Note: Descriptions are shown in the official language in which they were submitted.
~ HA125
~6629C~
This invention relates to novel cyclitol amines which
are useful in the treatment of hypertension.
The compounds of the present invention have the formula
ORl OR2 ' ORl oR2
~ R-~ or ¦ R-~
O~I/A ~ l~ l.A4
CH2~HR
R5/ \ R6
w~erein Y is a radical of the formula
R5
~(CH2)nN\
R
or of the formula
R
wherein (CH2)n is a straight or branched chain alkyl radical, n
is 1-6, m is 0 or l and R5 and R6 are the same or different and
are hydrogen, alkyl, arylalkyl, or R5 and R6 together with the
nitrogen to which they are attached are pyrrolidino, piperidino
or N'-alkyl piperazino; Rl, R2, R3 or R4 are the same or different
and are hydrogen; alkyl; trifluoromethyl; alkanoyl; haloalkanoyl,
alkoxycarbonyl of the formula -COR wherein R iS an alkyl radical;
alkoxyalkyl; aminoalkanoyl of the formula
I R5
C (CH2)pN \
R
. ~ ~125
1~66ZgO
wherein R5 and R6 are as previously defined and p is 0-3,
2-, 3-, or 4-pyridylcarbonyl; phenyl; monosubstituted phenyl
wherein the substituent is alkyl, alkoxy, hydroxy, nitro, .. . .
amino, or dialkylamino; alkenoyl; or aroyl; R7 and R8 are the
same or different and are hydrogen or alkyl, or R7 and R8
taken together with the carbon atoms bearing substituents
OR and oR4 optionally form a cycloalkyl ring of from 5 to
7 carbon atoms and R9 is alkyl of l to 4 carbons, phenyl,
hydrogen, alkyl of 1 to 4 carbon atoms substituted by phenyl
or phenoxy or by a substituted phenyl or phenoxy radical wherein
the substituent is halogen, amino, alkyl of 1 to 4 carbon atoms, .
alkoxy of 1 to 4 carbon atoms or dialkyl amino wherein each
alkyl radical has 1 to 4 carbon atoms. ~,
The invention also provides a process for preparing a
compound of the formula
OR oR2 ORl oR2 ~ ..
`~ ~ R7-~
_~l' or ( ~ ( R 9
Y I 2I R Ia
N\ ~.
R5 R6
wherein Y is a radical of the formula
R
(CH ) N ~
R6
or of the formula
-(CH2)n ~ (CH )
N~ 2 m
R5
.: . .
~125
6Z5~(~
wherein (CH2)n is a straight or branched chain alkyl radical,
n is 1-6, m is 0 or 1 and R5 and R6 are the same or different
and are hydrogen, alkyl, aryla1ky1,or R5 and R6 together with
the nitrogen to which they are attached are pyrrolidino, piperidino
or N'-alkyl piperazino; Rl, R2, R3 or R4 are the same or dif~erent
and are hydrogen; alkyl; trifluoromethyl; alkanoyl; haloalkanoyl;
alkoxycarbonyl of the formula -COR wherein R is an alkyl radical;
alkoxyalkyl; aminoalkanoyl of the formula
0 R5
-C-(CH2)pN
R
wherein R5 and R6 are as previously defined and p is 0-3; 2-,
3-, or 4-pyridylcarbonyl; phenyl; monosubstituted phenyl wherein
the substituent is alkyl, alkoxy, hydroxy, nitro, amino, or
dialkylamino; alkenoyl; or aroyl; R7 and R8 are the same or
different and are hydrogen or alkyl, or R7 and R8 taken together
with the carbon atoms bearing substituents oR2 and oR4 optionally
form a cycloalkyl ring of from 5 to 7 carbon atoms and R9 is
alkyl of 1 to 4 carbons, phenyl, hydrogen, alkyl of 1 to 4 carbon
atoms substituted by phenyl or phenoxy or by a substituted phenyl
or phenoxy radical wherein the substituent is halogen, amino,
alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or
dialkyl amino wherein each alkyl radical has 1 to 4 carbon atoms
which comprises treating with excess H202 and formic acid a com-
pound of the formula
~R~ or ~ R~'
CH2CH-R9
R5~ ~ R6
:. " : ' ' ' ' ' ', . , :
:, . . . .. . ..
~125
~66~90
wherein R , R , Y, R5, R6 and R9 are as defined above and,
where desired, treating the resultant tetrol with an esterifying
agent.
More specifically, in the compounds of the present invention,
Y is a radical of the formula
R5
- ( CH2 ) nN
R6
or of the formula
~ CH2)m
R5 :
wherein (CH2)n is a straight or branched chain alkyl radical,
n is 1-6, m is 0 or 1 and R5 and R6 are the same or different
-and are hydrogen, alkyl o from 1 to 3 carbon atoms, arylalkyl :
or R5 and R6 together with the nitrogen atom to which they are --
attached are pyrrolidino, piperidino of ~'-alkyl piperazino
wherein the alkyl radical has from 1 to 3 carbon atoms; Rl, R2,
R3 or R4 are the same or different and are hydrogen; alkyl of
from 1 to 4 carbon atoms; alkanoyl of from 1 to 4 carbon atoms,
haloalkanoyl of from 1 to 4 carbons wherein the halogen is F,
C1, Br or I; alkoxycarbonyl of the formula -COR wherein R is
an alXyl radical of from 1 to 4 carbon atoms; alkoxyalkyl or
ben~yloxyalkyl wherein the alkoxy radical has from 1 to 3 carbons
and the alkyl radical has from 1 to 3 carbons; aminoalkanoyl of
formula
O R5
-C-(CH2) N /
\ 6
wherein R5 and R6 are as previously defined and p is 0-3; 2-,
, - : ~ ` . .
