Note: Descriptions are shown in the official language in which they were submitted.
~Z36834
MY 556
SUBSTITUTED l-PYRIDYLOXY-3-
I~DOLY~ALKYLAMINO-2-PROPANOLS, PREPARATION, AND
USE THEREOF
The present invention is concerned with heterocylic carbon
compounds of the insole series having an amino substituent,
and with drug bio-affecting and body-treating processes
employing these compounds.
A rather large body of prior art exists relating to compounds
of 3-(aryloxy)-2-hydroxypropylamine series which have beta-adrenergic
receptor blocking activity and/or vasodilating properties and are
useful in treatment of cardiovascular diseases. Much of this prior
art concerns the beta-adrenergic blocking agent class of these series
of compounds. The prototype for these structures is propranolol;
chemically, l-(isopropylamino)-3-(1-naphthyloxy)-2-propanol. Propranolol
and some related naphthyloxy propanolamines are the subject of U.S.
Patent No. 3,337,628 issued August 22, 1967. Numerous subsequent
patents have been granted covering carbocyclic ethers in which other
aromatic rings or heterocyclic systems replaced the naphthyloxy group
of propranolol.
~;~36834
A series of patents has been granted to J. J. Baldwin
disclosing the employment of the pyridinyloxy group in this fashion.
These compounds and their salts are disclosed and claimed as useful
anti hypertensive agents. These patents, which are listed below,
generally disclose the following generic structure (1)
R2
O HO
(1)
wherein R is alkyd, phenalkyl, phenoxyalkyl, R is H, C-L, with L
being alkyd or aureole; R is H, ON, CF3, OH, C-L, Of, NO, F, puerilely,
oxadiazolyl.
The series of Baldwin patents, assigned to Merck & Co., Inc.,
comprise the following: 4,000,282, December 28, 1976; 4,060,601,
November 29, 1977; 4,091,104, May 23, 1978; 4,092,419, May 30, 1978;
4,144,343, March 13, 1979; 4,145,425, March 20, 1979; 4,151,284,
April 24, 1979; 4,210,653, July 1, 1980; 4,259,327, March 31, 1981;
4,263,307, April 21, 1981; 4,279,913, July 21, 1981; and 4,329,351,
May 11, 1982.
A preferred compound of this series, 2-[3-(tert.-butylamino)-
2-hydroxypropoxy]-3-cyanopyridine, also known as MCKEE, has undergone
considerable further study as described in: Sweet, et at., The
Journal Or Pharmacology and Experimental Therapeutics, 211/1, 195-296
(1979); Sweet, et at., Clinical and Experimental Hypertension, l,
449-471 (1979); and Tickers, et at., Drug Metabolism and Disposition,
8/3, 163-167 (1980). Acute studies in man were terminated, however,
when MCKEE was found to be teratogenic in rabbits after chronic
-- 2 --
~236834
administration at high doses (of: Journal of Medicinal Chemistry,
22/11, 1284-1290 (1979)).
ON
MCKEE
N O C(CH3)3 Hal
OH
A series of indol-3-yl-tert.butylaminopropanols (2,3) with
. anti hypertensive properties was described in: Kreighbaum, et at.,
US Patent No. 4,234,595 patented November 18, 1980; U.S. Patent No.
4,314,943 patented February 9, 1982; and Journal of medicinal
Chemistry, 23;3, 285-289 (1980).
R3 "I` O-Ar-Xn
(2)
R3 Orate
(3)
A preferred compound of the series represented by
structure (2) is designated MY 13105, also known as bucindolol, and
10 is currently undergoing evaluation clinically as an anti hypertensive
agent.
ON
XHN
MY 13105
1;~36834
SUMMARY OF THE INVENTION
Thus the present invention provides a compound having
the formula
Y I C
OR
(I) 8
and the acid addition salts thereof wherein
X $6 elected from the group consisting of -SHEA, -ON,
-CF3, -Choirboy, or -CROOK with I and Rub being independently
S chosen from hydrogen or Arc end wherein Arc can be lower
alkyd (I by C4), E~3lyl, substituted p*~3lyl, or F*Y~lyl-lower alkyd;
Y represents a second ~ubstitutent on the pyridlne ring
and us hydrogen, halogen, lower clue to C4) alkoxy,
aryl-lower alkoxy, hydrDxy, or -Colloquial wherein
alkyd is Cl-C6alkyl;
the lndolylalkylaminopropoxy side chain is coupled at the pardon
2- or 4- position; O
R us hydrogen or -C-L with L being selected from Of to
C10 alkyd, phenol, or phenalkyl;
Rl,R2,A and B are independently chosen from hydrogen or lower alkyd;
C represents a substituent in the buoyancy ring of insole
and is selected from hydrogen, halogen, lower alkyd,
lower alkoxy, or hydroxy; and
the intolyl system it attached by tic 2- or 3- position,
The invention also provides novel pharmaceutical
compositions, and a process for making a novel compound.
it ,,
I, I I.
