CA1102333A - Substituted quinolizidine- and indolizidine-methanol derivatives and the process for the preparation thereof - Google Patents
Substituted quinolizidine- and indolizidine-methanol derivatives and the process for the preparation thereofInfo
- Publication number
- CA1102333A CA1102333A CA315,580A CA315580A CA1102333A CA 1102333 A CA1102333 A CA 1102333A CA 315580 A CA315580 A CA 315580A CA 1102333 A CA1102333 A CA 1102333A
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- Prior art keywords
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- derivatives
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- formula
- quinolizidine
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
- C07D455/02—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing not further condensed quinolizine ring systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
The present invention relates to substituted quinolizidine-and indolizidine-methanol derivatives, which are useful for a pharmaceutical agent or as an intermediate for producing the same, and to a process for the preparation thereof.
Such derivatives provide pharmaceutical agents having antihistaminic- , antiemetic- and antiacetylcholinergic activities with particularly strong antiacetylcholinergic activity such as spasmolytica or anti-ulcer agent in the form of quaternary salts thereof.
The present invention relates to substituted quinolizidine-and indolizidine-methanol derivatives, which are useful for a pharmaceutical agent or as an intermediate for producing the same, and to a process for the preparation thereof.
Such derivatives provide pharmaceutical agents having antihistaminic- , antiemetic- and antiacetylcholinergic activities with particularly strong antiacetylcholinergic activity such as spasmolytica or anti-ulcer agent in the form of quaternary salts thereof.
Description
3;~3 1 The present invention relates to substituted quinolizi-dine and indolizidine-methanol derivatives, which are useful for a pharmaceutical agent or as an intermediate for pro-ducing the same, and to a process for the preparation thereof.
The preparation of diphenyl-quinolizidyl (1) - carbinol has heen already described in chem. Ber. 90, 863-~867 (1957).
However, the use of this compound is not disclosed. Recently, the inventors have found substituted quinolizidine and indo-lizidine derivatives having strong anticholinergic activity with reduced side effects (c.f. our case H-125).
An object of the present invention is to provide pharma-ceutical agents having antihistaminic-, antiemetic- and antia-cetylcholinergic activities, particularly strong antiacetyl-cholinergic activity such as spasmolytica or anti-ulcer agent in the form of quaternary salts thereof.
Another object of the present lnvention is to provide intermediates for producing the substituted quinolizidine '~ and indolizidine derivatives described in our case H-125 in a simple manner with high yield.
The compounds of the invention are a,a - disubsti-tuted ; quinolizidine - and indolizidine - methanol derivatives of the formula (I):
~ -(CH2)n A
N ~ ¦ \ A ~ ~
-' wherein A represents a phenyl group or a 2-thienyl group and n is an integer of 3 or 4, provided that the a, a - diphenyl hydroxymethyl residue is present in 2 - or 3 - position of the quinolizidine, when A is a phenyl group and n is an integer of 233'J~
9, and dCid adclitioll salts thereo:E as well. as cluaternary salts thereof.
These compounds of the present inverltion are ~ se useful as pharmaceutical ayents as well as useful as intermedi-a-tes for producing the substituted cluinol;zidi.ne and i.ndolizi-dine derivatives. Further, surprisi.ngly, the quaternary salts of these substi-tuted quinoli~idine and indolizidirle derivcltives represented by the formula:
~ < ~ ?
R ~OH
` ' wherein A, R and n each has the same meaning as defined above, and Y represents an acid residue, are also useful as drugs having strong antiacetvlcholinergic activlty such as spasmoly-: tica or anti-ulcer agents.
The compounds of the formula (I), acid addition salts and quaternary salts thereoE can be prepared accordinq to the : 20 invention, by reacting a compound of the formula (II) or (III):
(CE-I ) l NI ~ CO
:
or .' ~(CH2) _ ~ COOR (I:[I) ~ N
"'''' ' '', ' .
wherein n and A have the same meanings as above and R repre-sents a lower alkyl group, with a metal compound of the for~
mula (IV) or (V):
"
32~33 1 A - M X (IV) or A - Li (V) wherein A has the same meanlngs as above and X represents a halogen atom, optionally followed by reacting the result-ing compound with a pharmaceutically acceptable inorganic or organic acid or with a ~uaternizing agent.
The reaction of the compound of the formula (II) or (III) with the metal compound of the formula (IV) or (V) is performed at room temperature or by heating under reflux in -~
an organic solvent. As solvents, dry ether or tetrahydrofuran etc. is preferred. When the compound of the formula (II) is ; employed, the metal compound Oe the Eormula (IV) or (V) is used in an amount of one mole or more. On the other hand, when the compound of the formula (III) is employed, the metal compound of the formula (IV) or (V) should be used in an - amount of 2 moles or more.
The starting materials of the formula (II) and (III) in-clude steric isomers and can be used as a mixture of dia-stereomers or a pure isomer isolated. The compounds of the forumula (I) can be obtained correspondingly as a mixture of the diastereomers or a pure isomer. The pure isomer can be obtained also by fractional recrystallization of the mixture of the diastereomers or by column chromatography.
,i~ .
The compounds of the formula (I) can be converted into the corresponding acid addition salts with pharaceutically -; acceptable inorganic acids, such as hyrdrochloric acid, hydro-bromic acid, sulfuric acid, etc. or organic acids such as maleic acid, fumaric acid, citric acid, tartaric acid, oxalic .
