CA1125657A - 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
- Publication number
- CA1125657A CA1125657A CA311,555A CA311555A CA1125657A CA 1125657 A CA1125657 A CA 1125657A CA 311555 A CA311555 A CA 311555A CA 1125657 A CA1125657 A CA 1125657A
- Authority
- CA
- Canada
- Prior art keywords
- acid
- eseroline
- formula
- hexahydropyrrolo
- pharmaceutical composition
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
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Classifications
-
- 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
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
Abstract
ABSTRACT OF THE DISCLOSURE
New derivatives of 1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole having the formula
New derivatives of 1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole having the formula
Description
25~7 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 pharmaceutical compositions containing the same.
Useful analgesic activity is displayed by 1,2,3,3a,8,8a-hexahydro-pyrrolo[2,3-b]indole compounds having the formula I
R H R
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 `~ 10 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 in which Rl is hydrogen, hydroxy, methoxy or ethoxy, R2 is methyl and R3 and R4 are hydrogen or methyl are known.
This application is directed to pharmaceutical compositions containing a suit-:,:
able carrier and, as active substance, a compound of formula I in which Rl is hydrogen, hydroxy, methoxy or ethoxy, R2 is methyl and R3 and R4 are the same ~- or different and are hydrogen or methyl, or a pharmaceutically acceptable salt . .
thereof.
Novel compounds of formula I are the subject of a divisional applica-tion.
- ~ Examples of pharmaceutically acceptable salts of the compounds of formula I are those formed with both inorganic acids, for instance hydrochloric -~ ~ ~3 1-. . .
.
. . ... .. ~ ~.
z~
acid, hydrobromic acid, sulphuric acid, and with organic acids such as for instance benzoic acid, p-hydroxybenzoic acid, salicylic acid, tartaric acid (both laevorotatory and dextrorotatory and racemic), mesotartaric acid, fumaric acid, maleic acid, citric acid, gentisic acid, hydroxyphthalic acid, creatinin-sulphuric 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 I 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, hydroxyphthalic acid, creatininsulphuric acid and succinic acid.
:~ `
5~7.
The alkyl, alkoxy, alkenyl and alkenyloxy groups of the described compounds can have either a linear or a branched chain of carbon atoms.
Pre:Eerably 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 or specific active substances of the pharmaceutical compositions in accordance with the inven~ion 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-hexa-hydropyrrolo[2,3-b]indol-5-ol; (4) 1-ethyl-8-dimethyl-1,2,3,3a,8,8a-hexa-~ hydropyrrolo[2,3-b]indol-5-ol; ~5) 1,8-dimethyl-3a-ethyl-5-methoxy-1,2,3,3a, ; : 8,8a-hexahydropyrrolo[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;
;
., .
: '' .
' :
:~
.--' ~ ' , ' . '. ~ ' -7) 1,3a,8-trimethyl-5-propyloxy-1,2,3,3a,8,8a-hexahydro-pyrrolo [2,3-b~ indol-5-ol;
8) 3a-methyl-1,2,3,3a,8,8a-hexahydropyrrolo [2,3-b]
indol-5-ol (1,8-dinor-eseroline);
9) 1,3a-dimethyl-1,2,3,3a,8,8a-hexahydropyrrolo [2,3-b~
indol-5-ol (H8-nor-eseroline);
10) 1,8-diethyl-3a-methyl-1,2,3,3a,8,8a-hexahydropyrrolo ~2,3-b~ indol-5-ol;
11) 1-ethyl-3a,8-dimethyl-1,2,3,3a,8,8a-hexahydropyrrolo ~2,3-b~ indole;
12) 1,3a,8-trimethyl-1,2,3,3a,8,8a-hexahydropyrrolo ~2,3-b] indol-5-ol (eseroline);
13) 1,3a,8-trimethyl-5-methoxy-1,2,3,3a,8,8a-hexahydropyrrolo [2,3-b~ indol-5-ol (eseromethole);
1~) 1,3a-8-trimethyl-5-ethoxy-1,2,3,3a,8,8a-hexahydropyrrolo ~2,3-b~ indol-5-ol (eserethole);
15) 1,3a-8-trimethyl-1,2,3,3a,8,8a.-hexahydropyrrolo ~2,3-b~ indole (desoxyeseroline);
- 16) 3a,8-dimethyl-1,2,3,3a,8,8a-hexahydropyrrol ¦2,3-b~
indole (desoxy-Nl-noreseroline);
17) 1,3a-dimethyl-1,2,3,3a,8,8a-hexahydropyrrolo ~2,3-b~
: indole (desoxy-N8-noreseroline);
18) 3a-methyl-1,2,3,3a,8,8a-hexahydropyrrolo ~2,3-b~
indole (Nl,N~-dinor-desoxyeseroline);
19) 3a,8-dimethyl-1,2,3,3a,8,8a-hexahydropyrrolo ~2,3-b~
indol-5-ol (Nl-nor-eseroline);
as well as the salts o~ the compounds iormed with pharmaceutic-cally acceptable acids, in particular those re~erred to above.
