CA1054601A - Process for the production of 1-amino-3-phenyl indoles derivatives having antimicrobial and antidepressant properties - Google Patents
Process for the production of 1-amino-3-phenyl indoles derivatives having antimicrobial and antidepressant propertiesInfo
- Publication number
- CA1054601A CA1054601A CA223211A CA223211A CA1054601A CA 1054601 A CA1054601 A CA 1054601A CA 223211 A CA223211 A CA 223211A CA 223211 A CA223211 A CA 223211A CA 1054601 A CA1054601 A CA 1054601A
- Authority
- CA
- Canada
- Prior art keywords
- amino
- alkyl
- indole
- phenyl
- alkanoyl
- 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
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/26—Psychostimulants, e.g. nicotine, cocaine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/16—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms condensed with carbocyclic rings or ring systems
- C07D249/18—Benzotriazoles
Abstract
ABSTRACT OF THE DISCLOSURE
A process is disclosed for the preparation of novel 1-amino-3-phenylindole derivatives having pharmacological activity, the compounds having the general formula wherein R1 is hydrogen, C1-C3 alkyl or C1-C3 dialkylamino-C2-C5 alkyl:
R2 is C1-C3 dialkylamino-C2-C5 alkyl, C2-C4 alkanoyl, C1-C3 dialkylamino-C2-C4 alkanoyl, aroyl or nicotinoyl;
R3 is hydrogen, C1-C3 alkyl or halogen; and R4 is hydrogen, C1-C3 alkyl, C1-C3 alkoxy or halogen;
the process requiring coupling of 1-secondary amino-3-phenylindoles with the appropriate alkyl, alkanoyl, aroyl or nicotinoyl halide or precursor therof wherby a product is obtained into which an appropriate dialkylamino group may be introduced.
A process is disclosed for the preparation of novel 1-amino-3-phenylindole derivatives having pharmacological activity, the compounds having the general formula wherein R1 is hydrogen, C1-C3 alkyl or C1-C3 dialkylamino-C2-C5 alkyl:
R2 is C1-C3 dialkylamino-C2-C5 alkyl, C2-C4 alkanoyl, C1-C3 dialkylamino-C2-C4 alkanoyl, aroyl or nicotinoyl;
R3 is hydrogen, C1-C3 alkyl or halogen; and R4 is hydrogen, C1-C3 alkyl, C1-C3 alkoxy or halogen;
the process requiring coupling of 1-secondary amino-3-phenylindoles with the appropriate alkyl, alkanoyl, aroyl or nicotinoyl halide or precursor therof wherby a product is obtained into which an appropriate dialkylamino group may be introduced.
Description
~)5~
This invention rela~es to new hydrazines, and more particu-larly to a process for the production thereof.
Relatively few chemical compounds have hitherto been des-cribed which consist of a six-membered ring having Eused ~hereto a five-membered ring containing at least one ring nitrogen atom and comprising a secondary or tertiar~ amino group bonded to a ring nitrogen atom. Such systems can be considered to be hydra- `
zines in which one of the nierogen atoms forms a ring member of the five-membered ring of a 4.3.0 hetero~icyclic compound.
Compounds of this type which have hitherto been characterised include l-dimethylamino-3-phenyl-indole and 1-phenyl-amino-3- ~ ~ -phenyl-indole, as well as their 5-chloro analogues. Reference is made in this connection to F. Troxler, in Indoles, Part II, pages 191-i92, edited by W.J. Houlihan, Wiley-Interscience, Ne~
York-London, 1972, and to-R.J. Sundberg, The Chemistry of Indoles~
: page 397, Academic Press, New York-London, 1970. The aforesaid compounds have beèn produced by procedures specific to indivldual compounds and not applicable to the production of structurally related compounds.
According to the present invention, there is provided a pro-~ .
cess for the production of a compound having the general farmula.
~J
Rl R2 mjpj .,.:: . :: .. -.: : .- . :, :...... :
.:-.~: , : . . , . . .. , -- :
)59~6~
wherein Rl is hyd~ogen, Cl-C3 alkyl or Cl-C3 dialkylamino~
C2~Cs alkyl;
R2 is Cl-C3 dialkylamino-C2-Cs alkyl, C2-C4 alkanoyl, Cl-C3 dialkylamino-C2-C4 alkanoyl, aroyl or nicotinoyl;
R3 is h~drogen, Cl-C3 alkyl or halogen; and R4 is hydrogen, Cl-C3 alkyl, Cl-C3 alkoxy or halogen;
which process comprises reacting a compound having the general formula:
3 ~
NHR
wherein R3 and R4 have the aforesaid meanings and R is hydr~gen;
~CrC3 alkyl, Cl-C3 dialkylamino-C2-Cs alkyl, C2-C4 alkanoyl~, -- Cl-C3 dialkylamino-C2-C4 alkanoyl, a:royl or nicotinoyl with a compound of formula R'X in which R' :is substituted C2-Cs alkyl, C2-C4 alkanoyl, substituted C2-C4 alkanoyl, aroyl or nicotinoyl i~
when ~ is hydrogen or Cl-C3 alkyl; R' is Cl-C3 alkyl, substituted C2-Cs alkyl, C2-C4 alkanoyl, substituted C2-C4 alkanoyl, aroyl or nicotinoyl when R is Cl-C3 dialkylamino-C2-Cs alkyl; and R' is Cl-C3 alkyl or substituted C2-Cs alkyl when R is C2-C4 alkanoyl, Cl-C3 dialkylamino-C2-C4 alkanoyl, aroyl or nicotinoyl; and X is a radical which is split off in a reactîon wherein a ~-R' bond is formed and combined with a hydrogen atom split off from the nitrogen atom, said substituted C2-Cs alkyl and C2-C4 alkanoyl groups being C2-Cs alkyl and C2-C4 alkanoyl groups respectively ~-substituted by a Cl-C3 dialkylamino group or a group which can be replaced by a tertiary amino group, and when the substituent is . ::
, 2 :.:
., '~
mjp/
' ' ' , ' '; '"''. -. ''' ' ; ~ ~ . - ,` ,,- .
,~ , .
an atom or group which can be replaced by a tertiary amino group, substituting it by a Cl-C3 dialkylamino group, and isolating the compound obtained as such or as a pharmacologically acceptable salt thereof.
The process of this invention yields novel compounds ~hich have been found to possess anti~microBial properties, in particu-lar fungistatic and bacteriostatic properties~ ~hich render them suitable for use for chemotherapeutic purposes, and additionally possess pharmacodynamic effects in a number of respects. Thus the compounds possess anti~depressant properties, this being the case to a conspicuous degree with the compound l-[N-methyl-N(2'-dimethylamlnoethyl)-amino]-3-phenyl-indole hydrochloride.
The compounds of this invention are rendered particularly suit- ;
able for use in pharmaceutical compositions by their xemarkably low toxicity.