~2333 1 acid, succlnic acid etc.
The quaternary salts of the compounds of the formula (I) can be represented by the formula (VI):
~ (CH2) / A (VI) R
w~erein n and A have the same meanings as above, R is a lower alkyl group and Y is an acid residue, and prepared by reacting the compounds of the forrnula (I) with the compounds of the ~ -formula (VII~
R - Y (VII) ' wherein R and Y have the same meanings as above.
Specific examples of alkyl groups for the R include methyl, ethyl, propyl, butyl, etc. Specific examples of acid residues are a chlorine atom, a bromine atom, and a idodine atom, a sulfuric acid residuej an alkyl sulfate residue, and the like.
The aforementioned quarternizing reaction can be per- ;~
formed in the presence of or in the absence of solvents.
Typical examples of solvents to be employed are ether, acetone, '~
alcohols such as methanol or ethanol, etc. This reaction pro- ~
ceeds at temperatures between 5 and 100C., preferably 10 and ;~ ~ ;
40C., more preferably room temperature (ca. 20C), if neces~
sary in a sealed tube. -~
The quaternary salts of the formula (VI) include also the stereoisomers (trans - and cis-isomer) and can be used as a mixture of the isomers or as a pure isomer.
The starting materials of the formula (II) and (III) are ".~
.~ .
. :
ll(~Z33~3 l are in part known and in part novel. The novel starting materials can be prepared, for example, as follows:
~ ~ COA
The quaternary salts of the present invention have little side effects such as thirsty and dilation of the pupil, and therefore are effective as spasmolytic and anti-ulcer agents for clinical use as compared to atropin. Upon clinical use thereof, these compounds are employed in a dosage of 1 to 100 mg., preferably 3 to 30 mg., and administered three times a day orally; or, can be parenterally administered in the cor-~ 15 responding dosage. ~ ;
;~ The present invention will be explained hereafter in more ;
- detail with reference to the examples below.
Example 1 3 - [1, 1 - (Dithien - 2 - yl) - 1 - hydroxymethylJ
-~ 20 (a) - trans-quinolizidine A solution of 0.34g 3 - (thenoyl) (a) - trans-quinolizi-dine in dry ether is dropwise added to a solution of thienyl-magnesium bromide prepared from 0.5 g magnesium and 0.35 g
The preparation of diphenyl-quinolizidyl (1) - carbinol has heen already described in chem. Ber. 90, 863-~867 (1957).
However, the use of this compound is not disclosed. Recently, the inventors have found substituted quinolizidine and indo-lizidine derivatives having strong anticholinergic activity with reduced side effects (c.f. our case H-125).
An object of the present invention is to provide pharma-ceutical agents having antihistaminic-, antiemetic- and antia-cetylcholinergic activities, particularly strong antiacetyl-cholinergic activity such as spasmolytica or anti-ulcer agent in the form of quaternary salts thereof.
Another object of the present lnvention is to provide intermediates for producing the substituted quinolizidine '~ and indolizidine derivatives described in our case H-125 in a simple manner with high yield.
The compounds of the invention are a,a - disubsti-tuted ; quinolizidine - and indolizidine - methanol derivatives of the formula (I):
~ -(CH2)n A
N ~ ¦ \ A ~ ~
-' wherein A represents a phenyl group or a 2-thienyl group and n is an integer of 3 or 4, provided that the a, a - diphenyl hydroxymethyl residue is present in 2 - or 3 - position of the quinolizidine, when A is a phenyl group and n is an integer of 233'J~
9, and dCid adclitioll salts thereo:E as well. as cluaternary salts thereof.
These compounds of the present inverltion are ~ se useful as pharmaceutical ayents as well as useful as intermedi-a-tes for producing the substituted cluinol;zidi.ne and i.ndolizi-dine derivatives. Further, surprisi.ngly, the quaternary salts of these substi-tuted quinoli~idine and indolizidirle derivcltives represented by the formula:
~ < ~ ?
R ~OH
` ' wherein A, R and n each has the same meaning as defined above, and Y represents an acid residue, are also useful as drugs having strong antiacetvlcholinergic activlty such as spasmoly-: tica or anti-ulcer agents.
The compounds of the formula (I), acid addition salts and quaternary salts thereoE can be prepared accordinq to the : 20 invention, by reacting a compound of the formula (II) or (III):
(CE-I ) l NI ~ CO
:
or .' ~(CH2) _ ~ COOR (I:[I) ~ N
"'''' ' '', ' .
wherein n and A have the same meanings as above and R repre-sents a lower alkyl group, with a metal compound of the for~
mula (IV) or (V):
"
32~33 1 A - M X (IV) or A - Li (V) wherein A has the same meanlngs as above and X represents a halogen atom, optionally followed by reacting the result-ing compound with a pharmaceutically acceptable inorganic or organic acid or with a ~uaternizing agent.
The reaction of the compound of the formula (II) or (III) with the metal compound of the formula (IV) or (V) is performed at room temperature or by heating under reflux in -~
an organic solvent. As solvents, dry ether or tetrahydrofuran etc. is preferred. When the compound of the formula (II) is ; employed, the metal compound Oe the Eormula (IV) or (V) is used in an amount of one mole or more. On the other hand, when the compound of the formula (III) is employed, the metal compound of the formula (IV) or (V) should be used in an - amount of 2 moles or more.
