Note: Descriptions are shown in the official language in which they were submitted.
rIJ-582
~l'7~3~
l-PHENOXY-3-HYDROXYINDOLYL-
ALKYLAMINO-3-PROPANOLS AND PREPARATION
The present invention is concerned with heterocyclic carbon
compounds of the iDdole serles having an ami~o substituent,
and with drug b~o-affecting and body treating proce6ses
employing these compounds.
A large body ~f prior art exists for msny aeries of compounds
classified as 3-tarYloxY)-2-hYdroxyProPylamines. ~o~t of these
series clai~ utility as useful agents in treatmen~ of cardiovascular
diseases, particularly beta-adrenergic recep~or blocking act~vity.
Many compounds in this general class also possess a degree of vaso-
dilating effectiveness due, in some instances, to inherent alph~-
adrenergic receptor blo~ing activity. ~arious other cardiovasoular
dru~ effects, or ~heir lack, combine to make s~me of these c~mpounds ~:
appear to be us~ful as antihypertensive agents. Most prior art,
ho~ever, concerns the beta-adrenergic blocking agent proper~y for
"
3~
~hese series of compounds. The prototype or structures of this kind
is propranolol; chemically, l-(isopropylamino)-3-(1-naphthyloxy)-2-
propanol. Propranolol and some related naphthyloxy propanolamines
are the sub~ect of U.S. Patent No. 3,337,628 issued August 22, 1967.
Numerous subsequent patents have been granted coverlng series of
compounds representing structurally modified 3-~aryloxy)-2-hydro~y-
propylamines.
A series of indol-3-yl-tert.-butylaminopropanols (1,2) ~ith
antihypertensive properties was described in: Kreighbaum, et alO,
U.S. Patent No. 4,234,595 patented November 18, 1980; U.S. Pat&nt No.
4,314,943 patented February 9, 1982; and Journal of Medicinal
Chemistr~, 23:3, 285-289 (1980~.
X3 ~ J ~ 03
tl)
R3 ~ ~XN~ O-Ar-Het
~N R2 OH
Rl
(2)
36
In these foregoing structural for~ulas, the symbol R c~n
be hy~rogen, halogen, lower alkyl or alkoxy but not hydroxyl.
A preferred compound of the ~tructural For~ula ~1) series
is deslgnated MJ 13105, also known by the ~nited States Adopted ~ame
85 bucindolol, and is currently undergoing evaluation cllnically as
an antlhypertensive ~gent.
CN
D -
MJ 13105
It is of lnterest in regsrd to the instant co~pounds that a
~aior metabolic pathway for ~J 13105 involves 6-hydroxylation of the
indole ring. This was confirmed by comparison nf ~etabolic ~solates
with the synthetically ~vailable correspondin~ 6-hydroxyindolyl
compound of the insta~t invention.
Attention is also called to applicsnt~s pending Canadian Appli-
cation Serial No. 435,880, filed September 19 1983, ~hich discloses a
series of vasodilating agents hav$ng a ran~e of beta-adrenerglc
blocking potency 2nd possessing structural for~ula ~3).
A l 2
R ~
C ~ ~Y
B
~3
7~
While in the foregoing structural formula (3), C can be
hydroxyl, among other ~ubstituents, the series in general is
dis~inguishable from tha lrlstant invention in that compGunds of
structure (3) are pyridinyloxypropanolamines.
The present invention ~ncludes the compounds of Formula I
and the acid addition salts of these substances.
HO ~ ~ ~ r ~ RS
(I)
In th~ fore~olng structural formul~ the symbols R -~5
have the follo~ing meanings. One of Rl and R2 is hydrogen and the
other is hydro~en or Cl 4 alkyl, R3 and R4 are independently selected
from hydrogen or Cl 4 alkyl, and R5 can be halogen, hydrogen, hydroxy,
or Cl 4 alkyl. For prefesred csmpounds Rl is H, R2 is 2-H, R3 and
R are methyl, and R5 is hydrogen or 5-fluoro. The compounds of ~he
present inventlon are useful as antlhypertenslve agents due in part
to a combination of their adrenergic receptor-blockin~ and vasodilator
activi~ies.
7~6
The invention includes compounds having the foregoing
structural formula (I) and the acid addition salts thereof. In
structural formula I, Rl, R2, R3, and R4 can be hydrogen or alkyl
having 1 to 4 carbon atoms. One of Rl and R2 will always be hydrogen
whereas R and R4 are independently selected and can both be slkyl.
R can be halogen, preferably fluoro or chloro; hydrogen; hydroxyl;
or lower alkyl. The lndolyl syste~ is attached to the side ch~in
at either the 2- or 3- position and the hydroxyl substituent occupies
either the 4-, 5-, 6-, or 7- ring position of indole. F~r preferred
compounds, Rl is hydrogen; R2 is 2-hydrogen (the indole moiety being
coupled to the main side chain through its 3-position); R3 and R4 are
methyl; and R5 is hydrogen or 5-fluoro.
For medicinal use, the pharmaceutically acceptable acid
addition salts, those salts in which the anion does not contribute
significantly to toxicity or pharmacological activity of their
organic eation, are preferred. The acid addition salts are obtained
either by react~on of an organic base of structure I with an organic
or inorganic acid, preferably by contact in solution, or by any of
the standard methods detailed ln the llterature and available to any
practitioner skilled in the art. Examples of useful organic acids
are carboxyllc acids such as maleic acid, acetic acid, tartaric acid,
proplonic scid, fumaric acid, isethionic acid, succinic acid, pamoi~
~cld, cycl~mic acid, pavalic acid, and the like; useful inorgan$c
acid are hydrohalid~ acids such as HCl, ~Br, HI; sulfuric ~cid;
phosphoric acid; and the like.
'7~ 6
It is also to be understood that ~he compounds of the
present invention include all the optical isomer forms, that is,
mi~tures of enantiomers, e.g., r~cemlc modifications as well as the
individual enantiomers. These individual enantiomers are commonly
desi~nated according to the optlcal rotation they effect, by (+) and
(-), (1) and (d), or combinations of these symbols. The symbols (L)
and (D) and the symbols (S) and (R), which stand for sinister and
rectus, respectively, designate an absolute spatial conf~guration of
the enantiomer. Whese no isomer designation ls given fo~ a compound,
the compound is the racemic modification.