,,
`~ HA125
~6zso
3-, or 4-pyridylcarbonyl; phenyl; monosubstituted phenyl
wherein the substituent is alkyl of from 1 to 4 carbons,
alkoxy of from 1 to 4 carbons, hydroxy, nitro, amino, or
dialkylamino wherein each alkyl radical has from 1 to 4
carbon atoms; or alkenoyl of 3 or 4 carbon atoms; or aroyl
of the formula
~-(C~2)qC~
wherein q is 0-3; R7 and R8 are the same or different and are
hydrogen or alkyl of from 1 to 4 carbons, or R7 and R8 taken
togather with the carbon atoms bearing substituents oR2 and
oR4 may form a cycloalkyl ring having from 5 to 7 carbon atoms
and R9 is alkyl of 1 to 4 carbon atoms, phenyl, hydrogen, alkyl
of 1 to 4 carbon atoms substituted by phenyl or phenoxy or by
a substituted phenyl or phenoxy radical wherein the substituent
is halogen, amino, alkyl of 1 to 4 carbon atoms, alkoxy of 1
to 4 caxbon atoms, alkoxy of 1 to 4 carbon atoms or dialkylamino
wherein each alkyl radical has 1 to 4 carbon atoms.
In the foregoing formula I,Y may be a radical of the formula
/ R5
(~H2)nN \ 6
or of the formula
.
2 n ~ H2)m
wherein (CH2)nis a straight or branched chain alkyl radical,
n is 1 to 6, m is 0 or 1 and R5 and R are as previously
defined. Examples of specific radicals for Y are the following:
~5~
. '' ~.
.. ... , . . .. .. .. . :
(
HA125
.
1066Z90 ~ ~
.
:
-CH N''' 3 , / C2H
3 -CH2
2 5 : ~
~ H3 ~ -.
-CH2N~ --CH2N~
C3H7 .
-CH2~ < 2
f H3
-CH2CH2N ~ -CH2CH2N
! CH3
'' ' 10 ' , . , "
-cH2cH2cH2N\ --CH2CH2CH2N~>.
CH3
fH3 ~ CH3 3
-C~2 HCH2N \ ( 2)6N <
CH3 3
~H3 / IH3
-C~2CH2 HN ~ -CH2CHCH2CH2N ~
2 5 : .
; 20 -CH2 ~ -CH2CH2 ~ ~ CH3
~ CH3
~ ..' . ' .
.
,: '.
~0 ~ ; -6- . :
.,~..,
',''': . .','.,,.', , " . ' ' . , '' ' '''~ ;' ',' ''
, ... . . . . . .
~ Zg~ ~125
-CH ~ -CH2 ~ N-CH3 -CH
CH3 . H
., .
I~
CH2CH~ l ~ -(CH2)6 N
. N ' H
-(c~2)4-N(cH3)2
. IH3
-CH ~ -CH2CH2C ~
C2H5 2 2CH3
CH3
3 -CH2C}3C3 ~--~~ 2H5
. H3 2H5
~'~,' '
In the foregoing formula, Rl, R2, R3 and R4 may be the
`- same or different. Examples of specific radicals for each .:
of Rl, R , R3 and R4 are the following: hydrogen, methyl,
- ethyl,n-propyl , i-propyl, n-butyl, i-butyl or t-butyl: .
c trifluoromethyl; formyl, acetyl, propionyl, isopropionyI, . :
. butanoyl, isobutanoyl, or t-butanoyl; chloroacetyl, bromo-
; acetyl, trifluoroacetyl, 2-bromopropionyl, 3-bromopropionyl, ~ :~
2-chloropropionyl, 3-chloropropionyl, 2,3-dibromopropionyl, :
or 2,3-dichlorobutanoyl; methoxycarbonyl, ethoxycarbonyl, .
propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, iso- :
butoxycarbonyl or t-butoxycarbonyl; methoxyethyl, methoxypropyl
.
- -7-
.:~ ,., . :
: .. '' : : . . . . .
~al66Z90
~125-
methoxymethyl, ethoxymethyl,.ethoxyethyl, ethoxypropyl,propoxymethyl, propoxyethyl, propoxypropyl, i-propoxymethyl,
i-propoxyethyl, l-propoxypropyl, methoxyisopropyl, ethoxy-
isopropyl, propoxyisopropyl; amido, dimethylamido,
diethylamido, dipropylamido, diisopropylamido, pyrrollidino-
carbonyl, piperidinocarbonyl; 2-aminoacetyl, 3-aminopropionyl,
4-aminobutanoyl, dimethylaminoacetyl, diethylaminopropionyl,
dimethylaminobutanoyl, diisopropylaminoacetyl; 2-, 3- or
4-pyridylcarbonyl, phenyl, o-tolyl, -tolyl, ~-tolyl, ~ .
o-ethylphanyl, m-propylphenyl, ~-butylphenyl; o-hydroxy-
phenyl, _-methoxyphenyl, ~-ethoxyphenyl; o-nitrophenyl, : :~
_-nitrophenyl, ~-aminophenyl; ~-dimethylaminophenyl;
o-allylphenyl or m-crotonylphenyl;
R7 and R8 may be hydrogen, methyl, ethyl, propyl
-propyl, butyl, sec-butyl, t-butyl or together may be
'
-CH2 -CH2 2 \
~CH2 , ' 7H2 ' fH2
-CH2 /CH2 fH2 .:
-CH2 CH2
: ~ :
, -8-
1066290 EL~ 12 5
,. 1. .: ~ ' .
