Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
s~
3-INDOLYL-TERTIARY BUTYLAMINOPROPANOLS
_ield of hc Invelltion
The prcsent lnvelltion is concerned witll heterocyclic
carboll compounds of the i~tdole series having an amino substituent
(Class 260/326.15~, and with drug, bio-af~ecting and body-crcating
processes employing these compounds (Class 424/2i4).
Description of the Prior Art
I. A substantial body of prior art has developed during the
last ten years involving compounds of the 3-aryloxy-2-hydroxypropyl-
amine series whicil have ~-adrenergic receptor blocking activity and
are useful in the treatment of cardiovascular diseases. These
structures are typified by the substance l-isopropylamino-3-(1-
naphthoxy)-2-propanol which is currently in mcdical use under tlle
non-proprietary name propranolol. Propranolol and a related ~roup of
naphthoxypropanolamine~s arc the subject of U.S. ~atent No. 3,337,628
patented ~ugust 22, 1967. A large number of patents have been
&ranted since that time on carbocyclic ethers in which other aromatic
rings replace thc naphthoxy group o~ propranolol. ~lany of these
compounds are in tlle phenoxy series and others are phenoxy compounds
~lth a fused heterocyclic ring.
II. The follol~in~ patents and publications describe 3-indolyl-
alkylamino compounds.
Robinson, U.S. 2,908,691 patented October 13, 1959
describcs a group of 3-indolylalky]amines having an aralkyl substituent
attached to the amlno nitrogen atom. These substanccs l-ave utility
as hypnotic, anti-se~cretory, and anti-emetic agents. The product
of Example 7 th~reof ilas been referred to as SC10049 having broncho-
dLlator anclllyperg1ycemlc action (Van ~rman, J. Pharmacol. and
Exptl. Therap. 133, 90-97 ~1961)).
~lasson, ct al., U.S. 3,946,009 patented ~arch 23, 1976
discloses a group of pyra~inyloxypropanolamines among which the
3-indolyl-tert.-butyl group is mentioned as an amino substituent.
~efer to column 22, line 15. These substances have adrenergic
~-receptor blocking properties.
Jackman, G. B., et al., J. Pharm. Pharmacol., 1965 17,
742-746 entitl~d "Some Tryptamine Derivatives; 1-Aryloxy-3-C~2-
indole-3-ethyl)amino]propanols". 3-Indolylethylaminopropanols w~re
conceived of as central nervous system agents of the tranquilizer
type. The only compound found to possess any activity had the
structural formula shown below. It reflected only a fraction of
the CNS activity of chlorproma~ine hydrochloride in laboratory
tests, and was considered not worthy of detailed biological
study.
cH3~J CH2CH2NIICH2CHCH2-O~
C~12C - C~l
III. The following patent discloses various heterocyclic
20 al~ylaminopropanols but no indole compounds are disclosed.
-- 2 --
~65~3
Augsteln, et al. U.S. 3,852,291 patented December 3, 1974.
Pyrimidinyl alkylamino and imidazolinylalkylamir)o propanols are
described which llave adrenergic ~-receptor blocking action.
IV. The following patents describe arylo~ypropanolamino
compounds in which the aryloxy group bears a heterocyclic substituent.
McLoughlin, et al. U.S. 3,328,417 patented June 27, 1967
discloses phenoxypropanolamines in which the phenoxy substituent is
further substituted by the 2-indolyl group (column 2, line 12?.
Muchowski, et al. U.S. 3,940,407 patented February 24, 1976
discloses a s~ries of phenoxypropanolamine compounds in which the
phenoxy substLtuent is further substituted by a 1,2,3-thiadiazole
substituent.
Seeman, Il.S. 3,965,095 patented June 22, 1976 dlscloses a
series of oxindole ethers in which the etherifying group is attaclled
to the phenyl rlng and has an esterlfied aminopropanol configuration.
These substances are antiarrhythmic ancl ~-blocking agents.
Trcxler, Canadian Patent No. 834,751 issued February l7
1970 discloses a series of indole derivatives having a 3-(N-
- substituted amino)-2-propanoloxy substituent in the 4-position of
the indole ring. The compounds are useful in the therapy of
coronary disease, angina, cardiac arrhyt~ia, and hypertension.
Jaeggi, et al., U.S. 3,984,436 patented October 5, 1976
discloses a series of phenoxypropanolamines in which the phenoxy
substituent is further substituted by the l-pyrrolyl group. These
compouds are blockers of adrenergic ~-receptors.
Summary of the Invention
___
The present invention illcludes a process for the
preparation of a compound having ~ormula I or Formula II and
the acid addition salts of these substances
CH, OH
CH ~ - C- NUCll, Cll CII ~ - O-Ar-X Fo rmu l:l I
C~, 0~1
~;~ CU,-C-NUCll,CllCU,-~}Ar-Uec F-rmula 11
In the fore~oing structural formulas the symbols Ar, ~,
n, and l-let have the following meanings.