' ' . - .
-Amon~ the compounds previously mentioned, the first eleven arenew compounds whereas the others are;known per se, but their use for therapeutic purposes or as active substances in pharmac-euticals is unknown. In particular eseroline is described in J.Chem.Soc.lOlJ 978 (1912); eseromethole and eserethole in J.A.C.S., 57, 755 (1935); desoxyeseroline in J.A.C.S., 57, 755 (1935), in C.A., 63, 18059a (1965), in Chem.Ber.108(1), 208 (1975) and in C.~., 82, 11978n; desoxy-Nl-noreseroline in C.A., 63, 18059a (1965) and in Tetrahedron Letters, 52, 4539 (1970) and in J.A.C.S., 56, 1797 (1934); desoxy-N8-noreseroline in Ann.520, 11 (1935); Nl,N8-dinor-desoxyeseroline in Ann.539, 213 (1939); Nl-nor-eseroline in Chem.and Ind.87 (1965).
In addition, hydrochloride and picrate of (-) eseroline for instance, are described in J.Chem.Soc.)101, 978 (1912), hydrobromide and sulphate of (-) eseroline in Bull.Soc.Chim.~, ; 17, 2~0 (1915) and benzoate of (-) eseroline is described in Ann.,~01, 350 (1913).
As active substances in pharmaceutical compositions, the salts of the compounds o~ ~ormula (I) with pharmaceutically acceptable acids are preferred over the ~ree bases, since the free bases can be easily oxidised, for instance in aqueous solution, giving degradation products having a quinone type structure and thereby losing its pharmacological proper-ties.
~he easy oxidation and degradation of the ~ree bases of ~, the invention and/or of the corresponding salts can be eliminated by using special pharmaceutical techniques, for . .
.: .
~ ~: ~ i - . . :
' . ' ., , ~ - '~
:: . :
~5~57 instance keeping the pll value of the solutions 1OWJ or protecting the bases and their salts against attack from atmospheric oxygen, or by the addition of compounds which can be oxidized more easily and so act as antioxidant agents.
Particularly preferred active substances for pharmaceutical composi-tions are both isomers of eseroline, preferably the ~-) eseroline and in particular the salts of (-) eseroline, such as for instance salicylate, fumarate, tartrate.
The derivatives of the 1,2,3,3a,8,8a-hexahydropyrrolo~2~3-b]indole in accordance with the invention can be prepared by the following processes, 1 10 (a) by reductive cyclization a compound of formula II
Rl lR2 C - C~l2 II
N ~ ~0 / 12 R
'~ R3 : wherein Rl, R2, R3 and R4 are as referred to above or (b) by o~idative cyclization of a compound of formula III
~ CH2 CH2 III
k N~ H
~ R4 R3 ; or a salt thereof wherein:
.
'~
..
Rl is hydrogen 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 a Y ;
c) by reduction of a compound of formula (IV) R~
(IV) wherein:
Rl, R2, R3 and R4 are as defined above;
or d) by hydrolysis of a compound of formula (V) R
~ J (v) : R4 R3 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) 1 ~ T CN2-cN2NNR3 (Vl) wherein Rl, R3 and R4 are as described previously, first with a halide of alkylmagnesium ~MgX 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 addition 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.
l'he reductive cyclization of the compound of formula (II) is preferably carried out using sodium in an aliphatic 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 ins-tance 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 .
, .
_ 9 _ solution, using as oxidating agent an alkaline ferricyanide for instance, potassium ferricyanide, in the presence of an alkaline bicarbonate, for instance sodium bicarbonate. The cyclisation is carried out under stream of inert gas, for instance nitrogen, at a temperature of about 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 compourld of formula (IV) 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, ~or 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 Rl is Cl-C12 alkoxy or C2-C12 alkenyloxy by etheri~ication, 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 (C~3NHCOO-). 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 - ~ ' , ' ' : , ' ' 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.
For 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 orhydroxyJ 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 reactLon 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 R~ 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 .
: . i 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 mi~ture 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 solven-ts.
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 .
- ::
. ~ ''" ' ~z~
of tartaric dextrorotatory acid in the same solvent, thus obtaining crystallizing and precipitating the acid tar-trate of (+) eseroline((3aR, 8aS) 1,3a,8-trimethyl-1,2,3,3a,8,8a-hexahydropyrrolo [2,3-b~ indol-5-ol).
The acid tartrate oflaevorotatory isomer (-j 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, alkalinizing 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 a.bove-mentioned salt using a similar method.
The compound of ~ormula (II) can be prepared by reaction of a compound of ~ormula tVII) (Vll) R
wherein: .
Y is an akaline metal, preferably sodium, and Rl,R2 and Rg are as defined previously with a compound o~ formula (VIII) X-C~2 CH2 (VIII) .
