 0 C, the residue taken up in a chloroform/ methanol mixture, the resulting mixture is filtered and 2.7 g of expected product are obtained after drying at 80 0 C. M.p. 263 0
C.
Stage C: 5-acetylamin -2-hydroxy-N-(IH-indol-4-yl)benzamide.
1.5 g of sodium borohydride is added at room temperature to a suspension containing 1.5 g of product ob- 3 tained in the preceding stage and 150 cm of methanol, and the mixture is heated for 2 hours under reflux. The metha- S* nol is partially removed under reduced pressure at 50 C, and the mixture is diluted with 200 cm 3 of water and 200 cm 3 of ethyl acetate and then extracted with ethyl acetate.
The -extracts are dried, the solvents are removed under reduced pressure at 50 0 C and 1.35 g of expected product is collected, which is used without further treatment for the following stage.
Stage D: 5-acetylamino-2-E(2-oxiranyl)methoxy-N-(1Hindol-4-yl)benzamide.
g of product prepared as in stage C, 150 cm 3 of acetone, 1.6 g of potassium carbonate and 9 cm 3 of epibromohydrin are heated under reflux for 2 hours. 9 cm 3 of epibromohydrin are added again and refluxing is continued for 20 hours. After filtration, washing with acetone and removal of the solvent under reduced pressure at 50 0 C, the residue is taken up in ether and, after filtration and 10 drying at 80 0 C, 3.4 g of expected product are recovered.
M.p. 230 0
C.
Stage E: 5-acetyLamino-2-{3-E(1,1-dimethyLethyL)aminol- 2-hydroxypropoxy)-N-(1H-indoi-4-yL)benzamideii and its neutraL oxalate.
3.4 g of the product obtained above is heated under reflux for 1 hour in 200 cm 3 of ethanoL and 20 cm 3 of tert-butylamine. The solvents are removed under reduced pressure at 50 0 C, the residue is chromatographed on silica (eluant: chLoroform/methano/triethyLamine 8:1:1) and 3.9 g of expected base are collected.
Preparation of the oxalate.
goes 3 *g 2.7 g of base are dissolved in 200 cm of ethanoL and 330 mg of oxalic acid are added. The product is filtered off and dried at 80 0 C under reduced pressure and *se 2.2 g of the expected oxalate are obtained. M.p. 2600C.
Analysis: C 24
H
3 0
N
4 0 4 .1/2 C 2
H
2 0 4 423.549 Calculated: C% 62.10 H% 6.46 N% 11.59 Found 61.9 6.2 11.5 20 Example 4: 2-f3-E(1,1-dimethytethyl)amino3-2-hydroxypropoxy)-N-(1H-indoL-4-yL)-4-methoxybenzamide and its benzoate.
Stage A: 4-methoxy-2-C(2-oxiranyL)methoxy3-N-( 1H-indoL- 4-yl)benzamide.
The procedure is as in stage D of Example 3, Sstarting with 5 g of 4-methoxy-2-hydroxy-N-(1H-indot-4- SyL)b-enzamide, 150 cm of acetone, 2.45 g of potassium carbonate and 14 cm 3 of epichlorohydrin. 7.3 g of expected product are obtained. M.p. 157oC.
Stage B: 2-c3-E 1,1-dimethyLethyL )aminol-2-hydroxypropoxy}-N-(1H-indoL-4-yL)-4-methoxybenzamide and its benzoate.
The procedure is as in stage E of Example 3, starting with 6 g of the product prepared in stage A above, 100 cm 3 of ethanoL and 9.2 cm 3 of tert-butyLamine, refluxing being maintained for 3 hours. 6.1 g of expected base are obtained, which is dissolved in 300 cm 3 o isopropano at the reflux, and 1.8 g of benzoic acid is then added. The mixture is partially concentrated, chiLLed 1 '4 11 and fiLtered, the product is dried under reduced pressure and 5.1 g of expected benzoate are obtained. M.p. 195 0 after recrystallization in ethanoL.
