CA1041505A - Trifluoromethylated-phenyl-aminopropane compounds - Google Patents
Trifluoromethylated-phenyl-aminopropane compoundsInfo
- Publication number
- CA1041505A CA1041505A CA193,534A CA193534A CA1041505A CA 1041505 A CA1041505 A CA 1041505A CA 193534 A CA193534 A CA 193534A CA 1041505 A CA1041505 A CA 1041505A
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- Canada
- Prior art keywords
- acid addition
- trifluoromethylphenyl
- addition salts
- toxic acid
- aminopropane
- Prior art date
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
- C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
ABSTRACT
The present invention is concerned with novel trifluoromethylated-phenyl aminopropanes, processes for the production thereof and pharmaceutical compositions having a content of same as active constituent. The compounds have desirable anorectic properties and show little or no central nervous system stimulation.
The present invention is concerned with novel trifluoromethylated-phenyl aminopropanes, processes for the production thereof and pharmaceutical compositions having a content of same as active constituent. The compounds have desirable anorectic properties and show little or no central nervous system stimulation.
Description
6.30.5537 ~`~r~
This invention relates generally to new organic compounds possessing significant pharmacolo~ical activity and to processes for preparing such compounds. In particular, this ~nvention is concerned with novel trifluoromethylated-phenyl-aminopropane derivatives.
Certain trifluoromethylated-phenyl-aminopropane compounds are known in the art. For instance, United States patent specification No. 3,198,833 describes a broad class of such compounds having the formula:
CF ~ CH2- CH- CH3 \ / I -----.-(I) ~ - / NH
R
wherein R is a lower alkyl group containing from 1 to 5 carbon atoms. In the specification, the compounds of the foregoing formula I are said to be useful pharmaceutically in that they exhibit anoroctic and/or sedative activity.
Probably the best known of such compounds at the present tlme 18 1-(3'-trifluoromethylphenyl)-2-ethylaminopropane, commonly known as fenfluramine, which is useful pharmaceuti-I cally as an appetite inhibitor that may be employed in the treatmont of obe~ity. In this role, the fenfluramine typlcally in the form of the hydrochloride salt, is associated in pharmaceutical compositions with pharmaceuti-cally acceptable organic or inorganic solid or liquid diluents or carriers. It has been recognized (cf. British patent No. 1,182,557) that such compounds, in addition to the desired anorectic properties, tend to have central nervous system stimulating and pressor activity which is :~, ~' - ~041SU5 undesirable when patients are treated for obesity.
It is, accordingly, an o~ject of the present invention to provide novel trifluoromethylated-phenyl-aminopropane compounds which possess the desirable anorectic properties but show little or no central nervous stimulation, as evidenced by standard pharmacological evaluation, for example, by animal tests.
According to the invention therefore, in one of its aspects, there are provided, as new compounds, trifluoromethylated-phenyl-amir.opropanes of the general formula:
CF3 ~ c~ -C~ -CK3 - R - N - Alk- X ............ (II) .- ~ '' . ' and the acid addition salts thereof, wherein R represents ~
a hydrogen atom or a lower alkyl group, Alk represents a -lower alkylene group and X represent9 substituted or un-substituted amino group.
The terms "lower alkyl" and "lower alkylene" as employed herein, connote both straight and branched chain radicals containing not more than 6 carbon atoms.
In the above compound~ wherein R represents a lower alkyl group, this group may, for example, be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl or tertiary butyl.
The divalent lower alkylene group,represented by the symbol Alk in the compounds of Formula II, is a saturated aliphatic hydrocarbon rad~cal derived from a straight or branched-chain hydrocarbon residue such as, for example, ethylene, propylene, butylene, trimethylene, ~-, . .
lO'~ 9~
tetra~ethyl~ne or l-metil;~lethylcne. ~uch al~ylen~ groups may include substitutes.
The symbol X is defined as being a primary, secondary or tertiary amino group of the following general designations:
it will be noted that some of the general designations are further explained by reference to specific compounds falling within the scope of the designation which are not to be construed as being limited to such specific compounds.
The symbol X is therefore defined as an unsubstituted amino(-NH 2 ); ( lower alkyl)-amino; di-(lower alkyl)-aminoi (lower alkenyl)-amino; di-(lower alkenyl)-amino; phenylamino;
(hydroxy-lower alkyl)-amino; di-(hydroxy lower-alkyl)-amino;
(amino-lower alkyl)-amino; di-(amino-lower alkyl)-amino heterocyclic groups of less than 12 carbon atoms as exemplified by piperidino; (lower alkyl)-piperidino, e.g. 2-,3-, or 4-(lower alkyl)-piperidino; di-(lower alkyl)-piperidino;
(lower alkoxy)-piperidino; pyrrolidino; (lower alkyl)-pyrrolidino; di-(lower alkyl)-pyrrolidino; (lower alkoxy)-pyrrolidino; morpholino; (lower alkyl)-morpholino; di-(lower alkyl)-morpholino; (lower alkoxy)-morpholino; thiomorpholino;
(lower alkyl)-thiomorpholino; di-(lower alkyl)-thiomorpholino;
piperazino; (lower alkyl)-piperazino (e.g. C or N- methyl piperazino); di-C-(lower alkyl)-piperazino; (lower alkoxy)-piperazino and (lower carbalkoxy)-piperazino and R3-(lower alkyl)-amino wherein R3 is a 5- or 6- membered heterocyclic ring containing nitrogen, oxygen or sulphur and 0-2 ethylenic double bonds.
One pharmaceutically preferred group of compounds in view of their favorable utility are compounds of the general formula: .
. ~ CH2-CH-CH3 NH ~ ..................... (IIA) CF3 ~CH2)n-N~
and acid addition salts thereof, wherein R~ and R2 individually repre~nt a methvl, an ethyl, a ~ro~yl or an isopropyl group or, taken together with the nitrogen atom to .: ~
10415(~S
which they are attached, together represent a 5- or 6-membered ~-heterocyclic rin~ such as, for example, morpholino, piperidino, pyrrolidino, piperazino or N-methyl-piperazino and n is 1, 2, 3 or 4.
Another pharmaceutically preferred group of compounds, again in view of their favorable utility, are compounds of the general formula:
~C~ CII-C~13 NH
~ - I ..... (IIb ) CF3 (CH2)n -NH-(CH2)m~ R3 and acid addition salts thereof, wherein R3 represents a 5- or 6- member heterocyclic ring containing an atom selected from the group nitrogen, oxygen or sulfur and up to 2 ethylenic double bonds, and n and m, which may be the same or different, are 1, 2, 3 or 4.
; With regard to the acid-addition salts, when the compounds are to be used as intermediates for preparing other compounds or for any othèr non-pharmaceutical use, the toxicity or non-toxicity of the salt is usually immaterial.
When the compounds are to be used as pharmaceuticals, they are most conveniently used in the form of water-soluble, non-toxic, acid-addition salts. Both toxic and non-toxic ~ salts are, therefore, within the purview of this invention.
The acids which can be used to prepare the preferred non-toxic, acid-addition salts are those which produce, when combined with the free bases, salts whose anions are 30 relatively innocuous to the animal organism in therapeutic :,..
.
: . - . ' . ' ~ ' : ~ -- - --:: -- , . ~.
. . .~ , , - .
1041~0S
doses of the salts, so that the beneficial physiological properties inherent in the free bases are not vitiated by side-effects ascribable to the anions. Appropriate acid-addition salts are those derived from mineral acids such as, for example, hydrochloric acid, hydrobromic acid, hydriodic acid, nitric acid, boric acid and phosphoric acid; and organic acids such as, for example, acetic acid, tartaric acid, citric acid, succinic acid, lactic acid and maleic acid.