; R
'
Useful analgesic activity is displayed by 1,2,3,3a,8,8a-hexahydro-pyrrolo[2,3-b]indole compounds having the formula I
R H R
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 `~ 10 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 in which Rl is hydrogen, hydroxy, methoxy or ethoxy, R2 is methyl and R3 and R4 are hydrogen or methyl are known.
This application is directed to pharmaceutical compositions containing a suit-:,:
able carrier and, as active substance, a compound of formula I in which Rl is hydrogen, hydroxy, methoxy or ethoxy, R2 is methyl and R3 and R4 are the same ~- or different and are hydrogen or methyl, or a pharmaceutically acceptable salt . .
thereof.
Novel compounds of formula I are the subject of a divisional applica-tion.
- ~ Examples of pharmaceutically acceptable salts of the compounds of formula I are those formed with both inorganic acids, for instance hydrochloric -~ ~ ~3 1-. . .
.
. . ... .. ~ ~.
z~
acid, hydrobromic acid, sulphuric acid, and with organic acids such as for instance benzoic acid, p-hydroxybenzoic acid, salicylic acid, tartaric acid (both laevorotatory and dextrorotatory and racemic), mesotartaric acid, fumaric acid, maleic acid, citric acid, gentisic acid, hydroxyphthalic acid, creatinin-sulphuric 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 I 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, hydroxyphthalic acid, creatininsulphuric acid and succinic acid.
:~ `
5~7.
The alkyl, alkoxy, alkenyl and alkenyloxy groups of the described compounds can have either a linear or a branched chain of carbon atoms.
Pre:Eerably 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 or specific active substances of the pharmaceutical compositions in accordance with the inven~ion 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-hexa-hydropyrrolo[2,3-b]indol-5-ol; (4) 1-ethyl-8-dimethyl-1,2,3,3a,8,8a-hexa-~ hydropyrrolo[2,3-b]indol-5-ol; ~5) 1,8-dimethyl-3a-ethyl-5-methoxy-1,2,3,3a, ; : 8,8a-hexahydropyrrolo[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;
;
., .
: '' .
' :
:~
.--' ~ ' , ' . '. ~ ' -7) 1,3a,8-trimethyl-5-propyloxy-1,2,3,3a,8,8a-hexahydro-pyrrolo [2,3-b~ indol-5-ol;
8) 3a-methyl-1,2,3,3a,8,8a-hexahydropyrrolo [2,3-b]
indol-5-ol (1,8-dinor-eseroline);
9) 1,3a-dimethyl-1,2,3,3a,8,8a-hexahydropyrrolo [2,3-b~
indol-5-ol (H8-nor-eseroline);
10) 1,8-diethyl-3a-methyl-1,2,3,3a,8,8a-hexahydropyrrolo ~2,3-b~ indol-5-ol;
11) 1-ethyl-3a,8-dimethyl-1,2,3,3a,8,8a-hexahydropyrrolo ~2,3-b~ indole;
12) 1,3a,8-trimethyl-1,2,3,3a,8,8a-hexahydropyrrolo ~2,3-b] indol-5-ol (eseroline);
13) 1,3a,8-trimethyl-5-methoxy-1,2,3,3a,8,8a-hexahydropyrrolo [2,3-b~ indol-5-ol (eseromethole);
1~) 1,3a-8-trimethyl-5-ethoxy-1,2,3,3a,8,8a-hexahydropyrrolo ~2,3-b~ indol-5-ol (eserethole);
15) 1,3a-8-trimethyl-1,2,3,3a,8,8a.-hexahydropyrrolo ~2,3-b~ indole (desoxyeseroline);
- 16) 3a,8-dimethyl-1,2,3,3a,8,8a-hexahydropyrrol ¦2,3-b~
indole (desoxy-Nl-noreseroline);
17) 1,3a-dimethyl-1,2,3,3a,8,8a-hexahydropyrrolo ~2,3-b~
: indole (desoxy-N8-noreseroline);
18) 3a-methyl-1,2,3,3a,8,8a-hexahydropyrrolo ~2,3-b~
indole (Nl,N~-dinor-desoxyeseroline);
19) 3a,8-dimethyl-1,2,3,3a,8,8a-hexahydropyrrolo ~2,3-b~
indol-5-ol (Nl-nor-eseroline);
as well as the salts o~ the compounds iormed with pharmaceutic-cally acceptable acids, in particular those re~erred to above.
' ' . - .
-Amon~ the compounds previously mentioned, the first eleven arenew compounds whereas the others are;known per se, but their use for therapeutic purposes or as active substances in pharmac-euticals is unknown. In particular eseroline is described in J.Chem.Soc.lOlJ 978 (1912); eseromethole and eserethole in J.A.C.S., 57, 755 (1935); desoxyeseroline in J.A.C.S., 57, 755 (1935), in C.A., 63, 18059a (1965), in Chem.Ber.108(1), 208 (1975) and in C.~., 82, 11978n; desoxy-Nl-noreseroline in C.A., 63, 18059a (1965) and in Tetrahedron Letters, 52, 4539 (1970) and in J.A.C.S., 56, 1797 (1934); desoxy-N8-noreseroline in Ann.520, 11 (1935); Nl,N8-dinor-desoxyeseroline in Ann.539, 213 (1939); Nl-nor-eseroline in Chem.and Ind.87 (1965).
