CA1137489A - Derivatives of 1,2,3,3a,8,8a-hexadydropyrrolo (2,3-b) indole - Google Patents
Derivatives of 1,2,3,3a,8,8a-hexadydropyrrolo (2,3-b) indoleInfo
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Abstract
Abstract of the Disclosure The invention provides novel compounds which display useful analgesic properties. The compounds are 1,2,3,3a,8,8a-hexahydropyrrolo [2,3-b] indoles of formula I
and pharmaceutically acceptable salts thereof, wherein R1 is selected from the group consisting of hydrogen, hydroxy, C1 - C12 alkoxy and C2 - C12 alkenyloxy;
R2 is selected from the group consisting of hydrogen and C1 - C12 alkyl; R3 and R4 are the same or different and are selected from the group consisting of hydrogen, C1 - C12 alkyl and C2 - C12 alkenyl, provided that when R1 is selected from the group consisting of hydrogen, hydroxy, methoxy and ethoxy, and R2 is methyl, at least one of R3 and R4 is other than hydrogen or methyl.
and pharmaceutically acceptable salts thereof, wherein R1 is selected from the group consisting of hydrogen, hydroxy, C1 - C12 alkoxy and C2 - C12 alkenyloxy;
R2 is selected from the group consisting of hydrogen and C1 - C12 alkyl; R3 and R4 are the same or different and are selected from the group consisting of hydrogen, C1 - C12 alkyl and C2 - C12 alkenyl, provided that when R1 is selected from the group consisting of hydrogen, hydroxy, methoxy and ethoxy, and R2 is methyl, at least one of R3 and R4 is other than hydrogen or methyl.
Description
1~L3~
The present invention relates to derivatives of 1,2,3,3a,8,8a-hexa-hydropyrrolo [2,3-b] indole and their salts with pharmaceutically acceptable acids and to processes for their preparation.
Useful analgesic activity is displayed by 1,2,3,3a,8,8a-hexahydro-pyrrolo [2,3-b] indole compounds having the formula ~I) 3 (I) and their salts with pharmaceutically acceptable acids wherein: Rl is selected from the group consisting of hydrogen, hydroxy, Cl - C12 alkoxy and C2 - C12 alkenyloxy; R2 is selected from the group consisting of hydrogen and Cl - C12 alkyl; R3 and R4 are the same or different and are selected from the group con-sisting of hydrogen~ Cl ~ C12 alkyl and C2 ~ C12 alkenyl.
Of these compounds, compounds of formula I in which Rl is hydrogen, hydroxy, methoxy or ethoxy, R2 is methyl and R3 and R4 are hydrogen or methyl are known. Pharmaceutical compositions containing these known compounds are the subject of our patent Application -Serial No. 311,555. This application, which is divided out of Application Serial No. 311,555, is directed to novel compounds of formula I and their pharmaceutically acceptable salts wherein Rl, R2, R3 and R4 are as defined above, provided that when Rl is hydrogen, hydroxy, methoxy or ethoxy, and R2 is methyl, at least one of R3 and R4 is other than hydrogen or methyl.
Examples of pharmaceutically acceptable salts of the compounds of formula (I) are those formed with both inorganic _ 2 _ ,; .
1~l3741~5~
acids, for instance hydrochloric acid, hydrobromlc acid, sulphuric acid, and with organic acids such as for instance benzoic acid, p-hydroxybenzoic acid, salicylic acid, tartaric acid (bothlaevorotatory and dextrorotatory and racemic), mesotartatic acid, fumaric acid, maleic acid, citric acid, gentisic acid, hydroxyphtalic acid, creatinin-su]phuric acid and succinic acid.
Compounds having the above mentioned formula (I) include both the optically active isomers and their mixtures. In the compounds of the above formula (Ij the substituent R2 in position 3a and the hydrogen atom in position 8a are in the cis configuration i.e. on the same side with respect to the plane of the heterobicyclic ring.
Of particular importance are the salts of eseroline 1,3a, 8-trimethyl-1,2,3,3a,8,8a-hexahydropyrrolo ~2,3-b~ indol-5-ol , especially the (-) eseroline ~ (3aS,8aR)-1,3a-8-trimethyl-1,
The present invention relates to derivatives of 1,2,3,3a,8,8a-hexa-hydropyrrolo [2,3-b] indole and their salts with pharmaceutically acceptable acids and to processes for their preparation.
Useful analgesic activity is displayed by 1,2,3,3a,8,8a-hexahydro-pyrrolo [2,3-b] indole compounds having the formula ~I) 3 (I) and their salts with pharmaceutically acceptable acids wherein: Rl is selected from the group consisting of hydrogen, hydroxy, Cl - C12 alkoxy and C2 - C12 alkenyloxy; R2 is selected from the group consisting of hydrogen and Cl - C12 alkyl; R3 and R4 are the same or different and are selected from the group con-sisting of hydrogen~ Cl ~ C12 alkyl and C2 ~ C12 alkenyl.
Of these compounds, compounds of formula I in which Rl is hydrogen, hydroxy, methoxy or ethoxy, R2 is methyl and R3 and R4 are hydrogen or methyl are known. Pharmaceutical compositions containing these known compounds are the subject of our patent Application -Serial No. 311,555. This application, which is divided out of Application Serial No. 311,555, is directed to novel compounds of formula I and their pharmaceutically acceptable salts wherein Rl, R2, R3 and R4 are as defined above, provided that when Rl is hydrogen, hydroxy, methoxy or ethoxy, and R2 is methyl, at least one of R3 and R4 is other than hydrogen or methyl.
Examples of pharmaceutically acceptable salts of the compounds of formula (I) are those formed with both inorganic _ 2 _ ,; .
1~l3741~5~
acids, for instance hydrochloric acid, hydrobromlc acid, sulphuric acid, and with organic acids such as for instance benzoic acid, p-hydroxybenzoic acid, salicylic acid, tartaric acid (bothlaevorotatory and dextrorotatory and racemic), mesotartatic acid, fumaric acid, maleic acid, citric acid, gentisic acid, hydroxyphtalic acid, creatinin-su]phuric acid and succinic acid.
Compounds having the above mentioned formula (I) include both the optically active isomers and their mixtures. In the compounds of the above formula (Ij the substituent R2 in position 3a and the hydrogen atom in position 8a are in the cis configuration i.e. on the same side with respect to the plane of the heterobicyclic ring.
Of particular importance are the salts of eseroline 1,3a, 8-trimethyl-1,2,3,3a,8,8a-hexahydropyrrolo ~2,3-b~ indol-5-ol , especially the (-) eseroline ~ (3aS,8aR)-1,3a-8-trimethyl-1,
2,3,3a,8,8a-hexahydropyrrolo [2,3-b~ indol-5-ol~, with pharmaceutically acceptable acids, not including chloride, bromide, sulphate, picrate, methopicrate, benzoate, methiodide, and ethiodide salts.
Of particular interest are the salts of eseroline with salicylic acid, tartaric acid (both laevorotatory and dextrorotatory and racemic), mesotartaric acid, p-hydroxybenzoic acid, fumaric acid, maleic acid, citric acid, gentisic acid, hydroxyphtalic acid, creatininsulphuric acid and succinic acid.
In accordance with the invention, pharmaceutical composi-tions can be prepared containing a suitable carrier and, as 1~37481~
active substance, a compound of formula (I), or a salt thereof with a pharmaceutically acceptable acid, wherein the substituents Rl, R2, R3 and R4 can be any of the groups referred to above, without any of the above-mentioned limitations.
The alkyl, alkoxy, alkenyl and alkenyloxy groups of the described compounds can have either a linear or a branched chain of carbon atoms, Preferably the alkyl and alkoxy groups contain from 1 to 6 carbon atoms, in particular from 1 to 4 carbon atoms while the alkenyl and alkenyloxy groups contain preferably from 2 to 6 carbon atoms, in particular from 2 to 4 carbon atoms.
Specific examples of new compounds in accordance with the invention will now be given by way of example. They are:-1) 1, 8-dimethyl-3a-ethyl-1,2,3,3a,8,8a-hexahydropyrrolo [2,3-b] indol-5-ol;
2) 1,3a-dimethyl-8-ethyl-1,2,3,3a-8,8a-hexahydropyrrolo ~2,3-b] indol-5-ol; -
Of particular interest are the salts of eseroline with salicylic acid, tartaric acid (both laevorotatory and dextrorotatory and racemic), mesotartaric acid, p-hydroxybenzoic acid, fumaric acid, maleic acid, citric acid, gentisic acid, hydroxyphtalic acid, creatininsulphuric acid and succinic acid.
In accordance with the invention, pharmaceutical composi-tions can be prepared containing a suitable carrier and, as 1~37481~
active substance, a compound of formula (I), or a salt thereof with a pharmaceutically acceptable acid, wherein the substituents Rl, R2, R3 and R4 can be any of the groups referred to above, without any of the above-mentioned limitations.
The alkyl, alkoxy, alkenyl and alkenyloxy groups of the described compounds can have either a linear or a branched chain of carbon atoms, Preferably the alkyl and alkoxy groups contain from 1 to 6 carbon atoms, in particular from 1 to 4 carbon atoms while the alkenyl and alkenyloxy groups contain preferably from 2 to 6 carbon atoms, in particular from 2 to 4 carbon atoms.
