CA1066290A - Cyclitolamines - Google Patents
CyclitolaminesInfo
- Publication number
- CA1066290A CA1066290A CA226,312A CA226312A CA1066290A CA 1066290 A CA1066290 A CA 1066290A CA 226312 A CA226312 A CA 226312A CA 1066290 A CA1066290 A CA 1066290A
- Authority
- CA
- Canada
- Prior art keywords
- alkyl
- carbon atoms
- formula
- hydrogen
- radical
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/80—Acids; Esters in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
Abstract
Abstract The compounds of the invention have the formula or I Ia wherein Y is a radical of the formula or of the formula 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, arylalkyl, or R5 and R6 together with the nitrogen to which they are attached are pyrrolidino, pipera-dino or N'-alkyl piperazino R1, R2, R3 or R4 are the same or different and are hydrogen; alkyl, trifluoromethyl; alkanoyl:
haloalkanoyl: alkoxycarbonyl of the formula -?OR wherein R is an alkyl radical; alkoxyalkyl; aminoalkanoyl of the formula 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 form a cycloalkyl ring and R9 is alkyl of 1 to 4 carbons, phenyl, hydrogen, alkyl of 1 to 4 carbon atoms sub-stituted 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 carbons or di-alkyl amino wherein each alkyl radical has 1 to 4 carbon atoms.
These compounds have been found useful in the treatment of hypertension in mammalian species, e.g., rats, as surface active agents, as in vitro antibacterial compounds and as water softeners.
haloalkanoyl: alkoxycarbonyl of the formula -?OR wherein R is an alkyl radical; alkoxyalkyl; aminoalkanoyl of the formula 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 form a cycloalkyl ring and R9 is alkyl of 1 to 4 carbons, phenyl, hydrogen, alkyl of 1 to 4 carbon atoms sub-stituted 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 carbons or di-alkyl amino wherein each alkyl radical has 1 to 4 carbon atoms.
These compounds have been found useful in the treatment of hypertension in mammalian species, e.g., rats, as surface active agents, as in vitro antibacterial compounds and as water softeners.
Description
~ 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 ~(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 C (CH2)pN \
R
. ~ ~125 1~66ZgO
wherein R5 and R6 are as previously defined and p is 0-3,
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 ~(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 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\ ~.
wherein Y is a radical of the formula R
(CH ) N ~
or of the formula -(CH2)n ~ (CH ) N~ 2 m .: . .
~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 -C-(CH2)pN
R
wherein R5 and R6 are as previously defined and p is 0-3; 2-,
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\ ~.
wherein Y is a radical of the formula R
(CH ) N ~
or of the formula -(CH2)n ~ (CH ) N~ 2 m .: . .
~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 -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~' 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 - ( CH2 ) nN
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 -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 (~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~
. '' ~.
.. ... , . . .. .. .. . :
( .
1066Z90 ~ ~
.
:
-CH N''' 3 , / C2H
2 5 : ~
~ H3 ~ -.
-CH2N~ --CH2N~
C3H7 .
-CH2~ < 2 f H3 -CH2CH2N ~ -CH2CH2N
! CH3 '' ' 10 ' , . , "
-cH2cH2cH2N\ --CH2CH2CH2N~>.
fH3 ~ CH3 3 -C~2 HCH2N \ ( 2)6N <
~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 ~
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 .
.:~ ,., . :
: .. '' : : . . . . .
~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,
:, . . . .. . ..
~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 - ( CH2 ) nN
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 -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 (~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~
. '' ~.
.. ... , . . .. .. .. . :
( .
1066Z90 ~ ~
.
:
-CH N''' 3 , / C2H
2 5 : ~
~ H3 ~ -.
-CH2N~ --CH2N~
C3H7 .
-CH2~ < 2 f H3 -CH2CH2N ~ -CH2CH2N
! CH3 '' ' 10 ' , . , "
-cH2cH2cH2N\ --CH2CH2CH2N~>.
fH3 ~ CH3 3 -C~2 HCH2N \ ( 2)6N <
~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 ~
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 .
.:~ ,., . :
: .. '' : : . . . . .
~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 .:
: ~ :
, -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 ~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 .
' '~
,. , :' " , , ' ', ~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.
~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.
., : . . . . ..
. ., -, , '. ~ : , '' , ' ' . . ..
~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.
-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
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 .:
: ~ :
, -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 ~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 .
' '~
,. , :' " , , ' ', ~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.
~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.
., : . . . . ..
. ., -, , '. ~ : , '' , ' ' . . ..