The individual optical isomers of the aryloxypropanolamlne
class of compounds, of which the instant compounds are members~ have
most generally been obtained by one of four basic methods. These
are: 1) the fractional recrystalli~ation of chiral acid salt derivatives;
2) derivatization wi~h a chiral organic reagent, resolution and
regene~at~on of the ori~inal compound ln optically active form
3) synthesis of the single op~ical isomer usin~ ch~ral in~ermediates;
and 4) column chromatography utilizing chiral statio~sry phases.
Applications of these various methods are well known to practitioners
in the art.
Biological testing of representative subject compounds of
Formula I in animals demonstrates that they possess biological
propertiPs which ~ould make them useful as antihypertensive agents.
In addition to antihypertensive activi~y demonstrable in animal
~esting, the instant compounds also possess vasodilating properties
along ~ith varying degrees of adrenergic alpha- a~d bet~-receptor
blocking properties and intrinsic sympathomimetic activ~ty. h more
detailed description of the specific pharmacological tests employed
and the criteria used to judge the pertinent biological activity
is contained in the Description of Specific Embodiments section
under the subheading Biological Evaluation. Preferred representative
members have a particularly desirable combination of the foregoing
actions, and ancillary pharmacological effects, or lack thereof,
which particularly suits them for specific cardiovascular indications,
e.g. use as antihypertensives. The utility of the compounds of
Formula I can be demonstrated in these various animal models, as
referred to above, which include antagonism of isoproterenol in the
anesthetized dog treated intravenously (adrenergic beta-receptor
action), the spontaneous hypertensive and DOCA salt hypertensive rat
(antihypertensive action), antiotensin-maintained ganglion-blocked
rat model (vasodilator action), and an anesthetized rat model (alpha-
andrenergic blockade), and in various other animal laboratory models
(cf: Deitchman, et al., Journal Pharmacological Methods, 3, 311-321
(1980)).
As examples, two of the representative compounds of
Formula I; 2-[2-hydroxy-3-[[2-(6-hydroxy-1H-indol-3-y1)-1,1-dimethyl-
ethyl]amino]propoxy]benzonitrile and 2-[2-hydroxy-3-[[2-(5-hydroxy-
1H-indol-3-y1)-1,1-dimethylethyl]amino]propoxy]bennzonitrile caused
greater than 20 mmHg mean drop in systolic blood pressure of rats
in one or both of the antihypertensive tests when given at a dose
level of 30 mg/kg p.o. A 3 mg/kg intravenous dose of these compounds
resulted in over a 20% drop in mean arterial blood pressure (taken
30 minutes after dosing) in the vasodilation test.
- 7 -
36
For use as antihypertensives, ~asodllators, ~nd¦or
adrenergic blocking agents, the apeu~:Lc proc~sses ~f this inven~ion
comprise sgstemic admin~st.a~ion, by both oral ard parenteral L~o~ tes~
of an ~ffective9 non-toxic amount of a compound of Formula I or a
pharmaceutically acceptable acid additlon salt thereof. An effective
amount is construed to mean a dose which exerts the desired phar~a-
cological actlvity, such as those stated hereinabove, without undue
toxic side effects when administered to a mammal in need of such
treatment. Dosage will Yary, according to the subject and route of
administration selected, with an expected range of about 0.1 mcg to
100 mg/kg body weight of a compound of Formula I or a pharmaceutically
acceptable acid addition salt thereof generally providing ~he desired
therapeutic effect. A preferred range for an effective dose would
be about 0.1 to 0.5 mg/kg when gi~en intravenously and about 0.5 to
5 mg/kg when gi~en orally.
The compounds of t~e present in~ention can be prepared by a
~onvenient general yrocess. This process is outlined below in Scheme ~.
~ hroughout this application, r~ stand~ for a methyl grou~? and ~c
sta~ds for the acet~ta ion, C2H302 .
5cheme 1
R4 3 R2
~~ '
(IV) (III)
CN R4 3 R2
B ~ R5 ~ ~ ~ OM
(II)
R R R
H~--o~R5
. (I)
Rl-R5 are as defined above.
This process ln~olves the coupling of a suitable
methoxylated indolalkylamine (III~ with an R~ substi~uted pheno~y
epoxide iDtermediate (IV). Synthetic methodology required ~o reach
this pD$nt iD the preparation of Formula I products is analo~ous
to a syDthetic process used to prepare bucindololiin the per~aining
Krei~hb~um, et ~1. patents U.S. 4,234,595 ~nd U.S. 4,314,943, ~nd
~79~6
J. Med. Chem., 23:3, 2B5-2B9 (198~) artlcle. An
additional ~tep, however, is required as ~he resulting ~ethoxylated
indole analog (II) is converted to the desired (I) product by
cleavage of the methoxy group with boron tribromide in methylene
chloride aolution. Other synthetic methods resulting in CDnVersion
to hydroxylated products, e.g. such as hydrogenolysis of benzyloxy
precursors, are well known to the chemical practitioner and may also
be adapted for use in a modified process.
The coupling of the epoxy ether int~nmediate (IV) with the
indolylalkylamine (III) to give in ermediate (II) is carried out
si~ply by heat:ing the epoxy ether eieher neat or ln the presence of a
reactioD iner~ organic sol~ent with an appropriate indolylalkylamine
as shown. No catalyst or condensation a~ent is usually requlred.
Suitable solvents include 95Z ethanol but other reaction-inert
organic liquids in which the reactants are soluble may be employed~
These may inçlude but are not limited to be~ene, tetrahydrofuran,
dibutyl ether, butanol, hexanol, methanol, dimethoxyethane, ethylene
glycol, etc. Suitable reaction temperatures are from about 6Q 200C.
The requi~ed reaction in~ermedlates, Ill and IV, ~ay be
obtained by se~eral methods and are not lImlted to the follo~ing.