Specific examples of new compounds in accordance with the invention will now be given by way of example. They are:-1) 1, 8-dimethyl-3a-ethyl-1,2,3,3a,8,8a-hexahydropyrrolo [2,3-b] indol-5-ol;
2) 1,3a-dimethyl-8-ethyl-1,2,3,3a-8,8a-hexahydropyrrolo ~2,3-b] indol-5-ol; -
3) 1,3a,8-triethyl-1,2,3,3a,8,8a-hexahydropyrrolo [2,3-b]
indol-5-ol;
indol-5-ol;
4) l-ethyl, 8-dimethyl-1,2,3,3a,8,8a-hexahydropyrrolo [2,3-b] indol-5-ol;
5) 1,8-dimethyl-3a-ethyl-5-methoxy-1,2,3,3a,8,8a-hexa-hydropyrrolo [2,3,-b] indol-5-ol;
6) 1,8-dimethyl-3a-propyl-1,2,3,3a,8,8a-hexahydropyrrolo [2,3-b] indol-5-ol;
1137f~8~
1137f~8~
7) 1,3a,8-trimethyl-S-propyloxy-1,2,3,3a,8,8a-hexahydro-pyrrolo [2,3-b] indol-5-ol;
8) 1,8-diethyl-3a-methyl-1,2,3,3a,8,8a-hexahydropyrrolo [2,3-b] indol-5-ol;
9) 1-ethyl-3a,8-dimethyl-1,2,3,3a,8,8a-hexahydropyrrolo [2,3-b] indole;
as well as the salts of the compounds formed with pharmaceutically acceptable acids, in particular those referred to above.
As active substances in pharmaceutical compositions, the salts of the compounds of formula (I) with pharmaceutically acceptable acids are preferred over the free bases, since the free bases can be easily oxidised, for instance in aqueous solution, giving degradation products having a quinone type structure.
The easy oxidation and degradation of the free bases of the invention and/or of the corresponding salts can be eliminated by using special pharmaceutical techniques, for instance keeping the pH value of the solutions low, or protecting the bases and their salts against attack from atmospheric oxygen, or by the addition of compounds which can be oxidised more easily and so act as antioxidant agents.
11374~39 The derivatives of the 1,2,3,3a,8,8a-hexahydropyrrolo [2,3-b] indole in accordance with the inven~ion can be prepared by the following processes, (a) by reductive cyclization of a compound of formula (II) Rl lR2 \ ~ C - CH
W ` N J ~o / 2 (II) I NH
wherein Rl, R2, R3 and R4 are as referred to above or (b) by oxidative cyclization of a compound of formula (III) fH3 C - CH
2 (III) 1 o ¦ f H H
N / N ~
or a salt thereof wherein:
1137~9 Rl is hydlogen or hydroxy, R3 and R4 are the same, and as referred to above but not hydrogen. Thus compounds of formula (I) are obtained wherein Rl is hydrogen or hydroxy and R3=R4 which are Cl-C12 alkyl or C2 C12 Y
c) by reduction Oe a compound of formula (IV) N 1 N ~ Q (IV) wherein:
Rl, R2, R3 and R4 are as defined above;
or d) by hydrolysis of a compound of formula (V) R~ I N J (V) wherein:
R2, R3 and R4 are as previously mentioned and R"l is an acyloxy, carbamoyloxy or alkylcarbamoyloxy group. Thus compounds of , formula (I) are obtained wherein Rl is a hydroxy group which can, if desired, undergo etherification to give compounds of formula (I) wherein Rl is Cl-C12 alkoxy or C2-C12 alkenyloxy; or e) by reaction of a compound of formula (VI) l\ ~ R4 CH2-CH~NHR3 (Vl) ~137~9 ~, wherein Rl, R3 and R4 are as described previously, first with a halide of alkylmagnesium RMgX wherein R is a general Cl-C6 alkyl, and with an alkyl halide R2X, wherein R2 is Cl-C12. Thus compounds of formula (I) are obtained wherein R2 is Cl-C12 alkyl.
In addi-tion compounds of formula (I) can be produced by the transformation of other compounds of formula (I) having different Rl, R2, R3 and/or R4 substituents and/or by salifying a compound of formula (I) with a pharmaceutically acceptable acid, and/or by separating a mixture of optical enantiomers of formula (I) into the single enantiomers.
The reductive cyclization of the compound of formula (Il) is preferably carried out using sodium in an alipha-tic low molecular weight alcohol, for instance methanol or ethanol.
Metal sodium is added in small portions to an alcoholic solution ofthe compound of formula (II), preferably at temperatures of about room temperature, at intervals of about two hours. The resulting solution is then acidified with a mineral acid, for instance hydrochloric acid, and the alochol evaporated under reduced pressure. The solution is then made alkaline, preferably by the addition of an inorganic base, for instance an alkaline hydroxide. The product is then extracted into a suitable organic solvent, for instance ethyl ether, which is evaporated to dryness.
The oxidative cyclization of the compound of formula (III), preferably salified with acids, for instance inorganic acids, such as hydrobromic acid, is preferably carried out in aqueous 1~37~8~
solution, using as oxidating agent an alkaline ferricyanide for instance, potassium ferricyanide, in the presence of an alkaline bicarbonate, Lor instance sodium bicarbonate. The cyclisation is carried out under st:ream of inert gas, for instance nitrogen, at a temperature of abou-t the room temperature.
The reduction of the compound of formula (IV) is preferably carried out using a mixed hydride, for instance lithium alumin-ium hydride. The compound of formula tIV) is refluxed in a suitable organic solvent such as ethyl ether or tetrahydro-furan.
The hydrolysis of the compound of formula (V) is prefer-ably carried out by reacting with an alkaline hydroxide, for instance sodium or potassium hydroxide, in a hydroalcoholic solution, for instance hydroethanolic solution, in a stream of hydrogen, or preferably nitrogen, at a temperature of about the room temperature. The compounds of formula (I) produced by the hydrolysis, have Rl as a hydroxy group. These can be converted to compounds of formula (I) wherein R1 is Cl-C12 alkoxy or C2-C12 alkenyloxy by etherification, preferably by treatment with a corresponding Cl-C12 alkyl or C2-C12 alkenyl tosylate or mesylate.
In the compound of formula (V) R"l is preferably methyl-carbamoyloxy (CH3NHCOO-). When R"l is acyloxy, the acyl group is preferably a Cl-C12 aliphatic acyl group, or a benzoyl group or a p-hydroxybenzoyl group.
All the compounds of formula (II), (III), (IV) and (V) can 1~379~8~1 I () be either optically active or racemic, and thus the compounds of formula (I) obtained by the previously described reactions are also either optically active or racemic. As mentioned above, a compound of formula (I~ can be transformed into another compound of formula (I) having different Rl, R2, R3 and/or R4 substituents and such transformation can be carried out according to any of the methods used in organic chemistry.
~ or instance a compound of formula (I) wherein Rl is hydrogen or hydroxy and R3 and R4 are both hydrogen, can be transformed into a compound of formula (I) wherein Rl is hydrogen orhydroxy, R3 is hydrogen and R4 is Cl-C12 alkyl or C2-C12 alkenyl by reaction of one of its salts, for instance hydrochloride or hydrobromide, with an alkyl halide having formula R4X, wherein R4 is Cl-C12 alkyl or C2-C12 alkenyl and X is halogen, preferably iodine. The reaction is carried out in an alcoholic solvent, for instance ethyl alcohol, in a sealed tube, by boiling the reaction mixture on water bath for about 7 hours. By the same method but with a reaction time of about 15 hours, a compound of formula (I) wherein Rl is hydrogen or hydroxy, R4 is hydrogen and R3 is Cl-C12 alkyl, can be transformed into the corresponding compound of formula (I) wherein R3 and R4 are both Cl-C12 alkyl.
A compound of formula (I) wherein Rl is Cl-C12 alkoxy can be transferred into the corresponding compound of formula (I) wherein Rl is hydroxy by heating with anhydrous aluminium chloride in an inert solvent such as for instance petroleum ether, according to the procedure described in J.Am.Chem.Soc.
57, 1935, p.757. Alternatively, it can be treated with 113~4~^~
halogenhydric acids such as hydrobromic acid, according to the method referred to for instance in Chemistry and Ind., 1965, page 87.
The reaction of a compound of formula (I) with a pharmac-eutically acceptable acid to form a salt is carried out using conventional methods, for instance a solution of the base of formula (I) is added -to a solution of the pharmaceutically acceptable acid in the same solvent, that can be for instance ethyl ether, and the salt is precipitated, or a solution of the pharmaceutically acceptable acid in a given solvent, e.g.
ethanol is added to a solution of the base of formula (I) in a different solvent, for instance ethyl ether, and again the salt is precipitated. In both these cases the salification reaction can be carried out in a stream of nitrogen and is preferably carried out at room temperature.
Also the separation of a mixture of optical enantiomers into the individual enantiomers can be carried out according to methods known in organic chemistry, for instance by reacting the racemic compound of formula (I) with an optically active acid, thus obtaining the two diastereoisomeric salts which can then be separated from each other using their different solubilities in various solvents.
Thus for instance the separation of racemic eseroline into the two opticallaevorotatory and dextrorotatory enantiomers can be carried out by adding, at room temperature, to a solution of racemic eseroline in a low molecular weight aliphatic alcohol, for instance ethanol or methanol, a solution 1~L374~
of tartaric dextrorotatory acid in the same solvent, thus obtaining crystalli~-ing and precipitating the acid tartrate of (+) eseroline ((3aR, 8aS) 1,3a,8-trimethyl-1,2,3,3a,8,8a-hexahydropyrrolo [2,3-b] indol-5-ol).
The acid tartrate of laevorotatory isomer (-) of eseroline, (i.e. the 3aS, 8aR-derivative) remains in solution in the alcoholic mother liquor, from which free (-) eseroline can be obtained by evaporating the solvent at a reduced pressure, alkalini~ing the residue, extracting the (-) eseroline into an organic solvent, for instance, ethyl ether and evaporating this solvent at a reduced pressure. Free (+) eseroline can be obtained from the above-mentioned salt us-ing a similar method.
Other compounds of formula I can be separated into their opticalenantiomers in a similar manner.
