Note: Descriptions are shown in the official language in which they were submitted.
llZ7:164
This invention relates to derivatives of
l-phenyl-l-propanol of the general formula I
R 1 ~ C H O I I C ~1 - R 2 - ( I )
CH3
wherein :
(a) Rl represents hydrogen, a linear or ramified alkylthio
(Cl-C3), linear or ramified alkylsulfinyl (Cl-C3), li-
near or ramified alkylsulfonyl (Cl-C3) or mercapto radi-
cal ;
(b) R2 represents :
b-l a hydroxy radical ;
b-2 an oxo-2-pyrrolidinyl-1 radical which may be subs- tituted by a hydroxy group ;
b-3 a NHR3 radical wherein R3 represents :
- hydrogen
- a linear or ramified alkyl (C6-C16) radical or a
linear alkyl (C2-C4) radical substituted by a phe-
~: nyl or phenoxy group, with the proviso that Rl is
not an alkylthio radical
- a linear or ramified alkyl (Cl-C7) radical substi-
tuted by a lower carboxy or carbalkoxy (Cl-C
. group in the position ~ ;
as well as non toxic apd pharmaceutically acceptable salts
and esters of these derivatives.
A preferred class of compounds according to
the invention comprises derivatives of formule I wherein :
(a) Rl represents a linear or ramified alkylthio (Cl-C3) ra-
,
.:
, ~ . . .
, -
,
llZ7~64
dical
(b) R2 representts a NHR3 radical in which R3 is a linear or
ramified alkyl (C1-C3) radical substituted by a carboxy
or carbomethoxy group in the position~.
Another preferred class of compounds accor-
ding to the invention comprises derivatives of formula I
wherein :
(a) Rl represents a linear or ramified alkylsulfinyl (C1-C3)
radical
(b) R2 represents a NHR3 radical in which R3 is a linear or
ramified alkyl (C6-C14) radical, a linear alkyl ~Cl-C3)
radical substituted by a carboxy or carbomethoxy group
in the position~ .
Examples of compounds according to the inven-
tion are :
1-(4-isopropylsulfinylphenyl)-2-n.octylamino-1-propanol.
1-(4-isopropylthiophenyl)-2-~3-(methoxycarbonyl)propylami-
; no~-1-propanol.
1-(4-isopropylthiophenyl)-2-~3-(carboxy)propylaminoJ-l-pro-
panol.
1-(4-methylthiphenyl)-2-~3-(methoxycarbonyl) propylamino~
-l-propanol.
1-(4-methylthiophenyl~-2-C3-(carboxy)propylamin ~-1-pro-
panol.
1-(4-isopropylsulfinylphenyl)-2-~3-(methoxycarbonyl)propy-
lamino~-l-propanol.
1-(4-isopropylsulfinylphenyl)-2-~3-(carboxy)propylamino?
-l-propanol.
1-(4-isopropylsulfinylphenyl)-2-~i-(2-oxopyrrolidinyl)~7-1-
- 30 propanol.
- .
~1~7164
1-(4-mercaptophenyl)-2-n.octylamino-1-propanol.
Derivatives of formula I may be isolated as
salts, in particular hydrochlorides and sulfates.
Derivatives of formula I may be transformed
according to usual processes into salts with acids and, when
the derivatives are directly obtained as salts, they may al-
so be transformed into their free base or into salts with
other acids.
According to the invention, these are more
particularly pharmaceutically acceptable non toxic acid
addition salts, formed with suitable inorganic acids, for
example hydrochloric, sulfuric or phosphoric acid or with
suitable organic acids, such as aliphatic, cycloaliphatic,
aromatic, araliphatic or heterocyclic, carboxylic or sulfo-
nic acids, for example formic, acetic, propionic, succinic,
glycolic, gluconic, lactic, malic, tartaric, citric, ascor-
bic, glucuronic, maleic, fumaric, pyruvic, aspartic, gluta-
mic, benzoic, anthranilic, hydroxybenzoic, salicylic, phe-
nylacetic, mandelic, embonic, methanesulfonic, ethanesulfo-
;:
nic, panthatenic, toluenesulfonic, sulfanilic, cyclohexyl-
aminosulfonic, stearic, alginic~ ~ -hydroxypropionic, ~ -hy-
droxybutyric, oxalic, malonic, galactaric, galacturonic
acids. These salts can also derive from amino-acids, which
are natural or not, such as lysine, glycine, arginine, orni-
thine, asparagine, glutamine, alanine, valine, threonine,
serine, leucine, cysteine, and the like.
Most of the products according to the inven-
tion have two asymmetry centres. Derivatives where Rl repre-
sents an alkylsulfinyl radical have three asymmetry centres.
:,
;.
- ,
.
llZ7164
With products of the invention having two
asymmetry centres, two racemates corresponding to erythro
and threo configurations respectively may be obtained ; the-
se two racemats may be resolved by conventional processes,
for e~ample by formation of diastereoisomer salts by action
of optically active acids, such as tartaric, diacetyltarta-
ric, tartranilic, dibenzoyltar~aric, ditoluoyltartaric acids
and separation of the diastereoisomer mixture by crystalli-
zation, distillation, chromatography, then liberation of op-
tically active bases from said salts.
