Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
~.069~Z3
The present invention concerns the manufacture of
- new l-(aralkoxyphenyl)-2 or 3-(bis-arylalkylamino~-alkanes
of the general formula I
CnH2n~l Ar~ ~ r3
1 mH2m Ph-(CH2)r~CH-NH-CpH2 -C-Rl (I)
wherein each of Arl, ~r2 and Ar3 is unsubstituted phenyl or
phenyl substituted by one or more than one member of lower
alkyl, lower alkoxy, halogeno, trifluoromethyl, nitro, amino,
mono-lower alkylamino or di-lower alkylamino, lower alkanoyl-
amino, cyano, carbogy, carbo-lower alkoxy, carbamoyl, amino-
methyl, mono-lower alkylaminomethyl or di-lower alkylamino-
methyl, Ph is unsubstituted phenylene or phenylene substitutedby one member listed for Arl, n is an integer from O to 4,
each of m and p is an integer from 1 to 4, r is the in~eger
1 or 2 and Rl is hydrog~n or hydroxy, or salts thereof.
- Of the phenyl radicals Arl is preferably phenyl
substituted by up to five, advantageously one or two mem~ers - `
of ~he group consisting of lower alkyl, e.g. methyl, ethyl,
n- or i-propyl or -butyl; lower alkoxy, e.~. methoxy, ethoxy,
n- or i-propoxy or -butoxy; halogeno, e.g. ~luoro, chloro or
bromo; trifluoromethyl; nitro; amino; mono- or ~i-lower
alkylamino, e.g. mono- or dimethylamino, mono- or diethyl~
amino; lower alkanoylamino, e.g. acetylamino, propionylamino
` - 2 ~
, . . . .
` ', . `, ' ' '.: 1.. ." .. ' ; ` " .~' , ., ~, ., .,. ` ,. ",1 ," , ... .
~06~9;23
or pivaloylamino; cyano; carboxy; carbo- lower alkoxy, e.g.
carbomethoxy or carbethoxy; carbamoyl; aminomethyl; mono-
or di-lower alkylaminomethyl, eOg. mono- or dimethylamino-
met~yl. Each of Ar2 and Ar3 is preferably unsubstituted phenyl,
or phenyl substituted by one member of the group listed for
Arl .
The term "lower", referred to above or herein-
after in conneGtion with organic radicals or compounds
respectively, defines such with up to 4, preferably up to
3, advantageously such with one or two carbon atoms.
The phenylene radical Ph is preferably unsubstituted
1,4-phenylene, but also 1,2- or 1,3-phenylene, or such
phenylene substi~uted by one member of lower alkyl, lower
alkoxy, halogeno or trifluoromethyl, e.g. those listed for
Arl; and Rl is preferably hydrogen, but also hydroxy.
The lower alkyl group CnH2n+l preferably represents
methyl, but also any other member mentioned above. The lower
alkylene group CmH2m preferably stands for (CH2)m, especially
methylene, but also for 1,1- or 1,2-ethylene, 1~1-, 2,2 , 1,2-
or 1,3-propylene or -butylene; and CpH2p preferably represents
~CH2)p, especially 1,2-ethylene, but also any other of said
alkylene groups.
Salts of the compounds of Formula I are preferably
therapeutically acceptable acid addition salts, e.g. those
derived from the acids listed below.
-- 3 --
.
:. . - . , : , .: . . : . :: , ., , : , . ~
, , : .. :: . , , , : : : :, .. ..
,. :- : .. ,: . . . :
. . , : .::
~C~6~23
The compounds of the invention exhibit valuable
pharmacological properties, primarily hypotensive, anti-
hypertensive and bradycardic activity. This is demonstrable
in animal tests, using advantageous'ly mammals, e~g. rats,
c~ts or monkeys, as test objects. The animals may either be
normotensive or hypertensive, e.gl genetically or adrenal
regeneration hypertensive rats. Said compounds can be applied
to them enterally or parenterally, advantageously orally, or
subcutaneously, intraveneously, intraperitoneally or intra-
duodenally, for example within gelatin capsules or in the
form of starchy suspensions or aqueous solutions respectively.
The applied dosage may range between about 0.1 and 100 mg/kg/
day, preferably between a'bout 1 and 50 mg/kg/day, advantageous-
ly between about 5 and 25 mg/kg/clay. The lowering effect on the
blood pressure is recorded either directly by means of a
catheter, for example placed in the rat's caudal artery, or
indirectly by sphygmomanometry at the ra~'s tail, and a
transducer, expressing the blood pressure prior and after
dosing in mm Hg~ Thus, for example, the d~2 ~ 4-(4-chloro-
benæyloxy~-phenyl~-2-~3,3-diphenylpropylamino)-propane, a '~
representative member of the compounds of the invention,
advantageously in the form of i~s hydrochloride, or preferably
the levorotatory antipode thereof, are very effective in said
hypertensive rats at p,o. doses as low or lower than 5 mg/kg/
day and maxima'lly about 24 hours after dosing. Antihyperten-
sive doses cause only minor impairment of sympathetic nerve
,. . . .
.: .; ,; . .. . . ., . : . .. .. . . ~ . . ,
~ ~69~;~3
function, unlike antihypertensive agents which act by
adrenergic neuron blockade, as assessed by pressor responses
to electrical stimulation of the spinal cord of pithed rats~
Said member also differs from certain centrally acting
antihypertensive agents which cause sedation. Moreover~ said
d,~ -hydrochloride does not cause brain catecholamine-
depletion, unlike said centrally acting agents, although it
does cause depletion in peripheral tissues, such as the heart.
