CA1068279A - 2,4,5-trimethyl-thieno (3,2-f) morphan, and intermediates - Google Patents
2,4,5-trimethyl-thieno (3,2-f) morphan, and intermediatesInfo
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- CA1068279A CA1068279A CA261,567A CA261567A CA1068279A CA 1068279 A CA1068279 A CA 1068279A CA 261567 A CA261567 A CA 261567A CA 1068279 A CA1068279 A CA 1068279A
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- thenyl
- dimethyl
- thienyl
- formula
- dimethylpyridine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/84—Nitriles
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract
ABSTRACT OF THE DISCLOSURE
2,4,5-Trimethyl-theino[3,2-f]morphan, a comound having analegisic activity, is prepared from 3,4-dimethylpyridine-N-oxide via series of intermediates: 2-cyano-4,5-dimethlpyridine, 2-thienyl-(4,5-dimethyl-2-pyridyl)-ketoned, 2-(2-thienyl)-4,5-dimethylpyridine and 2-(2-thienyl)-1,4,5-trimethyl-1,2,3,6-tetrahydropyridine which are novel compounds and mostly also show analgesic activity.
2,4,5-Trimethyl-theino[3,2-f]morphan, a comound having analegisic activity, is prepared from 3,4-dimethylpyridine-N-oxide via series of intermediates: 2-cyano-4,5-dimethlpyridine, 2-thienyl-(4,5-dimethyl-2-pyridyl)-ketoned, 2-(2-thienyl)-4,5-dimethylpyridine and 2-(2-thienyl)-1,4,5-trimethyl-1,2,3,6-tetrahydropyridine which are novel compounds and mostly also show analgesic activity.
Description
The present invention is concerned with certain novel compounds, with processes for their preparation, and with pharmaceutical compositions containing them.
We have found that 2,4,5-trimethyl-thieno [3,2-f]morphan of the formula:
~ tl), ; 10 CH3 : CH3
We have found that 2,4,5-trimethyl-thieno [3,2-f]morphan of the formula:
~ tl), ; 10 CH3 : CH3
2-(2-thenyl)-1,4,5-trimethyl-1,2,3,6-tetrahydrcpyridine of the formula:
~, CH3 ~.
~, CH3 ~.
3 ( ., : 2-~2-thenyl)-4,5-dimethylpyridine o~ the formula:
( ~ ~ ~CH3 tlll).
i CH3 . ~ .
... .
:::
. .
. ~
-" 1068279 2-thienyl-(4,5-dimethyl~2-pyridyl~-ketone of the formula:
O
C ~ ~ N ~ (IV), and 2-cyano-4,5-dimethylpyridine of formula:
NaC `I~ N ~ (V), ~ .
CH
and their physiologically acceptable acid addition salts, such as their hydro-chlorides, possess valuable pharmacological properties. In particular, these compounds have analgesic activity.
Ths compounds o formulae (I) to ~V) and their physiologically acceptable addition salts are novel.
According to the invention, there is provided a process for the preparation of the compound of formula (IV) -:
C ~ N ~ (IV) ; ~ CH3 OT a pharmaceutically acceptable acid addition salt thereof, which comprises reacting 2-cyano-4,5-dimethylpyridine of the formula N_C~ ~CH3 (V) CH
with 2-thienyl lithium under an inert atmosphere, subjecting the resulting ; ; product to hydrolysis, and where required converting a product obtained in Y ~ - 2 -` 1068Z79 free base form into a pharmaceutically acceptable acid addition salt, or a product obtained in salt form into the free base of formula tIV).
A preferred procedure for preparing the compounds of formulae (I) to ~V) is shown in the following reaction scheme:
, ~ ~
i~:
, ' b~-'~
. - 2a -.. ,~ ~\
_, tn . .
~ ~ ''" ~
I ~"
~_ =\ ~ : -cn Q ~ ~
=~ I ~
~ Q
~,~ 1` 1=
i ~ 4 =o i ~ ~ ~ /
~ < 4~
i ~3~Z Q
'~:
~068'~79 In the first step of this preferred procedure, the N-oxide of 3,4-dimethylpyridine is reacted with an alkylating agent, such as dimethyl sulphate, and the methyl sulphate of l-methoxy-3,4-dimethylpyridium thus obtained is treated with an alkali metal cyanide in the presence of an inert atmosphere, preferably in an aqueous reaction medium at a temperature of from 0 to 5C for 24 hours. Extraction of the reaction mixture with chloroform provides a crude mixture of 2-cyano-3,4-dimethylpyridine and 2-cyano-4,5-dimethylpyridine (V~ from which the latter can be separated by crystallization.
In the second step, the 2-cyano-4,5-dimethylpyridine tV) is re-acted with freshly prepared 2-thienyl-lithium tobtained by the reaction o butyl lithium and thiophene). The reaction with 2-thienyl-lithium is carried out at reflux temperature in the presence of an inert atmosphere, the com-pound (V~ dissolved in an anhydsous solvent being added to an ethereal sol-ution of 2-thienyl-lithium. The reaction mixture obtained is hydrolyzed with hydrochloric acid, rendered alkaline with aqueous caustic soda, and then extracted with an organic solvent to yield 2-thienyl-t4,5-dimethyl-2-pyridyl)-ketone tIV), which is recrystallized from acetone.
;1 In the third step, the ketone tIV) is reacted with hydrazine in r a strongly basic medium, for example potassium hydroxide, and with heating ;i 20 at the reflux temperature of a high boiling point solvent, such as diethylene glycol. The resulting reaction mixture is poured on to ice and extracted with ether to give 2-t2-thenyl)-4,5-dimethyl-pyridine tIII).