~R ~R [~3\R
II III IV
~ ;
7 HO OH ORl oR2
~R8 ~ IR8--/ ~ R8
V VI
A compound of formula II wherein R7 and R are as
previously defined is converted by means of a Birch reduction -~
under conventional conditions, e.g., by reaction with lithium in
the presence of liquid ammonia, and a proton source such as a
lower alkanol and a cosolvent such as ethyl ether, to yield a
compound of formula III. The latter upon treatment with NaNH2
in refluxing NH3 forms an anion of formula IV, which is in turn
converted to a compound of formula V by treatment in refluxing
~H3 with a halide of formula X-Y wherein X is Cl or sr,
preferably Cl. A compound of formula V is treated with excess
H2O2 and formic acid at about room temperature with cooling.
After completion of the reaction the mixture is rendered
alkaline by treating with a ba~e. The resultant tetrol of
formula VI is converted to the final compound of formula I
~ -
_g_
- , . . . . . . .
, ,. ' ,~" '.. ' , . ' ', ".: ', , ,. .; ' : .
.. ,: "
.. . : : , .... . .
r~
~0~ 125
. by treatment with the appropriate esterifyiny agent in the
; presence of an acidic catalyst such as HC104, with cooling.
CÉl2 \CH-R ~ ~ ¢ ~
H2lH-R CH2lH-R
OH X
VII VIII IX
7 OH OH ORl oR2 .
8,'~ R8,
~ CH2fH-R OH JH C~2CH-R9
R R R~ ~ 6 R \ R
X XI Ia
An alternate procedure is to react a compound of formula
IV with an epoxide of formula VII in the presence of an alkali
metal amide in refluxing ammonia to yield a compound of formula
VIII. In the compound of formula VII, R is alkyl of 1 to
4 carbons, phenyl, hydrogen, alkyl of 1-4 carbons substituted
by phenyl or phenoxy or by a substituted phenyl or phenoxy
radical wherein the substituent is halogen, amino, alkyl of
1 to 4 carbons, alkoxy of 1 to 4 carbons or dialkyl amino
wherein each alkyl radical has 1 to 4 carbon atoms. The compound
--10--
~125
1~66Z~
of formula VIII is then converted to the halide of formula IX
wherein X is chlorine or bromine and the latter compound in
turn is converted to the compound of formula X by conventional
techniques. The compound of formula X is then converted to
the tetrol of formula XI and the latter to the compound of
formula Ia under the same conditions respectively as
employed in proceeding from compound V to VI to I.
Alternatively, a solution of substituted cyclohexadiene
of formula V is dissolved in a carboxylic acid and treated in
the cold portionwise with about 1 equivalent of a strong acid ~ -
with a non-participating anion, i.e., one which does not open
an epoxide, e.g., perchloric, sulfuric or nitric. The resulting -
solution of the salt at temperatures of from about 10 to about 20
is treated with at least about 2 e~uivalents of peracid correspon~-
ing tQ the carboxylic acid employed maintaining temperatures
of up to about 35-40. The mixture is stirred at from about
30 to about 55 for several hours, then cooled in ice and
: . . ..
slowly diluted with ether to precipitate the salt of the
partially acylated tetrol as an oil product. The product of
formula I is washed with ether, cooled in a dry ice-acetone
bath to about -30 and treated with the appropriate acid
anhydride followed by a small amount of a strong acid, e.g.,
perchloric, sulfuric or paratoluenesulphonic. After about
1 hour at a temperature of from about -30 to about -15, the
mixture is held overnight at a temperature of from about -15
to about 0. Excess acylating agent is then destroyed at
temperatures of from about -10 to about 0 by addition of
.
' '~
-11-
,. , :' " , , ' ',
~125
~C~Ifi6Z9O
. excess methanol. The mixture is then poured into cold
concentrated ammonia and the product extracted into dichloro-
methane, treated and freed of solvent. ~he product is then
purified by recrystallization or chromatography.
The compounds of the present invention include the stereo-
isomers, optical isomers and conformers having the structural
formula I or Ia. The compounds of the present inventlon have a -~
lowering effect on blood pressure and are useful in the treat- ,
ment of hypertension in mammalian species, e.g., dogs and rats.
In addition the compounds of the present invention are useful
surface active agents, as in vitro antibacterial compounds
and as water softeners. A compound of formula I or Ia as well
as its physiologically acceptable salts may be compounded
according to pharmaceutical practice in oral or parenteral
dosage form such as tablets, capsules, elixirs, injectables
or powders for administration in quantities of from about
10 mg to about 400 mg per day, preferably from about 50 mg
to about 200 mg per day, in l dose or from 2 to 4 divided
doses.
-12-
~66Z9~ HA125
The following examples illustrate the present
invention without, however, limiting the same thereto.
All temperatures are expressed in degrees Centigrade.
