CA1100970A - Substituted quinolizidine-and indolizidine- derivatives and process for preparation thereof - Google Patents
Substituted quinolizidine-and indolizidine- derivatives and process for preparation thereofInfo
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- CA1100970A CA1100970A CA302,858A CA302858A CA1100970A CA 1100970 A CA1100970 A CA 1100970A CA 302858 A CA302858 A CA 302858A CA 1100970 A CA1100970 A CA 1100970A
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- Prior art keywords
- prepared
- preparation
- dithien
- quinolizidine
- ylmethylene
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Classifications
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- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- 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
Abstract
ABSTRACT OF THE DISCLOSURE
The present invention relates to substituted quinolizidine and indolizidine derivatives having anticholinergic, anti-histamic, antitussive and analgetic activities and to a process for producing the same. It has been found that the substituted quinolizidine and indolizidine derivatives having the following formula
The present invention relates to substituted quinolizidine and indolizidine derivatives having anticholinergic, anti-histamic, antitussive and analgetic activities and to a process for producing the same. It has been found that the substituted quinolizidine and indolizidine derivatives having the following formula
Description
1 ~ The present i.nvention relates to substitu~ed quinolizidine ancl indolizidine derivatives haviny an-ticholineryic, antihistamic, antitussive and analgetic activities, and to a process fo~ producing the same, ~nd to therapeutie agents eontaininy the same.
Atropine e~hibits strong antiacetylcholinergic activity ~.
and has been empLoyed as a spasmolytic agent for a long -time.
However, clinical use of atropine has been lim.ited because slde eEfeets sueh as thirsty, dilation o-f the pupil, inerease in ;~
blood pressure are accompanied. Therefore, conventional synthe-tie spasmolytic agents such as diphemanilme-thyl sulfa-te (see, U.S.. Patent 2,739,969, Merek Index, 9th Edition, paye . : :
3309), priElnium bromide ~see, Merck Index, 9th Edition, page 7540), timepidiurn bromide (see, J. Med. Chem. ].5, 9].~(1972)) have been proposed and employed. These compounds, however, are not satisfaetc)ry because strong antieholinergie main aetivity is neeessarily aceompanied by strony side efEeets.
n object of the present invention is to.provide sa-tis-~ fac-tory and perfeet therapeutic agents whieh have antieh.olinergie activity as high as possible but side e:EEects as low a possibl.e.
It has been Eound that the substituted quinolizicline ancl indolizi.cline deriva-tives haviny the Eoll.owincJ fo:rmula-: ~ ~ A2 (I) wherein Al and A2 are eaeh a phenyl.group or each a 2-thienyl group ~ld n is an inteyer oE 3 or 4, and aeid addition salts thereof as well as quartenary salts thereoE, exhibit strong anticholinergic aetivity but have extremely low side efEects.
Another object of the present inven-tion is to provide a proGess for produeing the derivatives represen-tecl hy the , ~
.... ," . ..... ........
7~
`~ormula (I) and sal~s thereof which comprised clehydrating the compounds repre~ented by ~he formula ( CH2) n ~
N ~ C
~" I \A2 OH (I~) wherein A and A and n have the same ~eaninqs as cibove, optionally foIlowed by reacting the resulting compounds with pharmaceutically acceptable inorganic or organic acids or with quarternizing ;~
agents. Some of the raw materials represented by the formula (II) are novel and some are ]cnown, which are prepared by con-ventional methods, such as in accordance with the method described in Chem. Ber. 90, pages 863-867 (1957).
The dehydration of the compounds represented by the formula (II) is performed by heating at temperatures between about 20 to about 150C, preferably 50 to 100C, more preferabl.y at boil.ing points of solvents used, in a solvent in the presence of a dehydrating agent. As solvents, a variety of solvents such as water, methanol,~ethanol, benzené, toluene, etc. are employed as far as they do not inhibit the dehydration. Typical examples of dehydra-ting agents include hydrochloric ac.id, sulfuric acid, phosp.horic oxychloride, p-toluenesul.foni.c acid, ~tc.
The thus obtained compounds represented by the formula (I) can be converted into the corresponding acid addition salts with pharmaceutically acceptable salts, such as hydrochloric acid, hydrobromic acid, sulfuric acid, oxalic acid, maleic acid, ^ fumaric acid, citric acid, etc.
~ The quarternary salts of the compounds of the formula (I) can be represented by the formula (III):
Atropine e~hibits strong antiacetylcholinergic activity ~.
and has been empLoyed as a spasmolytic agent for a long -time.
However, clinical use of atropine has been lim.ited because slde eEfeets sueh as thirsty, dilation o-f the pupil, inerease in ;~
blood pressure are accompanied. Therefore, conventional synthe-tie spasmolytic agents such as diphemanilme-thyl sulfa-te (see, U.S.. Patent 2,739,969, Merek Index, 9th Edition, paye . : :
3309), priElnium bromide ~see, Merck Index, 9th Edition, page 7540), timepidiurn bromide (see, J. Med. Chem. ].5, 9].~(1972)) have been proposed and employed. These compounds, however, are not satisfaetc)ry because strong antieholinergie main aetivity is neeessarily aceompanied by strony side efEeets.
n object of the present invention is to.provide sa-tis-~ fac-tory and perfeet therapeutic agents whieh have antieh.olinergie activity as high as possible but side e:EEects as low a possibl.e.
It has been Eound that the substituted quinolizicline ancl indolizi.cline deriva-tives haviny the Eoll.owincJ fo:rmula-: ~ ~ A2 (I) wherein Al and A2 are eaeh a phenyl.group or each a 2-thienyl group ~ld n is an inteyer oE 3 or 4, and aeid addition salts thereof as well as quartenary salts thereoE, exhibit strong anticholinergic aetivity but have extremely low side efEects.
Another object of the present inven-tion is to provide a proGess for produeing the derivatives represen-tecl hy the , ~
.... ," . ..... ........
7~
`~ormula (I) and sal~s thereof which comprised clehydrating the compounds repre~ented by ~he formula ( CH2) n ~
N ~ C
~" I \A2 OH (I~) wherein A and A and n have the same ~eaninqs as cibove, optionally foIlowed by reacting the resulting compounds with pharmaceutically acceptable inorganic or organic acids or with quarternizing ;~
agents. Some of the raw materials represented by the formula (II) are novel and some are ]cnown, which are prepared by con-ventional methods, such as in accordance with the method described in Chem. Ber. 90, pages 863-867 (1957).
The dehydration of the compounds represented by the formula (II) is performed by heating at temperatures between about 20 to about 150C, preferably 50 to 100C, more preferabl.y at boil.ing points of solvents used, in a solvent in the presence of a dehydrating agent. As solvents, a variety of solvents such as water, methanol,~ethanol, benzené, toluene, etc. are employed as far as they do not inhibit the dehydration. Typical examples of dehydra-ting agents include hydrochloric ac.id, sulfuric acid, phosp.horic oxychloride, p-toluenesul.foni.c acid, ~tc.
The thus obtained compounds represented by the formula (I) can be converted into the corresponding acid addition salts with pharmaceutically acceptable salts, such as hydrochloric acid, hydrobromic acid, sulfuric acid, oxalic acid, maleic acid, ^ fumaric acid, citric acid, etc.
~ The quarternary salts of the compounds of the formula (I) can be represented by the formula (III):
- 2 - :
)~ ' .
1/ ~= ;~
CN ~3 ~ ~ I I I ) wherein R is a lower alkyl group and X is an acid residue.
The quarternary salts can be prepared by reac-tiny the compounds represented by the formula (I) wi-th the compounds represen-ted by the formula (IV):
R - X (IV) wherein R and X have the same meanings as defined above.
Specific examples of alkyl yroups for the R include methyl, ethyl, propyl, butyll etc. Specific examples of acld residues are a chlorine atom, a bromine atom, and a iodine atom, a sulfuric acid residue, an alkyl sulfa-te residue, and the like.
