Note: Descriptions are shown in the official language in which they were submitted.
ALKYLTHIOPHENOXYPROPANOLAMINES
Field of the Invention
_ _
This inventioll pertair.s to carbon compounds having drug
and bio-affecting properties. It is particularly concerned with new
and usefui al~ylthiophenoxypropanolamines use thereof in pharlna-
ceutical preparations and therapeutic methods and processes for
producing th~ alkylthiophenoxypropanolamines. The alkyltbio-
phenoxypropanola~ines of this invention increase peripheral. b-ood
flow, relax vascular smooth muscle, and inhibit p].atelet aggregatl~
and are considered to be particularly useful ln the ;reatDen~ of
obstructive ~erî.pltera; vascular diseases such as interlL.tLent
claudication and cerebrovasc~ r dericiencies associ.ated with
arteriosclerosis.
3~i
Description_of the Prior Art
Various alkylthiophenoxypropanolamine modifications have
been described and studied in the field of adrenergic agents primarily
for the purpose of uncovering more potent and selective beta-
adrenergic blocking agents free of unwanted pharmacologic effects.Such compounds are generally considered useful in treating certain
forms of hypertension, angina pectoris, heart arrhythmia and pheo-
chromocytoma. Representative of these efforts are compounds described
in the following patents and publications.
L. Villa, et al., Il. Farmaco. Sci., Ed. 24, 349-357
(1969) specifically discloses the following alkylthiophenoxypropanol-
amine compound as part of a structure-activity-relationship study.
~ OH
C~3S - ~ OcH2cHcH2NHc-~(cH3)2
Keizer, et al., U.S. 3,542,874 patented ~ovember 24, 1970
discloses 2-(alkylthio)phenoxypropanolamines of the formula
'OCH2CHCH2NH-R2
*
wherein Rl is an alkyl (Cl-C4) radical ahd R is inter alia an
alkyl (Cl-C12) or a cycloalkyl (C3-C12) radical. This paten,
teaches that co~pounds of this type have very effective beta-
adrenerg'c bloc~ing properties. Specific compounds disclosPd by
Keizer, et al. include ,hose wnerein R is methyl or ethyl and R is
isopropyl; Rl is methyl, ethyl, or propyl and R is tert -butyl; R~
ls methyl and R is cyclopropyl, cyclopentyl, or cyclohexyl; R is
tert.-butyl .~nd R is cyclopentyl.
Crowther, et al., U.S. 3,501,769 patented March 17, 1970
generically discloses compounds of the type
~} OCH2C-rlCH-N~-F2
Rls R3
wherein R is alkyl (up to 10 C); R is alkyl (up to 20 C), cyclo
alkyi (up to 10 C), etc.~ R is hydrogen or alkyl (up to 10 C).
~lotwithstanding the scope of the generic disclosure, Cro~ther, et al.
does not des;ribe a single example of a specif~ic "alkylthio' compound.
Koppe, et al., ~.S. 3,872,147 pa,ented March 18, 1975
generically discloses alkylthiophenoxypropanolamines illustrated by
tne formula
~ OC~2CUCH ~H R2
-~herein R is alkyl (1-4 C); ~ is alkyl (Cl-C5); R is alkyl ~C5-
C8) containing at least one quatPrnary carbon attached directly
through an alkylene chain (Cl-C4) to ths amino nitrogen atom. None
of the specifically disclosed ~oppe, et al. compounds, however,
constitute an example Gf an "alkylthiophenoxpropanolamine'~.
Offenlegungsschrift 2,551,141 published ~ay 18, 1977,
specifically ciescribes the al'.cylthiophenoxypropanolamine
.~ 63~
:.,
,
CH35 ~ OCUzCHCH2NH
3 : ;
~, ' .
As can be seen from the above prior art, numerous alkyl- : :
thiophenoxypropanolamines have been generically disclosed but ~-
relatively few alkylthiophenoxypropanolamines are specifically
described. Compared to the prior art compoDnds which are reportedly
beta-adrenergic blocking agents, the alkylthiophenoxypropanolami.nes
of the present invention are unique in that they redlue vascular
- ~', ':'`,''
resi6tance with minimal involvement of beta-adrenergic blocking :
effects.
Summary o~ the Inveotio~ :
:~
Broadly described,~the present invention is directed to .
a process for preparing an alkylthiophenoxypropanolamine compound
of formula I
R ~ OH A
~ B (I)
wherein A, B, and R are independently hydrogen or lower alkyl of 1 to
4 carbon a~oms lnclusive; Rl is alkyl of 1 to 8 carbon atoms inclusive;
R2 is alkyl of 6 to 12 carbon atoms inclusive or cycloalkylalkyl having
5 to 8 ring carbon atoms and from 2 to 6 carbon atoms in the alkylene
chain selected from the procesæ group consisting of:
(a) reacting an alkylthiophenol deriva~ive of formula Il
~ :.
Rl-S : :
B _ 4 _
- ' ,,, . . ~ ; ~ ,
i3~
wherein R and Rl have meanlngs hereinab.oye described with an epihalo-
hydrin of formula III
~ cu~cH2-X (III)
wherein X signifies halogen, preferably chlorine or bromine, and
condensing the epihalohydrin reaction product with an amine of
formula IV
H2N-R2 (TV2
wherein R2 has the meaning as in formula (I);
(b) reacting a formula II phenol with a compound of formula
VII in alkaline medium
~ O / 2 , 2 (YII2
to provide a compound of formula VIII
R
OH
~ OCH2CHCH2 N, R2 (VIII)
wherein R, Rl and R2 have the same meaning as in formula I and R3
stands for hydrogenolysable radicals benzyl or benzhydryl; and
converting said compound of formula VIII to an alkylthiophenoxy-
propanolamine of formula I by catalytic hydrogenation; and
(c) reducing a compound of formula IX
OH A
OCH2CH-C-N02 (IX)
Rl-S
wherein A, B, R and Rl are as defined to provide the primary amino
compound X
- 4a
~ ~6~36
~ OH A
OCH2CH~ (X)
Rl ,
and reductively alkylating a compound of formula X with an aldehyde
of formula XI
O
HC-Y (XI)
5 wherein Y is straight or branched chain alkyl of 5 to 11 carbon atoms :
inclusive or cycloalkylalkyl having 5 to 8 ring carbon atoms and 1 to
5 carbon atoms in the alkylene chain; and, if desired, reacting a compound
of formula I with an acid to form an acid addition salt thereof.
- 4b -
This invention is also concerned with pharmaceutical
compositions containing the alkylthiophenoxypropanolamines, and
further contemplates methods for both producing and employing the
compounds and compositions therapeutically.
Detailed Description of the Invention
The alkylthiophenoxypropanolamines provided by this invention
are represented by formula I
OH A
R ~
~ OCH2CH-C-NH-R2 (I)
Rl-S
wherein
A, B and R are independently selected from the group consisting
of hydrogen and lower alkyl of 1 to 4 carbon atoms
inclusive;
Rl is alkyl of 1 to 8 carbon atoms inclusive;
R2 is alkyl of 6 to 12 carbon atoms inclusive or
cycloalkylalkyl having 5 to 8 ring carbon atoms
inclusive and from 2 to 6 carbon atoms in the alkylene
chain, and
pharmaceutically acceptable acid addition salts thereof.
As used herein, the term "lower alkyl" refers to a carbon
chain comprised of both straight and branched chain carbon radicals
of 1 to 4 carbon atoms inclusive. Exemplary of these carbon chain
radicals are methyl, ethyl, propyl, isopropyl, l-butyl, l-methyl-
propyl, 2-methylpropyl, and tert.-butyl~
As used herein, the term "alkyl" refers to straight or
branched chain carbon radicals with the number of carbon atoms
comprising the particular alkyl radical specifically designated or
referred to by standard notations such as (Cl-C4), (Cl-C8) and
(C6-C12) .
As used herein, the term "cycloalkylalhyl" is intended to refer
to a cycloallcyl radical containing from 5 to 8 carbon atoms inclusive
(i.e., cyclopentyl, cyclohexyl~ cycloheptyl and cyclooctyl) connected
to the amino nitrogen atom by an alkylene chain of 2 to 6 carbons.
It is to be understood that the "alkylene chain" connecting the
cycloalkyl radical to the amino nitrogen atom may be linear or
branched.