With products of the invention having three
asymmetry centres, eight optical isomers may be obtained.
The same processes may be used for resolving said mixtures.
The most active derivatives of the invention
may thus be used as mixtures comprising several diastereoi-
somers whatever the relative proportions may be, or as enan-
tiomer pairs in equal proportions (racemic mixture) or not,
or also as optically pure compounds. However, derivatives of
the erythro configuration at the level of the two asymmetri-
cal carbon atoms of the propanol chain are preferred.
This invention also relates to a process for
preparing above-mentioned derivatives of l-phenyl-l-propanol
and corresponding salts and esters.
This process is characterized in that it con-
sists of transforming into one of the corresponding deriva-
tives of formula I, a compound having the formule II :
` 'Z ~ Q (~I)
.: , , :
` 1127164
wherein Z represents one of the substituents Rl such as he-
reinabove defined or corresponds to a group YS in which Y is
a protecting group replaceable by hydrogen and Q is one of
the following groups :
-CO-CO-CH3 ;
/ \
-CO-HOH-CH3 ; -CO-fH-X ; -CH-CH-CH3 ;-CO-CH-NHR3 ;
CH3 CH3
-CHOH-CH-~ ; -CHO~1-CH-R2,
CH3 CH3
where R2 and R3 have the above-mentioned meaning and X is a
halogen atom, such as Cl, Br, F.
Advantageously, derivatives of formula I whe-
rein R2 is a hydroxy group are obtained by reduction of cor-
responding ketones of general formulae III and IV :
`~1 ~ C0-C0-C~13 (IJI) Rl- ~ C0-~H~ CH3 (IV)
wherein Rl has the previously defined meaning.
This reduction may be made in the usual man-
ner, for example by action of hydrides such as NaBH~,
LiAlH4, LiAl(OAlkyl)3H, AlH3, (Alkyl)2AlH, NaB(OCH3)3H,
LiBH3CN, B2H6, (Alkyl)3SnH, (Alkyl)3SiH or NaH in solvents
such as ether, tetrahydrofuran, ethanol, methanol, diglyme,
toluene or xylene, by action of alkaline metals, such as so-
dium or lithium, in solvents such as ammoniac or ethanol, by
action of hydrogen in the presence of hydrogenation cata-
~ lysts, such as platinum or palladium, in solvents such as
: ethanol or by action of alwminium alkoxides, such as alumi-
~ - ~
11271~4
niunlisopropoxide, in a solvent such as isopropanol.
If the process of reduction of ketones of ge-
neral formulae III and IV is not stereoselective, erythro/
threo mixtures are separated according to conventional pro-
cesses (for example by distillation or plate or column chro-
matography).
The compounds of general formula I wherein R2
is an oxo-2-pyrrolidinyl-1 ring, optionally substituted by a
hydroxy group are advantageously obtained according to gene-
ral schemas such as hereinafter described :
a) R1~3 Cll-CII-C~ Rl~> CIIOII(`H-N~
(!
b) Rl ~> CO-CIl-Br ~ R ~ CH(~Hc~
Cll 1 N~(C112)3C~OCH3 1 ~ C1~3
3 2 . Reduc t i on
3. Ease (ring-clo~ure),
In these schemes, Rl has the previously given
meaning.
In reaction (a), condensation of an epoxide
with 2-pyrrolidinone is easily made either without solvent
while optionally using excess of 2-pyrrolidinone, or in the
presence of solvents, for example methanol or ethanol.
This method allows alcohols of threo configu-
ration to be obtained.
In reaction (b), condensation of a ~-bromoke-
tone with an ester of ~-aminobutyric acid will be made in a
solvent such as methanol, ethanol, chloroform, acetonitrile,
: .
llZ7~6~
benzene or a mixture thereof, most advantageously at room
temperature.
The reduction may be made with hydrides of
alkaline metals, more particularly with ~aNH4, in a solvent
such as methanol or ethanol at room temperature.
The ring-closure into pyrrolidinone may be
made by action of an organic or inorganic base, for example
an alkoxide or sodium or potassium hydroxyde in an alcoholic
; or hydro-alcoholic solvent such as methanol, ethanol or iso-
propanol at a temperature between room temperature and the
reflux temperature of the selected solvent but most advanta-
geously at room temperature.
This method allows alcohols of erythreo con-
figuration to be obtained.
The compounds of general formula I wherein R2
is a radical of the kind NHR3 may be obtained from a com-
pound of the general formule V :
Rl~ Q ( Y)
or optionally, according to the value of Q, from a salt of a
; ~0 compound having this formula, wherein R2 has the previously
given meaning and Q represents one of the following groups :
O
/ ~
-CH-CH-CH3 -COCH-NHR3 -CHOHCH-X -COCH-X
CH3 CH3 CH3
~ In these formulae, R3 has the previously gi-
`~ ven meaning while X represents a halogen atom.