The aforementioned quarterniziny reaction can be performed in the presence of or in the presence of solvents. Typical examples of solvents to be employed are e-ther, acetone, alcohols such as methanol or ethanol, etc. This reaction proceeds a-t temperatures between 5 and 100C., preferably 10 and 40C., more preferably room temperature (ca. 20C), if necessary i.n a sealed tube.
The quarternary salts of the formula (III) include steric isomers (trans- and cis-isomers), and they can be obtained as mixtures or pure isomers af-ter recrystallization.
Both isomers exhibit almost the same pharmacoloyical activities.
The compounds of the present invention represented by the formula (I) and acid addition salts -thereof as well as quarternary salts thereof exhibit s-trony spasmolytlc, anti-histamic, antitussive and analyetic activities. In particular, ~ - 3 -7~
l -the quartern~ry sa]ts have strorl~ anti-cholinergic and anti-ulcer activi-ties but have reduced side effects such as thirsty and dilation of the pupil.
The results of pharmacological tests with respect to the compounds of the present invention are shown below.
Test Me-thod:
The ED50 values of these compounds relating to protective activlty agains-t spasm induced by acetylcholine (lx 10 g/ml) were measured using isolated ileum of guinea pigs according to the Mag~us method, and relative potency was -thus examined, taking the ED50 of atropine as lØ
Compounds: Relative Potency 2-DiphenylmethyLenequinolizidine methyl bromide 1.12 (Compound of Example 2 ii)
)~ ' .
1/ ~= ;~
CN ~3 ~ ~ I I I ) wherein R is a lower alkyl group and X is an acid residue.
The quarternary salts can be prepared by reac-tiny the compounds represented by the formula (I) wi-th the compounds represen-ted by the formula (IV):
R - X (IV) wherein R and X have the same meanings as defined above.
Specific examples of alkyl yroups for the R include methyl, ethyl, propyl, butyll etc. Specific examples of acld residues are a chlorine atom, a bromine atom, and a iodine atom, a sulfuric acid residue, an alkyl sulfa-te residue, and the like.
The aforementioned quarterniziny reaction can be performed in the presence of or in the presence of solvents. Typical examples of solvents to be employed are e-ther, acetone, alcohols such as methanol or ethanol, etc. This reaction proceeds a-t temperatures between 5 and 100C., preferably 10 and 40C., more preferably room temperature (ca. 20C), if necessary i.n a sealed tube.
The quarternary salts of the formula (III) include steric isomers (trans- and cis-isomers), and they can be obtained as mixtures or pure isomers af-ter recrystallization.
Both isomers exhibit almost the same pharmacoloyical activities.
The compounds of the present invention represented by the formula (I) and acid addition salts -thereof as well as quarternary salts thereof exhibit s-trony spasmolytlc, anti-histamic, antitussive and analyetic activities. In particular, ~ - 3 -7~
l -the quartern~ry sa]ts have strorl~ anti-cholinergic and anti-ulcer activi-ties but have reduced side effects such as thirsty and dilation of the pupil.
The results of pharmacological tests with respect to the compounds of the present invention are shown below.
Test Me-thod:
The ED50 values of these compounds relating to protective activlty agains-t spasm induced by acetylcholine (lx 10 g/ml) were measured using isolated ileum of guinea pigs according to the Mag~us method, and relative potency was -thus examined, taking the ED50 of atropine as lØ
Compounds: Relative Potency 2-DiphenylmethyLenequinolizidine methyl bromide 1.12 (Compound of Example 2 ii)
3-Diphenylmethylenequinolizidine methyl bromide 0.58 (Compound of Example ~ ii) 3-Diphenylmethylenequinolizidine ethyl bromide 0.45 (Compound of Example 4 iii) 2-(Dithien-2-ylmethylene) quinolizidine methyl 1.16 bromide (Compound of Example 10 i) 3-(Dithien-2-ylmethylene) quinolizidine methyl 0.86 bromide (Compound of Example 12 ii) Atropine ]-Scopolamin n-butyl bromide 0.02 Diphemanil methyl sulfate 0.11 ~imepidium bromide 0.15 As can be seen Erom the results shown in -the table above, the compounds of the present invention have far stronger anti-cholinergic activity than scopolamine n-butylbromide, diphemanil me-thyl sulfate or timepidium bromide.
In addition, the compounds of the present invention have little side effects such as thirsty and dilation of the ~ - 4 -g7''C~ ' l pupil, and thereEore are efEective as spasmolytic and anti-ulcer ageilts ~or clin:ical use as compared -to atropin. Upon clinical use -thereof, these compounds are employed in a dosage of l to lO0 mg., preferably 3 to 30 mg., and administered three times a day orally; or, can be parenterally administered in the corresponding dosage.
~ he present invention will be explained hereaf-ter in more detail with reference to the examples below.
_xample l 2-Diphenylmethylenequinolizidirle Hydrochloride:
To 1.39 y. of~,~diphenylquinolizidine-2-methanol was added lO ml. of ethanolic hydrochloride. The resulting mixture was refluxed for 4 hrs. with stlrring. The residue remained after the removal of the et~hanol by distillation was dissolved in water. The solution was rendered alkaline with a potassium carbonate solution and extracted with chloroform. The chloro-form layer was washed with water and dried. A-E-ter -the solvent was removed by dlstil~lation, light yellow liquid was obtained.
The product was converted into the hydrochloride in a .
~ conventional manner. By recrystallization from acetone-e-ther, 0.47 g~ of colourless needle 2-diphenylmethylenequinolizidine hydrochloride showing a melt.ing point of 233-235C was obtained.
Elemental Analysis: C22H25N-HCl calcd. C, 77.74; H, 7.71; N, 4.12 found C, 77.48; ~I, 7.59; N, 3.78 Example 2 i) 2-(Diphenylmethylene)quinolizidine Methyl Iodide:
In lO ml. of acetone was dissolved 0.1 g. of ~ 2-diphenylmethylenequinolizidine. After l.0 ml. o~f methyl iodide was added to the resulting solution, the mi~ture w~s 97C~
~ .
1 stirred for 24 hrs. at room tempera-ture. The crystals precipitated were taken out by fil-tration. By recrystallization from methanol, 0.1 g. of colourless needles showing a meltlng point of 280-282C. (decompd.) were obtained.
Elemental Analysis: C23H28NI
calcd. C, 62.03; H, 6.34; N, 3.14 Eound C, 61.97; ~I, 6.43; N, 3.13 ~ii) 2-(Diphenylmethylene)quinolizidine Methyl ~romide:
a) In 50 ml. of acetone was dissolved 5.5 g. of 2-diphenylmethylenequinolizidine. After 5 ml. of me-thyl bromide was added to the solut1on, the mixture was allowed to stand for 48 hrs. at room temperature in a sealed tube. After the completion of the reaction, the residue obtalned'by removing 'the solvent by dis-ti]lation~ was recrystallized from methanol-acetone to obtaln 5.34 g. of colourless prism crystals showing a melting point of 261-263~C. (decompd.).
NMR (CDC13) ~ - 3.33 (~ -CH3) Elemental Analysis: C23H28N~r calcd. C, 69.34; H, 7.08; N, 3.52 ,~
;20 ~ found C,~ 69.08; ~l, 7.16; N, 3.26 b) llhe residue obtained by distilling the thus obtained mother'liquor of -the recrystallization above to dryness under reduced pressure was recrystallized rom methanol-acetone, which procedure was repeated twice -to obtain the mother liquors.
The combined mother liquors were distilled to dryness under reduced pressure. The resul-ting resldue was recrystallized ' from methanol-acetone to give 1.12 g. of colourless prism crystals showing a melting point of 235-236C.
