IE49629B1 - Imidazo-and pyrimido-pyridoindoles and pharmaceutical compositions - Google Patents

Imidazo-and pyrimido-pyridoindoles and pharmaceutical compositions

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Publication number
IE49629B1
IE49629B1 IE77/80A IE7780A IE49629B1 IE 49629 B1 IE49629 B1 IE 49629B1 IE 77/80 A IE77/80 A IE 77/80A IE 7780 A IE7780 A IE 7780A IE 49629 B1 IE49629 B1 IE 49629B1
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alkyl
radical
compound
formula
hydrogen atom
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IE77/80A
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IE800077L (en
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Synthelabo
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pain & Pain Management (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biomedical Technology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

1. Claims for the Contracting States : BE, CH, DE, FR, GB, IT, LU, NL, SE. Imidazo and pyrimido-pyrido-indoles in form of racemates or enantiomers corresponding to formula (I) see diagramm : EP0015786,P9,F1 wherein n is 1 or 0, R1 is a hydrogen or halogen atom, an alkyl or alkoxy radical or a CF3 group, R2 is an alkyl, cycloalkyl, cycloalkylalkyl, phenyl or benzyl radical, the two latter radicals being optionally substituted with a halogen atom or an alkyl or alkoxygroup, R3 is a hydrogen atom or an alkyl radical, R4 is a hydrogen atom or an alkyl radical, said alkyl and alkoxy radicals having 1 to 4 carbon atoms, with the exception of the compound for which n = 1, R1 = R3 = R4 = H and R2 = CH3 . 1. Claim for the Contracting State : AT A process for preparing imidazo and pyrimido-pyrido-indoles in form of racemates or enantiomers corresponding to formula (I) see diagramm : EP0015786,P11,F3 wherein n is 1 or 0, R1 is a hydrogen or halogen atom, an alkyl or alkoxy radical or a CF3 group, R2 is an alkyl, cycloalkyl, cycloalkylalkyl, phenyl or benzyl radical, the two latter radicals being optionally substituted with a halogen atom or an alkyl or alkoxy group, R3 is a hydrogen atom or an alkyl radical, R4 is a hydrogen atom or an alkyl radical, said alkyl and alkoxy radicals having 1 to 4 carbon atoms, with the exception of the compound for which n = 1, R1 = R3 = R4 = H and R2 = CH3 , characterized in that a compound of formula (II) see diagramm : EP0015786,P11,F4 is reacted with an amine R2 NH2 , then the intermediate compound obtained, of formula (III) see diagramm : EP0015786,P12,F1 is cyclized by means of formaldehyde in 30% aqueous solution, and, when R4 = H, the corresponding compound (I) may be alkylated to yield a compound (I) wherein R4 is alkyl.