The starting materials of the formula (II) and (III) in-clude steric isomers and can be used as a mixture of dia-stereomers or a pure isomer isolated. The compounds of the forumula (I) can be obtained correspondingly as a mixture of the diastereomers or a pure isomer. The pure isomer can be obtained also by fractional recrystallization of the mixture of the diastereomers or by column chromatography.
,i~ .
The compounds of the formula (I) can be converted into the corresponding acid addition salts with pharaceutically -; acceptable inorganic acids, such as hyrdrochloric acid, hydro-bromic acid, sulfuric acid, etc. or organic acids such as maleic acid, fumaric acid, citric acid, tartaric acid, oxalic .
~2333 1 acid, succlnic acid etc.
The quaternary salts of the compounds of the formula (I) can be represented by the formula (VI):
~ (CH2) / A (VI) R
w~erein n and A have the same meanings as above, R is a lower alkyl group and Y is an acid residue, and prepared by reacting the compounds of the forrnula (I) with the compounds of the ~ -formula (VII~
R - Y (VII) ' wherein R and Y have the same meanings as above.
Specific examples of alkyl groups for the R include methyl, ethyl, propyl, butyl, etc. Specific examples of acid residues are a chlorine atom, a bromine atom, and a idodine atom, a sulfuric acid residuej an alkyl sulfate residue, and the like.
The aforementioned quarternizing reaction can be per- ;~
formed in the presence of or in the absence of solvents.
Typical examples of solvents to be employed are ether, acetone, '~
alcohols such as methanol or ethanol, etc. This reaction pro- ~
ceeds at temperatures between 5 and 100C., preferably 10 and ;~ ~ ;
40C., more preferably room temperature (ca. 20C), if neces~
sary in a sealed tube. -~
The quaternary salts of the formula (VI) include also the stereoisomers (trans - and cis-isomer) and can be used as a mixture of the isomers or as a pure isomer.
The starting materials of the formula (II) and (III) are ".~
.~ .
. :
ll(~Z33~3 l are in part known and in part novel. The novel starting materials can be prepared, for example, as follows:
~ ~ COA
The quaternary salts of the present invention have little side effects such as thirsty and dilation of the pupil, and therefore are effective as spasmolytic and anti-ulcer agents for clinical use as compared to atropin. Upon clinical use thereof, these compounds are employed in a dosage of 1 to 100 mg., preferably 3 to 30 mg., and administered three times a day orally; or, can be parenterally administered in the cor-~ 15 responding dosage. ~ ;
;~ The present invention will be explained hereafter in more ;
- detail with reference to the examples below.
Example 1 3 - [1, 1 - (Dithien - 2 - yl) - 1 - hydroxymethylJ
-~ 20 (a) - trans-quinolizidine A solution of 0.34g 3 - (thenoyl) (a) - trans-quinolizi-dine in dry ether is dropwise added to a solution of thienyl-magnesium bromide prepared from 0.5 g magnesium and 0.35 g
2-bromothiophene in dry ether under cooling and then heated to reflex for 3 hrs. After completion of the reaction, water is added to the reaction mixture. The ethereal layer is sepa-rated and extracted with 10% aqueous hydrochloric acid. The water layer is adjusted to alkaline by adding a sodium hydrox-ide solution and then extracted with chloroform. The chloro-form layer is washed with water and dried. After evaporation . -5-, . .
~Z3~
1 of -the solvent, the residue is recrysta:Llized from isopropyl ether to obtain 0.55 g colorless needles of m.p. 147 -~148C.
Elemental Analysis for C18H23NOS2 C H N
Calcd. 64.82 6.95 4.20 found. 64.91 7.04 3.96 Example 2 2 -[1, 1 - ~dithien - 2 -yl) - 1 - hydroxymethyl ]
(e) - trans-quinolizidine ,~
A solution of 3.80 g 2-ethoxy carbonyl (e) -trans-quinolizidine in dry tetrahydrofuran is added to a solution of thieny magnesium bromide prepared from 1.35 g magnesium and 8.80 g 2-bromothlophene in dry tetrahydrofuran and the mixture is stirred. After completi~on of the rea~tion, the -~
mixture is mixed with a sodium hydroxide solution and fil-trated. The filtrate is concentrate~ and mixed with water and ether. The ethereal layer is separated and extracted ;~
with 5% aqueous hydrochloric acid solution. After adjusting ~
the water layer to be alkaline with a sodium hydroxide ~-solution, it is extracted with ether. The ethereal layer ;~
is washed with water and dried. The solvent is distilled :, :
out and the residue is recrystallized from benzene / isopro-pylether to obtain 4.64 g colorless prismlike crystals having `~
~ a melting point of 149 to 150C.
.,. : ~ ,, Elemental Analysis for C18H23NOS2 ~ -,- ,: .
C H N
:- ,.
Calcd. 64.82 6.95 4.20 found 64.99 6.96 3.85 ; Example 3 1-[1, 1-Dithien-2-yl)-1-hydroxymethl] (a) -trans-qunnoli-;,:.
~ ' ~
,
~Z3~
1 of -the solvent, the residue is recrysta:Llized from isopropyl ether to obtain 0.55 g colorless needles of m.p. 147 -~148C.