Furthermore, it does not produce sedation in monkeys at
hypotensive doses, as does ~-methyldopa. Accordingly, the
compounds of the invention are useful antihypertensive and
bradycardic agents, for example in the treatment or
management of primary or secondary hypertension, or angina
pectoris respectively~ They are also useful intermediates in
the preparation of other valuable products, especially of
pharmacologically active compositionsO
Partieularly useful are compounds of the general
Formula I, in which each of Arl, Ar2 and Ar3 is phenyl, (lower
alkyl)x-phenyl, (lower alkoxy)x-phenyl), (halogeno)x-phenyl or
(trifluoromethyl)-phenyl, Ph is 1,3- or 1,4-phenylene, (lower
àlkyl)-1,3- or 1,4-phenylene, (lower alkoxy) 1,3- or 1,4-
phenylene, (halogeno)-1,3- or 1,4-phenylene or (trifluoro-
methyl)-1,3 or 1,4-phenylene, n is an integer from 1 to 4,
each of m and p is an integer from 1 to 4, x is an integer from
1 to 5, r is the integer 1 or 2 and Rl is hydrogen or hydroxy,
-- 5 --
.. . .. . .. ...... . .. ... . ..
~ 9 2 ~
or a therapeutically useful acid addition salts thereof.
Outstanding compounds of the invention are those
of the general Formula II
R 1"~2n~1 ~ R'
)m- ~ -C~2 CH <
(II) NH ~ (CH~)p-~ ~ C
wherein each o R ~nd R' is hydrogen, methyl, me~hoxy, fluoro,
chlsro~ bromo or trifluoromethyl, each of m, n and p is the
integer 1 or 2, snd Rl is hydrogen or hydroxy~ or therapeuti-
c~lly useful acid addition sal~s thereof.
More preferred are those compounds of the gener~
Formula II, wherein in Rl, m, n and E~ have the meaning given
in the preceding paragraph, R is chloro and R' is hydrogen~
or therapeutically useful acid addit~on salts thereof,
Most pre~erred are the compounds of the general
Formula II, wherein R is chloro, advantageously in the
meta- or para-positi~n~ Rl and R' are hydrogen, each of m
and n is ~he integer 1 and p the integer 2, or therapeutically
useful acid addition salts thereof.
The compounds of the invention are prepared according
to methods known per se, by:
1) reducing a compound of the general formula III
ICnH2~1 0 A~2 ~r3
Ar~ mH~m--Ph- (~H2) r~-CH_N~ C-Cp---lH2p-2 ;~
6 --
,,,,r~
, i ~ i
~,? j~
. ~
~6~6~3;23
The reduction of the amides III is performed
according to known methods, advantageously with simple or
complex light metal hydrides, such as boranes or aluminium
hydride, preferably alkali metal boron or aluminium hydrides,
e.g. lithium aluminium hydride, sodium borohydride or lithium
or sodium tri-lower alkoxy or bis-alkoxyalkoxy-aluminium
hydrides, such as lithium ~ri-t.butoxy- or sodium bis-(2-
methoxy-ethoxy~-aluminium hydride.
The starting material can be prepared according to
methods known per se, for example, the starting materials of
the formula III are obtained from the corresponding phenolates,
such as alkali metal, e.g. sodium or potassium salts, of the
phenols HO-Ph-(C~2~ ~CH(CnH2n~l)~N~ CO Cp_l 2p-2 2 3
and reactive esters of the alcohols Arl-CmH2m-OH, e.g. such
der~ved from a strong inorganic or organic acid, preferably
a hydrohalic, e.g. hydrochlorlc, -bromic or -iodic acld, or
an alkane or benzene sulfonic acid, e.g. methane, p-toluene
or m-bromobenzene sulfonlc acid. Also amines Arl-CmH2m~0-Ph-
~cH2)r-cH-tcnH2n~ NH2 can be reacted with reactive,
functional derivatives of the acides HOOC-Cp lH2p 2-CRl(Ar2Ar3),
- e.g. halides or anhydrides thereof. The former amines or
ph~nols are either known or can be obtained by condensing
compounds of formula HO-Ph-(CH2)r-CH(CnH2n~l~ 2
alcohol or acid derivativ~ respectively, in subsequent steps.
Another method for preparing the compounds of the
general formula I consists in:
2) reducing a compound of formula IV
_ 7 _
, ~..
~,oG~923
~n 2n~1-s A~2 Ar3
Arl-C H2m q~-Ph~(CH2)r ~(Hl-u) [ p 2p-v 1 ~IV)
wherein one o q, s and v is the integer 2 and the others
O or 2, u is 0, and Z is free NH, or Z is N, u is 1, v is O
or 2 and the other integers have the meaning given above,
or Z is N, u is 0, v is 1 or 3 and the other integers have
the meaning glven above.
For compounds in which ~1 is hydrogen, the desired
compounds are prepared by reduclng olefines or Schiff's bases
f formula IVa
n~Zn+l~s Ar2
Ar -C H2 ~~Ph-(cH2)r-~(ul-u)zlclJtl~p~l-v Ar3
wherein one of q, s and v is the integer 2 and the others
O or 2, u is O and Z is free NH, or Z is N, u is 1, v is O
or 2 and the other integers have the meaning given above,
or Z is N, u is o, v is 1 or 3 and the other integers have
the meaning given above.
.
The reduction of the starting materials of the
formulae IV and IVa is carried out accordi~g to known methods,
for example with the use of hydrogen in the presence of
catalysts, e.g. platinum or nickel catalysts, or with nascent
hydrogen, e.g. generated electrolytically, which is advanta-
-- 8 --
. . , , . : : ,. :, : .: , " ; : .
.
9;~:3
geously applied to the Schiff's bases IV and IVa. They canalso be reduced with the reducing agents mentioned under item
1), preferably with simple light metal hydrides, e.g. boranes.