As used herein, the term "non-toxic pharmaceutically
acceptable acid addition salts" refers to salts of compounds of
formula I formed with a variety of inorganic and organic acids, the
anions of which are relatively non-toxic. Such acid addition salts
are considered pharmacologically equivalent to the bases charact~rized
by structural formula I. ~xamples of useful salt forming acids are
acetic, Iactic, succinic, maleic, tartaric, citric, gluconic,
ascorbic, benzoic, cinnamic, fumaric, sulfuric, phosphoric, hydro-
chloric, hydrobromic~ hydroiodic, sulfamic, sulfonic acids such as
methanesulfonic, benzenesulfonic, p-toluenesulfonic, and related
acids. Acid addition salts of this invention are prepared and
isolated by conventional means; for insLance, by treating a solu~ion
or suspension of the fr.~e base ~n a reaction inert solvent with the
~ 3 ~
desired acid and recovering the salts which form by concentration
under reduced pressure or by crystallization techniques or other
standard chemical manipulations. Acid addition salts which are
somewhat toxic and therefore do not meet the foregoing criteria for
pharmacetical acceptability are sometimes useful as intermediates
for isolation and purification of the bases of formula I or fcr
other chemical purposes such as separation of optical isomers. Such
salts are also considered part of the invention.
As will be apparent tO those skilled in the art, the
compounds characterized by general formula I have one or more
assymmetric carbon atoms and can thus exist as optically active
isomers, racemates and diastereoisomers all of which are considered
as part of the p_esent invention. The diastereoisomeric mixtures
may, depending on physical-chemical differences of the components,
be separated into diastereomeric pure racemates by conventional
means such as chroma,ography and/or fractional crystallizatJon.
~eso]ution of racemates of the instant invention to provide optically
active isomers of formula T compounds is carried out by conventional
resolution methods. For instance, reacting the bases of formula I
with optically active acids provides salts thereof from which the
enantiomers may be separated by fractional crystallization. Acids
suitable for resolving the compounds of formula I are the optically
active forms of tartaric acid, di-o-tolyltartaric acid, diacetyl-
tartaric acid, dibenzoyltartaric acid, malic acid, mandelic acid,
camphorsulfonic acid, and other optically active acids known to the
art. Preferably, the more bio1Ogically active optically active
stereoisomer is isolated.
/
Contemplated sub-classes within the ambit of formula I
which further characterize the alkylthiophenoxypropanolamines of
the invention are compounds of formula I wherein
(Ia~ A, B and R are hydrogen and substituents Rl and R2
are as previously defined for formula I;
(Ib) A, B and R are hydrogen, Rl is methyl and substituent
R2 is as previously defined for formula I;
(Ic) A, B and R are hydrogen, Rl is methyl and substituent
R2 is (C6-C12) alkyl;
(Id) A, B and R are hydrogen, Rl is lower ~Cl-C4) alkyl
and R2 is (C6-C12) alkyl;
(Ie) A, B and R are hydrogen, Rl is (Cl-C8) alkyl and
R is (C -C 2) alkyl;
2 6
(If) A, B and R are hydrogen, Rl is isopropyl and
substituent R2 is as previously defined for formula I;
(Ig) A, B and R are hydrogen, Rl is isopropyl and R2 is
(C6-C12) alkyl;
(Ih) A, B and R are hydrogen, Rl is (Cl-C8) alkyl and R2
is n-octyl;
(Ii) A, B and R are hydrogen, Rl is (Cl-C4) alkyl and R2
is n-octyl;
(Ij) A, B and R are hydrogen, Rl is (Cl-C8) alkyl with the
RlS radical in the para-position and R2 is (C6-C12) alkyl;
(Ik) A, B and R are hydrogen, Rl is (Cl-C4) alkyl ~-ith the
RlS radical în the para-position and R2 is (C6-C12) alky ;
(Il) A, B and R are hydrogen, Rl is (Cl-C4) alkyl with the
RlS radi cal in the pa a-position and R2 ls n-octyl;
,
(Im) A, B and R are hydrogen, Rl is (Cl-C8) alkyl wlth
the RlS radical in the ortho-position and R2 is
(C6-Cl~) alkyl;
(In) A, B and R are hydrogen~ Rl is (Cl-C4) alkyl with the
RlS radical in the ortho-posit:ion and R2 is n-octyl;
(Io) A and B are hydrogen, R is (Cl-C4) alkyl in the rtho-
position, and R2 is n-octyl;
(Ip) A and R are hydrogen, B is (Cl-C4) alkyl, Rl is
(Cl-C4) alkyl with the RlS radical in the ~ -position,
and R2 is (C6-C12) alkyl;
(Iq) A and R are hydrogen, B is (Cl-C4) alkyl, Rl is (Cl-C4)
alkyl with the RlS radical in the para-position, and R2
is n-octyl;
(Ir) A and R are hydrogen, B is methyl, Rl is (Cl-C8)
. alkyl and R2 is (C6-C12) alkyl~
(Is) A and R are hydrogen, B is methyl, Rl is (Cl C8)
alkyl and R2 is n-octyl.
(It) A, B and R are independently hydrogen or lower
(Cl-C4) alkyl, Rl is (Cl-C8) alkyl with the R,S
radical in the ~ -position and R2 is (C5-C8)
cycloallcyl attached through an alkylene chain of 2 to
6 carbon atoms inclusive tc the amino nitrogen atom;
~Iu) A, B and R ar~ hydrogen, Rl is (Cl-C8) alkyl with
the RlS radical in the para-position and R2 is
(C5-C8) cycloalkyl attached through an alkylene
chain of 2 to 6 carbon atoms inclusive to the amino
nitrogen atom,
(Iv) A, B and R are hydrogen, Rl is (Cl-C8) alkyl with the
RlS radical in the meto-position and R2 is (C6-C12)
alkyl,
(Iw) A, B and R are hydrogen, Rl is (Cl-C4) alkyl with
the RlS radical in the meta-position and R2 is n-octyl.
According to a feature of the present invention, there i~
provided a process for preparing those alkylthiophenoxypropanol-
amines of formula I wherein A and B are limited to hydrogen which
comprises reacting an alkylthiophenol derivative of formula II
R ~
~ /~ OH (II)
T
Rl-S
wherein R and Rl have meanings hereinabove described with an
epihalohydrin of for~ula III
CH ~ CH-CH2-X (III~
0/
wherein X signifies halogen, preferably chlorine or bromine, and
condensing the epihalohydrin reaction product with an amine of
formula IV
82N-R2 . ~IV)
wherein R2 has the meaning hereinabove described; whereafter, if desired,
the formula I product in free base form is reacted with an acid to
form an acid addition salt thereof.
-- 10 --
The required formula Il alkylthiophenols are ob~ained by
coupling a diazotized aminophenol with an alkyl mercaptan to form a
diazosulfide wilich is then decomposed providing the corresponding
alkylthiophenol. This is a conventional method and adaptations
thereof are described in R. B. Wagner, and H. D. Zook, ~y~ ic
Organic Chemistry, page 739 (1953 Wiley); E. Miller, et al., J. Am.
Chem. Soc., 55, 1224 ~1933); S. Asak3, et al., Chem. Abrs. 61,
13243a.
Suitable Alkylthiophenol reactants of formula II which may
be employed in the present process include:
4-methylthiophenol,
4-ethylthiophenol,
4-n-propylthiopheno~,
4-n-butylthiophenol,
4-n-pentylthiophenol,
4-n-hexylthiophenol,
4-n-heptylthiophenol,
4-n-octylthiophenol,
4-isopropylthiop'nenol,
4-(3-methylbutyltilio)phenol,
2-n-butylthiophenol,
3-n-butylthiophenol,
2-ethylthiophenol,
2-n-propylthiophenol,
2-isopropylthiophenol,
3-ethylthiophenol,
3-n-propylthiophenvl,
3-isopropylthiophenol,
2-methyl-4-(methylthio)phenol,
3-methyl-4-(methylthio)phenol.
Suitable amines of formula IV which may be employed in
the present process include:
n-hexylamine,
n-heptylamine,
n-octylamine,
n-nonylamine,
n-decylamine,
_
n-undecylamine,
n-dodecylamine,
n-isoactylamine,
2,2-dimethylhexylamine,
l,l-dimethylheptylamine.
Inasmuch as an epiha].ohydrin molecule of formula III has
two reactive positions, reaction with an alkylthiophenol of formula
II may yield a mixture of formulas V and VI reaction products
wherein R, P~l and X are as defined above.
OH R ~
OCH2CHCH2-x ~ CH2CH - CH
Rl-S ~l-S
(V) ~VI)
During the furtller course of the process, however, the two
possible intermediat~s of formula V and formula VI on. condensation
- .2 -
i3~.o
with a formula IV amlne yield the same final alkylthiophenoxypropanol-
amine product. Consequently, it i3 not necessary to effect a
separation of any mixtures of intermediates of formulas V and VI
which may result from interaction of a formula II phenol with a
formula III epihalohydrin. Under the reaction conditions employed
in the instant process, the epoxides of formula VI are preferentially
formed.