- Particularly promising results in general have been obtalned when the l-amino group of the reaction product is either substi-tuted by an aroyl group, for example a benzoyl group or an alkanoyl group containing up to 4 carbon atoms, for example an acetyl or propionyl group or by one or two alkyl groups containing from 2 to 5 carbon atoms. The aforesaid properties of the com-; pounds are further inteDsified if in such a case a C2-C4 alkanoyl ~roup or a C2-C5 alkyl group, preferably a pair of alkyl groups~ ;
is/are in turn substituted by a dialkylamino group who9e alkyl radicals contain up to 3 carbon atoms.
When preparing the aforesaid preferred types of compound according to this~invention, the radical R' in the compound R'X
will thus be an aroyl radical) for example a benzoyl radical which may be substituted on the benzene nucleus/ or au alkanoyl group.
~ -3-. . , mjp/
:~ . : :...................... - :
~.: ', ' :, . . . ' ' . ':, : . .': ' ' . ~, ' :. . . . .:
5~L6~1 R' can also be an alkyl group ~hich9 in its turn, can be substi tuted by a tertiary amino group. T~e tertiary amino group may be present in R' from the outset or may be produced subsequently.
Thus R' may be substituted by an atom or group replaceable by an amino group. ~hen the substituent is replaceable by an amino group, the amino group may be a tertiary amino group from the outset or a primary or secondar~ amino group w~ich is subsequently replaced by a ter~iary amino group. Examples of atoms or groups which may be replaced by ter~iary groups are halogen and hydroxyl groups which may be etherified.
The radical X ~hich combines with hydrogen in the reaction whereby the compounds of the present invention are formed is preferably a chlorine atom, a bromine atom or an alkoxy group, in particular a methoxy or an ethoxy group.
The starting compound of general formula II which is employed :. in the process of this invention is preferably one in which R is either hydrogen or a methyl group. A primary amino group can be incorpora~ed in the starting compouncl during the formation of the nltrogen-containing ring system. Thus, a dihydrocinnoline can be boiled with a dilute mineral acid at 100C to give a l-amino indole.
A l~m~th~lamino-3-methyl indole has been produced by boiling 1 formamido-3-methyl indole with formic acid. ~ -:
The heterobicyclic structure of the hydrazine used as start ing material can, as~already indicated above, be substituted at one or more of a number of positions, ~or example by halogen, alkyl,~ alkoxy, substituted alkyl, substituted alkoxy or phenyl groups.
The products obtained by the aforesaid process of this invention can be converted into the form of acid addition salts `,:
mjp/
-- -- - . - -. :, , . : :- . :
, : . ::: , , ~ .
:.: - , , . : :
- :: ` , ~ : i : , ,, :
~0~4~
by reactlon ~ith an inorganic acid, for e~ample hydrochloric acid, or an organic acid, for example an organlcally su~stituted sulphonic acid, for example cyclohexyl sulphonic acid. Depend-ing upon the nature of substituents in the product, it may even be possible to isolate the product in the orm of a salt with a base. The physical form of the product o~ the aforesaid resction may indeed be such that it cannot be readily isolated in other than salt form. The novel compounds o this invention can also be converted into ~uaternary ammonium salts~
It will be appreciated that for therapeutic use, the compound~
of this invention can be made up, in accordance with well known pharmaceutical techniques, into compositions having as an essential ac~ive ingredient the compound of the invention in assaciation ~ith a pharmaceutical carrier therefor. If desired, the compositions can be made up in a dosage unit form suitable for the particular - mode of administration, the quantity of active ingredient in each ~
~ ,....
dosage unit being such that one or more units are requir~d for each therspeutic administration. The dosage unit may exist, for example, in the form of a tablet, pill, sachet, packaged powder or encapsulated powder for oral administration or in the form of a sterile in~ectable solution or suspension, if d~sired contained in- ~ ;
~an ampoule, for parenteral administration.
; The following Examples illustrate the invention:-Example 1l-[bis-(2'-diethylaminoethyl)]-àmino-3~phenyl-indole hydrochlori~e 23.4 G of sodium amide (50%) in toluene ~0.3 mol) were added dropwise and while stirring to a suspension of 20.8 g (0.1 mol) of l-amino-3-phenyl-indole in 200 ml of toluene The temperature ;~
of the suspension rose to about 40~C, and the mixture became a 30 .
_5_ ~.
~: :
mjp/
.: . .. : :, .: : ,: .. , .. . -, ' '.' .. : ~ "
j :- : .. ,. .: .
~05~
light brown in colour. A sol~tion of 30 g (0.22 mol) of diethylaminoethyl chloride in 250 ml of toluene was then added dropwise to the warm reaction mixture which was th.en heated for 3 hours under reflux. The reaction mixtu~eAinitially darkened but subsequently developed a light yellow colouring.
The reaction mixture was then cooled and th.e reaction product was extracted t~.ree times ~ith, on each occasion, 150 ~1 of 2N .
~: acetic acid. Th.e aqueous phases o~ained were each. washed oncewith ether, made alkaline wi.th 2N-soaium carbonate solution and extracted with ether. The combined eth.er extracts were dried and concentrated. The resulting oil was supplied with benzene to a 300 ml Alox Woelm column and eluted. The rea~tion product, purified in th.is way and constituted ~y 31 g of light brown oil was taken up in anhydrous ether and ethereal hydrogen chloride ; was atded th.ereto while stirring until no more hydrochloride was ~.
~ precipitated. The precipitate was fi.ltered off, washed with ether and dried. A yield of hydrochloride of 26.0 g ~55% of the theoretical) was obtained. Th.e hydroch.loride had a melting point of 233-235C. Analysis of th~is product ~as as follo~s:
20 : C26E38N4 . 2 HCl ~479.55) Calculsted: C 65.12 H 8.41 N 11.68 Cl 14.78 Found: C 65.14 H 8.39 N 11.67 Cl 14.53 ~; -Example 2 ~.
l-~N-methyl-N-(3~-dimethylamino)-propylj-amino-3-phenyl-indole hydrochloride A suspension of 5.4 g of sodium amide ~50%~ in toluene, followed by a solution of 6.5 g (0.05 mol) of 3-dimethylaminopropyl chloride in 5Q ml of toluene, were added dropwise to a solution of ` 11.1 g (0.05 mol) of 1-meth.rlamino-3-ph.enyl-indole in 150 ml m~p/
.
" ~ . , : ' ' . ' ' " ' ' . ~;
'. , ; ' ., . ' , ~
4~
of anhydrous toluene, ~hile stirr:Lng vi~orously. The mixture obtained was then heated under reflux for 3 ~ours. The reaction mixture was cooled and extracted three t~mes, each time with 150 ml of 2N acetic acid. The acet~c acid e~tracts were made alkaline with ammonia and combined. Th~e crude product thu~
obeained, existing partially as an oil, ~as dissolved ln ethyl acetate. The c~olution was washed with water, dried and concen-tra~ed. The oil thus o~tained was purified by chromatography using a short column of ~lox Akt. II and was eluted with ether.