The olefine starting materials IV and IVa are
obtalned analogous to the carbonyl compounds III, by choosing
the abo~e condensations with the corresponding unsaturated
- ~ 7 ~-~
: / '
".i/ `
,,/'
~'',' '~
;~ :
,
,....... .
/
~ ' .
,~ 7
~ .
,: ': ' . ' ', . :; ::, ,. :; ~ .. '.. , :' ' . ' " ' ' ';., :' :; : : i;:
- ' ,' :: '- ' , ' ,: .:,, '.'. : :,. ,; '':".. ' .`"'~ "'' ': ' '
~L~6~ 3
compounds~ i~e~ reactive esters of the alcohol Arl-Cm H2m q~~
or derivatives of the acid HOOC[Cp lH2p 2 ~]C~lAr2Ar3 or
preparing IV, or derivatives of the acid HOOC[Cp H2p 1 v]Ar2
Ar3 for preparing IVa, and reducing in any resulting amide
the carbonyl group with said reducing agents rnentioned under
item 1), preferably with complex light metal hydrides, e.g.
lithium aluminium hydride~ The Schiff's bases of the formula
IV are obtained from the correspondi.ng free or protected
(CH2)r CHN~2~CnX2n~l_S by condensation ~ith the
[ p_lH2p_2_v]C~lAr2Ar3, followed by a reactive
ester o~ an alcohol Ar C H OH.
1 m 2m-q
Schif's bases IV are also obtained rom the corres
ponding free or protected ketones HO-Ph-(C~12)r-CO-CnH2n~l s
by condensation with an amine H2N[CpH2p v3CRl~r2Ar3 followed
by a reactive ester of an alcohol ArlCmH2m_qOH.
The Schiff's bases I~a are obtained from the free or
protected amines HO-Ph-(CH2)r-CHN~I2 CnH2n+l_s Y
with the aldehyde OHC-~CpH2p 1 v]Ar2Ar3, followed by a reactive
ester of an alcohol Arl-CmH2m q~OH~ Schiff's bases IVa are
also obtained from the corresponding free or protected ketones
Ph (C~12)r-CO-cnH2n~l_s by condensation with an amine
H2N-[Cp~lX2p~l v]Ar2Ar3, followed by a reactive ester of
an alcohol Arl-CmH2m_q~H
Another method for preparing the compounds of the
general ~ormula I consists in:
- 10 -
.~ .
. , . , .. , . ~ .. . .. ,, . . , . . " . ... ~ .. ... .
.
~6~23
3~ condensing a compound of th~ general formula V and a
compound VI
Arl C~2~ T and U-GpH2p-CRl~Ar2Ar3)
(V~ ~VI)
or reactive salts thereof, whereinl if T is the group
2 ~ (CnH2n~l)NH2, U is reactive esterified OH
or, if T ls a reactive estexified OH, U represents the yroup
o~ the ormula HO-Pho~CH2)r-CH(C~H2n~l)NH, and~ i~ desired,
converting any xesulting compound into another compound
of the lnve~ion, an~or, if desired, convertlng a resulting
free compound into a ~alt or a resulting ~alt into the free
compound or into another salt, and/or, if desired, resolving
a mixture of isomers or racemates obtained into the single
isomers or racemates, and~or if desi.red, resolving a racemate
obtained into the optical antipodes.
A reactive esterified hydroxy group is for example
derived from a strong inorganic or organic acid, preferably
a hydrohylic, e.g, hydrochloric-, -bromic or -~odic acld, or
an alkane or ben~ene sulfonic acid, e.g. methane, p-toluene
or m-bromobenzene sul~onic aoid.
The condensatlon o~ the starting materlals V and V
is preferably carried out with ~he use of reactive salts of
the phenols or amines respectively, such as alkali metal, e.g.
sodium or potassium salts, or in the presence of condensing
agents, neutrallzing the eliminated acids, such as inorganic
or organic (nitrogen) bases, e.g. alkall or alkalina earth
metal carbonates or hydrogencarbonates; trl-lower alkylamines
or pyrldines.
The starting materials V and VI are ~imilarly ~~
. . ..
. .
.:: . -, .:
, . .
:
~6~9Z3
prepared as the above starting material, e.g. from HO-Ph-(CH2)r
-CH(C H2n~l)Z" by condensation with Arl-CmH2m-T or
U-CpH2p-CH(Ar2Ar3), wherein T is reactive esteri~ied OH and
one of U and Z" is T and the other ~-I2. The protection o~
the amino groups can be carried out in the usual manner, e.g.
similar to the procedures shown in French Patents No.2~013,686
and 2 a 013,689.
Either in the course of the above reactions l~ LO
3), or subsequently, any protected or metallized amino group
æ arld ~ can be liberated in the usual manner, e.g. by
hydrolysis of the amide groupings, or by hydrogenolysis of
the ~-aralk~l groups, e.g. either with the use of water alone
or pre~erably aqueous acids or bases respectively, advantageous-
ly aqueous mineral acids or akali metal hydroYldes or catalyti
cally activated hydrogen.
The resulting compounds o~ the invention can be
converted into each other according to known ~ethods Thus,
for example, any resulting halogen compound can be dehaloge-
na~ed either in the course of any of the above hydrogenations
or subsequently under more drastic conditions, e.g. higher
temperature and/or pressure, and the course of these reactions
is easily observed and controlled by the amount of consumed
hydrogen.