If desired, the epihalohydrin reaction product may be
taken up in an inert solvent such as chloroform and shaken with
excess concentrated hydrochloric acid to convert epoxides of formula
VI into the corresponding formula V alkylthiophenoxy-halohydrin.
Conversely, if desired, the halGhydrins of formula V may be converted
to the corresponding formula VI by a conventional methods, e.g., by
treatment with base according to the procedure of 0. Ste?henson, J.
15 Chem. Soc., 1574 (1954).
The interaction of formula II phenols with fGrmula III
epihalohydrins is carried out in the presence of a sufficient amount
of a dilute aqueous alkaline metal hydroxide such as sodium hydroxide
to neutralize the acidic p~enolic group at temper tures in the range
20 of 0-100 and preferably at 25-35 according to the procedure of
Y. M. Beasley, et al., J. Pharm. Pharmacol., 10, 47-59 (195$).
Alternatively, the interaction of formula II phenols with
fornula III epihalohydrins can also be effected with catalysts such
as N-benzylisopropylamine hydrochloride, pyrrolidine, pyridine,
piperidine, piperidine acetate, piperidine hydrochloride, and the
like with an excess of epihalohydrin.
The condens~tion of the epillalohydrin reaction product of
formula V or VI with a formula IV amine is carried out ?referably in
organic solvent inert under the reaction conditions. Suitable
solvents include methanol, ethanol, butanol, hexanol, toluene,.
dioxane, tetrahydrofuran, dibutylether, dimethoxyethane, ethylene
glycol. The condensation can also be effected in the ab~ence of a
reaction solvent with equimolar amounts of the react&nts.
Another feature of the present invention involves an
alternate method for producing compounds of formula I wherein A
and B are limited to hydrogen which comprises reacting a formula II
phenol with a compound of formu.a VII in alkaline medium
,
C ~ ~-CH2-N-R (~II)
to provide a compound of f ormula VIII
R ~ OH
OcH2cHcH2-N-R2 (VIII)
Rl-S
wherein R, R~ and R~ have the same meaning as in formula I and R3
stands for hydrog~nolysabl.e radical such as ben~yl or benzhydryl;
and converting said compound of formula VIII to an alkylthiopheno~y-
propanolamine of formula 1. Removal of ,he hydrogenol-J~able blockirg
group may be effected by catalytic hydrogenation, for e~amp].e by
- 14 -
hydrogenation in the presence of palladium-on-charcoal catalyst, in
an inert solvent, e.g., ethanol or aqueous ethanol.
The compounds of formula ~II may be obtained according to
known methods. ~or example, l-[(N-ben~yl)-n-octylamino]-2,3-epo~y-
propane is obtainea by reaction of N-benzyl-n-octylamine and epichloro-
hydrin in alkaline medium (e.g., aqueous potassium hydroxide) accordingto the method described by L. Villa, et al., Farmaco., Ed. Sci.,
24(3), 349-357 (196g).
A further feature of the invention is directed to a method
for producing compounds of formula I wherein A, B, and R are
independently selected from the group consisting of hydrogen
and lower (Cl-C4) alkyl, Rl is (Cl-C8) alkyl, and R2 is (C6-C12)
straight or branched chain alkyl with the carbon atom thereof
attached through a divalent methylene (i.e. -CH2-) radical to the
amino nitrogen atom or (C5-C8) cycloalkyl attached through an alkylene
chain of 2 to 6 car~on atoms inclusive wherein said alkylene chain
is attached through a divalent methylene (i.e. -CH2-) radical to the
amino nitrogen atom which comprises sequenti~l steps of reducing a
compound of ~ormula IX
R OH A
OCH CH-C-NO2 (IX)
Rl-S
wherein A, B, R and Rl are as defined to provide the primary amino
compound X
OH A
'Q+s~ OC~12CH-C-~H~ (X~
Rl-S
- 15 -
&3~
wherein A, B, R and Rl are as defined, and reductively alkylating
compound of formula X with an aldehyde of formula XI
o
HC-Y (XI)
wherein Y is straight or branched chain alkyl of 5 to 11 carbon
atoms inclusive or cycloalkylalkyl having 5 to 8 ring carbon atoms
and 1 to 5 carbon atoms in the alkylene chain.
The nitro alcohols of formula IX are obtained by an aldol-
type condensation of a?propriate nitroalkanes and aldehydes in the
presence of base or by condensation oE the Rodium salt of the nitro
alkane with sodium bisulfite addition products of the aldehyde in
the presence of a trace of alkali or weak acid. Alkylthiophenoxy
aldehyde starting materials are obtained by reac~ng
the appropriate alkylthiophenol with the diethylacetal of bromo-
acetaldehyde followed by acid catalyzed hydrolysis of the acetal
g~oups .
As stated hereinabove, the alkylthiophenoxypropanolamines
of the present invention increase peripheral blood flow, relax
vascular smooth muscle, and inhibit platelet aggregation. The
compounds are substantially fr~e of beta-adrenergic blocking effects
which inhibit peripheral vasodilating activity of beta-adrenergic
stimulatory endogenous amines. Standard in vivo and in vitro
pharmacological test methods can be employed in assessing the
activity of compounds characterized by formula I. Among such tes.s
consider~d useful are the perfused dog hind limb preparation (vaso-
dilator action~, the spasmogen-challanged rabbit ~ortic strip
(antispasmodic activity) and nhibition of adenosine diphosphate and
-- 1 o
collagen-induced platelet aggregation in human platelet-rich plasma
(antithrombogenic action~. The isoproterenol chal'enged gulnea pig
trachea test, which is standard in the art, is suitable for mezsuring
beta-adrenergic blocking action.
In addition to having vasodilating, antispasmodic and
inhibition of blood platelet aggregation properties, some of the
compounds of Formula I inhibit lipoly3is (as shown in the rat
epidimal fat pad lipolysis model) and cholesterol biosynthesis.
Compounds of this type are of value as hypocholesterolemic agentC.
Another aspect of the in~tant invention concerns a thera-
peutic process for treating a mammal requiring vasodilation which
comprises systemically administerïng to the mammal an effective
vasodilating amount of a compound selected from the group charac-
terized by formula I and pharmaceutically acceptable non-toxic acid
addition salt thereof.
As used herein, the term "effective vasodilating amOuDt"
is construed to mean a dose which exerts a vasodilator effect in the
effected mammal without untoward side effects.
By systemic administration, it is intended to include both
oral and parenteral routes. ~xamples of parenteral administration
are intramuscular~ intravenous, intraperitoneal, rectal, and sub-
cutaneous administration. In rec,al adminlstration, both ointments
and suppositories may be employed. While the dosage will vary to
some extent with the mode of administration and the particular
compound chosen, from about 0.5 Dlg. per kg. body weight ~o 25 mg.
per ~g. body weight of a co~pound characterized by formula I or non-
toxic pnarmaceutlcaliy accepLable salts thereof administered i-.l
3~
effective single or multiple dosage units generally provides the
desired vasodilating e~fect.
In carrying out the therapeutic process of the instant
invention, the formula I compounds are generally administered for
vasodilating purposes in the form of a pharmaceutical preparation
containing either a formula I free base or a pharmaceutically
acceptable non-toxic acid addition salt thereof as the active
component in combination with a pharmaceutically acceptable carrier.
The carrier may be solid, semi-solid, liquid diluent or a capsule.
Accordingly, a further feature of the instant invention is directed
to pharmaceutical compositions containing the compounds of formula I
or non-toxic pharmaceutically acceptable acid addition salts thereof
in combinaticn with a pharm2ceutically acceptable carrier.
For the preparation of pharmaceutical compositions con-
taining the compounds of formula I in the form of dosage units fororal administration, the compound is mixed with a solid, pulverulent
carrier, (e.g. lactose, sucrose, sorbitol, manni,ol, potato starch,
corn starch, amylopectin, cellulose derivatives, or gelatin) as well
as with an anti-friction agent (e.g. magnesium stearate, calcium
stearate, polyethylene glycol waxes or the like) and pressed into
tablets. The tablets m~y be used uncoated or coated by conventional
techniques to delay disintegration and absorption in the gastro-
intestinal tract thereby providing a sustained actior. over a longer
time period. If co~ted tablets are wanted, the above prepared core
may be coated with concentrated solution of sugar, which solution
may contain e.g. gum, arabic, gelatin, talc, ~itanium dioxide, or
the like. Furthermore, tablets may be coated with a lacquer clissolved
3~
in an easily volatile organic solvent or mixture of solv~nts. If
desired, dye may be added to this coating.