NMR (CDC13) ~ : '3.67 (N -CH3) ~30 3~ 93t7a~
" ~ .
l iii) 2-(D_ henylmethylene)quinolizidine Ethyl Bromide: ;
This compound was prepared in a manner similar to the -above.
Melting point: 233-234C. (from acetone) Elemental Analysis: C24H30NBr ~;
calcd. C, 69.90; H, 7.33; N, 3.40 fo~md C, 69.58; H, 7.42; N, 3.26 Example 3 3-Diphenylmethylenequinolizidine:
a~ In 20 ml. of 60% sulfuric acid was heated 1.5 g. of ~ ,a -diphenylquinolizidine-3-methanol at 90 to 95C. for ~ -30 mins. with stirring. After the completion of the reaction, the reaction product was poured into water. The resulting solution was rendered alkaline with a 10% aq. sodium hydroxide ~ !
solution and then extracted with ether. The ethereal layer was washed with water and dried. The residue obtained after removing the solvent by distillation was recrystallized from hexane to obtain 1.1 g. of colourless needles showing a melting point of 118 to 120C.
Elemental Analysis: C22H25N
calcd. C, 87.08; H, 8.30; N, 4.62 found C, 87.30; H, 8.33; N, 4.48 In accordance with a conventional manner, the product was converted into the hydrochloride in a conventional manner.
By recrystallization from methanol, colourless plate-like crystals having a melting point of 225 to 228C. were obtained.
b) ~ Diphenylquinolizidine-3-methanol employed as a starting material was prepared in accordance with the following method:
~;~ 30 To a solution of phenyl lithium, which had been prepared _ 7 _ 7(~
l by -the reaction oE 1.23 g. of lithium and 16.80 g. oE bromo~
benzene, in 50 ml. of absolu-te ether was dropwise added a solution of 120 g. of 3-benzoylquinolizidine in absolute ether. The mix~ure was refluxed for 30 mins. with stirring.
After -the excess of phenyl lithium was decomposed with water, the reaction mixture was extracted with ether. The thus obtained ethereal layer was washed with water and dried.
After removing the solvent by distillation, ~ diphenyl-quinolizidine-3-methanol showing a melting point oE 166 to lO 167C. was obtained.
Example 4 i) 3-Diphenylmethylenequinolizidine Methyl Iodide:
This compound was prepared in a manner similar to Example 2 i) except that methanol was employed as the , :
reaction solvent, and the residue obtalned aEter remov:ing the solvent by distillation was recrystallized from me-thanol-acetone.
Melting poin-t: 221-224C. ~colourless prisms) lemental AnalySiS: C23H28NI
~ C H N
calcd. 62.03 6.34 3.14 found 61.94 6.34 3~00 ii) 3-Diphenylmethylenequinolizidine Methyl Bromide:
a) This compound was prepared in a manner similar to :
Example 2 ii) a)~.
; Melting point: 259-261C. (decompd., colourless needles) - NMR (CDC13) ~ : 2-97 (N~ -CH3) Elemental Analysis: C23H28N3r .
~30 7C~ , calcd. 69.34 7.08 3.52 found 69.60 7.29 3.26 b) In a manner similar to Example 2 ii) b), an isomer of the so obtained methyl bromide was prepared from the mother liquor of the recrystallization in accordance with similar procedures to Example 2 ii) b).
Colourless crystals having a melting point of 256 to 259C. tfrom methanol-ether) NMR (~DC13) ~ : 3.40 (N~ -CH3) -~
Elemental Analysiso C23H28NBr -C H N
calcd. 69.34 7.08 3.52 found 69.06 7.20 3.48 ,~
iii) 3 Diphenylmethylenequinoliz1dine Ethyl Bromide:
This compound was prepared in a manner similar to Example 2 ii) a).
Melting point: 225-228C (from acetone) Elemental Analysis: C24H30NBr C H N
calcd. 69.90 7.33 3.40 found 69.87 7.36 3.27 Example 5 l-Diphenylmethylenequinolizidine Sulfate:
3.5 g. of ~ Diphenylmethylenequinolizidine-l- ~ ;~
methanol was heated together with 35 ml. of 60% sulfuric acid at about 100C. for 20 mins. The reaction mixture was poured into water. After the mixture was rendered alkaline with a 20% aq. sodium hydroxide, the mixture was extracted with ether.
The ethereal layer was washed with water and dried. Ilhe residue 7a~
1 ~3.1 g) obtained after removing the solvent by distillation was treated with ethanolic sulfuric acid. By recrystallization of the thus obtained sulfate from ethanol, colourless needle crystals having a melting point of 219 to 221C. were obtained.
Elemental Analysis: C22H25N.H2SO4 C H N
calcd. 65.81 6.78 3.49 found 65.78 6.92 3.24 Example 6 _ _ :
i) l-Diphenylmethylenequinoliæidine Methyl Iodide:
In 20 ml. of acetone was dissolved 0.5 g. of l-diphenyl~
methylenequinolizidine. After 1.0 ml. of methyl iodide was added to the solution, the mixture was allowed to stand for 10 mins. The crystals precipitated were taken out by filtration.
sy recrystallization of the obtained crystals (0.53 g.) from methanol, colourless plate-like crystals having a melting point of 294 to 296C (decompd.) were obtained.
Elemental Analysis: C23H28NI
C H N
calcd. 62.03 6.34 3.14 found 61.92 6.41 2.82 ii) l-Diphenylme ~ lenequinolizidine Methyl Bromide:
This compound was prepared in accordance with the procedures similar to i) above.
Melting point: > 300C (from ethanol) NMR (CDC13 ~ 3.19 (N~--C~3) Elemental Analysis: C23H2gNBr ' ~
7~ ~ ~
1 ~ C H N
calcd. 69.34 7.08 3.52 ~;
found 69.29 7.19 3.27 iii) l-Diphenylmethylenequinolizidine Ethyl Bromide:
This compound was prepared in a manner similar to i) above.
Melting point: ~ 300C. (from ethanol) Elemental Analysis: C24H30NBr / 2 C H N
calcd. 68.40 7.41 3.32 found 68.61 7.313.24 Example 7 l-(Dithien-2-ylmethylene)quinolizidine Hydrochloride:~ ;
To 1.40 g. of ~,~-(dithen-2-yl)quinolizidine-1-methanol was added 15 ml. of ethanolic hydrochloric acid. The mixture ; ;
was stirred for 1 hr. at 60C. The residue obtained by ~-removing the solvent by distillation was dissolved in water.
The solution was rendered alkaline with a 10~ aq. sodium hydroxide and then extracted with ether. The ethereal layer was washed with water and dried. After removing the solvent by distillation, 1.29 g. of light brown liquid was obtained.
; In accordance with a conventional method, the product was converted into the hydrochloride. By recrystallization from ~ ~
isopropanol-isopropyl ether, the desired light brown prism 'r hydrochloride showing a melting point of 194 to 197C. was obtained. ~;
- ~lemental Analysis: C18H21NS2 .HCl C H N
; calcd. 61.43 6.30 3.98 found 61.13 6.64 3.84 1~ - 11 -, ... .. .
1 Example 8 1) 1-(Dithien-2-ylmeth_lene)quillolizidine Methyl Iodide:
I'his compound was prepared in good yield in a manner similar to`Example 6 i) except that anhydrous acetone was ~
employed as a reaction solvent. ~ ~-Light brown needles having a melting point of 284 to 285C. ~decompd., from isopropanol) Elemental Analysis: ClgH24INS2 C H N
calcd. 49.89 5.29 3.06 found 50.02 5.48 2.99 In an analogous manner, the following compounds were prepared:
ii) l~(Dithien-2-ylmethylene)quinolizidine Methyl Bromide:
Melting point: 294-297C. (from ethanol-isopropyl ether, decompd.) MNR (CDC13) g : 3.36 (N+ -CH~) Elemental AnalysiS: ClgH24Br NS2 C H N
calcd. 55.60 5.89 3.41 found 55.18 6.11 3.51 (Dithie ~ ethylene)quinolizidine Ethyl Bromide:
Melting point: 286-288C. (from ethanol-isopropyl ether, decompd.) Elemental An,alysis: C20H26BrNs2 C H N
:
calcd. 56.59 6.17 3.30 found 56.79 6.54 3.13 Example 9 2-(Dithien-2-ylmethylene)quinolizidine:
1 This compound was prepared from ~ (dithien-2-yl)-quinolizidine-2-methanol in a manner similar to Example 7 except that potassium hydroxide was used in place of sodium ~ '^
hydroxide and chloroform was used for the extraction in place of ether.