Ar iB selected from the group conslsting of phenyl
and naphthyl,
X refers to optional Ar-attached substituents which are
independe,ntly selected from the group con~isting of
alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkanoyl,
al~enoyl, alkanoyloxy, alkenoyloxy, alkylsulfonyl,
~lXylsulfinyl, alkylthio, alkanoamido, cycloalkyl.
having 3 to 6 ring ~embers and 1 to 3 optional alkyl
substieuents, cycloalkylalkyl having 3 to 5 ring
~embers and 1 to 3 optlonal alkyl sub~tituents wherein
each of the foregoin~ groups has up to 8 carbon atoms,
phenyl, trifluoromethyl, nitro, amino, hydroxyl,
halogen, carboxam1do, cyano, and cyanoalkyl having
from 2 to 4 carbon atoms,
;,~
-- 4 --
B
n is the integer 0, 1, or 2 signifying the number of
X groups, and
Het is an Ar-attached heterocyclic substituent selected
from the group consisting of
S l-pyrrolyl,
2-oxo-1-pyrrolidinyl having a substituent in the
4-position selected from aminocarbonyl,
alkylaminocarbonyl, dialkylaminocarbonyl,
and alkoxycarbonyl, wherein said alkyl and
alkoxy groups have 1 to 4 carbon atoms,
4-morpholinyl,
4~thiamorpholinyl,
3-oxo-1-pyrazolidinyl, and
2-imidazolyl,
: lS wherein
(a) an epoxypropyl ether starting material of the formula
Ar'-OCH2CHCH2 wherein Ar' is Ar-X or Ar-Het as deflned
above is contacted under reaction conditions with
[2-(3-indolyl)-1,1-dimethylethyl]amine wherein said
reaction conditions involve either heating neat or in
. ~
the presence of a reaction inert organic liquid medium
such as a lower alkanol including methanol, ethanol,
: butanol, or hexanol, a hydrocarbon such as benzene or
toluene, an ether such as tetrahydrofuran, dibutylether,
or dimethoxyethane, or ethyleneglycol at a temperature
of from about 60-200C. to yield a compound of Formula I
or Formula II, or
- 4a -
(b) contacting a phenolic compound of tl~e formula ~r'-OH
wherein Ar' is AR-X or Ar-Het as defined above with
an intermediate of Formula III or Formula IV
CH2C6H5
3-Indolyl-CH2-C - N - CH~CHCH2 Formula III
tCH3 ~ CH20S02R
3-Indolyl-CH2-C - N ~ ~ Formula IV
CH3
wherein R is a lower alkyl group of 4 or fewer carbon
S atoms under reaction conditions and when employing an
intermediate of Formula III debenzylating the resulting
product by Icnown means such as catalytic hydrogenation
or reaction with sodium in liquid ammonia to produce a
compound of Formula I or Formula II, and when employing
an intermediate of Formula IV recovering and converting
the resulting product to a product of Formula I or
Formula II by contact thereof with dilute aqueous mineral
acid at a temperature from 20-100C., and if desired
when the base of Formula I or Formula II i9 obtained
converting said base to a pharmaceutically acceptable
acid addition salt.
- 4b -
5i~
The compounds of the present invention are unique as anti-
hypertensive agents in that they combine adrenergic ~-blocking and
vasodilator activity. They also have utility as anti-anginal agents,
anti-stress agents, antiarrhythmic agents, antithrombogenic agents
S and in the treatment of conditions where it is desirable to reduce
the oxyg~n demand of the heart such as post-myocardial infarct
management. Preferred members have a particularly desirable com-
bination of the foregoing actions, and ancillary pharmacological
effects, or a lack thereof, which particularly suits them for
specific indications from among those listed. Those of Formula I
- wherein Ar is phenyl, n = 1, and X is located in the ortho position
are preferred for antihypertensive use. The utility of the compounds
of Formulas I and II can be demonstratecl in various animal models
including antagonism of isoproterenol in the conscious rat treated
orally (adrenergic ~-receptor blocking action), the spontaneous
X
i5~
hyperterlslve rat ~antihypertcnsive actioll), the dog hind limb prepara-
tion ~vasodilator actlon), ouabain-induced ventric~lar tachycardia
in the dog (antiarrllythmic action), in the coronary artery occluded
dog (antiarrhytlmlic action), in vitro by measuring platelet aggregation
ln platelet-rlch plasma photometrically followlng chal]enge with a
thrombogenic agent such as adenosine diphosphate or collagen (anti-
thrombogenic action), and in various other animal and laboratory
models.