. ..
~ Said process may be carried out according to
.
~-.
,:
,
1~2716~
two embodiments which are essentially determined by the
starting product, namely by the value of Q in formula V.
Embodiment A.
According to a first way of proceeding, a
~-aminoketone of formula V wherein Q represents a group :
CO-CH-NHR3, R3 having the previously defined meaning are re-
CH3
duced.
This reaction may be made in the usual way,
most easily for example by action of alkaline metal hydri-
des, such as sodium borohydride, in a solvent such as metha-
nol or ethanol, preferably at low temperature, or by action
of aluminiu~ or lithium hydride in a solvent such as diethyl
ether or tetrahydrofuran, or by action of an aluminium alko-
xide, such as aluminium propoxide in a solvent such as iso-
propanol, most advantageously at the reflux thereof. The re-
duction may also be made by hydrogenation in the presence of
a catalyst, such as palladium on carbon, Raney nickel, pla-
tinum oxide in a solvent, such as methanol, ethanol, dioxa-
ne.
As previously mentioned, the most interesting
products according to the invention may have two erythro and
threo configurations. The selection of the starting aminoke-
tone and of the reduction conditions allows either of these
two forms to be obtained stereoselectively. Thus the reduc-
tion of an aminoketone wherein Q represents : CO-CH-NHR3
CH3
leads to an amino-alcohol of erythro configuration under
~: the general hereinabove described conditions.
112~16~
In order to obtain a compound of the threo
configuration, reduction is made on an aminoketone wherein
Q represents : CO-CH-NH3R4 in which R3 has the previously
CH3
mentioned meaning and R4 is a protecting group which is la-
ter removable by hydrolysis or hydrogenolysis, such as ben-
zyl, trityl, acetyl, formyl, benzhydryl groups ; this reduc-
tion is then preferably made by action of alkaline metal hy-
drides, such as sodium borohydride or aluminium lithium hy-
dride.
The starting aminoketones are easily accessi-
; ble, for example by action of an amine R3NH2 or R3R4NH on
a ~-halogenoketone in solvents such as ether, benzene, chlo-
roform, dioxan, methanol, isopropanol or acetonitrile.
Embodiment B.
According to this preparation method, a com-
pound of the general formula V, in which Q represents a
group :
-CHOH-CH-X,
CH3
is reacted with an amine R3NH2, in which formulae R3 and
have the previously given meaning.
This reaction is made in a solvent such as
alcohols, chloroform, dioxan, carbon tetrachloride, most ea-
sily in the presence of a scavenger for the formed halogen
hydride, such as inorganic or organic bases, or in the pre-
- sence of excess of amine. It is well known that in these
cases, the -CHOH-fH-X group first gives an oxirane group
CH3
''
- ` :.: `L :
" -~ ~ ' `
~127164
11
f the type -CH-CH-CH3 which reacts with the amine compound.
Thus the present process also comprises pre-
paration of amino-alcohols from oxiranes.
The compounds of general formula I wherein Rl
is a mercapto radical may be obtained from compounds of the
general formula VI :
Y S ~ OH C ll - R 2 ( ~11 )
C113
wherein R2 has the previously indicated value and Y is a
protecting group which is replaceable by hydrogen according
to processes well known in the literature, for example an
alkyl group such as isopropyl, benzyl or substituted benzyl
group which is removable by action of alkaline metals, such
as sodium or lithium, in a solvent such as ammoniac, or by
action of hydrogen in the presence of hydrogenation cata-
lysts or by action of lead diacetate or hydrofluoric acid, a
diphenylmethyl group which is substituted or non removable
by action of aci~s such as trifluoroacetic acid or hydro-
bromic acid, a triphenylmethyl group which is substituted or
non removable by action of acids swch as hydrochloric or hy-
drobromic acid or of agents such as HgCl2, AgNO3 or
Hg (OAc)2, a benzylthiomethyl group which is removable by
action of oxidation agents such as HgCl2 or Hg(OAc)2, an
acetamidomethyl group which is removable for example with
mercury salts~ a carboxymethyl group which is removable with
oxidation agents in acid medium or a tetrahydropyranyl o;
tetrahydrofuranyl group which is removable with oxidation
1127~6
12
agents such as AgNO3, Ir, SO2C12, (SCN)2-Zn or with acids.
The compounds of general formula I, wherein
Rl is an alkylsulfinyl or alkylsulfonyl radical may be ob-
tained from compounds of general formula I wherein Rl is an
alkylthio radical, by oxidation according to processes well
known in the literature. This oxidation may be made at any
stage of the synthesis of the products according to the in-
vention.