The compounds of this invention can be prepared by a variety of processes, some of which are further described hereinafter. In the Formulae III to VIII, Alk and X have the same significance as in Formula II.
Process A
By subjecting an imine or Schiff's base of the formula:
, . .
CF ~ CH2-C - CH3 N- Alk -X ................ (III) wherein X has the same significance as defined with reference to Formula II above to reduction by known methods.
For example, reduction may be effected with a hydride, ~-preferably with a complex metal hydride such as sodium borohydride or lithium aluminum hydride. This reduction - can be carried out at room temperature or at temperatures ; below room temperature or with the application of heat, deyending upon the particular reagents employed. For instance, using sodium borohydride, it is preferably carried out by heating the reaction mixture under reflux ~- -conditions. The reduction is preferably carried out in an organic solvent such as, for example, methanol, etnanol, dioxan or tetrahydrofuran.
' .~ , . .
.
1(~41~0~
~rl~e term "known" as applied to the reduction and alkyla~i r~actions in this specification and appended claims refer~
to methods presently or heretofore in actual use and/or described in the literature on the subject.
Process B
-By subjecting an imine or Schiff's base of the Formula III to a catalytic hydrogenation, preferably with a nickel, platinum or palladium catalyst.
The imine or Schiff's base starting compounds of Formula III for Processes A and B may themselves be prepared by known methods such a~ by reacting a phenyl-acetone compound of the formula:
CF3 ~
CH2 C CH3 ..... (IV) :' with a diamine of the formula:
X- Alk -NHz ..... (V) ,~ wherein X has the same significance as defined with reference to Formula II above. Advantageously, the reaction is effected in a lower alkanol solvent preferably at tne reflux temperature thereof.
The resulting Schiff's ba8e need not be isolated from the reaction mixture prior to use in the reduction reactions of processes A and B.
Process C
By reacting a phenyl-2-halo-alkane of the formula:
CF, ~ CN~_ CH_ C3~
Y .................................................... (VI) .
~04lsas wherein Y represents a halogen atom, preferably a chlorine or bromine atom with an amine of Formula V above wherein all but one of the amino hydrogen atoms are preferably replaced by a protective group such as, for example, benzyl and and toluene-sulfonyl, ~hiCh is.~eadily remoYed by reduction or hydrolysis subsequent to th~ reaction.
Process D
By subjecting a phenylacetone of the Formula IV to catalytic hydrogenation, preferably using a nickel, platinum or palladium catalyst, in the presence of a diamine of the Formula V.
Process E
By subjecting a phenylacetone of the Formula IV to reductive amination with a hydride, preferably using a complex metal hydride such as sodium borohydride, in the presence of a diamine of the Formula V.
Process F
.
By reacting a phenylacetone of the Formula IV with a diamine of Formula V in the presence of a formic acid, obtained, say, by using formic acid itself, or a formic acid salt or a formyl compound of the diamine of Formula V.
The phenylacetone compounds of Formula IV may themselves be prepared according to conventional methods, such as by oxidizing a l-phenyl-2-propanol into the corresponding ketone CF~_ CU2--CHOH--CH3 ~ ~3CI:2--CO--Cl:3 ~ ~
3~ . :
- 7 _ :
- . '` ' , ' ~ ~ . ~ .
.: : , .,' : ` .
1041~S
~r~cess C
By subjecting an oxime of the formula:
CH2- C -CH3 ..... (VII) NOH
to catalytic reduction, preferably with a nickel or cobalt catalyst, followed by reaction of the primary amine so-obtained with a halide of the general formula:
Hal- Alk -X ............... (VIII) wherein Hal represents a halogen atom, preferably in the presence of an acid-binding agent.
Process H
By subjecting an oxime of the Formula VII to reduction with a hydride, preferably with a complex metal hydride such as sodium borohydride or lithium aluminum hydride, followed by reaction of the primary amine so-obtained with a halide of the general formula:
Hal- Alk- X ............... (YIII) wherein ~al represents a halogen atom, preferably in the presence of an acid-binding agent.
The oximes of Formula VII used as starting materials in Processes G and H may themselves be prepared by known methods, conveniently by reacting a phenylacetone of Formula IV with hydroxylamine. ~ -As a modification to the above processes A to H, when compounds of the formula Il wherein R represents a lower alkyl group are desired, the above processes are modified to include a step wherein the appropriate R substituent is introduced into the molecule by known alkylation procedures.
This may be conveniently achieved by the following procedures with particular reference to Process A described above.
In Process A, the alkyl group R can be introduced by alkylation of the Schiff's base to form a quaternary ammonium compound which can then be reduced by known methods to yield the desired tertiary amine. Alternatively, the Schiff's base can be reduced as described above, and the reduced compound subjected to an alkylation reaction to introduce the substituent R. The choice of alkylating agent required to introduce a selected group R to form the desired product will be apparent to one skilled in the art.
Representative new compounds and processes for their preparation are illustrated more fully by the following examples which are not to be construed as limiting the ' invention since many modifications in materials and procedures will be readily apparent to those skilled in the art. In these examples, the melting point data was obtained by the capillary tube method, and all temperatures are in degrees centigrade.
~xample l Part A
1-(3'-Trifluoromethylphenyl)-2--(N,N-dimethylaminopr'opyl)- ' .
a~ nopropane ~ ,.
A solution comprising 1 g. (0.005 mole) of m-trifluoro- -methylphenylacetone and 0.51 g. (0.005 mole) of N,~-dimethyl-; 1,3-propane diamine in 10 ml. of ethanol was heated under reflux for 3 hours. After cooling, 0.19 g. (0.005 mole) of sodium borohydride was slowly added to the solution containing the Schiff's base [1-(3'-trifluoromethylphenyl)-
This invention relates generally to new organic compounds possessing significant pharmacolo~ical activity and to processes for preparing such compounds. In particular, this ~nvention is concerned with novel trifluoromethylated-phenyl-aminopropane derivatives.
Certain trifluoromethylated-phenyl-aminopropane compounds are known in the art. For instance, United States patent specification No. 3,198,833 describes a broad class of such compounds having the formula:
CF ~ CH2- CH- CH3 \ / I -----.-(I) ~ - / NH
R
wherein R is a lower alkyl group containing from 1 to 5 carbon atoms. In the specification, the compounds of the foregoing formula I are said to be useful pharmaceutically in that they exhibit anoroctic and/or sedative activity.
Probably the best known of such compounds at the present tlme 18 1-(3'-trifluoromethylphenyl)-2-ethylaminopropane, commonly known as fenfluramine, which is useful pharmaceuti-I cally as an appetite inhibitor that may be employed in the treatmont of obe~ity. In this role, the fenfluramine typlcally in the form of the hydrochloride salt, is associated in pharmaceutical compositions with pharmaceuti-cally acceptable organic or inorganic solid or liquid diluents or carriers. It has been recognized (cf. British patent No. 1,182,557) that such compounds, in addition to the desired anorectic properties, tend to have central nervous system stimulating and pressor activity which is :~, ~' - ~041SU5 undesirable when patients are treated for obesity.
It is, accordingly, an o~ject of the present invention to provide novel trifluoromethylated-phenyl-aminopropane compounds which possess the desirable anorectic properties but show little or no central nervous stimulation, as evidenced by standard pharmacological evaluation, for example, by animal tests.
According to the invention therefore, in one of its aspects, there are provided, as new compounds, trifluoromethylated-phenyl-amir.opropanes of the general formula:
CF3 ~ c~ -C~ -CK3 - R - N - Alk- X ............ (II) .- ~ '' . ' and the acid addition salts thereof, wherein R represents ~
a hydrogen atom or a lower alkyl group, Alk represents a -lower alkylene group and X represent9 substituted or un-substituted amino group.
