GB2099815A - Intermediates useful in the preparation of pharmaceutical compounds - Google Patents

Intermediates useful in the preparation of pharmaceutical compounds Download PDF

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GB2099815A
GB2099815A GB8203820A GB8203820A GB2099815A GB 2099815 A GB2099815 A GB 2099815A GB 8203820 A GB8203820 A GB 8203820A GB 8203820 A GB8203820 A GB 8203820A GB 2099815 A GB2099815 A GB 2099815A
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acetyl
methyl
isoquinolin
hexahydroindolo
alkyl
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Lilly Industries Ltd
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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
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • 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
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61P25/20—Hypnotics; Sedatives
    • 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
    • A61P25/24—Antidepressants
    • 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
    • A61P25/26—Psychostimulants, e.g. nicotine, cocaine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/90—Benzo [c, d] indoles; Hydrogenated benzo [c, d] indoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/94—[b, c]- or [b, d]-condensed containing carbocyclic rings other than six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D457/00—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/06—Peri-condensed systems

Abstract

There are described compounds of the formula <IMAGE> where the moiety D-E represents a group of formula <IMAGE> or <IMAGE> where R represents hydrogen, C1-6 alkyl, C3-6 cycloalkyl or optionally substituted benzyl, where R<1> and R<2> each represent hydrogen or taken together represent a chemical bond, and where R<3> represents hydrogen, C1-6 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-4 alkyl, optionally substituted benzyl, C3-6 alkenyl or C1-4 alkanoyl; provided that when D- E is <IMAGE> R<1> and R<2> cannot together represent a chemical bond. The compounds are useful as intermediates in the preparation of certain isoquinoline compounds having pharmaceutical CNS properties, the subject of copending Patent Application 7929052.

Description

SPECIFICATION Intermediates useful in the preparation of pharmaceutical compounds This invention relates to certain intermediate compounds useful in the preparation of pharmaceutical compounds.
The compounds of the invention possess the formula
where the moiety D-E represents a group of formula
where R represents hydrogen, C16 alkyl, C3e cycioalkyl or optionally substituted benzyl, where R' and R2 each represent hydrogen or taken together represent a chemical bond, and where R3 represents hydrogen, C16 alkyl, C38 cycloalkyl, C3e cycloalkyl-C1-4 alkyl, optionally substituted benzyl, C36 alkenyl or C14 alkanoyl; provided that when D-E is
R' and R2 cannot together represent a chemical bond.
These compounds are useful in the preparation of isoquinoline pharmaceuticals which are the subject of our copending Patent Application No. 7,929,052, with the formula
wherein the moiety A-B represents a group of formula: -CH2-NR3- or -NR3-CH2-; wherein R3 represents hydrogen, C16 alkyl, C3e cycloalkyl, C3-6 cycloalkyl-C1-4 alkyl, optionally substituted benzyl, C3-6 alkenyl or C1-4 alkanoyl; wherein R represents hydrogen, C16 alkyl, C36 cycloalkyl or optionally substituted benzyl; wherein R' and R2 each represent hydrogen or taken together represent a chemical bond; provided that when A-B is -NR3-CH3-R1 and R2 cannot together represent a chemical bond; and wherein X is hydrogen or halogen; or an acid-addition salt thereof. Such compounds have been found to possess pharmaceutical properties and in particular central nervous system activity.
For compounds of formula lit is preferred that R' and R2 are each hydrogen. The term C16 alkyl includes both branched and straight chain groups, Such as for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, n-pentyl, and n-hexyl. Reference to C36 cycloalkyl means cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl and C36 cycloalkyl C14 alkyl includes groups such as those defined as C36 cycloalkyl linked to an alkyl group such as those listed above containing 1 to 4 carbon atoms. The benzyl group is preferably unsubstituted but substitution includes for example 1 to 3 substituents such as halogen, alkyl especially methyl, alkoxy especially methoxy, and nitro.The term C36 alkenyl includes for example, the radicals allyl and 3,3-dimethylpropen-2-yl and the term C14 alkanoyl includes for example, acetyl and propanoyl. Halogen includes fluorine, chlorine, bromine and iodine, and is most preferably chlorine and bromine.