In order to obtain sulfoxides, one may use
lQ oxidation agents, such as iodine, bromine in water or in the
presence of acetate ions or in a complex with pyridine, pe-
racids such as peracetic, monoperphthalic or m-chloroperben-
zoic acids, N-halosuccinimides, such as N-bromosuccinimide,
hypochlorites such as sodium, t-butyl or isopropyl hypochlo-
rites, periodates such as sodium periodate, hydrogen peroxi-
de in the presence of acetic anhydride or in the presence of
vanadium hemipentoxide in t-butanol, nitrates, such as ace-
tyl nitrate or ammonium and cerium nitrate, oxides such as
chromium (VI) oxide in pyridine or vanadium hemipentoxide in
; 20 the presence of oxygen or nitrogen hemipentoxide, peroxides,
ozone, oxygen, in the singlet or triplet state, acids such
as nitric acid, chromic acid or Caro acid or still ln other
agents, such as sulfuryl chloride, l-chlorobenzotriazole,
chloramine, N-chloro-nylon 66, iodobenzene dichloride, iodo-
~ sobenzene, iodobenzene diacetate, N-chlorotriazole,
2,4,4,6-tetrabromocyclohexadienone or auric acid (HAuC14~.
.~
These oxidation reactions will be carried out in solvents
such as for example water, acetic acid, chloroform, dichlo-j
romethane, carbon tetrachloride, methanol, t-butanol or ace-
, .. ~
:
-.
- :
11~7164
13
tone.
For obtaining sulfones, oxidation agents such
as hydrogen peroxide will be used, preferably in the presen-
ce of zirconium salts, peracids such as peracetic, monoper-
phthalic and m-chloroperbenzoic acids (in the case of oxida-
tion with peracids, catalysts based on transition metals
will be advantageously used), potassium permanganate in acid
or basic medium, sodium or potassium bichromate, osmium te-
troxide, selenium oxide) t-butyl hypochlorite, nitric aci~,
ozone, oxygen, advantageously in the presence of iridium or
rhodium salts, iodobenzene dichloride, periodic acid or by
electrochemical oxidation. These reactions will be made in
solvents, such as water, acetic acid, chloroform, dichloro-
methane, methanol, ethanol, isopropanol, t-butanol, dioxan
or acetone.
In some cases, it may be advantageous to car-
ry out the hereinabove described oxidation reactions on com-
pounds of general formula I wherein R1 is an alkylthio group
=~ and wherein the functions which are sensible to the oxida-
tion agent used will have been protected for example by for-
mation of esters in the case of hydroxy groups or of ketals
in the case of ketonic groups.
Hereinafter detailed examples of preparation
of some derivatives of l-phenyl-1-propanol according to the
` invention are given. These examples have mainly for their
object to more completely illustrate the particular features
of the process according to the invention.
Example 1
1-(4-Isopropylsulfinylphenyl)-2-n-octylaminopropanol.
. ,
, ~
~lZ~1~4
(Table I, n 6).
To 14 gr of 1-(~-isopropylthiophenyl)-2-n-
octylaminopropanol dissolved in 250 ml of chloroform, 6,4 gr
of m-chloroperbenzoic acid are slowly added. The mixture is
stirred overnight at room temperature, washed with an aque-
ous satured solution of NaHCO3 and evaporated under vacuum.
The so obtained residue is treated with 50 ml
of ether and filtered.
The organic phase is dried on MgS04, filtered
and evaporated. The oily residue is vacuum dried overnight,
redissolved in anhydrous ether and hydrochloride is obtained
by passing of a dry gaseous HCl stream through this residue.
After recrystallization with a mixture of methanol and
ether, 8,4 gr of product are obtained. Yield : 60% ; MP
(C): 167-169 (melting point).
Centesimal analysls
C H N
Calculated, % 61.59 9.30 3.59
Found, % 61.28 9.05 3.45
~20 Example 2.
1-(4-Isopropylthiophenyl)-2-~l-(2-oxopyrrolidiny~ -pr
panol.
(Table I, n7).
` a) 2-methyl-3-(4-isopropylthiophenyl)oxirane.
,~ To a solution containing 28.5 gr of 2-bromo-
, 1-(4-isopropylthiophenyl)-1-propanone, 350 ml of ethanol and
} 125 ml of ethoxyethanol, 3.83 gr of NaBH4 in 25 ml of water
are slowly added at -25QC while agitating. After the addi-
. . .
tion is complete, the mixture is allowed slowly to come
,' '
.
,
:,,
.
112~164
again to room temperature and stirring is carried on for
1.30 hour. 3.8 gr of KOH in 40 ml of water are then slowly
added and then stirring is followed for 30 minutes. The re-
action mixture is diluted with water and extracted from
chloroform. The chloroform solutions are collected, dried
and filtered, then the solvent is removed by vacuum distil-
lation. 23.6 gr of an oil are thus obtained, this oil being
vacuum redistilled. Weight : 19,2 gr ; yield 65% ; BP :
81-84C (0~7 mm) ; the NMR spectrum is in agreement with the
structure of 2-methyl-3-(4-isopropylthiophenyl)oxirane.
b) 1-(4-Isopropylthiophenyl)-2-/~-(2-oxopyrrolidinyl)~-1-
propanol.
10.4 gr of the preceding product, 4.25 gr of
2-pyrrolidinone and 0.5 gr of NaOH are heated under nitrogen
for 17 hours at 120C. After cooling, the oil so obtained is
solidified by addition of petroleum ether. The solid is fil-
tered, washed with a minimum of petroleum ether, dried and
recrystallized in diethyl ether. 4.68 gr of product are thus
obtained. Yield : 45% ; MP (C) : 115-116.