The phenoxy epDxide in~ermediates (IV3 can be obtained by alkylation
of the appropriate R5-substituted cyanophenol (V~ with epichlorohydrin as
ln Scheme 2; or in recalcitrant cases by usin~ epibromohydrin, R2C03
and dim~thylformamide.
-- 10 --
.. ~ . . . . .
~c '
~2~
Schema 2
R5 ~ Cl ~ ~ R
(V3 (IV)
While many cyanophenols (V) are commercially available, they may also
be conveniently prepared from readily availsble phenDls via the
synthesis outlined as Scheme 3.
Scheme 3
R5 ~ CHCl~ R5 ~ H2NOH 5 ~ CH=~O~
OH NaO~ OH OH
IAC~O
CN
OH
(V)
Thls sequence ~ssentially invol~es formylation of an R5-substi~uted
phenol accordiDg to Reimer-Tiemann conditions to afford the salicyl-
aldehyde deriva~ive which is converted via ebe oxime in~er~ediate to
the desired salicylonitrile (V). It s~ould be noted that when
Formula I products in which R5 is hydroxyl are desired, the IV
-- 11 --
intermedi~te in ~hich R5 is methoxy is to b~ used in Scheme 1.
Cleavage by BBr3 to the hydroxyl group is effected ln the last step
of ehe synehesis.
For the intermediate indolylalkylamines of structure III,
typical synthe~ic procedures for eheir preparation are ~vailable in
the Rreighbaum, et 81 ., patents and ehe J. Med. Chem. artiele c~ted
hereinabove. Although these refereneed procedures are applicable to the
preparation of o~her indolylalkylamine i~termediates which may be
desired but are not specifically disclosed there~n, representative
syntheses of ~ormula III compcunds will be given hereinbelow for
further ~xemplification of intermediates whlch may be required for
the present invention.
Finally, it is of interest that a 6-hydroxyindolyl
compound of Formula I (2-~2-hydroxy-3-[~2-(6-hydroxy-I~-indol-3-yl)-
l,l-dimethylethyl]amino~propoxy]benzonitrile) which structurally
corresponds to bucindolol ~Rl~ R , R5 are hydrogen and R3, R ~re
methyl) was used to confirm ~he identi~y of a ma~or ~etabol~te of
bucindolol. It ~s k~own that 6-hydroxylation is pPrhaps more import~nt
than 5-hydroxylation $n the metabol$sm of tryptamine derivatlves (cf:
Jepson, et al., Biochi~. Bio~ys. Acta., 62, 91 (1962); Jaccarini a~d
Jepson, Biochi~. Bioph~s. Acta., 156, 347 (1968)). This knowledge
suggested the possibility that 6-hydroxylation of bueindolol might be
sn important metabolic pathway. This has been confirmed by demonstr~tion
that this 6-hydroxyindolyl compound of the instant invention a~rees
in mass spectrum ant gas chromatographlc retention ti~e wieh a
corresponding major hydroxy ~etsboli~e of bucindolol. In this regard,
- 12 -
.
,,, , ~
, .
ano~her aspect of the instant lnvention comprises 2-~2-hydroxy-
3-[~2-(6-hydroxy-lH-lndol~3-yl~-1,1-dimethylethyl]amino]propoxy]-
benzonitrile in purified phar~aceutically scceptable for~.
The compounds of the present invention can be for~ulated
according ts conventional pharmaceutical practice to provide pharma-
ceutical compositions of unit dosage fsrm comprising, for example,
tablets9 capsules, powder~, granules, emulfiions, suspensions, and the
like. The solid preparations contain the actiYe lngredie.lt in
ad~ix~ure ~ith non-toxic pharmaceutical excipient6 such as lnert
diluents, for example, calcium carbonate, sodium carbonate, lactose,
calcium phosphate or sodium phosphate; granulating and ~isintegra~ing
a~ent~, for exa~ple9 maize, starch, or alginic ac$d; binding agents,
for exampl~, starch, gelatin or acacia; and lubricating agents, for
exa~ple, magnesium stearate, stearic acid sr talc. The tablets ~8y
be uncosted or ehey may be coated by known techniques so as to ret rd
disintegration and absorptioD in the gastrointestinal tract snd
thereby provide a sustained action over a longer period. Llquid
preparations suitable ~or parenteral administration include solutions,
suspensions, or emul~ions of the compounds of Formul~ I. The aqueo~s
~uspenslons of the pharmaceut$cal dosage for~s of the compounds of
Formula I contain the activ~ lngredient in admixture with one or more
non-toxic phar~aceutical excipients known to be suitable in the
manufacture of aqueous ~uspensions. Suitable exclpients are, for
example~ suspending agents such as sodium carbsxymethylcellulose,
2~ ~ethylcellulose, hydroxypropyl methylcellulose, sodium al~inate,
polyvinylpyrrolidone, gum tragecanth and gum acacia. Suitable
disbursing or wetting agents are naturally oc~urin~ phosphatides, for
example, lecithin, polyoxyethylen~ stearate.
. .
12 ~916
Non-aqueous suspensions may be formulated by suspending the
active ingredient in vegetable oil, for example, olive oil, sesame
oil, or coconut oil, or in a mineral oil, for example, liquid paraffin.
The suspensions may contain a thickening agent such as beeswsx, hard
paraffin, or cetyl alcohol. Sweetening and flavoring agent~ generally
used in pharmaceutical compositions may also be included such as
saccharin9 sodium cycla~ate, sugar and caramel to provide a palatable
preparation. The compositions may also contain other absorbing
agents, stabilizing agents, wetting agents, and buffers.
The compounds which constitute this invention, their
methods of preparation and their biologic actions will appear more
fully from consideration of the following examples, which are given
for the purpose of illustration only and are not to be co~strued as
limiting the invention in sphere or scope, and the appended claims.