The terms "lower alkyl" and "lower alkylene" as employed herein, connote both straight and branched chain radicals containing not more than 6 carbon atoms.
In the above compound~ wherein R represents a lower alkyl group, this group may, for example, be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl or tertiary butyl.
The divalent lower alkylene group,represented by the symbol Alk in the compounds of Formula II, is a saturated aliphatic hydrocarbon rad~cal derived from a straight or branched-chain hydrocarbon residue such as, for example, ethylene, propylene, butylene, trimethylene, ~-, . .
lO'~ 9~
tetra~ethyl~ne or l-metil;~lethylcne. ~uch al~ylen~ groups may include substitutes.
The symbol X is defined as being a primary, secondary or tertiary amino group of the following general designations:
it will be noted that some of the general designations are further explained by reference to specific compounds falling within the scope of the designation which are not to be construed as being limited to such specific compounds.
The symbol X is therefore defined as an unsubstituted amino(-NH 2 ); ( lower alkyl)-amino; di-(lower alkyl)-aminoi (lower alkenyl)-amino; di-(lower alkenyl)-amino; phenylamino;
(hydroxy-lower alkyl)-amino; di-(hydroxy lower-alkyl)-amino;
(amino-lower alkyl)-amino; di-(amino-lower alkyl)-amino heterocyclic groups of less than 12 carbon atoms as exemplified by piperidino; (lower alkyl)-piperidino, e.g. 2-,3-, or 4-(lower alkyl)-piperidino; di-(lower alkyl)-piperidino;
(lower alkoxy)-piperidino; pyrrolidino; (lower alkyl)-pyrrolidino; di-(lower alkyl)-pyrrolidino; (lower alkoxy)-pyrrolidino; morpholino; (lower alkyl)-morpholino; di-(lower alkyl)-morpholino; (lower alkoxy)-morpholino; thiomorpholino;
(lower alkyl)-thiomorpholino; di-(lower alkyl)-thiomorpholino;
piperazino; (lower alkyl)-piperazino (e.g. C or N- methyl piperazino); di-C-(lower alkyl)-piperazino; (lower alkoxy)-piperazino and (lower carbalkoxy)-piperazino and R3-(lower alkyl)-amino wherein R3 is a 5- or 6- membered heterocyclic ring containing nitrogen, oxygen or sulphur and 0-2 ethylenic double bonds.
One pharmaceutically preferred group of compounds in view of their favorable utility are compounds of the general formula: .
. ~ CH2-CH-CH3 NH ~ ..................... (IIA) CF3 ~CH2)n-N~
and acid addition salts thereof, wherein R~ and R2 individually repre~nt a methvl, an ethyl, a ~ro~yl or an isopropyl group or, taken together with the nitrogen atom to .: ~
10415(~S
which they are attached, together represent a 5- or 6-membered ~-heterocyclic rin~ such as, for example, morpholino, piperidino, pyrrolidino, piperazino or N-methyl-piperazino and n is 1, 2, 3 or 4.
Another pharmaceutically preferred group of compounds, again in view of their favorable utility, are compounds of the general formula:
~C~ CII-C~13 NH
~ - I ..... (IIb ) CF3 (CH2)n -NH-(CH2)m~ R3 and acid addition salts thereof, wherein R3 represents a 5- or 6- member heterocyclic ring containing an atom selected from the group nitrogen, oxygen or sulfur and up to 2 ethylenic double bonds, and n and m, which may be the same or different, are 1, 2, 3 or 4.
; With regard to the acid-addition salts, when the compounds are to be used as intermediates for preparing other compounds or for any othèr non-pharmaceutical use, the toxicity or non-toxicity of the salt is usually immaterial.
When the compounds are to be used as pharmaceuticals, they are most conveniently used in the form of water-soluble, non-toxic, acid-addition salts. Both toxic and non-toxic ~ salts are, therefore, within the purview of this invention.
The acids which can be used to prepare the preferred non-toxic, acid-addition salts are those which produce, when combined with the free bases, salts whose anions are 30 relatively innocuous to the animal organism in therapeutic :,..
.
: . - . ' . ' ~ ' : ~ -- - --:: -- , . ~.
. . .~ , , - .
1041~0S
doses of the salts, so that the beneficial physiological properties inherent in the free bases are not vitiated by side-effects ascribable to the anions. Appropriate acid-addition salts are those derived from mineral acids such as, for example, hydrochloric acid, hydrobromic acid, hydriodic acid, nitric acid, boric acid and phosphoric acid; and organic acids such as, for example, acetic acid, tartaric acid, citric acid, succinic acid, lactic acid and maleic acid.
The compounds of this invention can be prepared by a variety of processes, some of which are further described hereinafter. In the Formulae III to VIII, Alk and X have the same significance as in Formula II.
Process A
By subjecting an imine or Schiff's base of the formula:
, . .
CF ~ CH2-C - CH3 N- Alk -X ................ (III) wherein X has the same significance as defined with reference to Formula II above to reduction by known methods.
For example, reduction may be effected with a hydride, ~-preferably with a complex metal hydride such as sodium borohydride or lithium aluminum hydride. This reduction - can be carried out at room temperature or at temperatures ; below room temperature or with the application of heat, deyending upon the particular reagents employed. For instance, using sodium borohydride, it is preferably carried out by heating the reaction mixture under reflux ~- -conditions. The reduction is preferably carried out in an organic solvent such as, for example, methanol, etnanol, dioxan or tetrahydrofuran.
' .~ , . .
.
1(~41~0~
~rl~e term "known" as applied to the reduction and alkyla~i r~actions in this specification and appended claims refer~
to methods presently or heretofore in actual use and/or described in the literature on the subject.
Process B
-By subjecting an imine or Schiff's base of the Formula III to a catalytic hydrogenation, preferably with a nickel, platinum or palladium catalyst.
The imine or Schiff's base starting compounds of Formula III for Processes A and B may themselves be prepared by known methods such a~ by reacting a phenyl-acetone compound of the formula:
CF3 ~
CH2 C CH3 ..... (IV) :' with a diamine of the formula:
X- Alk -NHz ..... (V) ,~ wherein X has the same significance as defined with reference to Formula II above. Advantageously, the reaction is effected in a lower alkanol solvent preferably at tne reflux temperature thereof.
The resulting Schiff's ba8e need not be isolated from the reaction mixture prior to use in the reduction reactions of processes A and B.
Process C
By reacting a phenyl-2-halo-alkane of the formula:
CF, ~ CN~_ CH_ C3~
Y .................................................... (VI) .
~04lsas wherein Y represents a halogen atom, preferably a chlorine or bromine atom with an amine of Formula V above wherein all but one of the amino hydrogen atoms are preferably replaced by a protective group such as, for example, benzyl and and toluene-sulfonyl, ~hiCh is.~eadily remoYed by reduction or hydrolysis subsequent to th~ reaction.
Process D
By subjecting a phenylacetone of the Formula IV to catalytic hydrogenation, preferably using a nickel, platinum or palladium catalyst, in the presence of a diamine of the Formula V.
Process E
By subjecting a phenylacetone of the Formula IV to reductive amination with a hydride, preferably using a complex metal hydride such as sodium borohydride, in the presence of a diamine of the Formula V.
Process F
.
By reacting a phenylacetone of the Formula IV with a diamine of Formula V in the presence of a formic acid, obtained, say, by using formic acid itself, or a formic acid salt or a formyl compound of the diamine of Formula V.
The phenylacetone compounds of Formula IV may themselves be prepared according to conventional methods, such as by oxidizing a l-phenyl-2-propanol into the corresponding ketone CF~_ CU2--CHOH--CH3 ~ ~3CI:2--CO--Cl:3 ~ ~
3~ . :
- 7 _ :
- . '` ' , ' ~ ~ . ~ .