Analysis: C 2 3
H
2 9
N
3 0 4
.C
7
H
6 0 2 533.629 Calcuated: C% 67.53 H% 6.61 N% 7.87 Found 67.5 6.7 Preparation of 4-methoxy-2-hydroxy-N-( 1H-indoL-4-yL )benzamide used at the start of Example 4.
3.96 g of 4-amino-1H-indoe, 70 cm of tetrahydrofuran, 5 g of 2-hydroxy-4-methoxybenzoic acid and 6.2 g of dicyclohexylcarbodiimide are heated under refLux for 24 hours. The solvent is removed under reduced pressure at 50oC, the residue taken up in ethyL acetate and the Sunreacted 4-aminoindoLe removed by washing with 2N hy- 15 drochloric acid. The ethyl acetate is removed under re- 0@@O e 6 duced pressure, the residue taken up with ether and the se** product dried at 50 0 C. 7.1 g of expected product are obtained. M.p. 1900C Example 5: 5-chLoro-2-3-E (1,1-dimethyLethyL )amino3-2- 20 hydroxypropoxy)-N-(1H-indoL-4-y)benzamide and its neutral oxatate.
Stage A: 5-chLoro-1-E(2-oxiranyL)methoxy]-N-(1H-indoL-4yl)benzimide.
The procedure is as in stage D of Example 3, starting with 3 g of 5-chloro-2-hydroxy-N-(1H-indol-4-yl)- A: 3 ,benzamide, 100 cm of acetone, 1.47 g of potassium carbonate and 8.3 cm of epichlorohydrin. 3.35 g of expected product are obtained. M.p. 1750C.
Stage 8: 5-chLoro-2-f3-E(1,1-dimethyLethyL )amino-2-hydroxypropoxy)-N-(1H-indoL-4-yL)benzamide and its neutral oxalate.
The procedure is as in stage E of Example 3, starting with 3 g of product obtained in stage A, 60 cm 3 of ethano and 4.6 cm 3 of tert-butyamine. 2.6 g of expected base are obtained, and then 2.4 g of oxaLate.
M.p. 260oC.
Analysis: C 22
H
26
CLN
3 0 3 .1/2 C 2
H
2 0 4 460.941 Calculated: CL -59-93 H% 5.90 N% 9.12 CL% 7.69 Found 60.2 5.8 9.1 7.9 12 Preparation of 5-chloro-2-hydroxy-N-( H-indol-4-yl)benzamide used at the start of Example 3.96 of 4-amino-lH-indole in 75 cm of tetrahydrofuran are heated under reflux with 5.16 g of salicylic acid and 6.2 g of dicyclohexylcarbodiimide for 2 hours; 0.62 g of dicyclohexylcarbodiimide is added again, the mixture is heated for a further 1 hour under reflux, cooled and filtered and the solvent is removed under reduced pressure at 50 0 C. The residue is taken up in ethyl acetate and the resulting mixture washed with 2 N hydrochloric acid and dried, and the ethyl acetate is removed under reduced pressure at 30 0 C. After chromatography of the residue on silica (eluant: chloroform/ethyl acetate 3.9 g of expected product are recovered.
15 M.p. 248°C.
Example 6: Tablets corresponding to the following formula 0•0 are prepared: product of Example 50 mg excipient qs for a finished tablet weighing... 100 mg (detail of the excipient: lactose, starch, talc, magnesium "stearate).
Pharmacological study Antiarrhythmic action in rats Male rats weighing 300-350 g, anaesthetized intraperitoneally using 1.20 g/kg of urethane, are tracheotomized and subjected to artificial respiration (40-50 3-ml insufflations/minute).
Needles are implanted subcutaneously so as to record the electrocardiogram of the rats using the signal from DII leads.
The test products are administered intravenously Sor orally.