In the following examples, used to ~llustrate the foregoing syntheeic
processes, temperatures are expressed in degrees Celsius and melting
points are uncorrected. The nuclear magnetic resonances (MMR)
spectral characteristics refer to chemical shifts (~) expressed as
parts per million (ppm) versus tetramethylsilane (TMS) as reference
standard. The relative area reported for the various shifts in the
H NMR spectral data rorresponds to the number of hydrogen atoms of a
particular functional type in the molecule. The nature of the shift~
as to mul~iplicity is reported as broad sin~let (bs), singlet (s),
multiplet (m), or doublet (d). Abbreviations employed are DMS0-d6
(deuterodimethylsulfoxide), CDC13 (deuter~chloroform), and are
- 14 -
96
otherwise conventional. The infrared (IR) spectral descriptlons
include only absorption wave numbers (cm ) having functional group
identificatlon value. The IR determinations were e~ployed using
potassium bromide (KBr) as diluent. The elemen~al analyses are
j reported as pPrcent by ~eight.
Synthesis of Intermediates
A. Intermedl~tes of Formula III: General Procedures
EXAMPLE 1
Methoxyindol-3-vl-tert.-butylamine
To 15.2 ~L of a chilled 25% aqueous solution of dimethyl-
amine the followin~ are added sequentially with stirring snd contlnued
cooling: 16D9 ~L of ~c~tic acidg 7.2 mL of 37% for~aldehyde, 27 ~L
of 95% ethanol. The resulting stirred solution is kept at 0~ to -5
with a c~oling bath while the appropriate methoxyindole tlO.O g, 0.~7
mole) is added in portions. This mixture is stirred and gradually
warmed to 30 over a period of one-half hour and then held at 30~
with stirring for 3 hours. The reaction mixture is then chilled to
10-15 and acldified ~ith 17~ mL of 2N HCl. This acidic mixeure can be
decolorized ~Darco G-60), filtered and the filtrate made basic using
20 245 mL of 20% NaO~ ~hile being cooled and stirred. A resul~ing brown
oily precipitate is ether extracted, and the extracts are water-
washed, dried (MgS04) snd concentrated to a brown oily residue (14 g).
The residue is recrystallized, e.g. from isopropyl ether and hexane
to yield the desired methoxygramine, usually as a tan solid.
A mixture comprised of the appropriate methoxygramine
(7.7 g, 0.04 mole), 2-nitropropane (2~.5 g, 0.3 mole), and NaOH
(1.7 g pellets, 0.04 mole) is refluxed under a nitrogen atmosphere
..
,
for 3-5 hours. The reaction mixture is then cooled to room
tempera,ure, acidified with lOX acetic acid and extracted with ether.
The ether ~xtracts ~re water-washed, dried (~gSO~), and concentrated
in vacuo to a residue. Recrystallization of the residue, e.g. from
isopropyl alcohol-water gives a 3-(2-meehyl-2-nitropropyl)methoxyindole.
This nitropropylindole compound and activsted Raney Nickel
(4.2 g) are combined in 80 ~L 95~ ethanol and heated to reflux.
Heating is halted as a solution comprised of 85% hydrazine hydrate
(7.8 g) in 8 mL of 95% ethanol is added dropwise. The reaction
mixture is then heated at reflux for 2 hours, cooled to room temperature
and filtered. The filtrate is concentrated to an oily residuç which
can be recrystalli7ed, e.g. from ethyl acetate-isopropyl ether to
give the desired ~ethoxyindol-3-yl-t-hutylamine product.
EXAMPLE la
6-MethoxYindol-3-yl-tert.-butylamine
A mixture of 6-methoxy gramine (0.9 g, 0.004 ~ol~,
prepared from 6-methoxyindole by the procedure of Example 1), 3.0 g
(0.034 mole) of 2-nitropropane and 0.19 g (0.005 mole) of ~aO~
pell~ts was stirred a~ reflux in an oil ba~h under a nitrogen atmos-
phere for 2 hours, as dimethylamine escaped through the condenser.The resulting mixtus~ was cooled to 25, treated with a solution of
0.47 mL of glacial acetic acid ln 4.1 mL of ~ater and extracted with
ether. The ether ~tract was washed with three portionæ of water,
dried (M~SO~ and evaporated to dryness. The residual brown oil
crystallized upon rubbing and coolir.g in a small amount of isopropyl
ether. The solid was isolated by filtration, washed with cold
isopropyl ether and drled in air to give 0.6 g of tan solid which was
- 16 -
,
3~
recrystalli~ed from isopropyl alcohol-water to give 0.52 g (46X)
of 3-~2-m2thyl-2 nitropropyl)~ etho~yindole, m.p. 9B-99 DC.
A slurry of 8.0 & ~0.32 ~ole) of the nltro compound as
prepared above, 80 mL of 95% ethanol and 4.2 g of Raney Nickel
~washed with water and 95% ethanol) was heated to reflux ~ith paddle
stirring. Exterior heatlng was halted and a solution of 7.8 g of 85%
hydrazine hydrate in 8 mL of 95% ethanol was added dropwise at a
sufficient rate to maintain a gentle reflux. After the addition, the
mixture was reheated at reflux for two hours and then cooled to 25C.
Filtering and concentrating the filtrate to dryness gave a crude
syrup ~hich was chromatographed on silica gel column, eluting with
CH2C12-CH30H-concentrated NH40H (90:10:1). The tan solid th~s
obtained ~2.9 g, m.p. 125-128~C) was recrystallized from ethyl
acetate-isopropyl ether to afford 1.27 g (18~) of 6~methoxylndol-3-
yl-tert.-butylamine, m.p. 125-128.
EXAMPLE 2
- Methoxyindol-~-yl-ter~-butylamine
(~1 R2 = ~, R3. R4 ~ Me) _
In this ~eneral procedure a solution comprising the
appropriate m2thoxyindole-2-carboxylic acid (0.06 mole) and thionyl
chloride (2.0 g, 0.17 mole) in 130 mL of dry ether is stlrred for 12-
18 hours at room temperature under a nitrogen atmosphere. The
reaction mixture is flltered and the filtrate is concentrated to an
oily residue which i~ taken up ln 150 mL of dry ether. This ether
solution is ~reated uith 80 mL of dimethylamine in 90 mL of ether.
The ethereal reactlon mixture is concentrated to dryness aDd the
- 17 -
residue crystallized in i~opropyl alcohol~ The solid i8 isolated by
filtratioIl to give a ~0-40X y~elt of the metiIvxyiTldole-2-carboxamide
product.