~236834
This invention concerns a series of vasodilating agents
having a singe of beta-adrenergic blocking potency and possessing the
general formula I and the pharmaceutically acceptable acid addition
salts thereof.
Y C
(I)
In the foregoing structural formula, X is CHOW SHEA, ON, CF3,
CORN Rub or CRY with Ray and Rub being independently chosen from
hydrogen or R , and R being lower alkyd, aureole, or arylalkyl; Y is
hydrogen, halogen, acyloxy, alkoxy, aralkyloxy, airlocks, or hydroxyl;
lo R is hydrogen or LC-LJ with L being selected from alkyd, aureole,
substituted aureole, or arylalkyl; R , R , A and B are independently
selected from hydrogen or alkyd; and C can be halogen, hydrogen,
hydroxy, alkyd or alkoxy. Preferred compounds have X in the 3-
position of the pardon ring and the indolylalkylaminopropoxy side
chain is attached to the 2- position of the pardon nucleus.
The invention includes compounds having the foregoing
structural formula (I) and the acid addition salts thereof. In
structural Formula I, X can be -COO, -ON, -CF3, -CORN R , or -CRY .
Ray and Rub aye independently chosen from hydrogen or Arc which can be
lower alkyd (Of to C4); aureole; or aryl-lower alkyd, aureole being preferably
i236834
phenol. It is also preferred that X be attached to the 3- position
in the pardon ring system. Y represents a second substituent on
the pardon ring and may be hydrogen, halogen, lower (Cl-C4)alkoxy,
aryl-lower alkoxy hydroxy, or -Colloquial wherein alkyd is Cluck
alkyd. The entire pyridinyl group is coupled to the indolylalkyl-
aminopropoxy side chain at the pardon 2- position. R is hydrogen
O
or C-L with L being selected from Cluck alkyd, phenol, substituted
phenol, or phenalkyl. Al, R2, A, and B are independently chosen from
hydrogen or lower alkyd. C represents a substituent in the buoyancy
ring of insole and is selected from hydrogen, halogen, lower alkyd,
lower alkoxy, or hydroxy. The insole moiety itself is preferably
coupled to the main side chain through its 3- position.
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 the organic
cation, are preferred. The acid addition salts are obtained either
by reaction 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 in the literature and available to any
practitioner skilled in the art. examples of useful organic acids
are carboxylic acids such as malefic acid, acetic acid, tartaric acid,
prop ionic acid, fumaric acid, isethionic acid, succinic acid, pamoic
acid, cyclamic acid, pivalic acid, and the like; useful inorganic
acids are hydrohalide acids such as Hal, Her, HI; sulfuric acid;
phosphoric acid; and the like.
It is also to be understood that the compounds of the
present invention include all the optical isomer forms, that is,
mixtures of enantiomers, e.g., rhizomic modifications as well as the
~L236834
individual enantiomers. These individual enantiomers are commonly
designated according to the optical 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
rictus respectively, designate an absolute spatial configuration of
the enantiomer. Where no isomer designation is given for a compound,
the compound is the rhizomic modification.
Biological testing of the subject compounds of Formula I in
animals demonstrates that they possess potent vasodilating properties
along with varying degrees of adrenergic beta receptor blocking
properties and intrinsic sympathomimetic activity. Preferred members
have a particularly desirable combination of the foregoing actions,
and ancillary pharmacological effects, or a 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 various animal models including antagonism of
isoproterenol in the anesthetized dog treated intravenously (adrenergic
beta receptor action), the spontaneous hypertensive and DOCK salt
hypertensive rat (anti hypertensive action), angiotensin-maintained
ganglion-blocked rat model (vasodilator action), and in various other
animal and laboratory models (of: Deitchman, et at., Journal
Pharmacological Methods, 3, 311321, (1980)). No evidence of turret-
genicity or mutagenicity has been found to be associated with the
compounds of formula I.