Elemental Analysis for C18H23NOS2 C H N
Calcd. 64.82 6.95 4.20 found. 64.91 7.04 3.96 Example 2 2 -[1, 1 - ~dithien - 2 -yl) - 1 - hydroxymethyl ]
(e) - trans-quinolizidine ,~
A solution of 3.80 g 2-ethoxy carbonyl (e) -trans-quinolizidine in dry tetrahydrofuran is added to a solution of thieny magnesium bromide prepared from 1.35 g magnesium and 8.80 g 2-bromothlophene in dry tetrahydrofuran and the mixture is stirred. After completi~on of the rea~tion, the -~
mixture is mixed with a sodium hydroxide solution and fil-trated. The filtrate is concentrate~ and mixed with water and ether. The ethereal layer is separated and extracted ;~
with 5% aqueous hydrochloric acid solution. After adjusting ~
the water layer to be alkaline with a sodium hydroxide ~-solution, it is extracted with ether. The ethereal layer ;~
is washed with water and dried. The solvent is distilled :, :
out and the residue is recrystallized from benzene / isopro-pylether to obtain 4.64 g colorless prismlike crystals having `~
~ a melting point of 149 to 150C.
.,. : ~ ,, Elemental Analysis for C18H23NOS2 ~ -,- ,: .
C H N
:- ,.
Calcd. 64.82 6.95 4.20 found 64.99 6.96 3.85 ; Example 3 1-[1, 1-Dithien-2-yl)-1-hydroxymethl] (a) -trans-qunnoli-;,:.
~ ' ~
,
3~3 1 zidine me-thyl bromide A solution of 0.05 g 1-[1, l-(dithien - 2yl) - l-hydroxy-methyl] (a) -trans-quinolizidine in 2 ml aceton is added to 1.0 ml methylbromide and stirred at room temperature for 60 hrs. The crystals separated out is filtered and recrystallized from aceton/methanol -to give 0.03 g colorless prism crystals with m.p. 167~V170OC (decomposition).
Elemental Analysis for ClgH26BrNOS2 C ~I N
Calcd. 53.26 6.12 3.27 found 52.96 6.15 3.21 Example 4 2-[1,1-Diphenyl-l-hydroxymethyl] (e) -trans-quinolizidine A solution of 5.3 g 2-benzoyl (e) -trans-quinolizidine -~
in dry ether is dropwise added to a solution of phenvllithium --prepared from 0.46 g lithium and 5.2 g bromobenzene in dry ~
ether and heated under reflux for 15 minutes. After completion ~ ~ -of the reaction, the reaction mixture is mixed with water and ;
then ether is distilled out. The residue is added to n-hexane to separate out crystals which are then filtered out and washed with water and then n-hexane. After drying, 4.76 g of colorless crystals are obtained. Recrystallization from isopropanol glves colorless plate-like crystals with a melting point of 188 to 189C.
IR (KBr) : 3400 cm (OH) Elemental Analysis for C22H27NO. 1/4 H2O
C H N
Calcd. 81.06 8.50 4.30 found 81.11 8.63 4.30 Example 5 ~,~?¦ -7 , ~ ".
~la~33 1 2-~1,1-diphenyl-1-hydroxymethyl] (e) -trans-quinolizidine A solution of 5.3 g 2-ethoxycarbonyl (e)-trans-~uinoli~
zidine in dry ether is dropwise added to a solution of phenyl-lithium prepared from 0.39 g lithium and 4.79 g bromobenzene in dry ether. The mixture is refluxed for 30 minutes and then ~ ' treated analogously to Example 4 to give 2.77 g of colorless ~-crystals. Recrystallization from isopropanol gives colorless plate-like crystals with a melting point of 188 to 189C.
This compound is consistent with the product of Example 4 in 10 IR and TLC and does not show the depression of -the melting point.
,:
Example 6 -~
rel-(2S, 8aR) -2- [1, l-(Dithien -2-yl)-1-hydroxymethyl~
,, . ~: .
indolizidine A solution of 0.37 g of rel-(2S, 8aR) 2-ethoxy carbonyl indolizidine in dry ether is dropwlse added to a solution of . . .- ~, , .
thienyl-magnesiumbromide prepared from 0.14 g magneslum and 1.8 g of 2-bromothiophen in drv ether under cooling and stirred at room temperature for 10 minutes. After completion of the reaction, the reaction mixture is mixed with water and extracted with ether. The ethereal layer is washed with water ' ,:
and dried. After removing the solvent by distillation, the ~ ~
.~
residue is recrystallized from isopropylether to give 0.10 g , of colorless needles with a melting point of 130 to 131C.
. .
IR (CHC13) : about 3200 cm (OH) ;
Elemental analys 17 21 2 C H N
:, Calcd. 63.91 6.63 4.38 found 63.61 6.65 4.13 -Example 7 ~ I -8-, " j ' ' ' , ' :
~2~3;3 1 rel-(2R, 8aR)-2-(1,1-Diphenyl -l-hydroxymethyl) indoli-zidine ~A) and rel-(2S, 8aR) -2-(1, l-diphenyl -l-hydrox-yme-thyl)- indolizidine (B) 2-senzoylindolizidine is added to a solution of phenyl-lithium prepared from 1.09 g metal lithium and 12.3 g bromo-benzene in dry ether and heated under reflux for 20 minutes.