The methoxyindol-2-yl carboxamide is dissolved in lOO mL
of THF and this solution is add~d dropwise to a stirred suspension
comprised of 3 g of lithium aluminum hydride in 50 mL of I~IF under a
nitrogen atmosphere. After heating at reflux for 2 hours, the
reaction mixture is cooled and decomposed with a ~mall a~ount of
water and dilute NaOH solution. This mixture is filtered and the
filtrate is concentrated to a residual oil which is taken up in
absolute ethanol and tre2ted with a slight excess of dimethyl sulf~te.
The resulting alcoholic solution is stirred at room temperature for
four hours and then concentrated in vacuo to dryness giving as
residue a tr$methylam$ne quaternary salt.
l~ The crude quaternary salt product (0.01 mole) is combined
with NaOH ~2.0 g pellets, 0.05 mole) and 2-nitropropane (15 mL) and
the mixture is heated at reflux under a nitrogen atmosphere for
1 hour. The resultant dark thick mixture is cooled, diluted ~ith
water, acidified with acetic acid to a pH of approx$mately 6 and then
extracted with ether. These ether extracts are combined, washed with
water, dried (MgS04) and concentrated to a dark residue which is
chromatographed on a silica column and diluted with methylene chloride.
Removal of the methylene chloride ~olvent and recrystallization of
the crude material from isopropyl alcohol-water gives a methoxyi~dole
substituted in the 2-position with a 2-methyl-2-nitropropyl moiety.
R~duction of this n$tro product ~i~h Raney Nickel and
hydrazine according to the procedure used in Example 1 above will
yield the desired methoxy~ndol-2-yl-tert.-butylEmine.
- 18 -
,
EXAMPLE 3
l-~ethylation of Methoxyindolylalkylamines:
3-(2-A~ino-2-methylpropyl~ methyl-methoxyindole
(Rl R3 R4 - Me, R2 ~ H)
In this general proc~ss 7 g (0.11 mole) of ~5% ~OH ls
ground in a mortar and quickly transferred to a nitrogen-flushed
25-mL Erlenmeyer flask. DMSO (55 mL) is added and the mixture is
stirred fDr 5 mlnutes. Additions of methoxyindolyl-tert.-butylamine
(0.27 mole) and iodomethane (3.78 g, 0.03 mole or any other s~itable
alkylating agent~ are each followed by 45 minutes of stirring after
which the suspension is quenched in 300 ~L o water. Extraction of
the mix~ure with ethyl acetate9 followed by washing of the extracts
~ith water and brine affords a clear solution which is dried (MgSO4)
and evaporated in vacuo to an olly product. This free base ~ay be
used as a ineermediate without further purification. Chsracteriza~ion
is usually made by converting the oily base to the hydrochloride salt
in order to obtain a crystalline product.
EXAMPL~ 4
Methox~indol-2-ylethylamine
In this pro~edure whlch iB essentially that of Bhat and
Siddappa, J. Chem. Soc. (C), 1971, 178-81; va~ious methoxyindol-2-
carboxylate esters (commercially available or prepared by literature
methods) is reduced to the corresponding 2-hydroxymethylindole
derivative by reduction with lithium aluminum hydride in ether.
Conversion to the indol-2-carbaldehyde ls accomplish~d by dissolving
a 2-hydroxymethyl-methoxyindole (4 g~ in dichloromethane (2~0 mL) and
adding activated manganese dioxide (10 g~ followet by stirring of the
reaction mixture at room temperature for 20-30 hours. The reaction
-- 19 --
is followed by TLC, monitoring the di~appearance of the starting
2-hydroxymethyl~ndDle spot. If neces~ary, fresh quantities of
manganese dioxide ~2-3 g) can be ~dded. l'he reaction mix~ure
is filtered and the residual manganese dioxide washed repeatedly with
~ little fresh dichloromethsne. The combined filtrate i8 ev~porated
~o dryness to give the crude methoxyindol 2-carbaldehyde ~s a pale
yellow solid which is then r~crystsllized.
The me~hoxyindol-2~carbaldehyde (5 g), nitromethane (B mL),
and ammonium acetate (1 g) are h ated under reflux for 1/2 hour.
The reaction mixture is cooled and the dark red crystals that separate
are collected, washed thoroughly with water, dried and crystallized
from ethanol. The nitrovinylmethoxyindole thus prepared is then
reduced to the desired methoxyindol-~~ylethylamine by treatment with
lithium aluminum hydride in dry ether. The reduction mixtu~e is
gently heated under reflux for lo hours following which the excess
lithium aluminum hydride is deco~posed. Follo~in~ filtsation, the
-filtrate is concentrated in vacuo to give a residu~ which is
crystallized from a suitable solvent to give ~he desired ~ethoxy-
indol-2~ylethylamine.
EXAMPLE 5
MethoxYindol~2~y~prop~1am$ne
Modifying the procedure of Exa~ple 4, an appropriate
methoxyindol~2~carbaldehyde tl g) in nitroethane (O.S mL~ is treated
with four drops of benzylamine; following which the mixture is heated
at reflux for one hour. The cool reaction mixture on standin~
deposits d~rk red crystals which may be collected, washed with a
little ether, dried, and crystallized from ethanol. ~hese nitro-
propenyl indoles thus prepared are reduced with lithium alu~inum
- 20 -
36
hydride ns described above In Ex~ple 4. Solid products are
crystallized and the liquids are characterized as benzoyl derivatives.
EXAMPLE 6
Methoxyindol-3-ylethyl~mine
Cf: Young, J. Chem. Soc., 1958, 3493-96; This synthesis
starts with methoxylndol-3-aldehydes which are either available
commercially or prepared from literature methods. Using the pro-
cedure outlined in Ex2mple 4 abo~e, an appropriate methoxyindol-3-
carbaldehyde is condensed with a nitromethane using ~mmonium acetate
as a catalyst~ On standing, the cooled solution grsdually deposits
dark red crystals which can be recrystallized from benzene or methanol
to give the 3-nitrovinyl-methoxyindole which is reduced wi~h lithium
aluminum hydride, as ~bove to yield the desired methoxyindol-2-
ylethylamine.