.: : , .,' : ` .
1041~S
~r~cess C
By subjecting an oxime of the formula:
CH2- C -CH3 ..... (VII) NOH
to catalytic reduction, preferably with a nickel or cobalt catalyst, followed by reaction of the primary amine so-obtained with a halide of the general formula:
Hal- Alk -X ............... (VIII) wherein Hal represents a halogen atom, preferably in the presence of an acid-binding agent.
Process H
By subjecting an oxime of the Formula VII to reduction with a hydride, preferably with a complex metal hydride such as sodium borohydride or lithium aluminum hydride, followed by reaction of the primary amine so-obtained with a halide of the general formula:
Hal- Alk- X ............... (YIII) wherein ~al represents a halogen atom, preferably in the presence of an acid-binding agent.
The oximes of Formula VII used as starting materials in Processes G and H may themselves be prepared by known methods, conveniently by reacting a phenylacetone of Formula IV with hydroxylamine. ~ -As a modification to the above processes A to H, when compounds of the formula Il wherein R represents a lower alkyl group are desired, the above processes are modified to include a step wherein the appropriate R substituent is introduced into the molecule by known alkylation procedures.
This may be conveniently achieved by the following procedures with particular reference to Process A described above.
In Process A, the alkyl group R can be introduced by alkylation of the Schiff's base to form a quaternary ammonium compound which can then be reduced by known methods to yield the desired tertiary amine. Alternatively, the Schiff's base can be reduced as described above, and the reduced compound subjected to an alkylation reaction to introduce the substituent R. The choice of alkylating agent required to introduce a selected group R to form the desired product will be apparent to one skilled in the art.
Representative new compounds and processes for their preparation are illustrated more fully by the following examples which are not to be construed as limiting the ' invention since many modifications in materials and procedures will be readily apparent to those skilled in the art. In these examples, the melting point data was obtained by the capillary tube method, and all temperatures are in degrees centigrade.
~xample l Part A
1-(3'-Trifluoromethylphenyl)-2--(N,N-dimethylaminopr'opyl)- ' .
a~ nopropane ~ ,.
A solution comprising 1 g. (0.005 mole) of m-trifluoro- -methylphenylacetone and 0.51 g. (0.005 mole) of N,~-dimethyl-; 1,3-propane diamine in 10 ml. of ethanol was heated under reflux for 3 hours. After cooling, 0.19 g. (0.005 mole) of sodium borohydride was slowly added to the solution containing the Schiff's base [1-(3'-trifluoromethylphenyl)-
2-(N,N-dimethylaminopropylimino)-propane] and the resultant suspension stirred at ambient temperature for 1 hour and, .' ' .
_ g _ , .. ; : , - . : :
sodium borohydride was slowly added and the resultant suspension stirred at ambient temperature for 1 hour and, thereafter, heated under reflux for 3 hours. Dilute hydro-chloric acid was added slowly to the cooled solution until an acidic pH was obtained, whereupon the ethanol was distilled off under reduced pressure. The aqueous residue was extracted with ether, basi~ied with 20% aqueous sodium hydroxide solution and then extracted twice with methylene chloride. The extracts were washed with water, dried and evaporated to give the desired product, 1-(3'-trifluoro-methylphenyl)-2-(N,N-dimethylaminopropyl)-aminopropane, in the form of a pale yellow oil.
~ Part B
- 1-(3'-Trifluoromethylphenyl)-2-(N,N-dimethylaminopropyl)-minoproPane dihydrochloride monohydra*e The free base of Part A was trans~ormed into the dihydrochloride monohydrate salt by treatment with methanolic hydrogen chloride followed by addition of acetone to precipitate the salt. The salt, in good yield and in the form of a ~; while crystalline solid, was isolated by filtration. An analysis sample was recrystallized from acetone/methanol.
Melting point: 208 to 212C.
Elementary analysis:
C(%) H(%) Cl(%) N(%) Calculated 47.50 7.18 18.69 7.39 C~sH23F3N22HCl. H20 Found 47.32 6.88 18.53 7.64 Solubility: Very soluble in water, ethanol, dimethylsulfoxide and propylene glycol.
:
10415(~5 Example 2 Part A
1-(3'-Trifluoromethylphenyl)-2-(N,N-dimethylaminoethyl)-aminopropane This free base was obtained following essentially the same procedure as set forth in Part A of Example 1 by reacting together m-trifluoromethylphenylacetone and N,N- .
dimethyl-1,2-ethylenediamine.
Part B
1-(3'-Trifluoromethylphenyl)-2-(N,N-dimethylaminoethyl~-aminopropane dihydrochloride The free base obtained in Part A was converted into the corresponding dihydrochloride salt following essentially the same procedure as set forth in Part ~ of Example 1. An analysis sample was recrystallized from acetone/methanol.
Melting point: 224 to 226.
Elementary analysis:
C(%) H(%) C1~%) N(%) Calculated 48.42 6.68 20.42 8.Q7 Cl4H2lF3N22HCl ~ound 48.21 6.90 20.13 8.30 Solubility: Very soluble in water, ethanol, dimethylsulfoxide and propylene glycol.
Example- 3 Part A
1-(3'-Trifluoromethylphenyl)-2-(N-morpholinoethyl)-Aminopropane.
.. .
The free base was obtained following essentially the same procedure as set forth in Part A of Example 1 by reacting together m-trifluormethylphenylacetone and N-(2-aminoethyl~-- J morpholine.
.
- : - , ~:
. , , :
- - , . . - ' --Part B
1-(3'-Trifluoromethylphenyl)-2-(N-morpholinoethyl)-aminopropane dihydrochloride.
The free base obtained in Part A was converted into the corresponding dihydrochloride salt following essentially the same procedure as set forth in Part B of Example 1. An analysis sample was recrystallized from acetone/methanol.
Melting point: 222 to 225.
Elementary analysis:
C(%) H(~) Cl(~) N(%) Calculated 49.36 6.47 18.22 7.20 Cl 6H2 3F3N20.2HCl Found 48.98 6.27 18.56 7.52 Solubility: Very soluble in water, dimethylsulfoxide and - propylene glycol; soluble in ethanol.
Example 4 Part A
, 1-~3'-Trifluoromethylphenyl)-2-(N-piperidinoethyl)-aminopropane The free base was obtained following essentially the same procedure as set forth in Part A of Example 1 by reacting together m-trifluoromethylphenylacetone and N-(2-aminoethyl)-piperidine.
Part B
1-(3'-Trifluoromethylphenyl)-2-(N-piperidinoethyl)-aminopropane dihydrochloride.
The free base obtained in Part A was converted into the - corresponding dihydrochloride salt following essentially the - same procedure as set forth in Part B of Example 1. An -G analysis sample was recrystallized from acetone~methanol.
. ~ .
Melting point: 238 to 242.
Elementary analysis:
C(%) H(%) Cl(~) N(%) Calculated 52.71 7.03 18.31 7.23 . .
Cl7H2sF3N2.2HCl Found 52.52 7.04 17.96 7.52 Solubility: Very soluble in water, dimethylsulfoxide and propylene glycol, soluble in ethanol.
Example 5 -~ 10 Part A
1-(3'-Trifluoromethylphenyl)-2-(4"-methylpiperazinopropyl)-aminopropane ; The free base was obtained following essentially the same procedure as set forth in Part A of Example 1 by reacting together m-trifluoromethylphenylacetone and N-methyl-N'-(3-aminopropyl)-piperazine.
Part B
1-(3'-~rifluoromethylphenyl)-2-(4"-methylpiperazino~ropyl) aminopropane trihydrochloride The free base obtained in Part A was converted into the corresponding trihydrochloride salt following essentially the same procedure as set forth in Part B of Example 1.