In addition, hydrochloride and picrate of (-) eseroline for instance, are described in J.Chem.Soc.)101, 978 (1912), hydrobromide and sulphate of (-) eseroline in Bull.Soc.Chim.~, ; 17, 2~0 (1915) and benzoate of (-) eseroline is described in Ann.,~01, 350 (1913).
As active substances in pharmaceutical compositions, the salts of the compounds o~ ~ormula (I) with pharmaceutically acceptable acids are preferred over the ~ree bases, since the free bases can be easily oxidised, for instance in aqueous solution, giving degradation products having a quinone type structure and thereby losing its pharmacological proper-ties.
~he easy oxidation and degradation of the ~ree bases of ~, the invention and/or of the corresponding salts can be eliminated by using special pharmaceutical techniques, for . .
.: .
~ ~: ~ i - . . :
' . ' ., , ~ - '~
:: . :
~5~57 instance keeping the pll value of the solutions 1OWJ or protecting the bases and their salts against attack from atmospheric oxygen, or by the addition of compounds which can be oxidized more easily and so act as antioxidant agents.
Particularly preferred active substances for pharmaceutical composi-tions are both isomers of eseroline, preferably the ~-) eseroline and in particular the salts of (-) eseroline, such as for instance salicylate, fumarate, tartrate.
The derivatives of the 1,2,3,3a,8,8a-hexahydropyrrolo~2~3-b]indole in accordance with the invention can be prepared by the following processes, 1 10 (a) by reductive cyclization a compound of formula II
Rl lR2 C - C~l2 II
N ~ ~0 / 12 R
'~ R3 : wherein Rl, R2, R3 and R4 are as referred to above or (b) by o~idative cyclization of a compound of formula III
~ CH2 CH2 III
k N~ H
~ R4 R3 ; or a salt thereof wherein:
.
'~
..
Rl is hydrogen 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 a Y ;
c) by reduction of a compound of formula (IV) R~
(IV) wherein:
Rl, R2, R3 and R4 are as defined above;
or d) by hydrolysis of a compound of formula (V) R
~ J (v) : R4 R3 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) 1 ~ T CN2-cN2NNR3 (Vl) wherein Rl, R3 and R4 are as described previously, first with a halide of alkylmagnesium ~MgX 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 addition 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.
l'he reductive cyclization of the compound of formula (II) is preferably carried out using sodium in an aliphatic 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 ins-tance 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 .
, .
_ 9 _ solution, using as oxidating agent an alkaline ferricyanide for instance, potassium ferricyanide, in the presence of an alkaline bicarbonate, for instance sodium bicarbonate. The cyclisation is carried out under stream of inert gas, for instance nitrogen, at a temperature of about 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 compourld of formula (IV) 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, ~or 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 Rl is Cl-C12 alkoxy or C2-C12 alkenyloxy by etheri~ication, 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 (C~3NHCOO-). 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 - ~ ' , ' ' : , ' ' 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.
For 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 orhydroxyJ 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 reactLon 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 R~ 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 .
: . i 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 mi~ture 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 solven-ts.
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 .
- ::
. ~ ''" ' ~z~
of tartaric dextrorotatory acid in the same solvent, thus obtaining crystallizing and precipitating the acid tar-trate of (+) eseroline((3aR, 8aS) 1,3a,8-trimethyl-1,2,3,3a,8,8a-hexahydropyrrolo [2,3-b~ indol-5-ol).
The acid tartrate oflaevorotatory isomer (-j 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, alkalinizing 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 a.bove-mentioned salt using a similar method.
The compound of ~ormula (II) can be prepared by reaction of a compound of ~ormula tVII) (Vll) R
wherein: .
Y is an akaline metal, preferably sodium, and Rl,R2 and Rg are as defined previously with a compound o~ formula (VIII) X-C~2 CH2 (VIII) .
; R
'
2~S7 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, Eor instance ethyl ether, and after alkalinization e.g. with an alkaline hydroxide, i-t is extracted again into an organic solvent, for instance e-thyl ether, and the solvent is evapora-ted at a reduced pressure.
Alternatively the compound of :Eormula (II) can be obtained by reaction of a compound of formula (VII) with a compound of formula (IX) (IX) wherein:
X is halogen, preferably chlorine or bromine, thus obtaining a compound of formula (X) , :
5~
'C~,~ CH2-cH2-x ( X ) N~C~o R~
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 conclitions as described above for the reaction between a compound of Eormula (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 :Eormula (VII) can be pre~pared according to P.L.