For use as antihypertensives, vasodilators, and/or beta-
adrenergic blocking agents, therapeutic processes of this invention
comprise systemic administration, by both oral and parenteral routes,
~L2~6834
of an effective, nontoxic amount of a compound of Fox mute I or a
pharmaceutically acceptable acid addition salt thereof. An effective
amount is construed to mean a dose which exerts the desired forum-
ecological activity, such as those stated hereinabove, without undue
toxic side effects when administered to a mammal in need of such
treatment. Dosage will vary, according to the subject and route of
administration selected, with an expected range of about 0.1 mug to
100 mg/kg body weight of a compound of Formula I or a pharmaceutically
acceptable acid addition salt thereof generally providing the desired
therapeutic effect.
The compounds of the present invention can be prepared by a
convenient general process. This process involves the coupling of a
Z-substituted pardon (IV) with a suitable W-substituted propanol or
incipient propanol intermediate (II).
General Process
W Jo
O -G
/ (IDA)\ Hydrolysis
/X
y W Go (I)
, z
(IV) \ (JIB)
W I HUNG
(TIC)
:~L236834
In the foregoing general process, D is hydrogen, or preferably, phenol;
G is the radical [ I; Z is hydroxyl or halogen, preferably
chloride; W is halogen, preferably chloride, when Z is hydroxyl and is
hydroxyl when Z is halogen. Generally, the hydroxyl-bearing reactant
is initially converted to the oxide anion with a strong base prior to
reaction with the halogen-bearing intermediate.
This process employs methods known in the prior art for the
preparation of substituted amino)-3-(hetaryloxy)-2-propanols as
represented by the patents and publications cited in "Background of
the Invention". The process involves reaction of the appropriately
substituted pardon with either 1) a [3-(indolylalkyl)oxazolidin-5-
yl]methanol (or methyl halide) of Formula IDA, or 2) an indolylalkyl-
am mopropanediol (or halopropanol) of Formula JIB, or 3) glycidol of
Formula TIC.
The intermediate from reaction of-IV and IIa-i~ converted to
the product I by hydrolysis under acidic conditions. This hydrolysis
is accomplished with dilute mineral acid of from Own to lo concern-
traction at temperatures of from about 20-100C. The product of
Formula I can be recovered as the free base by neutralization of the
hydrolysis mixture and collecting the precipitate. Acid addition
salts may be obtained by evaporating the hydrolysis mixture or by
reaction of the free base with acid. Purification is accomplished by
conventional means such as recrystallization.
The conversion of the epoxide intermediate resulting from
the reaction of IV with TIC into the product of Formula I is carried
out simply by heating the epoxy ether either neat or in the presence
~236834
of a reaction inert organic solvent with an amine of the formula HUNG
as shown. No catalyst or condensation agent is required. Suitable
solvents include 95% ethanol but other reaction-inert organic liquids
in which the reactants are soluble may be employed. These include
but are not limited to Bunsen, tetrahydrofuran, dibutylether,
buttonhole, hexanol, methanol, dimethoxyethane, ethylene glycol, etc.
Suitable reaction temperatures are from about 60-200C.
he single step process pathway involves the reaction of IV
with JIB and this is the preferred pathway for synthesis of the
products of this invention.
This process is illustrated by the following specific
reaction equation which shows the preferred synthetic method of the
above as Reaction 1.
Reaction 1
R R A C
Y halo + Ho Y H C
(IV! (JIB) (I)
In the foregoing scheme, X, Y, R, Al, R2, A, B, and C are as defined
in Formula I. Essentially this process involves heating the selected
substituted halopyridine with the appropriate indolylalkylamino-
propanol intermediate (JIB) in the presence of a base, all in an
inert organic liquid under mild conditions. Standard strong bases
such as potassium t-butoxide, potassium hydroxide, or sodium hydrides
may be employed but the sodium hydrides is preferred. Similarly, any
of a number of inert organic liquids may be chosen as the reaction
SUE
medium or the cyanopyridine and indolylalkylaminopropanol may be
reacted neat in the presence of the base. Suitable solvents include
but are not limited to Bunsen, Tulane, tetrahydrofuran, dibutylether,
dimethoxyethane, etc. Suitable reaction temperatures are from about
20-80 C. Addition of a suitable crown ether, such as 18-crown-6
ether, aids the reaction process.