In the case of both formulae II and 111 above, it is preferred that R and/or R3 should be C14 alkyl groups especially methyl and X is hydrogen. A further preferred group is one in which X is chlorine or bromine.
The compounds of the invention can be prepared from the ketone of formula (IV):
described, for example, by Kornfeld et al in the Journal of the American Chemical Society, 78, 3087 (1956) using the following reaction schemes:
Reaction (a) can be effected by forming the corresponding enolate with lithium diisopropylamide in any suitable inert organic solvent such as tetrahydrofuran at temperatures between -700C and OOC, followed by alkylation with any suitable acetonylating agent such as a 2-nitroalkene, for example 2nitropropene, after which alkylation, hydrolysis with a strong acid for example perchloric acid gives the diketone.
The cyclisation step (b) is an aldol condensation which can be effected by refluxing the diketone with a strong base such as potassium hydroxide in an alkanoic solvent such as ethanol. During the cyclisation step the N-benzoyl protecting group is cleaved. After partial work-up, crude indoline is reacted with acetic anhydride or a similar acetylating agent to protect the 1-nitrogen atom of the system.
Reaction (c) involves an aldol condensation similar to that of reaction (b) to provide the indoline cyclic structure but the nitrogen atom is not protected in this stage. Instead the indole fragment is formed by aromatisation with active manganese dioxide or any other suitable dehydrogenating agent using an organic solvent such as acetone.
Reactions (d), (e) and (p) can be accomplished in two ways. The first of these methods involves the well-known Schmidt reaction in which the ketone is reacted with hydrazoic acid in the presence of a suitable acid such as sulphuric acid. Alternatively, the ketone can be converted to the corresponding oxime which is then subjected to the Beckmann rearrangement.
Reactions (f), (i) and (q) involve the sequential deprotection of the 1-nitrogen atom using a strong base such as potassium hydroxide followed by aromatisation using similar conditions to those specified for reaction (c) above.
The N-alkylation reactions (g) and (r) can be effected by generating the anion with a strong base such as sodium hydride at a temperature of 60 to 650C followed by alkylation with any suitable alkylating agent. The reaction (I) is carried out at a slightly higher temperature, for example from 70 to 750C and for a period of about three hours.
Reaction (n) involves the reduction of the ketone of formula (II) by catalytic hydrogenation using hydrogen in the presence of Adam's catalyst and reaction (m) is carried out by the same procedure.
The reaction (o) can be effected by any suitable oxidative procedure, using for instance Jones reagent or pyridinium chlorochromate.
The following Examples illustrate the invention.
Example 1 1 -Benzoyl-4-acetonyl-1 ,2,2a,3-tetrahydrobenz[cd] indol-5(4H)-one Methyllithium (1.3 M soln., 4 ml, 0.0052 m) in tetrahydrofuran (20 ml) distilled from lithium aluminiumhydride) was cooled to 250 C. Diisopropylamine (0.8 ml, 0.006 m) was added and stirred until gas evolution ceased. The solution was cooled to -700C and 1-benzoyl-1,2,2a,3tetrahydrobenz[cd]indo-5(4H)one (1.4 g, 0.004 m) added in one portion, warmed to -200C and stirred until a clear brown solution formed (45 minutes). Cooled to -700C and 2-nitropropene (0.5 g, 0.006 m) added dropwise, warmed to -300C and stirred for two hours.Perchloric acid (1 ml) was added arid the reaction mixture stirred for 1 8 hours. The reaction mixture was then poured into water (1 00 ml), extracted into ethyl acetate, washed with water, dried (MgSO4) and evaporated to dryness.
Chromatography on Sorbsil U 30 silica gel (50% EtoAc/hexane) and crystallisation from methanol gave the title compound, yield 0.6 g (45%), m.p. 117-11 90C.
Example 2 1 -Benzoyl-4-(2-oxobutyl)-l ,2,2a,3-tetrahydrobenz[cd]indol-5(4H)-on was similarly prepared from 1-benzoyl-1 ,2,2a,3-tetrahydrobenz[cd]indol-5(4H)-one and 2-nitrobutene as a noncrystallisable oil, 66% yield, b.p. 1 200C/0.05 mm. Kugelrohr.
Example 3 1-Benzoyl-4-(2-oxopentyl)-1,2,2a,3-tetrahydrobenz[cd]indol-5(4H)-one was prepared in a similar way to that described in Example 2. It was an oil.