Julian and J.Pike, J.A.C.S., 57, 563 (1935) 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 Ri is hydrogen or hydroxy and R3 and R4, are the same, and are Cl-C12 alkyl or C2-C12 alkenyl, can be obtained by reaction of a compound of formula (XI) Rl ~ H2_cH2_N_cH_c~H5 (XI) - wherein:
;
, ~
;
.
, ~5~
R is a Cl C6 alkyl radical and Rl has any of the above mentioned definitions with a Cl-Cl2 alkyl or C2-Cl2 alkenyl halide, preferably iodide. The reactive 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 (195~).
The compound of formula (IV) can be prepared by reaction of a compound of formula (XII) ~7~o (XII) R~
wherein:
Rl, R2 and R~ are as defined above, with ammonium hydrate or with an amine of formula NH2R3.
; The reaction is pre~erably 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 (~), in particular when R"l is methylcarbamoyloxy, is known per se and can be prepared using ~ S ~
known methods (J.Prakt, Chem.116, 59 (1927)). The compounds of formula (VI) are also described in literature, for instance in Ann.Chem.500, 42 (1933), Ann.Chem.516, 76 (1935), Ann.Chem.
516, 81 (19~5), Ann.Chem.520, 11 (1935).
The described compounds have an analgesic activity,as shown for instance by the fact that they are active in the mouse tail pinch test, carried out according to the technique described by P.Haffner Deutsche Med.Wecherschr.,55, 731 (1929) and in the mouse hot plate 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, ~or 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 ~ , ' '.
.~
;
~.~.....
:~ ' .
. ~ -- - , ' s , ~ :
.:
. .
5~
object of the presen-t invention can be in the form of for instance vials, vials for extemporary solution, lyophilized vials, troches, pills, tablets, drops, syrups, supposi-tories, 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, saccha.rose, 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 a.nd 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.
Example 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 solution 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 iunnel. Then 100 ml o~ 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. A~ter evaporation of the ethyl ether white crystals of (-) eseroline were obtained which melted at 129C (yield 95%).
The ~ollowing compounds were obtained by a si~ilar 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 J 3-b indol-5-ol;
1,8-dimethyl-3a-propyl J 1 J 2 J 3 J 3a J 8,8a-hexahydropyrrolo [2,3-b]
indol~5-ol;
3a-methyl-1,2 J 3 J 3a,8,8a-hexahydropyrrolo [2,3-b~ indol-5-ol;
1 J 3a-dimethyl-1,2 J 3,3a,8,8a-hexahydropyrrolo [2,3-b~
indol-5-ol;
.
--: ~ ' :.
-. . . , ~:
5~
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 wi-th a nitrogen stream, was added to a solution o~
salicylic acid (1.3 g) in ether (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 o~ 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,~,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-dimethyl-3a-propyl-1,2,3,3a,8,8a-hexahydropyrrolo. [2,3-b]
indol-5-ol;
5~7 1,3a,8-trimethyl-5-propy].oxy-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-~imethyl-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 l2,3-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).
, ', .:
Ex~mple 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 whi-te 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 ~
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. ]97-200C
(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 :
: . ., ' ' :
.
' ~
~ ' . ' , ethyl e-ther 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 puri~ied by distillation under vacuum (4 g). This latter compound (4 g) was added to a solution obtained by dissolving (+) tartaric acid (2.~ g) in ethyl alcohol (30 ml). The mixture was added to some ethyl ether and left overnight. Crystalline masses separated out which were ~iltered and ~ound to melt at about 150-160C.
A~ter several crystallizations ~rom ethyl alcohol containing tartaric acid needle-like colourless crystals o~
(+)-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 d:istilled under vacuum.
A colourless oil was obtained consisting o~ (-)-1-ethyl-3a, 8-dimethyl-5-ethoxy-1,2,3,3a,~,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 ~or 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 trea-ted with sodium bicarbonate and repeatedly extracted into ethyl ether. The residue obtained a~ter removing the solvent was distilled under high vacuum and the oil obtained was dissolved in ethyl ether-petroleum ether ~rom which needle-like crystals o~ (-)-l-ethyl-3a,8-dimethyl-1,2,3,3a,8,8a-hexahydropyrrolo . .
'' ' ' ` ' :
' . ~ . . .
5~5~
[2,3-b~ indol-5-ol were obtained.
Example 6 A mixture o~ ethyl iodide (2 moles) and o~ dibenzyliden-derivative of 2-methyl-2-(3,6-dimethoxyphenyl)-butyl-1,4-diamine (1 mole) was heated to 100C for about 2 hours in a closed tube. The solid o~tained was extracted into aqueous ethanol, the solvent was evaporated and the residue dissolved in diluted hydrochloric acid. An extraction into ethyl ether was carried out and the benzaldehyde ~ormed by extraction with ethyl ether was removed. The aqueous phase was then saturated with potassium carbonate and extracted again wi-th ethyl ether.