An analysis sample was xecr~stallized from methanol.
: Melting point: 297 to 305 (decomposition) .
Elementary analysis:
C(%) H(%) Cl(%) N(%) Calculated 47.74 6.90 23.49 9.28 ~ .
C~aH2aF3N3.3HCl Found 47.49 7.12 23.35 9.49 : :
_O
' , .
' :
. - .
~041505 Solubility: Very soluble in water and propylene glycol;
slightly soluble in dimethylsulfoxide; and insoluble in ethanol.
Example 6 Part A
1-(3'-Trifluoromethylphenyl)-2-(N,N-diethylaminoethyl)--aminopropane The free base was obtained following essentially the same procedure as set forth in Part A of Example 1 by reacting together m-trifluoromethylphenylacetone and N,N-diethyl-ethylenediamine.
Part B
.
1-(3'-Trifluoromethylphenyl)-2-(N,N-diethylaminoethyl)-aminOprOpane dihydrochloride monohydrate The free base obtained in Part A was converted into the corresponding dihydrochloride salt following essentially the same procedure as set forth in Part B of Example 1. An analysis sample was recrystallized from acetone/isopropanol.
Melting point: 126 to 131.
Elementary analysis:
C(%) H(%) Cl(%) N(%) Calculated 48.85 7.43 18.03 7.12 C18H2sF9N2.2HCl.H20 Found 48.60 7.65 17.87 7.50 Solubility: Very soluble in water, ethanol, dimethyl sulfoxide and propylene glycol.
- Example 7 1-(3'-Trifluoromethylphenyl)-2-(l"-ethyl-2"-pyrrolidinomethyl) aminopropane The free base was obtained following essentially the same procedure as set forth in Part A of Example 1 by reacting together m-trifluoromethylphenylacetone and l-eth~l-2-aminomethylpyrrolidine.
Part B
1-(3'-Trifluoromethylphenyl~-2-(1"-ethvl-2"-pyrrolldinomethyl)-dminopropane dihydrochloride The free base obtained in Part A was converted into thecorresponding dihydrochloridemonohydrate salt following e~sentially the same procedure as set forth in Part B of Example 1.
An analysis sample was recrystallized from acetone/methanol.
Melting point:
Elementary analysis:
- C(%~ H(%) N(~) - Calculated 50.37 7.21 6.91 C 1 7H2 sF3N 2 2HCl.H20 Found 50.26 7.31 7.02 ':
. . - .
, .
As indicated hereinbefore, it has been found in accordance with this invention that the novel compounds of the formula II and salts thereof have interesting pharmacological properties. More particularly, such compounds when subjected . - , - - : . . ', :
.
1()4i~ 5 to standaxd pharmacologica~ evalu~tion,for example, by animal tests, exhibit marked anorexigenic activity coupled with very low central nervous system stimulating activity.
Compounds acting in this way may be expected to be of use for curbing the appetites of warm-blooded animals.
Accordingly, this invention further provides in another of its aspects a pharmaceutical composition comprising as an essential active ingredient at least one active compound of the Formula II or an acid addition salt thereof in association with a pharmaceutically acceptable carrier therefor.
The compositions of the present invention are preferably administered either orally or rectally.
Advantageously, the composition is in a dosage unit form appropriate to the desired mode of administration. For example, the dosage unit may be a tablet, capsule, pill, powder, packet, granule, wafer, elixir, suppository, or a measured quantity of a suspension, solution, a syrup or segregated multiples of the foregoing. The term "dosage unit form" as used herein refers to physically discrete units suitable as unitary dosages for human subjects and animals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in admixture, or otherwise ln association, with a pharmaceutical carrier therefor, the quantity of the active ingredient being such that one or more units are normally required for a single therapeutic administration or that, in the case of severable units such as scored tablets, at least one fraction such as a half or a quarter of a severable unit is required for a single thera~eutic administration.
Advantageously, the compositions of this invention - lG -contain the active ingredient in an ~mount of at least 0.5~
and not more than 95~ by weight based on the total weight of the composition. Conveniently, the compositions of the invention when in dosage unit form contain 0.5 mg. to 1000 mg., and more conveniently from 5 mg. to 250 mg., of the active ingredient of formula I.
The compositions of the present invention will normally consist of at least one compound of formula I, typically in the form of an acid addition, say, hydrochloride or maleate salt thereof admixed with a carrier, or diluted by a carrier, or enclosed or encapsulated by a carrier in the form of a capsule, sachet, catchet, paper or other container. A carrier which ser~es as a vehicle, excipient or diluent medium for the therapeutically active ingredient may be a solid, semi-solid or a sterile liquid.
Some examples of the carriers which may be employed in the pharmaceutical compositions of the invention are lactose, dextrose, sorbitol, mannitol, starches such as wheat, corn, , , . -or potato starch, gum acacia, calcium phosphate, liquid paraffin, cocoa butter, oil of theobroma, alginates, tragacanth, gelatin, syrup B.P., methyl cellulose, polyoxethylene sorbitan monolaurate, methyl and propyl hydroxybenzoateS, sterile pyrogen-free water and substantially isotonic saline solution. The choice of carrier is determined by the preferred form of administration~ the solubility of the compound and standard pharmaceutical practice. In the case of tablets a lubricant may be incorporated to prevent sticking and binding of the powdered ingredients in the dies and on the punch of the tabletting machine. For such purpose, there may be employed, for example, talc, aluminum, : . , 1~141SOS
magnesium or calcium stereates or polyethylene glycols (Carbowaxes) of suitable molecular weight.
The pharmaceutical compositions of this invention may contain, in addition to the active ingredient of the general Formula II,one or more other pharmacologically active ingredients which elicit desirable complementary effects.
Two examples of suitable pharmaceutical compositions according to this invention are presented below for the purpose of facilitating a better understanding of this aspect of the invention.
Example A
For oral administration, sugar coated tablets of the following composition were prepared following standard pharmaceutical practice.
Formulation:
Ingredient Content (gms.) 1-(3'-Trifluoromethylphenyl)-2-(4"-methylpiperazinopropyl)-aminOpropane trihydrochloride ............................ 25 Lactose .................................................. 60 Sugar .................................................... 75 Talc ...................................................... 5 Magnesium stearate ........................................ 5 Example B
Hard gelatin capsules were made following standard pharmaceutical practice from a mixture of the following ingredients:
Formulation:
Ingredient Content (gms.) 1-(3'-Trifluoromethylphenyl~-2-(N-morpholinoethyl)-aminopropane dihydrochloride ................. ,........... 100 1~415(JS
Calcium ph~sphate ~,,,.,,.,.,~..,.,,,.,.,..,,..,..,,.... 20 In the foregoing Examples A and B, the active ingredient specified may be wholly ox partly replaced by another pharmacologically active compound of the invention.
The novel method of the invention for curbing appetites in warm blooded animals comprises administering to the animals an anorexigenically effective amount of at least one compound of the ~rmula II and their non-toxic pharmaceutically acceptable acid addition salts. The usual effective dose of said compounds is between about 0.01 to ~-5 mg./kg of body weight of the warm-blooded animals.
While in the foregoing specification various embodiments of this invention have been ~et forth and specific details elaborated upon for the purpose of illustration, it will be apparent to those skilled in the art that this invention is susceptible to other embodiments and that many of the details - may be varied widely without departing from the spirit and scope of the invention as defined in the appended claim~.
:
- ~ . ...