The compound of formula (II) can be prepared by reaction of a compound of formula (VII) Rl ~ (VII) ,C ,~
wherein:
Y is an alkaline metal, preferably sodium, and Rl, R2 and R4 are as defined previously with a compound of formula (VIII) / CH2 (VIII) RN
3 .
.
1~3 ~
wherein:
X is halogen, preferably bromine or chlorine, and R3 is as defined previously.
The reaction between the compound of formula (VII) and the compound of formula (VIII) is preferably effected by adding the compound of formula (VIII), for instance a chlor-hydrate or bromhydrate, to a solution, cooled to 0-10C, of the compound of formula (VII) in an organic solvent such as for instance benzene, xylene or ethyl ether, in the presence of a base, preferably triethylamine. The reaction mixture is maintained at room temperature for some hours and then heated under reflux for 1-2 hours. The solvent is evaporated and the residue is treated with water and acidified e.g. with hydrochloric acid or hydrobromic acid. An organic extraction is carried out using solvent, for instance ethyl ether, and after alkalinization e.g. with an alkaline hydroxide, it is extracted again into an organic solvent, for instance ethyl ether, and the solvent is evaporated at a reduced pressure.
Alternatively the compound of formula (II) can be obtained by reaction of a compound of formula (VII) with a compound of formula (IX) f CH2 (IX) X
wherein:
X is halogen, preferably chlorine or bromine, thus obtaining a compound of formula (X) 113~48.9 n~ C}12-c~l2-x ~X~
wherein:
Rl, R2, R4 and X have the previously mentioned meanings, and by subsequent reaction of a compound of formula (X) with an amine of formula R3NH2, wherein R3 is as defined above.
The reaction of a compound of formula (VII) and a compound of formula (X) can be carried out using approximately the same reaction conditions as described above for the reaction between a compound of formula (VII) and a compound of formula (VIII).
The reaction between a compound of formula (X) and an amine of formula R3NH2 can be effected by heating the reactants in a closed tube without solvents, preferably using 2 moles of amine per one mole of the compound of formula (X). The compound of formula (VII) can be prepared according to P.L.
Julian and J.Pike, J.A.C.S., 57, 563 (l935) and J.A.C.S., 57, 755 (1935) preferably, replacing metal sodium, used by these authors, by sodium hydride. The compound of formula (III), wherein Rl and R2 are as defined above and R3 and R4, are the same, and are Cl-Cl2 alkyl or C2-Cl2 alkenyl, can be obtained by reaction of a compound of formula (XI) _CH2_N=CH_C6115 (XI) N~CH_C6H
wherein:
37~1~R9 R is a Cl-C6 alkyl radical and Rl a~lR2 have any of the above mentioned definitions with a Cl-C12 alkyl or C2-C12 alkenyl halide, preferably iodide. The reaction is preferably effected by maintaining -the reactants in a closed tube at a temperature of about 100C for a reaction time of about 2 hrs and subsequently heating them with a halogenhydric acid, for instance hydrobromic acid, thus obtaining the salt e.g. the dibromhydrate of the compound of formula (III). The compound of formula (XI) can be obtained according to J.Harley-Mason and A.H.Mackson, J.Chem.Soc.3651 (1954).
The compound of formula (IV) can be prepared by reaction of a compound of formula (XII) ~ t o ~0 (Xll~
wherein:
Rl, R2 and R4 are as defined above, with ammonium hydrate or with an amine of formula NH2R3.
The reaction is preferably carried out at a temperature of about 50C and in a low molecular weight aliphatic alcohol, e.g.methanol.
The compound of formula (XII) can be prepared according to the method of P.Rosenmund and A.Sotiriou, Angew.Chemie 76, 187 (1964), The compound of formula (V), in particular when R''l is methylcarbamoyloxy, is known per se and can be prepared using 1137~
- ~6 -kno~vn me~hods (J.Prakt, Chem.116, 59 (1927)). The compounds of formula (VI) are also described in literature, for instance in Ann.Chem.500, ~2 (1933), Ann.Chem.516, 76 (1935), Ann.Chem.
516, 81 (1935), ~nn.Chem.520, 11 (lg35).
The described compounds have an analgesic activity,as shown for instance by the fact that they are active in the mouse tail pinch tes-t, carried out according to the technique described by P.llaffner Deutsche Med.Wecherschr.,55, 731 (1929) and in the mouse hot pla-te test, carried out according to the technique described by Eddy N.B.et al., J.Pharmacol.Exp.Ther., 07, 385 (1953).
They are useful therefore for treating a variety of pains such as those resulting from fractures.
The toxicity of these compounds is very low; for instance for salicylate of (-) eseroline the toxicity (LD 50) in a mouse, as determined by the administration of a single oral dose and ascertained on the seventh day from treatment, was found to be 600 mg/Kg.
The compounds of the invention are active both parenterally and enterally, for instance by mouth. The parenteral adminis- -tration is generally preferred.
The doses (e.g. for salicylate of (-) eseroline are preferably 2-20 mg (calculated on the free base) per dose given from~l to 4 times a day if administered parenterally and 5-80 mg, preferably 10-30 mg (calculated on free base), per dose given 1 to 4 times a day if administered orally.
Pharmaceutical compositions containing the compounds ~1374~C~
object of the present invention can be in the form of for instance vials, vials for extemporary solution, lyophilized vials, troches, pills, tablets, drops, syrups, suppositories, or gelatinous capsules containing the active substance possibly together with stabilizing or antioxidant substances such as e.g. sodium pyrosulphite, ascorbic acid and suitable carriers, for instance diluents, lubricants, bonding agents, disintegrating agents, effervescents, dyes, edulcorating agents, wetting agents etc.
Diluents for the vials can be for instance water and physiological solutions. Diluents for the oral administration of the product can be for instance lactose, dextrose, saccharose, mannitol, sorbitol or cellulose.
Lubricants can be for instance silica, talc, stearic acid, magnesium stearate or calcium stearate and/or polyethylene glycols.
Further, as mentioned above, the pharmaceutical composition can contain bonding agents such as starches, gelatin, gum arabic, gum tragacanth and polyvinylpyrrolidone, disintegrating agents such as alginic acid and alginates; effervescent agents, dyes, edulcorating agents, wetting agents such as lecithins and polysorbates, as well as any other pharmacologically non-toxic carrier employed in conventional pharmaceutical formulations.
The pharmaceutical preparations containing the compounds are produced according to the usual methods.
The following examples are given by way of illustration only.
Some of the products of the examples are novel compounds and some are known compounds whose use in pharmaceutical compositions is the subject of our Patent Application Serial No. 311,555.
~1~7'4B~
I,~ample 1 In this preparation, 2 g of (-) physostigmine dissolved in 12 ml of ethyl alcohol were placed in a flask and a stream of nitrogen passed through the so]ution to expel air. Then
as well as the salts of the compounds formed with pharmaceutically acceptable acids, in particular those referred to above.
As active substances in pharmaceutical compositions, the salts of the compounds of formula (I) with pharmaceutically acceptable acids are preferred over the free bases, since the free bases can be easily oxidised, for instance in aqueous solution, giving degradation products having a quinone type structure.
The easy oxidation and degradation of the free bases of the invention and/or of the corresponding salts can be eliminated by using special pharmaceutical techniques, for instance keeping the pH value of the solutions low, or protecting the bases and their salts against attack from atmospheric oxygen, or by the addition of compounds which can be oxidised more easily and so act as antioxidant agents.
11374~39 The derivatives of the 1,2,3,3a,8,8a-hexahydropyrrolo [2,3-b] indole in accordance with the inven~ion can be prepared by the following processes, (a) by reductive cyclization of a compound of formula (II) Rl lR2 \ ~ C - CH
W ` N J ~o / 2 (II) I NH
wherein Rl, R2, R3 and R4 are as referred to above or (b) by oxidative cyclization of a compound of formula (III) fH3 C - CH
2 (III) 1 o ¦ f H H
N / N ~
or a salt thereof wherein:
1137~9 Rl is hydlogen or hydroxy, R3 and R4 are the same, and as referred to above but not hydrogen. Thus compounds of formula (I) are obtained wherein Rl is hydrogen or hydroxy and R3=R4 which are Cl-C12 alkyl or C2 C12 Y
c) by reduction Oe a compound of formula (IV) N 1 N ~ Q (IV) wherein:
Rl, R2, R3 and R4 are as defined above;
or d) by hydrolysis of a compound of formula (V) R~ I N J (V) wherein:
R2, R3 and R4 are as previously mentioned and R"l is an acyloxy, carbamoyloxy or alkylcarbamoyloxy group. Thus compounds of , formula (I) are obtained wherein Rl is a hydroxy group which can, if desired, undergo etherification to give compounds of formula (I) wherein Rl is Cl-C12 alkoxy or C2-C12 alkenyloxy; or e) by reaction of a compound of formula (VI) l\ ~ R4 CH2-CH~NHR3 (Vl) ~137~9 ~, wherein Rl, R3 and R4 are as described previously, first with a halide of alkylmagnesium RMgX wherein R is a general Cl-C6 alkyl, and with an alkyl halide R2X, wherein R2 is Cl-C12. Thus compounds of formula (I) are obtained wherein R2 is Cl-C12 alkyl.
In addi-tion compounds of formula (I) can be produced by the transformation of other compounds of formula (I) having different Rl, R2, R3 and/or R4 substituents and/or by salifying a compound of formula (I) with a pharmaceutically acceptable acid, and/or by separating a mixture of optical enantiomers of formula (I) into the single enantiomers.
The reductive cyclization of the compound of formula (Il) is preferably carried out using sodium in an alipha-tic low molecular weight alcohol, for instance methanol or ethanol.
Metal sodium is added in small portions to an alcoholic solution ofthe compound of formula (II), preferably at temperatures of about room temperature, at intervals of about two hours. The resulting solution is then acidified with a mineral acid, for instance hydrochloric acid, and the alochol evaporated under reduced pressure. The solution is then made alkaline, preferably by the addition of an inorganic base, for instance an alkaline hydroxide. The product is then extracted into a suitable organic solvent, for instance ethyl ether, which is evaporated to dryness.