Colourless crystals having a melting point of 88 to 90C. (from isopropyl ether) Elemental Analysis: C18H21NS2 C H N ;
calcd. 68.53 6.71 4.44 found 68.34 6.72 4.26 Example 10 i) 2-(Dithien-2-ylmethylene)quinolizidine Methyl Bromide:
In a manner similar to Example 2 i), the following compound was prepared.
Colourless crystals having a melting point of 246 to 248C. (from ethanol, decompd.) NMR (CDC13) ~ : 3.42 (N - CH3) Elemental Analysis: ClgH24Br NS2 C H N
calcd. 55.60 5.89 3.41 found 55.31 5.88 3. ln ii) 2-(Dithien-2-ylmet_ylene)quinolizidine Ethyl Bromide: ~ ;
This compound was prepared in a manner similar to Example 2 ii) a) except that the reaction mixture was heated to 50C.
Colourless crystals having a melting point of 217 to 218C. (from isopropanol) Elemental Analysis: C20H26Br NS2 7~
calcd. 56.59 6.17 3.30 found 56.30 6.15 3.31 Example 11 3-(Dithien-2-ylmethylene)quinolizidine:
This compound was prepared in a manner similar to Example 7.
Colourless needles having a melting point of 128 to 130C. (from isopropyl ether) Elemental Analysis: C18H21NS2 C H N
calcd. 68.53 6.71 4.44 found 68.35 6.74 4.36 Example 12 In a manner similar to Example 6 i), the ollowing compounds were prepared:
i) 3-(Dithien-2-ylmethylene)quinolizidine Methyl Iodide:
Melting point: 223 to 224C (from ethanol) Elemental Analysis: 19 24 2 C H N
calcd. 49.89 5.29 3.06 ound 49.66 5.35 2.72 ii) 3 (Dithien-2-ylmethylene)quinoliæidine Methyl Bromide:
Melting point: 278 to 280C. (from ethanol: decompd.) NMR (CDC13) ~ : 2.92 (N - CH3) Elemental Analysis: ClgH24BrNS2 C H N ;
calcd. 55.60 5.89 3.41 found 55.78 5.89 3.37 ,~
9'7~
. iii) 3-(Dithien-2-ylmethylene)~uinolizidine Ethyl Bromide:
Melting point: 226 to 22~C~ (from isopropanol-acetone; decompd.) Elemental Analysis: C20H26BrNS2- 1/5 H2O
C
calcd. 56.12 6.22 3.27 found 56.13 6.18 3.G8 Example 13 l-Diphenylmethyleneindolizidine:
-This compound was prepared from ~,~-diphenylindolizidine-1-methanol in a manner similar to Example 5. ;;
Yellow viscous substance Mass spectrum (C21H23N) : m/e: 289 (M ), 212 -Diphenylindolizidine-l-methanol employed as a starting material was prepared as follows:
To a phenyl lithium solution prepared by dissolving 0.51 g. of metallic llthium and 6.32 y. of bromobenzene in ; 50 ml. of absolute ether, was dropwise added a solution of 2.40 g. of l-ethoxycarbonylindolizidine in 20 ml. of absolute ;~
ether under ice cooling. After refluxing for about 10 mins., water was dropwise added thereto, followed by extrackion with ether. The ethereal layer was further extracted with dil.
hydrochloric acid. The aqueous layer was rendered alkaline with an aq. sodium hydroxide solution and then extracted with ether. The ethereal layer was washed with water and dried.
After removiny the solvenk by distillation, 3.5~ g. of light yellow viscous substance was obtained.
Mass spectrum (C21~25NO) m/e : 307 (M ~), 230, 123 ~basic peak) The product was a mixture of two diastereoisomers and 1 used for the reac-tion above as i-t was.
e 14 In a manner similar to Example 6 i), the following compounds were prepared:
i) l-Diphenylmethyleneindolizidine Methyl Bromide:
Colourless, plate-like crystals having a melting ~ -poin~ of 210 to 211C. (from ethanol-acetone) NMR (CDCl3) ~ : 3-49 (N ~ - CH3) Elemental Analysis: C22H26NBr ~;
C H N `
calcd. 68.75 6.82 3.64 found 68.56 6.85 3.51 ii) l-Diphenylmethyleneindolizidine Methyl Iodide:
Melting point: 189 to 190C. (colourless needles) iii) l-Diphenylmethyleneindolizidine Ethyl Bromide:
Melting point: 163 to 164C. (colourless plate-like crystals) Example 15 2-Dlphenylmethyleneindolizidine:
This compouna was prepared in a manner similar to Example 5.
Melting point: 76 to 79C. (from n-hexane, colourless needles) Elemental Analysis: C21H23N
C H N
calcd. 87.15 8.014.84 found 87.08 8.144.76 Example 16 ln a manner similar to Example 6 i), the following compounds were prepared:
9~ :
i i) 2-Diphenylmethyleneindolizidine Methyl Iodide:
Melting point: 242 to 244C. (from methanol-acetone, colourless needles) Elemental Analysis: C22H26NI
C H N
calcd. 61.26 6.08 3.25 found 61.00 6.15 3.13 ii) 2-Diphenylmethyleneindolizidine Methyl Bromide~
::
Melting point: 267 to 269C. (from methanol-acetone, decompd.) NMR (CDC13)~ : 3-08 (M~ -CH3) Elemental Analysis: C22H26~Br C H M
calcd. 68~75 6.82 3.64 found 68.57 6.82 3.53 ~Example 17 -2-(Dithien-2-ylmethylene)indolizidine:
To 2.66 g. of ~ (dithien-2-yl)indolizidine-2-methanol was added 20 ml. of ethanolic hydrochloric acid. The mixture was st1rred for 1.5 hrs. with heating at 60C. Water was .
added to the resldue obtained ater removing ethanol by , distillation to dissolve. Thereafter, the solution was rendered alkaline with a 10% aq. sodium hydroxide solution and then extracted with ether. The ethereal layer was washed with water and dried. The residue remained after removing the solvent by distillation was distilled -to obtain 1.76 g. of ~ .
yellow liquid showing a boiling point of 195 to 197C. (3mmHg).
In accordance with a conven-tional manner, the product was converted into the hydrochloride. By recrystallization from 3 isopropanol, yellow prisms having a melting point of 197 to 7~
., :
1 200C. (decompd.) were obtained.
Elemental Analysis: C17lll9NS2 . HCl C H N
calcd. 60.42 5.97 4.14 found 60.17 6.12 3.87 Example 18 In a manner similar to E~ample 2, the following compounds were prepared:
) 2-(Dithien-2 ylmethylene)indolizidine Methyl Iodide:
Meltlng point: 222 to 225C. (from isopropanol, colourless ;~
to llght brown prlsms) Elemental AnalyslS: Cl8H22INS2 C H N
calcd. 48.76 5.00 3.16 found 48.60 5.04 2.85 il) 2-(Dithien~2-ylm thylene)indolizldine Methyl Bromlde:
Melting point: 200 to 202C. (from isopropanol) ~ NMR (CDCl3) ~ : 3-49 (N~ -CH3) `~ Elemental Analysis: C]8H22BrNS2 1/5 H20 C H N
calcd. 54.05 5.64 3.50 found 54.02 5.59 3.24 iii) 2-(Dithien-2-ylmethylene)indolizidine Et_yl Bromide:
Melting point: 212 to 214C. (from isopropanol-acetone) l AnalySiS: ClgH24BrNS2 C H N
calcd. 55.60 5.89 3.41 found 55.33 5.91 3.16 - 18 ~
In addition, the compounds of the present invention have little side effects such as thirsty and dilation of the ~ - 4 -g7''C~ ' l pupil, and thereEore are efEective as spasmolytic and anti-ulcer ageilts ~or clin:ical use as compared -to atropin. Upon clinical use -thereof, these compounds are employed in a dosage of l to lO0 mg., preferably 3 to 30 mg., and administered three times a day orally; or, can be parenterally administered in the corresponding dosage.