In the fourth step, the compound tIII) is heated to reflux temp-erature in ~he presence of an excess of methyl iodide in an anhydTous sol-;~ vent, such as acetone or benzene. 2-t2-thenyl)-1,4,5-trimethyl-pyridinium iodide, which is unstable in air and to light, is precipitated from the re-action mixture, separated, and, without purification, dissolved in methanol and reducet with sodium borohydride, the reduction suitably being carsied out at reflux temperature for 4 hours. The sesulting reaction mixture is diluted with-water and extracted with ether to give 2-t2-thenyl)-1,4,5-
( ~ ~ ~CH3 tlll).
i CH3 . ~ .
... .
:::
. .
. ~
-" 1068279 2-thienyl-(4,5-dimethyl~2-pyridyl~-ketone of the formula:
O
C ~ ~ N ~ (IV), and 2-cyano-4,5-dimethylpyridine of formula:
NaC `I~ N ~ (V), ~ .
CH
and their physiologically acceptable acid addition salts, such as their hydro-chlorides, possess valuable pharmacological properties. In particular, these compounds have analgesic activity.
Ths compounds o formulae (I) to ~V) and their physiologically acceptable addition salts are novel.
According to the invention, there is provided a process for the preparation of the compound of formula (IV) -:
C ~ N ~ (IV) ; ~ CH3 OT a pharmaceutically acceptable acid addition salt thereof, which comprises reacting 2-cyano-4,5-dimethylpyridine of the formula N_C~ ~CH3 (V) CH
with 2-thienyl lithium under an inert atmosphere, subjecting the resulting ; ; product to hydrolysis, and where required converting a product obtained in Y ~ - 2 -` 1068Z79 free base form into a pharmaceutically acceptable acid addition salt, or a product obtained in salt form into the free base of formula tIV).
A preferred procedure for preparing the compounds of formulae (I) to ~V) is shown in the following reaction scheme:
, ~ ~
i~:
, ' b~-'~
. - 2a -.. ,~ ~\
_, tn . .
~ ~ ''" ~
I ~"
~_ =\ ~ : -cn Q ~ ~
=~ I ~
~ Q
~,~ 1` 1=
i ~ 4 =o i ~ ~ ~ /
~ < 4~
i ~3~Z Q
'~:
~068'~79 In the first step of this preferred procedure, the N-oxide of 3,4-dimethylpyridine is reacted with an alkylating agent, such as dimethyl sulphate, and the methyl sulphate of l-methoxy-3,4-dimethylpyridium thus obtained is treated with an alkali metal cyanide in the presence of an inert atmosphere, preferably in an aqueous reaction medium at a temperature of from 0 to 5C for 24 hours. Extraction of the reaction mixture with chloroform provides a crude mixture of 2-cyano-3,4-dimethylpyridine and 2-cyano-4,5-dimethylpyridine (V~ from which the latter can be separated by crystallization.
In the second step, the 2-cyano-4,5-dimethylpyridine tV) is re-acted with freshly prepared 2-thienyl-lithium tobtained by the reaction o butyl lithium and thiophene). The reaction with 2-thienyl-lithium is carried out at reflux temperature in the presence of an inert atmosphere, the com-pound (V~ dissolved in an anhydsous solvent being added to an ethereal sol-ution of 2-thienyl-lithium. The reaction mixture obtained is hydrolyzed with hydrochloric acid, rendered alkaline with aqueous caustic soda, and then extracted with an organic solvent to yield 2-thienyl-t4,5-dimethyl-2-pyridyl)-ketone tIV), which is recrystallized from acetone.
;1 In the third step, the ketone tIV) is reacted with hydrazine in r a strongly basic medium, for example potassium hydroxide, and with heating ;i 20 at the reflux temperature of a high boiling point solvent, such as diethylene glycol. The resulting reaction mixture is poured on to ice and extracted with ether to give 2-t2-thenyl)-4,5-dimethyl-pyridine tIII).
In the fourth step, the compound tIII) is heated to reflux temp-erature in ~he presence of an excess of methyl iodide in an anhydTous sol-;~ vent, such as acetone or benzene. 2-t2-thenyl)-1,4,5-trimethyl-pyridinium iodide, which is unstable in air and to light, is precipitated from the re-action mixture, separated, and, without purification, dissolved in methanol and reducet with sodium borohydride, the reduction suitably being carsied out at reflux temperature for 4 hours. The sesulting reaction mixture is diluted with-water and extracted with ether to give 2-t2-thenyl)-1,4,5-
-4-. .~ .
.. , ~ . .: , ~ . .. . . . . . .. . . . .
106~279 trimethyl-1J2,3,6-tetrahydropyridine ~ . This product is purified by dis-tillation.
In the final step, the compound (II) is heated in the presence of strong acid, for example 48% aqueous hydrobromic acid, suitably at 135C for 4 hours, to effect cyclization. The reaction mixture is poured into aqueous ammonium chloride solution, rendered alkaline by the addition of ammonium hydroxide, and extracted with ether to give 2,4,5-trimethyl-thieno~3,2-f]
morphan tI).
Each of the compounds tI) to tV) may, if desired, by converted in-to its acid addition salts such as its hydrochloride.
Each of the above steps forms a further aspect of the present in-vention, as does the combination of steps to produce the co~pound (I).
According to a further aspect of the present invention, we provide a pharmaceutical composition which comprises at least one compound according to the invention and an inert, physiologically acceptable carrier.
In order that the invention may be more fully understood, the following Examplss are given by way of illustration only:
Example 1 ; Preparation of 2-cyano-4 5-dimethylpyridi-ne--(v) .~
J 20 126 g (1 mol) of sulphuric acid-free dimethyl sulphate were added dropwise, under a nitrogen atmosphere and with vigorous agitation, to 123 g ~1 mol) of 3,4-dimethylpyridine-N-oxide which had been carefully dried and powdered, while maintaining the temperature of the reaction mixture between 80 and 90C. When the addition had been completed, the mixture was heated .
to 100C for 2 hours.