The hydrochloride of the reaction product was precipitated from the ethereal solution by adding e~her/HCl and was filtered off :~ .
and dried. The melting point of the hydroc~loride was 183-185~C
and the yield of hydrochloride was about 80% of theoretical.
Analytical data:
C20~26N3Cl t343.9) Calculated in atoms: C20H26N3 - 10.31% Cl Found: C19.6H25.7N3 - 11.15% Cl -~
The 1 methylamino-3-phenyl-indole starting material has not hitherto been described and may be prepared by the following method:
25 G (0.1 mol) of 1-acetylamino-3-phenyl-indole tWhich can be obtained with a good yield from 1,4-dihydro-4-phenyl cinnoline in 5% acetic acid?, 48 g tO.2 mol) of the methyl ester of p-toluen~e sulphonic acid and 12.8 g tO.2 mol) of finely powdered potassium hydroxide were suspended in 150 ml of toluene and heated for 4 hours under reflux. After cooling, the reaction product was poured into water. The organic phase was separated out, dried over sodium sulphate and concentrated. 31 G of a crude oil com-prising 1-tN-methyl-N-acetylamino)~3-phenyl-indole were obtained. ~ ~;
~, 7 mjp/
'`,', ' . ' ' ~ .: ' ' ` ' . . : ' `: : ~ ` ' ~ "
: ~: . - - , , . ~: ., . ., . , ; , ~
:: , . . . . . . . .
54~
The oil was purified ~sing an Alo~ Akt. II column with benzene and the reaction product was dissolved in 610 ~1 o ethanol and 210 ml of hydrochloric acid and heated for ~ hours under reflux.
The reaction mixture was then poured onto ice and made alkaline with ammonia, the reaction product precipltating as a white, crystalline precipitate. ~iltering, drylng and recrystallisation of t~e reaction product from ethanol/water yielded l-methylamino-3-phenyl-indole of melting point 60-62C (yield 6~ based on the dihydrophenyl cinnoline original starting material~.
Analysis:
C15H14N2 (222.0~
Found in atoms: C15~13.9~2 Example 3 l-(p-acetaminobenzene sulphonylamino)-3-phenyl-indole 11.7 G (0.05 mol) of p-acetaminobenzene sulph;onyl chloride - ~
- were added in portions and wlth stirring to a solution of 15.6 g ~ ~:
~0.075 mol) of 1-amino-3-phenyl-indole in 100 ml of pyridine.
The temperature of the mixture rose to about 45C. The mixture was then heated to 60C and stirred for 3 hours at this tempera-ture. The red solution obtained was then concentrated by evapo-ration under vacuum. The viscous,oily residue whic~ was obtained .
was taken up in a mixture o~ b&nzene and chloroform ~1:1 by volume) and chromatographically purified through a column o~ 300 ml Alox Woelm neutral Akt. II. The resulting oily product was crystalll~ea - from a little ethanol and was recrystallised from ethanol/water~
The crystals of l-(p-acetamlnobenæene sulphonylamino)-3-phenyl-indole melted at 190-193C and were obtained in a yield of 16.5 g (55% of the theoretical~.
- ~'.
mjp/
, . . , : , ~ ~, . .
~, . .::
., , ~ . .
)59~6~
Analys i5:
C22H19N33S (332.5~
Found in atoms: C21.8H18.7N3 l-(p-aminobenzene sulphonylamino~-3-phenyl-inaole melting at 176-177C could ~e obtained from this product b~ deacetylation.
Example 4 1-(3'-dimethylaminopropionylamino~-3-p~enyl-indole . .
4.75 G (0.028 mol~ of ~-~romopropionic acid chloride in 10 ml of toluene and 2.55 g (0.025 mol~ of trlethylamine in 10 ml of toluene were added dropwise and while stirring to a solution of 5 g (0.025 mol) of 1-amino-3-phenyl-indole in 80 ml of anhydrous tetrahydrofuran. The temperature of the solution rose to about 55C. Stirring of the reactian mixture thus obtain-ed ~as then effected for 1 hour without application of heat and for 1 hour while heating it at 60C. The triethylamine hydro-chloride which precipitated was then removed by filtration and the clear light brown filtrate was completely concentrated by evaporation in a rotary evaporator and the residue was recrystallised from ethanol. 1-(3'-bromopropionylamino?-3-phenyl-20 ~ indole which was obt~ined as an intermediate product in a yieldof 6.3 g (77% of theoretical), melted at 185-186C.
; ~ 5 G (0.015 mol) of this intermediate product were suspe~dea in 50 ml of anhydrous dioxane and a mixture of 10 ml of chilled ; ~ tetrahydrofuran and 1.8 g tO.04 mol) of dimethylamine was added - -thereto. The entire reaction mixture was kept at 40C in a gîass autoclave for 16 hours while stirring. The dimethylamine hydro-bromide which separated out was the~ removed and the solution which~
remained was concentrated by evaporation and the residue obtained was recrystallised from ethanol. 3.85 G ~86% of the theoretical?
. ~
. .
~q~p/ ~ .
. . , , A . ' ' . ' ' ' ' ' ' ~ ' '/ ' ,' , ' ~ ' `', ' '. ', ' "~ ', ',, ' . ' S4~
oE 1-~3~-dimethylaminopropionyl~-3-phenyl-indole of melting point 137-138C wera o~tained.
Analytical data:
19H21N3 ~307.4~
Calculated: C 74.23 H 6.89 N 13.67 Found: C 74.13 ~ 6.84 N 13.83 Additional examples of compounds according to the present invention which have been prepared,are:
1. 1-(3'-Carboxypropionylamino~-3-phenyl- ~ -indole M.p.189-190~C
This invention rela~es to new hydrazines, and more particu-larly to a process for the production thereof.
Relatively few chemical compounds have hitherto been des-cribed which consist of a six-membered ring having Eused ~hereto a five-membered ring containing at least one ring nitrogen atom and comprising a secondary or tertiar~ amino group bonded to a ring nitrogen atom. Such systems can be considered to be hydra- `
zines in which one of the nierogen atoms forms a ring member of the five-membered ring of a 4.3.0 hetero~icyclic compound.
Compounds of this type which have hitherto been characterised include l-dimethylamino-3-phenyl-indole and 1-phenyl-amino-3- ~ ~ -phenyl-indole, as well as their 5-chloro analogues. Reference is made in this connection to F. Troxler, in Indoles, Part II, pages 191-i92, edited by W.J. Houlihan, Wiley-Interscience, Ne~
York-London, 1972, and to-R.J. Sundberg, The Chemistry of Indoles~
: page 397, Academic Press, New York-London, 1970. The aforesaid compounds have beèn produced by procedures specific to indivldual compounds and not applicable to the production of structurally related compounds.
According to the present invention, there is provided a pro-~ .
cess for the production of a compound having the general farmula.