Description

The present invention relates to imidazoand pyrimido-pyridoindole derivatives, in the form of racemates or enantiomers, their addition salts with pharmaceutically acceptable acids, and their application in therapy.
The imidazo-and pyrimido-pyridoindole derivatives have the formula (I) in which n is 1 or 0,R^ is a hydrogen or halogen atom, an alkyl or alkoxy radical or a CF3 group, R2 is an alkyl, cycloalkyl, cycloalkylalkyl, phenyl or benzyl radical, the two latter radicals being optionally substituted with a halogen atom or an alkyl or alkoxy group, R^ is a hydrogen atom or an alkyl radical and R^ is a hydrogen atom or an alkyl radical, the alkyl and alkoxy radicals having from 1 to 4 carbon atoms, with the exception of the compound in which n = 1, R^ = R3 = R^ = H and R2 = CH3< but including the pharmaceutically acceptable acid addition salts of these conpounds.
The above derivatives are herein referred to for brevity as the therapeutic conpounds.
They have an asymmetric carbon in the 12b-position (n=l) or lib-position (n=0) and the above definition includes them in the form of their racemates and enantiomers.
A preferred class of the therapeutic compounds is those in which R^ is a hydrogen atom, a chlorine or fluorine atom or a methyl radical, R2 is a methyl or ethyl radical, R3 is a hydrogen atom or a methyl radical and R^ is a hydrogen atom or a methyl radical.
In another embodiment of the invention the therapeutic compounds are those in which (i) n, R^, R2 and R3 are as defined for formula (I) and is an alkyl radical of 1 to 4 carbon atoms; or (ii) n, R2, R3 and R^ are as defined for formula (I) and R-l is a trifluoromethyl radical; or (iii) n, Ry R3 and R^ are as defined for formula (I) and R2 is a phenyl radical unsubstituted or substituted by a halogen atom or an alkyl or alkoxy radical; or (iv) n, Rj, R3 and R^ are as defined for formula (I) and is an alkoxy radical; with the exception of the compounds in which simultaneously n=l, Ry R^ and R^ are hydrogen atoms and Sj is a methyl radical.
The invention includes the above-defined compounds in the particular context of their use in therapy and especially in the form of a pharmaceutical composition thereof which also contains a pharmaceutically acceptable excipient. This utility is referred to hereinafter.
According to the invention, the therapeutic compounds are prepared from a compound of the formula (II) which is reacted with an amine in a solvent such as an alcohol or the amine a^ a temperature e.g. from ambient temperature to 100°C, and the resulting intermediate of the formula (III) r4 (CH,) CONHR, 2 n 2 (III) *1 is then cyclised by reaction with aqueous formaldehyde, preferably of 30% strength, at a temperature e.g. from ambient up to 70"C„ R^, R^, R^ and n in the above reactants are defined as for formula (I).
If R^ is a hydrogen atom in the compound {I), the latter can then be alkylated, preferably by an alkyl iodide in a strong base in order to obtain a derivative (I) in which R^ is an alkyl radical. The reaction is particularly useful to produce a conpound in which R2 is also an alkyl radical.
The starting conpounds (II) in which R^ = alkyl can be prepared from substituted or unsubstituted tryptamine in accordance with the following scheme, R^ and n being as defined above: This reaction is described in the literature by J.A. MACLAREN, Aust. J. Chem. (1977) ^0, 2,045-51.
The starting compounds (II) in which = H and n = lean be prepared from the hydrochloride of substituted or unsubstituted tryptamine in accordance with the following reaction scheme , being as defined above: CH-COOEt (ID 2 The compound (II) in which R^ is H and n is 1 is 5 described by L.H. GROVES and G.A. SWAN, J. Chem. Soc. (1952) 650.
The starting compounds (II) in which R^ is different from H are new.