Example 1
3a,7a-trans-5,6-trans=Hexahydro-4-(3-piperidinopropyl)-
3a,5,6,7a-indantetrol
To a suspension of 1.0 mole of NaNH2 in 1 liter
liquid NH3 there is added 60 g (0.50 mole) of 4,7-dihydro-
indan in 125 ml ether. After 15 minutes stirring, the
mixture is treated portionwise with solid N-bromo-
propylpiperidine hydrobromide at a rate slow enough
to ensure the return of a slight yellow color to the
mixture between portions. After addition is completed,
stirring is continued 1 hour before the addition of
500 ml of ether and quenching with solid NH4Cl as
rapidly as possible. After NH3 has evaporated, solids
~are removed by filtration and solvents and starting
material removed ultimately by means of an oil pump.
There is thus obtained 52 g (82%) of aminoalkyl diene
whose vapor phase chromatography indicates a mixture
of 80~/c desired isomer contaminated with 20~/o of a second
; isomer but no bisalkylation product.
The above 52 g is dissolved in 500 ml of cold
88% formic acid and treated in 3 portions over 2 hours
with 150 ml 30~/c H2O2 at 15-20. After stirring over-
night in a bath of water, the mixture is freed of
solvent at the pump, and the residue taken up in 250 ml
ethanol and hydrolyzed by the addition of 75 ml 5~/c NaOH.
-13-
., : . . . . ..
. ., -, , '. ~ : ,
'' , ' ' . . ..
~066Z9(~ ~lA125
The temperature is allowed to rise to 65 and stirring
continued for 1 hour. The mixture is poured into water
and the product extracted into ether. After drying
and solvent removal, the residue (36 g) is taken up
in ethyl acetate and left to stand~ A 25 g first
crop is deposited. A sample recrystallized from
isopropanol-ether has mp 191-200.
Example 2
3a~7a-trans-5~6-trans-Hexahydro-~-(3-piperidinopropyl)
3a,5,6,7a-indantetrol, tetraacetate ester
3a,7a-trans-5,6-trans-Hexahydro-4-(3-piperidino-
propyl)-3a,5,6,7a-indantetrol, (1.4 g, 0.0046 M),
prepared as described in example 1 is dissolved in 30 ml
acetic anhydride and 1.5 ml glacial acetic acid. The
solution is cooled to -30 and perchloric acid (3.0 ml
of 7OD/C) is added dropwise over a period of 20 mlnutes.
After standing at -15 for 20 hours, the mixture is
again cooled to -30 and methanol (15 ml) is added
20 dropwise over a period of 30 minutes. The mixture is
then poured into 60 ml cold concentrated NH40H. The
product is extracted into chloroform and the chloroform
solution is dried. The solvent is removed in vacuo
leaving tan crystalline material. This material is
recrystallized from hexane to yield the -title compound,
mp 107-110C.
-
--14--
1~ 6629~ HA125
Example,3
3a,7a-trans-5,6-trans-1-Hexahydro-4-(3-piperidinopropyl)-
3a,5 6,7a-indanetetrol, tetraacetate ester
_ _ _ _ _ _ _._ . _ _
A solution of 0.1 mole of aminoalkyl diene prepared as
described in paragraph 1 of example 1 in 144 ml of glacial
acetic acid at 5C is treated in three portions over
5 minutes with 15 g (0.105 mole) of 70~/c perchloric acid.
To the solution of perchlorate at 15C is added 47.7 g
(0.25 mole) of 4~/c peracetic acid over 10 minutes maintaining
the temperature at 35C with an ice bath. After the addition
is complete the bath is removed and the mixture maintained
at 32C temperature for 1 hour, then is heated at 40-55C
for 2 hours. The heat is removed and replaced by an ice
bath. When cold(5C) the mixture is slowly diluted with --
700 ml of ether, the oil allowed to settle, and the super- -
natant solution decanted. The oil is washed with 2 x 300 ml ~-
portions of ether, then covered with a blanket of nitrogen
and cooled in a dry ice-acetone bath to -30C. To this is
~ added 250 ml of cold (5C) acetic anhydride, followed by
2 ml of 70~/O perchloric acid. The mixture is stirred for
1 hour at -30 to 0 to dlssolve all the oil, then~cooled
at -15C overnight without stirring.
The stirred mixture in an ice-acetone bath at -10C
is treated with 120 ml of methanol at a rate to maintain
the temperature at 10C. After 30 minutes the temperature
drops sharply as the last of the excess anhydride is consumed,
and the mixture is poured into 500 ml of concentrated
-15-
.
~6~9~ ~125
ammonium hydroxide cooled in an ice bath. This is then
extracted with dichloromethane (1 1.), dried for 1 hour
over magnesium sulfate, filtered and evaporated completely
to a tan solid. Hexane (400 ml) is added and boiled
and the solid is filtered, washed with hexane, and dried
in air to give 20 g of solid. The hexane filtrates deposit
another 1.3 g of crystalline solid.
The solids are combined and taken up in 500 ml of
hot ethyl acetate cooled to 25C and suction filtered
through a dry pad of 350 g of Woelm neutral alumina,
activity II, layered over with Celite. The filter cake is
washed with another 500 ml of ethyl acetate and the resulting
solid swirled with 300 ml hexane, filtered and dried to give
the tetraacetate product, m.p. 107-110C.