Example 4 1 -Acetyl-2.3,4,5-tetrahydro-l H-indolo[3,4-fg] indan-716H)-one 1 -Benzoyl-4-acetonyl-1 ,2,2a,3tetrahydrnbenzkd]indol-5(4H)-one (1.3 g, 0.004 m) in ethanol (100 ml) under a nitrogen atmosphere was treated with potassium hydroxide (2.0 g) and refluxed for 2 hours. The reaction mixture was poured onto ice/water, extracted with chloroform and dried (Mg504).
Acetic anhydride (1 ml) was added to the dried extracts and stirred for 1 hour. Evaporation to dryness and crystallisation from ethyl acetate/hexane gave the title product, yield 0.6 g (64%) m.p. 1 80- 1820C.
Example 5 1-Acetyl-8-methyl-2,3,4,5-tetrahydro-1 H-indolo[3,4-fg]indan-7(6H)-one was similarly prepared from 1 -benzoyl-4-(2-oxobutyl)-l ,2,2a,3-tetrahydrobenz[cd]indol-5(6H)-on yield 57%, m.p. 223- 50C.
Example 6 1 -Acetyl-8-ethyl-2,3,4,5-tetrahydro-1 H-indolo[3,4-fg]indan-7(6H)-one was similarly prepared from 1 -benzoyl-4-(2-oxopentyl)-1 ,2,2a,3-tetrahydrobenz[cd]-indol-5(6H)-one, yield 38%, m.p. 1 68- 9"C.
Example 7 1-Acetyl-2,3,4,5-tetrahydro-1 H-indolo[3,4fg]indan-7(6H)-one oxime 1 -Acetyl-2,3,4,5-tetrahydro-1 H-indolo[3,4-fg]indan-7(6H)-one (200 mg), hydroxylamine hydrochloride (100 mg) and sodium acetate (50 mg) in methanol (10 ml) were refluxed for 2 hours.
The reaction mixture was allowed to cool, the title product recovered by filtration and washed with water, yield 200 mg. (95%). Structure confirmation was effected by NMR and mass spectral data.
Example 8 1-Acetyl-8-methyl-2,3,4,5-tetrahydro-1 H-indolo[3,4-fg]indan-7(6H)-one oxime was similarly prepared from 1 -acetyl-8-methyl-2,3,4,5-tetrahydro-1 H-indolo[3,4-fg]indan-7(6H)-one, yield 95%.
m.p. > 3200C (dec).
Example 9 1 -Acetyl-2,3,4,5-tetrahydro-1 H-indolo[3,4-fg]indan-7(6H)-one oxime 200 mg) in polyphosphoric acid (2 ml) was stirred and heated to 600C for 2 hours. The reaction mixture was diluted with cold water, extracted with chloroform, washed with water, dried (MgSO4) and evaporated to dryness.
Crystallisation from methanol gave the title product yield 1 60 mg (90%) m.p. 300--5 OC (dec).
Example 10 1 -Acetyl-9-methyl-1 ,2,3 ,4,5,6-hexahydroindolo[4,3-fg]isoquinolin-8(7 H)-one was similarly prepared from 1 -acetyl-8-methyl-2,3,4,5-tetrahydro-1 H-indolo[3,4-fg]indan-7(6H)-one oxime, yield 180 mg (90%) m.p. 21 4--6 OC.
Example 11 1 -Acetyl-1 ,2,3,4,5,6-hexahydroindolo[4,3-fg]isoquinolin-817H)-one 1-Acetyl-2,3,4,5-tetrahydro-1 H-indolo[3,4-fg]indan-7(6H)-one (2.2 g, 0.0087 m) in glacial acetic acid (20 ml) was stirred and warmed to 600 C. Sodium azide (0.6 g, 0.0087 m) was added followed by concentrated sulphuric acid (2 ml) dropwise over 5 minutes. The reaction mixture was stirred at 60-650C until effervescence ceased. Two further additions of sodium azide and concentrated sulphuric acid were made to complete the conversion of all starting material. The reaction mixture was then poured onto a mixture of ice/saturated sodium bicarbonate solution, extracted into chloroform, washed with water, dried (MgSO4) and evaporated to dryness.
