CA1066283A - 2,5-dimethyl-thieno-(3,2-f)-morphan and intermediates - Google Patents
2,5-dimethyl-thieno-(3,2-f)-morphan and intermediatesInfo
- Publication number
- CA1066283A CA1066283A CA261,490A CA261490A CA1066283A CA 1066283 A CA1066283 A CA 1066283A CA 261490 A CA261490 A CA 261490A CA 1066283 A CA1066283 A CA 1066283A
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- Prior art keywords
- thenyl
- methyl
- dimethyl
- iii
- pyridine
- Prior art date
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-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/08—Bridged systems
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- Pain & Pain Management (AREA)
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- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pyridine Compounds (AREA)
- Saccharide Compounds (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
As novel industrial products, 2,5-dimethyl-thieno-[3,2-f]-morphan (I), 2-thienyl-(4-methyl-2-pyridyl)-ketone (II), 2-(2-thenyl)-4-methyl-pyridine (III), 2-(2-thenyl)-1,4-di-methyl-1,2,3,6-tetrahydro-pyridine (V), 2-(2-thenyl)-1,4-dimethyl-1,2,5,6-tetrahydropyridine (VI), the pharmacologically acceptable acid addition salts thereof, for example, the hydro-chlorides and 2-(2-thenyl)-1,4-dimethyl-pyridinium bromide (IV).
Their process of production. These products have good analgesic activity.
As novel industrial products, 2,5-dimethyl-thieno-[3,2-f]-morphan (I), 2-thienyl-(4-methyl-2-pyridyl)-ketone (II), 2-(2-thenyl)-4-methyl-pyridine (III), 2-(2-thenyl)-1,4-di-methyl-1,2,3,6-tetrahydro-pyridine (V), 2-(2-thenyl)-1,4-dimethyl-1,2,5,6-tetrahydropyridine (VI), the pharmacologically acceptable acid addition salts thereof, for example, the hydro-chlorides and 2-(2-thenyl)-1,4-dimethyl-pyridinium bromide (IV).
Their process of production. These products have good analgesic activity.
Description
66'~3 The present invention relates to a process for the preparation of 2,5-dimethyl-thieno-[3,2-f]-m~rphan of formula I ~ ;
below and its pharmacologically acceptable acid addition salts, for example hydrochlorides. -The process of the invention comprises starting with
below and its pharmacologically acceptable acid addition salts, for example hydrochlorides. -The process of the invention comprises starting with
2-cyano-4-methyl-pyridine of formula A, whereby via the sequence of reactions indicated hereinafter the product of formula I
is obtained. ~ ~-11 :
N S S C N S CH N
~CaN ~ ~_ Li ~ ~ ~ 2 c~3 (II) CH3 (III) CH
(A) S CH~ N : :
f ~ (VI) CHJ ~ ~ C~2 ~
H3 ~ ~ (IV~ CH3 (V) 3 The compound of formula I, indicated hereinbefore, 2-thienyl-(4-methyl-2-pyridyl)-ketone of formula II, 2-(2-thenyl)-4-methyl-pyridine of formula III, 2-(2-thenyl)-1,4-dimethyl-pyridinium bromide of formula IV, 2-(2-thenyl)-1,4-dimethyl-1,2,
is obtained. ~ ~-11 :
N S S C N S CH N
~CaN ~ ~_ Li ~ ~ ~ 2 c~3 (II) CH3 (III) CH
(A) S CH~ N : :
f ~ (VI) CHJ ~ ~ C~2 ~
H3 ~ ~ (IV~ CH3 (V) 3 The compound of formula I, indicated hereinbefore, 2-thienyl-(4-methyl-2-pyridyl)-ketone of formula II, 2-(2-thenyl)-4-methyl-pyridine of formula III, 2-(2-thenyl)-1,4-dimethyl-pyridinium bromide of formula IV, 2-(2-thenyl)-1,4-dimethyl-1,2,
3,6-tetrahydropyridine of formula V, and 2-(2-thenyl)-1,4- .
dimethyl-1,2,5,6-tetrahydropyridine of formula VI, together with ""': "' - 1- ~ .
: , .
- ~L0~6Z~33 the pharmacologically acceptable acid addition salts thereof are novel substances having an analgesic activity.
In the first part of the process 2-cyano-4-methyl-pyridine is reacted with 2-thienyl-lithium prepared just before-hand by the action of butyl-lithium on thiophene. The reaction is performed at reflux temperature in an inert atmosphere, whereby the 2-cyano-4-methyl-pyridine dissolved in an anhydrous solvent is added to the ethereal solution of 2-thienyl-lithium.
After hydrolysing the resulting mixture with hydrochloric acid and rendering it alkaline with NaOH, extraction takes place with ~n organic solvent, leading to 2-thienyl-(4-methyl-2- ~ -pyridyl) ketone (II).
.