Formula I products in which Y and/or C are hydroxy, are
prepared by cleavage of the corresponding methoxy precursor as shown
in Reaction 2:
Reaction 2
I Y 011
Other synthetic methods resulting in conversion to hydroxylated
products, e.g. such as hydrogenolysis of Benelux precursors, are
well known to the chemical practitioner and may also be applied in
these cases.
Requisite halopyridines are available commercially or may
be prepared using standard methods for their preparation reported in
the literature. Preparation of related trisubslituted pardons is
disclosed in U.S. 4,329,351, issued May 11, 1982 to Baldwin, et at
and which is hereby incorporated by reference in its entirety.
The intermediate indolylalkylaminopropanols (JIB; R = H),
preferred synthetic intermediates, are conveniently prepared by
reacting an appropriately substituted indolylalkylamine (III) with
-- 10 --
123683~
3-chloro-1,2-propanediol in refluxing alcohol containing sodium
carbonate. This process is illustrated by reaction equation 3.
Reaction 3
HO Of + Ho Base F C
B B
(III) (JIB)
In reaction scheme 3, R , R , A, B, and C are 25 defined in Formula I.
Formula I products of the present invention wherein R is
other than hydrogen are conveniently prepared by treating the corresponding
Formula I product wherein R is hydrogen with an appropriate assaulting
agent such as an azalea halide, e.g. undecanoyl chloride, pivaloyl
chloride, bouncily chloride, para-methoxybenzoyl chloride, or android,
e.g. acetic android, and the like. The reaction is illustrated by
the following equation shown below as Reaction 4:
Reaction 4
_[~ R;C-C~ C
B o 2 OR B
The indolylalkylamines (III) are described in the alone-
mentioned Kreighbaum, et at. patents and Journal of Medicinal Chemistry
6834
article, which are hereby incorporated by reference, as well as
certain references cited therein. Although these referenced procedures
are applicable to the preparation of other indolylalkylamine intermediates
not specifically disclosed therein but which are required as inter-
mediates for the present invention, representative syntheses of
Formula III compounds are given hereinbelow for further exemplification.
The compounds of the present invention can be formulated
according to conventional pharmaceutical practice to provide forum-
ceutical compositions of unit dosage form comprising, for example,
tablets, capsules, powders, granules, emulsions, suspensions, and the
like. The solid preparations contain the active ingredient in
admixture with non-toxic pharmaceutical excipients such as inert
delineates, for example, calcium carbonate, sodium carbonate, lactose,
calcium phosphate or sodium phosphate; granulating and disintegrating
agents, for example, maize, starch, or alginic acid; binding agents,
for example, starch, gelatin or Acadia; and lubricating agents, for
example, magnesium Stewart, Starkey acid or talc. The tablets may
be uncoated or they may be coated by known techniques so as to defy
disintegration and absorption in the gastrointestinal tract and
thereby provide a sustained action over a longer period.
Liquid preparations suitable for parenteral administration
include solutions, suspensions, or emulsions of the compounds of
Formula I. The aqueous suspensions of the pharmaceutical dosage
forms of the compounds of Formula I contain the active ingredient in
admixture with one or more non-toxic pharmaceutical excipients known
to be suitable in manufacture of aqueous suspensions. Suitable
excipients are, for example, suspending agents such as sodium car boxy-
methyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose,
- 12 -
AYE
sodium allegiant, polyvinyl pyrrolidone, gum tragecanth, and gum
Acadia. Suitable disbursing or wetting agents are naturally occurring
phosphatides, for example, lecithin, polyoxyethylene Stewart.
Non-aqueous suspensions may be formulated by suspending the
active ingredient in a 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 beeswax, hard
paraffin, or Seattle alcohol. Sweetening and flavoring agents generally
used in pharmaceutical compositions may also be included such as
lo saccharin, sodium cyclamate, sugar and caramel to provide a palatable
oral 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
a consideration of the following examples and appended claims which are
given for the purpose of illustration only and are not to be construed
as limiting the invention in sphere or scope. In the following examples,
used to illustrate the foregoing synthetic processes, temperatures
are expressed in degrees Celsius I and melting points are uncorrected.
The nuclear magnetic resonance (No) spectral characteristics refer
to chemical shifts (I expressed as parts per million (ppm) versus
tetramethylsilane (THIS) as reference standard. The relative area
reported for the various shifts in the H NOR spectral data corresponds
to the number of hydrogen atoms of a particular functional type in the
molecule. The nature of the shifts as to multiplic try is reported as
broad singlet (by), singlet (s), multiple (m), or doublet (d).