In the preparation of soft gelatin capsules or in the
preparation of similar closed capsules, the active compound is mixed
with a vegetable oil. Hard gelatin capsules may contain granules of
the active ingredient in combination with a solid, pulverulent
carrier such as lactose, saccharose, sorbitol, starch, (e.g., potato
starch, corn starcn, or amylopectin), cellulose derivatives or
gelatin.
Dose units for rectal administration may be prepared in
the form of suppositories containing the active substance oE formula I
in mixture with a neucral fat base, or they may be prepared in form
Gf gelatin-rectal capsules conta~ning the active substance in a
mixture with a vegetable oil or paraffin oil.
Liquid preparations for oral administration may be present
in the form of elixirs, syrups or suspensions containing from about
0.2% by weight to about 20% by weight of the ac~ive ingre~ient.
Such liquid preparations may contain coloring agents, flavoring
agents, sweetening agents, and carboxymethylcellulose as a thickening
agent.
Suitable solutions for parenteral administration by
injection may be prepared as an aqueous solution of a water-soluhle
pharmaceutically acceptab]e salt of the comT)ounds of formula I
adiusted to a physiologically acceptable p~. These solutions may
also contain stabilizing agents.
Pharmaceutical tab~ets for ora] use are prepar~d by conventional
methods involvil~g mixing the ~herapeutic compound of formula I and
necessary axillarv agents.
_ 19 _
Specific alkylthiophenoxypropanolamines of the invention
are those hereinafter described in the examples. Of these9 compo~mds
particularly preferred for their vasodilating properties and
absence of significant beta-adrenergic blocking activity are:
1-[4-(methylthio)phenoxy]-3-(octylamino)-2-propanol,
1-[4-[(1-methylethyl)thio]phenoxy]-3-(octylamino)-2-
propanol,
1-[3-[(1-methylethyl)thio]phenoxy]-3-(octylamino)-2-
propanol,
1-[4-[(1-methylethyl)thio]phenoxy]-3-(dodecylamino)-2-
propanol,
1-[(2-cyclohexylethyl)amino]-3-[4-[(1-methylethyl)thio]-
phenoxy]-2-propanol,
1-[(4-cyclohexylbutyl)amino]-3-[4-~(1-methylethyl~thio]-
phenoxy]-2-propanol,
1-[2-methyl-4-(methylthio)phenoxy]-3-(octylamino)-2-
propanol,
1-[2-(methylthio)phenoxy]-3-(octylamino)-2-propanol.
The following examples illustrate but do not limit the
scope of the invention. All temperatures expressed herein are in
degrees centigrade.
EXAMPLE 1
l-[4-(Methylthio)phenoxy]-3-(octylamino)-2-propanol
~ OH
3 ~ OCH2CHCH2~H-(CH2)7CH3
A solution of 4-(methylthio)phenol (5,6 g., 0.04 moles)
25 and soclium hydroxide ~2.4 g., 0.06 moles) in 50 ml. of water is
- 20 -
treated ~ith epichiorohydrin (7.4 g., 0.08 moles). The resulting
mixture is first stirred at 30-35 for 24 hr. and then extracted
with chloroform. After washing the chloroform extract with water
and drying over magnesium sulfate, distilla~les are removed under
reduced pressure to provide the epichlorohydrin derivative 1-(4-
methylthlo)phenoxy-2,3-epoxypropane which is taken up in 30 ml. of
ethanol, treated with n-octylamine (7.5 g., 0.06 mole) and refluxed
for a period of 4 hr. Concentration of the reaction mixture under
reduced pressure to about one-half volume provides a white solid
which is collected and crystallized from ethanol to afford a 21%
yield of analytically pure 1-[4-(methylthio)phenoxy]-3-'octylamino)-
2-propanol, m.p. 79.5-80.5 (corr.).
Anal. Calcd. for C18H31NO2S: C, 66.42; H, 9.60; N, 4.30;
S, 9.85. Found: C, 66.30; H, 9.69; N, 4.13; S, 9.58.
EXAMPL~ 2
1-[4-~(1-Methylethyl)thio]phenoxy]-3-
(octylamino)-2-propanol Hydrochloride
~ OH
(Cl~3)2cH-s ~ OcH2cHcH2~-(cH2)7c~3
(a) 4-(Isopropylthio)phenol.- A solution of sodiun
nitrite (113.8 ~., 1.65 mole) in 210 ml. of water is added to a
stirred solutiGn of p-aminophenol (163.7 g., 1.5 mGle) in 825 ml.
of 4 N hydrochloric acid at -5 . After stirring for an additional
2 hr. period at -5, the solution of the diazotized phenol is added
over a 45 min. period to a previously prepared cold (-5) solution
of sodium hydroxide (270.6 g., 6.77 moles) and 2-propanethiol
- 21 -
(126.4 g., 1.66 moles) in 525 ml. of water with the reaction maintained
under a nitrogen atmosphere. I~hen addition is complete, the mixture
is permitted to warm to 27 and is kapt at that temperature for a
period of 16 hr. Then, the mixture is cooled to Oc and acidified
with 570 ml. of 12 N hydrochloric acid. Excess 2-propanethiol is
removed by bubbling nitrogen gas through the acidified solution
into a permanganate trap for a 2 hr. period. The resulting solution
is extracted with several portions of dichloromethane and the combined
extracts washed with water, dried over magnesium sulfate containing
charcoal and filtered. Concentration of the filtrate under reduced
pressure provides a residual oil which is distilled affordirg 81 g.
(32% yield) of 4-(isopropylthio)phenoi, b.p. 114-123 (1.2 mm Hg).
(b) A solution of 4-(isopropylthio)phenol, ($.6 g., 0.04
mole) and sodium hydroxide (2.6 g., 0.065 mole) in 50 ml. of water
15 is treated with epichlorohydrin (7.4 g., 0.08 moles). T-ne resulting
mixture is first stirred at 30-35 for 24 hr. &nd then extracted
with chloroform. After washing the chloroform extract with water
and drying over magnesium sulfate, distillables are removed under
reduced pressure to provide the epichlorohydrin intermediate 1-(4-
isopropylthiophenoxy)-2,3-epoxypropane. The epichlorohydrin inter-
mediate is taken up in 30 ml. of ethanol, treated with n-octylamine
(7.5 g., 0.06 mole) and refluxed for a period of 4 hr. Concen-
tration of the reaction mixture under reduced pressure affords a
residue which is taken Up in ethanol and treatet with 5 ml. of 12 N
hydrochloric acid. Concentration of the asidified solution under
reduced pressure and crystalli~ation of residual material from
ethanol provid~s an analytically pure (20~ yielt) 1-[4-i(l-methyl-
ethyl)thio]pheno~y]-3-(octylamino)-2-propanol hydrochloride, m.p. 171-
173-186.5 (corr.) (double melting point).
Anal. Calcd. for C2 H ~O2S.HCl: C, 61.59; H, 9.30; N, 3.59;
- 0 35
S9 8.22; Cl, 9.09. Found: C, 61.68, H, 9.29; N, 3.47; S, 8.15; Cl,
9.15.
EXAMPLE 3
1-[3-[(1-Methylethyl)thiolphenoxy]-3-
(octylamino)-2-propanol Hydrochloride
OH
~ OCH2CHCH2NH-(CH2)7CH3
(Ca3) 2CH-S
Reaction of the epichlorohydrin derivative of 3-(isopropyl-
thio)phenol (4.85 g., 0.029 mole) with n-octylamine (4 g., 0.031
mole) according to the procedure of Example 2~b) and crystalliæation
of the crude product from ethanol-ether affords a 13% yield of
analytically pure 1-[3-[(1-methylethyl)thio]phenoxy]-3-(c.tylamino)-
2-propanol hydrochloride, m.p. 12;-127 (corr.).
Anal. Calcd. for C20H35N02S.HCl: C, 61.59; H, 9.30; N,
3.59. Found: C, 61.22; H, 9.09; N, 3.53.
EXAMPLR 4
1-[4-[(1-Methylethyl)thio]phenoxy]-3-
(dodecylamino)-2-Propanol Hydrochloride
OH
(CH3?2CH-S - ~ OCH2CHCH2~H-(cH2)l1c 3
Reaction of the epichlorohydrin derivative of 4-(isopropyl-
thio)phenoi ~15.7 g., 0.07 mole) with n-dodecylamine (13.9 g., 0.075
mole) according to the procedure of Example 2(b) and crystallization
of the crude product lrom n;ethanol affords a 13~ yield of analytically
pure 1-[4-[(1-methylethyl)thio]phenoxy]-3-dodecylamino)-2-propanol
hydrochloride, m.p. 153.5-156.6-190.5 (corr.) (double melting
pOillt).