The thus prepared ketone II is converted into 2-(2-thenyl)-4-methyl-pyridine (III) by the action of hydrazine in a strong basic medium for example, potassium hydroxide heated to reflux in a solvent with a high boiling point such as diethylene glycol. On pouring the resulting mixture over ice and extracting with ether, 2-(2-thenyl)-4-methyl-pyridine (III) ~
is obtained and from this compound the hydrochloride is prepared. ~ ;
sroadly stated, the compound o~ formula (III) is prepared by reducing 2-thienyl-(4-methyl-2-pyridyl)-ketone (II) in a basic medium in the presence of hydrazine hydrate.
In the next stage of the process, the compound of formula III is heated to reflux temperature in the presence of an excess of a methyl halide, for exemple methyl bromide, in an anhydrous solvent. 2-(2-Thenyl)-1,4-dimethyl-pyridinium bromide (IV) is precipitated from the solution: it is thereafter dis-solved in methanol, treated with sodium borohydride and heated to reflux for six hours. By diluting with water and extraction with ether a mixture of 2-(2-thenyl)1,4-dimethyl-1,2,3,6-tetra- _ ~ ".
' .' :. ,, ', ' . . ' '~ ~,,' ' .
.
6~z~3 hydropyridine (V~ and 2-(2-thenyl)-1,4-dimethyl-1,2,5,6-tetra-hydropyridine (VI) is obtained which is purified by distillation and from which the two components are separated by fractional crystallisation of their hydrochlorides.
~ ; -2a-.. ~ : ,.
.
66Z~33 In the final stage of the process of the present invention, the mixture of tetrahydropyridines V and VI is heated to 135C for 4 hours in the presence of a strong acid, for example, 48% aqueous hydrobromic acid. The mixture is -~
poured over water and is rendered alkaline with ammonium hydroxide, which after prior extraction with ether leads to 2,5-dimethyl-thieno-[3,2-f]-morphan (I) from which the hydrochloride can be obtained.
The following non limitative examples illustrate the invention.
EXAMPLE 1: Obtainina 2-thi~ 4-methyl-2-pyridyl)-ketone (II~
25.5 g of thiophene dissolved in 70 ml of anhydrous ether are introduced into a flask, followed by external cooling at between -5 and -10C. 400 ml of a 1.03 N ethereal solution of butyl lithium which has been prepared just beforehand are -added dropwise during 1-1/2 hours to the said solution under a ~-nitrogen atmosphere. Stirring takes place for 15 minutes and the mixture is permitted to reach ambient ternperature, followed by refluxing for 45 minutes. At the end of this period the reaction mixture is cooled to a temperature between -10 and -20C, followed by the dropwise addition of 24.5 g of 2-cyano-
dimethyl-1,2,5,6-tetrahydropyridine of formula VI, together with ""': "' - 1- ~ .
: , .
- ~L0~6Z~33 the pharmacologically acceptable acid addition salts thereof are novel substances having an analgesic activity.
In the first part of the process 2-cyano-4-methyl-pyridine is reacted with 2-thienyl-lithium prepared just before-hand by the action of butyl-lithium on thiophene. The reaction is performed at reflux temperature in an inert atmosphere, whereby the 2-cyano-4-methyl-pyridine dissolved in an anhydrous solvent is added to the ethereal solution of 2-thienyl-lithium.
After hydrolysing the resulting mixture with hydrochloric acid and rendering it alkaline with NaOH, extraction takes place with ~n organic solvent, leading to 2-thienyl-(4-methyl-2- ~ -pyridyl) ketone (II).
.
The thus prepared ketone II is converted into 2-(2-thenyl)-4-methyl-pyridine (III) by the action of hydrazine in a strong basic medium for example, potassium hydroxide heated to reflux in a solvent with a high boiling point such as diethylene glycol. On pouring the resulting mixture over ice and extracting with ether, 2-(2-thenyl)-4-methyl-pyridine (III) ~
is obtained and from this compound the hydrochloride is prepared. ~ ;
sroadly stated, the compound o~ formula (III) is prepared by reducing 2-thienyl-(4-methyl-2-pyridyl)-ketone (II) in a basic medium in the presence of hydrazine hydrate.
In the next stage of the process, the compound of formula III is heated to reflux temperature in the presence of an excess of a methyl halide, for exemple methyl bromide, in an anhydrous solvent. 2-(2-Thenyl)-1,4-dimethyl-pyridinium bromide (IV) is precipitated from the solution: it is thereafter dis-solved in methanol, treated with sodium borohydride and heated to reflux for six hours. By diluting with water and extraction with ether a mixture of 2-(2-thenyl)1,4-dimethyl-1,2,3,6-tetra- _ ~ ".
' .' :. ,, ', ' . . ' '~ ~,,' ' .
.
6~z~3 hydropyridine (V~ and 2-(2-thenyl)-1,4-dimethyl-1,2,5,6-tetra-hydropyridine (VI) is obtained which is purified by distillation and from which the two components are separated by fractional crystallisation of their hydrochlorides.
~ ; -2a-.. ~ : ,.
.
66Z~33 In the final stage of the process of the present invention, the mixture of tetrahydropyridines V and VI is heated to 135C for 4 hours in the presence of a strong acid, for example, 48% aqueous hydrobromic acid. The mixture is -~
poured over water and is rendered alkaline with ammonium hydroxide, which after prior extraction with ether leads to 2,5-dimethyl-thieno-[3,2-f]-morphan (I) from which the hydrochloride can be obtained.