- 13 -
1236834
Abbreviations employed are D~;SO-d6 (deuterodimethylsulfoxide), CDC13
(deuterochloroform) and are otherwise conventional. The infrared
(IT) spectral descriptions include only absorption wave numbers
(cm ) having functional group identification value. The IT deter-
munitions were employed using potassium bromide tKBr) as delineate.
The elemental analyses are reported as percent by weight.
Synthesis of Intermediates
A. Intermediates of Formula III
EXAMPLE 1
3-(21Amin2-2-methylpropyl)-6-methoxyindole
(R = R = Me, A and B = H, C = Moe)
To 15.2 my of a chilled 25% aqueous solution of dim ethyl-
amine the following were added sequentially with stirring and continued
cooling: 16.9 my of acetic acid, 7.2 my of 37% formaldehyde, 27 my
of 95% ethanol. The resulting stirred solution was kept at 0
to -5 with a cooling bath while 6-methoxyindole (10.0 g, 0.07 mole)
was added in portions. This mixture was stirred and gradually warmed
to 30 over a period of one-half hour and then held at 30 with
stirring for 3 his. The reaction mixture was then chilled to 10-15
and acidified with 170 my of ON Hal. This acidic mixture was decolonized
(Marco G-60), filtered and the filtrate made basic using 245 my of
20% Noah while being cooled and stirred. A resulting brown oily
precipitate was ether extracted, and the extracts were water-washed,
dried (McCoy) and concentrated to a brown oily residue (14 g). The
residue was recrystallized from isopropyl ether and hexane to yield
9 g (65%) of 6-methoxygramine as a tan solid, mop. 88-90.
- 14 -
1236834
A mixture comprised of the 6-methoxygramine (7.7 g, 0.04
mole), 2-nitropropane (26.5 g, 0.3 mole), and Noah (1.7 g pellets,
0.04 mole) was reflexed under a nitrogen atmosphere for 3-5 his. The
reaction mixture was cooled to room temperature, acidified with 10%
acetic acid and extracted with ether. The ether extracts were
water-washed, dried (McCoy), and concentrated in vacua to a residue.
Recrystallization of the residue from isopropyl alcohol-water gave
7.6 g (80%) of 3-(2-methyl-2-nitropropyl)-6-methoxyindole as a tan
solid, mop. 98-100.
The nitropropylindole compound and activated Rangy nickel
(4.2 g) were combined in 80 my 95% ethanol and heated to reflex.
Heating was halted as a solution comprised of 85% hydrazine hydrate
(7.8 g) in 8 my 95% ethanol was added drops. The reaction mixture
was then heated at reflex for 2 his, cooled to room temperature and
filtered. The filtrate was concentrated to a residual oil which
slowly solidified and was recrystallized from ethyl acetate-isopropyl
ether to give 4.2 g of product, mop. 125-128.
EXAMPLE 2
2-(~-Ami~o-2-methylpropyl)indole
(R = R = Me, A, B, and C = H)
A solution comprising indole-2-carboxylic acid (10.0 g,
0.06 mole) and thinly chloride (20.0 g, 0.17 mole) in 130 my of dry
Eta was stirred for 12-18 his at room temperature under a nitrogen
atmosphere. The reaction mixture was filtered and the filtrate was
concentrated to an oily residue which was taken up in 150 my of dry
Eta. This ether solution was treated with 80 my of dimethylamine in
90 my of Eta. The ethereal reaction mixture was concentrated to
dryness and the residue crystallized in isopropyl alcohol. The solid
~236834
was isolated by filtration to give 4.0 g (347~) of the 2-indolylamide
product, mop. 181-183 .
The aside was dissolved in 100 my THY and this solution was
added drops to a stirred suspension comprised of 3 g lithium
aluminum hydrides in 50 my of THY under a nitrogen atmosphere. After
heat at reflex for 2 ho, the reaction mixture was cooled and decomposed
with a small amount of water and dilute Noah solution. This mixture
was filtered and the filtrate concentrated to a residual oil which
was taken up in absolute ethanol and treated with a slight excess of
dim ethyl sulfate. The resulting alcoholic solution was stirred at
room temperature for 4 his and then concentrated in vacua to dryness
giving as residue the trimethylamine qua ternary salt.