Anal. Calcd. for C24H43N02S.HCl: C, 64.61; H, 9.94, ~,
3.14. Found: C, 64.38; H, 10.07; N, 2.97.
EXAMPLE 5
1-[(2-Cyclohexylethyl)amino]-3-~4-[(1-
methylethyl)thio]phenoxy3-2-propanol Hydrochloride
OH
(CH3)2CH-S ~ OcH2cHcH2~H-(cH2)2 3
Reaction of the epichlorohydrin derivative of 4-(isopropyl-
thio)phenol (5.0 g., 0.022 mole) with cyclohexylethylamine (3.3 g.,
0.026 mole) according to the procedure of Example 2(b) and crystal-
lization of the crude product from isopropyl alcohol affords an 18
yield of analytically pure 1-[(2-cyclohexylethyl)amino]-3-[4-
[(l-methylethyl)thio]phenoxy]-2-propanol hy~rochloride, m.p. 180-
182 (corr.).
Anal. Calcd. for C20H33N02S.HCl: C, 61.91; H, 8.83;
N, 3.61. Found: C, 61.73; H, 8.71; N, 3.88.
EXAMPLE 6
1-[~4-Cyclohexylbutyl)amino]-3-[4-[(1-
methylethyl)thio]phenoxy]-2-propanol Hydrochloride
( 3j2 S ~ OCH2C~cH2NH~(c~2)4
- 24 -
3~`.i
Reaction of the epichlorohydrin derivative of 4-(iso-
propylthio)phenol ~9.0 g., 0.04 mole) with cyclohexylbutylamine
(6.7 g., 0.043 mole) according to procedure of Example 2 (D) and
crystallization of the crude product from ethanol affords an 11.4%
yield of analytically pure 1-[(4-cyclohexylbutyl)amino]-3-[4-
[(l-methylethyl)thio]phenoxy]-2-propanol hydrochloride, m.p. 179
with prior softening from 118.
Anal. Calcd. for C22H37N02S-HCl: C, 63-51; H~ 9-20;
N, 3.37. Found: C, 63.46; H, 9.35; N, 3.29.
E~AMPLE 7
1-[2-Methyl-4-(methylthio)phenoxy]-
3-(octylamino)-2-propanol
OH
3 ~ OCH2CHCH2NH-(CH2)7CH3
The epichlorohydrin derivative of 2-methyl-4-(methylthio)-
phenol (3.14 g., O.OlS mole) is reacted with n-octylamine (1.93 g.
0.015 mole) according to the procedure of Example 1. Concentrating
the reaction mixture and crystallization of residual material from
ethylacetate-hexane affords a 19% yield of analytically pure 1-[2-
methyl-4-(methylthio)phenoxy]-3-(octylamino)-2-propanol, m.p. 59-
60 (corr.).
Anal. Calcd. for ClgH33N02S: C, 67-21; H, 9-80; N~ 4-13-
Found: C, 66.80; E, 9.92; N, 3.81.
- ~5 -
EXAMPLE 8
1-[2-(Methyithio)phenoxy]-3-
(octylamino)-2-propanol Hydrochloride
OH
CH2CHCH2N~-(cll2)7cH3
-CH3
Reactior. of the epichlorhydrin derivative of 2-(methyl-
5 thio)phenol (14 g., 0.071 mole) with n-octylamine (9.04 g., 0.07
mole) according to the procedure of Example 2(b) and crystalli~ation
of the crude product from methanol-ether affords an 18~ yield of
analytically pure 1-[2-(methylthio)phenoxy]-3-(octylamino)-2-propanol
hydrochloride, m.p. 105.5-107.5 (corr.).
10Anal. Calcd. for C18H31N02S.HCl: C, 59.73; H, 8-91
N, 3.87. Found: C, 59.86; H, 9.07; N, 3.71.
EXAMPLE 9
1-[4-[(1-Methylethyl)thio]phenoxy]-3-
[(2,2-dimethyl-1-hexyl)amino]-2-propanol
~ OH ,CH3
( 3)2 ~ OCH2CHCH2NH-CH2,C-(CH2)3CH3
(a~ 2,2-Dimethylhex-l-ylamine.- A solution of capro-
nitrile (25 g., 0.26 mole) and methyl iodide (75 g., 0.53 mole) in
80 ml. of dry toluene is warmed to 80 and treated gradually
~ith a suspension of sodium amide (25.4 g., 0.65 mole~ in 100 ml.
of toluene at 2 rate sufficient to maintain general reflux. After
addition is compl~te, the mixture is stirred and refl1lxed for an
additional 2 hr. per~od, cooled and treated with 150 ml. of water.
The organic layer is separated, washed with water and dried over
magnesium sulfate. Concentral-ion of the dried solution under reduced
pressure and distillation of residual material affords an 8l% yield
of 2,2-dimethylcapronitrile.
A solution of 2,2-dimethylcapronitrile (10.0 g., 0.078 mole)
in 100 ml. of ether is added slowly to a suspension of lithium
aluminum hydride (6.0 g., 0.158 mole) in 200 m~. of ether while
maintaining the reaction at 0-5 . After stirring the reaction
mixture for an additional 2 hr. at 0.5 , the mixture is hydrolyzed
by sequentially adding 6.0 ml. of water, 6.0 ml. of 15% sodium
hydroxide solution, and finally 18 ml. of water. The hydrolyzed
mixture i5 stirred for an additional hour, filtered and the ether
pha~e concentrated under reduced pressure. Distillation of residual
material provides 2,2-dimethylhex-1-ylamine.
(b) Reaction of the epichlorhydrin derivative of 4-
(isopropylthio)phenol with 2,2-dimethylhex-1-ylamine according to
the procedure of Example 2(b) and conversion of the free base to
the hydrochloride provides 1-[4-[(1-methylethyl)thio]phenoxy]-3-
[(2,2dimethyl-1-hexylamino]-2-propanol hydrochloride.
EXAMPLE 10
1-[4-[(1-Methylethyl)thio]phenoxy]-3-
[(2-methyl-2-octyl)amino]-2-propanol
~ 0,Y. CH3
(CH3)2CH-S--~ OCH2CT~CH2NH-C, (Cff2)5 3
(a) 2-Ketnyl-2-octanol.- A solution of ~ethyl-
heptanoate (14.5 g., Q.l mole) in 200 ml. of ether is added to
.. . .
3~
200 ml. of 3~1 solutioll (0.6 mole) of methyl magnesium bromide in
ether at a rate sufficient to maintain refluxing. After addition
is complete, the resulting mixture is refluxed for l hr. and then
stirred at 26 for a 16 hour period. The mixture is hydrolyzed
by the addition of d lute ammonium chloride solution, filtered and
the filter cake dissolved in 2N hydrochloric acid and extracted with
ether. The ethereal extract and filtrate are combined, sequen~ially
washed with water, dilute sodium bicarbonate solution and brine and
dried over magnesium sulfate. Concentration of the dried solution
and distillation of residual material under reduced pressure provides
13.1 g. (91% yield) of 2-methyl-2-octanol, b.p. 130 (100 mm Hg).
(b) N-(2-~lethyl-2-octyl)acetamide.- A solution of con-
centrated sulfuric acid (5.55 g., 0.055 mole) in 32 ml. of glacial
acetic acid is treated with acetonitrile (2.5 g., 0.016 mole) and 2-
15 methyl-2-octanol (8.0 g., 0.055 mole) ~nd the resulting mixture
stirred at 26 for a 17 hr. period. After diluting with 125 ml. o
water, the mixture is extracted with ether and the ethereal extract
sequentially ~ashed with water, dilute sodium bicarbonate solution
and brine and dried over magnesium sulfate. Concentration of the
20 dried solution provides 8.7 g. (85% yield) of N-(2-methyl-2-octyl)-
acetan~ide which is used in the next step without further purification.
(c) 2-Methyl-2-octylamine.- A solution of potassium
hydroxide (10.0 g., 0.18 mole) in lO0 ml. of ethylene glycol is
treated with N-(2-metnyl-2-octyl)acetamide (13.0 g., 0.07 mole) and
25 the mixture heated at 200 for a 64 hr. period. The reaction
m xture is diluted with 400 ml. of water and extracted with ether.
The ethereal extract is washed with water and brine and then dried
- 2~ -
.. . .