EXANPLE 7
Methoxvindol-3-ylpropylamiDe
A selected methoxyindol-3-carbaldehyde (5 g), nitroethane
(10 ~L)~ snd ammonium acetate ~l ~) are heated on a ~team bath with
occasional shaking for 1/2 hour. On cooling, the crystals are
collected, washed with hot ~ater (2 x 50 mL) and crystallized from
methanol. The resulting 3-(2-nitropropenyl)-methoxy~ndole is reduced
to the desired 3-(2-aminopropyl)-methoxyindole by treatment with
lithium al~minum hydride as detailed in the above procedures.
- 2~ -
B. Inter~ediates of Formula IV
EXAMPLE 8
2-[(2,3-Epoxy)propoxy~benzonitrile
A solution of 2-cyanophenol (25.0 g, 0.21 mole), epichloro-
S hydrin (117 g, 0.26 mole)~ and piperidine (10 drops) was stirred and
- heated at 115-120 in an oil bath for 2 hours. The reaction mixture
was then concentrated (90~30 Torr.) to remo~e unreacted epichlorohydrin.
The residue was diluted with toluene and concen~rated to dryness
twice to help remove the last traces of volatile material. The
residual oil ~as dissolved in 263 mL of tetrahydrofuran and this
solution was stirred at 40-50~ for one hour ~ith 263 mL of lN NaOH.
The organic layer was s¶ted and concentrated to give an oil which
~as combined with the aqueous phase. The mixture was extracted
(CH2C12), and the extract dried (MgS04) and concentrated to ~ive
36.6 g (100~ of oil which slowly csystalli~ed to a waxy solid. This
intermediate product may be used without further purlfication in the
preparation of Formula I products.
EXAMPLE 9
2-~(2,3-Epoxy)propox~1-4-methoxybenzonitrile
The requisite 5-methoxysalicylaldehyde can be obtained from
4-methoxyphenol by the Reimer-Tiemann procedure which is well
described in the l~erature~ e.g. CE: Rappe, et al., Arch. Pharm.,
308/5, 339 (1975). A solution comprising O.OOS mole o~ the starting
salicylaldehyde in 6 mL of pyridine and 6 mL ~f absolote ethanol is
trea~ed with 0.4 g (0.02 mole) of hydroxylamine hydrochloride and
heated at reflux for 4 hours. The mixture is concentrated in vacuo
to a gray syrup ~h~ch is stirred with 50 mL of H20 and the suspension
- 22 -
~;23L~7~4~6
decanted. Addition ~f 10 ~L of ~0 to the residual glassy material
followed by chilllng at 5 affords, upon filtration, approximately
1.2 g of crude solid which is taken up in 25 mL of 50~ ethyl e~her-
isopropyl ether. The ether solution ic filtered, dried ~MgS04),
ereated with Darco G-60 and Celite, filtered ant concentrated in
vacuo to a waxy solid. Recrystallization from ethyl ether~Skelly B
gives the corresponding ben~aldehyde oxime.
A m~xture of 0.002 mole of the oxime and 1.02 g ~0.01 mole)
of acetic anhydride is heated at reflux for 30 ~inutes and then
cooled to 25. Wa~er (50 mL) was added~ followed by dropwise addit~on
of 20% ~aO~ ~o p~ 10. The resulting suspension was ~tirred at 253
fos 20 hours (to hydrolyze any acetate ester of the desired phenol
derivative. The pH is adjusted to about 2 using ~_ HCl and the
resulting mixture i6 extracted with 40 mL of ethyl acetate to give an
organic layer which is separated, dried (MgS04) end evaporated at
65/70 Torr. to give a tan syrup which sti:Ll consists mainly of the
acetate ester. Further hydrolysis of the syrup in a mixture of 7 mL
of methanvl, 7 mL of water ~nd D.l g of ~a~H pellets at 25 for
3 hourc ~s followed by remo~al of the methaDol at 6~7~ torr.
Dilution of the aqueous residue with 0.5~ HCl affords a precipitate
which can be recrystallized ~rom isopropyl ether and dried to give
the desired benzonitrile intermediate.
A mixture of 0.015 mole of the 2-hydroxy-5-methoxybenzo-
nitrile, 4.2 ~ (0.03 mole) of finely powdered anhydroue potassium
25 carbonate and 140 mL of D~F was stirred at 50 for 15 minuteæ.
Epibromohydrin (2.8 g or 0.02 mole) was added in one portioD ~nd
stirring was continued for 3 days. The reaction mixture was
- 23 -
'3~i
poured into 1 liter of brine and the resulting suspension stirred for
3 hours at 0-5~. Filtering the mixture and washing the ftlter cake
with water gave upon drying in air the crude lntermediate compound
which could be used without further purification.
Similarly, using other substituted 2-cyanophenol~ in
modifications of the above procedures will provide the other inter-
mediate compounds of Formula IV to be used in synthesis of the
vsrious Formula I compounds of this invention~
Synthesis of Products
EXAMPLE 10
General Procedure: 2-~2-Hydroxy-3-[(hydroxy-
indolYl)alk~lamino]propoxy]benzonitrile
A selected methoxyindolylalkylamine (III~ is mixed with an
equimolar or slight excess amount of a selected epoxy propoxy benzo-
nitrile (IV) and the coupling is accomplished by either refluxing a
solution of the ~eactants for apprDximately 18 to 24 hours or heating
-a neat mixture at a temperatu~e of about 120L13~ for abQut lJ2 t~
2 hours. Ethanol and tol~ene are the usual solvents chosen for the
reaction ~edium for coupling via refluxing a solution of III and IV.
In some instances, it is advantageous to follow the course of the
reaction by TLC, adding addltional IV epoxide un~il all indolylamine
III has disappeared. FO11DWing reaction the ~ixture is concentrated
to dryness and the residue is either washed and used crude in the
next step or the intermediate methoxy product may be pur$fied by
crystallization-recrystallization either as the base or a suitable
acid addition salt.