The following non limitative examples illustrate the invention.
EXAMPLE 1: Obtainina 2-thi~ 4-methyl-2-pyridyl)-ketone (II~
25.5 g of thiophene dissolved in 70 ml of anhydrous ether are introduced into a flask, followed by external cooling at between -5 and -10C. 400 ml of a 1.03 N ethereal solution of butyl lithium which has been prepared just beforehand are -added dropwise during 1-1/2 hours to the said solution under a ~-nitrogen atmosphere. Stirring takes place for 15 minutes and the mixture is permitted to reach ambient ternperature, followed by refluxing for 45 minutes. At the end of this period the reaction mixture is cooled to a temperature between -10 and -20C, followed by the dropwise addition of 24.5 g of 2-cyano-
4-methyl-pyridine dissolved in anhydrous toluene. The addition lasts 30 minutes and subsequently refluxing takes place for 45 minutes. This is followed by cooling after which 100 ml of 50% hydrochloric acid are added, followed by the elimination by distillation of any substance boiling below 100C. This temperature is maintained for 1-1/2 hours. 50% sodium hydroxide is added until the pH is basic, followed by extraction with ether. The organic phase is dried with anhydrous sodium sul-30 phate and the solvent is eliminated at reduced pressure. 32.7 g -of crude product are obtained yielding 27.6 g of ketone (II) by ;~', '', ""'".
:
'. . ' . . - - . ..
.. ,, ,, . ,., ~, ~ ,. . , . ~. , 66'~33 distillation at 103-115C/0.7 mm/Hg. Yield 66%. An analytical ;-sample is crystallised from methanol. Melting point: 61-61.5C.
Analysis:
Calculated for CllHgNSO C: 65.02, H: 4.46, N: 6.89; S: 15.74 Found C: 65.01, H: 4.48, N: 6.91 S: 15.76.
EXAMPLE 2: Obtaininq 2-(2-thenyl)-4-methyl-pyridine (III) 160 ml of diethylene glycol and 28.2 of potassium hydro-xide are introduced into a 500 ml flask, followed by heating 10 until potassium hydroxide dissolves. Cooling takes place to `
100C, followed by the addition of 29 g of 2-thienyl-(4-methyl-2-pyridyl)-ketone (II) and 22.7 ml of 80% hydrazine hydrate. The mixture is refluxed for one hour. All the substance which boils at below 223C is eliminated by distillation and this temperature is then maintained for 4 hours. The reaction mixture is permitted to cool and is poured over 200 g of ice.
The aqueous solution is extracted several times with ether, the combined ethereal phases are washed with large quantities of water, followed by drying with anhydrous magnesium sulphate 20 and the elimination of the solvent at reduced pressure. The ~-resulting oily residue is distilled at a pressure of 0.5 mm/Hg and the fraction between 86 and 120C is collected. 17.5 g of 2-(2-thenyl)-4-methyl-pyridine (III) are obtained with a yield of 65%. The hydrochloride is precipitated from a sample weigh-ing 3 g and which when recrystallised from acetone yields 2.7 g with a melting point of 140-141C.
Analysis:
Calculated for CllH12NSCl: C: 58.48, H: 5.36; N: 6.20 Cl: 15.70;
S: 14.20 30 Found: C: 58.61, H: 5.42, N: 6.21, Cl: 15.60, S: 13.86 ., .
, ' ' ` `
~1)66Z83 EXAMPLE 3: Obtainin~ 2-(2-thenyl)-1,4-dimethyl-pyridinium ~-bromide (IV) 30.1 g of 2-(2-thenyl)-4-methyl-pyridine (III) are dissolved in 120 ml of anhydrous acetone and 40 ml of anhydrous benzene. The mixture is cooled down to 0C while 60 g of methyl bromide are bubbled therethrough. Stirring takes place for 30 minutes at 0C and the solution is left to rise to ambient temperature. The flask is then heated to reflux for 4 hours giving a precipitate which when washed and dried weighs 29.7 g, giving a yield of 66%. Melting point: 214-215C (absolute -~
ethanol - acetone).
Analysis:
Calculated for C12H14NSBr: C: 50.70, H: 4.96, N: 4.92, S: 11.28 Br: 28.11 -Found: C: 51.13, H: 5.12, N: 4.89, S: -Br: 28.22 -~
EXAMPLE 4: Obtaini~ 2-(2-thenyl)-1,4-dimethy~ 2 ! 3,6-tetra~
hydropyridine (V) and 2-(2-thenyl)-1,4-dimethyl-1, 2~5~6-tetrahydropyridine (VI) 16.9 g of 2-(2-thenyl)-1,4-dimethyl-pyridinium bromide (IV) are dissolved in 120 ml of methanol. 2.3 g of sodium borohydride are slowly added to this solution accompanied by external cooling with ice. Refluxing takes place for 6 hours, followed by dilution with water and extraction with ether. The ethereal phase is dried with anhydrous magnesium sulphate followed by the elimination of the solvent and distillation. -The fraction between 95 and 125C/0.07 mm/Hg. is collected. In this way 3.2 g of a mixture of 2-(2-thenyl)-1,4-dimethyl-1,2, 3,6-tetrahydropyridine (V) and 2-(2-thenyl)-1,4-dimethyl-1,2,
:
'. . ' . . - - . ..