Crystallisation from methanol gave the title product, yield 1.7 g (73%) m.p. 300--5 OC (dec).
Example 12 1 -Acetyl-9-methyl- 1 ,2,3,4,5,6-hexahydroindolo[4,3-fg]isoquinolin-8(7H)-one was similarly prepared from 1 -acetyl-8-methyl-2,3,4,5-tetrahydro-1 H-indolo[3,4-fg]indan-7(6H)-one (75%) m.p.
214-60C.
Example 13 1 -Acetyl-9-ethyl-1 1,2,3 ,4,5,6-hexahydroindolo[4,3-fg] isoquinoline-8(7 H)-one was similarly prepared from 1 -acetyl-8-ethyl-2,3,4,5-tetrahydro-1 H-indolo[3,4-fg]indan-7(6H)-one (85% m.p.
213-21 50C.
Example 14 1 -Acetyl-7-methyl-1 ,2,3,4,5,6-hexahydroindolo[4,3-fg]isoquinolin-817H)-one 1 -Acetyl-1 ,2,3,4,5,6-hexahydroindolo-[4,3-fg]isoquinolin-8(7H)-one (140 mg, 0.0005 m) was added to a stirred suspension of sodium hydride (50% dispersion, 30 mg, 0.0006 m) in dimethylformamide (10 ml) at 600C. The reaction mixture was stirred for 30 minutes, cooled to 100C and methyl iodide (100 mg, 0.0007 m) added. Stirring was continued for a further 30 minutes, the reaction mixture diluted with water, extracted with chloroform, washed with water, dried (MgSO4) and evaporated to dryness: The title product was crystallised from ethyl acetate, yield 60 mg, (37%) and its structure was confirmed by mass spectral evidence.
Example 15 1 -Acetyl-7,9-dimethyl-1 ,2,3,4,5,6-hexahydroindolo[4,3-fg]isoquinolin-8(7H)-one was similarly prepared from 1 -acetyi-9-methyl-1 ,2,3,4,5,6-hexahydroindolo[4,3-fg]isoquinolin-8(7H)-one, (75%) m.p. 210-21 20C.
Example 16 1 -Acetyl-7-methyl-1 ,2,3,4,5,6-hexahydroindolo[4,3-fg]isoquinoline-817H)-one 1 -Acetyl-1,2,3,4,5 ,6-hexahydroindolo[4,3-fg] isoquinolin-8(7 H)-one (2.7 g, 0.01 m) and cetyl trimethylammonium bromide (3.7 g, 0.01 m) suspended in tetrahydrofuran (50 ml) and stirred at room temperature. Methyl iodide (3.0 g, 0.02 m) and 50% sodium hydroxide (50 ml) were added and the mixture stirred vigorously for 1 8 hours. The reaction was poured into ice water, extracted with ethyl acetate, washed with water, dried (MgSO4) and evaporated to dryness. Chromatography on U30 silica gel by elution with 1 % methanol in chloroform and crystallisation from ethyl acetate gave the title compound 1.3 g (48%) m.p. 250-2550C.
Example 17 1 -Acetyl-7,9-dimethyl-1 ,2,3,4,5,6-hexahydroindolo[4,3-fg]isoquinoline-8(7H)-one was similarly prepared from 1 -acetyl-9-methyl-1 ,2,3,4,5,6-hexahydroindole[4,34g]isoquinoline-8(7H)-one, (58%) m.p. 210-2120C.
Example 18 1 -Acetyl-9-ethyl-7-methyl- ,2,3,4,5,6-hexahydro-indolo[4,3-fg]isoquinoline-8(7H)-one was similarly prepared from 1 -acetyl-9-ethyl-1 ,2,3,4,5,6-hexahydroindole[4,3-fgjisoquinolin-8(7H)-one (61%) m.p. 179-800C.
Example 19 1 -Acetyl-9-methyl-7-n-propyl-1 1,2,3,4,5,6-hexahydroindolo[4,3-fg]isoquinolin-8(7 H)-one was similarly prepared from 1 -acetyl-9-methyl-1 ,2,3,4,5,6-hexahydroindolo[4,3-fg]isoquinolin-8(7H)-one (91%) m.p. 75-780C.