The oxidative cyclization of the compound of formula (III), preferably salified with acids, for instance inorganic acids, such as hydrobromic acid, is preferably carried out in aqueous 1~37~8~
solution, using as oxidating agent an alkaline ferricyanide for instance, potassium ferricyanide, in the presence of an alkaline bicarbonate, Lor instance sodium bicarbonate. The cyclisation is carried out under st:ream of inert gas, for instance nitrogen, at a temperature of abou-t the room temperature.
The reduction of the compound of formula (IV) is preferably carried out using a mixed hydride, for instance lithium alumin-ium hydride. The compound of formula tIV) is refluxed in a suitable organic solvent such as ethyl ether or tetrahydro-furan.
The hydrolysis of the compound of formula (V) is prefer-ably carried out by reacting with an alkaline hydroxide, for instance sodium or potassium hydroxide, in a hydroalcoholic solution, for instance hydroethanolic solution, in a stream of hydrogen, or preferably nitrogen, at a temperature of about the room temperature. The compounds of formula (I) produced by the hydrolysis, have Rl as a hydroxy group. These can be converted to compounds of formula (I) wherein R1 is Cl-C12 alkoxy or C2-C12 alkenyloxy by etherification, preferably by treatment with a corresponding Cl-C12 alkyl or C2-C12 alkenyl tosylate or mesylate.
In the compound of formula (V) R"l is preferably methyl-carbamoyloxy (CH3NHCOO-). When R"l is acyloxy, the acyl group is preferably a Cl-C12 aliphatic acyl group, or a benzoyl group or a p-hydroxybenzoyl group.
All the compounds of formula (II), (III), (IV) and (V) can 1~379~8~1 I () be either optically active or racemic, and thus the compounds of formula (I) obtained by the previously described reactions are also either optically active or racemic. As mentioned above, a compound of formula (I~ can be transformed into another compound of formula (I) having different Rl, R2, R3 and/or R4 substituents and such transformation can be carried out according to any of the methods used in organic chemistry.
~ or instance a compound of formula (I) wherein Rl is hydrogen or hydroxy and R3 and R4 are both hydrogen, can be transformed into a compound of formula (I) wherein Rl is hydrogen orhydroxy, R3 is hydrogen and R4 is Cl-C12 alkyl or C2-C12 alkenyl by reaction of one of its salts, for instance hydrochloride or hydrobromide, with an alkyl halide having formula R4X, wherein R4 is Cl-C12 alkyl or C2-C12 alkenyl and X is halogen, preferably iodine. The reaction is carried out in an alcoholic solvent, for instance ethyl alcohol, in a sealed tube, by boiling the reaction mixture on water bath for about 7 hours. By the same method but with a reaction time of about 15 hours, a compound of formula (I) wherein Rl is hydrogen or hydroxy, R4 is hydrogen and R3 is Cl-C12 alkyl, can be transformed into the corresponding compound of formula (I) wherein R3 and R4 are both Cl-C12 alkyl.
A compound of formula (I) wherein Rl is Cl-C12 alkoxy can be transferred into the corresponding compound of formula (I) wherein Rl is hydroxy by heating with anhydrous aluminium chloride in an inert solvent such as for instance petroleum ether, according to the procedure described in J.Am.Chem.Soc.
57, 1935, p.757. Alternatively, it can be treated with 113~4~^~
halogenhydric acids such as hydrobromic acid, according to the method referred to for instance in Chemistry and Ind., 1965, page 87.
The reaction of a compound of formula (I) with a pharmac-eutically acceptable acid to form a salt is carried out using conventional methods, for instance a solution of the base of formula (I) is added -to a solution of the pharmaceutically acceptable acid in the same solvent, that can be for instance ethyl ether, and the salt is precipitated, or a solution of the pharmaceutically acceptable acid in a given solvent, e.g.
ethanol is added to a solution of the base of formula (I) in a different solvent, for instance ethyl ether, and again the salt is precipitated. In both these cases the salification reaction can be carried out in a stream of nitrogen and is preferably carried out at room temperature.
Also the separation of a mixture of optical enantiomers into the individual enantiomers can be carried out according to methods known in organic chemistry, for instance by reacting the racemic compound of formula (I) with an optically active acid, thus obtaining the two diastereoisomeric salts which can then be separated from each other using their different solubilities in various solvents.
Thus for instance the separation of racemic eseroline into the two opticallaevorotatory and dextrorotatory enantiomers can be carried out by adding, at room temperature, to a solution of racemic eseroline in a low molecular weight aliphatic alcohol, for instance ethanol or methanol, a solution 1~L374~
of tartaric dextrorotatory acid in the same solvent, thus obtaining crystalli~-ing and precipitating the acid tartrate of (+) eseroline ((3aR, 8aS) 1,3a,8-trimethyl-1,2,3,3a,8,8a-hexahydropyrrolo [2,3-b] indol-5-ol).
The acid tartrate of laevorotatory isomer (-) of eseroline, (i.e. the 3aS, 8aR-derivative) remains in solution in the alcoholic mother liquor, from which free (-) eseroline can be obtained by evaporating the solvent at a reduced pressure, alkalini~ing the residue, extracting the (-) eseroline into an organic solvent, for instance, ethyl ether and evaporating this solvent at a reduced pressure. Free (+) eseroline can be obtained from the above-mentioned salt us-ing a similar method.
Other compounds of formula I can be separated into their opticalenantiomers in a similar manner.
The compound of formula (II) can be prepared by reaction of a compound of formula (VII) Rl ~ (VII) ,C ,~
wherein:
Y is an alkaline metal, preferably sodium, and Rl, R2 and R4 are as defined previously with a compound of formula (VIII) / CH2 (VIII) RN
3 .
.
1~3 ~
wherein:
X is halogen, preferably bromine or chlorine, and R3 is as defined previously.
The reaction between the compound of formula (VII) and the compound of formula (VIII) is preferably effected by adding the compound of formula (VIII), for instance a chlor-hydrate or bromhydrate, to a solution, cooled to 0-10C, of the compound of formula (VII) in an organic solvent such as for instance benzene, xylene or ethyl ether, in the presence of a base, preferably triethylamine. The reaction mixture is maintained at room temperature for some hours and then heated under reflux for 1-2 hours. The solvent is evaporated and the residue is treated with water and acidified e.g. with hydrochloric acid or hydrobromic acid. An organic extraction is carried out using solvent, for instance ethyl ether, and after alkalinization e.g. with an alkaline hydroxide, it is extracted again into an organic solvent, for instance ethyl ether, and the solvent is evaporated at a reduced pressure.
Alternatively the compound of formula (II) can be obtained by reaction of a compound of formula (VII) with a compound of formula (IX) f CH2 (IX) X
wherein:
X is halogen, preferably chlorine or bromine, thus obtaining a compound of formula (X) 113~48.9 n~ C}12-c~l2-x ~X~
wherein:
Rl, R2, R4 and X have the previously mentioned meanings, and by subsequent reaction of a compound of formula (X) with an amine of formula R3NH2, wherein R3 is as defined above.
The reaction of a compound of formula (VII) and a compound of formula (X) can be carried out using approximately the same reaction conditions as described above for the reaction between a compound of formula (VII) and a compound of formula (VIII).
The reaction between a compound of formula (X) and an amine of formula R3NH2 can be effected by heating the reactants in a closed tube without solvents, preferably using 2 moles of amine per one mole of the compound of formula (X). The compound of formula (VII) can be prepared according to P.L.
Julian and J.Pike, J.A.C.S., 57, 563 (l935) and J.A.C.S., 57, 755 (1935) preferably, replacing metal sodium, used by these authors, by sodium hydride. The compound of formula (III), wherein Rl and R2 are as defined above and R3 and R4, are the same, and are Cl-Cl2 alkyl or C2-Cl2 alkenyl, can be obtained by reaction of a compound of formula (XI) _CH2_N=CH_C6115 (XI) N~CH_C6H
wherein:
37~1~R9 R is a Cl-C6 alkyl radical and Rl a~lR2 have any of the above mentioned definitions with a Cl-C12 alkyl or C2-C12 alkenyl halide, preferably iodide. The reaction is preferably effected by maintaining -the reactants in a closed tube at a temperature of about 100C for a reaction time of about 2 hrs and subsequently heating them with a halogenhydric acid, for instance hydrobromic acid, thus obtaining the salt e.g. the dibromhydrate of the compound of formula (III). The compound of formula (XI) can be obtained according to J.Harley-Mason and A.H.Mackson, J.Chem.Soc.3651 (1954).
The compound of formula (IV) can be prepared by reaction of a compound of formula (XII) ~ t o ~0 (Xll~
wherein:
Rl, R2 and R4 are as defined above, with ammonium hydrate or with an amine of formula NH2R3.
The reaction is preferably carried out at a temperature of about 50C and in a low molecular weight aliphatic alcohol, e.g.methanol.
The compound of formula (XII) can be prepared according to the method of P.Rosenmund and A.Sotiriou, Angew.Chemie 76, 187 (1964), The compound of formula (V), in particular when R''l is methylcarbamoyloxy, is known per se and can be prepared using 1137~
- ~6 -kno~vn me~hods (J.Prakt, Chem.116, 59 (1927)). The compounds of formula (VI) are also described in literature, for instance in Ann.Chem.500, ~2 (1933), Ann.Chem.516, 76 (1935), Ann.Chem.
516, 81 (1935), ~nn.Chem.520, 11 (lg35).
The described compounds have an analgesic activity,as shown for instance by the fact that they are active in the mouse tail pinch tes-t, carried out according to the technique described by P.llaffner Deutsche Med.Wecherschr.,55, 731 (1929) and in the mouse hot pla-te test, carried out according to the technique described by Eddy N.B.et al., J.Pharmacol.Exp.Ther., 07, 385 (1953).