.. ,, ,, . ,., ~, ~ ,. . , . ~. , 66'~33 distillation at 103-115C/0.7 mm/Hg. Yield 66%. An analytical ;-sample is crystallised from methanol. Melting point: 61-61.5C.
Analysis:
Calculated for CllHgNSO C: 65.02, H: 4.46, N: 6.89; S: 15.74 Found C: 65.01, H: 4.48, N: 6.91 S: 15.76.
EXAMPLE 2: Obtaininq 2-(2-thenyl)-4-methyl-pyridine (III) 160 ml of diethylene glycol and 28.2 of potassium hydro-xide are introduced into a 500 ml flask, followed by heating 10 until potassium hydroxide dissolves. Cooling takes place to `
100C, followed by the addition of 29 g of 2-thienyl-(4-methyl-2-pyridyl)-ketone (II) and 22.7 ml of 80% hydrazine hydrate. The mixture is refluxed for one hour. All the substance which boils at below 223C is eliminated by distillation and this temperature is then maintained for 4 hours. The reaction mixture is permitted to cool and is poured over 200 g of ice.
The aqueous solution is extracted several times with ether, the combined ethereal phases are washed with large quantities of water, followed by drying with anhydrous magnesium sulphate 20 and the elimination of the solvent at reduced pressure. The ~-resulting oily residue is distilled at a pressure of 0.5 mm/Hg and the fraction between 86 and 120C is collected. 17.5 g of 2-(2-thenyl)-4-methyl-pyridine (III) are obtained with a yield of 65%. The hydrochloride is precipitated from a sample weigh-ing 3 g and which when recrystallised from acetone yields 2.7 g with a melting point of 140-141C.
Analysis:
Calculated for CllH12NSCl: C: 58.48, H: 5.36; N: 6.20 Cl: 15.70;
S: 14.20 30 Found: C: 58.61, H: 5.42, N: 6.21, Cl: 15.60, S: 13.86 ., .
, ' ' ` `
~1)66Z83 EXAMPLE 3: Obtainin~ 2-(2-thenyl)-1,4-dimethyl-pyridinium ~-bromide (IV) 30.1 g of 2-(2-thenyl)-4-methyl-pyridine (III) are dissolved in 120 ml of anhydrous acetone and 40 ml of anhydrous benzene. The mixture is cooled down to 0C while 60 g of methyl bromide are bubbled therethrough. Stirring takes place for 30 minutes at 0C and the solution is left to rise to ambient temperature. The flask is then heated to reflux for 4 hours giving a precipitate which when washed and dried weighs 29.7 g, giving a yield of 66%. Melting point: 214-215C (absolute -~
ethanol - acetone).
Analysis:
Calculated for C12H14NSBr: C: 50.70, H: 4.96, N: 4.92, S: 11.28 Br: 28.11 -Found: C: 51.13, H: 5.12, N: 4.89, S: -Br: 28.22 -~
EXAMPLE 4: Obtaini~ 2-(2-thenyl)-1,4-dimethy~ 2 ! 3,6-tetra~
hydropyridine (V) and 2-(2-thenyl)-1,4-dimethyl-1, 2~5~6-tetrahydropyridine (VI) 16.9 g of 2-(2-thenyl)-1,4-dimethyl-pyridinium bromide (IV) are dissolved in 120 ml of methanol. 2.3 g of sodium borohydride are slowly added to this solution accompanied by external cooling with ice. Refluxing takes place for 6 hours, followed by dilution with water and extraction with ether. The ethereal phase is dried with anhydrous magnesium sulphate followed by the elimination of the solvent and distillation. -The fraction between 95 and 125C/0.07 mm/Hg. is collected. In this way 3.2 g of a mixture of 2-(2-thenyl)-1,4-dimethyl-1,2, 3,6-tetrahydropyridine (V) and 2-(2-thenyl)-1,4-dimethyl-1,2,
5,6-tetrahydropyridine (VI) (yield 51%) is obtained. The hydro-chloride is precipitated from this mixture and on recrystallising , .: - ,' , : , . .. . . . . ... . . . ...
: . . :
' ~q~6Çi~
''. ' , . .
from acetone gives the pure compound (V), melting point 137-139C.
nalysis:
Calculated for C12H18NSCl: C: 59.11; H 7.44, N 5.7~; S
Cl: . ., Found:C: 58.90, H: 7.57, N: 5.50, S: ;
Cl:
Once concentrated the mother liquors give a small quantity of tetrahydropyridine VI which is purified by re-crystallisation from acetone. Melting point 108-109C.