Example 20 1 -Acetyi-7-n-hexyl-9-methyl- 1,2,3 ,4,5,6-hexahydrnindolo[4,34gjisoqui nolin-8(7 H)-one was similarly prepared from 1 -acetyl-9-methyl-1 ,2,3,4,5,6-hexahydroindolo[4,3-fg]isoquinolin-8(7H)-one (81%) m.p. 82-840C.
Example 21 1 -Acetyl-7-allyl-9-methyl- ,2,3,4,5,6-hexahydroindolo[4,3-fg]isoquinolin-8(7H)-one was similarly prepared from 1 -acetyl-9-methyl-1 ,2,3,4,5,6-hexahydroindolo[4,3-fg]isoquinolin-8(7H)-one (94%) m.p. 1350C.
Example 22 1 -Acetyl-7-(3,3-dimethylpropen-2-yl)-methyl- 1,2,3,4,5,6-hexahydroindolo[4,3-fg]isoquinolin- 8(7H)-one was similarly prepared from 1 -acetyl-9-methyl-1 ,2,3,4,5,6-hexahydroindolo[4,3- fg]isoquinolin-8(7H)-one (71%) m.p. 89-90 C.
Example 23 1 -Acetyl-7-cyclopropyl methyl-9-ethyl- 1,2,3,4,5,6-hexahydroindolo[4,3-fg]isoquinolin-8(7H)-one was similarly prepared from 1 -acetyl-9-methyl-1 ,2,3,4,5,6-hexahydroindolo[4,3-fg]isoquinolin-8(7H)- one (42%) m.p. 1 77-800C.
Example 24 1 -Acetyl-7-benzyl- 1 ,2,3,4,5,6-hexahydroindolo[4,3-fg]isoquinolin-8(7H)-one was similarly prepared from 1 -acetyl-1 ,2,3,4,5,6-hexahydroindolo[4,34g]isoquinolin-8(7H)-one (39%) (39%) m.p. 215- 2180C.
Example 25 1 -Acetyl-7,9-dimethyl-1 ,2,3,4,9, 1 0-hexahydroindolo[4,34g]isoquinoline-8(7H)-one was prepared as Example 14 except that the reaction mixture was stirred at 75"C for 3 hours m.p. 233- 235"C.
Example 26 1 -Acetyl-7,9-dimethyl-1 ,2,3,4,5,6,9,1 O-octahydroindolo[4,3-fgjisoquinolin-8(7H)-one 1 -Acetyl-7,9-dimethyl-1 ,2,3,4,9, 1 0-hexahydroindolo[4,3-fg]isoquinolin-8(7H)-one (100 mg.) in ethanol (20 ml) was hydrogenated at 60 p.s.i. over platinium oxide (10 mg) for 4 hours. The catalyst was removed by filtration and the solvent removed in vacuo. Crystallisation from acetonitrile-diethyl ether gave the title compound m.p. 204-206 C.
Example 27 7-Methyl-1,4,5,6-tetrahydroindolo[4,3-fg]isoquinolin-8(7H)-one 1 -Acetyl-7-methyl-1 ,2,3,4,5,6-hexahydroindolo[4,3-fg]isoquinolin-8(7 H)-one (1 00 mg) in ethanol (20 ml) was treated with 50% NaOH solution (5 ml) and stirred at 600C for 18 hours. The reaction mixture was poured onto ice-water, extracted into chloroform, washed with water, dried (MgSO4) and evaporated to dryness. The crude 7-methyl-1 ,2,3,4,5,6-hexahydroindolo[4,3- fg]isoquinolin-8(7H)-one was dissolved in acetone and stirred for 18 hours with manganese dioxide on activated carbon (1 g) [Journal of Organic Chemistry, 35,3971(1970)]. The manganese dioxide was removed by filtration and the solution evaporated to dryness.Crystallisation from ethyl acetate gave the title product as a crystalline product the structure of which was confirmed by mass spectral evidence.
Example 28 7,9-Dimethyl-l ,4,5,6-tetrahydroindolo[4,3-fg]isoquinolin-8(7H)-one was similarly prepared from 1 -acetyl-7,9-dimethyl-1 ,2,3,4,5,6-hexahydroindolo[4,34g]isoquinolin-8(7H)-one, m.p. 23790 C.