~J
Rl R2 mjpj .,.:: . :: .. -.: : .- . :, :...... :
.:-.~: , : . . , . . .. , -- :
)59~6~
wherein Rl is hyd~ogen, Cl-C3 alkyl or Cl-C3 dialkylamino~
C2~Cs alkyl;
R2 is Cl-C3 dialkylamino-C2-Cs alkyl, C2-C4 alkanoyl, Cl-C3 dialkylamino-C2-C4 alkanoyl, aroyl or nicotinoyl;
R3 is h~drogen, Cl-C3 alkyl or halogen; and R4 is hydrogen, Cl-C3 alkyl, Cl-C3 alkoxy or halogen;
which process comprises reacting a compound having the general formula:
3 ~
NHR
wherein R3 and R4 have the aforesaid meanings and R is hydr~gen;
~CrC3 alkyl, Cl-C3 dialkylamino-C2-Cs alkyl, C2-C4 alkanoyl~, -- Cl-C3 dialkylamino-C2-C4 alkanoyl, a:royl or nicotinoyl with a compound of formula R'X in which R' :is substituted C2-Cs alkyl, C2-C4 alkanoyl, substituted C2-C4 alkanoyl, aroyl or nicotinoyl i~
when ~ is hydrogen or Cl-C3 alkyl; R' is Cl-C3 alkyl, substituted C2-Cs alkyl, C2-C4 alkanoyl, substituted C2-C4 alkanoyl, aroyl or nicotinoyl when R is Cl-C3 dialkylamino-C2-Cs alkyl; and R' is Cl-C3 alkyl or substituted C2-Cs alkyl when R is C2-C4 alkanoyl, Cl-C3 dialkylamino-C2-C4 alkanoyl, aroyl or nicotinoyl; and X is a radical which is split off in a reactîon wherein a ~-R' bond is formed and combined with a hydrogen atom split off from the nitrogen atom, said substituted C2-Cs alkyl and C2-C4 alkanoyl groups being C2-Cs alkyl and C2-C4 alkanoyl groups respectively ~-substituted by a Cl-C3 dialkylamino group or a group which can be replaced by a tertiary amino group, and when the substituent is . ::
, 2 :.:
., '~
mjp/
' ' ' , ' '; '"''. -. ''' ' ; ~ ~ . - ,` ,,- .
,~ , .
an atom or group which can be replaced by a tertiary amino group, substituting it by a Cl-C3 dialkylamino group, and isolating the compound obtained as such or as a pharmacologically acceptable salt thereof.
The process of this invention yields novel compounds ~hich have been found to possess anti~microBial properties, in particu-lar fungistatic and bacteriostatic properties~ ~hich render them suitable for use for chemotherapeutic purposes, and additionally possess pharmacodynamic effects in a number of respects. Thus the compounds possess anti~depressant properties, this being the case to a conspicuous degree with the compound l-[N-methyl-N(2'-dimethylamlnoethyl)-amino]-3-phenyl-indole hydrochloride.
The compounds of this invention are rendered particularly suit- ;
able for use in pharmaceutical compositions by their xemarkably low toxicity.
- Particularly promising results in general have been obtalned when the l-amino group of the reaction product is either substi-tuted by an aroyl group, for example a benzoyl group or an alkanoyl group containing up to 4 carbon atoms, for example an acetyl or propionyl group or by one or two alkyl groups containing from 2 to 5 carbon atoms. The aforesaid properties of the com-; pounds are further inteDsified if in such a case a C2-C4 alkanoyl ~roup or a C2-C5 alkyl group, preferably a pair of alkyl groups~ ;
is/are in turn substituted by a dialkylamino group who9e alkyl radicals contain up to 3 carbon atoms.
When preparing the aforesaid preferred types of compound according to this~invention, the radical R' in the compound R'X
will thus be an aroyl radical) for example a benzoyl radical which may be substituted on the benzene nucleus/ or au alkanoyl group.
~ -3-. . , mjp/
:~ . : :...................... - :
~.: ', ' :, . . . ' ' . ':, : . .': ' ' . ~, ' :. . . . .:
5~L6~1 R' can also be an alkyl group ~hich9 in its turn, can be substi tuted by a tertiary amino group. T~e tertiary amino group may be present in R' from the outset or may be produced subsequently.
Thus R' may be substituted by an atom or group replaceable by an amino group. ~hen the substituent is replaceable by an amino group, the amino group may be a tertiary amino group from the outset or a primary or secondar~ amino group w~ich is subsequently replaced by a ter~iary amino group. Examples of atoms or groups which may be replaced by ter~iary groups are halogen and hydroxyl groups which may be etherified.
The radical X ~hich combines with hydrogen in the reaction whereby the compounds of the present invention are formed is preferably a chlorine atom, a bromine atom or an alkoxy group, in particular a methoxy or an ethoxy group.
The starting compound of general formula II which is employed :. in the process of this invention is preferably one in which R is either hydrogen or a methyl group. A primary amino group can be incorpora~ed in the starting compouncl during the formation of the nltrogen-containing ring system. Thus, a dihydrocinnoline can be boiled with a dilute mineral acid at 100C to give a l-amino indole.
A l~m~th~lamino-3-methyl indole has been produced by boiling 1 formamido-3-methyl indole with formic acid. ~ -:
The heterobicyclic structure of the hydrazine used as start ing material can, as~already indicated above, be substituted at one or more of a number of positions, ~or example by halogen, alkyl,~ alkoxy, substituted alkyl, substituted alkoxy or phenyl groups.
The products obtained by the aforesaid process of this invention can be converted into the form of acid addition salts `,:
mjp/
-- -- - . - -. :, , . : :- . :
, : . ::: , , ~ .
:.: - , , . : :
- :: ` , ~ : i : , ,, :
~0~4~
by reactlon ~ith an inorganic acid, for e~ample hydrochloric acid, or an organic acid, for example an organlcally su~stituted sulphonic acid, for example cyclohexyl sulphonic acid. Depend-ing upon the nature of substituents in the product, it may even be possible to isolate the product in the orm of a salt with a base. The physical form of the product o~ the aforesaid resction may indeed be such that it cannot be readily isolated in other than salt form. The novel compounds o this invention can also be converted into ~uaternary ammonium salts~
It will be appreciated that for therapeutic use, the compound~
of this invention can be made up, in accordance with well known pharmaceutical techniques, into compositions having as an essential ac~ive ingredient the compound of the invention in assaciation ~ith a pharmaceutical carrier therefor. If desired, the compositions can be made up in a dosage unit form suitable for the particular - mode of administration, the quantity of active ingredient in each ~
~ ,....
dosage unit being such that one or more units are requir~d for each therspeutic administration. The dosage unit may exist, for example, in the form of a tablet, pill, sachet, packaged powder or encapsulated powder for oral administration or in the form of a sterile in~ectable solution or suspension, if d~sired contained in- ~ ;
~an ampoule, for parenteral administration.
; The following Examples illustrate the invention:-Example 1l-[bis-(2'-diethylaminoethyl)]-àmino-3~phenyl-indole hydrochlori~e 23.4 G of sodium amide (50%) in toluene ~0.3 mol) were added dropwise and while stirring to a suspension of 20.8 g (0.1 mol) of l-amino-3-phenyl-indole in 200 ml of toluene The temperature ;~
of the suspension rose to about 40~C, and the mixture became a 30 .