Exam~le 4
3a,7a,-trans-5,6-trans-Hexahydro-4-[4-(dimethylamino)-
, . .
butyl]-3a,5,6,7a-indanetetrol
Following the procedure of example 1 but substituting
for N-bromopropylpiperidine hydrobromide an equivalent
amount of dimethylaminobutyl chloride hydrochloride, the
title cornpound is obtained.
Example 5
~a,7a-trans-5,6-trans-Hexahydro-4-[3-(dimethylamino)-
.
propyl~-3a,5,6,7a-indanetetrol
Following the procedure of e~ample 1 but substituting
for N-bromopropylpiperidine hydrobromide an equivalent
-16-
, .' '
: . . . .
`. ' ~
.
~6~Z90 ~A125
amount of dimethylaminopropyl chloride hydrochloride,
the title compound is obtai~ed, mp 138-139~C.
ExamPle 6 .
3a,7a-trans-5,6-trans-Hexahydro-4-~i-(diethylamino)ethyl]-
3a,5,6,7a-indanetetrol
Following the procedure of example 1 but substituting
for N-bromopropylpiperidine hydrobromide an equivalent amount
of diethylaminoethyl chloride hydrochloride, the title compound
is obtained.
, '
Example 7
3a,7a-trans-5,6-trans-Hexahydro-4-[(4-methyl-1-piperazinyl)-
methyll-3a,5,6,7a-indanetetrol
Following the procedure of example 1 but substituting
for N-bromopropylpiperidine hydrobromide an equivalent amount
. of l-chloromethyl-4-methylpiperazine, the title compound
is obtained. :
''" ''-'""~
Example 8
..
3a,7a-trans-5,6-trans-Hexahydro-4-[(1-methyl-4-piperidyl)- :
. . . _ .
methyll-3a,5,6,7a-indanetetrol ' ,:
Following the procedure of example 1 but substituting ~ -
for N-bromopropylpiperidine hydrobromide an equivalent amount
of N-methyl-4-chloromethylpiperidine hydrochloride, the title
compound is obtained.
,
Example 9
3a,7a-trans-5,6-trans-Hexahydro-4-[2-(1-methyl-4-piperidyl)-
, .. .. .
ethyll-3a,5,6,7a-indanetetrol
-17- . . i
~. .
, c. .,, ,, ~
:,........ , . . ' '
1~6629~ 1~125
Following the procedure of example 1 but substituting
for N-bromopropylpiperidine.hydrobromide an equivalent amount
of N-methyl-4-chloroethylpiperidine hydrochloride, the title
compound is obtained.
Example 10
3a,7a-trans-5,6-trans-Hexahydro-4-[3-(diethylamino)propyl]-
3a,5,6,7a-indanetetrol
Following the procedure of example 1 bu-t substituting
for N-bromopropylpiperidine hydrobromide an equivalent amount
of diethylaminopropyl chloride, the title compound is obtained.
.
Ex mple 11
3a,7a ~ dro-4-[(1-me-thyl-3-pyrrolidinyl)-
methyll-3a ! 5,6,7a-indanetetrol
Following the procedure o~ example 1 but substituting
for N-bromopropylpiperidine hydrobromide an equivalent amount
; of l-methyl-3-chloromethylpyrrolidine, the title compound
is obtained.
Example 12
3a,7a-trans-5,6-trans-Hexahydro-4-(piperidinyl~me-thyl-3a,5,
6,7a-indanetetrol
Following the procedure of example 1 but substituting
for N-bromopropylpiperidine hydrobromide an equivalent amount
of 4-chloromethylpiperidine, the title compound is obtained.
'
Example 13
- 3a,7a-trans-5,6-trans-Hexahydro-4-[1-methyl-2-(~-chloro-
. .
ethyl)piperidinel-3a,5,6,7a-indanetetrol
~ ,
-18-
:
:. - ,, . ,, ,, . . :
:: . ~ : , . . . .. . . .
~6629~
HA125
Following the procedure of example 1 but substituting
for N-bromopropylpiperidine hydrobromide an equivalent amount
of l-methyl-2-(~-chloroethyl)-piperidine, the title compound
is obtained. : :
Example 14 :
3a,7a-trans-5,6-trans-Hexahydro-4-[(1-methyl-2-pyrrolidinyl)-
-- .
ethyll-3a~ 7a-indanetetrol .
Following the procedure of example 1 but substituting . :--
for N-bromopropylpiperidine hydrobromide an equivalent amount ~.
of l-methyl-2~ chloro-ethylpyrrolidine, the title compound ~-~
is obtained.
."~":'~ . .
Examples 15 - 24 -
Treating the tetrols of examples 4-14, respectively,
according to the procedure of example 2 but substituting for ..
acetic anhydride and glacial acetic acid an equivalent amount
of the anhydride listed in column I below, there is obtained
the corresponding tetraester wherein each of Rl, R2, R3 and
R4 is the radical shown in column II below:
Starting Material I II
Tetrol of example anhYdride Rl-4
15. 4 propionic propionyl
16. 5 trifluoroacetic trifluoroacetyl
17. 6 dichloroacetic dichloroacetyl
18. 7 monochloroacetic monochloroacetyl
19. 8 monobromoacetic monobromoacetyl
20. 9 ~-iodopropionic ~-iodopropionyl
21.10 ~-methoxypro- ~-methoxypropionyl
pionic
--19--
. , . . . . :
; . , .