Example 29 9-Ethyl-7-methyl-1,4,5,6-tetrahydroindolo[4,3-fg]isoquinolin-8(7H)-one was similarly prepared from 1 -acetyl-9-ethyl-7-methyl- 1 ,2,3,4, 5,6-hexahydroindolo[4,3-fg]isoqui nolin-8(7 H)-one (53%) m.p.
246-90C.
Example 30 9-Methyl-7-n-propyl-1,4,5,6-tetrahydroindolo[4,3-fg]isoquinolin-8(7H)-one was similarly prepared from 1 -acetyl-9-methyl-7-n-propyl- ,2,3,4,5,6-hexahydroindolo[4,3-fgjisoquinolin-8(7H)- one (36%) m.p. 192-1950C.
Example 31 7-n-Hexyl-9-methyl-1 ,4,5,6-tetrahydroindolo[4,3-fg]isoquinolin-8(7H)-one was similarly prepared from 1 -acetyl-7-n-hexyl-9-methyl- 1 ,2,3,4,5,6-hexahydroindolo[4,3-fg]isoquinolin-8(7 H)-one (35%) m.p. 139-1410C.
Example 32 F 7-AIlyl-9-methyl-1 ,4,5,6-tetrahydroindolo[4,3-fg]isoquinolin-8(7H)-one was similarly prepared from 1 -acetyl-7-allyl-9-methyl- 1,2,3,4,5,6-hexahydroindolo[4,3-fg]isoquinolin-8(7 H)-one (55%).
Example 33 7-(3,3-Dimethylpropen-2-yl)-9-methyl-1 ,4,5,6-tetrahydroindolo[4,3-fg]isoquinolin-8(7 H)-one was similarly prepared from 1 -acetyl-7-(3,3-dimethylpropen-2-yI)-9-methyl-1 ,2,3,4,5,6 hexahydroindolo[4,3-fg]isoquinolin-8(7H)-one (48%) m.p. 225--300C.
Example 34 7-Cyciopropyl methyl-9-ethyl- 1 ,4,5,6-tetrahydroindolo[4,3-fg]isoquinolin-8(7 H)-one was similarly prepared from 1 -acetyl-7-cyclopropyl methyl-9-ethyl-1 2,3 ,4,5,6-hexahydroindolo[4,3- fg]isoquinolin-8(7H)-one m.p. 213-21 50C.
Example 35 7-Benzyl-1,4,5,6-tetrahydroindolo[4,3-fg]isoquinolin-8(7H)-one was similarly prepared from 1 acetyl-7-benzyl-1,2,3,4,5,6-hexahydroindolo[4,3-fg]isoquinolin-8(7H)-one (47%) m.p. 207--2080C.
Example 36 7,9-Dimethyl-1,4,5,6,9,10-hexahydroindolo[4,3-fg]isoquinolin-8(7H)-one was similarly prepared from 1-acetyl-7,9-dimethyl-1,2,3,4,5,6,9,10-octahydroindolo[4,3-fg]isoquinolin-8(7H)-one m.p.
217-2190C.
Example 37 1,4,5,6-Tetrahydroindolo[4,3-fg]isoquinolin-8(7H)-one 1 -Acetyl-1 ,2,3,4,5,6-hexahydroindolo[4,3-fg]isoquinolin-8(7H)-one (100 mg) in ethanol (5 ml) and dioxan (5 ml) was treated with 50% sc sodium hydroxide solution (5 ml) and stirred for 18 hours. The reaction mixture was poured into ice-water, extracted into chloroform, washed with water, dried (MgSO4) and evaporated to dryness. The crude 1 ,2,3,4,5,6-hexahydroindolo[4,3-fg]-isoquinolin-8(7H)- one was dissolved in acetone and stirred for 18 hours with manganese dioxide on activated carbon (1 g). The manganese dioxide was removed by filtration and the solution evaporated to dryness.
Crystallisation from ethyl acetate gave the title product. m.p. 142-1 440 C. The structure was confirmed by a combination of infra-red, ultra-violet and mass spectral data.
Example 38 9-Methyl-1,4,5,6-tetrahydroindolo[4,3-fg]isoquinolin-8(7H)-one was similarly prepared from 1 acetyl-9-methyl- ,2,3,4,5,6-hexa hydroindolo[4,3-fg]isoquinolin-8(7 H)-one, m.p. 1980 C (ethyl acetate).