The structure conformity is checked by mass
spectrometry and NMR (threo configuration).
Centesimal analysis
C H N
Calculated, % 65.4~7.90 4.77
Found, % ~5.~57.80 4.70
Example 3.
1-4-Isopropylsulfonylphen~1)-2-~1-(2-oxopyrrolidinyl)~-1-
propanol.
(Table I, n9).
` ` -
- ~ ~
716~
1~
A solution containing 2.93 gr of 1-(4-isopro-
pylthiophényl)-2~ (2-oxopyrrolidinyl)~-1-propanol, 6.5 ml
of acetic acid and 6.5 ml of 30 % H2O2 is progressively hea-
ted to 85-90C and maintained at this temperature for 2
hours. After cooling, a solution of 6 gr of Na2S2O5 in 15 ml
of water are slowly added, then it is diluted with 50 ml of
water. The residue is extracted from chloroform, the organic
phase is dried on MgSO4, filtered and evaporated. The oily
residue so obtained is solidified by addition of petroleum
ether and recrystallized with a mixture of ether and metha-
nol.
1.95 gr of product are so obtained.
MP(C) : 170.5.
;i Centesimal analysis
~!
C H N
Calculated, % 59.5 7.12 4.30
:. .
Found, % 58.95 7.15 4,10
The NMR spectrum confirms the threo configu-
.
ration.
~:
~; 20 Example 4.
1-(4-Isopropylthiophenyl)-2-~3-(carbomethoxy~propylamino~-
`~: 1-propanol.
(Table I, n 13).
17 gr of 2-bromo-1-(4-isopropylthiophenyl~-1-
propanone, 200 ml of methanol, 17.3 ml of triethylamine and
10 gr of methyl ~-aminobutyrate (hydrochloride) are refluxed
- for 17 hours.
The solution is then cooled to a temperature
of 5C and 4.5 gr of NaBH4 are slowly added. The reaction
i~
.~
-
, :...... - ' . ' ' . - ' .
: ~: - ~
il2716
17
mixture is then stirred overni~ht at room temperature. ~fter
vacuum evaporation of the solvent and dilution of the resi-
due with water, it is extracted from chloroform. The chloro-
fornl solutions are collected, dried and filtered, then the
solvent is eliminated by vacuum distillation. Thus 13.4 gr
of crude product are obtained ; this crude product, after
having prepared hydrochloride in a diethyl ether-methanol
(50/50) mixture, gives 12.4 gr of product. Yield : 58% ; MP
(C) : 175.6.
The conformity of the structure has been che-
cked by mass spectrometry.
Centesimal analysis.
C H N
Calculated, % 56.41 7.79 3.87
Found, % 56.10 7.65 3.75
; The NMR spectrum confirms the erythro confi-
guration.
; Example 5.
1-(4-Isopropylthiophenyl)-2-~3-(carboxy)propylamino~-1-pro-
panol.
(Table I, n23).
7 gr of 1-(4-isopropylthiophenyl)-2-~3-me-
thoxycarbonyl)propylamino~-l-propanol are dissolved in 70 ml
of water and 7 ml of concentrated hydrochloric acid are ad-
ded thereto. The solution is heated at 80C for 1 hour,
allowed to cool, ~he solvent is driven out under vacuum,
then one crystallizes in a methanol-ether mixture.
Weight : 4.5 gr ; Yield : 68% ; MP (C) : 197.5
l~Z~64
~8
Centesimal analysis :
C ll N
Calculated, % 55.24 7.53 4.03
Found, % 55.35 7.50 3.80
Example 6.
1-(4-Isopropylthiophenyl)-2-~ 2-oxopyrrolidinyl)~-1-pro-
panol(erythro).
(Table I, n24.
6 gr of 1-(4-isopropylthiophenyl-2-~3-(carbo-
xy)propylamino~ propanol are dissolved in a mixture con-
taining 100 ml of methanol and 50 ml of water. The pH is
brought to 13 by addition of a lON sodium hydroxide solu-
tion. After stirring for 1 hour at room temperature, metha-
nol is evaporated, extraction is made with chloroform, the
organic phase is dried on MgSO4 and the solvent is evapora-
ted. The product solidifies in petroleum ether and is then
recrystallized with ether. 1.3 gr of product are collected,
namely a yield of 27%. MP (C) : 80. The conformity of the
structure is established by NMR and mass spectrometry (ery-
thro configuration).
, Centesimal analysis.
I C H N
; Calculated, % 65.49 7.90 4.77
Found, % 65.15 7.70 4.75
Example 7.
1-(4-Isopropy~thiophenyl)-1,2-propanediol.
(Table I, n 18).
; 170 gr of 1-(4-isopropylthiophenyl)-2-hydro-
~ xy-1-propanone are dissolved in 1500 ml of methanol, then
' : - .