~ he present invention will be explained hereaf-ter in more detail with reference to the examples below.
_xample l 2-Diphenylmethylenequinolizidirle Hydrochloride:
To 1.39 y. of~,~diphenylquinolizidine-2-methanol was added lO ml. of ethanolic hydrochloride. The resulting mixture was refluxed for 4 hrs. with stlrring. The residue remained after the removal of the et~hanol by distillation was dissolved in water. The solution was rendered alkaline with a potassium carbonate solution and extracted with chloroform. The chloro-form layer was washed with water and dried. A-E-ter -the solvent was removed by dlstil~lation, light yellow liquid was obtained.
The product was converted into the hydrochloride in a .
~ conventional manner. By recrystallization from acetone-e-ther, 0.47 g~ of colourless needle 2-diphenylmethylenequinolizidine hydrochloride showing a melt.ing point of 233-235C was obtained.
Elemental Analysis: C22H25N-HCl calcd. C, 77.74; H, 7.71; N, 4.12 found C, 77.48; ~I, 7.59; N, 3.78 Example 2 i) 2-(Diphenylmethylene)quinolizidine Methyl Iodide:
In lO ml. of acetone was dissolved 0.1 g. of ~ 2-diphenylmethylenequinolizidine. After l.0 ml. o~f methyl iodide was added to the resulting solution, the mi~ture w~s 97C~
~ .
1 stirred for 24 hrs. at room tempera-ture. The crystals precipitated were taken out by fil-tration. By recrystallization from methanol, 0.1 g. of colourless needles showing a meltlng point of 280-282C. (decompd.) were obtained.
Elemental Analysis: C23H28NI
calcd. C, 62.03; H, 6.34; N, 3.14 Eound C, 61.97; ~I, 6.43; N, 3.13 ~ii) 2-(Diphenylmethylene)quinolizidine Methyl ~romide:
a) In 50 ml. of acetone was dissolved 5.5 g. of 2-diphenylmethylenequinolizidine. After 5 ml. of me-thyl bromide was added to the solut1on, the mixture was allowed to stand for 48 hrs. at room temperature in a sealed tube. After the completion of the reaction, the residue obtalned'by removing 'the solvent by dis-ti]lation~ was recrystallized from methanol-acetone to obtaln 5.34 g. of colourless prism crystals showing a melting point of 261-263~C. (decompd.).
NMR (CDC13) ~ - 3.33 (~ -CH3) Elemental Analysis: C23H28N~r calcd. C, 69.34; H, 7.08; N, 3.52 ,~
;20 ~ found C,~ 69.08; ~l, 7.16; N, 3.26 b) llhe residue obtained by distilling the thus obtained mother'liquor of -the recrystallization above to dryness under reduced pressure was recrystallized rom methanol-acetone, which procedure was repeated twice -to obtain the mother liquors.
The combined mother liquors were distilled to dryness under reduced pressure. The resul-ting resldue was recrystallized ' from methanol-acetone to give 1.12 g. of colourless prism crystals showing a melting point of 235-236C.
NMR (CDC13) ~ : '3.67 (N -CH3) ~30 3~ 93t7a~
" ~ .
l iii) 2-(D_ henylmethylene)quinolizidine Ethyl Bromide: ;
This compound was prepared in a manner similar to the -above.
Melting point: 233-234C. (from acetone) Elemental Analysis: C24H30NBr ~;
calcd. C, 69.90; H, 7.33; N, 3.40 fo~md C, 69.58; H, 7.42; N, 3.26 Example 3 3-Diphenylmethylenequinolizidine:
a~ In 20 ml. of 60% sulfuric acid was heated 1.5 g. of ~ ,a -diphenylquinolizidine-3-methanol at 90 to 95C. for ~ -30 mins. with stirring. After the completion of the reaction, the reaction product was poured into water. The resulting solution was rendered alkaline with a 10% aq. sodium hydroxide ~ !
solution and then extracted with ether. The ethereal layer was washed with water and dried. The residue obtained after removing the solvent by distillation was recrystallized from hexane to obtain 1.1 g. of colourless needles showing a melting point of 118 to 120C.
Elemental Analysis: C22H25N
calcd. C, 87.08; H, 8.30; N, 4.62 found C, 87.30; H, 8.33; N, 4.48 In accordance with a conventional manner, the product was converted into the hydrochloride in a conventional manner.
By recrystallization from methanol, colourless plate-like crystals having a melting point of 225 to 228C. were obtained.
b) ~ Diphenylquinolizidine-3-methanol employed as a starting material was prepared in accordance with the following method:
~;~ 30 To a solution of phenyl lithium, which had been prepared _ 7 _ 7(~
l by -the reaction oE 1.23 g. of lithium and 16.80 g. oE bromo~
benzene, in 50 ml. of absolu-te ether was dropwise added a solution of 120 g. of 3-benzoylquinolizidine in absolute ether. The mix~ure was refluxed for 30 mins. with stirring.
After -the excess of phenyl lithium was decomposed with water, the reaction mixture was extracted with ether. The thus obtained ethereal layer was washed with water and dried.
After removing the solvent by distillation, ~ diphenyl-quinolizidine-3-methanol showing a melting point oE 166 to lO 167C. was obtained.
Example 4 i) 3-Diphenylmethylenequinolizidine Methyl Iodide:
This compound was prepared in a manner similar to Example 2 i) except that methanol was employed as the , :
reaction solvent, and the residue obtalned aEter remov:ing the solvent by distillation was recrystallized from me-thanol-acetone.
Melting poin-t: 221-224C. ~colourless prisms) lemental AnalySiS: C23H28NI
~ C H N
calcd. 62.03 6.34 3.14 found 61.94 6.34 3~00 ii) 3-Diphenylmethylenequinolizidine Methyl Bromide:
a) This compound was prepared in a manner similar to :
Example 2 ii) a)~.
; Melting point: 259-261C. (decompd., colourless needles) - NMR (CDC13) ~ : 2-97 (N~ -CH3) Elemental Analysis: C23H28N3r .
~30 7C~ , calcd. 69.34 7.08 3.52 found 69.60 7.29 3.26 b) In a manner similar to Example 2 ii) b), an isomer of the so obtained methyl bromide was prepared from the mother liquor of the recrystallization in accordance with similar procedures to Example 2 ii) b).
Colourless crystals having a melting point of 256 to 259C. tfrom methanol-ether) NMR (~DC13) ~ : 3.40 (N~ -CH3) -~
Elemental Analysiso C23H28NBr -C H N
calcd. 69.34 7.08 3.52 found 69.06 7.20 3.48 ,~
iii) 3 Diphenylmethylenequinoliz1dine Ethyl Bromide:
This compound was prepared in a manner similar to Example 2 ii) a).
Melting point: 225-228C (from acetone) Elemental Analysis: C24H30NBr C H N
calcd. 69.90 7.33 3.40 found 69.87 7.36 3.27 Example 5 l-Diphenylmethylenequinolizidine Sulfate:
3.5 g. of ~ Diphenylmethylenequinolizidine-l- ~ ;~
methanol was heated together with 35 ml. of 60% sulfuric acid at about 100C. for 20 mins. The reaction mixture was poured into water. After the mixture was rendered alkaline with a 20% aq. sodium hydroxide, the mixture was extracted with ether.
