GB1602927A - Substituted quinolizidine and indolizidine derivatives and the preparation thereof - Google Patents
Substituted quinolizidine and indolizidine derivatives and the preparation thereof Download PDFInfo
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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
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- 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
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- 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
Novel substituted quinolizidine and indolizidine derivatives of the general formula: <IMAGE> where A denotes a phenyl or 2-thienyl group and n denotes an integer of 3 or 4, and their acid addition salts and quaternary salts which have a strong antiacetylcholinergic action coupled with decreased side effects and can be prepared by dehydration of a compound of the general formula: <IMAGE> where A and n have the abovementioned meanings, and if appropriate by reaction of the resulting compounds with the appropriate acid or quaternising agent.
Description
(54) SUBSTITUTED QUINOLIZIDINE AND
INDOLIZIDINE DERIVATIVES AND THE
PREPARATION THEREOF
(71) We, HOKURIKU PHARMACEUTICAL CO. LTD., a Company
organised and existing under the laws of Japan, of l-chome 3-14 Tatekawacho
Katsuyamashi, Fukui/Japan, do hereby declare the invention, for which we pray
that a patent may be granted to us, and the method by which it is to be performed,
to be particularly described in and by the following statement:- The present invention relates to substituted quinolizidine and indolizidine
derivatives having anticholinergic, antihistamic, antitussive and analgetic activities,
and to a process for producing the same, and to therapeutic agents containing the
same.
Atropine exhibits strong antiacetylcholinergic activity and has been employed
as a spasmolytic agent for a long time. However, clinical use of atropine has been
limited because side effects such as thirst, dilation of the pupils, and increase in
blood pressure are noted. Therefore, conventional synthetic spasmolytic agents
such as diphemanilmethyl sulfate (see, U.S. Patent 2,739,969, Merck Index, 9th
Edition, page 3309), prifinium bromide (see, Merck Index, 9th Edition, page 7540),
timepidium bromide (see, J. Med. Chem. 15 914 (1972)) have been proposed and employed. These compounds, however, are not satisfactory because their strong anticholinergic activity is necessarily accompanied by strong side effects.
The present invention provides substituted quinolizidine and indolizidine derivatives having the following formula:
wherein A represents a phenyl group or a 2-thienyl group and n is an integer of 3 or 4, and pharmaceutically acceptable acid addition and quaternary salts thereof, these can exhibit anti-cholinergic activity with low side effects.
The present invention also provides a process for producing a derivative represented by the formula (I) or a pharmaceutically acceptable salt thereof which comprises dehydrating a compound represented by the formula (II):
wherein A and n have the same meanings as above, optionally followed by reacting the resulting compound with an inorganic or organic acid or a quaternizing agent which forms therewith a pharmaceutically acceptable salt. Some of the raw materials represented by the formula (II) can be prepared by conventional 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) can be performed by in a solvent in the presence of a dehydrating agent at temperatures between about 20 to about 1500C, preferably 50 to 1000C, more preferably at the boiling point of the solvent used. Any of a variety of solvents such as water, methanol, ethanol, benzene and toluene can be employed provided that they do not inhibit the dehydration. Typical examples of dehydrating agents include hydrochloric acid, sulfuric acid, phosphorus oxychloride, and p-toluenesulfonic acid.
The thus obtained compounds represented by the formula (I) can be converted into the corresponding pharmaceutically acceptable acid addition salts with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, oxalic acid, maleic acid, fumaric acid, and citric acid.
Quaternary salts of the compounds of the formula (I) represented by the formula (III):
wherein R is a C to C, alkyl group and X is an acid residue can be prepared by reacting compounds represented by the formula (I) with compounds represented by the formula (IV): R-X (IV) wherein R and X have the same meanings as defined above.
Specific examples of alkyl groups for the R include methyl, ethyl, propyl and butyl. Specific examples of acid residues are a chlorine atom, a bromine atom, an iodine atom, a sulfuric acid residue, and an alkyl sulfate residue.
The aforementioned quaternizing reaction can be performed in the presence or absence of solvents. Typical examples of solvents to be employed are ether, acetone, and alcohols such as methanol or ethanol. This reaction proceeds at temperatures between 5 and 1000C., preferably 10 and 40"C., more preferably room temperature (ca. 20"C), if necessary in a sealed tube.