~12716
cooled to 0C, 57.4 gr of sodium borohydride are slowly ad-
ded ~ith stirring overnight at room temperature. The solvent
is evaporated, one dilutes with water, then e~tracts from
chloroform and dries on MgS04. After solvent evaporation,
recrystallization is made in a benzene-hexane mixture.
; Weight : 66.8 gr ; yield : 39 % ; MP (C) 83-85.
The NMR spectrum confirms the erythro confi-
guration of the product so obtained.
Centesimal analysis :
C H
Calculated, % 63.68 8.01
Found, % 63.50 8.05
Example 8.
1-(4-Mercaptophenyl)-2-n-octylamino-1-propanol.
(Table I, n40).
To a solution containing 5.25 gr of lithium,
1000 rnl of liquid ammoniac and 500ml of tetrahydrofuran, a
~, solution comprising 16 gr of 1-(4-isopropylthiophenyl)-2-n-
octylamino-l-propanol in 500 ml of tetrahydrofuran is slowly
added. After the addition is complete, stirring is still
continued for about 15 minutes, then 16 ~r of NH4Cl are ad-
ded in small portions.
The ammoniac is slowly evaporated in a wa-
ter-bath, then the residue is diluted with water. The solid
so obtained is filtered and recrystallized with methanol.
12 gr of 1-(4-mercaptophenyl)-2-n-octylami-
no-l-propanol are thus obtained.
MP (C) : 110-112 ; Yield : 82,1%.
- ~ :, :
~1~716
Centesimal analysis
C H N
Calculated, % 69.10 9.90 4.74
Found, % 69.40 10.10 4.60
As already hereinabove mentioned, the deri-
vatives according to the invention may be as their salts or
esters.
` Specific esters are those having the formw-
lae
Cl~3 cH-cll-N~ c8ll]7 . I~Cl
0,C,-c~2-C(C1~)3
l MP ( C) : 112-114
i! '
C 1/- S 0 ~3 C H - CH - NH nC8H 17 . HC 1
. O-C-Ct~3
O
MP (C) : 14~,5 _ 150
The melting points of the derivatives mentio-
ned in the examples, as well as of other derivatives prepa-
red according to the invention are given in the following
table.
~, ~
~127164
`" 21
~ _ " _ ~
_ . ~ ~ C Z
~-- Z L~ O T
., ~ I~ O C~ O
~ D ¦ ~ T C 1 C T ~o ~` ~ ~
~. ~ _
',, .
. ~
. ~ ¦ O O O O O C~
~: I
.,> t ~
O O o o O o O
H
_..
) W1~ O
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7164
26
(1) the recrystallization solvent is given between brackets.
(2) the elementary analyses were made for C, H, N elements
and are in agreement with theoretical values.
(3) melting point of hydrochloride.
(4) erythro configuration.
(5) threo configuration.
(6) erythro/threo mixture.
The compounds according to the invention,
while being sparingly to~ic, are generally endowed with ac-
tivities on the cardiovascular systems, in particular anti-
spasmodic, antihypertensive, peripheral vasodilator acti-
vies, hypolipidemient, normolipoproteinemic, antithrombic
activities, an inhibing activity against platelet aggrega-
tion. Thus they can in particular be useful in the treatment
of cardiovascular affections which are bound or not to athe-
rosclerosis. Furthermore, they could also reveal as useful
as agents stimulating cerebral metabolism or as tranquilli-
zers.
The effect on the behaviour has been studied
while using a method deriving from that of S.lrwin (Gordon
Res. Conf. on Medicinal Chem., 133, 1959). The substances in
suspension in a 1% tragacanth gum mucilage were administered
orally by means of an intragastric probe to 5 groups of male
mice (CCD1 strain, Charles River, fasted from 18 hours). If
the available amount of substance allowed it, the doses were
3000, 1000 and 300 mgr/kg. When the substance was active,
the effect of the drug was checked at 100, 30, 10 and possi-
bly 3 mg/kg. The behaviour was studied 2, 4, 6 and 24 hours
after treatment. The observation was continued when symptons
. .
llZ7164
were persistent at that time. The mortalities were registe-
red during the 14 day period following the treatment. The
LD50 values were calculated according to the Hitchfield and
Wilcoxon method (J.Pharmacol Exp. Ther., 96, 99, 1949) and
expressed as mgr/kg.
The results given as relating to the effects
on the behaviour show the minimal active dose in mgr/kg
(MAD) and the observed symptomatology. The LD50 values are
given with their confidence limits (p = 0.95). Under these
conditions, an appreciable activity level was observed, in
particular concerning compounds 6, 13 and 20.
The antihypertensive activity was tested by
oral administration to spontaneously hypertensed unanaesthe-
tized rats, of which the systolic arterial pressure was mea-
sured at the level of the median coccidial artery by means
; of a plethysmographic method (J.Roba, G.Lambelin, A.F. De
Schaepdryver, Arch.int.Pharmacodyn. 200, 182, 1972).
The arterial pressure was measured every 30 minutes, from
two hours before to three hours after oral administration of
the products tested at 60 mgr/kg or of a placebo (1% traca-
ganth gum mucilage).