_5_ ~.
~: :
mjp/
.: . .. : :, .: : ,: .. , .. . -, ' '.' .. : ~ "
j :- : .. ,. .: .
~05~
light brown in colour. A sol~tion of 30 g (0.22 mol) of diethylaminoethyl chloride in 250 ml of toluene was then added dropwise to the warm reaction mixture which was th.en heated for 3 hours under reflux. The reaction mixtu~eAinitially darkened but subsequently developed a light yellow colouring.
The reaction mixture was then cooled and th.e reaction product was extracted t~.ree times ~ith, on each occasion, 150 ~1 of 2N .
~: acetic acid. Th.e aqueous phases o~ained were each. washed oncewith ether, made alkaline wi.th 2N-soaium carbonate solution and extracted with ether. The combined eth.er extracts were dried and concentrated. The resulting oil was supplied with benzene to a 300 ml Alox Woelm column and eluted. The rea~tion product, purified in th.is way and constituted ~y 31 g of light brown oil was taken up in anhydrous ether and ethereal hydrogen chloride ; was atded th.ereto while stirring until no more hydrochloride was ~.
~ precipitated. The precipitate was fi.ltered off, washed with ether and dried. A yield of hydrochloride of 26.0 g ~55% of the theoretical) was obtained. Th.e hydroch.loride had a melting point of 233-235C. Analysis of th~is product ~as as follo~s:
20 : C26E38N4 . 2 HCl ~479.55) Calculsted: C 65.12 H 8.41 N 11.68 Cl 14.78 Found: C 65.14 H 8.39 N 11.67 Cl 14.53 ~; -Example 2 ~.
l-~N-methyl-N-(3~-dimethylamino)-propylj-amino-3-phenyl-indole hydrochloride A suspension of 5.4 g of sodium amide ~50%~ in toluene, followed by a solution of 6.5 g (0.05 mol) of 3-dimethylaminopropyl chloride in 5Q ml of toluene, were added dropwise to a solution of ` 11.1 g (0.05 mol) of 1-meth.rlamino-3-ph.enyl-indole in 150 ml m~p/
.
" ~ . , : ' ' . ' ' " ' ' . ~;
'. , ; ' ., . ' , ~
4~
of anhydrous toluene, ~hile stirr:Lng vi~orously. The mixture obtained was then heated under reflux for 3 ~ours. The reaction mixture was cooled and extracted three t~mes, each time with 150 ml of 2N acetic acid. The acet~c acid e~tracts were made alkaline with ammonia and combined. Th~e crude product thu~
obeained, existing partially as an oil, ~as dissolved ln ethyl acetate. The c~olution was washed with water, dried and concen-tra~ed. The oil thus o~tained was purified by chromatography using a short column of ~lox Akt. II and was eluted with ether.
The hydrochloride of the reaction product was precipitated from the ethereal solution by adding e~her/HCl and was filtered off :~ .
and dried. The melting point of the hydroc~loride was 183-185~C
and the yield of hydrochloride was about 80% of theoretical.
Analytical data:
C20~26N3Cl t343.9) Calculated in atoms: C20H26N3 - 10.31% Cl Found: C19.6H25.7N3 - 11.15% Cl -~
The 1 methylamino-3-phenyl-indole starting material has not hitherto been described and may be prepared by the following method:
25 G (0.1 mol) of 1-acetylamino-3-phenyl-indole tWhich can be obtained with a good yield from 1,4-dihydro-4-phenyl cinnoline in 5% acetic acid?, 48 g tO.2 mol) of the methyl ester of p-toluen~e sulphonic acid and 12.8 g tO.2 mol) of finely powdered potassium hydroxide were suspended in 150 ml of toluene and heated for 4 hours under reflux. After cooling, the reaction product was poured into water. The organic phase was separated out, dried over sodium sulphate and concentrated. 31 G of a crude oil com-prising 1-tN-methyl-N-acetylamino)~3-phenyl-indole were obtained. ~ ~;
~, 7 mjp/
'`,', ' . ' ' ~ .: ' ' ` ' . . : ' `: : ~ ` ' ~ "
: ~: . - - , , . ~: ., . ., . , ; , ~
:: , . . . . . . . .
54~
The oil was purified ~sing an Alo~ Akt. II column with benzene and the reaction product was dissolved in 610 ~1 o ethanol and 210 ml of hydrochloric acid and heated for ~ hours under reflux.
The reaction mixture was then poured onto ice and made alkaline with ammonia, the reaction product precipltating as a white, crystalline precipitate. ~iltering, drylng and recrystallisation of t~e reaction product from ethanol/water yielded l-methylamino-3-phenyl-indole of melting point 60-62C (yield 6~ based on the dihydrophenyl cinnoline original starting material~.
Analysis:
C15H14N2 (222.0~
Found in atoms: C15~13.9~2 Example 3 l-(p-acetaminobenzene sulphonylamino)-3-phenyl-indole 11.7 G (0.05 mol) of p-acetaminobenzene sulph;onyl chloride - ~
- were added in portions and wlth stirring to a solution of 15.6 g ~ ~:
~0.075 mol) of 1-amino-3-phenyl-indole in 100 ml of pyridine.
The temperature of the mixture rose to about 45C. The mixture was then heated to 60C and stirred for 3 hours at this tempera-ture. The red solution obtained was then concentrated by evapo-ration under vacuum. The viscous,oily residue whic~ was obtained .
was taken up in a mixture o~ b&nzene and chloroform ~1:1 by volume) and chromatographically purified through a column o~ 300 ml Alox Woelm neutral Akt. II. The resulting oily product was crystalll~ea - from a little ethanol and was recrystallised from ethanol/water~
The crystals of l-(p-acetamlnobenæene sulphonylamino)-3-phenyl-indole melted at 190-193C and were obtained in a yield of 16.5 g (55% of the theoretical~.
- ~'.
mjp/
, . . , : , ~ ~, . .
~, . .::
., , ~ . .
)59~6~
Analys i5:
C22H19N33S (332.5~
Found in atoms: C21.8H18.7N3 l-(p-aminobenzene sulphonylamino~-3-phenyl-inaole melting at 176-177C could ~e obtained from this product b~ deacetylation.
Example 4 1-(3'-dimethylaminopropionylamino~-3-p~enyl-indole . .
4.75 G (0.028 mol~ of ~-~romopropionic acid chloride in 10 ml of toluene and 2.55 g (0.025 mol~ of trlethylamine in 10 ml of toluene were added dropwise and while stirring to a solution of 5 g (0.025 mol) of 1-amino-3-phenyl-indole in 80 ml of anhydrous tetrahydrofuran. The temperature of the solution rose to about 55C. Stirring of the reactian mixture thus obtain-ed ~as then effected for 1 hour without application of heat and for 1 hour while heating it at 60C. The triethylamine hydro-chloride which precipitated was then removed by filtration and the clear light brown filtrate was completely concentrated by evaporation in a rotary evaporator and the residue was recrystallised from ethanol. 1-(3'-bromopropionylamino?-3-phenyl-20 ~ indole which was obt~ined as an intermediate product in a yieldof 6.3 g (77% of theoretical), melted at 185-186C.