Five minutes after the intravenous administration of the product, the jugular vein of the rats is perfused with 10 pg/min of a solution of aconitine, and the time taken for the onset of the disorders of cardiac rhythm is noted (10 pg of aconitine corresponding to the perfusion of 0.2 ml of solution).
l i 1 1 1 width, on tough white paper of good quality and it is to be inserted inside this form.
S
13 The results are-ixpressed as a percentage pro- Longation of the time taken for the onset of the disorders of cardiac rhythm compared with controls and in terms of the dose of test product. The results recorde.d in the table below show that the products of the present patent application are endowed with exceptional antiarrhythmic properties.
ii i r r I u i: i 100 Product of: Exampl'e, Dose Percentage prolongaadm ini steredd iiv. in mg/kg tion of the time 1 1 2.5 +77% S1 +39% +17%2 4- 2.5 +38%4 1 Test of calcium-antagonistic activity in vitro Rat cauclal arteries are cut into a spiraL, connected to tension gauges and maintained in cells containing 25 mL of Krebs sodium bicarbonate buffer (NaCL: 120.8 mM; KCL: 5.9 mM; MgCL2: 1.2 mM; NaH2PO4: 1.2 mM; NaHC03: 15.5 mIM; gLucoSe: 12.6 W at 370C, gassed with a 95% 02/54% C02 mixture.
The preparations are depo~aried with a buffer soLLution containing K ions at a concentration of 100 mM (NaCL: 26.7 mM; KCL: 100 mM; MgCL2: 1.2 mM; NaH2PO4: .1.2 mM; NaHCOV ,15.5 mM; glucose: 12.6 Calcium chloricle is addel in a volume of ;25 IA 4o as to obtain a series of increasing concentrations of Ca 2+ions ranging from 0.1 to 3.0 mM the contractions of: the :arteries are recorded and a -control Series i~s thus estab~ished.: The opeeration is repeated with the s~eries -of Ca 2+ions every 15 minutes and the preparation is washed four times after each ~eries.
When a stable response is obtained, the. operation wihthe series of Ca 2 i-ons is performed in the presence o~f diifferent cioncentrations of th'e test product, untiL a 14 stable response is obtained.
The contractions of the arteries depend on the entry of Ca2+ ions into the cells of the smooth muscles, and are caused by the depolarization of the smooth muscle by the K ions and by the action of the noradrenaline released at presynaptic level. By starting the operation again with arteries denervated by the action of 6-OH-dopamine, the specific action due to noradrenaline is eliminated.
The results are expressed as IC 50 (inhibitory concentration 50 the concentration of the test product which inhibits by 50% the contraction due to K+ ions.
From the results recorded in the table below, it is observed that the products of the present patent appli- 15 cation possess strong calcium-antagonistic activity.
*O*O*1 0O*@ 0
S
S.
S
S.
20 Product of Example IC 5 0 in pM 4 8 5 5.4 Study of the acute toxicity The lethal dose LD 0 of the compound of Example 1 was assessed after oral administration after oral adminis- 25 tration in mice.
LD
0 designates the maximum dose causing no mortality in the course of 7 days.
The LD 0 was found to be 200 mg/kg.
Claims (6)
1. Compounds of formula x Y CH I 'CH H OH H 3 -N o H in which one or other of the substituents X or Y denotes an alkyl radical containing from 1 to 5 carbon atoms, an alkoxy radical containing from 1 to 3 carbon atoms, a :chlorine, bromine or iodine atom, a nitro radical or an amino radical optionally substituted with an aliphatic acyl group containing from 2 to 5 carbon atoms or one or two alkyl radicals containing from 1 to 5 carbon atoms, and the other substituent denotes a hydrogen atom, with the proviso that Y does not denote a methoxy group and X a chlorine atom, and also their addition salts with acids.
2. Compounds of formula as defined in Claim 1, characterized in that X denotes a methoxy, nitro, amino or acetylamino radical and Y denotes a hydrogen atom, or alternatively Y denotes a chlorine atom, a nitro, amino or acetylamino radical and X denotes a hydrogen atom, and also their addition salts with acids. S" 3. 2-{3-E(1,1-Dimethylethyl)amino3-2-hydroxypropoxyl- N-(1H-indol-4-yl)-5-nitrobenzamide and also its addition salts with acids.