In ~nother reaction vessel, 170 g (3.5 moles) of sodium cyanide 'j were dissolved in 570 ml of water with vigorous agitation for 1 hour under a nitrogen atmosphere. The previously obtained methyl sulphate of N-methoxy-,;:
3,4-dimethylpyridinium dissolved in 250 ml of water was added to the sodium cyanide solution while externally cooling the reaction vessel to maintain the ~`
.
.. , ~ . .: , ~ . .. . . . . . .. . . . .
106~279 trimethyl-1J2,3,6-tetrahydropyridine ~ . This product is purified by dis-tillation.
In the final step, the compound (II) is heated in the presence of strong acid, for example 48% aqueous hydrobromic acid, suitably at 135C for 4 hours, to effect cyclization. The reaction mixture is poured into aqueous ammonium chloride solution, rendered alkaline by the addition of ammonium hydroxide, and extracted with ether to give 2,4,5-trimethyl-thieno~3,2-f]
morphan tI).
Each of the compounds tI) to tV) may, if desired, by converted in-to its acid addition salts such as its hydrochloride.
Each of the above steps forms a further aspect of the present in-vention, as does the combination of steps to produce the co~pound (I).
According to a further aspect of the present invention, we provide a pharmaceutical composition which comprises at least one compound according to the invention and an inert, physiologically acceptable carrier.
In order that the invention may be more fully understood, the following Examplss are given by way of illustration only:
Example 1 ; Preparation of 2-cyano-4 5-dimethylpyridi-ne--(v) .~
J 20 126 g (1 mol) of sulphuric acid-free dimethyl sulphate were added dropwise, under a nitrogen atmosphere and with vigorous agitation, to 123 g ~1 mol) of 3,4-dimethylpyridine-N-oxide which had been carefully dried and powdered, while maintaining the temperature of the reaction mixture between 80 and 90C. When the addition had been completed, the mixture was heated .
to 100C for 2 hours.
In ~nother reaction vessel, 170 g (3.5 moles) of sodium cyanide 'j were dissolved in 570 ml of water with vigorous agitation for 1 hour under a nitrogen atmosphere. The previously obtained methyl sulphate of N-methoxy-,;:
3,4-dimethylpyridinium dissolved in 250 ml of water was added to the sodium cyanide solution while externally cooling the reaction vessel to maintain the ~`
.
-5-.~
, 106827g temperature at between 0 and -5C~ The reaction mixture was then agitated at ambient temperature for 24 hours under a nitrogen atmosphere. The reaction mixture was then extracted with CHC13, the chloroform layer was dried with anhydrous magnesium sulphate, the dried extract was filtered and the CHC13 evaporated off. 69 g of a dark viscous liquid was obtained which was chrom-atographed on a column of silica gel using benzene as the eluant, to provide 57.5 g of a mixture of cyanopyridines which by cooling to 5C provided 22.5 g of 2-cyano-4,5-dimethylpyridine (V).
A sample of the product was recrystallized from ace~one, m.p. 77-78C.
Analysis: calculated for C8H8N2: C,72.70; H,6.10; N,21.30.
found : C,72.61; H,6,17; N,20.93.
Example 2 Preparation of 2-thienly-(4,5-dimethyl-2-pyridyl)-ketone (IV) 26.8 g of thiophene dissolved in 70 ml of anhydrous ether were . .
introduced into a flask which was externally cooled to between -5 and -10C.
To this solution, 375 ml of an 0.85N ethereal solution of freshly prepared butyl lithium were added dropwise over a period of 2 hours under a nitrogen atmosphere. The reaction mixture was then allowed to warm up to ambient ~; 20 temperature and was then boiled under reflux for 30 minutes. The reaction mixture was then cooled to a temperature of from -10 to -20C, and 28.2 g of 2 cyano-4,5-dimethylpyridine ~V) dissolved in anhydrous benzene were add-ed dropwise; the addition took 30 minutes, and boiling under reflux was carried out for a further 30 minutes. After cooling, 250 ml of 30% aqueous ~^~ hydrochloric acid were added and eve~ything which boiled below 100C was elim-ina~ed by distillation. The resulting aqueous solution was boiled under ' reflux for 1 hour, 50% aqueous sodium hydroxide was added until the pH ~as basic, and the mixture was extracted with ethyl acetate. The organic layer was dried with anhydrous sodium sulphate and the solvent was eliminated under reduced pressure. 45.5 g of a crude solid product were obtained, which was
, 106827g temperature at between 0 and -5C~ The reaction mixture was then agitated at ambient temperature for 24 hours under a nitrogen atmosphere. The reaction mixture was then extracted with CHC13, the chloroform layer was dried with anhydrous magnesium sulphate, the dried extract was filtered and the CHC13 evaporated off. 69 g of a dark viscous liquid was obtained which was chrom-atographed on a column of silica gel using benzene as the eluant, to provide 57.5 g of a mixture of cyanopyridines which by cooling to 5C provided 22.5 g of 2-cyano-4,5-dimethylpyridine (V).
A sample of the product was recrystallized from ace~one, m.p. 77-78C.
Analysis: calculated for C8H8N2: C,72.70; H,6.10; N,21.30.
found : C,72.61; H,6,17; N,20.93.
Example 2 Preparation of 2-thienly-(4,5-dimethyl-2-pyridyl)-ketone (IV) 26.8 g of thiophene dissolved in 70 ml of anhydrous ether were . .
introduced into a flask which was externally cooled to between -5 and -10C.