They are useful therefore for treating a variety of pains such as those resulting from fractures.
The toxicity of these compounds is very low; for instance for salicylate of (-) eseroline the toxicity (LD 50) in a mouse, as determined by the administration of a single oral dose and ascertained on the seventh day from treatment, was found to be 600 mg/Kg.
The compounds of the invention are active both parenterally and enterally, for instance by mouth. The parenteral adminis- -tration is generally preferred.
The doses (e.g. for salicylate of (-) eseroline are preferably 2-20 mg (calculated on the free base) per dose given from~l to 4 times a day if administered parenterally and 5-80 mg, preferably 10-30 mg (calculated on free base), per dose given 1 to 4 times a day if administered orally.
Pharmaceutical compositions containing the compounds ~1374~C~
object of the present invention can be in the form of for instance vials, vials for extemporary solution, lyophilized vials, troches, pills, tablets, drops, syrups, suppositories, or gelatinous capsules containing the active substance possibly together with stabilizing or antioxidant substances such as e.g. sodium pyrosulphite, ascorbic acid and suitable carriers, for instance diluents, lubricants, bonding agents, disintegrating agents, effervescents, dyes, edulcorating agents, wetting agents etc.
Diluents for the vials can be for instance water and physiological solutions. Diluents for the oral administration of the product can be for instance lactose, dextrose, saccharose, mannitol, sorbitol or cellulose.
Lubricants can be for instance silica, talc, stearic acid, magnesium stearate or calcium stearate and/or polyethylene glycols.
Further, as mentioned above, the pharmaceutical composition can contain bonding agents such as starches, gelatin, gum arabic, gum tragacanth and polyvinylpyrrolidone, disintegrating agents such as alginic acid and alginates; effervescent agents, dyes, edulcorating agents, wetting agents such as lecithins and polysorbates, as well as any other pharmacologically non-toxic carrier employed in conventional pharmaceutical formulations.
The pharmaceutical preparations containing the compounds are produced according to the usual methods.
The following examples are given by way of illustration only.
Some of the products of the examples are novel compounds and some are known compounds whose use in pharmaceutical compositions is the subject of our Patent Application Serial No. 311,555.
~1~7'4B~
I,~ample 1 In this preparation, 2 g of (-) physostigmine dissolved in 12 ml of ethyl alcohol were placed in a flask and a stream of nitrogen passed through the so]ution to expel air. Then
10 ml of a solution of 10% sodium hydroxide (p/p) previously de-aired was added, and the mixture maintained at room temperature for about 4 hours, under a nitrogen stream.
27.5 ml of hydrochloric acid lN were then added and the reaction mixture was poured into a separating funnel. Then 100 ml of ethyl ether and sodium chloride were added until the aqueous phase was saturated. The ether layer was washed with a saturated aqueous solution of sodium chloride previously de-aired. After evaporation of the ethyl ether white crystals of (-) eseroline were obtained which melted at 129C (yield 95%). .
The following compounds were obtained by a similar method:
1,8-dimethyl-3a-ethyl-1,2,3,3a,8,8a-hexahydropyrrolo [2,3-b~
indol-5-ol;
1,3a-dimethyl-8-ethyl-1,2,3,3a,8,8a-hexahydropyrrolo [2,3-b~
indol-5~ol;
1,3a,8-triethyl-1,2,3,3a,8,8a-hexahydropyrrolo [2,3-b~ indol-5-ol;
l-ethyl-3a,8-dimethyl-1,2,3,3a,8,8a-hexahydropyrrolo [2,3-b~ indol-5-ol;
1,8-dimethyl-3a-propyl,1,2,3,3a,8,8a-hexahydropyrrolo [2,3-b~
indol-5-ol;
3a-methyl-1,2,3,3a,8,8a-hexahydropyrrolo [2,3-b] indol-5-ol;
1,3a-dimethyl-1,2,3,3a,8,8a-hexahydropyrrolo [2,3-b]
indol-5-ol;
1~L379t~
1,8-diethyl-3a-methyl-1,2,3,3a,8,8a-hexahydropyrrolo ~2,3-b~
indol-5-ol;
1,3a,8-trimethyl-1,2,3,3a,8,8a-hexahydropyrrolo [2,3-b~
indol-5-ol;
3a,8-dimethyl-1,2,3,3a,8,8a-jexahydropyrrolo ~2,3-b~ indol-5-ol;
Example 2 A solution of (-) eseroline (1.5 g) in ethyl ether (100 ml) de-aired with a nitrogen stream, was added to a solution of salicylic acid (1.3 g) in e-ther (20 ml) with stirring. A
white crystalline solid was precipitated which was collected by filtration, washed with a small quantity of ether and dried under vacuum. Needle-like crystals of (-) eseroline salicylate which melt at 178-180C (with slight decomposition) were obtained.
The salts of the following compounds with salicylic acid were prepared in a similar manner;
1,8-dimethyl-3a-ethyl-1,2,3,3a,8,8a-hexahydropyrrolo ~2,3-b~
indol-5-ol;
1,3a-dimethyl-8-ethyl-1,2,3,3a,8,8a-hexahydropyrrolo ~2,3-b]
indol-5-ol;
1,3a,8-triethyl-1,2,3,3a,8,8a-hexahydropyrrolo [2,3-b] indol-5-ol;
l-ethyl-3a,8-dimethyl-1,2,3,3a,8,8a-hexahydropyrrolo [2,3-b] indol-5-ol;
1,8-dimethyl-3a-ethyl-5-methoxy-1,2,3,3a,8,8a-hexahydropyrrolo _ _ 2,3-b indol-5-ol;
1,8-dim ethyl-3a-propyl-1,2,3,3a,8,8a-hexahydropyrrolo [2,3-b~
indol-5-ol;
1~374~3 1,3a,8-trimethyl-5-propyloxy-1,2,3,3a,8,8a-hexahydropyrrolo ~2,3-b~ indol-5-ol;
_ _ 3a-methyl-1,2,3,3a,8,8a-hexahydropyrrolo 2,3-b indol-5-ol (1,8-dinor-eseroline);
1,3a-dimethyl-1,2,3,3a,8,8a-hexahydropyrrolo ~2,3-b~ indol-5-ol (N8-nor-eseroline);
1,8-diethyl-3a-methyl-1,2,3,3a,8,8a-hexahydropyrrolo ~2,3-b~
indol-5-ol;
l-ethyl-3a,8-dimethyl-1,2,3,3a,8,8a-hexahydropyrrolo [2,3-b~
indole;
1,3a,8-trimethyl-1,2,3,3a,8,8a-hexahydropyrrolo ~2,3-b~
indol-5-ol (eseroline);
1,3a-8-trimethyl-5-,ethoxy-1,2,3,3a,8,8a-hexahydropyrrolo ~2,3-b~ indol-5-ol (eseromethole);
1,3a,8-trimethyl-5-ethoxy-1,2,3,3a,8,8a-hexahydropyrrolo ~2,3-b] indol-5-ol (eserethole);
1,3a,8-trimethyl-1,2,3,3a,8,8a-hexahydropyrrolo ~2,3-b] indole (desoxyeseroline);
3a,8-dimethyl-1,2,3,3a,8,8a-hexahydropyrrolo ~2,3-b~ indole (desoxy-Nl-noreseroline);
1,3a-dimethyl-1,2,3,3a,8,8a-hexahydropyrrolo ~2,3-b] indole (desoxy-N8-noreseroline);
3a-methyl-1,2,3,3a,8,8a-hexahydropyrrolo ~2,3-b~ indole (Nl,N8-dinor-desoxyeseroline);
3a,8-dimethyl-1,2,3,3a,8,8a-hexahydropyrrolo [2,3-b~ indol-5-ol (Nl-nor-eseroline).
~137~
~, Example 3 A solution of (-) eseroline (0.005 moles) in ethyl ether (50 ml) was added to a solution of fumaric acid (0.006 moles) in ethanol (30 ml) under a nitrogen stream.
The white precipitate obtained was collected by filtration and dried, and white cyrstals of fumarate of (-) eseroline were obtained which after recrystallization from ethyl alcohol melted at 197-199C with decomposition.
The salts of all the compounds listed in Example 2 with fumaric acid were prepared in a similar manner.
Example 4 A de-aired solution of (-) eseroline (0.005 moles) in ethyl ether (50 ml) was added to a solution of (+)-tartaric acid (0.006 moles) in ethanol (30 ml).
The resulting precipitate was collected by filtration and re-crystallized from ethyl alcohol. The salt of the (+) tartaric acic with (-) eseroline was obtained, m.p. 197-200C
(decomposition).
The salts of all the compounds listed in Example 2 with tartaric acid were prepared in a similar manner.
Example 5 To a solution of 5-ethoxy-1,3-dimethyl-3-(~ -ethylamino-ethyl)-indolinone (5 g) in absolute ethanol (500 ml), metal sodium (20 g) was added over a period of two hours. After the sodium dissolution, de-aired water (200 ml) was added cautiously to the cooled solution and ethyl alcohol removed by distillation under vacuum. The residue was then repeatedly extracted into 74~
ethyl ether and the ether extracts evaporated to dryness give (~)-l-ethyl-3a,8-dimethyl-5-ethoxy-1,2,3,3a,8,8a-hexahydro-pyrrolo ~2,3-b] indole which was purified by distillation under vacuum (4 g). This latter compound (4 g) was added to a solution obtained by dissolving (+) tartaric acid (2.4 g) in ethyl alcohol (30 ml). The mixture was added to some ethyl ether and left overnight. Crystalline masses separated out which were filtered and found to melt at about 150-160C.