; ~ 5 G (0.015 mol) of this intermediate product were suspe~dea in 50 ml of anhydrous dioxane and a mixture of 10 ml of chilled ; ~ tetrahydrofuran and 1.8 g tO.04 mol) of dimethylamine was added - -thereto. The entire reaction mixture was kept at 40C in a gîass autoclave for 16 hours while stirring. The dimethylamine hydro-bromide which separated out was the~ removed and the solution which~
remained was concentrated by evaporation and the residue obtained was recrystallised from ethanol. 3.85 G ~86% of the theoretical?
. ~
. .
~q~p/ ~ .
. . , , A . ' ' . ' ' ' ' ' ' ~ ' '/ ' ,' , ' ~ ' `', ' '. ', ' "~ ', ',, ' . ' S4~
oE 1-~3~-dimethylaminopropionyl~-3-phenyl-indole of melting point 137-138C wera o~tained.
Analytical data:
19H21N3 ~307.4~
Calculated: C 74.23 H 6.89 N 13.67 Found: C 74.13 ~ 6.84 N 13.83 Additional examples of compounds according to the present invention which have been prepared,are:
1. 1-(3'-Carboxypropionylamino~-3-phenyl- ~ -indole M.p.189-190~C
2. 1-(a-Chlornicotinoyl-amino~-3-phenyl-indole M.p.16~-170C
3. 1-(p-Nitrobenzoylamino~-3-phenyl-5-chlor-indole M.p.233-241C
4. 1-(o-Chloro-p-nitrobenzoylamino~-3-phenyl-indole ~ M.p.187-189C
5. 1-(o-Chloro-p-aminobenzoylamino)-3-phenyl-indole M.p.189-190C
6. 1-[N-Methyl-M-(2'-dimethylaminoethyl)-amino]-3-phenyl-indole hydrochloride M.p.188-190C
7. 1-[N-Methyl-N-(2'-diethylaminoethyl~- -amino~-3-phenyl-indole hydrochloride M.p.140-143C
8. 1-[N-Methyl-N-(3'-dimethylaminopropyl)-amino]-3-phenyl-5-chloro-indole hydrochloride ~ M.p.184-186C
9. 1-[N-Methyl-N-~2'-dimethylaminoethyl~-amino~-3-phenyl-5-methyl-indoleB.p.165-170C
O.01
O.01
10. 1-~N-Methyl-N-(2'-dimethylaminoethyl~- ~
- amino]-3-(~'-methoxyphenyl~-indole B.p.215-22QC/ ~-0.01 ~'
- amino]-3-(~'-methoxyphenyl~-indole B.p.215-22QC/ ~-0.01 ~'
11. 1-[N-Methyl-N-(3'-dimethylaminopropyl~-amino]-3-p-tolyl-5-chloro-indole hydrochloride M.p.205-207C `
12. 1-[N-Methyl-N-(3'-dimethylaminopropyl~- .- .
aminv]-3-(p chlorophenyl~-5-chloro-lndole hydrochloride M.p.209-210C
aminv]-3-(p chlorophenyl~-5-chloro-lndole hydrochloride M.p.209-210C
13. 1-~N-Methyl-N-(2'-diethylaminoethyl) amino]-3-phenyl-5-fiuoro-indole ~-~ hydrochloride M.p.117-118C
m~p/
' ': ' : : ' :
6a~
].4. l-~N-~Iethyl-N-~3'-dimethylaminopropyl~- -amino]-3-phenyl-5-bromo-indole hydrochloride M.p.152-156C
15. 1-[bis-(2'Die~hylaminoethyl?~-amlno-3-phenyl-indole-di-met~iodide ~amorphous) -16. 1-~is-(3'-Dimethylamlnopropyl~-amino- ~.
3-phenyl-5-&hloro-indole di~ydrochloride M.p. 257C
17. 1-~bIs-(2'-Dimeth.ylaminoeth.yl)~-amino-3-phenyl-5-fluoro-indole dih.ydroch.loride M.p. 240C
18. 1-[~is-(2'-Diethylsminoethyl)]-amino-3-phenyl-5-bromo-indole dihydrochloride M.p. 90-95C
1~. 1-rbis-(2'-Dimethylaminoethyl~]-amino-3-phenyl-5-methyl-indole dihydrochloride M.p. 245-247~C
:~ 20. l-[bis-(2'-DimethylaMinoethyl)]-amino-3-.(p-chIorphenyl~-5-chloro-indole dihydrochloride M.p. 246-250aC:
21. 1-~bis-(2'-Diethylaminoethyl~]-amino~
~ ~ 3-(p-chlorphenyl~-5-chloro-indole ; 20 dihydrochloride semi.hydrate M.p. 24SC
22. 1-~bis-(3'-Dimethylaminopropyl~]~
amino-3-~p-chlorphenyl~-5-chloro-indole dihydrochloride . M.p. 278-27~C
23. l-[bis-(2'-Dimethylaminoethyl~]-amino 3-(p-chlorophenyl)-5-fluoro-indole dihydrochloride M.p. 270-271~C ~;.
24. 1-lbis-(2'-Diethylaminoethyl~]-amino-3-(p chlorphenyl)-5-fluoro-indole ~ :
dihydrochlorlde M.p. 50C
25. 1-¦bis-~3'-Dimethylaminopropyl~]-: amino-3-(.p-chlorphenyl)-5-fluoro-indole - ~ dihydrochloride ~.p. 275C
: :
.
:
,, -11- ' ~, ' mjp/ ~ :
'' ' ' ' ', ' ~; ~ , , ~
: ' ~ :
- : . , ~ ` ~
m~p/
' ': ' : : ' :
6a~
].4. l-~N-~Iethyl-N-~3'-dimethylaminopropyl~- -amino]-3-phenyl-5-bromo-indole hydrochloride M.p.152-156C
15. 1-[bis-(2'Die~hylaminoethyl?~-amlno-3-phenyl-indole-di-met~iodide ~amorphous) -16. 1-~is-(3'-Dimethylamlnopropyl~-amino- ~.