The compounds o~ the invention are obtained in the
free form or in the form of their acld addition salts;
- 12 -
, ~
,.,, , , ,, , .'. , ', .:: ,. . ' . , : ,, , '~:, , :: : ! ! ' '
~Q~99Z,3
depending on the conditions under which the process is carried
out. Salts that are obtained can be converted into the free
bases in known manner, for example, with ammonia, alkalies
or ion exchangers. Free bases that are obtained can be
converted into salts with acids, especially those that are
suitable for che formation of therapeutically useful acid
addition salts. Such acids are inorganic acids, for example,
mineral acids, such as a hydrohalic, e.g. hydrochloric or
hydrobromic acid; sulfuric~ phosphoric, nitric or perchloric
acid; or organic acids, such as aliphatic or aromatic carboxy- -
lic or sulfonic acids, such as formic, acetic, propionic,
succinic~ glycollic, lactic, malic, tartaric, citric, maleic,
hydroxymaleic, pyruvic, phenylacetic, benzoic, aminobenzoic,
anthranilic, 4-hydroxybenzoic, salicylic, 4-aminosalicylic,
embonic, nicotinic, methanesulfonic, ethanesulEonic, hydroxy-
ethanesulfonic) ethylenesulfonic, halobenzenesulfonic,
toluenesulfonic, naphthalenesulfonic, sulfanilic or cyclo-
hexylsul-famic acid; methionine, tryptophan~ lysine or arginine,
- or ascorbic acidO These or other salts, for example, the
picrates, can also be used in the purification of the free
:, . .
compounds.
In view of the close relationship between the salts ;~
and the free compounds, whenever such is referred to in this
context, a corresponding salt is also intended, provided~such
is possible or appropriate under the circumstances.
' ' , , .
- 13 -
''` ~ : . ,
~ ~9 ~ ~ 3
Resulting mixtures of isomers can be separated into
the single isomers by methods in themselves known, e.g. by
fractional distillation, crystallization and/or chromatography.
Racemic products can li~ewise ~e resolved into the optical
antipodes, for example, b-y separation of diastereomeric salts
thereof, e.g. by the fractional crystallization of d- or
R - ~artrates~ ~
The above mentioned reactions are carried out
according to standard methods, in the presence or absence
of filuents, preferably such as are inert to the r~agents
and are solvents thereof, of catalysts, condensing or said
other agents respectively and/or inert atmospheres, at low
temperatures, room temperature or elevated temperatures,
preferably at the boiling point of the solvents used, at
atmospheric or superatmospheric pressure.
The invention further includes any variant of the
present process, in which an in~ermediate product ob~ainable
at any stage of the process is used as starting material and
any remaining steps are carried out, or the proc~ss is
discontinued at any stage thereof, or in which the starting
materials are ~ormed under the reaction conditions~ or in
which the reaction components are used in the ~orm of their
salts or optical~y pure antipodes,
The pharmacologically active compounds of the
ir~vention are useful in the manufacture of pharmaceuticaI -
compositions containing an effective amount thereo~ in
'. ' '
~6~23
,~,
conjunction or admixture with excipients suitable for either
enteral or parenteral application. Preferred are table~s and
gelatin capsules comprising the active ingredient together
with diluents, e.g. lactose, dextrose, sucrose, mannitol,
sorbitol, cellulose and/or glycine, and lubricants, e.g.
silica, talcum, stearic acid, its magnesium or calcium salt
and/or polyethyleneglycol; for tablets also binders, e~g.
magnesium aluminium silicate~ starch paste~ gelatin,
tragacanth, methylcellulose, sodium carboxymethylcellulose
and/or polyvinylpyrrolidone, if desired, disintegrants, e.g~
starches~ agar, alginic acid or its sodium salt, enzymes of
the binders or efferverscent mixtures and/or adsorbents,
colorants, flavors and sweeteners. Injectable compositions
are preferably aqueous isotonic solutions or suspensions,
and suppositories are advantageously fatty emulsions or
suspensions. Théy may be sterilized and/or contain adjuvants,
such as preserving, stabilizing, wetting or emulsifying agents 9 :'
solution promoters, salts for regulating the osmotic pressure
and/or buffers. They may also contain other therapeutically
valuable substances. Said pharmaceutical compositions are
prepared according to conventional mixing, granulating or
coating methods respectively and contain about 0.1 to 75%,
preferably about 1 to 50% of the~active ingredient,
,~
- 15 -
: .
~69g23
The following examples illustrating the invention
are not to be construed as being limitations thereon~ Tempera-
tures are given in degrees Centigrade. If not specified, all
evaporations are carried out under reduced pressure.
:,
;.
- 16 - .
,
, , , "~; . .. , . ' i" . ' ' ;' ' ' ': " 'i' '~ ~ " i; " ';` i ' ' .
~ 99Z3
Example 1
A mixture of 210 g of 1-[4-(3-chlorobenzyloxy)-
phenyl]-2-aminopropane, 158 g of ~-phenylcinnamaldehyde and
1000 ml of dry benzene is stirred at reflux in an apparatus
containing a water trap until no more water is collected.
The solution is evaporated to dryness under reduced pressure.
The residue is triturated in 1000 ml of dry tetrahydrofuran
and added dropwise under nitrogen to a cooled, stirring
slurry of 86 5 g of lithium aluminium hydride in 1500 ml of
dry tetrahydrofuran. The whole is stirred at ambient tempera- ~-
ture for twenty hours, then cooled and treated cautiously
with saturated aqueous ammonium chloride solution until the
remaining hydride has been destroyed. The mixture is filtered
and the filter cake extracted wit:h chloroorm. The extract
and filtrate are combined, washed with water, dried over
sodium sulphate and concentrated to dryness under reduced
pressure to a~ford a free base of the product as an oil.