~ ~4fi3~
over sodium sulfate. Concentration of the dried solution under
reduced pressure affords 10.4 g. (62% yield) of 2-methyl-2-octyl-
amine which is used in the next step without further purification.
(d) 1-[4-[(1-Methylethyl)thio]phenoxy]-3-[(2-methyl-2-
S octyl)amino]-2-propanol Preparation.- A solution of the epichlo-
hydrin derivative of 4-(isopropylthio)phenol (7.8 g., 0.035 mole)
and 2-methyl-2-octylamine (5.0 g., 0.035 mole) in 100 ml. of ethanol
is refluxed for a 17 hr. period. The reaction mixture is concen-
trated under reduced pressure and residual material heated at 80
(0.5 mm Hg) to remove residual excess reagents. The crude free base
is treated with 6N hydrochloric acid to provide the hydrochloride
salt which crystallized from ether-hexane ~ffords 3.0 g. (21% yield)
of l-[4-[(1-methylethyl)thio]phenoxy]-3-[(2-methyl-2-octyl)a~ino]-2-
propanol hydrochloride, m.p. 165.
EXAMPLE 11
3-Methyl-1-[4-[(1-methylethyl)thio]-
phenoxy]-3-(octylamino)-2-butanol
-- OH CH
( 3)2C~ S ~ OcH2cH-c-NH-(cH2)7CH3
CH3
(a) Diethylacetyl of 4-[(1-methylethy])thio]phenoxy~
acetaldehyde.- A solution of 4-[(1-methylethyl)thio]phenol (24.2 g.,
0.144 mole) in 180 ml. of 2-ethoxyethanol is treated with 7.2 g.
of a 50% dispersion of sodium hydride in mineral oil and the mixture
stirred until hydrogen evolution ceases. The diethylacetal of
bromoacetaldehyde (30.0 g., 0.152 mole) is added to the reaction
mixture which is ~hen stirred and refluxed for a 19 hr. period,
-- 2g --
cooled, diluted with water and extracted with ether. Ether extracts
are combined, washed with water, dried over magnesium sulfate, and
concentrated under reduced pressure to an oil. Distillation of
residual oil under reduced pressure provides 28.1 g., (69% yield)
of the diethylacetal of 4-[(1-methylethyl),hio]phenoxyacetaldehyde,
b.p. 142-146 (0.07 mm Hg).
(b) 4-[(1-Methylethyl)thio]phenoxyacetaldehyde.-
solution of the diethylacetal of 4-[(1-methylethyl)thio]phenoxy-
acetaldehyde (10 g., 0.035 mole) in 100 ml. of aqueous ethanol
(60:40) is treated with 5 ml. of 6N hydrochlor~c acid and the
resulting mixture refluxed for a period of 2 hr. The cooled
mixture is partitioned between ether and water and the ethereal
phase washed with water and brine and then dried over magnesium
sulfate. Concentration of the dried ethereal solution under
reduced pressure and distillation of .esidual materia] affords
4-[(1-methylethyl)thio]phenoxyacetaldehyde.
(c) 3-Methyl-1-[4-[(1-methylethyl)thio]phenoxy]-3-
nitro-2-butano].- A solution of 2-nitropropane (1.8 g., 0.02 mole)
and 1.0 g. of sodium hydroxide in 10 ml. of water is added to a
stirred suspensior. of 4-[(1-methylethyl)thio]phenoxyacetaldehyde
(4.2 g., 0.02 mole) in a solution of sodium bisulfate (2.1 g.,
0.02 mole) in 10 ml. of water. The mixture is warmed on a steam
bath for 8 hr., cooled and acidified with glacial acetic acid.
The acidified mixture is extracted with ether, and the combined
ether extracts sequentially washed with watPr, dilute sodiurl
bicarbonate solution and brine and dried over magnesium sulfate.
Concentration of the dried etherea] solution under reduced ?ressure
- 3û --
6~
provides 3-methyl-1-[4-[(1-methylethyl)thio]phenoxy]-3-nitro-2-
butanol.
(d) 3-Amino-3-methyl-1-[4-[(1-methylethyl)thio]phenoxy]-
2-butanol.- A solution of 3-methyl-1-[4-[(1-methylethyl)thio]phenoxy]-
3-nitro-2-butanol (2.5 g., 0.008 mole) in 100 ml. of ether is treated
with lithium aluminum hydride (0.5 g., 0.013 mole). The mixture
is stirred at 25 for a 4 hr. period, cooled and then hydrolyzed by the
sequential addition of 0.5 ml. of water, 0.5 ml. of 15% sodium
hydroxide solution, and 1.5 ml. of water. After stirring at room
temperature for 1 hr., the solution is filtered and concentrated
under reduced pressure to p.ovide 3-amino-3-methyl-1-[4-[(1-methyl-
ethyl)thio]phenoxy]-2-butanol.
(e) 3-Methyl-1-[4-[(1-me.hylethyl)thio]phenoxy]-3-
(octylamino)-2-butanol Preparation.- A solution of 3-amino-3-
methyl-1-[4-[(1-methylethyl)thio]phenoxy]-2-butanol (2.0 g.,
0.007 mole) in 60 ml. of isopropyl alcohol is treated with
n-octanal (1.0 g., 0.008 mole) and sodium cyanoborohydride (1.0 g.,
0.017 mole). After stirrin~ at room temperature for a period of
16 hr., it is poured into water and the product extracted with
ether. The ethereal extract is washed with water and brine and
dried over magnesium sulfate. Concentration of the dried ethereal
solution and conversion of the residual free base to the hydrochloride
salt provides 3-methyl-1-i4-[(1-methylethyl)thio]phenoxy]-3--(octyl-
amino)-2-butanol hydrochloride.
- 3] -
;
3~;
E~LE 12
1-[4-[(l-Methylethyl)thic]-
phenoxy]-3-(octylamino)-2-butanol
~ OH
(CH3)~cH-S ~ ocb2cHcH~ -(cH2)7 3
(a) 3-Amino-1-[4-~(1-methylethyl?tnio]phenoxy]-Z-butanol.-
This amine precursor is obtair.ed by reducing 1-[4-[(l-methylethyl)-
thio]phenoxy]-3-nitro-2-butanol with lithium aluminum hydride
according to the procedure of Example ll(d). The nitro starting
material (l-[4-[~l-methylethyl)thio]phenoxy]-3-nitro-2-butanol~
is obtained by using an equivalent quantity of nitroethane ir. place
of the 2-nitropropane Jn the procedure of Example ll(c).
(b) 1-[4-[(l-Methylethyl)thio~phenoxy~-3-octylamino-2-
butanol Preparation.- Treatment of 3-ami.no-1-[4-[(l-methylethyl)-
thio]phenoxy~-2-butanol with n-octanal and sodium cyanoborohydride
according to the procedure of Example ll(e) affords the product :
1-[4-[(1-methyl.ethyl)thio]phenoxy]-3-octylamino-2-butanol.
EXAMPLES 13-28
The follo~ing compounds of Table A are prepared according
to the procedure of Example 1 by reacting the epichlorohydrin
derivative of the starting phenol with n-octylamine.
- 32 ~
TA~LE A
~ OH
Rl-S ~ ~---- OC~12CHCH2~H-(CH2)7CH3
`Product
_xample Star;ing Thiophenol RlS
13 4-ethylthiophenol 4 C2H5
5 14 4--n-propylthiophenol 4-n-C3H7S
4-n-butvlthiophenol 4-n-C4HgS
16 4-n-pentylthiophenol 4-n-C5HllS
17 4-n-hexylthiophenol 4-n-C6H13S
18 4-n-heptylthiop'lenol 4-n-C7Hl5s
1019 4-n-octylthiophenol 4-n-C8~17S
4-(3-methyl.butylthio)phenol 4-(CH3)2CXCH2CH2S
21 2-n-butylthiophenol 2-n-C4HgS
22 3-n-butylthiophenol 3-n-C4H9S
23 2-ethylthiophenol C2H5~
1524 2-n-propylthiophenol 2-n-C3H7S
2-isopropylthiophenol 2-i-C H7S
26 3-ethylthiophenol 3 C2 5S
27 3-n-propylthiophenol 3-n-C3H7S
28 3-isopropylthiophenol 3-i-C3H7S
EXA~LE 29
Tablets
The following ingredients are blended into proportion by
weight indicated according to conventional pharmaceutical tec'.miques
to provide a tabl.et base.
- 33 -
Amount
Lactose 79
Corn starch 10
Talcum 6
Tragancanth 4
Magnesium steara,e
This tablet base is blended with sufficîent 1-[4-[(l-methyl~
ethyl)thio]phenoxy]-3-(octylar,lino)-2-propanol hydrochloride to
provide tablets containing 10, 20, 40, 80, 160 and 320 mg. of active
ingredient and compressed into conventional tablet press.