The crude qua ternary salt product (3.0 g, 0.01 mole) was
combined with Noah (2.0 g pellets, 0.05 mole) and 2-nitropropane
(15 my) and the mixture was heated at reflex under a nitrogen atmosphere
for 1 hr. The resultant dark thick mixture was cooled, diluted with
water, acidified with acetic acid to a pi of approximately 6 and then
extracted with Eta. These Eta extracts were combined, washed with
water, dried (McCoy) and concentrated to a dark residue which was
chromatographed on a silica column and diluted with ethylene chloride.
Removal of the ethylene chloride and recrystallization of the crude
material from isopropyl alcohol-water gave 0.4 g of methyl-
nitropropyl)indole as a cream colored solid, mop. 102-103.
Reduction of this vitro product with Rangy nickel and
hydra2ine according to the procedure used in Example 1 above yields
the desired indolalkylamine as a white solid, mop. 130-133.
Additional examples of indolealkylamines are displayed in
Table 1.
1236~334
Table 1
Indolealkylamines
2 A C
Al
HEN
(III)
Example Al R2 A B C
3 Me H 3-H Me H
4 Me Me 2-Me H H
Me Me 2-H H Brie
6 Me Me 2-H H Rome
7 H Me 2-H H H
8 H Me 2-Me Me opera
9 H Me 3-Me Me Brie
Me Me 2-H H Rome
11 Me H 2-Et H clue
12 Me H 2-H H Rome
- 17 -
~X36834
B. Intermediates of Formula II
EYE 13
3-[[2-(3-Indolyl)-l,l-dimethylethyl]
amino]-1,2-propanediol Hydrate (JIB)
A mixture of ~,~-dimethyl-~-(3-indolyl)ethanamine (10.0 g,
0.05 mole), Nikko (11.3 g, 0.11 mole), 3-chloro-1,2-propanediol
(7.0 g, 0.06 mole) and Etch (250 my) was stirred overnight at reflex.
After cooling, the mixture was filtered and concentrated in vacua.
The residue was dissolved in EtOAc, decolonized (Marco G-60), and
evaporated to a volume of 100 my. The solution deposited a white
solid which was recrystallized from EtOAc to give 7.7 g (55~), mop.
112-114C. The material crystallized with one-fifth mole of water.
Using other intermediates of Formula III in this or a
similar procedure readily gives a variety of Formula JIB intermediates.
Synthesis of Products
EXILE 14
2-[2-Hydroxy-3-[[2-(lH-indol-3-yl)-1,1-dimethyl
ethyl]amino]propoxy]-3-pyr~dinecar2bonitrile Hydrochloride
(Y = H, X - ON, R = H, R and R = Me, A, B, and C = H)
` 20 3-[[2-(3-Indolyl)-l,l-dimethylethyl]amino]-1,2-proopanediol
(47.3 g, 0.18 mole) and sodium hydrides (7.6 g of 57~ dispersion in
oil, 0.18 mole) were stirred in 2.5 liters of Tulane and heated at
70 for 3 his under a nitrogen atmosphere. The mixture was then
allowed to cool to room temperature while being stirred and 18-crown-6
ether (0.5 g), Andy. powdered K2C03 (62.1 g of powder, 0.45 mole)
and 2-chloro-3-cyanopyridine (25.0 g, 0.18 mole) were added sequentially
to the stirring mixture and then the whole was stirred for an additional
42 his. Concentration to dryness gave a residue which was partitioned
between hot H20 and EtOAc. After cooling to room temperature, the
- 18 -
1236834
aqueous layer was separated, washed with additional EtOAc and this
wash combined with the original EtOAc layer. The EtOAc was dried
(McCoy) and concentrated hot to-about half volume. Upon cooling, a
solid precipitated and was isolated by filtration to give approximately
41 g (62%) of the crude product base.
Conversion of the base into the hydrochloride salt is
accomplished by treating an isopropyl alcohol solution of the base
with ethanolic Hal. Recrystallization of the crude hydrochloride
salt from absolute ethanol gives a white solid, mop. 181-183.
Anal. Caulked- for C21H24N42'HCl C, 62-92; Ho 6-29;
N, 13.98. Found: C, 62.85; H, 6.29; N, 14.04.