To this solution, 375 ml of an 0.85N ethereal solution of freshly prepared butyl lithium were added dropwise over a period of 2 hours under a nitrogen atmosphere. The reaction mixture was then allowed to warm up to ambient ~; 20 temperature and was then boiled under reflux for 30 minutes. The reaction mixture was then cooled to a temperature of from -10 to -20C, and 28.2 g of 2 cyano-4,5-dimethylpyridine ~V) dissolved in anhydrous benzene were add-ed dropwise; the addition took 30 minutes, and boiling under reflux was carried out for a further 30 minutes. After cooling, 250 ml of 30% aqueous ~^~ hydrochloric acid were added and eve~ything which boiled below 100C was elim-ina~ed by distillation. The resulting aqueous solution was boiled under ' reflux for 1 hour, 50% aqueous sodium hydroxide was added until the pH ~as basic, and the mixture was extracted with ethyl acetate. The organic layer was dried with anhydrous sodium sulphate and the solvent was eliminated under reduced pressure. 45.5 g of a crude solid product were obtained, which was
-6-i lOf~B~79 recrystallized ~rom acetone giving 39.2 g of pure product. The yield was 85%.
An analytical sample was recrystallized from acetone; m.p. 101-103C.
Analysis: calculated for C12HllNS0: C,66.35; H,5.10; N,6.45; S,14.75.
found : C,66.31; HJ5.11; N,6.24; SJ14.31.
Example 3 :
PreParation of 2-(2-thenyl)-4J5-dimethylpyridine tIII) and its hydrochloride 300 ml of diethylene glycol and 53 g of potassium hydroxide were introduced into a 1~ flask and heated until the caustic potash had dissolved.
After cooling to 100CJ 52 g of 2-thienyl-~4J5-dimethyl-2-pyridyl)-ketone ~IV~
and 42.5 ml of 80% hydrazine hydrate were added. The mixture was boiled under `reflux for 1 hour. Everything which boiled below 240C was then eliminated by distillation and this temperature was then maintained for a further 4 hours.
~; The mixture was then cooled to 100C and poured on to ice. The resulting aqueous solution was extracted several times with etherJ the ethereal layer was dried with anhydrous magnesium sulphate and the solvent was eliminated under reduced pressure. The oily residue obtained was distilled at a pressure of 0.5 mm Hg and the fraction boiling over the range of 72C to 113C was re-covered. 23.8 g of 2-(2-thenyl)-4J5-dimethylpyridine (III) was obtained (yield 49%)~
` The hydrochloride was precipitated andJ when recrystallized from anhydrous acetone-methanOlJ had m.p. 142-144C.
Analysis: calculated for C12H14NSCl: CJ6O 11~ HJ5.89; NJ5~85; C1J14.79;
found : CJ60~22; HJ5.95; NJ5.90; C1J14.8O;
SJ13.46.
xample 4 Preparation of 2-(2-thenyl)-1,4,5-trimethyl-1,2,3,6-tetrahydropyridi~e (II) and its hydrochloride A mdxture of 23.8 g of 2-(2-thenyl~-4J5-dimethylpyridine tIII) dissolved in 30 ml of anhydrous acetone and 7 ml of methyl iodide dissolved in 30 ml of anhydrous benzene was boiled under reflux for 8 hours. A white g l -7-10~8Z79 precipitate of 2-~2-thenyl)-1,4,5-trimethylpyridinium iodide was obtained, which when dried weighed 29.6 g. Yield 73~. M p. 159-161C.
This product was dissolved in 150 ml of absolute methanol, the solution was cooled externally with ice, and 6.48 g of NaBH4 was added. Boil-ing under reflux was carried out for 12 hours. The resulting solution was extracted with ether, the ethereal layer was dried with anhydrous MgS04, and the solvent was eliminated under reduced pressure, yielding an oil, (12.7 g, yield 67%), which was purified by distillation between 100 and 104C at 0.15 mm Hg.
The hydrochloride was precipitated and, when recrystallized from anhydrous acetone-absolute ethanol had m.p. 134-135C.
Analysis: calculated for C13H20NSCl: C,60,56; H,7.82; N,5.42; S,12.43; Cl,13.75 found : C,60.28; H,7.78; N,5.41; S,12.27; Cl,13.78 Example S
Preparation of 2,4,5-trimethyl-thienol3,2-f]morphane (I) and its hydrochlor-"
; ide.
4 g of 2-t2-thenyl)-1,4,5-trimethyl-1,2,3,6-tetrahydropyridine (II) and 48 ml of 48% aqueous hydrobromic acid were heated at 130-135C
for 3 1/2 hours. The mixture was then allowed to cool, poured on to a mix-ture of water and ice, rendered alkaline by the addition of concentrated ammonium hydroxide and extracted with ether. The ethereal extract was dried with magnesium sulphate and, after evaporation of the solvent, yielded an oil which was purified by distillation, the fraction which distilled at 100-102C/0.04 mm Hg being recovered. 2.7 g of ~I) were obtained, m.p. 67-68C ~acetone), yield 67%.
The hydrochloride was precipitated and, when recrystallized from acetone-ether, had m.p. 192-194C.
Analysis: calculated for C13H20NSCl.H20: C,56.61; H,8.~4; N,5.08;
found : C,56.57; H,8.06; N,4.61.
iO~Z'79 P~ARMACOLOGICAL TESTS
A comparison of the analgesic activity of the following compounds with respect to dextropropoxyphene was made.
tI~ 2,4,5-trimethyl-thieno[3,2-f]morphan;
(II) 2-~2-thenyl)-1J4,5-trimethyl-1,2,3,6-tetrahydro-pyridine;
(III) 2-(2-thenyl)-4,5-dimethylpyridine;
(IV) 2-thienyl-(4,5-dimethyl-2-pyridyl)-ketone.