De ailed Description of the Invention
The invention includes compounds havirg the foregoing
structural formulas and the acid addition sal~s thereof. For
medical use, the pharmaceutically acceptable acid addition salts
are pre~erred. The pharmaceutically acceptable acid addition
salts are tho~e salts in which the anion does not contribute
significantly to the toxicity or pharmacological activity of the
salt, and as such, they are the pharmacological equivalents of the
bases having the foregoing structural formulas. In some instances,
the salts have physical properties which make them more desirable for
pharmaceutical formulation purposes such as solubility, lack of
hygroscopicity, compressibiliey with respect to tablet formation
and compatibllity Wittl other ingredi~nts with which the substances
may be used for pharmaceutical purposes. Acid addition salts which
do not meet the foregoing criterla for pharmaceutical acceptability,
for instance as to toxicity, are sometimes useful as intermediates
for isolation and purification of the present suhstances nr for
other chemical synthetic purposes such ag separation of optical
isomers. Such salts are also part of the invention.
- 6 -
6S~?~3
The acld addltlon salts are made by reaction of a base o
the foregoing structural formula with the acid pre.erably by contact
in solution. They may also be made by metathesis or treatm~nt with
an anion exchange resin whereby the anion of one
salt of the substance is replaced by another anion under conditions
which allows for separation of the undesired species such as by
precipitation ~rom solution or extraction into a solvent or elution
from or retention on an anion exchange resin. Pharmaceutically
acceptable aciæs for the purposes of salt formation include hydro-
chloric, hydrobromic, hydroiodic, Gitric, acetic, benzoic, phosphor~c,nitric, mucic, isethionic, me~hanesulfonic, p-toluenesulfonic,
glucosaccharic, palmitic, heptanoic, oxalic, cyclamic, and others.
The compounds of the present invention shown by the fore-
going structural formula contain an asymmetric carbon atom in the
propanolamine side chain and occur as optically active isomers as
well as racemic mixtures thereof. The present invention is intended
to include each of the optically active and racemic forms. Some of the
substances o~ the present invention contain an asymmetric carbon
atom in the X or Het substituent, and diastereoisomeric pairs of
Iacemates exis~. These forms are also included.
Resolution of racemic mixtures to provide the optically
active isomers of the foregoing compounds is carried out, for
e~ample, by forming a salt with an optically active acid many of
which are known to those s~illed in the art such as optically
active tartaric, mandelic, cholic, 0,0-di-p-toluoyl tartaric, and
0,0-dibenzoyl tartaric acids, or other acids conventional]y
employed for this purpose. The claims, therefore, will bc ~mder-
stood to embrace the products in the forfn of the several racemic
i5~3
mixtures as well as in the form oE the optically active isomers
where appropriate.
The therayeutic processes of this invention comprise
systemic administration of an effective, non-toxic amount of a
compound of Formula I or TFormula II or a pharmaceutically acceptable
acid addition salt of either to a mammal having a disease state
resulting from excessive stimulation of the adrenergic ~-receptors,
or to a mammal requiring vasodilation, or to a mammal having hyper-
tension. An effective amount is construed to mean a dose which exerts
an adrenergic ~-receptor blocking action, a vasodilator effect, or
antihypertensive action in the affected animal without undue toxic
side effects. ~y systemic administration, it is intended to include
both oral and parenteral routes. Examples of parenteral administration
are intravenous injection or infusion, and intraperitoneal, intra-
muscular or subcutaneous injection. Rectal administration by ointmentor suppository may be employed. Dosage will vary according to the
route of administration with from about 0.1 mcg to 100 mg/kg body
weight of a compound of Formula I or Formula II or a pharmaceutically
acceptable acid addition salt thereof generally providing the desired
therapeutic effect. Acute toxicities measured in the mouse treated
orally are within the range of about ALD50 250 mg/kg to >2000 mg/kg
of body weight, with non-lethal signs of drug effect such as central
nervous system stimulation or depression, mydriasis, or lacrimation
appearing at from l/2 to l/lO that dose.
The combination of pharmacological properties of the com-
pound of Procedure lO, 1-[[2-~3-indolyl)-1,1-dimethylethyl]amino]-
3-(2-methylphenoxy)-2-propanol hydrochloride, indicates that it is
-- 8 --
B
partlcularly d~sirable for antihypertensive use. It has five-fold
~he adrenergic ~-receptor blocking potency o~ propranolol shown by
oral ad~inlstration to rats followed by challenge of the animals
with isoproterenol administered intravenously. The latter is a
well known adrener~ic ~-receptor stil~ulant which causes an increase
ln heart rate and a decrease in blood pressure. These effects of
isoproterenol are antagonized by adrenergic ~-receptor blocklng
agents, and the relative potency values given above were prepared by
regression analysis of log dose-response data for the two compounds.
For therapeutic use, dosage size and Erequency will vary with the
sub~ect and the route of administration, with from about 0.2 mg. for
intravenous administration up to about 100 mg orally being suitable
for man.