This material is dissolved in acetone and treated with
ethereal hydrogen chloride until acidic. On cooling and
adding dry ether little by little, the crystalline
1-~4-(3-chlorobenzyloxy)-phenyl3-2-(3,3-diphenylpropyl-
amino)-propane hydrochloride is obtained. Recrystallization
from methanol-ether yields analytically pure hydrochloride
melting at 157-160.
~ 17 -
.
,
~96~Z3
The starting material is obtained as follows:
To a stirring mixture of 2~4 g of p-hydroxybenzaldehyde~
360 g of potassium carbonatea 32 g of potassium iodide~
1200 ml of 95% aqueous ethanol and 160 ml of water, 367 g
of m-chlorobenzyl chloride are added slowly. The mixture
is stlrred at reflux for four hours, cooled to 80 and
2000 ml of warm water (80) are added under stirring The
mixture is cooled and the product which forms is collected,
washed with water and recrystallized from methanol to afford
the desired 4-(3-chlorobenzyloxy)-benzaldehyde melting at
51-5~
A mixture of 200 g of 4-(3-chlorobenzyloæy)-
benzaldehyde~ 40 g of ammonium atetate and 400 ml of nitro-
ethane is heated under reflux for forty minutes and then
allowed to cool. The precipitate which forms is collected
by filtration, pressed dry and recrystallized from ethanol
to yield 1-~4-(3-chlorobenzyloxy)-phenyl]-2-nitropropene
melting at 110-114~ -Recrystallization from ethanol raises
the melting point to 117-1185 but the crude material is
suitable for the next step.
To a cooled slurry of 57 g of lithium aluminium
hydride in 750 ml of dry tetrahydrouran under nitrogen, ~
91 g of 1-[4-(3~chlorobenzyloxy)--phenyl]-2-nitropropene in~ ;
600 ml oE dry tetrahydrofuran are added dropwise. The
mixture is stirred at ambient temperature for 18 hours and
then cautiously, under cooling, treated dropwise with
- 18 -
:, : - . : :: : ........ : . :,: . , .. .,: : ~ . . : , :
,. .: , , ~ : , ;, . . .
~ Z 3
saturated aqueous ammonium chloride solution until the remain-
ing hydride is destroyed. The mixture is filtered and the pre- ~:
cipitate extracted with chloroform. The filtrate and extracts
are combined, washed with wa~er, dried over anhydrous sodium
sulphate and concentrated to dryness under reduced pressure
to afford l-[4-(3-chloxobenzyloxy)-phenyl]-2-aminopropane as
an oil, suitable ~or use in the next step. The hydrochloride
salt melts at 152-154, .
. - 19 -
Example 2
In a like manner, as described in Example 1,
d, ~ 4-(4-chlorobenzyloxy)-phenyl]-2-(3,3-diphenylpropyl-
amino)-propane hydrochloride, m.p. 178 180 is obtained via
4-(4-chlorobenzyloxy)-benzaldehyde, m.pO 73-75, 1-[4-(4-
chlorobenzyloxy)-phenyl]-2-nitropropene~ m.p. 99-100,
and l-[4-(~-chlorobenzyloxy)-phenyl]-2-aminopropane, t~e
hydrochloride of the latter malts at 199-201,5,
.~ ~
,
~ 20 -
.
. . , : . . . : .: . . :.: ,. . : :. , .. ::... .
: : ~:: . ,: :: :: :: :~ : . .. :
~069923
Example 3
To a solution of 85 g of 1-(4-hydroxyphenyl)-2-
(3,3 diphenylpropylamino)-propane hydrochloride (m.p.
204-207C, prepared from the free base which, in turn, is
prepared as described by Ehrhart et al, U.S. Patent 3,152,173)
in 50 ml of dimethylsulphoxide, 4.1 ml of 10 N aqueous
sodium hydroxide solution are added and the whole is brought ;~
to 60 and maintained at this temperature for one hour.
To this solution 4 g of 3,4-dichlorobenzyl chloride are
added and the whole is stirred v:igorously at ambient tempera- ;
ture for twenty hours. The mixture is poured into 500 ml of
ic.e-water containing 5 ml of N aqueous sodium hydroxide
soLution and extracted with ethyL acetate. The organic layer
is washed with saturated aqueous sodium chloride solution,
dried over sodium sulphate and concentrated to dryness under
reduced pressure. The residue is dissolved in a little
iropropanol, treated with ethereal hydrogen chloride to
acidity and refrigerated whereupon white crystals of
1-~4-~3,4-dichlorobenzyloxy)-phenyl]~2-(3,3-diphenylpropyl-
amino)-propane hydrochloride are obtained, melting at
147-148.
- 21 -
.
~:
i99;Z3
When p-cyanobenzyl chloride is substituted for 3,4
: dichlorobenzyl chloride of example 3, 1~[4-t4-cyanobenzyloxy)-
phenyl]-2-(3,3-diphenylpropylamino)-propane is obtained.
Extraction of the aqueous mixture with ethyl acetate yields
the free base as a white crystalline solid melting at 132-133~5.
,' '':
" .
.
-
;'~
:: - .,.', .:
.:
^~
,,
- 22 -
:
~;36919;~3
Examp~e S
A mixture of llo 9 g of 4-(4-chlorobenzyloxy)-
phenylacetone, 9.8 g of 3,3-diphenyl-3-hydroxypropylamine
and 100 ml of absolute ethanol is heated under reflux for
one hour, cooled to room temperature and treated little
by little under stirring with 6 g of sodium borohydride in
25 ml of waterr The mixture is stirred for 18 hours, poured
into ice-water~ and the resulting precipitate collected,
washed with water and recrystallized from isopropanol. The
resulting material is taken up in chloroform, the solution
treated with charcoal, filtered, concentrated to dryness
under rèduced pressure and recrystallized from isopropanol
to afford pure d,~ 4-(4 chlorobenzyloxy~-phenyl~-2-
(3,3-diphenyl-3-hydroxypropylamino)-propane melting at
125-127.