~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.
-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 .
~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 , .' ' : . . . .
`. ' ~
.
~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,
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 .
~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 , .' ' : . . . .
`. ' ~
.
~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 ~ , :
:. - ,, . ,, ,, . . :
:: . ~ : , . . . .. . . .
~6629~
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 . , . . . . :
; . , .
~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 ;'' : .: , - : . :. . . :
,. :' ' ' . . .' ' . ' ~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.
' ' :
: :; :
: , ' ~ ' ' . .; ' . . .
.. . . . . . . . : . - , . . .
.. . . . ..
.
~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 ,.- .~ ' ,, ,' :".',.: ' ' ' . , " ' .. : ' ' ' ~' :, :: 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 ' , .' ' :- . '. ' '' , ' ' ~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 . , ' ' , , :
- `~
~66Z~O
. .
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 ~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 :
:
, : . '; ~. , ,' '' ' '. . , ,, ' ~' ... , ~' ' . ' , 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.
" ' . .
~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.
.
~. .
' Example 13 - 3a,7a-trans-5,6-trans-Hexahydro-4-[1-methyl-2-(~-chloro-. .
ethyl)piperidinel-3a,5,6,7a-indanetetrol ~ , :
:. - ,, . ,, ,, . . :
:: . ~ : , . . . .. . . .
~6629~
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 . , . . . . :
; . , .
~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 ;'' : .: , - : . :. . . :
,. :' ' ' . . .' ' . ' ~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.
' ' :
: :; :
: , ' ~ ' ' . .; ' . . .
.. . . . . . . . : . - , . . .
.. . . . ..
.
~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 ,.- .~ ' ,, ,' :".',.: ' ' ' . , " ' .. : ' ' ' ~' :, :: 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 ' , .' ' :- . '. ' '' , ' ' ~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 . , ' ' , , :
- `~
~66Z~O
. .
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 ~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 :
:
, : . '; ~. , ,' '' ' '. . , ,, ' ~' ... , ~' ' . ' , 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.
" ' . .
~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.
.
~. .
Claims (10)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. Process for preparing a compound of the formula wherein Y is a radical of the formula or of the formula wherein (CH2)n is an alkyl radical, n is 1-3, and R5 and R6 are the same or different and are alkyl of 1 to 3 carbon atoms, or R5 and R6 together with the nitrogen to which they are attached are piperidino; R1, R2, R3 or R4 are the same or different and are hydrogen or alkanoyl of 1 to 4 carbon atoms;
R7 and R8 are the same or different and are hydrogen or alkyl, or R7 and R8 taken together with the carbon atoms bearing sub-stituents OR2 and OR4 optionally form a cycloalkyl ring of from 5 to 7 carbon atoms and R9 is hydrogen which comprises a) treating with excess H2O2 and formic acid a compound of the formula or wherein R7, R8, Y, R5 and R9 are as defined above and, where desired, treating the resultant tetrol with an esteri-fying agent, or b) where esterified tetrols are to be produced directly, treating in a carboxylic acid solution a compound of the formula wherein R7, and R8 and Y are as defined above, with a strong acid having a non-participating anion which does not open an epoxide radical, followed by treatment with excess peracid followed by treatment with excess carboxylic acid anhydride in the presence of a strong acid.
R7 and R8 are the same or different and are hydrogen or alkyl, or R7 and R8 taken together with the carbon atoms bearing sub-stituents OR2 and OR4 optionally form a cycloalkyl ring of from 5 to 7 carbon atoms and R9 is hydrogen which comprises a) treating with excess H2O2 and formic acid a compound of the formula or wherein R7, R8, Y, R5 and R9 are as defined above and, where desired, treating the resultant tetrol with an esteri-fying agent, or b) where esterified tetrols are to be produced directly, treating in a carboxylic acid solution a compound of the formula wherein R7, and R8 and Y are as defined above, with a strong acid having a non-participating anion which does not open an epoxide radical, followed by treatment with excess peracid followed by treatment with excess carboxylic acid anhydride in the presence of a strong acid.
2. Process for preparing a compound of the formula wherein Y is a radical of the formula or of the formula wherein (CH2)n is an alkyl radical, n is 1-3, and R5 and R6 are the same or different and are alkyl of 1 to 3 carbon atoms, or R5 and R6 together with the nitrogen to which they are attached are piperidino; R1, R2, R3 or R4 are the same or different and are hydrogen or alkanoyl of 1 to 4 carbon atoms; 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 hydrogen which comprises treating with excess H2O2 and formic acid a compound of the formula or wherein R7, R8, Y, R5, R6 and R9 are as defined above and, where desired, treating the resultant tetrol with an esteri-fying agent.