The substance of Procedure 10 is distinguished from other
adrenergic B-receYtor blocking drugs in that it is effective in
lowering the blood pressure in the spontaneously hypertensive rat.
Although adrenergic ~-receptor blocking agents have come into
widespread usc ln human medicine for the treatment of hypertension,
their mechanism of action is unknown and their antihypertensive activity
cannot be detected by this animal test in most instances. With the
present substance in the spontaneously hypertensive rat~ a reduction
o blood pressure of 25 mm. of Hg occurs at a dose of 100 mg/kg of
body weight orally with only a minimal reduction in heart rate.
This is thought to be indicative of utility in hypertensive indications
where other adrenergic ~-receptor blocking drugs are inoperative or
less desirable.
The substance of Procedure 10 also causes a reduction in
blood pressure when ad~ninistered intravenously to the anesthetized
_ ~ _
b;S~B
dog in ~ dose of 3.33 mg/kg of body weight. It is further distJn-
gulshed in that it does not depress heart rate or right ventricular
cnntractile force as is the case with many prior adrenergic ~-
receptor blocking agents. Both a positive inotropic and a positive
chronotropic effect are exhibited by the substance, and th~se
effects are apparent even when the animal is first treated wlth an
adrenergic ~-recptor blocking agent such as sotalol. Pulmonary
artery pressure remains substantially unchanged, while aortic blood
flow and total peripheral resistance are decreased, all of the
foregoing ln the anesthetized dog.
I~le compound of Procedure 10 possesses vasodilator activity
which may account, in part, for its unique anti-hypertensive action.
In the anèsthetized ganglion blocked (chlorisondamine chloride)
angiotension supported rat, direct acting vasodilators such as
diazoxide exert a reduction in blood pressure. The substance of
Procedure 10 ls equivalent in potency to diazoxide in this test.
The vasodilator action thereof can also be shown in the pump-
perfused hind limb of the dog in doses of from 0.03 to 1.0 mg/min.
of perfuslon. Following oral administration to rats a decrease in
urine volume and a decrease in sodium ion excretion occurs whicll is
typical of vasodilator compounds.
The antithrombogenic action of the substance of Procedure 10
is reflected by its ability to reduce p]atelet aggregation in vitro
in platelet-rich plasma following challenge with ADP or collagen.
It is comparable in in vitro activity to suloctidil or to papaverine.
A hazard exists in the use oE a preponderance of adrenergic B-
receptor blocking agents in patients suffering from non-allergic
10 - -
i5~B
bronchodpasm in view of the telldency of these agents to provoke an
asthmatic attack or to render the subject re~ractory to treatment
with adrenergic ~-receptor stimulants such as isoproterenol which
are used in the treatment of acute attacks. The substance of
Procedure 10 lacks bronchospastic liability as is demonstrated by
the Eact that it does not reduce pulmonary ventriculatory pressure,
and evokes only moderate enhancement of the response of sensitized
rats to immunologically induced broncho-constriction at a dose of
0.5 mgtkg of body weight intravenously. In contrast~ propranolol
at a dose of 0.5 mg/kg of body weight intravenously reduces pulmonary
ventilatory pressure and precipitates an acute bronchospastic
response in sensitized rats to immunologically-induced broncho-
constriction.
For the preparation of pharmaceutical compositions con-
taining the compounds of Formula I or Formula II in the form of
dosage units for oral administrationl the compound is mixed with
a solid, pulverulent carrier such as lactose, sucrose, sorbitol,
mannitol, potato starch, corn starch, amylopectin, cellulose
derivatives, or gelatin, as well as with glidents such as magnesium
stearate, calcium stearate, polyethylene glycol waxes or the like and
pressed into tablets. The tablets may be used uncoated or coated by
known techniques to delay disintegration and absorption in the gastro-
intestinal tract and thereby provide a sustained action over a longer
period. When coated tablets are wanted, the above prepared core may
be coated with a concentrated solution of sugar, which solution
may contain e.g. gum arabic, gelatin, talc~ titanium dioxide
or the like. Furthermore, the tablets may be coated with a
- 11 -
5~i~
lac~uer dis.solve~ In an easlly volat~le orgallic solvent or mlxture
of solvenc~ and lf deslred, dye may be added to this coatlng.
In the preparatlon of so~t gelatin capsules conslsting of
gelatin an~ e.g. ~lycerine and the like, the active ingredient is
mixed with a vegetahle oil and encapsulated in conventional manner.
Hard gelatin capsules may contain granules of the active lngredient
in combination with a solid, pulverulent carrier such as lactose,
saccharose, sorbitol, mannitol, starch (such as e.g. potato starch,
corn starch, or amylopectin), cellulose derivatives or gelatin.
Dose units for rectal administration may be prepared in
the form of suppositories containing the compound in a mixture with
a neutra] fàt base, or in the form of a gelatin-rectal capsule with a
mixture of vegetable oil or paraffin oil.