_ g _ , .. ; : , - . : :
sodium borohydride was slowly added and the resultant suspension stirred at ambient temperature for 1 hour and, thereafter, heated under reflux for 3 hours. Dilute hydro-chloric acid was added slowly to the cooled solution until an acidic pH was obtained, whereupon the ethanol was distilled off under reduced pressure. The aqueous residue was extracted with ether, basi~ied with 20% aqueous sodium hydroxide solution and then extracted twice with methylene chloride. The extracts were washed with water, dried and evaporated to give the desired product, 1-(3'-trifluoro-methylphenyl)-2-(N,N-dimethylaminopropyl)-aminopropane, in the form of a pale yellow oil.
~ Part B
- 1-(3'-Trifluoromethylphenyl)-2-(N,N-dimethylaminopropyl)-minoproPane dihydrochloride monohydra*e The free base of Part A was trans~ormed into the dihydrochloride monohydrate salt by treatment with methanolic hydrogen chloride followed by addition of acetone to precipitate the salt. The salt, in good yield and in the form of a ~; while crystalline solid, was isolated by filtration. An analysis sample was recrystallized from acetone/methanol.
Melting point: 208 to 212C.
Elementary analysis:
C(%) H(%) Cl(%) N(%) Calculated 47.50 7.18 18.69 7.39 C~sH23F3N22HCl. H20 Found 47.32 6.88 18.53 7.64 Solubility: Very soluble in water, ethanol, dimethylsulfoxide and propylene glycol.
:
10415(~5 Example 2 Part A
1-(3'-Trifluoromethylphenyl)-2-(N,N-dimethylaminoethyl)-aminopropane This free base was obtained following essentially the same procedure as set forth in Part A of Example 1 by reacting together m-trifluoromethylphenylacetone and N,N- .
dimethyl-1,2-ethylenediamine.
Part B
1-(3'-Trifluoromethylphenyl)-2-(N,N-dimethylaminoethyl~-aminopropane dihydrochloride The free base obtained in Part A was converted into the corresponding dihydrochloride salt following essentially the same procedure as set forth in Part ~ of Example 1. An analysis sample was recrystallized from acetone/methanol.
Melting point: 224 to 226.
Elementary analysis:
C(%) H(%) C1~%) N(%) Calculated 48.42 6.68 20.42 8.Q7 Cl4H2lF3N22HCl ~ound 48.21 6.90 20.13 8.30 Solubility: Very soluble in water, ethanol, dimethylsulfoxide and propylene glycol.
Example- 3 Part A
1-(3'-Trifluoromethylphenyl)-2-(N-morpholinoethyl)-Aminopropane.
.. .
The free base was obtained following essentially the same procedure as set forth in Part A of Example 1 by reacting together m-trifluormethylphenylacetone and N-(2-aminoethyl~-- J morpholine.
.
- : - , ~:
. , , :
- - , . . - ' --Part B
1-(3'-Trifluoromethylphenyl)-2-(N-morpholinoethyl)-aminopropane dihydrochloride.
The free base obtained in Part A was converted into the corresponding dihydrochloride salt following essentially the same procedure as set forth in Part B of Example 1. An analysis sample was recrystallized from acetone/methanol.
Melting point: 222 to 225.
Elementary analysis:
C(%) H(~) Cl(~) N(%) Calculated 49.36 6.47 18.22 7.20 Cl 6H2 3F3N20.2HCl Found 48.98 6.27 18.56 7.52 Solubility: Very soluble in water, dimethylsulfoxide and - propylene glycol; soluble in ethanol.
Example 4 Part A
, 1-~3'-Trifluoromethylphenyl)-2-(N-piperidinoethyl)-aminopropane The free base was obtained following essentially the same procedure as set forth in Part A of Example 1 by reacting together m-trifluoromethylphenylacetone and N-(2-aminoethyl)-piperidine.
Part B
1-(3'-Trifluoromethylphenyl)-2-(N-piperidinoethyl)-aminopropane dihydrochloride.
The free base obtained in Part A was converted into the - corresponding dihydrochloride salt following essentially the - same procedure as set forth in Part B of Example 1. An -G analysis sample was recrystallized from acetone~methanol.
. ~ .
Melting point: 238 to 242.
Elementary analysis:
C(%) H(%) Cl(~) N(%) Calculated 52.71 7.03 18.31 7.23 . .
Cl7H2sF3N2.2HCl Found 52.52 7.04 17.96 7.52 Solubility: Very soluble in water, dimethylsulfoxide and propylene glycol, soluble in ethanol.
Example 5 -~ 10 Part A
1-(3'-Trifluoromethylphenyl)-2-(4"-methylpiperazinopropyl)-aminopropane ; The free base was obtained following essentially the same procedure as set forth in Part A of Example 1 by reacting together m-trifluoromethylphenylacetone and N-methyl-N'-(3-aminopropyl)-piperazine.
Part B
1-(3'-~rifluoromethylphenyl)-2-(4"-methylpiperazino~ropyl) aminopropane trihydrochloride The free base obtained in Part A was converted into the corresponding trihydrochloride salt following essentially the same procedure as set forth in Part B of Example 1.
An analysis sample was xecr~stallized from methanol.
: Melting point: 297 to 305 (decomposition) .
Elementary analysis:
C(%) H(%) Cl(%) N(%) Calculated 47.74 6.90 23.49 9.28 ~ .
C~aH2aF3N3.3HCl Found 47.49 7.12 23.35 9.49 : :
_O
' , .
' :
. - .
~041505 Solubility: Very soluble in water and propylene glycol;
slightly soluble in dimethylsulfoxide; and insoluble in ethanol.
Example 6 Part A
1-(3'-Trifluoromethylphenyl)-2-(N,N-diethylaminoethyl)--aminopropane The free base was obtained following essentially the same procedure as set forth in Part A of Example 1 by reacting together m-trifluoromethylphenylacetone and N,N-diethyl-ethylenediamine.
Part B
.
1-(3'-Trifluoromethylphenyl)-2-(N,N-diethylaminoethyl)-aminOprOpane dihydrochloride monohydrate The free base obtained in Part A was converted into the corresponding dihydrochloride salt following essentially the same procedure as set forth in Part B of Example 1. An analysis sample was recrystallized from acetone/isopropanol.
Melting point: 126 to 131.
Elementary analysis:
C(%) H(%) Cl(%) N(%) Calculated 48.85 7.43 18.03 7.12 C18H2sF9N2.2HCl.H20 Found 48.60 7.65 17.87 7.50 Solubility: Very soluble in water, ethanol, dimethyl sulfoxide and propylene glycol.
- Example 7 1-(3'-Trifluoromethylphenyl)-2-(l"-ethyl-2"-pyrrolidinomethyl) aminopropane The free base was obtained following essentially the same procedure as set forth in Part A of Example 1 by reacting together m-trifluoromethylphenylacetone and l-eth~l-2-aminomethylpyrrolidine.
Part B
1-(3'-Trifluoromethylphenyl~-2-(1"-ethvl-2"-pyrrolldinomethyl)-dminopropane dihydrochloride The free base obtained in Part A was converted into thecorresponding dihydrochloridemonohydrate salt following e~sentially the same procedure as set forth in Part B of Example 1.
An analysis sample was recrystallized from acetone/methanol.
Melting point:
Elementary analysis:
- C(%~ H(%) N(~) - Calculated 50.37 7.21 6.91 C 1 7H2 sF3N 2 2HCl.H20 Found 50.26 7.31 7.02 ':
. . - .
, .
As indicated hereinbefore, it has been found in accordance with this invention that the novel compounds of the formula II and salts thereof have interesting pharmacological properties. More particularly, such compounds when subjected . - , - - : . . ', :
.
1()4i~ 5 to standaxd pharmacologica~ evalu~tion,for example, by animal tests, exhibit marked anorexigenic activity coupled with very low central nervous system stimulating activity.
Compounds acting in this way may be expected to be of use for curbing the appetites of warm-blooded animals.