The quaternary salts of the formula (III) include steric isomers (trans- and cis isomers), and they can be obtained as mixtures or pure isomers after recrystallization. Both isomers exhibit almost the same pharmacological activities.
The compounds of the present invention represented by the formula (I) and acid addition and quaternary salts thereof can exhibit strong spasmolytic, antihistamic, antitussive and analgetic activities. In particular, the quaternary salts can have strong anticholinergic and anti-ulcer activities but have reduced side effects such as thirst and dilation of the pupils.
The results of pharmacological tests on compounds of the present invention are shown below.
Test Method
The EDso values of these compounds for protective activity against spasm induced by acetylcholine (1x10-7 g/ml) were measured using isolated ileum of guinea pigs accorbing to the Magnus method, and the relative potency was thus derived, taking the EDso of atropine as 1.0.
Relative
Compounds: Potency 2-Diphenylmethylenequinolizidine methyl bromide
(Compound of Example 2 ii)) 1.12 3-Diphenylmethylenequinolizidine methyl bromide
(Compound of Example 4 ii)) 0.58 3-Diphenylmethylenequinolizidine ethyl bromide
(Compound of Example 4 iii) 0.45 2-(Dithien-2-ylmethylene)quinolizidine methyl bromide
(Compound of Example 10 i)) 1.16 3-(Dithien-2-ylmethylene)quinolizidine methyl bromide
(Compound of Example 12 ii)) 0.86
Atropine 1.0
Scopolamin n-butyl bromide 0.02
Diphemanil methyl sulfate 0.11
Timepidium bromide 0.15
As can be seen from the results shown in the table above, the compounds of the present invention had stronger anticholinergic activity than scopolamine nbutylbromide, diphemanil methyl sulfate or timepidium bromide.
In addition, the compounds of the present invention can have little side effects such as thirst and dilation of the pupils, and can therefore be effective as spasmolytic and anti-ulcer agents for clinical use as compared to atropin. For clinical use, these compounds can be employed in a dosage of 1 to 100 mg., preferably 3 to 30 mg., and administered three times a day orally; or they can be parenterally administered in the corresponding dosage.
The invention also provides a spasmolytic, antihistamic, antitussive or analgetic agent including as an active component a compound according to the invention.
The present invention will be explained hereafter in more detail with reference to the Examples below.
Example 1
2-Diphenylmethylenequinolizidine Hydrochloride
To 1.39 g of cy,cr - diphenylquinolizidine - 2 - methanol was added 10 ml of ethanolic hydrochloride. The resulting mixture was refluxed for 4 hrs with stirring.
The residue remaining after the removal of the ethanol by distillation was dissolved in water. The solution was rendered alkaline with a potassium carbonate solution and extracted with chloroform. The chloroform layer was washed with water and dried. After the solvent was removed by distillation, light yellow liquid was obtained. The product was converted into the hydrochloride in a conventional manner. By recrystallization from acetone-ether, 0.47 g of colorless needle 2 diphenylmethylenequinolizidine hydrochloride showing a melting point of 233 235"C was obtained.
Elemental Analysis: C22H25N HCI calcd. C, 77.74; H, 7.71; N, 4.12
found C, 77.48; H, 7.59; N, 3.78
Example 2 i) 2-(Diphenylmethylene)quinolizidine Methyl Iodide
In 10 ml of acetone was dissolved 0.1 g of 2 - diphenylmethylenequinolizidine.
After 1.0 ml of methyl iodide was added to the resulting solution, the mixture was stirred for 24 hrs at room temperature. The crystals precipitated were taken out by filtration. By recrystallization from methanol, 0.1 g of colorless needles showing a melting point of 280--282"C (decompd.) were obtained.