After several crystallizations from ethyl alcohol containing (+)-tartaric acid needle-like colourless crystals of (+)-l-ethyl-3,3a,8-dimethyl-5-ethoxy-1,2,3,3a,8,8a-hexahydro-pyrrolo [2,3-b] indole-bitartrate were obtained (1.6 g).
The alcoholic filtrates were evaporated and a residue obtained which was treated with aqueous sodium hydroxide and extracted twice with ether. The ether extracts were concen-trated to dryness and the residue distilled under vacuum.
A colourless oil was obtained consisting of (-)-l-ethyl-3a, 8-dimethyl-5-ethoxy-1,2,3,3a,8,8a-hexahydropyrrolo ~2,3-b]
indole (2.6 g). To a solution of this latter compound (2.6 g) in petroleum ether (20 ml) aluminium trichloride (4 g) was added. The mixture was heated under reflux on a water bath for about 12 hours and the petroleum ether was removed by decanting, leaving a crystalline mass which was decomposed by treatment with ice. The aqueous solution obtained was treated with sodium bicarbonate and repeatedly extracted into ethyl ether. The residue obtained after removing the solvent was distilled under high vacuum and the oil obtained was dissolved in ethyl ether-petroleum ether from which needle-like crystals of (-)-l-ethyl-3a,8-dimethyl-1,2,3,3a,8,8a-hexahydropyrrolo 1~l3~8~1 - 2~3 -~2,3-b~ indol-5-ol were obtained.
Example 6 A mixture of ethyl iodide (2 moles) and oI dibenzyliden-derivative of 2-me-thyl-2-(3,6-dimethoxyphenyl)-butyl-1,4-diamine (l mole) was heated to 100C for about 2 hours in a closed tube. The solid obtained was extracted into aqueous ethanol, the solvent was evaporated and the residue dissolved in diluted hydrochloric acid. An extraction into ethyl ether was carried ou-t and the benzaldehyde formed by extraction with ethyl ether was removed. The aqueous phase was then saturated with potassium carbonate and extracted again with ethyl ether.
N,N-diethyl-2-(3,6-dimethoxy-phenyl)-2-methyl-butyl-1, 4-diamine (4 g) was obtained by evaporating the solvent and distilling under vacuum. This was dissolved in hydrobromic acid having a density of 1.49 (25 ml) and the solution was heated under reflux for about l hour, cooled and treated with a mixture of propyl alcohol and ethyl ether. The dibromhydrate obtained by filtration (1.3 g) was dissolved in water (75 ml) and mixed with an aqueous solution obtained by dissolving potassium ferricyanide (1.95 g) and sodium bicarbonate (l g) in water (75 ml). The reaction mixture was extracted several times into ethyl ether and the ether extracts were evaporated to dryness. Raw (+) 1,8-diethyl-3a-methyl-1,2,3,3a,8,8a-hexahydropyrrolo ~2,3-b~ indol-5-ol was obtained, which was purified by crystallization or by sublimation under high vacuum.
To a solution of the racemic compound thus obtained (0.5 g) in anhydrous ethanol (40 ml) ethyl p-toluenesulphonate was 1~l374t~
- 2~ -added together with a solution of metal sodium (0.1 g) in absolute ethanol (10 ml). The residue obtained after removing the solvent was treated with aqueous diluted sodium hydroxide and extracted several times into ethyl ether. By evaporation of the ether extracts the racemic mixture of (+) and (-) 1,8-diethyl-3a-methyl-5-ethoxy-1,2,3,3a,8,8a-hexahydropyrrolo [2,3-b~ indole was obtained, which was separated into the individual (+) and (-) isomers by the procedure described in the previous example. By treatment of the (-)-1,8-diethyl-3a-methyl-5-ethoxy-1,2,3,3a,8,9a-hexahydropyrrolo ~2,3-b~ indole thus separated with aluminium chloride in petroleum ether, following the procedure described in the previous example, one obtains (-)-1,8-diethyl-3a-methyl-1,2,3,3a,8,8a-hexahydro-pyrrolo [2,3~b~ indol-5-ol.
Example 7 A solution of (+)-3a,8-dimethyl-2,3,3a,8a-tetrahydrofuro [2,3-b~ indolin-2-one (5 g) in ethyl alcohol (100 ml) was mixed with ethylamine (excess 20%) and heated to 50C for some hours. By evaporation of the solvent, (+)-l-ethyl-3a, 8-dimethyl-2-oxa-pyrrolo ~2,3-b~ indole (3 g) was separated, which was suspended in anhydrous tetrahydrofuran (100 ml) and treated with a slight excess of lithium aluminium hydride. The reaction mixture was first heated under reflux with stirring for about 2 hours, and then cooled and decomposed by treatment with water. The ether phase was separated, dried and evaporated to dryness. Thus (+)-l-ethyl-3a,8-dimethyl-1,2,3,3a,8,8a-hexahydropyrrolo [2,3-b] indole (2.5 g) was obtained.
1137~
~xample 8 To an ether solution of ethyl magnesium iodide obtained from magnesium (2 g), e-thyl iodide (12.8 g) and ethyl ether (20 ml) 5-ethoxy-3-methyl-triptamine (5.8 g) was added in small portions. The reaction mixture was heated to 100 C
with stirring to fully evporate the ethyl ether. Then methyl iodide (15 g) was added over a period of about 3 hours.
After adding some benzole and ethyl ether to dissolve the excess of methyl iodide, the reaction mixture was treated with diluted acetic acid under cooling conditions. The aqueous phase was cautiously alkalinized with sodium hydroxide and repeatedly extracted with ethyl ether. The ether extracts were evaporated and the residue oil was distilled under vacuum.
Thus (+) -1,3a-dimethyl-5-ethoxy-1,2,3,3a,8,8a-hexahydropyrrolo [2,3-b~ indole was obtained which was converted into the corresponding (+)-1,3a-dimethyl-1,2,3,3a,8,8a-hexahydropyrrolo ~2,3-b] indol-5-ol, by treatment with aluminium trichloride in petroleum ether using the same procedure described in Example 5.
~xample 9 Tablets with a weight of 200 mg and containing 25 mg of active substance, calculated as free base, have been prepared as follows:
(composition for 10,000 tablets) (+) eseroline hydrogentartrate g 587 lactose g 893 mais starch g 450 talc powder g 50 magnesium stearate g 20 113748~
~xample lO
A pharmaceutical composition, that can be injected, has been prepared by dissolving 10 mg of (-) eseroline salicylate in 2 ml of sterile water or sterile physiological solution containing sodium pyrosulphite (2%) It is noted that eseroline in some cases and with certain dosages could give rise to an activity of cholinomimetic type.
This possible undesired effect is not due to eseroline itself, but to an oxidation product, rubrosine,whichforms more easily in an alkaline environment. To avoid this undesired effect in those few cases where it might appear,a very small quantity of atropine or some other muscarinic blocking agents can be included in the pharmaceutical preparations which would annul the cholinomimetic action without affecting the analgesic action of the product.
27.5 ml of hydrochloric acid lN were then added and the reaction mixture was poured into a separating funnel. Then 100 ml of ethyl ether and sodium chloride were added until the aqueous phase was saturated. The ether layer was washed with a saturated aqueous solution of sodium chloride previously de-aired. After evaporation of the ethyl ether white crystals of (-) eseroline were obtained which melted at 129C (yield 95%). .
The following compounds were obtained by a similar method:
1,8-dimethyl-3a-ethyl-1,2,3,3a,8,8a-hexahydropyrrolo [2,3-b~
indol-5-ol;
1,3a-dimethyl-8-ethyl-1,2,3,3a,8,8a-hexahydropyrrolo [2,3-b~
indol-5~ol;
1,3a,8-triethyl-1,2,3,3a,8,8a-hexahydropyrrolo [2,3-b~ indol-5-ol;
l-ethyl-3a,8-dimethyl-1,2,3,3a,8,8a-hexahydropyrrolo [2,3-b~ indol-5-ol;
1,8-dimethyl-3a-propyl,1,2,3,3a,8,8a-hexahydropyrrolo [2,3-b~
indol-5-ol;
3a-methyl-1,2,3,3a,8,8a-hexahydropyrrolo [2,3-b] indol-5-ol;
1,3a-dimethyl-1,2,3,3a,8,8a-hexahydropyrrolo [2,3-b]
indol-5-ol;
1~L379t~
1,8-diethyl-3a-methyl-1,2,3,3a,8,8a-hexahydropyrrolo ~2,3-b~
indol-5-ol;
1,3a,8-trimethyl-1,2,3,3a,8,8a-hexahydropyrrolo [2,3-b~
indol-5-ol;
3a,8-dimethyl-1,2,3,3a,8,8a-jexahydropyrrolo ~2,3-b~ indol-5-ol;
Example 2 A solution of (-) eseroline (1.5 g) in ethyl ether (100 ml) de-aired with a nitrogen stream, was added to a solution of salicylic acid (1.3 g) in e-ther (20 ml) with stirring. A
white crystalline solid was precipitated which was collected by filtration, washed with a small quantity of ether and dried under vacuum. Needle-like crystals of (-) eseroline salicylate which melt at 178-180C (with slight decomposition) were obtained.