Example of the preparation of a compound (II) [RT = 9-CH3, n = 1, R3 = H] 1. 52,62 g (0.25 mol) of 5-methyltryptamine hydrochloride are suspended in 250 ml of ethanol and the suspension is heated to the reflux temperature. 57.75g of 3-ethoxycarbonyl-l,2-dioxo-l-ethoxypropane are suspended in 250 ml of ethanol, and 25 ml of concentrated hydrochloric acid are added dropwise in the course of 10 minutes. The latter suspension is added to the 5-methyltryptamine suspension kept at the reflux temperature.
The mixture is allowed to cool overnight. The solvent is removed by evaporation, the residue is dissolved in 400 ml of water and the solution is rendered alkaline with ammonia. After extraction with ethyl acetate, an oil is obtained which is chromatographed on a silica column. After elution with an 8/2 mixture of chloroform and ethanol, an oil is obtained which solidifies on trituration with petroleum ether. After recrystallisation from hexane, the compound obtained 2. 45 g of the above compound are heated under reflux for 20 hours in 450 ml of a 10% strength aqueous solution of NaOH. Concentrated hydrochloric acid (100 ml) is added dropwise, in the course of 30 minutes, to the cooled reaction mixture. The resulting solid is filtered off and dried over P-,0... d 5 3. 99.6 g of the crude solid obtained above are heated under reflux in a mixture of 250 ml of ethanol and 20 ml of concentrated sulphuric acid for 9 hours. The mixture is left to stand overnight. The ethanol is removed by evaporation and the residual solid Is rendered alkaline with ammonia. The basic solution is extracted with 3 times 300 ml of ethyl acetate. The extract is evaporated. An oil is obtained which gives a white solid on trituration with petroleum ether. The solid is filtered off and dried.
After recrystallisation from hexane, the resulting compound (II) melts at 103°C.
The following examples illustrate the invention. The micro-analyses and the IR and NMR spectra confirm the structure of the compounds.
EXAMPLE 1 2,llb-Dimethyl-2,3,5» 6,11,llb-hexahydro-lHimidazo[l',5':l,2]pyrido[3,4-b]indol-l-one. [n=0, R1=H, R2=CH3, R3=CH3, R4=H] 1. l-Methylaminocarbonyl-l-methyl-2,3,4,9-tetrahydro-lH20 pyrido[3,4-b]indole. 4.8 g (0.02 mol) of methyl l-methyl-2,3,4,9-tetrahydro-lH-pyrido[3,4-b]indole-l-carboxylate (starting compound II) are dissolved in 100 ml of ethanol saturated with methylamine.
The solution is left at ambient temperature for hours. The solvent is removed and the residue is then taken up in 20 ml of ethanol. The mixture is fil49629 tered and the solid is washed with ethanol.
Melting point = 23O-231°C. 2. 2,llb-Dimethyl-2,3,5,6,11,llb-hexahydro-lH-imidazo[1',5':l,2]pyrido[3,4-b]indol-l-one. 12 g (0,05 mol) of the compound obtained above are placed in 200 ml of ethanol. 3 g of KOH pellets and then 25 ml of a 30# strength aqueous solution of formaldehyde are added.
The mixture, is stirred at 70°C for 12 hours.
The precipitate is filtered off and washed with ethanol. After recrystallisation from propanol, the compound melts at 252-253°C.
EXAMPLE 2 9-Chloro-3-methyl-3,4,6,7,12,12b-hexahydropyrimido[l',6':l,2]pyrido[3,4-b]indol-2(lH)~ one. [n=l, R1=9-C1, R2=CH3, R3=H, R^H] 1. N-Methyl-6-chloro-2,3,4,9-tetrahydro-lH-pyrido[3,4-bjindole-l-acetamide. g of ethyl 6-chloro-2,3,4,9-tetrahydro-lH20 pyrido[3,4-b]indole-l-acetate (starting compound (II)) are dissolved in a mixture of 150 ml of ethanol and 150 ml of a 33% strength solution of methylamine in ethanol.
The reaction mixture is heated at 200°C for 7 hours in an autoclave. It is left to cool overnight. The solu25 tion is evaporated.
The solid, which is recrystallised from ethanol, melts at 228-230°C. η 2. 9-Chloro-3-methyl-3,4,6,7,12,12b-hexahydropyrimido[1',6':l,2]pyrido[3,4~b]indol-2(lH)-one 1.7 g of the compound obtained above are dissolved in a mixture of 20 ml of ethanol and 2 ml of a 30% strength aqueous solution of formaldehyde,at ambient temperature.