3. Process for preparing a compound of the formula wherein Y is a radical of the formula or of the formula wherein (CH2)n is an alkyl radical, n is 1-3, and R5 and R6 are the same or different and are alkyl of 1 to 3 carbon atoms, or R5 and R6 together with the nitrogen to which they are attached are piperidino; R1, R2, R3 or R are the same or different and are hydrogen or alkanoyl of 1 to 3 carbon atoms;
R7 and R8 are the same or different and are hydrogen or alkyl, or R7 and R8 taken together with the carbon atoms bearing sub-stituents OR2 and OR4 optionally form a cycloalkyl ring of from 5 to 7 carbon atoms and R9 is hydrogen which comprises treating in a carboxylic acid solution a compound of the formula wherein R7, R8 and Y are as defined above, with a strong acid having a non-participating anion which does not open an epoxide radical, followed by treatment with excess peracid followed by treatment with excess carboxylic acid anhydride in the presence of a strong acid.
R7 and R8 are the same or different and are hydrogen or alkyl, or R7 and R8 taken together with the carbon atoms bearing sub-stituents OR2 and OR4 optionally form a cycloalkyl ring of from 5 to 7 carbon atoms and R9 is hydrogen which comprises treating in a carboxylic acid solution a compound of the formula wherein R7, R8 and Y are as defined above, with a strong acid having a non-participating anion which does not open an epoxide radical, followed by treatment with excess peracid followed by treatment with excess carboxylic acid anhydride in the presence of a strong acid.
4. A process in accordance with claim 2 wherein R1, R2, R3 and R4 are hydrogen or alkanoyl.
5. A process in accordance with claim 4 wherein R1, R2, R3 and R4 are acetyl.
6. A process in accordance with claim 2 wherein R7 and R8 together with the carbon atoms to which they are attached are a cycloalkyl ring of from 5 to 7 carbon atoms.
7. A compound of the formula I Ia wherein Y is a radical of the formula or of the formula wherein (CH2)n is an alkyl radical, n is 1-3, and R5 and R6 are the same or different and are alkyl of 1 to 3 carbon atoms, or R5 and R6 together with the nitrogen to which they are attached are piperidino; R1, R2, R3 or R4 are the same or different and are hydrogen or alkanoyl of 1 to 4 carbon atoms;
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 hydrogen, whenever prepared according to the process of claim 2.
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 hydrogen, whenever prepared according to the process of claim 2.
8. A compound of claim 7 wherein R1, R2, R3 and R4 are hydrogen or alkanoyl, whenever prepared according to the process of claim 4.
9. A compound of claim 8 wherein R1, R2, R3 and R4 are acetyl, whenever prepared according to the process of claim 5.
10. A compound of claim 7 wherein R7 and R8 together with the carbon atoms to which they are attached are a cyclo-alkyl ring of from 5 to 7 carbon atoms, whenever prepared according to the process of claim 6.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US46703374A | 1974-05-06 | 1974-05-06 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1066290A true CA1066290A (en) | 1979-11-13 |
Family
ID=23854067
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA226,312A Expired CA1066290A (en) | 1974-05-06 | 1975-05-06 | Cyclitolamines |
Country Status (5)
| Country | Link |
|---|---|
| JP (1) | JPS50154225A (en) |
| CA (1) | CA1066290A (en) |
| DE (1) | DE2520172A1 (en) |
| FR (1) | FR2269928A1 (en) |
| GB (1) | GB1495770A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2484415A1 (en) * | 1980-06-13 | 1981-12-18 | Pharmindustrie | NOVEL INDENE DERIVATIVES, METHODS FOR THEIR PREPARATION, AND THEIR USE AS MEDICAMENTS |
-
1975
- 1975-05-06 FR FR7514204A patent/FR2269928A1/fr not_active Withdrawn
- 1975-05-06 GB GB1905275A patent/GB1495770A/en not_active Expired
- 1975-05-06 DE DE19752520172 patent/DE2520172A1/en not_active Withdrawn
- 1975-05-06 JP JP50055360A patent/JPS50154225A/ja active Pending
- 1975-05-06 CA CA226,312A patent/CA1066290A/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| GB1495770A (en) | 1977-12-21 |
| JPS50154225A (en) | 1975-12-12 |
| FR2269928A1 (en) | 1975-12-05 |
| DE2520172A1 (en) | 1975-11-20 |
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