The salts of the following compounds with salicylic acid were prepared in a similar manner;
1,8-dimethyl-3a-ethyl-1,2,3,3a,8,8a-hexahydropyrrolo ~2,3-b~
indol-5-ol;
1,3a-dimethyl-8-ethyl-1,2,3,3a,8,8a-hexahydropyrrolo ~2,3-b]
indol-5-ol;
1,3a,8-triethyl-1,2,3,3a,8,8a-hexahydropyrrolo [2,3-b] indol-5-ol;
l-ethyl-3a,8-dimethyl-1,2,3,3a,8,8a-hexahydropyrrolo [2,3-b] indol-5-ol;
1,8-dimethyl-3a-ethyl-5-methoxy-1,2,3,3a,8,8a-hexahydropyrrolo _ _ 2,3-b indol-5-ol;
1,8-dim ethyl-3a-propyl-1,2,3,3a,8,8a-hexahydropyrrolo [2,3-b~
indol-5-ol;
1~374~3 1,3a,8-trimethyl-5-propyloxy-1,2,3,3a,8,8a-hexahydropyrrolo ~2,3-b~ indol-5-ol;
_ _ 3a-methyl-1,2,3,3a,8,8a-hexahydropyrrolo 2,3-b indol-5-ol (1,8-dinor-eseroline);
1,3a-dimethyl-1,2,3,3a,8,8a-hexahydropyrrolo ~2,3-b~ indol-5-ol (N8-nor-eseroline);
1,8-diethyl-3a-methyl-1,2,3,3a,8,8a-hexahydropyrrolo ~2,3-b~
indol-5-ol;
l-ethyl-3a,8-dimethyl-1,2,3,3a,8,8a-hexahydropyrrolo [2,3-b~
indole;
1,3a,8-trimethyl-1,2,3,3a,8,8a-hexahydropyrrolo ~2,3-b~
indol-5-ol (eseroline);
1,3a-8-trimethyl-5-,ethoxy-1,2,3,3a,8,8a-hexahydropyrrolo ~2,3-b~ indol-5-ol (eseromethole);
1,3a,8-trimethyl-5-ethoxy-1,2,3,3a,8,8a-hexahydropyrrolo ~2,3-b] indol-5-ol (eserethole);
1,3a,8-trimethyl-1,2,3,3a,8,8a-hexahydropyrrolo ~2,3-b] indole (desoxyeseroline);
3a,8-dimethyl-1,2,3,3a,8,8a-hexahydropyrrolo ~2,3-b~ indole (desoxy-Nl-noreseroline);
1,3a-dimethyl-1,2,3,3a,8,8a-hexahydropyrrolo ~2,3-b] indole (desoxy-N8-noreseroline);
3a-methyl-1,2,3,3a,8,8a-hexahydropyrrolo ~2,3-b~ indole (Nl,N8-dinor-desoxyeseroline);
3a,8-dimethyl-1,2,3,3a,8,8a-hexahydropyrrolo [2,3-b~ indol-5-ol (Nl-nor-eseroline).
~137~
~, Example 3 A solution of (-) eseroline (0.005 moles) in ethyl ether (50 ml) was added to a solution of fumaric acid (0.006 moles) in ethanol (30 ml) under a nitrogen stream.
The white precipitate obtained was collected by filtration and dried, and white cyrstals of fumarate of (-) eseroline were obtained which after recrystallization from ethyl alcohol melted at 197-199C with decomposition.
The salts of all the compounds listed in Example 2 with fumaric acid were prepared in a similar manner.
Example 4 A de-aired solution of (-) eseroline (0.005 moles) in ethyl ether (50 ml) was added to a solution of (+)-tartaric acid (0.006 moles) in ethanol (30 ml).
The resulting precipitate was collected by filtration and re-crystallized from ethyl alcohol. The salt of the (+) tartaric acic with (-) eseroline was obtained, m.p. 197-200C
(decomposition).
The salts of all the compounds listed in Example 2 with tartaric acid were prepared in a similar manner.
Example 5 To a solution of 5-ethoxy-1,3-dimethyl-3-(~ -ethylamino-ethyl)-indolinone (5 g) in absolute ethanol (500 ml), metal sodium (20 g) was added over a period of two hours. After the sodium dissolution, de-aired water (200 ml) was added cautiously to the cooled solution and ethyl alcohol removed by distillation under vacuum. The residue was then repeatedly extracted into 74~
ethyl ether and the ether extracts evaporated to dryness give (~)-l-ethyl-3a,8-dimethyl-5-ethoxy-1,2,3,3a,8,8a-hexahydro-pyrrolo ~2,3-b] indole which was purified by distillation under vacuum (4 g). This latter compound (4 g) was added to a solution obtained by dissolving (+) tartaric acid (2.4 g) in ethyl alcohol (30 ml). The mixture was added to some ethyl ether and left overnight. Crystalline masses separated out which were filtered and found to melt at about 150-160C.
After several crystallizations from ethyl alcohol containing (+)-tartaric acid needle-like colourless crystals of (+)-l-ethyl-3,3a,8-dimethyl-5-ethoxy-1,2,3,3a,8,8a-hexahydro-pyrrolo [2,3-b] indole-bitartrate were obtained (1.6 g).
The alcoholic filtrates were evaporated and a residue obtained which was treated with aqueous sodium hydroxide and extracted twice with ether. The ether extracts were concen-trated to dryness and the residue distilled under vacuum.
A colourless oil was obtained consisting of (-)-l-ethyl-3a, 8-dimethyl-5-ethoxy-1,2,3,3a,8,8a-hexahydropyrrolo ~2,3-b]
indole (2.6 g). To a solution of this latter compound (2.6 g) in petroleum ether (20 ml) aluminium trichloride (4 g) was added. The mixture was heated under reflux on a water bath for about 12 hours and the petroleum ether was removed by decanting, leaving a crystalline mass which was decomposed by treatment with ice. The aqueous solution obtained was treated with sodium bicarbonate and repeatedly extracted into ethyl ether. The residue obtained after removing the solvent was distilled under high vacuum and the oil obtained was dissolved in ethyl ether-petroleum ether from which needle-like crystals of (-)-l-ethyl-3a,8-dimethyl-1,2,3,3a,8,8a-hexahydropyrrolo 1~l3~8~1 - 2~3 -~2,3-b~ indol-5-ol were obtained.
Example 6 A mixture of ethyl iodide (2 moles) and oI dibenzyliden-derivative of 2-me-thyl-2-(3,6-dimethoxyphenyl)-butyl-1,4-diamine (l mole) was heated to 100C for about 2 hours in a closed tube. The solid obtained was extracted into aqueous ethanol, the solvent was evaporated and the residue dissolved in diluted hydrochloric acid. An extraction into ethyl ether was carried ou-t and the benzaldehyde formed by extraction with ethyl ether was removed. The aqueous phase was then saturated with potassium carbonate and extracted again with ethyl ether.
N,N-diethyl-2-(3,6-dimethoxy-phenyl)-2-methyl-butyl-1, 4-diamine (4 g) was obtained by evaporating the solvent and distilling under vacuum. This was dissolved in hydrobromic acid having a density of 1.49 (25 ml) and the solution was heated under reflux for about l hour, cooled and treated with a mixture of propyl alcohol and ethyl ether. The dibromhydrate obtained by filtration (1.3 g) was dissolved in water (75 ml) and mixed with an aqueous solution obtained by dissolving potassium ferricyanide (1.95 g) and sodium bicarbonate (l g) in water (75 ml). The reaction mixture was extracted several times into ethyl ether and the ether extracts were evaporated to dryness. Raw (+) 1,8-diethyl-3a-methyl-1,2,3,3a,8,8a-hexahydropyrrolo ~2,3-b~ indol-5-ol was obtained, which was purified by crystallization or by sublimation under high vacuum.
To a solution of the racemic compound thus obtained (0.5 g) in anhydrous ethanol (40 ml) ethyl p-toluenesulphonate was 1~l374t~
- 2~ -added together with a solution of metal sodium (0.1 g) in absolute ethanol (10 ml). The residue obtained after removing the solvent was treated with aqueous diluted sodium hydroxide and extracted several times into ethyl ether. By evaporation of the ether extracts the racemic mixture of (+) and (-) 1,8-diethyl-3a-methyl-5-ethoxy-1,2,3,3a,8,8a-hexahydropyrrolo [2,3-b~ indole was obtained, which was separated into the individual (+) and (-) isomers by the procedure described in the previous example. By treatment of the (-)-1,8-diethyl-3a-methyl-5-ethoxy-1,2,3,3a,8,9a-hexahydropyrrolo ~2,3-b~ indole thus separated with aluminium chloride in petroleum ether, following the procedure described in the previous example, one obtains (-)-1,8-diethyl-3a-methyl-1,2,3,3a,8,8a-hexahydro-pyrrolo [2,3~b~ indol-5-ol.
Example 7 A solution of (+)-3a,8-dimethyl-2,3,3a,8a-tetrahydrofuro [2,3-b~ indolin-2-one (5 g) in ethyl alcohol (100 ml) was mixed with ethylamine (excess 20%) and heated to 50C for some hours. By evaporation of the solvent, (+)-l-ethyl-3a, 8-dimethyl-2-oxa-pyrrolo ~2,3-b~ indole (3 g) was separated, which was suspended in anhydrous tetrahydrofuran (100 ml) and treated with a slight excess of lithium aluminium hydride. The reaction mixture was first heated under reflux with stirring for about 2 hours, and then cooled and decomposed by treatment with water. The ether phase was separated, dried and evaporated to dryness. Thus (+)-l-ethyl-3a,8-dimethyl-1,2,3,3a,8,8a-hexahydropyrrolo [2,3-b] indole (2.5 g) was obtained.
1137~
~xample 8 To an ether solution of ethyl magnesium iodide obtained from magnesium (2 g), e-thyl iodide (12.8 g) and ethyl ether (20 ml) 5-ethoxy-3-methyl-triptamine (5.8 g) was added in small portions. The reaction mixture was heated to 100 C
with stirring to fully evporate the ethyl ether. Then methyl iodide (15 g) was added over a period of about 3 hours.
After adding some benzole and ethyl ether to dissolve the excess of methyl iodide, the reaction mixture was treated with diluted acetic acid under cooling conditions. The aqueous phase was cautiously alkalinized with sodium hydroxide and repeatedly extracted with ethyl ether. The ether extracts were evaporated and the residue oil was distilled under vacuum.