Liquld preparations suitable for oral administration are
suspensions, syrups and elixirs containing from about 0.2% by weight
to about 20% by weight of the active ingredient.
A suitable injectible composition comprises an aqueous
solution of a water soluble pharmaceutically acceptable acid addition
salt ad~usted to physiologically acceptable pH.
The compounds of Formula I and Formula II are prepared by
application of known processes to the appropriate starting mater~als.
Representative known methods for the preparation of aryloxypropanol-
amine compounds are disclosed in the foregoing patents and publications
rited above under Description of the ~rior Art of which the Troxler
Canadian patent No. 834,751 and the Jaeg~l, et al., U.S. Patent No. 3,984~436
are illustrativeO More specifically, the present invention provides
a proc~ss for the preparation of the compounds of Formulas I and II
accordlng to the following reaction schcme.
- 12 -
~6S~
O (2~ CH3
Ar' O-CH~CI1C112 3-Indolyl-c~2c-NH2
(l) ~ CH~
CH3 (3) (4~
Ar'-011 + 3-Indolyl-Ci12C-B ~ ormulas I and II
CH9
C~2C6~1
1 ~ CH20SO2R
B a -N-CH2CHCH2 , or 1 1-
--N~_~,O
III IV
In the foregoing reaction scheme, the symbol Ar' represents the
groups ArXr~ and ArHet as they are defined in Formula I and Fo~lula
II, and the symbol B is deEined by Formulas III and IV in which R
is a lower alkyl group of 4 or fewer carbon atoms. The preferred
method is according to reactions (l) and (2) in which step ~l)
involves reactin~ the appropriately substituted phenolic cornpound
Ar'-OH with epichlorohydrin in the presence of a catalytic quantity
of an amine followed by treatment with aqueous alkali metal hydroxide,
or conducting the reaction in an aqueous alkali metal hydroxide
reaction medium whence the amine catalyst is not required. There
is produced in step ~l) an Arl epoxypropyl ether which is caused to
react in step (2) with 2-(3-indolyl)~ dimethylethylamine to yield
a product o Formula I or Formula II depending upon the nature of
- tl-e Ar'OH starting material employed. Each of reaction steps (l)
~nd (2) takes place acilely in ordinary laboratory or plant equip-
ment under convenient operating conditions.
- 13 -
5~
HcatLns of epichlorohydrin in s~lbstantial molecu]ar
excess amount wlth a phenol Ar'O}I containing a drop or two of
plperidine as catalyst on a steam bath overnight results in the
condensatlon shown in step (1)~ Some of the corresponding halohydrin
intermedlate is also produced and i8 converted without isolation
to the oxirane shown by treatment of the mixture with aqueous
alkali metal hydroxide. Alternatively, the Ar'OH phenol and epichloro-
hydrin can be caused to react in the presence of a sufficient amount of a
dilute aqueous alkali metal hydroxide to neutrali~e the acidic Ar 7 OH
group at room temperature with formation of the desired intermediate
Ar'OCII2C~CH~. Step (2) is carried out simply by heatin8 the o~irane
intermediate produced in step (1) with 2-(3-indolyl)-1,1-dimethyl-
ethylamine either neat or in the presence of a reaction inert organic
solvent. No catalyst or condensation agent is required. Suitable
solvents include 95% ethanol but other reaction inert organic liquids
in wllich the reactants are solu~le may he employed. Th~se include
but are not limited to benzene, tetrahydrofuran, dibutyl ether,
butanol, hexanol, methctnGl, dimethoxyethane, ethylene glycol, etc.
Suitable reaction temperatures are from about 60-200C.
An alternate variation of the process for the preparation
of compounds of Formulas I and II involves reaction of the Ar'OH
starting material as defined above with a reactant of the formula
ÇH9
3-Indolyl-CH2,C-B according to reaction (3) of the scheme to yield an
CH3
lntermediate which is transformed to the final product by hydrolysis
or hydrogenolysis. The substituent B in the reactant used in step (3)
is a group such as shown by IIL or IV which is reactive with the
phenolic hydroxyl group Ar'OH to incorporate into the product an
incipient propanolaminc slde chain.
. 6 ~
Thc reactarlts for step (3) wherein B has Formula III are
prepared by formlng the N--benzyl derivative of 2-(3--indolyl)~
dimethylethylaaline and rcacting the lattcir with epichlorohydrin by
adaptation of ~e ~ethod of L. Villa et al., Il. Farmaco. Sci.,
Ed., 2_, (3) 349 (1CJ69).