A - Acute toxicity .
Studies of acute toxicity were made on I.C.R. Swiss mice weighing 20 - 2 g, of both sexes. The products were administered intraperitoneally (i.p.); calculations of acute toxicity were made by the Litchfield-Wilcoxon method.
:;
.. ~ ..
~ Compound administered LD50 .;
I 61.25 kg/kg II 75 4 ,, III 501.5 "
IV 1,192.3 "
Dextropropoxyphene 140 "
~;!
B - Analgesic activity :::
< a) Thermal analgesia ::, $ The thermal analgesic effect on groups of ten I.C.R. Swiss albino ~ mice was studied using the hot plate technique at 55C.
. ,~ .
~~ The products under investigation were administered intraperitoneally ;~ and after 30 minutes, the mice were placed on the hot plate and the time that ,~
~'~ it took them to jump was measured in seconds. Control groups of animals which had only been injected with distilled water were used. The results obtained are given in Tables 2, 3, 4 and 5 below.
.
106~279 - `
. . .... __ ..
Compound Time to jump Significance of diff-adminis- Dose erences from Dextro-Control tered in secs.* propoxyphene ~ -; - _ .. Control - 28.7 - 3.780 - -I 30 mg/kg 57.8 - 11.078 N.S. p ~ 0.05 Dextropro- ~
Poxn h~ o30 mg/kg 60.9 - 7.785 - p < 0.001 .. , :' .
~ Mean values - standard mean error N.S. - no significance The results show that the compound of formula tI) has substantially the same analgesic activity as dextropropoxyphene, on an equal dose basis.
. . .
. .. ~ . I .
ompound Significance of dminis- Dose Time to jump differences from Dex- Control ered in seconds tropropoxyphene ..... _ .. __ . .... _ ¦ ontrol - 32 - 2.595 - -~,, 20 IV 50 mg/kg 49.8 - 5.000 p ~ 0.005p < 0.002 1 Dextropro-?XYPhone50 ng/kg 94.2 - 16.456 - p< 0.00005 The resulss show that the compound of formula ~lV) has thermal analgesic activity although on an equal dose basis~ it is of lower intensity y than dextropropoxyphene.
,__ _ ._ Compound Significance of.diff- ..
Admdnis- Dose Time to jump erences from Dextro- Control ~: _ered in seconds propoxyphene . _ .. __ . , ............. . __ .
l: Control 48.6 - 5.633 y 30 III 50 mg/kg 89 - 8.544 N.S. p < 0.005 i Dextropro- +
~ poxyphene50 mg/kg72.5 - 10.759 - p ~ 0.05 : ._...................................................... ... _ The results show that the compound of formula tIII) has substan-tially the same analgesic activity as dextropropoxyphene, on an equal dose basis.
TABLE S
.
Compound Time to jump Significance of Adminis- Dose . differences from Control tered m seconds Dextropropoxyphene . .. _..... . ._. . _ Control - 48.6 - 5.633 - -II 50 mg/kg 56 - 1.844 N.S. N.S.
Dextropro- +
poxyphene50 mg,/kg 72.5 - 10.759 - p < 0.05 , .. .. ~
The results show that the compound of formula (II) has no thermal ; analgesic activity.
B) Chemical anal~esia The analgesic effect was studied on groups of ten I.C.R. Swiss albino mice, using the acetic acid writhing technique.
The products under investigation were administered intraperitone-ally and, after 30 minutes, 0.25 ml of 1% acetic acid was injected by the same route. A control group of animals which only received acetic acid was ~, 20 ~' used. The number of writhes of each mouse in the 20 minutes following the administration of the acetic acid were counted.
The results are given in Tables 6, 7, 8 and 9 below.
^,: . -; ~ teredDose writhes ferences from Dextro- Control propoxyphene Control - 56.10 + 0.096 - -(I)30 mg/kg 14.10 - 0.038 p < 0.05P < 0.00005 Dextr~pro- ~
p~n~ ~ 30 me/kg28.30 - 4.721 - p < 0.005 i '' ~
i --1 1--.
The results show that the compound of formula tI) has greater chemical analgesic activity than dextropropoxyphene.
.
. .__ . .
Compound Significance of Adminis- Dose Number of differences from Control tered writhesDextropropoxyphene ~ . . . - .
Control - 73.2 - 9.14 tIV) 30 mg,'kg24.7 - 5.32 N.S. p< 0.002 Dextropro- +
poxyphene 30 mg/kg 35.1 - 6.34 - p ~ 0.01 I
The results show that the compound of formula (IV) has substant-ially the same chemical analgesic a~tivity as dextropropoxyphene.
J
"'i _ . _ Compound Significance of Adminis- Dose Num~er ofdifferences from Control tered WrithesDextropropoxyphene : _.~
Control - 82.7 - 5.687 - -(III) 30 mg/kg 87.8 - 4.661 p <0.0002 N.S.
Dextropro- +
poxythene 30 mg/kg 50.2 - 6.330 - p~ 0.002 ,! ._.. _ ~ . . _... _.. _ . ..... . .. _ ~ ~
~ The results show that the compound of formula tIII) has no chem-;I; ical analgesic activity.
:~ ~ . ._ . . __ ~ ~
Compound Significance of Adminîs- Dose Number of differences from Control tered Writhes Dextropropoxyphene ... ~ -: ~Control - 82.7 - 5.687 - -(II)30 mg/kg 63.7 - 5.235 N.S. p < 0.05 Dextropro- ~
poxyphene 30 mg/kg 50.2 - 6.330 - p < 0.002 , ~ ~
.