Thus (+) -1,3a-dimethyl-5-ethoxy-1,2,3,3a,8,8a-hexahydropyrrolo [2,3-b~ indole was obtained which was converted into the corresponding (+)-1,3a-dimethyl-1,2,3,3a,8,8a-hexahydropyrrolo ~2,3-b] indol-5-ol, by treatment with aluminium trichloride in petroleum ether using the same procedure described in Example 5.
~xample 9 Tablets with a weight of 200 mg and containing 25 mg of active substance, calculated as free base, have been prepared as follows:
(composition for 10,000 tablets) (+) eseroline hydrogentartrate g 587 lactose g 893 mais starch g 450 talc powder g 50 magnesium stearate g 20 113748~
~xample lO
A pharmaceutical composition, that can be injected, has been prepared by dissolving 10 mg of (-) eseroline salicylate in 2 ml of sterile water or sterile physiological solution containing sodium pyrosulphite (2%) It is noted that eseroline in some cases and with certain dosages could give rise to an activity of cholinomimetic type.
This possible undesired effect is not due to eseroline itself, but to an oxidation product, rubrosine,whichforms more easily in an alkaline environment. To avoid this undesired effect in those few cases where it might appear,a very small quantity of atropine or some other muscarinic blocking agents can be included in the pharmaceutical preparations which would annul the cholinomimetic action without affecting the analgesic action of the product.
Claims (5)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing a compound of 1,2,3,3a,8,8a-hexahydropyrrolo-[2,3-b]indole having the formula I
I
or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from the group consisting of hydrogen, hydroxy, C1 - C12 alkoxy and C2 - C12 alkenyl-oxy; R2 is selected from the group consisting of hydrogen and C1 - C12 alkyl;
R3 and R4 are the same or different and are selected from the group consisting of hydrogen, C1 - C12 alkyl and C2 - C12 alkenyl, provided that when R1 is selected from the group consisting of hydrogen, hydroxy, methoxy and ethoxy, and R2 is methyl, at least one of R3 and R4 is other than hydrogen or methyl, which process comprises:
(a) reductively cyclizing a compound of formula II
II
wherein R1, R2, R3 and R4 are as defined above;
(b) oxidatively cyclizing a compound of formula III
III
or a salt thereof wherein: R1 is selected from the group consisting of hydrogen and hydroxy, R3 and R4 are the same and selected from the group consisting of C1 - C12 and C2 - C12 alkenyl, thus being obtained a compound of formula I
wherein R1 is hydrogen or hydroxy and wherein R3 - R4 is C1 - C12 alkyl or C2 - C12 alkenyl;
(c) reducing a compound of formula IV
IV
wherein: R1, R2, R3 and R4 are as defined above;
(d) hydrolysing a compound of formula V
V
wherein: R2, R3 and R4 are as defined above and R? is selected from the group consisting of acyloxy, carbamoyloxy or alkylcarbamoyloxy group, thus obtaining a compound of formula I wherein R1 is hydroxy, and, if required, etherifying the compound of formula I obtained to obtain a compound of formula I wherein R1 is selected from the group consisting of C1 - C12 alkoxy and C2 - C12 alkenyloxy;
(e) reacting a compound of formula VI
VI
wherein: R1, R3 and R4 are as defined above, with a halide of alkylmagnesium RMgX, wherein R is a general C1 - C6 alkyl, and further reacting the product with an alkyl halide R2X, where R2 is C1 - C12 alkyl, thus obtaining a compound of formula I wherein R2 is C1 - C12 alkyl and, if required, converting the ob-tained compound of formula I into a pharmaceutically acceptable salt by reaction with a suitable acid.
I
or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from the group consisting of hydrogen, hydroxy, C1 - C12 alkoxy and C2 - C12 alkenyl-oxy; R2 is selected from the group consisting of hydrogen and C1 - C12 alkyl;
R3 and R4 are the same or different and are selected from the group consisting of hydrogen, C1 - C12 alkyl and C2 - C12 alkenyl, provided that when R1 is selected from the group consisting of hydrogen, hydroxy, methoxy and ethoxy, and R2 is methyl, at least one of R3 and R4 is other than hydrogen or methyl, which process comprises:
(a) reductively cyclizing a compound of formula II
II
wherein R1, R2, R3 and R4 are as defined above;
(b) oxidatively cyclizing a compound of formula III
III
or a salt thereof wherein: R1 is selected from the group consisting of hydrogen and hydroxy, R3 and R4 are the same and selected from the group consisting of C1 - C12 and C2 - C12 alkenyl, thus being obtained a compound of formula I
wherein R1 is hydrogen or hydroxy and wherein R3 - R4 is C1 - C12 alkyl or C2 - C12 alkenyl;
(c) reducing a compound of formula IV
IV
wherein: R1, R2, R3 and R4 are as defined above;
(d) hydrolysing a compound of formula V
V
wherein: R2, R3 and R4 are as defined above and R? is selected from the group consisting of acyloxy, carbamoyloxy or alkylcarbamoyloxy group, thus obtaining a compound of formula I wherein R1 is hydroxy, and, if required, etherifying the compound of formula I obtained to obtain a compound of formula I wherein R1 is selected from the group consisting of C1 - C12 alkoxy and C2 - C12 alkenyloxy;
(e) reacting a compound of formula VI
VI
wherein: R1, R3 and R4 are as defined above, with a halide of alkylmagnesium RMgX, wherein R is a general C1 - C6 alkyl, and further reacting the product with an alkyl halide R2X, where R2 is C1 - C12 alkyl, thus obtaining a compound of formula I wherein R2 is C1 - C12 alkyl and, if required, converting the ob-tained compound of formula I into a pharmaceutically acceptable salt by reaction with a suitable acid.
2. A process according to claim 1 wherein a pharmaceutically acceptable salt is obtained by reacting the compound of formula I with an acid selected from the group consisting of salicylic acid, p-hydroxybenzoic acid, tartaric acid, mesotartaric acid, fumaric acid, maleic acid, citric acid, gentisic acid, hydroxyphthalic acid, creatininsulphuric acid and succinic acid.
3. A process according to claim 1 wherein R1 is hydroxy, R3 is methyl, R2 is hydrogen, methyl or propyl and R4 is hydrogen, methyl or ethyl, provided that one of R2 and R4 is methyl.
4. A process according to claim 1, 2 or 3 which comprises the further step of separating a mixture of optical enantiomers of formula I into the indi-vidual enantiomers.
5. A compound of formula I or a pharmaceutically acceptable salt thereof when prepared by a process according to claim 1 or an obvious chemical equiva-lent thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000399054A CA1137489A (en) | 1977-09-20 | 1982-03-22 | Derivatives of 1,2,3,3a,8,8a-hexadydropyrrolo (2,3-b) indole |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT9574A/77 | 1977-09-20 | ||
| IT09574/77A IT1109003B (en) | 1977-09-20 | 1977-09-20 | DERIVATIVES OF 1 2 3 8 3 A 8 A ESAI DROPIRROLO 23 B INDOLO |
| CA311,555A CA1125657A (en) | 1977-09-20 | 1978-09-19 | Derivatives of 1,2,3,3a,8,8a-hexadydropyrrolo ¬2,3-b| indole |
| CA000399054A CA1137489A (en) | 1977-09-20 | 1982-03-22 | Derivatives of 1,2,3,3a,8,8a-hexadydropyrrolo (2,3-b) indole |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1137489A true CA1137489A (en) | 1982-12-14 |
Family
ID=27165867
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000399054A Expired CA1137489A (en) | 1977-09-20 | 1982-03-22 | Derivatives of 1,2,3,3a,8,8a-hexadydropyrrolo (2,3-b) indole |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1137489A (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5496957A (en) * | 1993-09-01 | 1996-03-05 | Virginia Commonwealth University | Tryptamine analogs with 5-HT1D selectivity |
| US5504101A (en) * | 1994-05-06 | 1996-04-02 | Allelix Biopharmaceuticals, Inc. | 5-HT-1D receptor ligands |
| US5547977A (en) * | 1986-07-16 | 1996-08-20 | Hoechst-Roussel Pharmaceuticals, Inc. | Memory enhancing and analgesic 1,2,3,3A,8,8A-hexahydro-3A,8(and 1,3A,8)-di (and Tri) methylpyrrolo (2,3-B) indoles |
| US10537552B2 (en) | 2015-05-05 | 2020-01-21 | Carafe Drug Innovation, Llc | Substituted 5-hydroxyoxindoles and their use as analgesics and fever reducers |
| CN115385916A (en) * | 2021-07-01 | 2022-11-25 | 江苏师范大学 | Chiral indoline pyrrole compound and synthesis method thereof |
-
1982
- 1982-03-22 CA CA000399054A patent/CA1137489A/en not_active Expired
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5547977A (en) * | 1986-07-16 | 1996-08-20 | Hoechst-Roussel Pharmaceuticals, Inc. | Memory enhancing and analgesic 1,2,3,3A,8,8A-hexahydro-3A,8(and 1,3A,8)-di (and Tri) methylpyrrolo (2,3-B) indoles |
| US5496957A (en) * | 1993-09-01 | 1996-03-05 | Virginia Commonwealth University | Tryptamine analogs with 5-HT1D selectivity |
| US5504101A (en) * | 1994-05-06 | 1996-04-02 | Allelix Biopharmaceuticals, Inc. | 5-HT-1D receptor ligands |
| US10537552B2 (en) | 2015-05-05 | 2020-01-21 | Carafe Drug Innovation, Llc | Substituted 5-hydroxyoxindoles and their use as analgesics and fever reducers |
| CN115385916A (en) * | 2021-07-01 | 2022-11-25 | 江苏师范大学 | Chiral indoline pyrrole compound and synthesis method thereof |
| CN115385916B (en) * | 2021-07-01 | 2023-08-15 | 江苏师范大学 | Chiral indoline pyrrole compound and synthesis method thereof |
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