NOR (DMSO-d6): 1.30 (6, s); 3.20 (4, m); 3.99 (3, m);
6.02 (1, d [4.0 Ho]); 7.30 (6. m); 8.31 (1, dud [2.0, 7.6 Ho]);
8.51 (1, dud [2.0, 5.6 Ho]); ô.82 (1, by); 9.32 (lobs); 11.27 (lobs).
IT (Kbr): 750, 1110, 1310, 1440, 1460, 1580, 1588, 2230,
2790, 2980, and 3400 cm
Preparation of the Cyclamate Salt
The cyclamate salt may be prepared by treating the crude
base synthesized above (2 g crude base) with cyclamic acid (1 g) in
50 my methanol. The methanol solution was warmed, filtered and the
filtrate concentrated in vacua to give a residue which was crystallized
in 10 my acetonitrile. Recrystallization of the crude salt from
methanol-acetonitrile gave 2.0 g of white solid, mop. 172-174 .
Anal. Caulked. for C21H24N4O2-C6H13NO3S: C, 59.65; H, 6.87;
25 N, 12.89. Found: C, 59.74; H, 6.77; N, 12.82.
- 19 -
~236834
EMPLOY 15
4-[2-Hydroxy-3-[~2-(lH-indol-3-yl)-1,1-
dimethylethyl]amino]propoxy]-3-pyridinecarbonitrilto
Using the procedure of Example 14 and utilizing 3-[[2-(3-
indolyl)-1,1-dimethylethyl]amino]-1,2-propanediol (10.4 g, 0.04
mole); sodium hydrides (1.7 g, 0.04 mole), 550 my Tulane, sheller-
cyanopyridine (5.5 g, 0.04 mole), Of: Wieland and Wiener, Chum.
Borscht., 96, pages 268-274 (1963)); 18-crown-6 ether (Oily g) and
an hydrous powdered K2CO3 (13.7 g, 0.1 mole), a gummy material (15 g)
was obtained. The gum was chromatographed on a silica column eluding
with ethylene chloride (90 parts), methanol (10 parts) and ammonium
hydroxide (1 part) to give 2 fractions. The second fraction to be
eluded gave 6.8 g of gum which was crystallized in ethyl acetate to
give 5 g of solid, mop. 124-126. Recrystallization of this material
15 from ethyl acetate gave 4.2 g of white solid, mop. 126-128.
Anal. Caulked- for C21H24N402 C, 69-21; Ho 6-64; No 15-38-
Found: C, 69.42; H, 6.75; N, 15.65.
NOR (DMS0-d6): 1.00 (6, s); 1.55 (lobs); 2.75 (4, m);
3.90 (1, m); 4.27 (2, m); 5.10 (lobs); 7.25 (6, m); 8.64 (1, d [6.0 Ho]);
20 8.78 (1, s); 10.82 (lobs).
IT (KBr): 745, 1010. 1190, 1290, 1315, 1455, 1495, 1520,
1590, 2225, 2970, and 3400 cm 1.
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EXAMPLE 16
2-[2-Hydroxy-3-[[2-(lH-indol-3-yl)-1,1-
dimethylethyllamino]propoxy]-3-pyridinecarboxamidee
Using a procedure similar to that outlined in Example 4
above,3-[[2-(3-indolyl)-1,1-dimethylethyl]amino~-1,2-proopanediol
(10.5 g, 0.04 mole), sodium hydrides (1.7 g, 0.04 mole), 400 my
Tulane, 2-chloronicotinamide (5.6 g, 0.04 mole), 18-crown-6 ether
(0.11 g) and an hydrous powdered K2CO3 (13.8 g, 0.1 mole) were reacted
to give 17 g of residual gum. The gum was chromatographed on a
silica column eluding with ethylene chloride (90 parts), methanol
(10 parts) and ammonium hydroxide (1 part). The product-containing
fractions were combined and concentrated to a residue which was
crystallized in ethyl acetate to give 5.2 g of material, mop. 68-72.
Recrystallization from ethyl acetate and drying in a vacuum oven
15 afforded 4 g of white solid, mop. 131-133.
Anal- Caulked- for C21H26N43 C, 65-95; Ho 6-86; No 14-65-
Found: C, 65.80; H, 6.85; N, 14.31.
NOR tDMSO-d6): 1.03 (6, s); 2.77 (4, m); 3.95 (1, m);
4.46 (2, m); 7.20 (6, m); 7.81 (2, by); ~.30 (2, d [6.1 Ho]);
20 10.85 (lobs).