EXAMPLE 30
Dry-Filled Capsules
The following ingredients are blended in a conventional
manner in the proportion by weight indicated.
Ingredient Amount
Lactose, U.S.P. 50
Starch 5
Magnesium stearate 2
Sufficient 1-~4-[(l-methylethyl)thio]phenoxy]-3-(octylamino)-
2-propanol hydrochloride is added to the blend to provide capsules
containing 10, 20, 40, 80, 160 and 320 mg. of active ingredient which
is filled into hard gelatin capsules of a suitable size.
EXAMPLE 31
Comparison of Peripherai Vasodilator
Activity In The ~nesthetized Dog
Test Method.- Mongrol dogs of either sex weighing between
11 and 16 kg., each, were anesthetized with pentobarbital (30 mg./kg.)
administered intravenously. The left brachia] vein was cannulated
and pentobarbital infused continuously throughout the experiment at a
rate of 5 mg./kg./hr. A tracheotomy was performed and dogs venti-
lated mechanically with room air at a rate of 18 strokes/min. and a
volume equivalent to 20 ml./kg. The vagi were sectiGned bilaterally
in the mid-cervical region of the neck. The right brachial vein and
artery were cannulated to inject drugs and to monitor blood pressure
via a Statham pressure transducer, respectively. All measurements
were recorded on a Beckman-Offner dynograph. The abdominal aorta was
exposed through midline incision and a loose ligature placed around
the aorta distal to the left renal artery. The right (donor) and
left (recipient) femoral arteries were exposed for cannulati,on and
subsequent hind-limb perfursion. Following intravenous administration
of heparin (5 mg./kg.) and gallamine triethiodide (2 mg./kg.), the
right femorel artery was cannulated and the tip of the catheter
advanced into the abdominal aorta to the level of the renal arteries.
The left femoral artery was cannulated and the hind-limb perfused
using a Harvard Perfusion pump. The ligature previously placed
around the aorta was subsequently tied to minimize collateral circu-
lation. Heparin and gallamine trietniodide were infused intravenouslyat rates of 2.5 and 1 mg./kg./hr. 5 respectively. Perfusion pressure,
measured at a point distal to the perfusion pump was set equal to
- 35 -
150 mm Hg. by adjusting pump speed. Blood flow to the limb was
determined volumetrically at the conclusion of the experiment. The
test agent was administered by infusion at a rate of from 0.1-1.0
m8./min. for a six-minute period and maximum reduction in pressure
determined. One to three animals were employed per test agent.
Results.- Table I below gives results obtained according
to the above test for representative alkylthiophenoxypropanolamines
of the instant invention. Data is also shown for the alkylthio-
phenoxypropanolamine prior art compounds of Keizer, et al., U.S.
3,542,874 "1-(isopropylamino)-3-[2-(methylthio)phenoxy]-2-propanol
(tiprenolol)" and Villa, et al., Il. Farmaco. Sci., Ed. 24, 349-357
(1969) "1-(isopropylamino)-3-[~l-(methylthio)phenoxy]-2-propanol"
identified herein as test agents "A" and "B", respectively, and the
reference standard papaverine.
With respect to prior art compounds "A" and "B" and ~he
compound of Example 2 (test agent 2), comparative testing was
repeated essentially as described above with the modification that
the three compounds were tested in the same dog preparation (blood
pressure was allowed to return to control values between infusion cf
test agents). This protocol precludes effects resulting from anima1
variation thus permitting a direct side-by-side comparison of vaso-
dilating activity. The results of this comparison are also set forth
in Table I.
- 3~ -
TABLE I
Vasodilator Activity - PerEused Dog Hlnd Limb
R ~ OH
O-CH2CHCH2NH-R2
R -S
Pressure Decreaseb
Test Dose (mg./m1n.)
5 ~ R _ Rl R2 --~ - 0 3 1.0
1 H 4-CH3 -8 17 -22 -59
2 H 4-i-Pr n C8H17 -63
3 H 3-i-Pr _ 8H17 -20 -87
10 5 H 4-i-Pr ( 2~2 ~ -63 -87
6 H 4-i-Pr ( 2)4 ~ -47 _74
7 2-CH3 4-CH3 - 8 17 -56 -80
8 H 2-CH3 - 8 17 -15 -64
A H 2-CH3 i-Pr _20d _27d
15 B H 4-CH3 i-Pr - 3d -29
Papaverine -31 -55
a. Test agent numbers correspond to example numbers.
b. Millimeters of mercury.
c. Infusion rate.
20 d. Side-by-side comparison in same animals.
~ 3~
Findings.- Compared to prior art compuounds "A and B", all
of the instant alkylthiophenoxypropanolamines tested (i.e. test
agents 1-3 and 5-8) provided substalltially greater vasodilating
effects in that at an infusion dose of 1.0 mg./min. they produced a
pressure reduction of from 59-99 mm Hg. whereas "A and B" at an
identical dose provide a reduction in pressure of some 27-'9 mm Hg.
In comparison to prior art compounds "A and B" at a dose of 0.3
mg./min. the compounds tested were, respectively, from 0.~ to 3.2 and
5 to 21 .imes more acti-~e. All of the compounds tested are of
interest with respect to vasodilator activity in that at an infusion
rate of l.0 mg./min. they produced a decrease in pressure substan-
tially greater than or approximately equivalent to papaverine.
According to the side-by-side comparison of test agent 2 and prior
art alkylthiophenoxyproparlolamines "A and B" at identical 0.3 mg./min.
dose levels~ test agent 2 has a vasodilator effect approximately 3.2
and 21 times greater than that of test agents "A" and l'B", respectively.
This i.llustrate~ that test agent 2 is a substantially superior vaso-
dilator compared to the prior art alkylthiophenoxypropanolamine "A
and B".
EXAMPLE 32
Inhibition of Platelet Aggregation
(Antithrombogenic Activity)
est Method.- A method similar to that descr bed in Born,
Nature 194, 927 (1962~ and O'~rien, J. Clinical Pathology lS, 446
(1962). This test compri~es ~ nephelometric method in which the
change in turbidity of a specimen of human platelet-rich plasma is
measured on causation of plate]et aggregation by addition of adenosine
diphosphate ~ADP) or collagen as the thrombogenic inducing agent. An
- 3g -
increase in transMittance light occurs when the thrombogenic agent is
added to the specimen or platelet-rich plasm due to clumping of
platelets. Ef.icacy of the test compound is determined by abili~y to
prevent the clumping and concommitant increase in transmittance.
Various concentrations of the test agent are tested and that con-
centration causing a 50% reduction in the thrombogenic response is
determined from a concentration-response curve.
Results.- Table II below provides results obtained
according to the above test for representative compounds of the
instant ~nvention and prior art compounds "A" and "B" of Example 31.
TABLE II
Inhibition of Platelet Agg~ation In Vitro
ED50b
Test Agenta ADP Coll
1 69 42
2 56 31
3 53 24
56 47
6 53 29
7 82 39
8 65 32
A 137 33
BC 107 28
a. Test agent numbers correspond to exampl~ numbers.
b. Microgram/0.5 ml. platelet--rich human plasma when
l mcg. of adenosine-5'-diphospahte (ADP) or the
minimal amollnt of collagen (coll~ producing
maximal degree nf aggregation are used to induce
aggregation.
c. Refer to Example 31.
- 39 -
Findings.- The abo~e data demonstrates that all of the
compounds tested are significantly more active in inhibiting ADP-
induced platelet aggregation than the prior art alkylthiophenoxq-
propanolamines "A" and "B".
EXAMPLE 33
Isolated Guinea Pig Trachea
(beta-Adrenergic Blo_king Activity)
Test Method.- Tracheas excised from adult guinea pigs
(body weight greater than 400 g.) are cut spirally and suspended
vertically in 20 ml. of modified Tyrode's bath solution maintained at
37.5C. and aerated continuously with oxygen. The lower end of a
tracheal segment is fixed to a stationary glass rod and the upper end
is threaded to an isometric tension transducer. Changes in the
spontaneous tonus of the tracheal smooth muscle are monitored via the
transducer and recorded continuously on an electronic recorder.