After completion of the reaction, the reaction mixture ls mixed with water and extracted with ether. The ethereal layer is washed with water and dried. The solvent is dis-tilled off and the residue is mixed with n-hexane. The re-sulting crystals are filtered with suction to give 11~75 g of colorless crystals. By recrystallizing from isopropyl ether, colorless needles (A) with a melting point of 136 to 138C are obtained.
IR (CHC13) ; 3600 cm (OH) ~ ~ -Elemental analysis for C21H25NO
C H N
Calcd. 82.04 8.20 4.56 found 81.91 8.23 4.44 The mother liquid from the recrystallization is evapor- ~ -ated under reduced pressure to dryness and the residue is recrystallized from isopropyl ether to give colorless needles (B) with a melting point of 132 to 134C.
IR (CHC13) : about 3200 cm (OH) Elemental analysis for C21H25NO
C H N
Calcd. 82.04 8.20 4.56 found 81.87 8.06 4.33 Example 8 1-(1, l-Diphenyl - l-hydroxymethyl) - indolizidine _ g _ ~,~,:, , , ~ .
1 A solution of 2.40 g of l-ethoxycarbonyl indolizidine in 20 ml of dry ether is dropwise added to a solution of phenyl lithium prepared from 0.51 g metal lithium, 6.32 g bromobenzene and 50 ml dry ether under cooling with ice.
After refluxing for about 10 mins, water is dropwise added to the reaction mixture. The mixture is extracted with ether. The ethereal layer is extracted with a diluted ~ ~
hydrochloric acid solution and the aqueous layer is adjusted - -to alkaline with a caus-tic soda solution and then extracted - 10 with ether. The ethereal layer is washed with water and dried. After removing the solvent by distillation, 3.58 g ~ ~ , of yellowish viscous substance is obtained. - ~-This substance is crystallized, followed by recrystalli zation from isopropyl ether to obtain colorless needles with ,~:
` 15 a melting point of 120 to 121C. ;
Elemental analysis for C21H25NO
C H N
Calcd. 82.04 8.20 4.56 found 81.92 8.29 4.40 - 20 Mass spectrograph : C21H25NO
m/e : 307 (M ), 230 123 (base peak) This product is a mixture of two diastereoisomers.
Compounds (9~ - (19) below are prepared according to the same method as described in the above examples.
; Compound Physical Data (9~ 2-[1,1-Dithien -2-yl) - l-hydroxymethyl] m.p.253 - 255C
(e)- trans-~uinolizidine methylbromide (acetone/methanol) (10) 3-[1,1-(Dithien -2-yl) -l-hydroxyme-thyl] m.p.272 - 273C
.
, 1 (a)-trans-quinolizidine methylbromide (decomp.)(ethanol) (11) 3-[1,1-(Dithien -2-yl) -l-hydroxy- m.p.286 - 288C
m~thyl](e)--trans-~uinolizidine methylbromide (decomp.)(acetone/
methanol) 5(12) l-[l,l-(Dithien -2-yl) -l-hydroxy- m.p.l86 - 187C
methyl] (a)-trans-quinoliz~idine (isoprophyl ether) (13) 3-[1,1-(Dithien -2yl) -l-hydroxy- m.p.l76 - 177C
; methyl (e)-trans-quinolizldine ~isopropanol/iso-prophyl ether) 10(14) 3-[1, l-Dlphenyl -l-hydroxymethyl] m.p.l88 - 189.5C
(a)- trans-quinolizidine (isopropanol) IR(CHC13) : 3000 cm (OH) ~
(15) 3-[1,1- iphenyl -l-hydroxymenthyl] m.p.166 - 167C -~;
(e)- trans-quinolizidine (isopropanol) ;~-IR(CHC13) : 3600 cm (OH) (16) rel-(2R, 8aR)-2-[1,1-(Dithien -2yl) m.p.l01 - 102C
-1- hydroxymethyl] indolizidine IR(CHC13) : 3590 cm (isopropyl ether) (17) 1 [1,1-(Dithien-2-yl)-1 hydroxymethyl] m.p. 139 - 140C
-indolizidine (isopropyl ether)~
(mixture of two diastereoisomer) (18) 3-(1,1-Diphenyl-l-hydroxymethyl) (a)- m.p. > 300C
- trans-quinolizidine methyl bromide (methanol-ether) (19) 3-(1,1-Diphenyl-l-hydrox~methyl) (e)- m.p~ ~ 300C
25trans-quinolizidine methyl bromide (methanol-ether) .
The results of pharmacological tests performed using the compounds of the present invention are shown below.
Test Method:
The ED~o values of these compounds with respect to protective activity against spasm induced by acetylcholine '1 --11 , ~ Z~33 1 (1 x 10 g/ml) were measured using isola-ted ileum of guinea pigs in accordance with the well-known Magnus method and relative potency was examined by taking the ED50 value of atropine as 1~0.
Compound Relative Potency Compound o:E Example 10 0.39 Compound of Example 11 0.12 ~ ' Compound of Example 18 0.20 Scopolamine n-butyl bromide 0.02 Diphemanil methyl sulEate 0.11 Atropine 1.0 As can be seen from the results shown in the table above, the compounds of the present invention have stonyer protective activity against spasm induced by acetylcholine than commer-cially available scopolamine n-butyl bromide and diphemanil methyl sulfate. The other compounds of this invention also exhibit this high order of antispasmodic activity.