The starting material is obtained as follows: ;
A mixture of 30.4 g of 1-[4-(4-chlvrobenzyloxy)-phenyl]-2-
nitropropene (intermediate in Example 2), 80 g of iron powder5
,
3.2 g of ferric chloride, 40 ml of concentrated hydrochloric
acid~ 400 ml of ethanol-and 1200 ml of water is stirred
vigorously at reflux for ten hours, cooled and then filtered.
The precipitate is extracted with methanol and the filtrate
and extracts are combined and concentrated to dryness at
reduced pressure. The residual solid is dissolved in hot
isopropanol, the solution treated with charcoal, filtered
- 23 -
.. ... . .. ... .. .. . . . .. .
: ' . ' : . : . ' ." ' . : !: ' . . . . ` ' ' ' :
~L069~:~3
and the filtrate refrigerated. The precipitate is collected,washed with petroleum ether and dried to afford 4-(4-chloro-
benzyloxy)~phenylacetone melting at 76-80.
. ' , '
- 24 -
.
., : , '
~10 69~a23
Example 6 ^~
The mixture of 16 g of ~ 4-hydroxyphenyl)-2-
(3,3-diphenylpropylamino)-propane hydrochloride, 50 ml of
dimethylsulfoxide and 3 4 g of sodium hydroxide in 10 ml of ~: :
water is stirred at 60 for 1 hour, whereupon 7,2 g of
4-chlorobenzyl chloricle are added and the whole is stirred
over night at room temperature~ The mixture is poured into
300 ml of N-aqueous sodium hydroxide solution, extracted
wîth methylene chloride, the extract dried and.evaporated.
The residue is dissolved in 250 ml of ethyl acetate, the
solution combined with that of 7 g of maleic acid in 25 ml
of methanol, the mixture stirred for 1 hour and filtered, to
yield the. Q -l-[4-(4-chlorobenzyloxy)-phenyl~-2-(3,3-diphenyl-
propylamino)~propane maleate melting at 177-178~, [M~D --58.1
(5% in methanol). .
The starting material is prepared as follows: The
mixture of 23 g of ~ (4-hydroxyphenyl)-2-aminopropane, ~.
31.2 g of 3,3-diphenylacrolein, 150 ml of anhydrous ethanol
and 4 g of 10% palladium on charcoal is hydrogenated at ~
3.3 atm. for 6 hours. It.is ~ ered, the filtrate evaporated,
the residue dissolved in 400 ml of isopropanol and the . ~.
solution com~ined with 12.5 ml of concentrated hydrochloric
acid. After standing overnight the precipitate is collected
and washed with isopropanol and diethyl ether, to yield the
.- - '
.
69ll923
Q-1-(4-hydroxyphenyl)-2-(3,3-diphenylpropylamino)-propane
hydrochloride melting at 244-247; 1M]D =-35.1 (5% 1n
methanol).
Analogously its dextrorotatory antipode is obtained,
melting at 244-246; [M]D =+31.9 (5% in methanol),which is `-
converted as shown above into the d-l-~4-(4-chlorobenzyloxy)-
phenyl]-2-(3,3-diphenylpropylamino~-propane maleate melting at
176-178, [M]D -+57.3 (5% in me~hanol).
- 26 -
,, .
- . . , - . ~- . .' : i ..
;-, , , , . :-,; : , , :, : , .
9 ~ 3 -
Example 7
The mixture of 11.85 g of 1-(4-hydroxyphenyl)-3-
(3,3-diphenylpropylamino)-butane (U.S.P. 3,262,977), S0 ml
of dimethylsulfoxide and 3.1 ml of 10 N-aqueous sodium
hydroxide solution is stirred at 80 for 1/2 hour, whereupon
5.1 g of 4-chlorobenzyl chloride are added and the whole is
stirred for 8 hours while allowing to cool to room temperature.
The mixture is poured into 600 ml of ice-cold N-aqueous
sodium hydroxide solution, extracted with a total of 700 ml
of ethyl acetate, the extract washed with saturated aqueous
sodium chloride solution, dried and evaporated. The residue
is taken up in the minimum amount of anhydrous ethanol, the
solution combined with that of 3.48 ~ of maleic acid in ~;
ethanol3 cooled and the precipitate collected, to yield the
1-14-(4-chlorobenzyloxy)-phenyl]-3-(3,3-diphenylpropylamino)-
butane malea~e melting at 154-156.
_ 27 -
..
6~ ~ ~ 3
Example 8
'-.
The mixture of 17.3 g of 1-(3-hydroxyphenyl)-2-(3,3-
diphenylpropylamino)-propane~ 100 ml of dimethylsul~oxide and
5 ml of lON-aqueous sodium hydroxide solution is stirred at
room temperature for 1/2 hour, combined with 8.05 g of
4-chlorobenzyl chloride and stirred 16 hours longer. It is
poured into water, extracted with ethyl acetate, the extract
washed with saturated aqueous sodium chloride solution, dried
and evaporated. The residue is taken up in diethyl ether,
the solution acidified with isopropanolic hydrogen chloride,
the precipitate collected and washed with diethyl ether,
to yield the 1-[3-(4-chlorobenzyloxy)~phenyl]-2-(3,3-diphenyl-
propylamino)-propane hydrochloride melting at 184-189.
Analogously the 1-~3-(2-chlorobenzylo~y~-phenyl]-2-
(3,3-diphenylpropylamino~-propane hydrochloride is prepared
melting at 165-167; as well as the 1-~2-(3-chlorobenzyloxy)-
phenyl]-2-(3,3-diphenylpropylamino)-propane hydrochloride,
melting at 144-145.