Those reactants wherein B has Formula IV are prepared by
reductive alkylation of 2-53-indolyl)-19l-dimethylethylamine with
glyceraldehvde according to known methocls, for instance, employing
5X palladium-on-carbon catalyst in an atmosphere of hydrogen with
methanol or other suitable non-reactive liquid as solvent. When
using an opticaliy active form of glyceraldehyde, an optically
active end product of Formula I or Formula II is obtained. The
amino prepanediol resulting from the foregoing reductive alkylation
reaction is then converted to the desired 2-(3-indolyl)-1,1-dimethyl-
ethyloxazolidinone reactant wherein B has Formula IV by reaction with
formaldehyde employing 37~ aqueous formaldehyde in refluxihg benzene with
continued removal of the water by distillation. Esterification with
an alkanesulfonyl chloride of the formula RS02Cl in which R is a
lower alkyl group of 1 to 4 carbon atoms introduces the necessary
group which is reactive with Ar'OH.
The intermediate produced by step (3? wherein the B has
Formula III is converted in step (4) to a product of Formula I or
Formula II by debenzylation by known means such as catalytic hydro-
genation or reaction with sodium in liquid ammonia. The intermediates
2$ produced in step (3) ~herein B has formula IV are converted to the
products of formulas I and II in step (4) by mild acid hydrol~sis.
In this instaoce, care must be taken to a~oid clecomposition of the
- 15 -
65i~3
rCaCtallt SillCe the 3-indolyl substitucnt is acld sen~sitlve. Aqueous
mineral nclds of from 0.1 N to 1 N concentration at temperatures of
from 20-100C. sre suitable. The product is recovered as the free
base from the hydrolysis mixture by neutrallzation thereof and
collectlng the precipitate.
Description of Speciflc Embodiment~
The 2-(3-indolyl)-1,1-dimethylethylamine employed is
prepared by tlle method of H. R. Snyder, et al., J. Am. Chem. Soc.,
69, 3140 (19S7) from 3~indoly]methyldimethylamine and 2-nitro-
lG propane followed by reductlon of the resulting 2-(3-indolyl)-1,1-
dimethylnitroethane.
In the following procedures temperatures are expressed in
degrees centigrade t). Melting points are corrected values according
to the U.S.P. method where indicated (corr.). The nuclear magnetic
resonance (MMR) spectral characteristics refer to chemical shift (~)
expressed as parts yer million (ppm) versus tetrarnethylsilane (TMS)
as reference standard. The relative area reported for the various
shifts corresponds to the number of hydrogen atoms of the particular
functional type in the molecule 9 and the nature of the shift as to
multiplicity is reported as broad singlet (bs), singlet (s),
multiplet (m)l doublee (d), triplet (t), or quadruplet (q) with
coupling constants (J) reported where appropriate. The format is
N~ (solvent): ~(relative area~ multiplicity, J value). Abbreviations
employed are MeOH (methanol), DMSO-d6 (deuterodimethylsulfoxide),
i-PrOH (isopropanol), abs.EtOH (absolute ethanol), EtOAc (ethyl
acetate), EtOH (95~ ethanol), i-PrOH (isopropanol), i-PrOAc (isopropyl
- 16 -
1~l16~
acetate), i-Pr2O tdi-lsoplopyl ether), d (decomposltion). Other
abbreviations have conventional established nleanings. The infrared
(IR) spectral descriptions include only absorption wave numbers
(cm ) having functional group identification value. KBr was
employed as diluent for ail IR spectral determinations. T~S was
used as internal reference for the NMR spectral determination. The
elemental analyses are reported as percent by weight.
Procedure 1. 4-(Methylsulfonyl)-m-tolyloxymethyl Oxirane.-
To a mixture of 3~methyl-4-methylsulfonylphenol, 8.1 g. (0.0435
mole), and 20.0 g. (0.216 mole) of epichlorohydrin, there are added
two drops of piperidine to serve as condensation catalyst and the
mixture is heated at 105-108 for 18 hrs. The excess epichlor-
hydrin is then removed by distillation using toluene as a chaser.
A solution of 2.1 g. of sodium hydroxide in 50 ml. of water and
70 ml. of dimethoxyethane is then added and the mixture is stirred
for 2 hrs. with occasional warming on the steam bath to convert any
phenoxychlorohydrin compound to the ox:lrane. The solvent is then
removed by distillation in vacuo and the residue is dissolved in a 1:1
(VIV) mixture of ether and benzene. ThP ~olution is dried over
~nhydrous sodium carbonate and examined by thin layer chromatography
for purity of the desired oxirane using a 9:1 mixture of chloroform
aud a methanol for development (Rf = 0.8). The solvent is then
removed by distillation to yield 10.7 g. of a residue constituting
the desired oxirane. ~easurement of th~ infrared absorption spectrum
is employed to confirm the substantial absence ~f hydroxyl containing
contaminallts. This material is suitable for further reaction in
Procedure 3 without further purification.