Elemental Analysis: C23H2E,NI calcd. C, 62.03; H, 6.34; N, 3.14
found C, 61.97; H, 6.43; N, 3.13 ii) 2-(Diphenylmethylene)quinolizidine Methyl Bromide
a) In 50 ml of acetone was dissolved 5.5 g of 2 diphenylmethylenequinolizidine. After 5 ml of methyl bromide was added to the solution, the mixture was allowed to stand for 48 hrs at room temperature in a sealed tube. After the completion of the reaction, the residue obtained by removing the solvent by distillation was recrystallized from methanol-acetone to obtain 5.34 g of colorless prism crystals showing a melting point of 261--263"C (decompd.).
NMR (CDCl3) : 3.33 (N±CH3) Elemental Analysis: C23H28NBr
calcd. C, 69.34 H, 7.08; N, 3.52
found C, 69.08; H, 7.16; N, 3.26
b) The rresidue obtained by distilling the thus obtained mother liquor of the recrystallization above to dryness under reduced pressure was recrystallized from methanol-acetone, which procedure was repeated twice to obtain the mother liquors. The combined mother liquors were distilled to dryness under reduced pressure. The resulting residue was recrystallized from methanol-acetone to give 1.12 g of colorless prism crystals showing a melting point of 235--236"C.
NMR (CDCl3) : 3.67 (N±CH3) iii) 2-(Diphenylmethylene)quinolizidine Ethyl Bromide:
This compound was prepared in a manner similar to the above.
Melting point: 233 -234"C. (from acetone)
Elemental Analysis: C24H3NBr calcd. C, 69.90; H, 7.33; N, 3.40
found 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,a diphenylquinolizidine - 3 - methanol at 90 to 950C 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 colorless needles showing a melting point of 118 to 120"C.
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, colorless plate-like crystals having a melting point of 225 to 2280C were obtained.
b) a,a - Diphenylquinolizidine - 3 - methanol employed as a starting material was prepared in accordance with the following method:
To a solution of phenyl lithium, which had been prepared by the reaction of 1.23 g of lithium and 16.80 g of bromobenzene, in 50 ml of absolute ether was dropwise added a solution of 120 g of 3 - benzoylquinolizidine in absolute ether.
The mixture 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, a,a - diphenylquinolizidine - 3 - methanol showing a melting point of 166 to 1670C 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 obtained after removing the solvent by distillation was recrystallized from methanol-acetone.
Melting point: 221--224"C (colorless prisms)
Elemental 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 pont: 259--261"C (decompd., colorless needles)
NMR (CDCl3) : 2.97 (N±CH3) Elemental Analysis: C23H28NBr
C H N
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).
Colorless crystals having a melting point of 256 to 2590C (from methanolether)
NMR (CDCl3) o: 3.40 (N±CH3) Elemental Analysis: C23H28NBr
C H N
calcd. 69.34 7.08 3.52
found 69.06 7.20 3.48 iii) 3-Diphenylmethylenequinolizidine Ethyl Bromide:
This compound was prepared in a manner similar to Example 2 ii) a).
Melting point: 225--228"C (from acetone)
Elemental Analysis: C24H30NBr
C H N
calcd. 69.90 7.33 3.40
found 69.87 7.36 3.27
Example 5 1 -Diphenylmethylenequinolizidine Sulfate
3.5 g of ez, - Diphenylmethylenequinolizidine - 1 - methanol was heated together with 35 ml of 60% sulfuric acid at about 100 C 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. The residue (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, colorless needle crystals having a melting point of 219 to 2210C were obtained.
Elemental Analysis: C22H2sN H2SO4
C H N
calcd. 65.81 6.78 3.49
found 65.78 6.92 3.24
Example 6 i) 1 -Diphenylmethylenequinolizidine Methyl Iodide:
In 20 ml of acetone was dissolved 0.5 g of 1 - Diphenylmethylenequinolizidine.
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. By recrystallization of the obtained crystals (0.53 g) from methanol, colorless plate-like crystals having a melting point of 294 to 2960C (decompd.) were obtained.
Elemental Analysis: C23H28NI
C H N
calcd. 62.03 6.34 3.14
found 61.92 6.41 2.82 ii) 1 -Diphenylmethylenequinolizidine Methyl Bromide:
This compound was prepared in accordance with procedures similar to i) above.