Analysis:
Calculated for C12H18NSCl'~ /H2O C 57-00, H 7-57, N 5-54, Cl: 14.04, S: ;
Found:C: 57.24; H- 7.57; N: 5.56;
Cl: 14.05; S:
EXAMPLE 5: Obtaininq 2,5-dimethyl-thieno=~3~2-fl-morphan (I) ;
4 g of a mixture of Tetrahydrophyridines V and VI ;~
; distilled just beforehand and 60 ml of 48% HBr are heated to i 130-135C for 4 hours. The mixture is left to cool, poured over ice and water, rendered alkaline with concentrated ammonium hydroxide and extracted with ether. The e-thereal extract dried with magnesium sulphate, accompanied by the evap-oration of the solvent, leads to an oil which is purified by distillation, whereby a fraction is obtained which distills between 135 and 175C/0.5 mm/Hg. In this way 1.94 g of (I) are obtained, yield 49%. The hydrochloride is precipitated and recrystallised from acetone-e-ther, melting point 203-204C.
Analysis:
Calculated for C12H18NSCl: C: 59.11; H: 7.44, N 5.7~; S: 13.15 ; Cl: 14.54 Found: C: 58.87; H: 7.68, N: 5.57, S:
Cl: 14.8~.
: . . :
' ~q~6Çi~
''. ' , . .
from acetone gives the pure compound (V), melting point 137-139C.
nalysis:
Calculated for C12H18NSCl: C: 59.11; H 7.44, N 5.7~; S
Cl: . ., Found:C: 58.90, H: 7.57, N: 5.50, S: ;
Cl:
Once concentrated the mother liquors give a small quantity of tetrahydropyridine VI which is purified by re-crystallisation from acetone. Melting point 108-109C.
Analysis:
Calculated for C12H18NSCl'~ /H2O C 57-00, H 7-57, N 5-54, Cl: 14.04, S: ;
Found:C: 57.24; H- 7.57; N: 5.56;
Cl: 14.05; S:
EXAMPLE 5: Obtaininq 2,5-dimethyl-thieno=~3~2-fl-morphan (I) ;
4 g of a mixture of Tetrahydrophyridines V and VI ;~
; distilled just beforehand and 60 ml of 48% HBr are heated to i 130-135C for 4 hours. The mixture is left to cool, poured over ice and water, rendered alkaline with concentrated ammonium hydroxide and extracted with ether. The e-thereal extract dried with magnesium sulphate, accompanied by the evap-oration of the solvent, leads to an oil which is purified by distillation, whereby a fraction is obtained which distills between 135 and 175C/0.5 mm/Hg. In this way 1.94 g of (I) are obtained, yield 49%. The hydrochloride is precipitated and recrystallised from acetone-e-ther, melting point 203-204C.
Analysis:
Calculated for C12H18NSCl: C: 59.11; H: 7.44, N 5.7~; S: 13.15 ; Cl: 14.54 Found: C: 58.87; H: 7.68, N: 5.57, S:
Cl: 14.8~.
- 6 -.
.
~)66~3 Pharmacoloqy_of the products accordinq to the invention -Products --I. 2,5-dimethyl-thieno-[3,2-f]-morphan ;~
II. 2-thienyl-(4-methyl-2-pyridyl)-ketone ~ -III. 2-(2-thenyl)-4-methyl-pyridine -IV. 2-(2-thenyl)-1,4-dimethyl-pyridinium bromide V. 2-(2-thenyl)-1,4-dimethyl-1,2,3,~-tetrahydropyridine VI. 2-(2-thenyl)-1,4-dimethyl-1,2,5,6-tetrahydropyridine. ~;;
These products have an analgesic activity. The 10 activity of these products has been studied by comparison with -dextropropoxyphene. -~
A. Acute toxicitY
The acute toxicity studies are performed on I.C.R.
Swiss mice weighing 20 + 2 g of both sexes. The products are -administered intraperitoneally (i.p.). The acute toxicity calculations are performed by the Litchfield-Wilcoxon method.
Table 1 Products Lethal dose 50 (LD50 ) I 83.05 mg/kg II 57.1 " -III 449.08 "
IV 51.71 "
V 90.22 "
VI 110.44 Dextropropoxyphene 140 "
Analqesic Activity -a) Thermal__nalqesia The thermal analgesic activity is studied on I.C.R.
Swiss albino mice using the hot plate method at 55C. Batches 30 each of 10 mice are used. -The products being studied are administered by intra- ' ' : '
.
~)66~3 Pharmacoloqy_of the products accordinq to the invention -Products --I. 2,5-dimethyl-thieno-[3,2-f]-morphan ;~
II. 2-thienyl-(4-methyl-2-pyridyl)-ketone ~ -III. 2-(2-thenyl)-4-methyl-pyridine -IV. 2-(2-thenyl)-1,4-dimethyl-pyridinium bromide V. 2-(2-thenyl)-1,4-dimethyl-1,2,3,~-tetrahydropyridine VI. 2-(2-thenyl)-1,4-dimethyl-1,2,5,6-tetrahydropyridine. ~;;
These products have an analgesic activity. The 10 activity of these products has been studied by comparison with -dextropropoxyphene. -~
A. Acute toxicitY
The acute toxicity studies are performed on I.C.R.
Swiss mice weighing 20 + 2 g of both sexes. The products are -administered intraperitoneally (i.p.). The acute toxicity calculations are performed by the Litchfield-Wilcoxon method.