~6;5~ `
Procedure 2. 2-CIllorophen_~ymethyl Oxlrane.- A solution
of 12.9 g. of 2-chlorophenol (0.1 mole) in 125 ml. of water con-
tainln~ 6.5 g. (0.162 mole) of sodium hydro~ide, and 18.5 g.
(0.2 mole) of epichlorohydrin are stirred together at 25 for
20 hrs. The mixture is then extracted twice with 70 ml. portions
of methylene chloride. The extract is dried over anhydrous sodium
carbo~ate and tlle solvent removed by distillation in vacuo. The
residue constltutes the desired oxirane and is suitable for further
transformation as is described in Procedure 4.
Procedure 3. 1-C[2-(3-Indolyl)-l,l-dimethylethyl]amino]-
3-[4-(methylsulfonyl)-m-tolyloxy~-2-propanol.- The oxirane of
Procedure 1, 10.7 g.,was dissolved in 150 ml. of toluene, 8.2 g.
(0.044 mole) of 2-t3-indolyl)-1,1-dimethylethylamine was added and
the mixture was refiuxed for 18 hrs. The toluene was removed by
distillation in vacuo and a portion of the residue was converted
_
to the acetate salt, m.p. 142 147C. The structure was confirmed
by examination of the infrared absorption and nuclear megne~ic
resonance spec~ra. The remainder of the sample was converted to
the hydrochloride salt by treatment of an acetonitrile solution
thereof with 8 N ethanolic HCl. After recrystalli~ation from
CH3CNIMeOH 12.5 g. of product was obtained, m.p. 174.0-177.0 (corr.).
Anal. Found: C, 59.40; H, 6.90; N, 5.87.
NMR (DMSO-d6): 1.29 ~6, s); 2.52 (3, s); 3.12 (3, s);
3.16 (4, ~); 4.18 (3, m); 5.95 (1, bs); 7.10 (8, m); 9.00 (2, bs);
and 11.12 (1, bs).
IR: 740, 765, 1120, 1290, 1450, 1590, and 3270.
Proccd~lr~ 4 . 1- (?- L ~)~, I_
-
dlmettl~leLhy11a ino]~ ropano1.- A portlc-n of thc oxirane
produced in Procedu1e 2, 7 g. (0.033 mole), was reflu~ed in
solution with 6.3 g. ~0.033 mole) of 2--(3-indolyl)~ dimethyl-
ethylamine ln 70 ml. oE ethanol. Afeer 24 hrs. the solvent wa.sremoved hy distlllation in vacuo and the viscous liquld residue
was dissolved in 200 ml. of ether, acidified with 8 N ethanolic HCl
and the solvents again removed by distl]lation. Crystallization
was induced by adding acetonitrile and rubbing with a glass rod.
Recystallized from acetonitrile and di-isopropyl ether to yield
4.8 g. of product, m.p. 150.5-153.5C. (corr.).
Anal. Found: C, 61.54; H, 6.41; N, 6.94.
N~fR (DMS0-d6): 1.28 (6, s); 3.22 (4, m); 4.25 (3, m); 5.96 (1, bs);
7.23 (9, m); 8.84 (2, bs); and 11.12 (1, bs).
IR: 745, 1250, 1455, 1480, 1590, and 2780.
By adaptation o~ the foregoing procedures, the products
listed in the following table were prepared.
,. 19
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Procedllre 15. Tablets.- ~e following ingredients are
blended in the proportion by weight indicated according to con-
ventional pharmaceutical technigues to provide a tablet base.
Ingredient ~mount
Lactose 79
Corn starch 10
Talcum 6
Tragacanth 4
Magnesium steara-te
This tablet base is blended with sufficient 1-[[2-(3-
indolyl)-l,l-dimethylethyl]amino]-3-(2-methylphenoxy)-2-propanol
hydrochloride (Procedure 10) to provide tablets containing 10,-20, 40,
80, 160 and 320 mg. oE active ingredient, and compressed in a conven-
tional tablet press.
Procedure 16. Dry ~illed 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-[[2-(3-indolyl)-1,1-dimethylethyl]amino]-3-
(2-methylphenoxy)-2-propanol hydrochloride (Procedure 10) 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.
- 24 -
~16~
Proc_dllr~ 17. So~ution.- /~ solution of l-Cc2-(3~ dolyl)-
1,1-dlmc-hylethyl]a~ lo]-3~ methylphenoxy)-2-propanol hydrochloride
(Procedure lO) is prepared from the followlng ingredients.
Inp~redient Amount
Ac.tive ingredient 20 g.
Sucrose, U.S.P. 400 g.
Sorbitol~ U.S.P. 100 g.
Bentonite 20 g.
Flavors, q.s.
Water, q.s. to make l liter
Each milllli.ter of the solution contains approximately 20 mg.
of the active ingredient.