Example 39 7-Cyclopropylacetamido-9-methyl-1,4,5,6-tetrahydroindolo[4,3-fg]isoquinolin-8(7H)-one To a solution of 9-methyl-1,4,5,6-tetrahydroindolo[4,3-fg]isoquinolin-8(7H)-one (40 mg) in methylene chloride (10 ml) was added triethylamine (5 drops) and cyclopropane carboxylic acid chloride (4 drops). The reaction was stirred for 4 hours diluted with more methylene chloride, washed with water, dried (MgSO4) and evaporated to dryness. Crystallisation from ethyl acetate gave the title compound.
Example 40 4,5-Dihydro-1 H-indolo[3,4-fg]indan-7(6H)-one 1 -Benzoyl-4-acetonyl-1 ,2,3,4-tetrahydrobenz[cd]indol-5(4H)-one (1.3 g, 0.004 m) in ethanol (100 ml) under a nitrogen atmosphere was treated with potassium hydroxide (2.0 g) and refluxed for 2 hours. The reaction mixture was poured onto ice/water, extracted into chloroform, dried (mgSO4) and evaporated to dryness. The crude 2,3,4,5-tetrahydro-1 H-indolo[4,3-ef]indan-7(6H)-one was dissolved in acetone (50 ml) and stirred with manganese dioxide on activated charcoal for 36 hours. The manganese dioxide was removed by filtration and the solution evaporated to dryness. Crystallisation from chloroform/ethyl acetate gave the title product as a crystalline solid.
Example 41 8-Methyl-4,5-dihydro-1 H-indolo[3,4-fg]indan-7(6H)-one was similarly prepared from 1-benzoyl- 4-(2-oxobutyl)-1 ,2,2a,3,tetrahydrobenz[cd]indol-5(4H)-one, 30% m.p. 2579O C.
Example 42 4,5-Dihydro-1 H-indolo[3,4-fg]indan-7(6H)-one oxime 4,5-Dihydro-1 H-indolo[3,4-fg]indan-7(6H)-one (200 mg), hydroxylamine hydrochloride (100 mg) and sodium acetate (50 mg) in n-propanol (10 ml) was refluxed for 18 hours. The reaction mixture was diluted with chloroform, filtered through a pad of alumina and evaporated to dryness. Crystallisation from carbon tetrachloride gave the title product, yield 1 50 mg (75%).
Example 43 8-Methyl-4,5-dihydro-1 H-indolo[3,4-fg]indan-7(6H)-one oxime was similarly prepared from 8methyl-4,5-dihydro-1 H-indolo[3,4-fg]indan-7(6H)-one m.p. 190--2000C.
Example 44 1 -Acetyl-7-hydroxy-8-methyl-2,3,4,5,6,7,8,9-octahydro-1 H-indolo[3,4-fg]indane 1 -Acetyl-8-methyl-2,3,4,5-tetrahydro-1 H-indolo[3,4-fg]indan-7(6H)-one (100 mg) in ethanol (100 ml) with platinum oxide (10 mg) was hydrogenated at 60 p.s.i. until hydrogen uptake ceased. The catalyst was removed by filtration and the solution evaporated to dryness. Crystallisation from ethanol gave the title product, yield 80 mg (80%) m.p. 223--40C.
Example 45 1 -Acetyl-8-methyl-2,3,4,5,8,9-hexahydro-1 H-indolo[3,4-fg] indan-7(6H)-one 1 -Acetyl-7-hydroxy-8-methyl-2,3,4,5,6,7,8,9-octahydro-1 H-indolo[3,4-fg]indane (50 mg) in acetone (10 ml) was stirred and treated with Jones reagent (1 ml). The stirring was continued for 1 8 hours and then excess methanol was added to destroy excess reagent. The reaction mixture was then evaporated to dryness and partitioned between water and chloroform, solvent, separated, washed with water, dried (MgSO4) and evaporated to dryness to yield the title product. The product was crystallised from ethyl acetate (68%) m.p. 171-1720C.