Table 1 Products Lethal dose 50 (LD50 ) I 83.05 mg/kg II 57.1 " -III 449.08 "
IV 51.71 "
V 90.22 "
VI 110.44 Dextropropoxyphene 140 "
Analqesic Activity -a) Thermal__nalqesia The thermal analgesic activity is studied on I.C.R.
Swiss albino mice using the hot plate method at 55C. Batches 30 each of 10 mice are used. -The products being studied are administered by intra- ' ' : '
- 7 -"` 1~)66~2133 peritoneal administration and after 30 minutes the mice are placed on a hot plate and the number of seconds before the animal starts to jump are counted. Batches of controls are .
also used and these are only injected with distilled water.
The results are given in Tables 2, 3, 4, 5, 6 and 7.
,: .
` `' 3L~6~Z~33 ~¦ h I O O ~ o o ~rl ~ Q~ P~ 0 ~ I V V
O ~ ~
00 ~ ~0~ Od) L~
3 Q ~ Q' 3 h ~ o ~, :
~: X C I V I X ~ X X \~ I 'X "'~
.. rl ~(^ ~ ~ ~rl ~
U~ ~ ~q ..
r` n ~ N r~ 00 '~
a) ~ co ~) a) ~ ~ ~ ,~
., * O N r~ ~ In N ~) o- + + I +I ~1 +I +I +I ~
~1 ~ ~ ~ ~ ~ n a) :
E~ n t O ~ .Ei .~ t ~
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:
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, nl I ~ ~ ~ 3 ~1 1 o? o~ ,~a2 H U~
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....
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. o ~ ...............
aU s~ ~1 ~ a ~
~ X ~ X ~ I V I X
u~ ~ X u~
~ ~ .
r~ .
o o ~ o oo ~ a +l +l +l .
d' ~ a.) ~ . ~
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E3 ~a:) ~) o ~ o ~D d' ~ ' E~ ,~ t ~ ~ - E~ ~ t ~ u~ ~ ~
U~ o `
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, ~ ~ ~ ~ , ~ ~ .. .
... ...
u ~1 ~ ~ ~ O ~ ~ O ": .
Ei ~ O X ~ Rl~i ,~ h O P~ ~
o P~ E~ C.) O
. . .
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.:
' '' ' 66'~83 b) Chemical analqesia The analgesic activity was studied in I.C.R. Swiss Albino mice using the acetic acid writhing method. Batches of 10 mice ; are formed.
The products being studied are administered intraper-itoneally and 30 minutes after the injection 0.25 ml of 1% acetic acid are injected intraperitoneally. The control batch only receives the acetic acid. The number of times that each mouse -writhes in the 20 minutes following the administration of acetic acid is counted.
The results are given in Tables 8, 9, 10, 11, 12 and 3.
. . .
1~6'~83 ~ .'.. ......
.~ ~ .,, ~
O u~ In o 3 U~ ~0 0 ~ ~o o o a) ~0 o o o s I I o o ~ s-l I o o a) a) o I v v ~: ~ o I V V ~ '.
t) Ql Q~ ~ ~.) Q1 ~4 o .~
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GO ~ ~ 0~ ~ ~ "
O O O X ~ O O O
a) ~ ~ o a) o ~ ~ o ~u ~ ~ ~ ~ ~ ~ ~ ~ d ~ ~ ~ ~
.Q a) ~ o X o ~ ~ ~ ~ o X o ~ , ~ s~ o ~ s~ o E~ E~ ~ 1 Q~ E~ t~ ~1 a ,: . , ~ . ~, ,.:
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.
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+l +l +
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+ u~ + ~D ~ cO U
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3 ~.
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O I o o O I O o ,~
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.. ,1~ ~) .
O ¦ H
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., ~ ~ O S~ (d S~ O
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. . . . : . .
~662~33 ~i '3 ~n O ~ u~ O
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I I ~1 . .
ql ~1 .. -O O "~ ' :
tq ~a
also used and these are only injected with distilled water.
The results are given in Tables 2, 3, 4, 5, 6 and 7.
,: .
` `' 3L~6~Z~33 ~¦ h I O O ~ o o ~rl ~ Q~ P~ 0 ~ I V V
O ~ ~
00 ~ ~0~ Od) L~
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r` n ~ N r~ 00 '~
a) ~ co ~) a) ~ ~ ~ ,~
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, nl I ~ ~ ~ 3 ~1 1 o? o~ ,~a2 H U~
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... ...
u ~1 ~ ~ ~ O ~ ~ O ": .
Ei ~ O X ~ Rl~i ,~ h O P~ ~
o P~ E~ C.) O
. . .
.. .
.:
' '' ' 66'~83 b) Chemical analqesia The analgesic activity was studied in I.C.R. Swiss Albino mice using the acetic acid writhing method. Batches of 10 mice ; are formed.
The products being studied are administered intraper-itoneally and 30 minutes after the injection 0.25 ml of 1% acetic acid are injected intraperitoneally. The control batch only receives the acetic acid. The number of times that each mouse -writhes in the 20 minutes following the administration of acetic acid is counted.