Adrenergic beta-receptor blocking activity is determined by the
ability of a test agent to inhibit the response of the isolated
tissue to the adrenergic beta-stimulant "isoproterenol" at a concen-
tration of 0.1 mcg./ml. bath fluid. The tissues are exposed to the
test agent solution for a 15-min. interval prior to the addition of
isoproterenol to the bath fluid. Beta-receptor blocking potencq of a
test drug is ascertained from concentration-response relationships
wherein the response is expressed as a percent inhibition of isoproterenol-
induced tissue response. The IC50 value, which is the concentration
of the test drug providing a 50% inhibition of the effect of the
relaxant dose of isoprGterenol, is determined by interpolation. Each
drug solution is added to the tissue bathing medium at a constant
volume of 0.2 m1./ml. of bath fluid and only one test drug concentration
- 40 -
3~ 3..~
is employed for an individual tissue segment. Potency of the test
agent relative to tbat of the beta-adrenergic blocking agent "propanolol"
as a reference standard is assessed by comparing the IC50 values.
Results.- Table III below provides results obtained
according to the above tèst for representative alkylthiophenoxy-
propanolamines of the instant invention identified by test number
(example No.) compared to the alkylthiophenoxypropanolamine prior art
compounds of Xeizer, et al. supra. and Villa, et al. supra. referred
to as test agents "A" and "B", re~pectively (consult ~xample 31 for
chemical name).
- 4
" .
TABLE III
Beta-Adrenergic Blocking ~ctivity
in the Isolated Guinea Pi~ Trachea
R ~ OH
~O-CH2CHCH2NH-R2
Rl-S
Test Beta-Adrenergic
5 Agenta R Rl R2 Blocking Potency
1 H 4-CH3 n-C8H17 < ~
2 H 4-i-Pr - 8 17 <0.001
3 H 3-i-Pr - 8 17 <0.001
4 }I 4-1-Pr - 12 25 <0.001
H 4-i-Pr ( 2)2 ~ <0.0006
H 4-i-Pr ( 2)4 ~ <0.002
7 2-CH3 4-CH3 - 8 17 <0.0006
8 H 2-CH3 n-C8H17 0-004
AC H 2-CH3 i-Pr 1.0
Bc H 4-CH3 i-Pr 0.2
a. Test agent numbers correspond to example nu~bers.
b. Potency relative to Dropanol (equals one) estimated from
determinations of test drug concentrations causing 50% bloc~ade
of isoproterenol-induced tissue response (propanol EC50 = 0.028
mcg./ml. ~ath fluid).
c. Refer to Example 31.
- 42 -
q~
_indings.- The date of Table III clearly establishes tha~,
with respect to beta-adrenergic bloc~ing activity, a marked distinc-
tion exists between the compounds of test agents 1 through 8 and the
prior art alkylthiophenoxypropanolamlnes. It is apparent that test
agents 1 through 8 are comparatively devoid of beta-adrenergic
blocking activity in contrast to the coresponding prior art alkyl-
thiophenoxypropanolamines "A" and "B" which have substantial activity.
Consequently, the instant compounds when used for purposes described
herein, would be relatively free of side effects associated with
beta-adrenergic blocking activity.
EXAMPLE 34
Isolated Rabbit Thoracic Aorta
(Antispasmctic Activity vs. Po~assium Chloride)
Test Methcd. Antispasmodic activi,y was assessed in vitro
lS by determining the effect OI the test subst2nce on induced contraction
of arterial smooth muscle as follows. Adult, ~ale, ~ew Zealand White
rabbits (body weight 2.5-~ kg.j were used. Each rabbit ~as killed by
i.v. air injection. The thorax was opened and the descending thoracic
aorta removed and placed in Kreb's-bicarbonate solution. Extraneous
tissue was r~moved and the aorta was cut spirally along its entire
length. Four spiral segments, each approximately 2 cm. in length
(unstretched), were obtained from each thoracic aorta. A spiral
segment was placed in a 10 ml. volume bath chamber, fixed at the
lower end to a glass rod tissue holder, and the upper, freP end
threaded to a tension transducer which exerted a constant baseline
tension of 3 gm on the tissue. The bath medium surrounding the
aortic spiral (Kreb's-bic~rbonate soiution) was maintained at
37.5C. and constantly aerated with ~5% 2 5% C0,. Activity of the
aortic smooth muscle was recorded on an electornic polygraph via its
connection to the tenslon transducer. After an equiiibration period
of 60 min., a cumulative dose-response curve was obtained to an
agonist (e.g. potassium chloride or norepinephrine) and the tissue
then washed. Seventy-five min. later, a second cumulative dose~
response curve to the agonist was obtained ~tld the tissue washed
again. Sixty min. later, a test drug solution was added to the
tissue bath fluid and, after 15 min., drug exposure and, without
washing, a third and final agonist-response curve W2S obtained. All
additions to the bath fluid were 0.1 ml. volumes of aqueous solutions.
Results.- Table IV below provides a comparison of potencies
relative to papaverine in the above test employing potassium chloride
as agonist for the instant alkylthiophenoxypropanolamines of Example 33
and prior art compounds of Keizer, et al., supra. ("A") and Villa,
et al., supra. ("B") (consult Example 31 for chemical name). Papaverine
is considered a direct-acting antispasmodic agent and is a standard
in the art.
;3~
TABLE I~
Antispasmodic Activity
(Rabbit Thcracic Aorta)
Antispasmgdic
Test Agent Potency
2 0.6
3 0.7
4 0.08
2.4
6 0.02
7 0.8
8 2.6
Ac 0.04
Bc 0.04
a. Test agent numbers correspond to example numbers.
b. Potency relaeive to papaverine (equals one)
estimated from PA2 values determined versus
potassium chloride-induced contractions. The PA2
value represents the negative log of the molar
concentration of the aDtagonist which reduces the
effect of a double dose of the agonist to that of
a single dose of the agonist without the antagonist
present.
c. Refer to Example 31.
Findin~~. Antagonist activity against potassium chloride-
induced spasms is indicative of non-adrenergic direct-acting anti-
spasmodic action. Accordingly, the results set forth Ln Table IV
illustrate that most of the in~stant co~.pounds tested have a sub-
3Q stantial level of antispasmodic activity whereas the prior art
_ ~5 _
compounds "A" and "B" have relatively weak acLivity. The datafurther establishes that relative to potassium chloride-induced
spasms, test agents 2, 3, 5, 7, and 8 are from about 15 to 65 times
more potent as non-adrenergic antispasmodic agents than the corres-
ponding prior art alkylthlophenoxypropanolamines "A" and "B". Theantispasmodic potencies of test agents 4 and 6 are approximately the
same as prior art compounds "A" and "B" with test agent 4 being twice
as potent and test agent 6 being about 1/2 as potent.
EXAMPLE 35
Isolated Rabbit Thoracic Aorta
~Antispasmodic Activity vs. Norepinephrine)
Test agents 1-8 and prior art compounds "~" and "B" of
Example 34 were further tested for anti-alpha-adrenergic activity
according to the method of Example 34 but employing the alpha-
adrenergic stimulant agent norepinephrine as the agonist rather thanpotassium chloride. Selective activity against norepinephrine-
induced spasms is indicative of alpha-adrenergic blocking ~i.e.
antispasmodic) activity. This modification of the antispasmodic test
established that all o the instant alkylthiophenoxypropanolamines
with exception of test agent 8, were essentially devoid of anti-
alpha-adrenergic action having 0.3% or less of the activity exhibited
by phentolamine. Phentolamine is an alpha-adrenergic blocking agent
and a standard reference in the art. While prior art compound "~" is
essentially inactive as an anti-alpha-adrenergic agent, test agent 8
and prior art compound "A" have some~Jhat more activity than compounds 1-
7 in that they are 1--2% as potent as phentolamine. This experi-ment
illustrates that the instant compounds are non-anti-alpha-adrenergic
- 46 -
antispasmodic a~2nts in that they have a substantial direct smooth
muscle relaxant effect (as shown in Example 3~) relatively uncom-
plicated by any significant selective alpha-adrenergic blocking
effect.
EXA~LE 36
Additional Biological Testing of 1-[4-[(1-Methyl-
ethyl)thi_ phenox~J]-3-(octy:lamino)-2-prcpanol
The vasoactivity of tne above compound of Example 2 was
further evaluated according to various pharmacological tests employed
for that purposc. Thus:
(a~ Rats with intra-arterial catheters have periods of
shortened platelet survival time. This shortened survival time is
normalized w~th the compound of Example 2.
(b) The compound of Example 2 elevated basal tone of
mesenteric arteries of dogs and rabbits. This effect is considered
valuable i~l the treatment of peripheral and cerebral vascular diseases.
(c) The compound of Example 2 decreased red 'olood cell
rigidity determined via a chromium labeling technique and accordingly
the cells are better able to pass through sclerosed narrowed capillaries
of tissues af f ected by vascular disease.