.,' .
An analytical sample was recrystallized from acetone; m.p. 101-103C.
Analysis: calculated for C12HllNS0: C,66.35; H,5.10; N,6.45; S,14.75.
found : C,66.31; HJ5.11; N,6.24; SJ14.31.
Example 3 :
PreParation of 2-(2-thenyl)-4J5-dimethylpyridine tIII) and its hydrochloride 300 ml of diethylene glycol and 53 g of potassium hydroxide were introduced into a 1~ flask and heated until the caustic potash had dissolved.
After cooling to 100CJ 52 g of 2-thienyl-~4J5-dimethyl-2-pyridyl)-ketone ~IV~
and 42.5 ml of 80% hydrazine hydrate were added. The mixture was boiled under `reflux for 1 hour. Everything which boiled below 240C was then eliminated by distillation and this temperature was then maintained for a further 4 hours.
~; The mixture was then cooled to 100C and poured on to ice. The resulting aqueous solution was extracted several times with etherJ the ethereal layer was dried with anhydrous magnesium sulphate and the solvent was eliminated under reduced pressure. The oily residue obtained was distilled at a pressure of 0.5 mm Hg and the fraction boiling over the range of 72C to 113C was re-covered. 23.8 g of 2-(2-thenyl)-4J5-dimethylpyridine (III) was obtained (yield 49%)~
` The hydrochloride was precipitated andJ when recrystallized from anhydrous acetone-methanOlJ had m.p. 142-144C.
Analysis: calculated for C12H14NSCl: CJ6O 11~ HJ5.89; NJ5~85; C1J14.79;
found : CJ60~22; HJ5.95; NJ5.90; C1J14.8O;
SJ13.46.
xample 4 Preparation of 2-(2-thenyl)-1,4,5-trimethyl-1,2,3,6-tetrahydropyridi~e (II) and its hydrochloride A mdxture of 23.8 g of 2-(2-thenyl~-4J5-dimethylpyridine tIII) dissolved in 30 ml of anhydrous acetone and 7 ml of methyl iodide dissolved in 30 ml of anhydrous benzene was boiled under reflux for 8 hours. A white g l -7-10~8Z79 precipitate of 2-~2-thenyl)-1,4,5-trimethylpyridinium iodide was obtained, which when dried weighed 29.6 g. Yield 73~. M p. 159-161C.
This product was dissolved in 150 ml of absolute methanol, the solution was cooled externally with ice, and 6.48 g of NaBH4 was added. Boil-ing under reflux was carried out for 12 hours. The resulting solution was extracted with ether, the ethereal layer was dried with anhydrous MgS04, and the solvent was eliminated under reduced pressure, yielding an oil, (12.7 g, yield 67%), which was purified by distillation between 100 and 104C at 0.15 mm Hg.
The hydrochloride was precipitated and, when recrystallized from anhydrous acetone-absolute ethanol had m.p. 134-135C.
Analysis: calculated for C13H20NSCl: C,60,56; H,7.82; N,5.42; S,12.43; Cl,13.75 found : C,60.28; H,7.78; N,5.41; S,12.27; Cl,13.78 Example S
Preparation of 2,4,5-trimethyl-thienol3,2-f]morphane (I) and its hydrochlor-"
; ide.
4 g of 2-t2-thenyl)-1,4,5-trimethyl-1,2,3,6-tetrahydropyridine (II) and 48 ml of 48% aqueous hydrobromic acid were heated at 130-135C
for 3 1/2 hours. The mixture was then allowed to cool, poured on to a mix-ture of water and ice, rendered alkaline by the addition of concentrated ammonium hydroxide and extracted with ether. The ethereal extract was dried with magnesium sulphate and, after evaporation of the solvent, yielded an oil which was purified by distillation, the fraction which distilled at 100-102C/0.04 mm Hg being recovered. 2.7 g of ~I) were obtained, m.p. 67-68C ~acetone), yield 67%.
The hydrochloride was precipitated and, when recrystallized from acetone-ether, had m.p. 192-194C.
Analysis: calculated for C13H20NSCl.H20: C,56.61; H,8.~4; N,5.08;
found : C,56.57; H,8.06; N,4.61.
iO~Z'79 P~ARMACOLOGICAL TESTS
A comparison of the analgesic activity of the following compounds with respect to dextropropoxyphene was made.
tI~ 2,4,5-trimethyl-thieno[3,2-f]morphan;
(II) 2-~2-thenyl)-1J4,5-trimethyl-1,2,3,6-tetrahydro-pyridine;
(III) 2-(2-thenyl)-4,5-dimethylpyridine;
(IV) 2-thienyl-(4,5-dimethyl-2-pyridyl)-ketone.
A - Acute toxicity .
Studies of acute toxicity were made on I.C.R. Swiss mice weighing 20 - 2 g, of both sexes. The products were administered intraperitoneally (i.p.); calculations of acute toxicity were made by the Litchfield-Wilcoxon method.
:;
.. ~ ..
~ Compound administered LD50 .;
I 61.25 kg/kg II 75 4 ,, III 501.5 "
IV 1,192.3 "
Dextropropoxyphene 140 "
~;!
B - Analgesic activity :::
< a) Thermal analgesia ::, $ The thermal analgesic effect on groups of ten I.C.R. Swiss albino ~ mice was studied using the hot plate technique at 55C.
. ,~ .
~~ The products under investigation were administered intraperitoneally ;~ and after 30 minutes, the mice were placed on the hot plate and the time that ,~
~'~ it took them to jump was measured in seconds. Control groups of animals which had only been injected with distilled water were used. The results obtained are given in Tables 2, 3, 4 and 5 below.
.