Accordingly, this invention further provides in another of its aspects a pharmaceutical composition comprising as an essential active ingredient at least one active compound of the Formula II or an acid addition salt thereof in association with a pharmaceutically acceptable carrier therefor.
The compositions of the present invention are preferably administered either orally or rectally.
Advantageously, the composition is in a dosage unit form appropriate to the desired mode of administration. For example, the dosage unit may be a tablet, capsule, pill, powder, packet, granule, wafer, elixir, suppository, or a measured quantity of a suspension, solution, a syrup or segregated multiples of the foregoing. The term "dosage unit form" as used herein refers to physically discrete units suitable as unitary dosages for human subjects and animals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in admixture, or otherwise ln association, with a pharmaceutical carrier therefor, the quantity of the active ingredient being such that one or more units are normally required for a single therapeutic administration or that, in the case of severable units such as scored tablets, at least one fraction such as a half or a quarter of a severable unit is required for a single thera~eutic administration.
Advantageously, the compositions of this invention - lG -contain the active ingredient in an ~mount of at least 0.5~
and not more than 95~ by weight based on the total weight of the composition. Conveniently, the compositions of the invention when in dosage unit form contain 0.5 mg. to 1000 mg., and more conveniently from 5 mg. to 250 mg., of the active ingredient of formula I.
The compositions of the present invention will normally consist of at least one compound of formula I, typically in the form of an acid addition, say, hydrochloride or maleate salt thereof admixed with a carrier, or diluted by a carrier, or enclosed or encapsulated by a carrier in the form of a capsule, sachet, catchet, paper or other container. A carrier which ser~es as a vehicle, excipient or diluent medium for the therapeutically active ingredient may be a solid, semi-solid or a sterile liquid.
Some examples of the carriers which may be employed in the pharmaceutical compositions of the invention are lactose, dextrose, sorbitol, mannitol, starches such as wheat, corn, , , . -or potato starch, gum acacia, calcium phosphate, liquid paraffin, cocoa butter, oil of theobroma, alginates, tragacanth, gelatin, syrup B.P., methyl cellulose, polyoxethylene sorbitan monolaurate, methyl and propyl hydroxybenzoateS, sterile pyrogen-free water and substantially isotonic saline solution. The choice of carrier is determined by the preferred form of administration~ the solubility of the compound and standard pharmaceutical practice. In the case of tablets a lubricant may be incorporated to prevent sticking and binding of the powdered ingredients in the dies and on the punch of the tabletting machine. For such purpose, there may be employed, for example, talc, aluminum, : . , 1~141SOS
magnesium or calcium stereates or polyethylene glycols (Carbowaxes) of suitable molecular weight.
The pharmaceutical compositions of this invention may contain, in addition to the active ingredient of the general Formula II,one or more other pharmacologically active ingredients which elicit desirable complementary effects.
Two examples of suitable pharmaceutical compositions according to this invention are presented below for the purpose of facilitating a better understanding of this aspect of the invention.
Example A
For oral administration, sugar coated tablets of the following composition were prepared following standard pharmaceutical practice.
Formulation:
Ingredient Content (gms.) 1-(3'-Trifluoromethylphenyl)-2-(4"-methylpiperazinopropyl)-aminOpropane trihydrochloride ............................ 25 Lactose .................................................. 60 Sugar .................................................... 75 Talc ...................................................... 5 Magnesium stearate ........................................ 5 Example B
Hard gelatin capsules were made following standard pharmaceutical practice from a mixture of the following ingredients:
Formulation:
Ingredient Content (gms.) 1-(3'-Trifluoromethylphenyl~-2-(N-morpholinoethyl)-aminopropane dihydrochloride ................. ,........... 100 1~415(JS
Calcium ph~sphate ~,,,.,,.,.,~..,.,,,.,.,..,,..,..,,.... 20 In the foregoing Examples A and B, the active ingredient specified may be wholly ox partly replaced by another pharmacologically active compound of the invention.
The novel method of the invention for curbing appetites in warm blooded animals comprises administering to the animals an anorexigenically effective amount of at least one compound of the ~rmula II and their non-toxic pharmaceutically acceptable acid addition salts. The usual effective dose of said compounds is between about 0.01 to ~-5 mg./kg of body weight of the warm-blooded animals.
While in the foregoing specification various embodiments of this invention have been ~et forth and specific details elaborated upon for the purpose of illustration, it will be apparent to those skilled in the art that this invention is susceptible to other embodiments and that many of the details - may be varied widely without departing from the spirit and scope of the invention as defined in the appended claim~.
:
- ~ . ...
Claims (22)
1. A process for the preparation of a 1-(trifluoro-methylphenyl)-2-aminopropane compound of the formula II':
......(II') wherein R represents a hydrogen atom, Alk represents a lower alkylene group and, X represents a di-(loweralkyl)amino, morphilino, piperidino, pyrrolidino or a N-methylpiperazino group and non-toxic acid addition salts thereof, comprising reacting a phenylacetone of the formula IV:
...... (IV') with a diamine of the formula V:
H2N-Alk-X ....... (V) wherein Alk and X are as defined above, and reducing the so-obtained Schiff's base of the formula III':
......(III') wherein Alk and X are as defined above, and, when necessary or desired, converting the so-formed free base into a non-toxic acid addition salt thereof.
......(II') wherein R represents a hydrogen atom, Alk represents a lower alkylene group and, X represents a di-(loweralkyl)amino, morphilino, piperidino, pyrrolidino or a N-methylpiperazino group and non-toxic acid addition salts thereof, comprising reacting a phenylacetone of the formula IV:
...... (IV') with a diamine of the formula V:
H2N-Alk-X ....... (V) wherein Alk and X are as defined above, and reducing the so-obtained Schiff's base of the formula III':
......(III') wherein Alk and X are as defined above, and, when necessary or desired, converting the so-formed free base into a non-toxic acid addition salt thereof.
2. A process for preparing a compound of the formula:
......(IIa') wherein n is an integer from the group 1, 2, 3 and 4, R1 and R2, taken individually each represents a hydrogen atom or a lower alkyl group, and when taken with the nitrogen atom to which they are attached, together represent morpholino, piperidino, pyrrolidino or N-methylpiperazino and non-toxic acid addition salts therof which comprises reacting a phenylacetone of the formula IV':
......(IV') with a diamine of the formula:
......( Va) wherein n, R1 and R2 have the same significance as defined above, and reducing the so-obtained Schiff's base of the formula.
......(IIIa') wherein n, R1 and R2 have the same significance as defined above and, when necessary or desired, converting the free base of the formula IIa' into a non-toxic acid addition salt.
......(IIa') wherein n is an integer from the group 1, 2, 3 and 4, R1 and R2, taken individually each represents a hydrogen atom or a lower alkyl group, and when taken with the nitrogen atom to which they are attached, together represent morpholino, piperidino, pyrrolidino or N-methylpiperazino and non-toxic acid addition salts therof which comprises reacting a phenylacetone of the formula IV':
......(IV') with a diamine of the formula:
......( Va) wherein n, R1 and R2 have the same significance as defined above, and reducing the so-obtained Schiff's base of the formula.
......(IIIa') wherein n, R1 and R2 have the same significance as defined above and, when necessary or desired, converting the free base of the formula IIa' into a non-toxic acid addition salt.
3. A process as claimed in Claim 1 wherein the reduction is effected by reaction with a metal hydride.
4. A process as claimed in Claim 2 wherein the reduction is effected by reaction with a metal hydride.
5. A process as claimed in Claim 3 or 4 wherein the metal hydride is sodium borohydride or lithium aluminum hydride.
6. A process as claimed in Claims 3 or 4 wherein the reaction is conducted in a lower alkanol solvent and at the reflux temperature thereof.