4. Process for preparing the products of formula characterized in that a compound of formula (II): SOH (II) H-N iNi H J -16 in which X and Y have the above meaning, is reacted with a halide of formula (Il): Hal-CH 2 -CH-CH 2 (II) to obtain a compound of formula (IV): X Y O-CH 2 -CH-CH 2 (IV) N H-H hich is reacted with tert-butylamine to obtain a compound of fhrmula which, if .desired, is subjected to the action of an inorganic or organic acid to obtain a salt. Medicinal products, characterized in that they consist of the N-(1H-indol-4-yl) .benzamide derivatives as defined by the formula of Claim 1, and also of their addition fq salts with pharmaceutically acceptable acids. i'6: Medicinal products, characterized in that they consist of the N-(1H-indol-4-yl) t enzamide derivatives as defined in Claim 2, and also of their addition salts with ;harmaceutically acceptable acids.
7. Medicinal products, characterized in that they consist of a N-(1H-indol-4-yl) benzamide derivative as defined in Claim 3, and also of its addition salts with pharmaceutically acceptable acids.
8. Pharmaceutical compositions, characterized in that they contain, by way of active principle, at least one of the medicinal products defined in one of Claims 5 to 7, in S association with pharmaceutically acceptable excipient. i 1- :i i: m
17- 9. Compounds of formula as claimed in any one of claims 1 to 3, substantially as hereinbefore described, with reference to any one of Examples 1 to A process as claimed in claim ri, substantially as hereinbefore described with reference to any one of Examples 1 to 11. A pharmaceutical composition as claimed in claim 8, substantially as hereinbefore described with reference to Example 6. D ATED this 12th day of July, 1991. i; r o r ROUSSEL-UCLAF By its Patent Attorneys: CALLNAN LAWRIE
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8700151A FR2609464B1 (en) | 1987-01-09 | 1987-01-09 | NOVEL N- (1H-INDOL 4-YL) BENZAMIDE DERIVATIVES AND THEIR SALTS, THEIR USE AS MEDICAMENTS, AND THE COMPOSITIONS CONTAINING THEM |
| FR8700151 | 1987-01-09 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU1012988A AU1012988A (en) | 1988-07-14 |
| AU619728B2 true AU619728B2 (en) | 1992-02-06 |
Family
ID=9346770
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU10129/88A Ceased AU619728B2 (en) | 1987-01-09 | 1988-01-08 | New N-(1H-indol-4-yl)benzamide derivatives and also their salts, their application by way of medicinal products and the compositions containing them |
Country Status (14)
| Country | Link |
|---|---|
| EP (1) | EP0275221B1 (en) |
| JP (1) | JPS63188664A (en) |
| KR (1) | KR880008988A (en) |
| AT (1) | ATE62673T1 (en) |
| AU (1) | AU619728B2 (en) |
| DE (1) | DE3862380D1 (en) |
| DK (1) | DK168377B1 (en) |
| ES (1) | ES2029033T3 (en) |
| FI (1) | FI85140C (en) |
| FR (1) | FR2609464B1 (en) |
| GR (1) | GR3002185T3 (en) |
| HU (1) | HU201910B (en) |
| IE (1) | IE60779B1 (en) |
| ZA (1) | ZA8837B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5234942A (en) * | 1984-10-19 | 1993-08-10 | Ici Americas Inc. | Heterocyclic amides and leucotriene antagonistic use thereof |