Melting point: > 300"C (from ethanol)
NMR (CDCl3) a: 3.19 (N±CH3) Elemental Analysis: C23H28NBr C H N
calcd. 69.34 7.08 3.52
found 69.29 7.19 3.27 iii) 1 -Diphenylmethylenequinolizidine Ethyl Bromide
This compound was prepared in a manner similar to i) above.
Melting point: > 3000C (from ethanol)
Elemental Analysis: C24H3ONBr- t/2 H2O
C H N
calcd. 68.40 7.41 3.32
found 68.61 7.31 3.24
Example 7 I-(Dithien-2-ylmethylene)quinolizidine Hydrochloride:
To 1.40 g of cr - (dithien - 2 - yl)quinolizidine - 1 - methanol was added 15 ml of ethanolic hydrochloric acid. The mixture was stirred for 1 hr at 600 C. 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 hydrochloride showing a melting point of 194 to 1970C was obtained.
Elemental Analysis: C,8H21NS2 - HCI C H N
calcd. 61.43 6.30 3.98 found 61.13 6.64 3.84
Example 8 i) I-(Dithien-2-ylmethylene)quinolizidine Methyl Iodide:
This 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 2850C (decompd., from isopropanol)
Elemental Analysis: C'gH24INS2 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) I-(Dithien-2-ylmethylene)quinolizidine Methyl Bromide:
Melting point: 29W297 C (from ethanol-isopropyl ether, decompd.)
MNR (CDCl3) a: 3.36 (N±CH3) Elemental Analysis: C19H24Br NS2
C H N
calcd. 55.60 5.89 3.41
found 55.18 6.11 3.51 iii) I-(Dithien-2-ylmethylene)quinolizidine Ethyl Bromide:
Melting point: 286--288"C (from ethanol-isopropyl ether, decompd.)
Elemental Analysis: C20H26Br NS2
C H N
calcd. 56.59 6.17 3.30
found 56.79 6.54 3.13
Example 9
2-(Dithien-2-ylmethylene)quinolizidine:
This compound was prepared from a, - (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.
Colorless crystals having a melting point of 88 to 900C (from isopropyl ether)
Elemental Analysis: C,8H2lNS2 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:
Colorless crystals having a melting point of 246 to 2480C (from ethanol, decompd.).
NMR (CDCl3) b: 3.42 (N±CH3) Elemental Analysis: C19H24Br NS2
C H N
calcd. 55.60 5.89 3.41
found 55.31 5.88 3.10 ii) 2-(Dithien-2-ylmethylene)quinolizidine Ethyl Bromide:
This compound was prepared in a manner similar to Example 2 ii) a) except that the reaction mixture was heated to 50"C.
Colorless crystals having a melting point of 217 to 2180C (from isopropanol)
Elemental Analysis: C20H2eBr NS2
C H N
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.
Colorless needles having a melting point of 128 to 1300C (from isopropyl ether)
Elemental Analysis: Cl8H21NS2 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 following compounds were prepared: i) 3-(Dithien-2-ylmethylene)quinolizidine Methyl Iodide:
Melting point: 223 to 2240C (from ethanol)
Elemental Analysis: C19H24INS2
C H N
calcd. 49.89 5.29 3.06
found 49.66 5.35 2.72 ii) 3-(Dithien-2-ylmethylene)quinolizidine Methyl Bromide:
Melting point: 278 to 2800C (from ethanol: decompd.)
NMR (CDCl3) 8: 2.92 (N±CH3) Elemental Analysis: C19H24BrNS2
C H N
calcd. 55.60 5.89 3.41
found 55.78 5.89 3.37 iii) 3-(Dithien-2-ylmethylene)quinolizidine Ethyl Bromide
Melting point: 226 to 2280C (from isopropanol-acetone; decompd.)
Elemental Analysis: C20H26Br NS2. 1/5 H2O
C H N
calcd. 56.12 6.22 3.27
found 56.13 6.18 3.04
Example 13
1 -Diphenylmethyleneindolizidine
This compound was prepared from a,a - diphenylindolizidine - 1 - methanol in a manner similar to Example 5.