The results are given in Tables 8, 9, 10, 11, 12 and 3.
. . .
1~6'~83 ~ .'.. ......
.~ ~ .,, ~
O u~ In o 3 U~ ~0 0 ~ ~o o o a) ~0 o o o s I I o o ~ s-l I o o a) a) o I v v ~: ~ o I V V ~ '.
t) Ql Q~ ~ ~.) Q1 ~4 o .~
X ,1 ~ ,. . . . .
O ~:5 S-l ~0 0~ ~ 0 ~1 u~ O M X
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U S I ~ ~ O ~ ~ ~
.
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5~ ~ O o ,1 S~ ~3 ~ .. : : .
o ~1 ~1 ~ E~ ~ .
U~~ ) Q U~
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a I ~ ~ ~ a I ~ ~ H
1-1 .
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a) ~ ~ o a) o ~ ~ o ~u ~ ~ ~ ~ ~ ~ ~ ~ d ~ ~ ~ ~
.Q a) ~ o X o ~ ~ ~ ~ o X o ~ , ~ s~ o ~ s~ o E~ E~ ~ 1 Q~ E~ t~ ~1 a ,: . , ~ . ~, ,.:
,. . , - :. -.~ , ~ , . . . . .
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~ O ~ I. I ~ ~1 O.C I . I
,~ ~I P I O I ~1 h ~ I O
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,U~
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~1 ~ 1` ,~ ~1 S-l ~ ~ ~1 1~ ~1 1~ ~ ~ ~a 3 ~ 0 ~i ~ o ~
+l +l +
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+ u~ + ~D ~ cO U
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., ~ ~ O S~ (d S~ O
E~ E~ ~ G a P~ P~ E~ E~ ~ a o ., ~ :
l; .~ . , , . , . , , , . . : ,, .:
. . . . : . .
~662~33 ~i '3 ~n O ~ u~ O
vl ~1 ' O ta ~1' O :' g ~0 I U~ o g ~0I U~ o ''',, ~ ~ V ~: ~ V ',,.'~1 O ~ O ~ P~ . ~', .
I I ~1 . .
ql ~1 .. -O O "~ ' :
tq ~a
8 o ~ 8 o ~ - --.~ o~$ ~ o~ , o .,, ~ ~ , o , .~ ~ P , o ~ X ~ ' V ~ ~: ~ ~ ' V ~ ... .. .
.~ ~ o .,, ~ o .
u~ a,P P~ u~ a P
~1 > ':': ' '' g `-$ ~d $ ~ ''. :.' u ~ u .. ~ :
~ ~ ~ ~ ~ ~ ~ ~ ~ ` ,......... ....
3 o 1~ 1~ u~ 3 O 1`1` o .: .:
O ~ ~
h ~+ l+ l+ l + I+ I+ l O ~ O O (~ O '`' ~ ~1 0 ~ ~1~ '`' '' + ~D d' 0 ~d + ~) o GO U ':
~i ~ o ~ o al I ~ ~ ,~ al I '~
~ ,~, .
~ o ~ ~ -~ O a, ~ ~ ~ ~ ~ ~ O a) ~ ~ ~ ~ ~ P~ ~:
R a) ~ O X O a) ~ I ~ O X O O
(~ h O ~ a ~1 O
E~ E~ o P~ ~ P~P~ El E~ c.) ~ ~ ~ Q~ '`''., ' - 15 - ;
.. , -,: ,"'~ ' ' " ,. ''':.'.,." ',' ' . ', , , :, . . , ' . . ,; . ,: . . ' . .
.~ ~ o .,, ~ o .
u~ a,P P~ u~ a P
~1 > ':': ' '' g `-$ ~d $ ~ ''. :.' u ~ u .. ~ :
~ ~ ~ ~ ~ ~ ~ ~ ~ ` ,......... ....
3 o 1~ 1~ u~ 3 O 1`1` o .: .:
O ~ ~
h ~+ l+ l+ l + I+ I+ l O ~ O O (~ O '`' ~ ~1 0 ~ ~1~ '`' '' + ~D d' 0 ~d + ~) o GO U ':
~i ~ o ~ o al I ~ ~ ,~ al I '~
~ ,~, .
~ o ~ ~ -~ O a, ~ ~ ~ ~ ~ ~ O a) ~ ~ ~ ~ ~ P~ ~:
R a) ~ O X O a) ~ I ~ O X O O
(~ h O ~ a ~1 O
E~ E~ o P~ ~ P~P~ El E~ c.) ~ ~ ~ Q~ '`''., ' - 15 - ;
.. , -,: ,"'~ ' ' " ,. ''':.'.,." ',' ' . ', , , :, . . , ' . . ,; . ,: . . ' . .
Claims (2)
1. A process of producing 2-(2-thenyl)-4-methyl-pyridine of formula (III) (III) which comprises reducing 2-thienyl-(4-methyl-2-pyridyl)-ketone in a basic medium in the presence of hydrazine hydrate.