The ethereal layer was washed with water and dried. Ilhe residue 7a~
1 ~3.1 g) obtained after removing the solvent by distillation was treated with ethanolic sulfuric acid. By recrystallization of the thus obtained sulfate from ethanol, colourless needle crystals having a melting point of 219 to 221C. were obtained.
Elemental Analysis: C22H25N.H2SO4 C H N
calcd. 65.81 6.78 3.49 found 65.78 6.92 3.24 Example 6 _ _ :
i) l-Diphenylmethylenequinoliæidine Methyl Iodide:
In 20 ml. of acetone was dissolved 0.5 g. of l-diphenyl~
methylenequinolizidine. After 1.0 ml. of methyl iodide was added to the solution, the mixture was allowed to stand for 10 mins. The crystals precipitated were taken out by filtration.
sy recrystallization of the obtained crystals (0.53 g.) from methanol, colourless plate-like crystals having a melting point of 294 to 296C (decompd.) were obtained.
Elemental Analysis: C23H28NI
C H N
calcd. 62.03 6.34 3.14 found 61.92 6.41 2.82 ii) l-Diphenylme ~ lenequinolizidine Methyl Bromide:
This compound was prepared in accordance with the procedures similar to i) above.
Melting point: > 300C (from ethanol) NMR (CDC13 ~ 3.19 (N~--C~3) Elemental Analysis: C23H2gNBr ' ~
7~ ~ ~
1 ~ C H N
calcd. 69.34 7.08 3.52 ~;
found 69.29 7.19 3.27 iii) l-Diphenylmethylenequinolizidine Ethyl Bromide:
This compound was prepared in a manner similar to i) above.
Melting point: ~ 300C. (from ethanol) Elemental Analysis: C24H30NBr / 2 C H N
calcd. 68.40 7.41 3.32 found 68.61 7.313.24 Example 7 l-(Dithien-2-ylmethylene)quinolizidine Hydrochloride:~ ;
To 1.40 g. of ~,~-(dithen-2-yl)quinolizidine-1-methanol was added 15 ml. of ethanolic hydrochloric acid. The mixture ; ;
was stirred for 1 hr. at 60C. The residue obtained by ~-removing the solvent by distillation was dissolved in water.
The solution was rendered alkaline with a 10~ aq. sodium hydroxide and then extracted with ether. The ethereal layer was washed with water and dried. After removing the solvent by distillation, 1.29 g. of light brown liquid was obtained.
; In accordance with a conventional method, the product was converted into the hydrochloride. By recrystallization from ~ ~
isopropanol-isopropyl ether, the desired light brown prism 'r hydrochloride showing a melting point of 194 to 197C. was obtained. ~;
- ~lemental Analysis: C18H21NS2 .HCl C H N
; calcd. 61.43 6.30 3.98 found 61.13 6.64 3.84 1~ - 11 -, ... .. .
1 Example 8 1) 1-(Dithien-2-ylmeth_lene)quillolizidine Methyl Iodide:
I'his compound was prepared in good yield in a manner similar to`Example 6 i) except that anhydrous acetone was ~
employed as a reaction solvent. ~ ~-Light brown needles having a melting point of 284 to 285C. ~decompd., from isopropanol) Elemental Analysis: ClgH24INS2 C H N
calcd. 49.89 5.29 3.06 found 50.02 5.48 2.99 In an analogous manner, the following compounds were prepared:
ii) l~(Dithien-2-ylmethylene)quinolizidine Methyl Bromide:
Melting point: 294-297C. (from ethanol-isopropyl ether, decompd.) MNR (CDC13) g : 3.36 (N+ -CH~) Elemental AnalysiS: ClgH24Br NS2 C H N
calcd. 55.60 5.89 3.41 found 55.18 6.11 3.51 (Dithie ~ ethylene)quinolizidine Ethyl Bromide:
Melting point: 286-288C. (from ethanol-isopropyl ether, decompd.) Elemental An,alysis: C20H26BrNs2 C H N
:
calcd. 56.59 6.17 3.30 found 56.79 6.54 3.13 Example 9 2-(Dithien-2-ylmethylene)quinolizidine:
1 This compound was prepared from ~ (dithien-2-yl)-quinolizidine-2-methanol in a manner similar to Example 7 except that potassium hydroxide was used in place of sodium ~ '^
hydroxide and chloroform was used for the extraction in place of ether.
Colourless crystals having a melting point of 88 to 90C. (from isopropyl ether) Elemental Analysis: C18H21NS2 C H N ;
calcd. 68.53 6.71 4.44 found 68.34 6.72 4.26 Example 10 i) 2-(Dithien-2-ylmethylene)quinolizidine Methyl Bromide:
In a manner similar to Example 2 i), the following compound was prepared.
Colourless crystals having a melting point of 246 to 248C. (from ethanol, decompd.) NMR (CDC13) ~ : 3.42 (N - CH3) Elemental Analysis: ClgH24Br NS2 C H N
calcd. 55.60 5.89 3.41 found 55.31 5.88 3. ln ii) 2-(Dithien-2-ylmet_ylene)quinolizidine Ethyl Bromide: ~ ;
This compound was prepared in a manner similar to Example 2 ii) a) except that the reaction mixture was heated to 50C.
Colourless crystals having a melting point of 217 to 218C. (from isopropanol) Elemental Analysis: C20H26Br NS2 7~
calcd. 56.59 6.17 3.30 found 56.30 6.15 3.31 Example 11 3-(Dithien-2-ylmethylene)quinolizidine:
This compound was prepared in a manner similar to Example 7.
Colourless needles having a melting point of 128 to 130C. (from isopropyl ether) Elemental Analysis: C18H21NS2 C H N
calcd. 68.53 6.71 4.44 found 68.35 6.74 4.36 Example 12 In a manner similar to Example 6 i), the ollowing compounds were prepared:
i) 3-(Dithien-2-ylmethylene)quinolizidine Methyl Iodide:
Melting point: 223 to 224C (from ethanol) Elemental Analysis: 19 24 2 C H N
calcd. 49.89 5.29 3.06 ound 49.66 5.35 2.72 ii) 3 (Dithien-2-ylmethylene)quinoliæidine Methyl Bromide:
Melting point: 278 to 280C. (from ethanol: decompd.) NMR (CDC13) ~ : 2.92 (N - CH3) Elemental Analysis: ClgH24BrNS2 C H N ;
calcd. 55.60 5.89 3.41 found 55.78 5.89 3.37 ,~
9'7~
. iii) 3-(Dithien-2-ylmethylene)~uinolizidine Ethyl Bromide:
Melting point: 226 to 22~C~ (from isopropanol-acetone; decompd.) Elemental Analysis: C20H26BrNS2- 1/5 H2O
C
calcd. 56.12 6.22 3.27 found 56.13 6.18 3.G8 Example 13 l-Diphenylmethyleneindolizidine:
-This compound was prepared from ~,~-diphenylindolizidine-1-methanol in a manner similar to Example 5. ;;
Yellow viscous substance Mass spectrum (C21H23N) : m/e: 289 (M ), 212 -Diphenylindolizidine-l-methanol employed as a starting material was prepared as follows:
To a phenyl lithium solution prepared by dissolving 0.51 g. of metallic llthium and 6.32 y. of bromobenzene in ; 50 ml. of absolute ether, was dropwise added a solution of 2.40 g. of l-ethoxycarbonylindolizidine in 20 ml. of absolute ;~
ether under ice cooling. After refluxing for about 10 mins., water was dropwise added thereto, followed by extrackion with ether. The ethereal layer was further extracted with dil.
hydrochloric acid. The aqueous layer was rendered alkaline with an aq. sodium hydroxide solution and then extracted with ether. The ethereal layer was washed with water and dried.