, : ~, '' ~ ~ -12-3~3 SUPPLEMENTARY DISCLOSURE -Compounds (20) and (21) below are also prepared according to the same method as described in Examples 1 to 8.
(20) 2-(1,1-diphenyl~-hydroxymethyl)-(e)-trans~
quinolizidine methyliodide, melting point 275-278C
(Methanol~/Acetone) (21) 2-(1,1-diphenyl-1-hydroxymethyl) Indolizidine methyl chloride, melting point ~ 300C
(Methanol~/Acetone) ;~
' ' '~' ' , , .
::, ,' ;.
.' ', ,~
~ ;
, . : .
' ~
~ :
-13- - ;
,' ~'.
.. . ..
.
Elemental Analysis for ClgH26BrNOS2 C ~I N
Calcd. 53.26 6.12 3.27 found 52.96 6.15 3.21 Example 4 2-[1,1-Diphenyl-l-hydroxymethyl] (e) -trans-quinolizidine A solution of 5.3 g 2-benzoyl (e) -trans-quinolizidine -~
in dry ether is dropwise added to a solution of phenvllithium --prepared from 0.46 g lithium and 5.2 g bromobenzene in dry ~
ether and heated under reflux for 15 minutes. After completion ~ ~ -of the reaction, the reaction mixture is mixed with water and ;
then ether is distilled out. The residue is added to n-hexane to separate out crystals which are then filtered out and washed with water and then n-hexane. After drying, 4.76 g of colorless crystals are obtained. Recrystallization from isopropanol glves colorless plate-like crystals with a melting point of 188 to 189C.
IR (KBr) : 3400 cm (OH) Elemental Analysis for C22H27NO. 1/4 H2O
C H N
Calcd. 81.06 8.50 4.30 found 81.11 8.63 4.30 Example 5 ~,~?¦ -7 , ~ ".
~la~33 1 2-~1,1-diphenyl-1-hydroxymethyl] (e) -trans-quinolizidine A solution of 5.3 g 2-ethoxycarbonyl (e)-trans-~uinoli~
zidine in dry ether is dropwise added to a solution of phenyl-lithium prepared from 0.39 g lithium and 4.79 g bromobenzene in dry ether. The mixture is refluxed for 30 minutes and then ~ ' treated analogously to Example 4 to give 2.77 g of colorless ~-crystals. Recrystallization from isopropanol gives colorless plate-like crystals with a melting point of 188 to 189C.
This compound is consistent with the product of Example 4 in 10 IR and TLC and does not show the depression of -the melting point.
,:
Example 6 -~
rel-(2S, 8aR) -2- [1, l-(Dithien -2-yl)-1-hydroxymethyl~
,, . ~: .
indolizidine A solution of 0.37 g of rel-(2S, 8aR) 2-ethoxy carbonyl indolizidine in dry ether is dropwlse added to a solution of . . .- ~, , .
thienyl-magnesiumbromide prepared from 0.14 g magneslum and 1.8 g of 2-bromothiophen in drv ether under cooling and stirred at room temperature for 10 minutes. After completion of the reaction, the reaction mixture is mixed with water and extracted with ether. The ethereal layer is washed with water ' ,:
and dried. After removing the solvent by distillation, the ~ ~
.~
residue is recrystallized from isopropylether to give 0.10 g , of colorless needles with a melting point of 130 to 131C.
. .
IR (CHC13) : about 3200 cm (OH) ;
Elemental analys 17 21 2 C H N
:, Calcd. 63.91 6.63 4.38 found 63.61 6.65 4.13 -Example 7 ~ I -8-, " j ' ' ' , ' :
~2~3;3 1 rel-(2R, 8aR)-2-(1,1-Diphenyl -l-hydroxymethyl) indoli-zidine ~A) and rel-(2S, 8aR) -2-(1, l-diphenyl -l-hydrox-yme-thyl)- indolizidine (B) 2-senzoylindolizidine is added to a solution of phenyl-lithium prepared from 1.09 g metal lithium and 12.3 g bromo-benzene in dry ether and heated under reflux for 20 minutes.
After completion of the reaction, the reaction mixture ls mixed with water and extracted with ether. The ethereal layer is washed with water and dried. The solvent is dis-tilled off and the residue is mixed with n-hexane. The re-sulting crystals are filtered with suction to give 11~75 g of colorless crystals. By recrystallizing from isopropyl ether, colorless needles (A) with a melting point of 136 to 138C are obtained.
IR (CHC13) ; 3600 cm (OH) ~ ~ -Elemental analysis for C21H25NO
C H N
Calcd. 82.04 8.20 4.56 found 81.91 8.23 4.44 The mother liquid from the recrystallization is evapor- ~ -ated under reduced pressure to dryness and the residue is recrystallized from isopropyl ether to give colorless needles (B) with a melting point of 132 to 134C.
IR (CHC13) : about 3200 cm (OH) Elemental analysis for C21H25NO
C H N
Calcd. 82.04 8.20 4.56 found 81.87 8.06 4.33 Example 8 1-(1, l-Diphenyl - l-hydroxymethyl) - indolizidine _ g _ ~,~,:, , , ~ .
1 A solution of 2.40 g of l-ethoxycarbonyl indolizidine in 20 ml of dry ether is dropwise added to a solution of phenyl lithium prepared from 0.51 g metal lithium, 6.32 g bromobenzene and 50 ml dry ether under cooling with ice.