N,N-diethyl-2-(3,6-dimethoxy-phenyl)-2-methyl-butyl-1, ~-diamine (4 g) was obtained by evaporating the solvent and distilling under vacuum. This was dissolved in hydrobromic acid having a density o~ 1.49 (25 ml) and the solution was heated under re~lux for about 1 hou:r, cooled and treated with a mixture o~ propyl alcohol and ethyl ether. The dibromhydrate obtained by ~iltration (1.3 g) was dissolved in water (75 ml) and mixed with an aqueous solution obtained by dissolving potassium ~erricyanide (1.95 g) and sodium bicarbonate (1 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 puri~ied 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 .
.. . :
., ~ .
.
5~, - 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.
Exam~le 7 A solut iOII 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 treatm,ent ``
:, , .
with water. The ether phase was separated, dried and evaporated to dryness. Thus (~ ethyl-3a,8-dimethyl-1,2,3,3a,8,8a-hexahydropyrrolo [2,3-b~ indole (2.5 g) was obtained. ~`~
~ ;.
~ - - - , . . . . .
:
;: '' ' ` . ' ' " ~ ~ , ' ., .
, ' .: , `- ~ : "~ , ~ 25 -Example 8 . .
To an ether solution of ethyl magnesium iodide obtained ~rom magnesium (2 g), ethyl iodide (12.8 g) and ethyl ether (20 ml) 5-ethoxy-3-methy1-triptamine (5.8 g) was added in small portions. The reaction mixture was heated to 100C
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 a~d 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 wit;h 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 ~ 5~
Example 10 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 cou]d 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 af~ecting the analgesic action of the product.
~.
'
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, Eor instance ethyl ether, and after alkalinization e.g. with an alkaline hydroxide, i-t is extracted again into an organic solvent, for instance e-thyl ether, and the solvent is evapora-ted at a reduced pressure.
Alternatively the compound of :Eormula (II) can be obtained by reaction of a compound of formula (VII) with a compound of formula (IX) (IX) wherein:
X is halogen, preferably chlorine or bromine, thus obtaining a compound of formula (X) , :
5~
'C~,~ CH2-cH2-x ( X ) N~C~o R~
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 conclitions as described above for the reaction between a compound of Eormula (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 :Eormula (VII) can be pre~pared according to P.L.
Julian and J.Pike, J.A.C.S., 57, 563 (1935) 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 Ri is hydrogen or hydroxy and R3 and R4, are the same, and are Cl-C12 alkyl or C2-C12 alkenyl, can be obtained by reaction of a compound of formula (XI) Rl ~ H2_cH2_N_cH_c~H5 (XI) - wherein:
;
, ~
;
.
, ~5~
R is a Cl C6 alkyl radical and Rl has any of the above mentioned definitions with a Cl-Cl2 alkyl or C2-Cl2 alkenyl halide, preferably iodide. The reactive 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 (195~).
The compound of formula (IV) can be prepared by reaction of a compound of formula (XII) ~7~o (XII) R~
wherein:
Rl, R2 and R~ are as defined above, with ammonium hydrate or with an amine of formula NH2R3.
; The reaction is pre~erably 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 (~), in particular when R"l is methylcarbamoyloxy, is known per se and can be prepared using ~ S ~
known methods (J.Prakt, Chem.116, 59 (1927)). The compounds of formula (VI) are also described in literature, for instance in Ann.Chem.500, 42 (1933), Ann.Chem.516, 76 (1935), Ann.Chem.
516, 81 (19~5), Ann.Chem.520, 11 (1935).
The described compounds have an analgesic activity,as shown for instance by the fact that they are active in the mouse tail pinch test, carried out according to the technique described by P.Haffner Deutsche Med.Wecherschr.,55, 731 (1929) and in the mouse hot plate 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, ~or 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 ~ , ' '.
.~
;
~.~.....
:~ ' .
. ~ -- - , ' s , ~ :
.:
. .
5~
object of the presen-t invention can be in the form of for instance vials, vials for extemporary solution, lyophilized vials, troches, pills, tablets, drops, syrups, supposi-tories, 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, saccha.rose, 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 a.nd 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.
Example 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 solution 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 iunnel. Then 100 ml o~ 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. A~ter evaporation of the ethyl ether white crystals of (-) eseroline were obtained which melted at 129C (yield 95%).
The ~ollowing compounds were obtained by a si~ilar 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 J 3-b indol-5-ol;
1,8-dimethyl-3a-propyl J 1 J 2 J 3 J 3a J 8,8a-hexahydropyrrolo [2,3-b]
indol~5-ol;
3a-methyl-1,2 J 3 J 3a,8,8a-hexahydropyrrolo [2,3-b~ indol-5-ol;
1 J 3a-dimethyl-1,2 J 3,3a,8,8a-hexahydropyrrolo [2,3-b~
indol-5-ol;
.
--: ~ ' :.
-. . . , ~:
5~
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 wi-th a nitrogen stream, was added to a solution o~
salicylic acid (1.3 g) in ether (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 o~ 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,~,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-dimethyl-3a-propyl-1,2,3,3a,8,8a-hexahydropyrrolo. [2,3-b]
indol-5-ol;
5~7 1,3a,8-trimethyl-5-propy].oxy-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-~imethyl-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 l2,3-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).