After removiny the solvenk by distillation, 3.5~ g. of light yellow viscous substance was obtained.
Mass spectrum (C21~25NO) m/e : 307 (M ~), 230, 123 ~basic peak) The product was a mixture of two diastereoisomers and 1 used for the reac-tion above as i-t was.
e 14 In a manner similar to Example 6 i), the following compounds were prepared:
i) l-Diphenylmethyleneindolizidine Methyl Bromide:
Colourless, plate-like crystals having a melting ~ -poin~ of 210 to 211C. (from ethanol-acetone) NMR (CDCl3) ~ : 3-49 (N ~ - CH3) Elemental Analysis: C22H26NBr ~;
C H N `
calcd. 68.75 6.82 3.64 found 68.56 6.85 3.51 ii) l-Diphenylmethyleneindolizidine Methyl Iodide:
Melting point: 189 to 190C. (colourless needles) iii) l-Diphenylmethyleneindolizidine Ethyl Bromide:
Melting point: 163 to 164C. (colourless plate-like crystals) Example 15 2-Dlphenylmethyleneindolizidine:
This compouna was prepared in a manner similar to Example 5.
Melting point: 76 to 79C. (from n-hexane, colourless needles) Elemental Analysis: C21H23N
C H N
calcd. 87.15 8.014.84 found 87.08 8.144.76 Example 16 ln a manner similar to Example 6 i), the following compounds were prepared:
9~ :
i i) 2-Diphenylmethyleneindolizidine Methyl Iodide:
Melting point: 242 to 244C. (from methanol-acetone, colourless needles) Elemental Analysis: C22H26NI
C H N
calcd. 61.26 6.08 3.25 found 61.00 6.15 3.13 ii) 2-Diphenylmethyleneindolizidine Methyl Bromide~
::
Melting point: 267 to 269C. (from methanol-acetone, decompd.) NMR (CDC13)~ : 3-08 (M~ -CH3) Elemental Analysis: C22H26~Br C H M
calcd. 68~75 6.82 3.64 found 68.57 6.82 3.53 ~Example 17 -2-(Dithien-2-ylmethylene)indolizidine:
To 2.66 g. of ~ (dithien-2-yl)indolizidine-2-methanol was added 20 ml. of ethanolic hydrochloric acid. The mixture was st1rred for 1.5 hrs. with heating at 60C. Water was .
added to the resldue obtained ater removing ethanol by , distillation to dissolve. Thereafter, the solution was rendered alkaline with a 10% aq. sodium hydroxide solution and then extracted with ether. The ethereal layer was washed with water and dried. The residue remained after removing the solvent by distillation was distilled -to obtain 1.76 g. of ~ .
yellow liquid showing a boiling point of 195 to 197C. (3mmHg).
In accordance with a conven-tional manner, the product was converted into the hydrochloride. By recrystallization from 3 isopropanol, yellow prisms having a melting point of 197 to 7~
., :
1 200C. (decompd.) were obtained.
Elemental Analysis: C17lll9NS2 . HCl C H N
calcd. 60.42 5.97 4.14 found 60.17 6.12 3.87 Example 18 In a manner similar to E~ample 2, the following compounds were prepared:
) 2-(Dithien-2 ylmethylene)indolizidine Methyl Iodide:
Meltlng point: 222 to 225C. (from isopropanol, colourless ;~
to llght brown prlsms) Elemental AnalyslS: Cl8H22INS2 C H N
calcd. 48.76 5.00 3.16 found 48.60 5.04 2.85 il) 2-(Dithien~2-ylm thylene)indolizldine Methyl Bromlde:
Melting point: 200 to 202C. (from isopropanol) ~ NMR (CDCl3) ~ : 3-49 (N~ -CH3) `~ Elemental Analysis: C]8H22BrNS2 1/5 H20 C H N
calcd. 54.05 5.64 3.50 found 54.02 5.59 3.24 iii) 2-(Dithien-2-ylmethylene)indolizidine Et_yl Bromide:
Melting point: 212 to 214C. (from isopropanol-acetone) l AnalySiS: ClgH24BrNS2 C H N
calcd. 55.60 5.89 3.41 found 55.33 5.91 3.16 - 18 ~
Claims (42)
OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of a substituted quinolizidine or indolizidine derivative represented by the following formula:
wherein A1 and A2 are both phenyl or both 2-thienyl and n represents 3 or 4 and the pharmaceutically acceptable acid addition and quarternary salts thereof, comprising dehydrating a compound of the formula:
wherein A1 and A2 and n are as defined, optionally followed by reacting with a pharmaceutically acceptable inorganic or organic acid or a quarternary agent of the formula R-X, where R
is lower alkyl and X is an acid residue
wherein A1 and A2 are both phenyl or both 2-thienyl and n represents 3 or 4 and the pharmaceutically acceptable acid addition and quarternary salts thereof, comprising dehydrating a compound of the formula:
wherein A1 and A2 and n are as defined, optionally followed by reacting with a pharmaceutically acceptable inorganic or organic acid or a quarternary agent of the formula R-X, where R
is lower alkyl and X is an acid residue
2. A process of claim 1, wherein n is 3.
3. A process of claim 1, wherein n is 4.
4. A process of claim 3 for the preparation of 1-diphenymethylenequinolizidine, wherein A1 and A2 are both phenyl.
5. A process of claim 3 for the preparation of 2-diphenylmethylenequinolizidine, wherein A1 and A2 are both phenyl.
6. A process of claim 3 for the preparation of 3-diphenylmethylenequinolizidine, wherein A1 and A2 are both phenyl.
7. A process of claim 3 for the preparation of 1-diphenylmethylenequinolidizine methyl bromide, wherein A1 and A2 are both phenyl and R is methyl and X is a bromine atom.
8. A process of claim 3 for the preparation of 2-diphenylmethylenequinolizidine methyl bromide, wherein A1 and A2 are both phenyl and R is methyl and X is a bromine atom.
9. A process of claim 3 for the preparation of 3-diphenylmethylenequinolizidine methyl bromide, wherein A1 and A2 are both phenyl and R is methyl and X is a bromine atom.
10. A process of claim 3 for the preparation of 1-(dithien-2-ylmethylene)quinolizidine, wherein A1 and A2 are 2-thienyl.
11. A process of claim 3 for the preparation of 2-(dithien-2-ylmethylene)quinolizidine, wherein A1 and A2 are 2-thienyl.
12. A process of claim 3 for the preparation of 3-(dithien-2-ylmethylene)quinolizidine, wherein A1 and A2 are 2-thienyl.
13. A process of claim 3 for the preparation of 1-(dithien-2-ylmethylene)quinolizidine methyl bromide, wherein A1 and A2 are 2-thienyl and R is methyl and X is a bromine atom.
14. A process of claim 3 for the preparation of 2-(dithien-2-ylmethylene)quinolizidine methyl bromide, wherein A1 and A2 are 2-thienyl and R is methyl and X is a bromine atom.
15. A process of claim 3 for the preparation of 3-(dithien-2-ylmethylene)quinolizidine methyl bromide, wherein A1 and A2 are 2-thienyl and R is methyl and X is a bromine atom.
16. A process of claim 2 for the prepartion of 1-diphenylmethyleneindolizidine, wherein A1 and A2 are phenyl.
17. A process of claim 2 for the preparation of 2-diphenylmethyleneindolizidine, wherein A1 and A2 are phenyl.
18. A process of claim 2 for the preparation of 1-diphenylmethyleneindolizidine methyl bromide, wherein A1 and A2 are phenyl and R is methyl and X is a bromine atom.
19. A process of claim 2 for the preparation of 2-diphenylmethyleneindolizidine methyl bromide, wherein A1 and A2 are phenyl and R is methyl and X is a bromine atom.