3-phenyl-5-&hloro-indole di~ydrochloride M.p. 257C
17. 1-~bIs-(2'-Dimeth.ylaminoeth.yl)~-amino-3-phenyl-5-fluoro-indole dih.ydroch.loride M.p. 240C
18. 1-[~is-(2'-Diethylsminoethyl)]-amino-3-phenyl-5-bromo-indole dihydrochloride M.p. 90-95C
1~. 1-rbis-(2'-Dimethylaminoethyl~]-amino-3-phenyl-5-methyl-indole dihydrochloride M.p. 245-247~C
:~ 20. l-[bis-(2'-DimethylaMinoethyl)]-amino-3-.(p-chIorphenyl~-5-chloro-indole dihydrochloride M.p. 246-250aC:
21. 1-~bis-(2'-Diethylaminoethyl~]-amino~
~ ~ 3-(p-chlorphenyl~-5-chloro-indole ; 20 dihydrochloride semi.hydrate M.p. 24SC
22. 1-~bis-(3'-Dimethylaminopropyl~]~
amino-3-~p-chlorphenyl~-5-chloro-indole dihydrochloride . M.p. 278-27~C
23. l-[bis-(2'-Dimethylaminoethyl~]-amino 3-(p-chlorophenyl)-5-fluoro-indole dihydrochloride M.p. 270-271~C ~;.
24. 1-lbis-(2'-Diethylaminoethyl~]-amino-3-(p chlorphenyl)-5-fluoro-indole ~ :
dihydrochlorlde M.p. 50C
25. 1-¦bis-~3'-Dimethylaminopropyl~]-: amino-3-(.p-chlorphenyl)-5-fluoro-indole - ~ dihydrochloride ~.p. 275C
: :
.
:
,, -11- ' ~, ' mjp/ ~ :
'' ' ' ' ', ' ~; ~ , , ~
: ' ~ :
- : . , ~ ` ~
Claims (20)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the production of a compound having the general formula:
I
wherein R1 is hydrogen, C1-C3 alkyl or C1-C3 dialkylamino-C2-C5 alkyl;
R2 is C1-C3 dialkylamino-C2-C5 alkyl, C2-C4 alkanoyl, C1-C3 dialkylamino-C2-C4 alkanoyl, aroyl or nicotinoyl;
R3 is hydrogen, C1-C3 alkyl or halogen; and R4 is hydrogen, C1-C3 alkyl, C1-C3 alkoxy or halogen;
which process comprises reacting a compound having the general formula:
II
wherein R3 and R4 have the aforesaid meanings and R is hydrogen, C1-C3 alkyl, C1-C3 dialkylamino-C2-C5 alkyl, C2-C4 alkanoyl, C1-C3 dialkylamino-C2-C4 alkanoyl, aroyl or nicotinoyl with a compound of formula R'X in which R' is substituted C2-C5 alkyl, C2-C4 alkanoyl, substituted C2-C4 alkanoyl, aroyl or nicotinoyl when R is hydrogen or C1-C3 alkyl; R' is C1-C3 alkyl, substituted C2-C4 alkanoyl, aroyl or nicotinoyl when R is C1-C3 dialkylamino-C2-C5 alkyl; and R' is C1-C3 alkyl or substituted C2-C5 alkyl when R is C2-C4 alkanoyl, C1-C3 dialkylamino-C2-C4 alkanoyl, aroyl or nicotinoyl; and X is a radical which is split off in a reaction wherein a N-R' bond is formed and combined with a hydrogen atom split off from the nitrogen atom, said substituted C2-C5 alkyl and C2-C4 alkanoyl groups being C2-C5 alkyl and C2-C4 alkanoyl groups respectively substituted by a C1-C3 dialkylamino group or a group which can be replaced by a tertiary amino group, and when the substituent is an atom or group which can be replaced by a tertiary amino group, substituting it by a C1-C3 dialkylamino group, and isolating the compound obtained as such or as a pharmacologically acceptable salt thereof.
I
wherein R1 is hydrogen, C1-C3 alkyl or C1-C3 dialkylamino-C2-C5 alkyl;
R2 is C1-C3 dialkylamino-C2-C5 alkyl, C2-C4 alkanoyl, C1-C3 dialkylamino-C2-C4 alkanoyl, aroyl or nicotinoyl;
R3 is hydrogen, C1-C3 alkyl or halogen; and R4 is hydrogen, C1-C3 alkyl, C1-C3 alkoxy or halogen;
which process comprises reacting a compound having the general formula:
II
wherein R3 and R4 have the aforesaid meanings and R is hydrogen, C1-C3 alkyl, C1-C3 dialkylamino-C2-C5 alkyl, C2-C4 alkanoyl, C1-C3 dialkylamino-C2-C4 alkanoyl, aroyl or nicotinoyl with a compound of formula R'X in which R' is substituted C2-C5 alkyl, C2-C4 alkanoyl, substituted C2-C4 alkanoyl, aroyl or nicotinoyl when R is hydrogen or C1-C3 alkyl; R' is C1-C3 alkyl, substituted C2-C4 alkanoyl, aroyl or nicotinoyl when R is C1-C3 dialkylamino-C2-C5 alkyl; and R' is C1-C3 alkyl or substituted C2-C5 alkyl when R is C2-C4 alkanoyl, C1-C3 dialkylamino-C2-C4 alkanoyl, aroyl or nicotinoyl; and X is a radical which is split off in a reaction wherein a N-R' bond is formed and combined with a hydrogen atom split off from the nitrogen atom, said substituted C2-C5 alkyl and C2-C4 alkanoyl groups being C2-C5 alkyl and C2-C4 alkanoyl groups respectively substituted by a C1-C3 dialkylamino group or a group which can be replaced by a tertiary amino group, and when the substituent is an atom or group which can be replaced by a tertiary amino group, substituting it by a C1-C3 dialkylamino group, and isolating the compound obtained as such or as a pharmacologically acceptable salt thereof.
2. A process as claimed in Claim 1, wherein R is a methyl group.
3. A process as claimed in Claim 1, wherein the compound obtained is isolated as its hydrochloride or organic sulphonate.
4. A process as claimed in Claim 1, wherein the reactants are so chosen that there is produced the compound 1-[N-methyl-N-(2'-dimethylaminoethyl)amino]-3-phenyl-indole or a pharmaco-logically acceptable salt thereof.
5. A process as claimed in Claim 1, wherein the reactants are so chosen that there is produced the compound 1-[N-methyl-N-(2'-diethylaminoethyl)-amino]-3-phenyl indole or a pharmaco-logically acceptable salt thereof.
6. A process as claimed in Claim 1, wherein the reactants are so chosen that there is produced the compound 1-[N-methyl-N-(2'-dimethylaminoethyl)-amino]-3-(4'-methoxy-phenyl)-indole or a pharmacologically acceptable salt thereof.
7. A process as claimed in Claim 1, wherein the reactants are so chosen that there is produced the compound 1-[N-methyl-N-(3'-dimethylaminopropyl)-amino]-3-phenyl indole or a pharmaco-logically acceptable salt thereof.
8. A process for the preparation of 1-bis-(2'-diethylamino-ethyl)]-amino-3-phenyl indole or a pharmacologically acceptable salt thereof, which comprises reacting 1-amino-3-phenyl indole with 2-diethyl-aminoethyl chloride and isolating the reaction product as such or as a said salt.
9 A process for the preparation of 1-[N-methyl-N-(3'-dimethylamino)-propyl]-amino-3-phenyl indole or a pharmaco-logically acceptable salt thereof, which comprises reacting 3-dimethylaminopropyl chloride with 1-methylamino-3-phenyl indole and isolating the reaction product as such or as a said salt.