Example 46 1 -Acetyl-9-methyl-1 2,3,4,5,6,9,1 0-octahydroindolo[3,4-ghjisoquinolin-7(8H)-one 1 -Acetyl-8-methyl-2,3,4,5,8,9-hexahydro-1 H-indolo[3,4,-fg]indan-7(8H)-one (100 mg) in glacial acetic acid (5 ml) was stirred and warmed to 500C. Sodium azide (40 mg) was then added followed by concentrated sulphuric acid (0.1 ml). Stirring continued at 50-550C until gas evolution ceased. A further addition of sodium azide and concentrated sulphuric acid ensured complete conversion of starting material. The reaction was poured onto ice/saturated sodium bicarbonate solution, extracted into chloroform, washed with water, dried (MgSO4) and evaporated to dryness. Crystallisation from ethyl acetate gave the title product, m.p. 224--2260C.
Example 47 9-Methyl-1,4,5,6,9,10-hexahydroindolo[3,4-gh]isoquinolin-7(8H)-one 1-Acetyl-9-methyl-1,2,3,4,5,6,9,10-octahydroindolo[3,4-gh]isoquinolin-7(8H)-one (100 mg) in ethanol (10 ml) was stirred at room temperature. 50% NaOH solution (5 ml) was added to the stirred mixture and stirring continued for 1 8 hours. The reaction mixture was then poured onto ice water, extracted into chloroform, washed with water, dried (MgSO4) and evaporated to dryness. The solid was redissolved in acetone (10 ml) and Mn2/C added. The mixture was stirred for 10 hours and the catalyst filtered off. Evaporation of the solvent in vacuo and crystallisation from ethyl acetate gave the title product, the structure of which was confirmed by NMR and mass spectral data.
Example 48 1 -Acetyl-8,9-dimethyl-1 2,3,4,5,9,1 0-octahydroindolo[3,4gh] isoquinolin-7(8H)-one A solution of 1 -acetyl-9-methyl- 2,3,4,5,9,1 0-octahydroindolo[3,4-gh]isoquinolin-7(8H)-one (100 mg) and sodium hydride (20 mg) in drydimethylformamide (20 ml) was stirred in a nitrogen atmosphere and warmed to 600C for 30 minutes. The reaction was cooled to 1 OOC and methyl iodide (0.1 ml) added. The reaction was stirred for 30 minutes and diluted with water. Extraction with chloroform, washing with water, drying (MgSO4) and evaporation to dryness gave the title compound which was crystallised from ethyl acetate m.p. 1 841860 C.
Example 49 8,9-Dimethyl-1 4,5,6,9,1 0-hexahydroindolo [3,4-gh] isoquinolin-7(8H)-one 1 -Acetyl-8,9-dimethyl-1 ,2,3,4,5,6,9,1 O-octahydroindolol3,4-gh]isoquinolin-7( (0.3 (0.3 g) in acetic acid (10 ml) and concentrated hydrochloric acid (10 ml) was refluxed for 5 hours. The reaction mixture was poured into ice water, basified with NaOH, extracted into chloroform, washed, dried (MgSO4) and evaporated to dryness. The white solid was redissolved in acetone (20 ml) and MnO2/C (3 g) added. The mixture was stirred for 10 hours and the catalyst filtered off, evaporation of the solvent in vacuo and crystallisation from ethyl acetate gave the title compound m.p. 250-2520C.

Claims (6)

Claims
1. A compound of the formula
where the moiety D-E represents a group of formula
where R represents hydrogen, C16 alkyl, C3-6 cycloalkyl or optionally substituted benzyl, where R' and R2 each represent hydrogen or taken together represents a chemical bond, and where R3 represents hydrogen, C16 alkyl, C36 cycloalkyl, C36 cycloalkyl-C1~4 alkyl, optionally substituted benzyl, C36 alkenyl or C14 alkanoyl; provided that when D-E is
R' and R2 cannot together represents a chemical bond.
2. A compound according to claim 1 in which D-E represents
and R1 and R2 each represent hydrogen.
3. A compound according to claim 1 in which D-E represents
4. A compound according to any of the preceding claims in which Rand R3 are C14 alkyl.
5. A compound according to claim 4 in which R and R3 are methyl.
6. A compound according to claim 1 substantially as described in any of the Examples.
GB8203820A 1978-05-23 1979-08-21 Intermediates useful in the preparation of pharmaceutical compounds Expired GB2099815B (en)

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