After refluxing for about 10 mins, water is dropwise added to the reaction mixture. The mixture is extracted with ether. The ethereal layer is extracted with a diluted ~ ~
hydrochloric acid solution and the aqueous layer is adjusted - -to alkaline with a caus-tic soda solution and then extracted - 10 with ether. The ethereal layer is washed with water and dried. After removing the solvent by distillation, 3.58 g ~ ~ , of yellowish viscous substance is obtained. - ~-This substance is crystallized, followed by recrystalli zation from isopropyl ether to obtain colorless needles with ,~:
` 15 a melting point of 120 to 121C. ;
Elemental analysis for C21H25NO
C H N
Calcd. 82.04 8.20 4.56 found 81.92 8.29 4.40 - 20 Mass spectrograph : C21H25NO
m/e : 307 (M ), 230 123 (base peak) This product is a mixture of two diastereoisomers.
Compounds (9~ - (19) below are prepared according to the same method as described in the above examples.
; Compound Physical Data (9~ 2-[1,1-Dithien -2-yl) - l-hydroxymethyl] m.p.253 - 255C
(e)- trans-~uinolizidine methylbromide (acetone/methanol) (10) 3-[1,1-(Dithien -2-yl) -l-hydroxyme-thyl] m.p.272 - 273C
.
, 1 (a)-trans-quinolizidine methylbromide (decomp.)(ethanol) (11) 3-[1,1-(Dithien -2-yl) -l-hydroxy- m.p.286 - 288C
m~thyl](e)--trans-~uinolizidine methylbromide (decomp.)(acetone/
methanol) 5(12) l-[l,l-(Dithien -2-yl) -l-hydroxy- m.p.l86 - 187C
methyl] (a)-trans-quinoliz~idine (isoprophyl ether) (13) 3-[1,1-(Dithien -2yl) -l-hydroxy- m.p.l76 - 177C
; methyl (e)-trans-quinolizldine ~isopropanol/iso-prophyl ether) 10(14) 3-[1, l-Dlphenyl -l-hydroxymethyl] m.p.l88 - 189.5C
(a)- trans-quinolizidine (isopropanol) IR(CHC13) : 3000 cm (OH) ~
(15) 3-[1,1- iphenyl -l-hydroxymenthyl] m.p.166 - 167C -~;
(e)- trans-quinolizidine (isopropanol) ;~-IR(CHC13) : 3600 cm (OH) (16) rel-(2R, 8aR)-2-[1,1-(Dithien -2yl) m.p.l01 - 102C
-1- hydroxymethyl] indolizidine IR(CHC13) : 3590 cm (isopropyl ether) (17) 1 [1,1-(Dithien-2-yl)-1 hydroxymethyl] m.p. 139 - 140C
-indolizidine (isopropyl ether)~
(mixture of two diastereoisomer) (18) 3-(1,1-Diphenyl-l-hydroxymethyl) (a)- m.p. > 300C
- trans-quinolizidine methyl bromide (methanol-ether) (19) 3-(1,1-Diphenyl-l-hydrox~methyl) (e)- m.p~ ~ 300C
25trans-quinolizidine methyl bromide (methanol-ether) .
The results of pharmacological tests performed using the compounds of the present invention are shown below.
Test Method:
The ED~o values of these compounds with respect to protective activity against spasm induced by acetylcholine '1 --11 , ~ Z~33 1 (1 x 10 g/ml) were measured using isola-ted ileum of guinea pigs in accordance with the well-known Magnus method and relative potency was examined by taking the ED50 value of atropine as 1~0.
Compound Relative Potency Compound o:E Example 10 0.39 Compound of Example 11 0.12 ~ ' Compound of Example 18 0.20 Scopolamine n-butyl bromide 0.02 Diphemanil methyl sulEate 0.11 Atropine 1.0 As can be seen from the results shown in the table above, the compounds of the present invention have stonyer protective activity against spasm induced by acetylcholine than commer-cially available scopolamine n-butyl bromide and diphemanil methyl sulfate. The other compounds of this invention also exhibit this high order of antispasmodic activity.
, : ~, '' ~ ~ -12-3~3 SUPPLEMENTARY DISCLOSURE -Compounds (20) and (21) below are also prepared according to the same method as described in Examples 1 to 8.
(20) 2-(1,1-diphenyl~-hydroxymethyl)-(e)-trans~
quinolizidine methyliodide, melting point 275-278C
(Methanol~/Acetone) (21) 2-(1,1-diphenyl-1-hydroxymethyl) Indolizidine methyl chloride, melting point ~ 300C
(Methanol~/Acetone) ;~
' ' '~' ' , , .
::, ,' ;.
.' ', ,~
~ ;
, . : .
' ~
~ :
-13- - ;
,' ~'.
.. . ..
.
Claims (10)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for producing .alpha.,.alpha.-disubstituted quinoli-zidine - and indolizidine-methanol derivatives of the formula (I) (I) wherein A represents a phenyl or 2-thienyl group and n is an integer of 3 or 4, provided that the .alpha.,.alpha. -diphenylhydroxy-methyl residue is present in 2- or 3-position of the quino-lizidine, when A is a phenyl group and n is an interger of 4, and acid addition salts thereof as well as quaternary salts thereof characterized by reacting a compound of the formula (II) or (III):
(II) (III) wherein n and A have the same meanings as defined above and R represents a lower alkyl group with a metal compound of the formula (IV) or (V):
A -Mg X (IV) or A -Li (V) wherein X represents a halogen atom, optionally followed by reacting the resulting compound with a pharmaceutically acceptable inorganic or organic acid or with a quaternizing agent.