10. A process for the preparation of 1-[p-acetamido-benzenesulphonylamino]-3-phenyl indole, which comprises reacting p-acetamidobenzene sulphonylchloride with 1-amino-3-phenyl indole.
11. A process for the preparation of 1-(3'-dimethylamino-propionyl amino)-3-phenyl indole which comprisee reacting .beta.-bromo propionic acid chloride with 1-amino-3-phenyl indole and reacting the 1-(3'-bromopropionylamino)-3-phenyl indole thereby obtained with dimethylamine.
12. A compound having the general formula:
R1, R2, R3 and R4 haying the meanings set out in claim 1, or a pharmacologically acceptable salt thereof, whenever produced by the process of Claim 1 or by an obvious chemical equivalent.
R1, R2, R3 and R4 haying the meanings set out in claim 1, or a pharmacologically acceptable salt thereof, whenever produced by the process of Claim 1 or by an obvious chemical equivalent.
13. 1-[N-methyl-N-(2'-dimethylaminoethyl)amino]-3-phenyl-indole or a pharmacologically acceptable sslt thereof, whenever produced by the process of Claim 4 or by an obvious chemical equivalent.
14. 1-[N-methyl-M-(2'-diethylaminoethyl)-amino]-3-phenyl indole or a pharmacologically acceptable salt thereof whenever produced by the process of Claim 5 or by an obvious chemical equivalent.
15. 1-[N-methyl-N-(2'-dimethylaminaethyl)-amino]-3-(4'-methoxyphenyl) indole or a pharmacologically acceptable salt thereof, whenever produced by the process of Claim 6 or by an obvious chemical equivalent.
16. 1-[N-methyl-N-(3'-dimethylaminopropyl)-amino]-3-phenyl indole or a pharmacologically acceptable salt thereof, whenever produced by the process of Claim 7 or by an obvious chemical equivalent.
17. 1-[Bis-(2'-diethylaminoethyl)]-amino-3-phenylindole or a pharmacologically acceptable salt thereof, wheneyer produced by the process of Claim 8 or by an obvious chemical equivalent.
18. 1-[N-Methyl-N-(3'-dimethylamino)-propyl]-amino-3-phenyl indole or a pharmacologically acceptable salt thereof, whenever produced by the process of Claim 9 or by an obvious chemical equlvalent.
19. 1-[p-Acetamido-benzene sulphonylamino]-3-phenylindole whenever produced by the process of Claim 10 or by an obyious chemical equivalent.
20. 1-[3'-Dimethylaminopropionylamino]-3-phenyl-indole, whenever produced by the process of Claim 11 or by an obvious chemical equivalent.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH439974A CH603581A5 (en) | 1974-03-29 | 1974-03-29 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1054601A true CA1054601A (en) | 1979-05-15 |
Family
ID=4275407
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA223211A Expired CA1054601A (en) | 1974-03-29 | 1975-03-21 | Process for the production of 1-amino-3-phenyl indoles derivatives having antimicrobial and antidepressant properties |
Country Status (15)
| Country | Link |
|---|---|
| JP (1) | JPS6036423B2 (en) |
| AT (1) | AT346840B (en) |
| BE (1) | BE827399A (en) |
| CA (1) | CA1054601A (en) |
| CH (1) | CH603581A5 (en) |
| DE (1) | DE2512702C2 (en) |
| DK (1) | DK133175A (en) |
| ES (1) | ES435944A1 (en) |
| FR (1) | FR2265365B1 (en) |
| GB (1) | GB1502821A (en) |
| IE (1) | IE41223B1 (en) |
| LU (1) | LU72170A1 (en) |
| NL (1) | NL7502722A (en) |
| SE (1) | SE409113B (en) |
| ZA (1) | ZA752001B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1113879B (en) * | 1979-03-15 | 1986-01-27 | Farmatis Spa | ISOINDOLINE DERIVATIVE, PROCESS FOR ITS PREPARATION AND THERAPEUTIC COMPOSITIONS THAT INCLUDE IT AS AN ACTIVE PRINCIPLE |
| DE3022097A1 (en) * | 1980-06-12 | 1981-12-24 | Siegfried AG, Zofingen | 1-AMINO-3-PHENYL INDOLES AND THEIR USE |
| ES2065324T3 (en) * | 1987-04-24 | 1995-02-16 | Hoechst Roussel Pharma | N- (PIRIDINIL) -1H-INDOL-1-AMINES, A PROCEDURE FOR ITS PREPARATION AND USE AS MEDICINES. |
-
1974
- 1974-03-29 CH CH439974A patent/CH603581A5/xx not_active IP Right Cessation
-
1975
- 1975-03-07 NL NL7502722A patent/NL7502722A/en not_active Application Discontinuation
- 1975-03-19 FR FR7508545A patent/FR2265365B1/fr not_active Expired
- 1975-03-21 CA CA223211A patent/CA1054601A/en not_active Expired
- 1975-03-22 DE DE2512702A patent/DE2512702C2/en not_active Expired
- 1975-03-24 ES ES435944A patent/ES435944A1/en not_active Expired
- 1975-03-25 AT AT226975A patent/AT346840B/en not_active IP Right Cessation
- 1975-03-26 GB GB12785/75A patent/GB1502821A/en not_active Expired
- 1975-03-26 SE SE7503533-7A patent/SE409113B/en not_active IP Right Cessation
- 1975-03-26 DK DK133175A patent/DK133175A/da not_active Application Discontinuation
- 1975-03-27 IE IE695/75A patent/IE41223B1/en unknown
- 1975-03-28 JP JP50037014A patent/JPS6036423B2/en not_active Expired
- 1975-03-28 LU LU72170A patent/LU72170A1/xx unknown
- 1975-03-28 BE BE154965A patent/BE827399A/en not_active IP Right Cessation
- 1975-04-01 ZA ZA00752001A patent/ZA752001B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| GB1502821A (en) | 1978-03-01 |
| DE2512702A1 (en) | 1975-10-09 |
| JPS50130758A (en) | 1975-10-16 |
| FR2265365A1 (en) | 1975-10-24 |
| CH603581A5 (en) | 1978-08-31 |
| SE7503533L (en) | 1975-09-30 |
| IE41223B1 (en) | 1979-11-21 |
| IE41223L (en) | 1975-09-29 |
| AT346840B (en) | 1978-11-27 |
| FR2265365B1 (en) | 1978-07-28 |
| SE409113B (en) | 1979-07-30 |
| BE827399A (en) | 1975-09-29 |
| NL7502722A (en) | 1975-10-01 |
| JPS6036423B2 (en) | 1985-08-20 |
| LU72170A1 (en) | 1976-02-04 |
| ES435944A1 (en) | 1976-12-16 |
| ZA752001B (en) | 1976-02-25 |
| DE2512702C2 (en) | 1982-09-23 |
| ATA226975A (en) | 1978-04-15 |
| DK133175A (en) | 1975-09-30 |
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