~6290 ~125
Starting Material I II
Tetrol of example anhydride Rl-4
22. 11 benzyloxyacetic benzyloxyacetyl
23. 12 N-methylpipera- N-methylpiperazino-
zinoacetic acetyl
24. 13 N-methylpyrroli- N-methylpyrroli-
dinoacetic dinoacetyl
Example 25
3a,7a-trans-5,6-trans-Hexahydro-4-(3-piperidinopropyl)-
_ .. _ .... . . _ .. _
3a,5,6,7a-indantetrol, tetrabenzoate ester
The product of example 1 (0.01 mole) is dissolved
in pyridine (25 ml) and 2.2 equivalents of benzoyl chloride
are added. The mixture is stirred at room temperature for
3 hours, then diluted with wa-ter, extracted into ether and
- dried to yield the title compound.
Examples 26 - 32
Following the procedure of example 25 but substituting
for benzoyl chloride the compound listed in column I, there
is obtained the corresponding tetraester wherein each of Rl,
R , R and R is the radical shown in column II:
Starting Material:
Tetrol of example I II
26. 1 acryloyl chloride acryloate
27. 1 crotonoyl chloride crotonoyl
28. 1 hydrocinnamo~l hydrocinnamoyl
anhydride -~
29. 4 phenacetyl chloride phenacetoyl
-20-
;''
: .: , - : . :. . . :
,. :' ' ' . . .' ' . '
~1066Zg~ HA125
:'
Starting Material:
Tet ol of example I II
30. 5 nicotinic anhydride nicotinoyl
31. 6 isonicotinic isonicotinoyl
anhydride
32. 6 picolinic anhydride picolinoyl
Example 33
3a,7a:5,6-trans-4-[3-(Dimethylamino)propyl~-hexahydro-lH-
.. . _ _ _ .. _ . . . . .. _ _ _ .
10 indene-3a,5,6,7a-tetrol, tetraacetate ester
A 4.1 g sample of the product of example 5 (0.015 mole)
in 125 ml of acetic anhydride is cooled to -78C and treated
with 2.260 g (0.016 moles) of 70/c perchloric asid. The
slurry is allowed to warm to -20. After standing at -20
for 20 hours, the mixture is again cooled to -78 and 70 ml
of methanol is added dropwise over a period of 30 minutes.
The mixture is then poured into 150 ml cold concentrated
aqueous ammonia. The product is extracted into chloroform
and the chloroform solution is dried. The solvent is removed
ln vacuo leaving tan crystalline material 6.3 g. This is -
recrystallized from ethyl acetate-hexane to give 3.1 g of
analytical sample of 3a,7a:5,6-trans-4-[3-(dimethylamino)-
propyl~hexahydro-l~I-indene-3a,5,6,7a-tetrol, tetraacetate
ester, mp 73-74C.
'
' :
: :; :
-30
--21--
: , ' ~ ' ' . .; ' . . .
.. . . . . . . . : . - , . . .
.. . . . ..
.
~06~290 HA125
xample 34
1,2:4,5-trans-3-[3-(Dimethylamino)propyl]~1,2-dimethyl-1,2,4,5-
cyclohexanetetrol, tetraacetate ester
To a suspension of 1.0 mole of sodium amide in 1 liter
liquid ammonia is added 67.6 g (0.5 moles, 80~/c purity),
1,2-dimethyl-1,4-cyclohexadiene in 125 ml of ether. After
15 minutes of stirring, the mixture is -treated portionwise
with 62 g (0.5 moles) of dimethylaminopropyl chloride in
125 ml of ether. After addition is completed stirring is
continued for 1 hr, before the addition of 500 ml of
ether and quenching wlth solid ammonium chloride as rapidly
as possible. After ammonia has evaporated solids are removed
by filtration and solvents removed ln vacuo to give 60 g
of liquid. This liquid on acid base extraction gives 40 g
of the alkylated dienes. This li~uid is distilled at the
oil pump to give 26.8 g of the monoaminoalkyl diene bp
62-64/0.05 mm and 10.8 g of bis-alkylation product,
bp 110/0.05 mm.
An amount of 19.3 g (0.1 mol) of N,N,2,3-tetramethyl-
2,5-cyclohexadiene-1-propanamine is dissolved in 200 ml of
cold 88% formic acid, and treated over a period of 15 minutes
with 24.1 ml of 30/O hydrogen peroxide (0.280 moles). The - ~ ;
temperature rises from 20 to 48 during the next 20 minutes.
A cold bath is applied for a few minutes to maintain ternperature
between 48-42. The bath is r0moved and the temperature
drops from 42 to 30 in the next 60 minutes, the solution
is left stirring overnight at room temperature. The solution
is diluted with 200 ml of water and the total solution is
-22-
,.- .~ ' ,, ,' :".',.: ' ' ' . , " ' .. : ' ' ' ~' :,
:: l ' , ' ' ' " . , ., ' , , '
' ' ' ': - ''' ' : , ,. ' ,
. . . .. .. . . . . .. . . .
1~6Z9~ ~125
evaporated ln vacuo. The liquid residue thus obtained is
suspended; in a mixture of I00 ml each 25% sodium hydroxide
and 90~/c ethanol and heated on water bath for 1 hour. The
mixture is cooled and the product extracted with ether and
ethyl acetate. After drying the organic layers and solvent
removal, the residue, 13.8 g, is chromatographed on 450 g
of neutral alumina (gradeII). Elution with chloroform-
methanol (95:5%) gives 5.8 g of the desired tetrol as a
colorless foam.