| DE4119611A1 (en) * | 1991-06-14 | 1992-12-17 | Bayer Ag | AGENTS FOR CONTROLLING PESTS BASED ON SUBSTITUTED OXAZOLIDINONE, NEW SUBSTITUTED OXAZOLIDINONE, THEIR PRODUCTION AND USE |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU6003286A (en) * | 1985-07-11 | 1987-01-15 | Roussel-Uclaf | New derivatives of carboxamide indole, their salts, process and intermediates for preparation, use as medicaments and compositions containing them |
| AU8280587A (en) * | 1986-12-19 | 1988-06-23 | Roussel-Uclaf | New indolecarboxamide derivatives as well as salts thereof, process and intermediates for preparation, application of these derivatives by way of medicinal products and compositions containing them |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4853408A (en) * | 1985-04-23 | 1989-08-01 | Roussel Uclaf | 4-phenylpropyl-indoles having antiarythmic activity |
| FR2583047B1 (en) * | 1985-06-05 | 1988-01-08 | Roussel Uclaf | PROCESS FOR THE PREPARATION OF INDOLE 4-PHENYLPROPYL DERIVATIVES AND INTERMEDIATES |
-
1987
- 1987-01-09 FR FR8700151A patent/FR2609464B1/en not_active Expired - Lifetime
-
1988
- 1988-01-05 ZA ZA8837A patent/ZA8837B/en unknown
- 1988-01-06 DK DK003288A patent/DK168377B1/en active
- 1988-01-08 AU AU10129/88A patent/AU619728B2/en not_active Ceased
- 1988-01-08 AT AT88400036T patent/ATE62673T1/en active
- 1988-01-08 ES ES198888400036T patent/ES2029033T3/en not_active Expired - Lifetime
- 1988-01-08 FI FI880064A patent/FI85140C/en not_active IP Right Cessation
- 1988-01-08 EP EP88400036A patent/EP0275221B1/en not_active Expired - Lifetime
- 1988-01-08 JP JP63001420A patent/JPS63188664A/en active Pending
- 1988-01-08 HU HU8854A patent/HU201910B/en not_active IP Right Cessation
- 1988-01-08 DE DE8888400036T patent/DE3862380D1/en not_active Expired - Fee Related
- 1988-01-08 IE IE3988A patent/IE60779B1/en not_active IP Right Cessation
- 1988-01-09 KR KR1019880000113A patent/KR880008988A/en not_active Application Discontinuation
-
1991
- 1991-06-26 GR GR90400513T patent/GR3002185T3/en unknown
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU6003286A (en) * | 1985-07-11 | 1987-01-15 | Roussel-Uclaf | New derivatives of carboxamide indole, their salts, process and intermediates for preparation, use as medicaments and compositions containing them |
| AU8280587A (en) * | 1986-12-19 | 1988-06-23 | Roussel-Uclaf | New indolecarboxamide derivatives as well as salts thereof, process and intermediates for preparation, application of these derivatives by way of medicinal products and compositions containing them |
Also Published As
| Publication number | Publication date |
|---|---|
| ZA8837B (en) | 1989-03-29 |
| ATE62673T1 (en) | 1991-05-15 |
| DK168377B1 (en) | 1994-03-21 |
| FI880064A (en) | 1988-07-10 |
| FI880064A0 (en) | 1988-01-08 |
| IE880039L (en) | 1988-07-09 |
| IE60779B1 (en) | 1994-08-10 |
| FI85140C (en) | 1992-03-10 |
| EP0275221A2 (en) | 1988-07-20 |
| AU1012988A (en) | 1988-07-14 |
| HUT45491A (en) | 1988-07-28 |
| KR880008988A (en) | 1988-09-13 |
| HU201910B (en) | 1991-01-28 |
| DE3862380D1 (en) | 1991-05-23 |
| FI85140B (en) | 1991-11-29 |
| DK3288A (en) | 1988-07-10 |
| EP0275221A3 (en) | 1988-08-24 |
| DK3288D0 (en) | 1988-01-06 |
| FR2609464B1 (en) | 1990-12-07 |
| FR2609464A1 (en) | 1988-07-15 |
| JPS63188664A (en) | 1988-08-04 |
| GR3002185T3 (en) | 1992-12-30 |
| ES2029033T3 (en) | 1992-07-16 |
| EP0275221B1 (en) | 1991-04-17 |
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