(II) (III) wherein n and A have the same meanings as defined above and R represents a lower alkyl group with a metal compound of the formula (IV) or (V):
A -Mg X (IV) or A -Li (V) wherein X represents a halogen atom, optionally followed by reacting the resulting compound with a pharmaceutically acceptable inorganic or organic acid or with a quaternizing agent.
2. A process according to Claim 1 wherein n is 3.
3. A process according to Claim 1 wherein n is 4.
4. A process according to Claim 1 wherein A is a phenyl group.
5. A process according to Claim 1 wherein A is a 2-thienyl group.
6. .alpha., .alpha. - disubstituted quinolizidine - and indolizi-dine methanol derivatives of the formula (I) (I) wherein A represents a phenyl or 2-thienyl group and n is an integer of 3 or 4, provided that the .alpha., .alpha. - diphenyl-hydroxymethyl residue is present in 2- or 3- position of the quinolizidine, when A is a phenyl group and n is an integer of 4, and acid addition salts thereof as well as quaternary salts thereof when prepared by the process of Claim 1.
7. Derivatives as claimed in Claim 6, wherein n is 3, when prepared by the process of Claim 2.
8. Derivatives as claimed in Claim 6, wherein n is 4 when prepared by the process of Claim 3.
9. Derivatives as claimed in Claim 6, wherein A is a phenyl group when prepared by the process of Claim 4.
10. Derivatives as claimed in Claim 6, wherein A is a 2-thienyl group when prepared by the process of Claim 5.
Applications Claiming Priority (8)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JPSHO-53-31652 | 1978-03-22 | ||
| JP3165278A JPS54125696A (en) | 1978-03-22 | 1978-03-22 | Alpha*alphaadithienylquinolitidine methanol derivative and its manufacture |
| JPSHO-53-31653 | 1978-03-22 | ||
| JP3165378A JPS54125697A (en) | 1978-03-22 | 1978-03-22 | Alpha*alphaadithienylquinolitidine methanol quaternary salt derivative |
| JPSHO-53-60654 | 1978-05-23 | ||
| JP6065478A JPS54154794A (en) | 1978-05-23 | 1978-05-23 | Alpha*alphaadiphenylquinolytidine methanol derivative and its manufacture |
| JP6065678A JPS54154795A (en) | 1978-05-23 | 1978-05-23 | Indolytidine methanol derivative and its manufacture |
| JPSHO-53-60656 | 1978-05-23 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1102333A true CA1102333A (en) | 1981-06-02 |
Family
ID=27459471
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA315,580A Expired CA1102333A (en) | 1978-03-22 | 1978-10-31 | Substituted quinolizidine- and indolizidine-methanol derivatives and the process for the preparation thereof |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP0004260B1 (en) |
| AT (1) | AT363089B (en) |
| CA (1) | CA1102333A (en) |
| DE (1) | DE2846880A1 (en) |
| DK (1) | DK482878A (en) |
| ES (1) | ES474640A1 (en) |
| SU (1) | SU982538A3 (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5650413A (en) * | 1995-06-07 | 1997-07-22 | Glycodesign Inc. | Derivatives of swainsonine, processes for their preparation and their use as therapeutic agents |
| AU736668B2 (en) * | 1996-10-01 | 2001-08-02 | Glycodesign Inc. | Novel 3, 5, and/or 6 substituted analogues of swainsonine, processes for their preparation and their use as therapeutic agents |
| CA2286766A1 (en) | 1997-04-15 | 1998-10-22 | Glycodesign Inc. | Alkaloid halide salts of swainsonine and methods of use |
| EP1023290A1 (en) * | 1997-10-24 | 2000-08-02 | Glycodesign Inc. | Synthesis of swainsonine salts |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1545661A1 (en) * | 1964-03-30 | 1969-08-07 | Chugai Pharmaceutical Co Ltd | Process for the preparation of new quinolizidine derivatives |
-
1978
- 1978-10-27 EP EP19780101241 patent/EP0004260B1/en not_active Expired
- 1978-10-27 DE DE19782846880 patent/DE2846880A1/en not_active Withdrawn
- 1978-10-27 ES ES474640A patent/ES474640A1/en not_active Expired
- 1978-10-27 AT AT771578A patent/AT363089B/en not_active IP Right Cessation
- 1978-10-30 DK DK482878A patent/DK482878A/en not_active Application Discontinuation
- 1978-10-31 SU SU782684151A patent/SU982538A3/en active
- 1978-10-31 CA CA315,580A patent/CA1102333A/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| DE2846880A1 (en) | 1979-10-04 |
| AT363089B (en) | 1981-07-10 |
| SU982538A3 (en) | 1982-12-15 |
| DK482878A (en) | 1979-09-23 |
| EP0004260B1 (en) | 1980-10-29 |
| ES474640A1 (en) | 1980-12-16 |
| EP0004260A1 (en) | 1979-10-03 |
| ATA771578A (en) | 1980-12-15 |
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