A suspension of 5.8 g (0.22 moles) of noncrystalline
tetrol in 200 ml of acetic anhydride is cooled in a dry
ice-acetone bath while 3.36 g of 70~/c HC104 (0.0234 moles)
is added. The resulting pink solution is stored at -20 for
16 hours. The solution is cooled in a dry ice-acetone
bath while 125 ml of dry methanol is added dropwise. The
solution i5 then basified with cold concentrated aqueous
ammonia and extracted with chloroform. The organic layer is
dried and evaporated ln vacuo to give 8.2 g of semisolid
which is filtered to give 4.3 g of the acetate. A sample
recrystallized from ethyl acetate-hexane has mp 103-105.
~ Example 35
2,3;4a,8a-trans-Decahydro~ methyl-3-pyrrolidinyl)methyl]-
.. . . ~
2,3,4a,8a-naphthalenetetrol
-- :
To a suspension of 0.5 moles of sodium amide in 500 ml of
liquid ammonia is added 48 g (0.26 moles) 1,2,3,4,5,8-hexahydro-
naphthalene in 125 ml of ether. After 15 minutes of stirring,
the mixture is treated portionwise with 35.5 g (0.26 moles) of
n-methyl-(2-chloromethyl)pyrrolidine in 125 ml of ether. After
addition is completed stirring is continued for 1 hour before
the addition of 500 ml of ether and quenching with solid ammonium
chloride as rapidly as possible. After ammonia has evaporated
-23-
' , .' ' :- . '. ' '' , ' '
HA125
~06ÇiZ~)
solids are removed by filtration and solvents removed 1n
vacuo to give 59 g of liquid. This liquid on acid and base
extraction gives 35 g of oil which is distilled at the oil
pump to give 28 of monoamino alkyldiene bp 105-106/0.05 mm
and 5 g of bis-alkylation product, bp 155-163/0.05 mm.
An amount 23.1 g (0.1 mol) of the monoalkylated diene is
dissolved in 200 ml of cold 88% formic acid and treated over a
period of 15 minutes with 24.1 ml (0.27 moles) of 30% hydrogen
peroxide. The solution is permitted to warm from 20 to 35
during this addition and 35 to 48D in the next five minutes.
A cold bath is applied for 15 minutes to mainta~ the temperature
between 38-42C, in the next 45 minutes, the solution is left
stirring overnight at room temperature. The solution is diluted
with 200 ml of water, and the solvents are evaporated in vacuo.
The liquid residue is then taken up in 300 ml of ethanol and
hydrolyzed by the addition of 125 ml of 25% sodium hydroxide
solution. The temperature is allowed to rise to 65 and stirring
continued for one hour. The mixture is cooled and the product
extracted into ether and ethyl acetate. After drying the organic
layers and solvent removal the residue 17.9 g is chromatographed
on 500 g of neutral alumina. Elution with chloroform-methanol
(95:5%) gives 8.2 g of oil which on trituration gives a solid 6 g,
mp 172-174. A sample recrystallized from ethyl acetate has
mp 176-178C.
Example 36
. , . '
2,3:4a,8a-trans-Decahydro-l-[(l-methyl-3-pyrrolidinyl)methyl]-
_ . . :
2,3,4a,8a-naphthalenetetrol, tetraacetate ester, hydrochloride
A 2.99 g sample of the product of example 35 (0.01 moles)
in 75 ml of acetic anhydride and 5 ml of acetic acid is cooled
to -78C and treated with 1.2 g (0.012 moles) of 70% perchloric
-24-
. , ' ' , , :
- `~
~66Z~O
HA125
. .
acid. The slurry is allowed to warm to -20C overnight,
then with carbon-dioxide acçtone coupling, the resulting
clear solution is treated with 50 ml of dry methanol over
30 minutes. The cold mixture is added to an ice-cooled
mixture of chloroform and concentrated aqueous ammonia,
the layers separated, and the aqueous extracted again with
chloroform. The organics are dried (sodium sulfate and
then magnesium sulfate) and evaporated to give 3.6 g of
tetraacetate as an oil. A 1.6 g of the sample is dissolved
in 50 ml of anhydrous ether and dry hydrochloric acid in
isopropanol-ether is added until the solution is acidic
to pH paper. The solid is filtered and recrystallization
from ethyl acetate-hexane affords the analytical sample
0.8 g, mp 85-87.
Example 37
2,3:2,4a:4a,8a-trans-1-[3-(Dimethylamino)propyl]decahydro-
2,3 ! 4a,8a-naPhthalenetetrol, tetraacetate ester -
To a suspension of 1.0 mole of sodium amide in 1 liter
liquid ammonia is added 75 g (0.5 moles, 90~/c purity) 1,2,3,4,-
5,8-hexahydronaphthalene in 125 ml of ether. After 15 minutes
of stirring, the mixture is -treated portionwise with 62 g
(0.5 moles) of dimethylaminopropyl chloride in 125 ml of
ether. After addition is completed stirring is continued
1 hour, before the addition of 500 ml of ether and quenching
with solid ammonium chloride as rapidly as possible. After
ammonia has evaporated solids are removed by filtration and
solvents removed ln vacuo to give 71 g of liquid. This
--25--
~66~90 ~125
liquid on acid and base extraction gives 60 g of oil which
is distilled at the oil pump to give 48 g of monoaminoalkyl
diene bp 87-90/0.05 mm and 6 g of bis-alkylation product,
bp 90-100/0.05 mm.