21 A process of claim 2 for the preparation of 2-(dithien-2-ylmethylene)indolizidine, wherein A1 and A2 are 2-thienyl.
21. A process of calim 2 for the preparation of 2-(dithien-2-ylmethylene)indolizidine methyl bromide, wherein A1 and A2 are 2-thienyl and R is methyl and X is a bromine atom.
22. A substituted quinolizidine or indolizidine derivative represented by the formula:
wherein A1 and A2 are both phenyl or both 2-thienyl and n represents 3 or 4, and a pharmaceutically acceptable acid addition or quarternary salt thereof, when prepared by the process of claim 1.
wherein A1 and A2 are both phenyl or both 2-thienyl and n represents 3 or 4, and a pharmaceutically acceptable acid addition or quarternary salt thereof, when prepared by the process of claim 1.
23. A compound according to claim 22, wherein n is 3 when prepared by the process of claim 2.
24. A compound according to claim 22, wherein n is 4, when prepared by the process of claim 3.
25. 1-Diphenylmethylenequinolizidine, when prepared by the process of claim 4.
26. 2-Diphenylmethylenequinolizidine, when prepared by the process of claim 5.
27. 3-Diphenylmethylenequinolizidine, when prepared by the process of claim 6.
28. 1-Diphenylmethylenequinolizidine methyl bromide, when prepared by the process of claim 7
29. 2-Diphenylmethylenequinolizidine methyl bromide, when prepared by the process of claim 8.
30. 3-Diphenylmethylenequinolizidine methyl bromide, when prepared by the process of claim 9.
31. 1-(Dithien-2-ylmethylene)quinolizidine, when prepared by the process of claim 10.
32. 2-(Dithien-2-ylmethylene)quinolizidine, when prepared by the process of claim 11.
33. 3-(Dithien-2-ylmethylene)quinolizidine, when prepared by the process of claim 12.
34. 1-(Dithien-2-ylmethylene)quinolizidine methyl bromide, when prepared by the process of claim 13.
35. 2-(Dithien-2-ylmethylene)quinolizidine methyl bromide when prepared by the process of claim 14.
36. 3-(Dithien-2-ylmethylene)quinolizidine methyl bromide, when prepared by the process of claim 15.
37. 1-Diphenylmethyleneindolizidine, when prepared by the process of claim 16.
38. 2-Diphenylmethyleneindolizidine, when prepared by the process of claim 17.
39. 1-Diphenylmethyleneindolizidine methyl bromide, when prepared by the process of claim 18.
40. 2-Diphenylmethyleneindolizidine methyl bromide, when prepared by the process of claim 19.
41. 2-(Dithien-2-ylmethylene)indolizidine, when prepared by the process of claim 20.
42. 2-(Dithien-2-ylmethylene)indolizidine, when prepared by the process of claim 21.
Applications Claiming Priority (12)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP5526677A JPS53141294A (en) | 1977-05-16 | 1977-05-16 | 22diphenylmethylenequinolitidine and process for preparing same |
| JPSHO52-55266 | 1977-05-16 | ||
| JPSHO52-107270 | 1977-09-08 | ||
| JP10727077A JPS5441892A (en) | 1977-09-08 | 1977-09-08 | Quaternary salt derivative |
| JP13352677A JPS5467020A (en) | 1977-11-09 | 1977-11-09 | 33diphenylmethylenquinolysine quarternary salt derivative |
| JPSHO52-133526 | 1977-11-09 | ||
| JP14661377A JPS5481297A (en) | 1977-12-08 | 1977-12-08 | 11diphenylmethylene quinolitidine tertiary salt derivative |
| JPSHO52-146613 | 1977-12-12 | ||
| JPSHO52-152841 | 1977-12-21 | ||
| JP15284177A JPS5488293A (en) | 1977-12-21 | 1977-12-21 | Quaternary salt derivative |
| JPSHO53-21534 | 1978-02-28 | ||
| JP2153478A JPS54115396A (en) | 1978-02-28 | 1978-02-28 | 22dithienylmethylene quinolitidine quaternary salt derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1100970A true CA1100970A (en) | 1981-05-12 |
Family
ID=27548989
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA302,858A Expired CA1100970A (en) | 1977-05-16 | 1978-05-08 | Substituted quinolizidine-and indolizidine- derivatives and process for preparation thereof |
Country Status (24)
| Country | Link |
|---|---|
| AR (1) | AR223814A1 (en) |
| AT (1) | AT364362B (en) |
| BE (1) | BE866988A (en) |
| BG (1) | BG30018A3 (en) |
| CA (1) | CA1100970A (en) |
| CH (1) | CH635341A5 (en) |
| CS (1) | CS211388B2 (en) |
| DD (1) | DD142447A5 (en) |
| DE (1) | DE2820687C2 (en) |
| DK (1) | DK211278A (en) |
| FI (1) | FI64368C (en) |
| FR (1) | FR2390956A1 (en) |
| GB (1) | GB1602927A (en) |
| GR (1) | GR64422B (en) |
| HU (1) | HU181441B (en) |
| IT (1) | IT1113139B (en) |
| NL (1) | NL186006C (en) |
| NO (1) | NO149432C (en) |
| NZ (1) | NZ187258A (en) |
| PL (1) | PL115343B1 (en) |
| PT (1) | PT68009B (en) |
| SE (1) | SE443787B (en) |
| SU (1) | SU953980A3 (en) |
| YU (1) | YU40705B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1994013289A1 (en) * | 1992-12-10 | 1994-06-23 | Tsentr Po Khimii Lekarstvennykh Sredstv | Pharmaceutical compound with anti-ulcer properties |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4089961A (en) * | 1976-11-08 | 1978-05-16 | Smithkline Corporation | Antipsychotically useful quinolizidylidene derivatives of xanthenes, thioxanthenes and dibenzoxepins |
-
1978
- 1978-04-24 BG BG7839520A patent/BG30018A3/en unknown
- 1978-05-03 IT IT7822967A patent/IT1113139B/en active
- 1978-05-08 PT PT68009A patent/PT68009B/en unknown
- 1978-05-08 GR GR56170A patent/GR64422B/en unknown
- 1978-05-08 CA CA302,858A patent/CA1100970A/en not_active Expired
- 1978-05-11 FR FR7814002A patent/FR2390956A1/en active Granted
- 1978-05-11 AT AT0342378A patent/AT364362B/en not_active IP Right Cessation
- 1978-05-11 CS CS783027A patent/CS211388B2/en unknown
- 1978-05-11 DE DE2820687A patent/DE2820687C2/en not_active Expired
- 1978-05-12 NO NO781693A patent/NO149432C/en unknown
- 1978-05-12 SU SU782616071A patent/SU953980A3/en active
- 1978-05-12 DK DK211278A patent/DK211278A/en not_active Application Discontinuation
- 1978-05-12 BE BE2056968A patent/BE866988A/en not_active IP Right Cessation
- 1978-05-12 DD DD78205365A patent/DD142447A5/en unknown
- 1978-05-12 SE SE7805513A patent/SE443787B/en not_active IP Right Cessation
- 1978-05-12 NZ NZ187258A patent/NZ187258A/en unknown
- 1978-05-15 PL PL1978206809A patent/PL115343B1/en unknown
- 1978-05-15 FI FI781525A patent/FI64368C/en not_active IP Right Cessation
- 1978-05-16 YU YU1177/78A patent/YU40705B/en unknown
- 1978-05-16 CH CH528678A patent/CH635341A5/en not_active IP Right Cessation
- 1978-05-16 NL NLAANVRAGE7805272,A patent/NL186006C/en not_active IP Right Cessation
- 1978-05-16 AR AR272202A patent/AR223814A1/en active
- 1978-05-16 GB GB17814/78A patent/GB1602927A/en not_active Expired
- 1978-05-16 HU HU78HO2074A patent/HU181441B/en not_active IP Right Cessation
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