A jolution of the methoxyindolyl product ~II) dissolved
in ~ethylene ehloride ~nd stirred under a nitrogen at~ofiphere at
0-10 ~hile a several-fold excess of lN boron tribromide ln me~hylene
chloride i6 added dropwise. Following ~dditlon, the resction mlxture
is stirred a~ room ~e~p~rature for about 6-8 hours. The excess boron
tribromide is decomposed by chilling the reaction mixtu~e And dropwlse
addition of excess waeer. The crude hydrobromlde salt of the Formula I
product may be worked up in a number of GonventioDal ways ~uch as
recrystallization, conversion to the base and purification, co~verslon
to the base followed by conversion to a tifferent acid addition salt,
and 60 forth.
The modific~eions necessary to ~dapt thi6 procedure for the
preparatlon of speclfic compounds of Formula I are well wiehin the
skill of any ordinary practitloner in ehe chemichl arts.
E~AMPLE 11
2-[2-Hydroxy-3-[[2-(6-hydroxy-lH-indol-3-yl)- --
1.l-dimeth~lethyl~amino~proPoxy]benzonitr~le
A solution of 6-methoxyindol-3-yl-t-butylamine ~2.S g,
0.012 mole; prepared ~n Exa~ple la), 2 ~(2,3-epoxy)propoxy~benzo-
20 ni~ril2 (2.1 g, 0.012 mole; prep~red in Example 8)~ and 100 mL of
absolute ethanol was stirred ae reflux for 20 hours. Additional
epoxide ~0.21 g) was added aDd reflux was continued for 4 hours,
after which the mixture ~as concentrated to dryne~s s~d the r~sidue
trituratPd in isopropyl alcohol to induce crystallization. The
produc~ ~as collected by filtration, washed with cold isopropyl
~lcohol and dried in ~ir to give 4.0 g (85~) of the me hoxy pr~duct
(II), m.p. 145-146~, which was used directly in the next step.
- 25 ~
, ~ . ~ .,
2 .:. '
7~3~i
A ~olutlon o ehe methoxyindole product prepared ~bove
~1.5 g, 0.004 mole) in 225 mL o~ methylene ~hlo~lde W~6 6tirr~d under
~ nitrogen atmospherP ac 5-lD~C wh~le 15.3 mL (0.015 ~ole) of lM
boron t~ibrom~de in methylene chlorite was added dropwlse. F~lluwing
~he addi~lon, the ice b~th ~as removed and the re~ction mixtuse was
stir~ed it 25~ for 6 hours b~fore refrigeratlon to 5~10~ and dropwlse
~ddition of 47.5 ~L of H20. The result$ng ml~ture was decanted ~nd
the residual ~ummy solid rinsed wlth 2 portions of ~0. Dissolving
~his crude hydrobromide salt ln 50 mL of hot H20 followed by treatment
with Darco G-60, fil~eri~g, cool~ng (25) aDd basifying ~p~ B) with
conc. N~40H gave 1.2 g of tan morphous sol~d wh~ch was chromatographed
(silica gel 609 230-400 mesh, ~M Reagenes) o~ ~ medium pre~sure
syste~ with chloroform-methanol-conc. N~40~ (90:10:1). The prDduct
ob~ain~d in this manner crystallized from a small amount of 95Z
ethanol to afford, by gradual add~tion of H20, 1.~3 g ~71%) of the
desired ~hydro~yindole protuct (I) as a t~n ~olid, m.p. 90-94.
Anal. Calcd- for C22~25N33-1/3~ C~ 68-56; ~ 6-67;
N, 10.90; ~2~ 1054. Found: C, 6~.69; ~ 6.68; ~, 10.68; ~2~ l.B0.
NMR (DMS0-d6): 0.98 t6.s); 2.70 (4,m); 3.30 ~2~s);
3.83 (l~m); 4.11 (2,d [5.8 Hz)); 5.00 (l,bs); S.65 ~3,m), 7.20 (3,m);
7.60 (2,m); 8.71 (l,bs); 10.35 ~l,bs).
IR (K~r): 760, 800, 1260l 1290, 1450, 1495, 1600, 1630,
2230. and 3300 c~ 1.
*Trademark
- 2~ -
t ............................. .. . . . .
EXAMPLE 12
2-[2-Hydroxy-3-[[2~(5-hydroxy-lH indol-3~yl)-
1 =~l~oxy]ben:ollitrile
A solution of 5-methoxyindol-3-yl-t-butylamine (2.7 g,
0.0125 mole; prepared from 5-methoxyindole utilizing the procedure
g1ven in Example 1), 2-1(2,3-epoxy)propoxy]ben~onltrile (2.2 g,
0.0125 mole)9 and 20 mL of acetone was refluxed for 1/2 hour. The
acetone solvent was then allowed to boil off and the oily
residueheated neat at 100 for 2 hours. Isopropyl alcohol (20 mL)
was added and the reaction solution refluxed for 4 hours following
wh~ch it was cooled to room temperature, diluted with 50 ~L of
ether and a stirring rod was used to rub out a white powder, 4.7 g
(96~), m.p. 119~124; TLC (9:1 CHC13-methanol) cxhibits a single
spot, Rf 0.25. This crude methoxy product ~ay be used direotly in
the next seep or be purified via conversion to the RCl salt. Con-
version to the ~Cl salt by treatment of an ~cetonitrile solution with
ethanvlic HCl gives a crude product which is recrystallized ln
butanone-95~ ethanol ~20:1) to off-~hite powder, m.p. 164-166.
Anal. Calcd. for C23~27N303-HCl: C, 64.~5; ~, ~.56;
20 N, 9.77. Found: C, 64.14; H, 6.54; N, 9.68.
Using the procedure given above in Example 11 for boron
tribromide cleavage of the methoxy group, bu~ employing the 5-methoxy-
indole intermediate product (II) prepared above, the d~sired
5-hydroxy indole product (I) in the form of its hydrDbrGmide salt may
be obtained. The pure hydrobromide salt is a beige powder, m.p.
219-221 .
Anal. Calcd. for C22H25N303oHBr: C, 57.40; H, 5.70;
N, 9.13. Found: C, 56.90; H, 5~67; N, 9.45.