106~279 - `
. . .... __ ..
Compound Time to jump Significance of diff-adminis- Dose erences from Dextro-Control tered in secs.* propoxyphene ~ -; - _ .. Control - 28.7 - 3.780 - -I 30 mg/kg 57.8 - 11.078 N.S. p ~ 0.05 Dextropro- ~
Poxn h~ o30 mg/kg 60.9 - 7.785 - p < 0.001 .. , :' .
~ Mean values - standard mean error N.S. - no significance The results show that the compound of formula tI) has substantially the same analgesic activity as dextropropoxyphene, on an equal dose basis.
. . .
. .. ~ . I .
ompound Significance of dminis- Dose Time to jump differences from Dex- Control ered in seconds tropropoxyphene ..... _ .. __ . .... _ ¦ ontrol - 32 - 2.595 - -~,, 20 IV 50 mg/kg 49.8 - 5.000 p ~ 0.005p < 0.002 1 Dextropro-?XYPhone50 ng/kg 94.2 - 16.456 - p< 0.00005 The resulss show that the compound of formula ~lV) has thermal analgesic activity although on an equal dose basis~ it is of lower intensity y than dextropropoxyphene.
,__ _ ._ Compound Significance of.diff- ..
Admdnis- Dose Time to jump erences from Dextro- Control ~: _ered in seconds propoxyphene . _ .. __ . , ............. . __ .
l: Control 48.6 - 5.633 y 30 III 50 mg/kg 89 - 8.544 N.S. p < 0.005 i Dextropro- +
~ poxyphene50 mg/kg72.5 - 10.759 - p ~ 0.05 : ._...................................................... ... _ The results show that the compound of formula tIII) has substan-tially the same analgesic activity as dextropropoxyphene, on an equal dose basis.
TABLE S
.
Compound Time to jump Significance of Adminis- Dose . differences from Control tered m seconds Dextropropoxyphene . .. _..... . ._. . _ Control - 48.6 - 5.633 - -II 50 mg/kg 56 - 1.844 N.S. N.S.
Dextropro- +
poxyphene50 mg,/kg 72.5 - 10.759 - p < 0.05 , .. .. ~
The results show that the compound of formula (II) has no thermal ; analgesic activity.
B) Chemical anal~esia The analgesic effect was studied on groups of ten I.C.R. Swiss albino mice, using the acetic acid writhing technique.
The products under investigation were administered intraperitone-ally and, after 30 minutes, 0.25 ml of 1% acetic acid was injected by the same route. A control group of animals which only received acetic acid was ~, 20 ~' used. The number of writhes of each mouse in the 20 minutes following the administration of the acetic acid were counted.
The results are given in Tables 6, 7, 8 and 9 below.
^,: . -; ~ teredDose writhes ferences from Dextro- Control propoxyphene Control - 56.10 + 0.096 - -(I)30 mg/kg 14.10 - 0.038 p < 0.05P < 0.00005 Dextr~pro- ~
p~n~ ~ 30 me/kg28.30 - 4.721 - p < 0.005 i '' ~
i --1 1--.
The results show that the compound of formula tI) has greater chemical analgesic activity than dextropropoxyphene.
.
. .__ . .
Compound Significance of Adminis- Dose Number of differences from Control tered writhesDextropropoxyphene ~ . . . - .
Control - 73.2 - 9.14 tIV) 30 mg,'kg24.7 - 5.32 N.S. p< 0.002 Dextropro- +
poxyphene 30 mg/kg 35.1 - 6.34 - p ~ 0.01 I
The results show that the compound of formula (IV) has substant-ially the same chemical analgesic a~tivity as dextropropoxyphene.
J
"'i _ . _ Compound Significance of Adminis- Dose Num~er ofdifferences from Control tered WrithesDextropropoxyphene : _.~
Control - 82.7 - 5.687 - -(III) 30 mg/kg 87.8 - 4.661 p <0.0002 N.S.
Dextropro- +
poxythene 30 mg/kg 50.2 - 6.330 - p~ 0.002 ,! ._.. _ ~ . . _... _.. _ . ..... . .. _ ~ ~
~ The results show that the compound of formula tIII) has no chem-;I; ical analgesic activity.
:~ ~ . ._ . . __ ~ ~
Compound Significance of Adminîs- Dose Number of differences from Control tered Writhes Dextropropoxyphene ... ~ -: ~Control - 82.7 - 5.687 - -(II)30 mg/kg 63.7 - 5.235 N.S. p < 0.05 Dextropro- ~
poxyphene 30 mg/kg 50.2 - 6.330 - p < 0.002 , ~ ~
.
.,' .
7 `.... '~ ` ~. ~ . ` ` .. , ~O~i8'~79 The results show that the compound of formula tII) has sukstantially the same chemical analgesic activity as dextropropoxyphene.
;
i ~
~-.~ ;
~ 13-
;
i ~
~-.~ ;
~ 13-
Claims (6)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of the compound of formula (IV) (IV) or a pharmaceutically acceptable acid addition salt thereof, which comprises reacting 2-cyano-4,5-dimethylpyridine of the formula (V) with 2-thienyl lithium under an inert atmosphere, subjecting the resulting product to hydrolysis, and where required converting a product obtained in free base form into a pharmaceutically acceptable acid addition salt, or a product obtained in salt form into the free base of formula (IV).
2. A process according to claim 1 wherein the hydrolysis is effected with hydrochloric acid.
3. The compound of formula (IV) defined in claim 1 and its physio-logically acceptable acid addition salts, when prepared by the process of claim 1 or 2 or by an obvious chemical equivalent thereof.