Only rats with a systolic pressure of 180 to
220 mm Hg were used. Two rats were used for each product.
The treatments were administered without the knowledge of
the persan making the measures. The antihypertensive effects
` were noted by a score followed by an index. The scoring sys-
tem was as follows.
0 : reduction < lO mm Hg
+ : reduction of 10 to 20 mm Hg
,
11~,716~a
2~
++ : reduction of 20 to 30 ~m H~
+++ : reduction of 30 to 50 mm Hg
++++ : reduction > 50 mm Hg.
The index was calculated by multiplying the
systolic pressure difference (cm Hg) measured every 30 minu-
tes after the treatment, by a coefficient of 1 to 6 corres-
ponding to the time periods of 30 to 180 mintes.
Vnder the test conditions,~ -methyldopa has
been scored ~++ (47) at 100 mg/kg ; reserpine +++ (53) at
3 mgr/kg ; and guanethidine : +++ (62) at 60 mgr/kg.
In these tests, an interesting antihyperten-
slve activity was presented in particular by products 6 and
7.
The peripheral vasodilator activity of the
products was measured on anaesthetized dog at the level of
the femoral arterial circulation. To this end, the femoral
artery whose the collaterals have been ligatured was perfu-
sed with a steady flow rate of blood taken from aorta. The
' :
perfusion pressure, measured at the level of the femoral ar-
~,~ 20 tery, thus varied as a function of the resistance of the
perfused area. The tested products and the corresponding
solvents were directly injected into the stream at a dose of
30 mg/kg. The blood circulation being maintained constant, a
vasodilation was thus measured by a decrease of the perfu-
.;
sion pressure. The latter was scored with respect to the ac-
tion of papaverine, considered as standard and injected once
per group of four products.
When being interesting, the products were
tested at other doses under the same conditions. The vasodi-
- . . . . -
: , ,.: - -
1127164
29
lator activity was appreciated as follows :
0 : inactive, reduction < 10 mm HG
+ : 1/3 of the papaverine activity
++ : 2/3 of the papaverine activity
+++ : activity equal to that of papaverine
++++ : activity higher than that of papaverine.
Amongst the products according to the inven-
tion, a peripheral vasodilator activity equal or higher than
that of papaverine was observed in particular with compounds
5, 6 and 20.
The antispasmodic activity of the studied
substances was examined against contractions of guinea pig
ileum such as induced by histamine and acetylcholine. These
tests allow to reveal an antihistaminic, anticholinergic or
musculotropic activity. The response to the contracting
agent (sub-maximum concentration) was obtained every 5 minu-
tes before and after injection of increasing doses of the
; tested products (10 7 M to 10 4 M). The inhibition percen-
tage under the influence of the tested products was calcu-
lated and the theoretical concentration giving 50% inhibi-
tion was graphically determined for each experience. Theses
values are expressed as -log IC50 (M). In this test, com-
pounds 5 and 6 in particular revelated as active.
The blood platelet aggregation was studied
according to the turbidimetric method of G.V.R. Born and
N.J. Cross (J.Physiol., 168, 178-195, 1973). The plasma rich
in platelets was preincubated for 4 minutes before introduc-
tion of the inductor (Thrombofax). The slight variations we-
re registered for a period of 10 minutes with a aggregometer
- . : ~ . . .
'' ' '
11;2~164
"Upchurch". The inhibition of the amplitudes of the maximum
aggregation was measured. This test has shown that in parti-
cular compounds 5, 6, 13 and 14 were active.
For the e~amination of the lipolysis inhibi-
tion, epididymal fat was taken from fasted rats. Fragments
of adipose tissue (+ 150 mgr) were incubated in the Krebs-
Ringer buffer containing 3% albumin of bovine serum and thesubstance to be studied. A sample at the time 0 was taken
after an incubation of 30 minutes at 37C. Norepinephrine
was used for inducing lipolysis. The rate of free amino-
acids was measured after 20 minutes of incubation (Duncombe,
W.G., Clin.Chim.Acta. 8, 122, 1964). In this test, compounds
5, 6, 8 and 13 were in particular active.
The inhibition of the cholesterol biosynthe-
sis was studied as follows.
Buffered homogenates of rat liver were enri-
ched with suitable cofactors. Aliquots were incubated for 60
minutes with 1-14C acetate and the compound to be studied.
After saponification of the medium, sterols were extracted
from petroleum ether and the dry residue was precipitated by
digitonine in a alcohol-acetone solution. The content in 14C
of the precipitate dissolved in pyridine was measured by li-
qwid scintillation counting according to the method descri-
bed by N.Bucher (~.Biol.Chem., 222, 1-15, 1956~. Under these
conditions, an appreciable activity level was shown by com-
pounds 1, 13 and 15 in particular.
The inhibition of bioamine uptake by synapto-
somes was studied by isolating synaptosomes of rat brains
after partial subcellular fractionation in sucrose gradient
:
112'71~4
31
(Gray R. G. and Whittaker V.P., J.Anat. 92, 79, 1962). The
uptake of 5-HT (serotonine) was made as follows.