The starting material is prepared as follows- The
mixture of 100 g of m-methoxyphenylacetone, 129 g of 3,3-
diphenylpropylamine and S00 ml of anhydrous ethanol is
refluxed for 2 hours, cooled to 20 and the solution of 95 g
of sodium borohydride in 300 ml of water is added dropwise
while stirring at room temperature. After stirring overnight
the mixture is poured into water, extracted with methylene
- 28 -
.
, , ~ ,. : i. ; .
~ 9 ~3
chloride, the extract dried and evaporated. The residue is
taken up in diethyl ether, the solution acidified with
isopropanolic hydrogen chloride and the precipitate collected,
to yield the 1-(3-methoxyphenyl)-2-(3,3-diphenylpropylamino)-
propane hydrochloride melting at 95-98o
The mixture of 145 g of 1-(3-methoxyphenyl)-2-
(3,3~diphenylpropylamino)-propane hydrochloride and 1500 ml
of 48% hydrobromic acid is refluxed for 45 minutes and allowed
to stand at room temperature overnight. It is poured onto
4000 g of ice and 1000 ml of concentrated ammonium hydroxide,
the mixture extracted with methylene chloride, the extract
dried, evaporated and the residue recrystallized from ethyl
acetate, to yield the 1-(3-hydroxyphenyl)-2-(3,3-diphenyl-
propylamino)-propane melting at :L22-124o
Reacting the (3-methoxy-4-hydroxyphenyl)-acetone
with the 3,3-diphenylpropylamine, reducing the resulting
5chiff's base as shown above and reacting the resulting
saturated compound with 3-trifluoromethylbenzyl chloride,
the l-[3-methoxy-4-(3-trifluoromethyl~enzyloxy)-phenyl~-2-
(3,3-diphenylpropylamino)~propane hydrochloride is obtained,
melting at 142 to 146 after recrystallization from isopropanol.
- 29 -
,, .
., . : .. . .. : ........... . . ., : ;~ : . : .
. ,. ~ ' ' . i :: ,,.,, ",,","",,, ,, " ", "". ~ ," ,., ~
,:
Example 9 -~
The mixture of 7.18 g of 1-(3-methyl-4-hydroxy-
phenyl)-2-(3,3~diphenylpropylamino)-propane, 50 ml of
dimethylsulfoxide and 2 ml of lON-aqueous sodium hydroxide
solution is stirred for 1 hour at 60. After cooling to
room t~mperature 3.32 g of 4-chlorobenzyl ~hloride are added
and the mixture stirred overnight at said tempexature. It~
is poured into water, extracted with ethyl acetate, the
extract dried and evaporated. The residue is taken up in
isopropanol, the solution acidified with isopropanolic
hydrogen chloride, the precipitate collected and washed with
diethyl ether, to yield the 1-[3-methyl-4~(4-chlorobenzyloxy)-
phenyl]-2-(3~3-diphenylpropylamino)-propane hydrochloride
melting at 166-168.
Analogously the 1~3 fluoro-4-(4-chlorobenzyloxy)-
phenyl]-2-(393-diphenylpropylamino)-propane hydrochloride
is obtained, melting at 183 187.
The starting material is prepared as follows: The
mixture of 100 g of 3-methyl-4-methoxy~enzaldehyde, 300 ml
of nitroethane and 52 g of ammonium acetate is refluxed for
4 hours and evaporated, to yield the 1 (3-methyl-4-methoxy-
phenyl)-2-nitropropene.
The solution of 185.9 g of l-(3-methyl-4-methoxy-
phenyl)-2-nitropropene in 500 ml of tetrahydrofuran is added
,:
- 30 -
,
, . , , . , ,,,, , . , . " .... , . , .. " . .. ... . , . . , . ~ ,
~ 0 ~9 9 Z 3
dropwise to the slurry of 76 g of lithium aluminium hydride
in 250 ml of tetrahydrofuran while stirring and cooling with
ice-sodium chloride, and stirring is continued overnight at -
room temperature under nitrogen. The mixture is slowly
combined with 300 ml of saturated aqueous ammonium chloride
solution, diluted with 2000 ml of diethyl ether to facilitate
stirring and filtered. The residue is washed with a total of
1500 ml of diethyl ether, the filtrate washed with saturated
a~ueous sodium chloride solution, dried and evaporated. The
residue is taken up in diethyl ether, the solution acidified
with ethanolic hydrogen chloride and the precipitate collected,
to yield the l-~3-methyl-4-methoxyphenyl)-2-aminopropane
hydrochloride melting at 200-205.
1~,7 g of 1-(3-methyl-4-methoxyphenyl)-2 aminopro-
pane hydrochloride are added to the solution of ~.93 g of
sodium methoxide in 300 ml of anhydrous ethanol while stirring.
After a few minutes the mixture is filtered, the filtrate
evaporated and the residue taken up in 500 ml of benzene.
The solution is combined with 19.01 g o~ 3,3-diphenylacrolein,
refluxed for 2 1/2 hours on a water trap and evaporated, The
residue is taken up in 250 ml of tetrahydrofuran, the solution
combined with 14 g of lithium aluminium hydride and the
mixture refluxed for 60 hour~ while stirring under nitrogen.
It is combined with 250 ml of saturated aqueous ammonium
chloride solution, filtered, the residue washed with diethyl
ether and ethyl acetate. The filtrate is washed with saturated
- 31 -
, .