IT (KBr): 740, 780, 1100, 1235, 1430, 1460, 1585, 1670,
2970, 3330, and 3470 cm 1.
EXAMPLE 17
Conversion of Methoxy Products to
Hydroxy Pry ducts - General Procedure
Dissolve the methoxy product in ethylene chloride and stir
under a nitrogen atmosphere while keeping chilled with an ice bath.
Add drops 3 equivalents of boron tribromide in ethylene chloride
solution. Following addition, remove the ice bath and allow the
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reaction mixture to stir at room temperature for 6-8 his. Again,
chill the reaction mixture with an ice bath and decompose excess
reagent by adding excess Ho drops, causing a gummy material to
precipitate. The supernatant is decanted from the gummy material
which is rinsed with two portions of water. The gum is dissolved in
hot water, treated with activated charcoal (Marco), filtered, the
filtrate chilled and made basic with ammonium hydroxide to a pi of
approximately 8. The resultant precipitate is filtered, washed with
water, dried and further purified by column chromatography on silica
lo gel, eluding with SCHICK (90 parts) - methanol lo parts) - ~H40H
(1 part). Concentration of product-containing fractions gives a
residue which is recrystallized from ethanol-water to give pure
hydroxy product.
Starting with the appropriate pardon and indolylalkyl-
amine, additional examples of Formula I products may be synthesized
using substantially the same procedures as outlined hereinabove.
Some additional products of Formula I which may be synthesized are
shown in Table 2. G in the formulae represents the C
group as determined by the intermediate III selected
(of: examples 1-12).
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12368;~4
Table 2
Example Formula Example Formula
o
18 O NO 25 Cue
F CCH3 OH
F 'CO'NHMeO F ON
O NO 26 N O NO
H
20~ Ox NO Of O NO
OH OKAY
21N COWAN HO COWAN
ox NO O NO
OH OH
F~C CUT 29 N COO
OH
~C~CH3
23~ KIWI Charlie
DO Octet
CF3 o
24
O NO
.,
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Biological Evaluation
These biological tests were used to gauge the cardiovascular
profile of a number of the compounds of Formula I as vasodilators
with a range of beta-adrenergic blocking activity.
E ALE 31
The efficacy of anti hypertensive agents other than adrenergic
beta-receptor blocking agents is commonly estimated in the spontaneous
hypertensive rat. Blood pressure values are determined for test
animals prior to and 24 hours after oral doses of 50 mg/kg of test
compounds; the observed percentage change in heart rate is noted as
well. A fall in blood pressure in the range of 19-24 mmHg is considered
"questionable". "Active" and "inactive" designations are decreases
greater and less than that range.
EXPEL 32
The angiotensin-maintained ganglion-blocked rat model is
utilized as a screening test for estimation of the vasodilator
component of activity. Percentage changes in blood pressure in
anesthetized rats 30 minutes after intravenous dosing are determined.
The intravenous dosing is done with test compound at 3 mg/kg.
Borderline activity is defined as a 15-20% decrease in blood pressure
- measured 30 minutes after dosing. "Active" and "inactive" designations
are increases greater and less than that range.
EXPEL 33
Diastolic blood pressure and heart rate responses to a fixed
challenge dose of isoproterenol are obtained before and 15-minutes
after graded doses of test compound administered intravenously over a
Mooney interval to anesthetized dogs. A branch of a femoral artery and
vein are cannulated to record blood pressure and to administer the
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~Z3~ 4
drugs which are dissolved in saline. The voyage were sectioned bilaterally
in the mid-cervical region of the neck and the dogs are ventilated
mechanically (Harvard respirator) with room air at a rate of 20/minute
and a stroke volume of 20 mL~kg. Heart rate is monitored with a
cardiotachometer triggered by the pressure pulse. All measurements
are recorded on a Beckman R-612 recorder. The drug effect is expressed
in terms of a cumulative dose (microgram/kg) causing 50% inhibition of
isoproterenol response.
The following abbreviations used herein have the following
meanings: Pi stands for a phenol group, Pry stands for
a propel group, Me stands for methyl group, and Et stands
for an ethyl group.
Additionally, an accepted convention in modern organic
cher.listry has been used throughout. For alkyd structures, in a
shorthand form, joined line segments substitute for explicit
notation of C and H groups. Thus, for example, formula I
can also be written:
I SHEA / C N '
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