After incubation for 5 mintes of the tested
product with synaptosomes, the preparation was incubated for
5 minutes at 37C in the presence of 14C-5HT, filtered on a
"Millipore" filters and filters were washed with iced
buffer. The radioactivity of the filters was measured by li-
quid scintillation counting. The uptake is the difference
between the radioactivity measured at 37~C and that measured
at 0C. In this test, compounds 5, 6, 13 and 14 were active
in particular.
The active compounds according to the inven-
tion may be administered in association with various phar-
maceutical exceptients orally, parenterally or rectally.
For oral administration, pills, granules, lo-
zenges, capsules, and tablets and capsules with controlled
release of the active agent will be used, and also sublin-
gual tablets, solutions, syrups, emulsions containing tra-
ditional additives or excipients in galenic pharmacy. For
parenteral administration, sterile water or an oil, such as
peanut oil or ethyl oleate will be used. For rectal adminis-
tration, suppositories or rectal capsules will be used.
These active compounds may be used alone or
in association with other active products ha-ving a similar
or different activity.
The products of the invention may be used as
different forms. The following examples are not limitative
and relate to galenic formulations containing as active pro-
., duct, designated by "A" hereinafter, one of the following
~ ;
11;~3~64
32
compounds :
1-(4-isopropylsulfinylphenyl)-2-~1-(2-oxopyrrolidinyl)~-1-
propanol
1-(4-isopropylsulfinylphenyl)-2-n-octylamino-1-propanol.
Intramuscular injection
A 10 mgr
Isopropyl myristate 0,75 ml
Peanut oil, q.s.ad 3 ml
Intravenous injection
A 10 mgr
L-aspartic acid 6 mgr
Benzyl alcohol 50 mgr
Distilled water, q.s.ad 5 ml
Solution for oral administration
A 5 mgr
Ethyl alcohol 0,1 ml
Propylene glycol 0,05 ml
10% Acetic acid 0,05 ml
Simple syrup (65% saccharose) q.s.ad 1 ml
A 5 mgr
Ethyl alcohol 0,2 ml
10% Acetic acid 0~04 ml
Simple syrup 3 q . S . ad 1 ml
Tablets
A 50 mgr
716~ ,
33
Lactose 20 mgr
Aerosil 2 mgr
Starch STA-RX 1500 (Trademark) 18 mgr
Calcium phosphate (CaHPO4)25 mgr
Microcrystalline cellulose100 mgr
Sodium acetate 15 mgr
A 50 mgr
Corn starch 50 mgr
Sodium acetate 15 mgr
10 Magnesium stearate 2 mgr
Aerosil (Trademark) 3 mgr
Starch STA- RX 1500 (Trademark) 80 mgr
Sublingual tablets
A 25 mgr
Lactose 117,75 mgr
Soluble starch 10 mgr
; Sodium saccharine 0,25 mgr
i Gelatine 3 mgr
A 25 mgr
20 Lactose 150 mgr
Saccharose 25 mgr
glycine 2.5 mgr
Stearic acid 0.5 mgr
Capsules
A 50 mgr
~1
.
11271¢4
34
Starch STA-RX 1500 (Trademark)100 mgr
Magnesium stearate 1 mgr
Sodium laurylsulfate 10 mgr
Microcrystalline cellulose 30 mgr
Aerosol (Trademark) 1 mgr
Soft capsules
A 220 mgr
Liquid paraffin 222 mgr
Soja lecithin 8 mgr
Controlled release capsules
A 50 mgr
Lactose 45 mgr
Polyvinyl pyrrolidone 15 mgr
Mannitol 5 mgr
Eudragit E (Trademark) 1 mgr
Suppositories
A 150 mgr
Lidocaine 20 mgr
Novata 299 grad. (Trademark~2000 mgr
20 A 100 mgr
Witepsol S 58 grad. (Trademark) 2000 mgr
The meaning of some terms used in the above galenic
formulations is given hereinafter -
- Aerosol (Trademark): finely divided silicium dioxide
~'
6~
- Starch STA-RX 1500 (Trademark): cornstarch
- ~idocaine : trade name for lignocaine
- Novata 299 grad. (Trademark) : mixture of saturated Cll-C17
fatty acid triglycerides with
partial glycerides of acetyla-
ted fatty acid
- Novata B grad. (Trademark) : mixture of saturated Cll-C17
fatty acid tri-, di- and mono-
glycerides
- Witepsol S 58 grad. (Trademark): mixture of C12-C18 natural
triglycerides
- Eudragit E (Trademark) (Rohm) : polymer of acrylic acid di-
methylaminoethyl ester
According to the case, the administration way, the
kind of researched activity and the kind of specific compound
used, l-phenyl-l-propanol derivatives according to the invention
are administered at daily doses of 5 to 3000 mgr and as intra-
venous injection the l-phenyl-l-propanol derivatives according
to the invention are administered at daily doses of 1 to 20 mgr;
~,.
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