7. A process as claimed in Claim 1 for the preparation of1-(3'-trifluoromethylphenyl)-2-(N,N-dimethylamino-propyl)-aminopropane and non-toxic acid addition salts thereof which comprises reacting m-trifluoromethyl-phenylacetone and N,N-dimethyl-1,3-propane diamine and reducing the so-obtained 1-(3'-trifluoromethylphenyl)-2-(N,N-diemthylaminopropylimino)- propane with sodium borohydride and, when necessary or desired, converting the free base into non-toxic acid addition salts thereof.
8. A process as claimed in Claim 1 for the preparation of 1-(3'-trifluoromethylphenyl)-2-(N,N-dimethylaminoethyl)-aminopropane and non-toxic acid addition salts thereof which comprises reacting m-trifluoromethylphenylacetone and N,N-dimethylethylene diamine and reducing the so-obtained 1-(3'-trifluoromethylphenyl)-2-(N,N-dimethylaminoehtylimino) propane with sodium borohydride and, when necessary or desired, converting the free base into non-toxic addition salts thereof.
9. A process as claimed in Claim 1 for the preparation of 1-(3'-trifluoromethylphenyl)-2-(N-morpholino-ethyl)-aminopropane and non-toxic acid addition salts thereof which comprises reacting m-trifluoromethyl-phenylacetone and N-(2-aminoethyl)-morpholine and reducing the so-obtained 1-(3'trifluoromethylphenyl)-2-(N-morpholinoethylimino)-propane with sodium borohydride and, when necessary or desired, converting the free base into non-toxic acid addition salts thereof.
10. A process as claimed in Claim 1 for the preparation of 1-(3'-trifluoromethylphenyl)-2-(N-piperidinoethyl)-aminopropane and non-toxic acid addition salts thereof which comprises reacting m-trifluoromethylphenylacetone and N-(2-aminoethyl)piperidine and reducing the so-obtained 1-(3'-trifluoromethylphenyl)-2-(N-piperidino-ethylimino)- propane with sodium borohydride and, when necessary or desired, converting the free base into non-toxic acid addition salts thereof.
11. A process as claimed in Claim 1 for the preparation of 1-(3'-trifluoromethylphenyl)-2-(4"-methyl-piperazinopropyl)-aminopropane and non-toxic acid addition salts thereof which comprises reacting m-trifluoromethylphenylacetone and N-methyl-N'-(3-amino-propyl)-piperazine and reducing the so-obtained 1-(3'-trifluoromethylphenyl)-2-(4"-methylpiperazino-propylimino)-propane with sodium horohydride and, when necessary or desired, converting the free base into non-toxic acid addition salts thereof.
12. A process as claimed in Claim 1 for the preparation of 1-(3'-trifluoromethylphenyl)-2-(N,N-diethylaminoethyl)-aminopropane and non-toxic acid addition salts thereof which comprises reacting m-trifluoromethylphenylacetone and N,N-diethylethylene diamine and reducing the so-obtained 1-(3'-triofluoromethylphenyl)-2-(N,N-diethyl-aminoethylimino)-propane with sodium borohydride and, when necessary or desired, converting the free base into non-toxic acid addition salts thereof.
13. A process as claimed in Claim 1 for the preparation of 1-(3'-trifluoromethylphenyl)-2-(1"-ethyl-2"-pyrrolidino-methyl)-aminopropane and non-toxic acid addition salts thereof which comprises reacting m-trifluoromethylphenyl-acetone and 1-ethyl-2-aminomethylpyrrolidine and reducing the so-obtained 1-(3'-trifluoromethylphenyl)-2-(1"-ethyl-2"-pyrrolidinomethylimino)-propane with sodium borohydride and, when necessary or desired, converting the free base into non-toxic acid addition salts thereof.
14. A 1-(trifluoromethylphenyl)-2-aminopropane compound of the formula:
...... (II') wherein R represents a hydrogen atom , Alk represents a lower alkylene group, and X represents a di-(loweralkyl)amino, morpholino, piperidino, pyrrolidino or a N-methylpiperazino group and non-toxic acid addition salts thereof whenever prepared by a process as claimed in Claim 1 or an obvious chemical equivalent thereof.
...... (II') wherein R represents a hydrogen atom , Alk represents a lower alkylene group, and X represents a di-(loweralkyl)amino, morpholino, piperidino, pyrrolidino or a N-methylpiperazino group and non-toxic acid addition salts thereof whenever prepared by a process as claimed in Claim 1 or an obvious chemical equivalent thereof.
15. A compound of the formula:
...... (II') wherein n represents an integer from the group 1, 2, 3 and 4, and R1 and R2, taken individually each represents a hydrogen atom or a lower alkyl group, and taken with the nitrogen atom to which they are attached together represent morpholino, piperidino, pyrrolidino or N-methylpiperazino and non-toxic acid addition salts thereof whenever prepared by a process as claimed in Claim 2 or any obvious chemical equivalent thereof.
...... (II') wherein n represents an integer from the group 1, 2, 3 and 4, and R1 and R2, taken individually each represents a hydrogen atom or a lower alkyl group, and taken with the nitrogen atom to which they are attached together represent morpholino, piperidino, pyrrolidino or N-methylpiperazino and non-toxic acid addition salts thereof whenever prepared by a process as claimed in Claim 2 or any obvious chemical equivalent thereof.
16. 1-(3'-Trifluoromethylphenyl)-2-(N,N-dimethylamino-propyl)-aminopropane and non-toxic acid addition salts thereof whenever prepared by a process as claimed in Claim 7 or any obvious chemical equivalent thereof.
17. 1-(3'-Trifluoromethylphenyl)-2-(N,N-dimethylamino-ethyl)-aminopropane and non-toxic acid addition salts thereof whenever prepared by a process as claimed in Claim 8 or any obvious chemical equivalent thereof.
18. 1-(3'-Trifluoromethylphenyl)-2-(N-morpholinoethyl)-aminopropane and non-toxic acid addition salts thereof whenever prepared by a process as claimed in Claim 9 or any obvious chemical equivalent thereof.
19. 1-(3'-Trifluoromethylphenyl)-2-(N-piperidinoethyl)-aminopropane and non-toxic acid addition salts thereof whenever prepared by a process as claimed in Claim 10, or any obvious chemical equivalent thereof.
20. 1-(3'-Trifluoromethylphenyl)-2-(N,N-diethylamino-ethyl)-aminopropane and non-toxic acid addition salts thereof whenever prepared by a process as claimed in Claim 12 or any obvious chemical equivalent thereof.
21. 1-(3'-Trifluoromethylphenyl)-2-(4"-methylpiperazino-propyl)-aminopropane and non-toxic acid addition salts thereof whenever prepared by a process as claimed in Claim 11 or any obvious chemical equivalent thereof.
22. 1-(3'-Trifluoromethylphenyl)-2-(1"ethyl-2"-pyrrolidinomethyl)-aminopropane and non-toxic acid addition salts thereof whenever prepared by a process as claimed in Claim 13, or any obvious chemical equivalent thereof.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB924173A GB1414223A (en) | 1973-02-26 | 1973-02-26 | Trifluoromethylated phenyl aminopropane compounds |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1041505A true CA1041505A (en) | 1978-10-31 |
Family
ID=9868149
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA193,534A Expired CA1041505A (en) | 1973-02-26 | 1974-02-26 | Trifluoromethylated-phenyl-aminopropane compounds |
Country Status (2)
| Country | Link |
|---|---|
| CA (1) | CA1041505A (en) |
| GB (1) | GB1414223A (en) |
-
1973
- 1973-02-26 GB GB924173A patent/GB1414223A/en not_active Expired
-
1974
- 1974-02-26 CA CA193,534A patent/CA1041505A/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| GB1414223A (en) | 1975-11-19 |
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