2. 2-(2-Thenyl)-4-methyl pyridine of formula (III) (III) whenever produced by the process of claim 1, or its obvious chemical equivalents.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ES441142A ES441142A1 (en) | 1975-09-20 | 1975-09-20 | 2-(2-thenyl)-1,4-dimethylpyridinium halides |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1066283A true CA1066283A (en) | 1979-11-13 |
Family
ID=8470020
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA261,490A Expired CA1066283A (en) | 1975-09-20 | 1976-09-17 | 2,5-dimethyl-thieno-(3,2-f)-morphan and intermediates |
Country Status (16)
| Country | Link |
|---|---|
| JP (1) | JPS5257193A (en) |
| AR (1) | AR214297A1 (en) |
| AT (1) | AT352299B (en) |
| AU (1) | AU502649B2 (en) |
| BE (1) | BE845756A (en) |
| CA (1) | CA1066283A (en) |
| CH (1) | CH615682A5 (en) |
| DE (1) | DE2641320C3 (en) |
| ES (1) | ES441142A1 (en) |
| FR (5) | FR2324302A1 (en) |
| GB (1) | GB1553614A (en) |
| NL (1) | NL7610438A (en) |
| NZ (1) | NZ181891A (en) |
| PT (1) | PT65595B (en) |
| SE (2) | SE7610336L (en) |
| SU (5) | SU604494A3 (en) |
-
1975
- 1975-09-20 ES ES441142A patent/ES441142A1/en not_active Expired
-
1976
- 1976-08-30 NZ NZ181891A patent/NZ181891A/en unknown
- 1976-09-01 BE BE170278A patent/BE845756A/en unknown
- 1976-09-06 AT AT657776A patent/AT352299B/en not_active IP Right Cessation
- 1976-09-09 GB GB37473/76A patent/GB1553614A/en not_active Expired
- 1976-09-10 AU AU17623/76A patent/AU502649B2/en not_active Expired
- 1976-09-13 CH CH1161476A patent/CH615682A5/en not_active IP Right Cessation
- 1976-09-14 DE DE2641320A patent/DE2641320C3/en not_active Expired
- 1976-09-15 SU SU762396747A patent/SU604494A3/en active
- 1976-09-15 PT PT65595A patent/PT65595B/en unknown
- 1976-09-17 CA CA261,490A patent/CA1066283A/en not_active Expired
- 1976-09-17 JP JP51110937A patent/JPS5257193A/en active Pending
- 1976-09-17 SE SE7610336A patent/SE7610336L/en unknown
- 1976-09-20 NL NL7610438A patent/NL7610438A/en not_active Application Discontinuation
- 1976-09-20 FR FR7628180A patent/FR2324302A1/en active Granted
- 1976-11-27 AR AR264477A patent/AR214297A1/en active
-
1977
- 1977-04-22 SU SU772472890A patent/SU637084A3/en active
- 1977-04-22 SU SU772473620A patent/SU626699A3/en active
- 1977-04-22 SU SU772474104A patent/SU633481A3/en active
- 1977-04-22 SU SU772472888A patent/SU625611A3/en active
- 1977-06-03 FR FR7717091A patent/FR2339610A1/en not_active Withdrawn
- 1977-06-03 FR FR7717090A patent/FR2339609A1/en not_active Withdrawn
- 1977-06-03 FR FR7717089A patent/FR2339608A1/en not_active Withdrawn
- 1977-06-03 FR FR7717092A patent/FR2339611A1/en not_active Withdrawn
-
1980
- 1980-01-10 SE SE8000206A patent/SE8000206L/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| AU502649B2 (en) | 1979-08-02 |
| GB1553614A (en) | 1979-09-26 |
| AR214297A1 (en) | 1979-05-31 |
| DE2641320A1 (en) | 1977-03-24 |
| FR2339610A1 (en) | 1977-08-26 |
| SU637084A3 (en) | 1978-12-05 |
| FR2324302B1 (en) | 1978-12-15 |
| AT352299B (en) | 1979-09-10 |
| BE845756A (en) | 1977-03-01 |
| DE2641320B2 (en) | 1979-08-02 |
| FR2339611A1 (en) | 1977-08-26 |
| SE8000206L (en) | 1980-01-10 |
| ES441142A1 (en) | 1977-07-01 |
| AU1762376A (en) | 1978-03-16 |
| FR2339609A1 (en) | 1977-08-26 |
| NZ181891A (en) | 1979-01-11 |
| SU625611A3 (en) | 1978-09-25 |
| ATA657776A (en) | 1979-02-15 |
| FR2339608A1 (en) | 1977-08-26 |
| FR2324302A1 (en) | 1977-04-15 |
| NL7610438A (en) | 1977-03-22 |
| SU633481A3 (en) | 1978-11-15 |
| SU626699A3 (en) | 1978-09-30 |
| PT65595A (en) | 1976-10-01 |
| PT65595B (en) | 1978-03-28 |
| DE2641320C3 (en) | 1980-04-03 |
| SU604494A3 (en) | 1978-04-25 |
| JPS5257193A (en) | 1977-05-11 |
| CH615682A5 (en) | 1980-02-15 |
| SE7610336L (en) | 1977-03-21 |
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