, ', .:
Ex~mple 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 whi-te 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 ~
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. ]97-200C
(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 :
: . ., ' ' :
.
' ~
~ ' . ' , ethyl e-ther 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 puri~ied by distillation under vacuum (4 g). This latter compound (4 g) was added to a solution obtained by dissolving (+) tartaric acid (2.~ g) in ethyl alcohol (30 ml). The mixture was added to some ethyl ether and left overnight. Crystalline masses separated out which were ~iltered and ~ound to melt at about 150-160C.
A~ter several crystallizations ~rom ethyl alcohol containing tartaric acid needle-like colourless crystals o~
(+)-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 d:istilled under vacuum.
A colourless oil was obtained consisting o~ (-)-1-ethyl-3a, 8-dimethyl-5-ethoxy-1,2,3,3a,~,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 ~or 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 trea-ted with sodium bicarbonate and repeatedly extracted into ethyl ether. The residue obtained a~ter removing the solvent was distilled under high vacuum and the oil obtained was dissolved in ethyl ether-petroleum ether ~rom which needle-like crystals o~ (-)-l-ethyl-3a,8-dimethyl-1,2,3,3a,8,8a-hexahydropyrrolo . .
'' ' ' ` ' :
' . ~ . . .
5~5~
[2,3-b~ indol-5-ol were obtained.
Example 6 A mixture o~ ethyl iodide (2 moles) and o~ dibenzyliden-derivative of 2-methyl-2-(3,6-dimethoxyphenyl)-butyl-1,4-diamine (1 mole) was heated to 100C for about 2 hours in a closed tube. The solid o~tained was extracted into aqueous ethanol, the solvent was evaporated and the residue dissolved in diluted hydrochloric acid. An extraction into ethyl ether was carried out and the benzaldehyde ~ormed by extraction with ethyl ether was removed. The aqueous phase was then saturated with potassium carbonate and extracted again wi-th ethyl ether.
N,N-diethyl-2-(3,6-dimethoxy-phenyl)-2-methyl-butyl-1, ~-diamine (4 g) was obtained by evaporating the solvent and distilling under vacuum. This was dissolved in hydrobromic acid having a density o~ 1.49 (25 ml) and the solution was heated under re~lux for about 1 hou:r, cooled and treated with a mixture o~ propyl alcohol and ethyl ether. The dibromhydrate obtained by ~iltration (1.3 g) was dissolved in water (75 ml) and mixed with an aqueous solution obtained by dissolving potassium ~erricyanide (1.95 g) and sodium bicarbonate (1 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 puri~ied 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 .
.. . :
., ~ .
.
5~, - 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.
Exam~le 7 A solut iOII 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 treatm,ent ``
:, , .
with water. The ether phase was separated, dried and evaporated to dryness. Thus (~ ethyl-3a,8-dimethyl-1,2,3,3a,8,8a-hexahydropyrrolo [2,3-b~ indole (2.5 g) was obtained. ~`~
~ ;.
~ - - - , . . . . .
:
;: '' ' ` . ' ' " ~ ~ , ' ., .
, ' .: , `- ~ : "~ , ~ 25 -Example 8 . .
To an ether solution of ethyl magnesium iodide obtained ~rom magnesium (2 g), ethyl iodide (12.8 g) and ethyl ether (20 ml) 5-ethoxy-3-methy1-triptamine (5.8 g) was added in small portions. The reaction mixture was heated to 100C
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 a~d 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 wit;h 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 ~ 5~
Example 10 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 cou]d 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 af~ecting the analgesic action of the product.
~.
'
Claims (8)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A pharmaceutical composition containing a suitable carrier and, as active substance, a compound of formula I
1 or a pharmaceutically acceptable salt thereof wherein: Rl is selected from the group consisting of hydrogen, hydroxy, methoxy and ethoxy; R2 is methyl; and R3 and R4 are the same or different and are selected rom the group consisting of hydrogen and methyl.
1 or a pharmaceutically acceptable salt thereof wherein: Rl is selected from the group consisting of hydrogen, hydroxy, methoxy and ethoxy; R2 is methyl; and R3 and R4 are the same or different and are selected rom the group consisting of hydrogen and methyl.
2. A pharmaceutical composition according to claim 1 wherein the active substance is selected from the group consisting of 1,3a,8-trimethyl-1,2,3,3a,8, 8a-hexahydropyrrolo[2,3-b]indol-5-ol (eseroline) and pharmaceutically accept-able salts formed with a suitable acid.
3. A pharmaceutical composition according to claim 2, wherein eseroline is (-) eseroline.
4. A pharmaceutical composition according to claim 2, wherein eseroline is salified with a pharmaceutically acceptable acid selected from the group consisting of hydrochloric acid, hydrobromic acid, sulphuric acid, salicylic acid, benzoic acid, p-hydroxybenzoic acid, tartaric acid, mesotartaric acid, fumaric acid, maleic acid, citric acid, gentisic acid, hydroxyphthalic acid, creatininsulphuric acid and succinic acid.