Yellow viscous substance
Mass spectrum (C2tH23N): m/e: 289 (my), 212 a,a - Diphenylindolizidine - 1 - methanol employed as a starting material was prepared as follows:
To a phenyl lithium solution prepared by dissolving 0.51 g of metallic lithium and 6.32 g of bromobenzene in 50 ml of absolute ether, was dropwise added a solution of 2.40 g of 1 - ethoxycarbonylindolizidine in 20 ml of absolute ether under ice cooling. After refluxing for about 10 mins. water was dropwise added thereto, followed by extraction 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 removing the solvent by distillation, 3.58 g of light yellow viscous substance was obtained.
Mass spectrum (C2,H25NQ) m/e: 307 (M+), 230, 123 (basic peak)
The product was a mixture of two diastereoisomers and used for the reaction above as it was.
Example 14
In a manner similar to Example 6 i), the following compounds were prepared: i) I-Diphenylmethyleneindolizidine Methyl Bromide:
Colorless, plate-like crystals having a melting point of 210 to 211"C (from ethanol-acetone)
NMR (CDCl3) b: 3.49 (N±CH3) Elemental Analysis: C22H25NBr C 'H N
calcd. 68.75 6.82 3.64
found 68.56 6.85 3.51 ii) I -Diphenylmethyleneindolizidine Methyl Iodide:
Melting point: 189 to 1900C (colorless needles) iii) 1 -Diphenylmethyleneindolizidine Ethyl Bromide:
Melting point: 163 to 1640C (colorless plate-like crystals)
Example 15
2-Diphenylmethyleneindolizidine:
This compound was prepared in a manner similar to Example 5.
Melting point: 76 to 790C (from n-hexane, colorless needles)
Elemental Analysis: C2,H23N
C H N
calcd. 87.15 8.01 4.84
found 87.08 8.14 4.76
Example 16
In a manner similar to Example 6 i), the following compounds were prepared: i) 2-Diphenylmethyleneindolizidine Methyl Iodide:
Melting point: 242 to 2440C (from methanol-acetone, colorless 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 269"C (from methanol-acetone, decompd.)
NMR (CDCl3) b: 3.08 (N±CH3) Elemental Analysis: C22H2aNBr C H N
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 a,a - (dithien - 2 - yl)indolizidine - 2 - methanol was added 20 ml of ethanolic hydrochloric acid. The mixture was stirred for 1.5 hrs. with heating at 60"C. Water was added to the residue obtained after 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 remaining after removing the solvent by distillation was distilled to obtain 1.76 g of yellow liquid showing a boiling point of 195 to 1970C (3 mmHg). In conventional manner, the product was converted into the hydrochloride. By recrystallization from isopropanol, yellow prisms having a melting point of 197 to 2000C (decompd.) were obtained.
Elemental Analysis: C17H19NS2. HCI C H N
calcd. 60.42 5.97 4.14
found 60.17 6.12 3.87
Example 18
In a manner similar to Example 2, the following compounds were prepared: i) 2-(Dithien-2-ylmethylene)indolizidine Methyl Iodide:
Melting point: 222 to 2250C (from isopropanol, colorless to light brown prisms)
Elemental Analysis: C,8H22INS2
C H N
calcd. 48.76 5.00 3.16
found 48.60 5.04 2.85 ii) 2-(Dithien-2-ylmethylene)indolizidine Methyl Bromide:
Melting point: 200 to 202"C (from isopropanol)
NMR (CDCl3) : 3.49 (N±CH3) Elemental Analysis: C,8H22BrNS2- 1/5 H2O C H N
calcd. 54.05 5.64 3.50
found 54.02 5.59 3.24 iii) 2-(Dithien-2-ylmethylene)indolizidine Ethyl Bromide:
Melting point: 212 to 2140C (from isopropanol-acetone)
Elemental Analysis: C,9H24BrNS2 C H N
calcd. 55.60 5.89 3.41
found 5533 5.91 3 16
Other compounds according to the invention include 3
Diphenylmethyleneindolizidine and 3- Diphenylmethyleneindolizidine methyl bromide.
WHAT WE CLAIM IS:
1. A substituted quinolizidine- or indolizidine derivative represented by the formula:
wherein A represents a phenyl or 2-thienyl group and n represents 3 or 4, or a pharmaceutically acceptable acid addition or quaternary salt thereof.