By application of the methods of Procedures l or 2 to the
ap~-ropriate phcnol,~or by other conventional method~, the following
oxiranes are prepared and then converted to products of Formula I
- or II by reaction ~ith 2-(3-indolyl)-l ! l-dimethyl.ethylamine according
to Procedures 3 or 4.
~ O-CH,CHCH, ~ CH,CH-CH
Proc. 18 Proc. l9
O
Cll,CH=CHC - ~ _ OCU,CIICH, Cl1350 ~ OCH,CNCH~
Proc. 20 Proc. 21
- 25 - ~
5~ ~
OCH2CH~H2 C
OCH HCH2
Proc. 22 Proc. 23
O O
OCH2 ~CH2 ~ OCH2CHCH2
NHCOCH3 CONH2
Proc. 24 Proc. 25
OCII, ~CH, ~ OCH,CHCU~
N OCH2CH=CH2
Proc. 26 Proc. 27
O O
Cl ~ OCH2CHCH, F ~ OCII,CHCH,
Cl
Proc. 28 Proc. 29
O O
OCH,C~ICH, ~ D~H ~CH,
CONHC~13
Proc~ 30 Proc. 31
- 26 -
, oc~l2c~lCI~2 / I
C}12CHCH2
CON(CI13) 2
Pr~c. 32 Proc. 33
CH3 0
--OCH2fHCH2 ~CH2CHCH2
CH H3
Proc. 34 - Proc. 35
pCH 2 CH)CH 2
~OCH 2CHCH2
CONU2 CH90
CONI12 ~r
Proc. 36 Proc. 37
;lUCN~ OCU l~l~C I
~ CO2C2H5 ~
Proc. 38 Proc. 39
-- 27 --
s~
~OCI},CHC}I ~U;II 1,
Proc. 40
Proc. 41
/ ~ /01
2~GCH 2 CHC:H 2G( QCH 2 CUCH 2
CH9CO H2CN CH2CH(C~3) 2
Proc. ~2 Proc. 43
~HCH, ~C2H~
Proc. 44 Proc. 45
01 O
~OCH,CHCII, ex OC'.12CI}CH,
SO2CH~, CF9
Proc. 45 Prclc. 47
-- 2~ --
~6~
o o
OCH2CHC}I2 ~ OCH2CHCH2
NO2 NH2
Proc. 48 Proc. 49
o n
~ ~ oru,c/u~cu. ~ \cu~
Proc. ~O Proc. 51
~ UCH, ~ OCU,CUCH:
Proc. 52 Proc. 53
Physic~l properties were deter~lned as follows:
.~9 _
5~3
_roccdurc 1'3.- 1-Cr2-(3-indolyl~ dime~hylethyllam1no~-
3-~2-(2-prope~yl)phenoxy } 2-propanol hydrochloride, m.p. 163.0-
168.6 (corr.), recrystallized from MeOI~/i-Pr~O.
_ . Found: C, 69.22; H, 7.56; N, 6.70.
NMR (DMSO-d6): 1.30 (6,s); 3.32 (6,m); 4.20 (3,m); 5.03
(~,m); 6.00 (2,m); 7.25 (9,m); 8.90 (l,bs); 9.60 (l,bs); and 11.40
(l,bs).
IR: 752, 1120, 1245, 1455, 1490~ 1590, 1600, 2790, 2980,
and 3350.
Procedure 43. 1-~C2-(3-Indolyl)-1,1-dimethylethyl]amino~-
3-C2-(2-methyl-1-propyl)phenoxy }2-propanol hydrochloride, m.p.
163.0-166.0~ tcorr-), recrystallized from MeOH/CH3CN.
_nal. Found: C, 69.34; H, 8.19; N, 6.49.
NMR (DMSO-d6): 0.81 (3,t, 7.0 Hz); 1.17 (3,d, 7.0 Hz);
1.32 (6,s); 1.39 (2,m); 3.28 (5,m); 4.22 (3,m); 6.04 (l,bs); 7.22
(9,m); 9.00 (l,bs); 9.60 (l,bs); 11.20 (l,bs).
IR: 750, 1100, 1240, 1450, ;1490, 1582, 1600, 2780, 2960,
and 3320.
Procedure 45.- 3-~2-Ethylphenoxy)-1-~C2-(3-indolyl)-1,1-
di~leehyleehyl]am~no]-2-propanol hydrochloride, m.p. 170.0-171.5 ~Corr.)
recrystallized from EtOH.
Anal. Found: C, 68.36; H, 7.95; N, 6.85.
N~ MSO-d~): 1.21 (3,5, 7.0 Hz); 1.33 (6.s); 2.64
(2,m); 3.24 (4,m); 4.21 (3,m); 6.00 ~l,bs); 7.25 (9,m); 9.00 (l,bs);
and 9.55 (l,bs~
IR: 750, 1130, 1240, 1460, 1495, 1590, 1605, 2800, 2970,
and 3350.
- 30 -