5. A pharmaceutical composition according to claim 4, wherein the pharm-aceutically acceptable acid is salicylic acid.
6. A pharmaceutical composition according to claim 2, wherein the active substance is the salicilate of (-) eseroline.
7. A pharmaceutical composition according to claim 1, in combination with relatively very small quantities of atropine or another muscarinic blocking agent.
8. A pharmaceutical composition according to claim 1 wherein the active substance is selected from 1,3a-dimethyl-l,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]
indol-5-ol and pharmaceutically acceptable salts formed with a suitable acid.
indol-5-ol and pharmaceutically acceptable salts formed with a suitable acid.
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 (2)
| 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 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1125657A true CA1125657A (en) | 1982-06-15 |
Family
ID=11132370
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA311,555A Expired CA1125657A (en) | 1977-09-20 | 1978-09-19 | Derivatives of 1,2,3,3a,8,8a-hexadydropyrrolo ¬2,3-b| indole |
Country Status (7)
| Country | Link |
|---|---|
| JP (1) | JPS54112897A (en) |
| AR (1) | AR222311A1 (en) |
| CA (1) | CA1125657A (en) |
| DE (1) | DE2839279A1 (en) |
| FR (1) | FR2434167A1 (en) |
| GB (1) | GB2005259B (en) |
| IT (1) | IT1109003B (en) |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1199076B (en) * | 1984-03-01 | 1988-12-30 | Consiglio Nazionale Ricerche | PHYSOSTIGMINE DERIVATIVES WITH PROPERTY OF INHIBITION OF ACETICOLINESTERASI AND RELATED PRODUCTION PROCESS |
| GB8616089D0 (en) * | 1986-07-02 | 1986-08-06 | Univ Manchester | Organic compounds |
| US4791107A (en) * | 1986-07-16 | 1988-12-13 | 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, compositions and use |
| IT1225462B (en) * | 1987-04-03 | 1990-11-14 | Mediolanum Farmaceutici Srl | ORGANIC SALTS OF PHYSOSTIGMIN DERIVATIVES |
| AT400331B (en) * | 1987-05-15 | 1995-12-27 | Hoechst Roussel Pharma | 1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethylpyrrolo(2,3- b)indoles, a process for their preparation and their use as pharmaceuticals |
| US4971992A (en) * | 1989-03-27 | 1990-11-20 | Hoechst-Roussel Pharmaceuticals Inc. | Carbonate derivatives of eseroline |
| US4914102A (en) * | 1989-09-28 | 1990-04-03 | Hoechst Roussel Pharmaceuticals, Inc. | N-aminocarbamates related to physostigmine, pharmacentical compositions and use |
| US5260452A (en) * | 1989-11-03 | 1993-11-09 | Hoechst-Roussel Pharmaceuticals Inc. | 4- and 6-carbamates related to physostigmine and intermediates for the preparation thereof |
| US5206260A (en) * | 1991-11-07 | 1993-04-27 | Merck & Co., Inc. | Hexahydropyrrolo[2,3-b]indole derivatives |
| GB9205670D0 (en) * | 1992-03-16 | 1992-04-29 | Indena Spa | New derivatives of physostigmine,their use and pharmaceutical formulations containing them |
| WO1999019329A1 (en) * | 1997-10-10 | 1999-04-22 | Chiesi Farmaceutici S.P.A. | A process for the preparation of aminocarbonyl derivatives of geneseroline having selective brain anticholinesterase activity |
| US6495700B1 (en) * | 2002-01-09 | 2002-12-17 | Axonyx, Inc. | Process for producing phenserine and its analog |
-
1977
- 1977-09-20 IT IT09574/77A patent/IT1109003B/en active
-
1978
- 1978-09-07 AR AR273611A patent/AR222311A1/en active
- 1978-09-09 DE DE19782839279 patent/DE2839279A1/en not_active Withdrawn
- 1978-09-15 GB GB7837048A patent/GB2005259B/en not_active Expired
- 1978-09-19 CA CA311,555A patent/CA1125657A/en not_active Expired
- 1978-09-20 FR FR7826975A patent/FR2434167A1/en active Granted
- 1978-09-20 JP JP11470178A patent/JPS54112897A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| JPS54112897A (en) | 1979-09-04 |
| FR2434167A1 (en) | 1980-03-21 |
| GB2005259B (en) | 1982-06-23 |
| IT1109003B (en) | 1985-12-16 |
| FR2434167B1 (en) | 1983-03-18 |
| AR222311A1 (en) | 1981-05-15 |
| DE2839279A1 (en) | 1979-03-29 |
| GB2005259A (en) | 1979-04-19 |
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| Date | Code | Title | Description |
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| MKEX | Expiry |