The solution is stirred for 30 minutes. The solvent is removed, the white solid is taken up in cold ethanol and the mixture is filtered. The product is recrystallised from ethanol.
Melting point = 257°C.
EXAMPLE 3 3,12b-Dimethyl-3,4,6,7,12,12b-hexahydropyrimido[l',6':l,2]pyrido[3,4-b]indol-2(lH)~ one. [n=l, R-^H, R2=CH3’ r3=CH3’ R4=H] 1. N-Methyl-l-methyl-2,3,4,9-tetrahydropyrido[3,4-b]indole-l-acetamide. 36.9 g of ethyl l-methyl-2,3,4,9-tetrahydro-lHpyrido[3,4-b]indole-l-carboxylate are introduced into an autoclave together with 300 ml of a 33% strength solution of CHjNI^ in ethanol. The mixture is heated at 100°C for 8 hours. The solvent is driven off and the residue is crystallised from ethanol.
Melting point = 182-183°C. 2. 3,12b-Dimethyl-3,4,6,7,12,12b-hexahydropyrimido25 [l*,6':l,2]pyrido[3,4-b]indol-2(lH)-one. g of the above compound and 150 ml of ethanol are introduced into a round-bottomed flask. A 33% ,. 49629 strength aqueous solution of formaldehyde is added and the mixture is stirred at ambient temperature for 3 hours. The solvent is driven off and the residue is dried by azeotropic distillation with toluene. The residue is dissolved in 500 ml of chloroform and the solution is dried over NagSO^. After evaporating the solution, an oil is obtained. Dry tetrahydrofurane is added and then driven off. A white solid is obtained which is recrystallised from ethyl acetate.
Melting point = 204°C.
EXAMPLE 4 3,12,12b-Trimethyl-3,4,6,7,12,12b-hexahydropyrimido[l',6':l,2]pyrido[3,4-h]indol-2(lH)one. [n=l, R1=H, R2=CH3, R3=CH3, R4=CH3] '3 g of the compound obtained in Example 2 and ml of dimethylformamide are introduced, into, a roundbottomed flask. 0.53 g of sodium hydride is· added’ and the mixture is stirred at ambient temperature for 2 hours. 0.9 ml of methyl iodide is added and the mixture is stirred for 1 minute at ambient temperature.
The solvent is driven off and the residue is chromatographed on Si02· Elution is carried out with an 8/2 mixture of CHCl3/EtOH. A white solid is obtained which is recrystallised from CH3QCH2CH20CH3.
Melting point = 159-l6O°C.
The compounds of formula (1)- which were prepared hy way of examples are shown in the Table belew.
The ring-numbering system referred to in the Table is shown below: Formula Ia (= formula I 5 when n = 0) Formula lb (= formula I when n = 1) 9 6 29 TABLE Compound no. nR1R2R3 ' R4 Characteristics Melting pcanfc (oc) 1 0 HCH3 ch3 H 252-3 2 1 H h-C4H9 H H 232 3 1 H >- H H 2'33 4 1 HC6H5CH2 H H 204 5 1 9-C1CH3 H H 257 6 1 9-F ch3 H H 223 7 1 H ch3 H ch3 165-6 8 1 9-CH3 ch3 H H 225 9 1 9-CH3 ch3 H ch3 136-8 10 1 H ch3 ch3 ch3 160 ii 1 H ch3 ch3 H 204 12 1 HC2H5 H H 227 13 1 3-CHjO ch3 H H • 224 l4 1 K ~@-och3 H H >260 15 1 9-C1C2H5 H H 256-7 16 1 9-C1 H H 264 17 0 8-FC2H5 ch3 H 207 18 0 HC2H5 ch3 H .205 19 0 8-F ch3 ch3 H 223 20 0 8-C1 ch3 ch3 H 248 21 0 8-F -<] ck3 H' 215 22 0 H -< ch3 H 214 23 1 9-CF3 CK3 K H 230 The therapeutic compounds were subjected to pharmacological tests in which they showed themselves to be active as anti-convulsive agents.
The acute toxicity to mice was determined by 5 intraperitoneal administration. The LD varies from 200 to 2,000 mg/kg.
The anti-convulsive activity was determined by means of the test for the antagonism towards the convulsions induced by bicuculline in mice (M. Perez de la Mora and R. Tapia (1973), Biochem. Pharmacol. 22, 2,635-2,639).
The ad50 of th® therapeutic compounds varies between 30 and 50 mg/kg, administered intraperitoneally.
The above results show that the compounds can 15 be used for treating epilepsy.
The therapeutic compounds can be presented in any form which is suitable for oral, parenteral or endorectal administration, for example in the form of tablets, dragees, sugar-coated pills, solutions to be taken orally or injected, and the like, together with any suitable excipient.
The daily posology can range from 200 to 1,500 mg.