2. A substituted indolizidine derivative as claimed in Claim 1.
3. A substituted uinolizidine derivative as claimed in Claim 1.
4. I-Diphenylmethylenequinolizidine.
5. 2-Diphenylmethylenequinolizidine.
6. 3-Diphenylmethylenequinolizidine.
7. I-Diphenylmethylenequinolizidine methyl bromide.
8. 2-Diphenylmethylenequinolizidine methyl bromide.
9. 3-Diphenylmethylenequinolizidine methyl bromide.
10. 1-(Dithien-2-ylmethylene)quinolizidine.
11. 2-(Dithien-2-ylmethylene)quinolizidine.
12. 3-(Dithien-2-ylmethylene)quinolizidine.
13. 1-(Dithien-2-ylmethylene)quinolizidine methyl bromide.
14. 2-(Dithien-2-ylmethylene)quinolizidine methyl bromide.
15. 3-(Dithien-2-ylmethylene)quinolizidine methyl bromide.
16. 1 -Diphenylmethyleneindolizidine.
17. 2-Diphenylmethyleneindolizidine.
18. 3-Diphenylmethyleneindolizidine.
19. 1 -Diphenylmethyleneindolizidine methyl bromide.
20. 2-Diphenylmethyleneindolizidine methyl bromide.
21. 3-Diphenylmethyleneindolizidine methyl bromide.
22. 2-(Dithien-2-ylmethylene)indolizidine.
23. 2-(Dithien-2-ylmethylene)indolizidine methyl bromide.
24. A process for producing a compound according to Claim I which comprises dehydrating a compound represented by the formula:
wherein A and n have the same meanings as defined above, and optionally reacting the product with an inorganic or organic acid or a quaternizing agent which forms therewith, a pharmaceutically acceptable salt.
25. A substituted quinolizidine- or indolizidine derivative according to Claim I and substantially as hereinbefore described in any one of the Examples.
26. A dehydration process according to Claim 24 and substantially as hereinbefore described in any one of the Examples.
27. A spasmolytic, antihistamic, antitussive or analgetic agent including as an active component a compound according to any of Claims I to 23 and 25.
28. A pharmaceutically acceptable acid addition salt of a compound according
Claims (1)
- to Claim 5.29. A pharmaceutically acceptable CX to C6 alkyl quaternary salt of a compound according to Claim 6.30. A methyl iodide salt according to Claim 29 31 A pharmaceutically acceptable C, to C6 alkyl quaternary salt of a compound according to Claim 4.32. A pharmaceutically acceptable C1 to t 6 alkyl quaternary salt of a compound according to Claim 5.33. A C, to C6 alkyl quaternary salt according to Claim 1 wherein n is 3 and A is a 2-thienyl group.34. A C, to C6 alkyl quaternary salt according to Claim I wherein n is 4 and A is a 2-thienyl group.35. A process for preparing a compound according to Claim 5 or 28 which comprises dehydrating a,cr - diphenylquinolizidine - 2 - methanol and optionally reacting the product with an acid which forms therewith a pharmaceutically acceptable acid addition salt.
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP5526677A JPS53141294A (en) | 1977-05-16 | 1977-05-16 | 22diphenylmethylenequinolitidine and process for preparing same |
| 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 |
| JP14661377A JPS5481297A (en) | 1977-12-08 | 1977-12-08 | 11diphenylmethylene quinolitidine tertiary salt derivative |
| JP15284177A JPS5488293A (en) | 1977-12-21 | 1977-12-21 | Quaternary salt derivative |
| JP2153478A JPS54115396A (en) | 1978-02-28 | 1978-02-28 | 22dithienylmethylene quinolitidine quaternary salt derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| GB1602927A true GB1602927A (en) | 1981-11-18 |
Family
ID=27548989
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB17814/78A Expired GB1602927A (en) | 1977-05-16 | 1978-05-16 | Substituted quinolizidine and indolizidine derivatives and the 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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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PS | Patent sealed [section 19, patents act 1949] | ||
| PCNP | Patent ceased through non-payment of renewal fee |
Effective date: 19950516 |