: ~ : ::: ;: : :
~69923
aqueous sodium chloride solu~ion, dried and evaporated. The -~
residue is taken up in diethyl ether, the solution neutralized .-
with ethanolic hydrogen chloride and the precipitate re-
crystallized from isopropanol, to yield the 1-(3-methyl-4-
methoxyphenyl)-2-(393-diphenylpropylamino)-propane hydro-
chloride melting at 174-179,
The mixture of 20.5 g of 1-(3-methyl 4-methoxyphenyl)-2-
(3,3-diphenylpropylamino)-propane hydrochloride~ 100 ml of
methylene chloride and S0 g of boron tribromide is stirred
at 0 for 9 hours and at room temperature for 9 hours. It is
evaporated, the residue poured onto ice and saturated
ammonium hydroxide, the mixture filtered and the precipitate
recrystallized from benzene, to yield the 1-(3-methyl-4-
hydroxyphenyl)-2-(3~3-diphenylpropylamino)-propane melting
at 115-118.
The similarly prepared 1-(3-fluoro-4-hydroxyphenyl)-2-
(3,3-diphenylpropylamino)-propane melts at 186-188 after
recrystallization from mcthT~-l cello~ol-r~
'' '' ' . ,
- 32
.
-
:Lo~9~Z3
;,:
Example 10
According to the methods illustrated by the previousexamples, preferably according to those mentioned under item
3) herein, the following racemic products are prepared from
equivalent amounts of the corresponding starting materials:
1) 1-[4-~4-fluorobenzyloxy)-phenyl]-2 (3,3~diphenyl-
propylamino)-propane maleate, m.p. 161-163;
2~ 4-(pentafluorobenzyloxy) phenyl]-2-(3,3-
diphenylpropylamino)-propane maleate, mOp. 156~158;
3) 1-~4-(4-chlorobenzyloxy)-phenyl] 2 (3,3~diphenyl-
--propylamino)-propane maleate, m.p~ 183-184;
4) 1-~4-(4-bromobenzyloxy)~-phenyl]-2-(3~3-diphenyl-
propylamino)-propane maleate, mOp. 183-185;
5) 1-~4-(3-trifluoromethylbenzyloxy)-phenyl]-2-
~3,3-dîphenylpropylamino)-propane maleate, m,p. 135-137;
6) 1-[~-(4-cyanobenzyloxy)-phenyl]-2-(3,3-dipllenyl-
propylamlno)-propane maleate, m.p. 8C-82;
- 7) 1-L4-(4-carbamoylbenzyloxy)-phenyl]-2-(3,3
diphenylpropylamino)-propane maleate, m.p. 184-185.
. " .
.
_ ' ' .
- 33 ~
.
, . ,.; ~, : . .:. ., , .: . ,: , .. ~
06~9~ ~ 3
Example 11
The mixture of 4.8 g of 1-[4 (4-carbamoylbenzyloxy)-
phenyl]-2-(3,3-diphenylpropylamino)-propane (prepared from the
maleate of Example 10/7 by extracting the suspension thereof
in 100 ml of N-aqueous sodium hydroxide solution with
methylene chloride and evaporating the dried extract), 25 ml
of ethanol, 10 ml of water and 5.6 g of potassium hydroxide
is refluxed for 18 hours under nitrogen. It is concentrated,
the concentrate diluted with 75 ml of water and acidified
with 10 ml of concentrated hydrochloric acid. The precipltate
is filtered, washed with water, dried and triturated with
diethyl ether, to yield the 1-[4-(4-carboxybenzyloxy~ phenyl]
-2-(3,3-diphenylpropylamino~-propane hydrochloride melting
~t 188 190~
.~ '
- ,
-.
- : ,
.
.
''
- 34 -
.
: . ... : . , . .. ,. ::. .. :: : : .::.,: . , , . ~ , . .. : , , .
3iZ3
Example 12
Preparation of 10,000 tablets each containing 50 mg of
the active ingredient:
Formula:
e ~ 4-c4-chlorobanzylox~-phenyl]-
2-C3,3-diphenylprop~lamino~-propane maleate 500 g
Lactose 1,706 g
Corn starch go g
Polyethylene glycol 6,000
Polyethylene glycol of the formula HCOCH2CH ) OH,
~here n is between 158 and 204 2 n 90 g
Talcum powder 90 g
Magnesium stearate 24 g
Purified water q.s.
Procedure:
.
All the powders are passed t]hrough a screen with
openings of 0.6 mm. Then the drug substance, lactose, talcum,
magnesium stearate and half of the starch are mixed in a
suita~le mixer. The other half of the starch is suspended in
45 ml of water and the suspension added to the boiling
salution of the polyethylene glycol in 180 ml of water. The
paste fo~med is added to the pouders which are granulated,
if necessary, with an additional amount o~ water. The granulate
is dried overnight at 35, broken on a screen with 1.2 mm
openings and compressed into tablets using concave punches
with 7.1 mm diameter, uppers bisected.
,
- - 35 -
: .
~al6~3
Preparation of 10,000 capsules each containing
100 mg of the active ingredient:
Formula~
d, R-1-[4-(4-chlorobenzyloxy)-phenyl]-
2-(3,3-diphenylpropylamino)~propane
hydrochloride 1,000 g
Lactose 2,800 g
T~lcum powder 200 g
Procedure:
All the powders are passed through a screen with
openings of 006 mm. Then the drug substance is placed in a
suitable mixer and mixed first with the tal.cum, then with :;
the lactose until homogenous No. 1 capsules are filled with
400 mg each, using a filling machine.
Analogously.tablets and capsules are prepared from
the remaining compounds illustrated by the previous examples,
- ,.
''
~ ', ' " '
' . .
- 36 -
:
' ' ' ' ' ' ;;' ' ' ~ ' . ~ . ! ,. . .