Claims (11)

1. Imidazo and pyrimido-pyrido-indoles in form of racemates or enantiomers corresponding to formula (I) 5 wherein n is 1 or is a hydrogen or halogen atom, an alkyl or alkoxy radical or a CFj group, R 2 is an alkyl, cycloalkyl, cycloalkylalkyl, phenyl or benzyl 10 radical, the two latter radicals being optionally substituted with a halogen atom or an alkyl or alkoxygroup, R^ is a hydrogen atom or an alkyl radical, R 4 is a hydrogen atom or an alkyl radical, said alkyl and alkoxy radicals having 1 to 4 carbon atoms, with the except15 ion of the compound for which n = 1, R^ = R^ = R 4 = H and R 2 = CH^, and the pharmaceutically acceptable salts of these compounds.
2. Derivatives according to claim 1, wherein n is 1.
3. Derivatives according to claim 2, characterized in 20 that R^ is a hydrogen atom, a chlorine atom, a fluorine atom or a methyl radical, R 2 is a methyl or ethyl radical, R 3 is a hydrogen atom or a methyl radical and R 4 is a 4. 9 6 29 hydrogen atom or a methyl radical.
4. Imidazo- and pyrimido-pyridoindole derivatives in the form of racemates or enantiomers which have the general formula (I) given in claim 1 in which: (i) n, R^, R 2 and Rg are as defined in claim 1 and is an alkyl radical of 1 to 4 carbon atoms; or (ii) n, R 2 , R 3 and R 4 are as defined in claim 1 and R^ is a trifluoromethyl radical; or (iii) n, R 1# Rg and R^ are as defined in claim 1 and R 2 is a phenyl radical unsubstituted or substituted by a halogen atom or an alkyl or alkoxy radical; or (iv) n, R 2 , Rg and R^ are as defined in claim 1 and R^ is an alkoxy radical and their pharmaceutically acceptable acid addition salts; with exception of the compounds in which simultaneously n = 1, Rp Rg and R 4 are hydrogen atoms and R 2 is a methyl radical.
5. Each of the pyrimido-pyridoindole derivatives 2, 3, 6. 14, 15, 16 and 23 mentioned in the Table hereinbefore set forth.
6. Each of the imidazo-pyridoindole derivatives 1, 17, 18 and 20 to 22 mentioned in the Table hereinbefore set forth.
7. Pharmaceutically acceptable acid addition salts of each of the compounds of formula (I) defined in claim 1, 2 or 3.
8. A process for preparing the compounds of claim 1 characterized in that a compound of the formula (11) - COO (II) (Et or Me) is reacted with an amine R 2 NH 2 , then the intermediate 5 compound obtained, of formula (111) (HI) is cyclised by means of formaldehyde in 30% aqueous solution, and, when R^ = H, the corresponding compound (1) may be alkylated to yield a compound (1) wherein R^ is 10 alkyl, the radicals having the meanings given in claim 1.
9. A process as claimed in claim 8, substantially as herein described.
10. A compound claimed in claim 1, whenever prepared by a process claimed in a preceding claim. 4 9629
11. A pharmaceutical composition which comprises as active ingredient a compound as claimed in any of claims 1-7, together with a pharmaceutically acceptable carrier or diluent.
IE77/80A 1979-02-05 1980-01-15 Imidazo-and pyrimido-pyridoindoles and pharmaceutical compositions IE49629B1 (en)

Applications Claiming Priority (1)

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FR7902839A FR2447921A1 (en) 1979-02-05 1979-02-05 IMIDAZO AND PYRIMIDO-PYRIDO-INDOLES AND THEIR APPLICATION IN THERAPEUTICS

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IE800077L IE800077L (en) 1980-08-05
IE49629B1 true IE49629B1 (en) 1985-11-13

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EP (1) EP0015786B1 (en)
JP (1) JPS55104282A (en)
AT (1) ATE878T1 (en)
AU (1) AU528425B2 (en)
CA (1) CA1129412A (en)
DE (1) DE3060292D1 (en)
DK (1) DK17080A (en)
ES (1) ES487712A1 (en)
FR (1) FR2447921A1 (en)
GR (1) GR74450B (en)
IE (1) IE49629B1 (en)
IL (1) IL59127A (en)
NO (1) NO151289C (en)
PT (1) PT70697A (en)
ZA (1) ZA80241B (en)

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FR2485538B1 (en) * 1980-06-24 1985-01-11 Chinoin Gyogyszer Es Vegyeszet NEW PROCESS FOR THE PREPARATION OF INDOLO (2 ', 3'; 3,4) -PYRIDO (1,2-B) QUINAZOLINE-5-ONES
DE3827727A1 (en) * 1988-08-16 1990-02-22 Boehringer Ingelheim Kg ANALYZED TETRAHYDROPYRIDINE IGNESE DERIVATIVES, METHOD FOR THE PRODUCTION AND USE OF SUCH CONNECTIONS FOR CARDIRO PROTECTION

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EP0015786B1 (en) 1982-04-21
IL59127A (en) 1983-12-30
DK17080A (en) 1980-08-06
FR2447921A1 (en) 1980-08-29
GR74450B (en) 1984-06-28
ES487712A1 (en) 1980-06-16
NO794270L (en) 1980-08-06
NO151289C (en) 1985-03-13
ZA80241B (en) 1980-12-31
DE3060292D1 (en) 1982-06-03
AU528425B2 (en) 1983-04-28
IE800077L (en) 1980-08-05
NO151289B (en) 1984-12-03
CA1129412A (en) 1982-08-10
IL59127A0 (en) 1980-05-30
ATE878T1 (en) 1982-05-15
EP0015786A1 (en) 1980-09-17
PT70697A (en) 1980-02-01
FR2447921B1 (en) 1982-01-29
AU5462980A (en) 1980-08-14
JPS616073B2 (en) 1986-02-24
JPS55104282A (en) 1980-08-09

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