~'7~3~i
N~R (DMSO-d6):- 1.32 t6,s~; 3.08 (2,m); 3.36 (2,m); 4.30
(3,m); 5.90 (l,bs); 7.10 (6,m); 7071 (2,m); 'Q.55 {3,bs); 10.95 (l,bs).
IR (~Br): 750, 800~ 1265, 1290, 1455, lb95, 1580, 1600,
7230, and 3300 cm 1.
5tartin~ with appropriate methoxyindolalkylamines (III) and
epoxypropoxybenzonitriles (IV), additional examples of Formula I
products may be synthesized using substantially the same procedures
as outlined hereinabove with only slight mod$fications which would be
well within the skill of a practitioner in the chemical arts. Some
additional products of Formula I which may be synthesized by these
means are shown in Table 1.
- 28 -
'9~
Table 1
HO ~ O ~ R5
(I) CN
Example -OH R R2 R3 R R5
13 4- H 2-H Me Me H
14 7- ~ 2-H Me Me
5 . 15 4- Me 2-H Me Me H
16 5- Me 2-H Me Me 5-F
17 6- Me 2-H Me Me 5-OH
18 7- Me 2-H ~e Me H
19 4- Me 3-H H Me H
5- Me 3-H H Me 5-F
21 6- Me 3-H H Me H
22 7- Me 3-H H H 4-Me
23 4- H 2-Me H Me
24 5- M 2-Me H ~ H
6- H 2-Me Me Me H
26 7- H 2-Me Me Me
27 4- H 3-Me. H H 5-OH
28 5- H 3-Me H Me 5-F
29 6- H 3-Me H Me H
7- H 3-Me H H 5-Br
31 4- H 2-H H Me 5-Me
32 5- H 2-H H Me 4-Cl
33 6- H 2-H H Me
34 7- H 2-H B Me 4-OH
- 29 -
'7~
Biolo~icsl E~aluation
These biologica~ tests were used to gauge the antihyper-
tensive profile of selected co~pounds of Formuls I.
EXA~PLE 35
The efficacy of antihypertensive agents other than adrener~c
beta-receptor blocking agent~ is commonly estimated in the spontaneously
hypertensive rat. Blood pr~ssure vslues are determined for test
animals prior to and 2 and 4 hours after oral doses of 30-10~ mg/k~
of test compounds. Heart rate is dete D ined w~th each pressure
measure~ent as well. A fall in blood pressure at 2 or 4 hours after
the single dose in the range of 15-2~ mm~g is considered "questionable"O
"Active" and "inactive" designations are decreases greater and less
than ~hat range, respectively.
EXA~LE 36
Another test useful in determining efficacy of antihyper-
tensive agents utilizes DOCA-salt hypertensive rats. These hyper-
tensive rats are prepared as follows: male rst6 of ~he Sprague-
Dawley strain weighing approximately 90 g are iDdividually c~ged ~ith
~ree access ~o foDd and ~ater for a 5-day pretreatment period, afeer
which, the drinking water is replaced with 1~ saline solution.
During a 3-week ~reatment period, ~he rats are given a total of 10
subcutaneous injections containing 10 ~g of DOCA (deoxycortico6terone
acetate) in 0.2 mL suspending vehicle (0.25% Tween B0 and 0.125~ CMC
in normal saline solution). After the final injection, the 1~ saline
i6 replaced by distilled water and the animals are available for
use one week later.
*Trademark
- 30 -
The test i6 made by selecting non-fasted animals with
elevated systol~c blood pressures ~>160 mmHg). Blood pressure values
are dete~mined for these test animals prior to and fsur hours after
oral do~es of 30-100 mg/kg of test compounds. During the test period
5 the animals are housed in metabolism cages without feed or water and
urine is collected for 4 hours. Heart rate and body weight are both
determined with each pressure measurement as ~ell. A all in blood
pressure 4 hours after dosing ~hich lies in the range of 15-20 mmHg
is considered "q~estionable"O "Active" and "inactive" designations
10 are decreases greatel and less than that range.
EXAMPLE 37
The angiotensin II-~upported ganglion-blocked rat model is
utilized as a screening test for estimation of the direct vasodilator
component of activity. Percentage changes in blood pressure in
15 anesthetized rats 30 minutes after intravenous dosing are determined.
~ne intravenous dosing is done with test compounds at 3 mg/kg
Borderllne activiey is defined as appr~x~mately a 10% tecrease in
blood pressure measured 30 ~inutes after dosing. "Active" and
"inactive" desigDations are increases greater and less than that.
EXAMPLE 38
Dias~olic blood pressure and heart rate responses to a
fixed challenge dose of isoproterenol are obtained before and 15
minutes after graded doses of ~est compound administered intravenously
over a 3 minute interval to ~nesthetized dogs. A branch of a femoral
25 artery and vein are cannulated to record blood pressure and t~
administer the drugs which are dissolved in saline. The ~agi were
sectioned bilaterally in the mid-cervical region of the neck and the
1~ 36
dogs are ventilated mechanically (~arvard respiratory) with room air
at a rate of 20/minute and a stroke volu~e of 20 nI,/kg. Heart rate
is monitored with a cardiotachometer triggered by the pressure pulse.
All measurements are recorded on a Beck~an R 612 recorder. The drug
effect is expressed in terms of a cumulative dose (microgram/kg)
causing 50% inhibition of isoproterenol response.
EXAMPL~ 39
Rats (male Wistar) are anesthetized with ~ co~bination of
urethane and chlcralase intraperitoneally. Following induction of
anes~hesia, chlorisondamine ls in~ected into the peritoneal c~vity to
produce ganglion blockage. A femoral artery was cannulsted to
~oni~or blood pressure and heart rate and two femoral veins were
cannulated to administer compounds. The trachea was intubated and
rats were allowed ~o breath spontaneously. Animals were challenged
before and 15 minutes after intravenous administration of test
compound with graded doses of phenylephrine and the changes in blood
pressure recorded. Data were plotted to obtain dose-response curves
and the dose of phenylephrine required to elicit a 50 ~mHg (ED5~)
inerease in blood pressure was interpolated fro~ the curv~s. Dose
shifts are calculated by divid~ng the ED50 after drug by the ED50
before drug.