An amount of 32.90 g (0.15 moles) of 5-[3-(dimethyl-
amino)propyl~ 1,2,3,4,5,8-hexahydronaphthalene is dissolved
in 250 ml of cold 88% formic acid, and treated over a period
of 15 minutes with 39 ml of 30~/c hydrogen peroxide (0.41 moles). -
The temperature rises from 20 to 48~ during the next 20 minutes.
A cold bath is applied as needed to maintain temperature
between 48-42C. The bath is removed and the temperature
drops from 42 to 30 in the next 60 minutes, the solution
is left stirring overnight at room temperature. The solution
ls diluted with 250 ml of water and total solution is
evaporated in vacuo. The liquid residue is suspended in
a mixture of 400 ml each 25% sodium hydroxide and 90~/c
ethanol and heated on water bath for 1 hour. The mixture
is cooled and the product extracted with ether and ethyl
acetate. After drying the organic layers and solvent
removal the residue, 40 g, is chromatographed on 1 kg of
neutral alumina (grade II). Elution with chloroform-
methanol (95:5%) gives 17 g of the desired tetrol as a
colorless foam.
~ suspension of 5.74 g (0.02 moles) o~ 4-[3-(dimethyl-
amino)propyl]decahydro-2,3,4a,8a-naphthalenetetrol in 150 ml
of acetic anhydride is cooled in a dry ice-acetone bath while
3.014 g of 7~/c HC104 (0.022 moles) is added. The resulting
pink solution is stored at -20 for 16 hours. The solution
:
:
-26-
, : . '; ~. ,
,' '' ' '. . , ,, ' ~' ... , ~' ' . ' ,
1~6~ 91D
HAl25
is cooled in a dry ice-acetone bath while 100 ml of methanol
is added dropwise over 45 minutes. The solution is then
basified with cold concentratad aqueous ammonia and extracted
with chloroform. The chloroform layer is washed with
saturated sodium chloride solution dried on magnesium sul-
fate and evaporated ln vacuo, to give 8.2 g of an oil,
which on trituration gives a solid melting point 112-114
(3.9 g). A sample recrystallized from ethyl acetate-hexane ;
has mp 117C.
_xample 38
Preparation of capsule fo_mulation
Inqredlent Milliqrams per Ca~sule
3a,7a-trans-5,6-trans-Hexahydro-4-(3-
piperidinopropyl)-3a,5,6,7a-indantetrol,
tetraacetate ester . . . . . . . . . . . . . 400
Starch . . . . . . . . . . . . . . . . . . . 80
Magnesium stearate . . . . . . . . . . . ~ . 5
The active ingredient, starch and magnesium stearate are
blended together. The mixture is used to fill hard shell
capsules of a suitable size at a fill weight of 485 mi]li-
grams per capsule.
" ' . .
-27-
~662go HA125
Exampl~ g
Preparation of tablet formulation
~ . .
Inqredient Milliqrams per Tablet
3a,7a:5,6-trans-4-[3-(Dimethylamino)-
propyl]-hexahydro-lH-indene-3a,5,6,7a-
tetrol, tetraacetate ester . . . . . . . . . 100
Lactose ................................. 200
Corn starch (for mix) . . . . . . . . . . . . 50
Corn starch (for paste) . . . . . . . . . . . 50
Magnesium stearate. . . . . . . . . . . . . . 6
The active ingredient, lactose and corn starch (for mix) are
blended toqether. The corn starch ~for paste) is suspended
in water at a ratio of 10 grams of corn starch per 80
milliliters of water and heated with stirring to form a
paste. This paste is then used to granulate the mixed
powders. The wet granules are passed through a No. 8 screen
and dried at 120F. The dry granules are passed through a
No. 16 screen. The mixture is lubricated with magnesium
stearate and compressed into tablets in a suitable tableting
machine. Each tablet contains 100 milligrams of active
ingredient.
- -2~-
,
~06~Z9~ ~125
Example ~0
Preparation of_oral syrup formulation
Inqredient Amount
1,2:4,5-trans=3-[3-(Dimethylamino)propyl]-
1,2-dimethyl-1,2,4,5-cyclohexanetetrol,
tetraacetate ester . . . . . . . . . ~ . . 500 mg.
Sorbitol solution (70~/c N.F.) . . . . . . . 40 ml.
Sodium benzoate . . . . . . . . . . . . . . 150 mg.
Sucaryl . . . . . . . . . . . . . . . . . . 90 mg. -
Saccharin . . . . . . ~ . . . . . . . . . . 10 mg.
Red Dye (F.D. & Co. No. 2) . . . . . . . . 10 mg.
Cherry flavor . . ~ . . . . . . . . . . . . 50 mg.
: Distilled water . . . . . qs to . . . . . . 100 ml.
The sorbitol solution is added to 40 milliliters of distilled
water and the active ingredient is suspended therein. The
sucaryl, saccharin, sodium benzoate, flavor and dye are added
and dissolved in the above solution. The volume is adjusted
to 100 milliliters with distilled water.
Other ingredients may replace those listed in the
above formulation. For example, a suspending agent such as
bentonite magma, tragacanth, carboxymethylcellulose, or
methylcellulose may be used. Phosphates, citrates or tartrates
may be added as buffers. Preservatives may include the
parabens, sorbic acid and the like and other flavors and dyes
may be used in place of those listed above.
.
-29-
~. .