4. A process according to claim 1 or 2 which includes the additional step of reducing the 2-thienyl-(4,5-dimethyl-2-pyridyl)-ketone obtained with hydrazine hydrate in a basic medium to form 2-(2-thenyl)-4,5-dimethylpyridine.
5. A process according to claim 1 or 2 which includes the additional steps of reducing the 2-thienyl-(4,5-dimethyl-2-pyridyl)-ketone obtained with hydrazine hydrate in a basic medium to form 2-(2-thenyl)-4,5-dimethylpyridine;
reacting the latter 2-(2-thenyl)-4,5-dimethyl pyridine with methyl iodide to form 2-(2-thenyl)-1,4-5-trimethylpyridinium iodide and reducing the last named product with sodium borohydride to form 2-(2-thenyl)-1,4,5-trimethyl-1,2,3,6-tetrahydropyridine.
reacting the latter 2-(2-thenyl)-4,5-dimethyl pyridine with methyl iodide to form 2-(2-thenyl)-1,4-5-trimethylpyridinium iodide and reducing the last named product with sodium borohydride to form 2-(2-thenyl)-1,4,5-trimethyl-1,2,3,6-tetrahydropyridine.
6. A process according to claim 1 or 2 which includes the additional steps of reducing the 2-thienyl-(4,5-dimethyl-2-pyridyl)-ketone obtained with hydrazine hydrate in a basic medium to form 2-(2-thenyl)-4,5-dimethyl-pyridine; reacting the latter 2-(2-thenyl)-4,5-dimethyl pyridine with methyl iodide to form 2-(2-thenyl)-1,4,5-trimethylpyridinium iodide, reducing the last named product with sodium borohydride to form 2-(2-thenyl)-1,4,5-tri-methyl-1,2,3,6-tetrahydropyridine, and heating this reduction product in the presence of a strong acid to effect cyclization thereof to 2,4,5-tri-methyl-thieno[3,2-f]morphan.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ES441097A ES441097A1 (en) | 1975-09-19 | 1975-09-19 | Tetrahydropyridine derivatives and preparation thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1068279A true CA1068279A (en) | 1979-12-18 |
Family
ID=8470007
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA261,567A Expired CA1068279A (en) | 1975-09-19 | 1976-09-20 | 2,4,5-trimethyl-thieno (3,2-f) morphan, and intermediates |
Country Status (15)
| Country | Link |
|---|---|
| JP (1) | JPS5248694A (en) |
| AR (1) | AR210612A1 (en) |
| AT (1) | AT347051B (en) |
| BE (1) | BE845755A (en) |
| CA (1) | CA1068279A (en) |
| CH (1) | CH617195A5 (en) |
| DE (1) | DE2639181C3 (en) |
| ES (1) | ES441097A1 (en) |
| FR (5) | FR2362128A1 (en) |
| GB (1) | GB1513980A (en) |
| NL (1) | NL7610437A (en) |
| NZ (1) | NZ181870A (en) |
| PT (1) | PT65547B (en) |
| SE (2) | SE7609357L (en) |
| SU (3) | SU620210A3 (en) |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR1274913A (en) * | 1959-09-09 | 1961-11-03 | Rohm & Haas | Process for cyanidation of nu-heterocyclic compounds and nitriles thus obtained |
-
1975
- 1975-09-19 ES ES441097A patent/ES441097A1/en not_active Expired
-
1976
- 1976-08-24 SE SE7609357A patent/SE7609357L/en not_active Application Discontinuation
- 1976-08-25 GB GB35397/76A patent/GB1513980A/en not_active Expired
- 1976-08-26 NZ NZ181870A patent/NZ181870A/en unknown
- 1976-08-26 AR AR264463A patent/AR210612A1/en active
- 1976-08-31 DE DE2639181A patent/DE2639181C3/en not_active Expired
- 1976-09-01 BE BE170277A patent/BE845755A/en unknown
- 1976-09-02 PT PT65547A patent/PT65547B/en unknown
- 1976-09-09 FR FR7627080A patent/FR2362128A1/en not_active Withdrawn
- 1976-09-16 AT AT687976A patent/AT347051B/en not_active IP Right Cessation
- 1976-09-17 JP JP51110886A patent/JPS5248694A/en active Pending
- 1976-09-17 SU SU762401851A patent/SU620210A3/en active
- 1976-09-17 CH CH1182776A patent/CH617195A5/en not_active IP Right Cessation
- 1976-09-20 NL NL7610437A patent/NL7610437A/en not_active Application Discontinuation
- 1976-09-20 CA CA261,567A patent/CA1068279A/en not_active Expired
-
1977
- 1977-02-21 SU SU772455453A patent/SU671731A3/en active
- 1977-02-21 SU SU772453400A patent/SU650506A3/en active
- 1977-03-30 FR FR7709582A patent/FR2361397A1/en not_active Withdrawn
- 1977-03-30 FR FR7709583A patent/FR2361388A1/en not_active Withdrawn
- 1977-03-30 FR FR7709585A patent/FR2361390A1/en not_active Withdrawn
- 1977-03-30 FR FR7709584A patent/FR2361389A1/en not_active Withdrawn
-
1979
- 1979-08-27 SE SE7907106A patent/SE7907106L/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| ES441097A1 (en) | 1977-03-16 |
| PT65547A (en) | 1976-10-01 |
| SU620210A3 (en) | 1978-08-15 |
| DE2639181A1 (en) | 1977-03-31 |
| FR2361389A1 (en) | 1978-03-10 |
| JPS5248694A (en) | 1977-04-18 |
| NL7610437A (en) | 1977-03-22 |
| DE2639181C3 (en) | 1979-05-31 |
| FR2361397A1 (en) | 1978-03-10 |
| SU671731A3 (en) | 1979-06-30 |
| DE2639181B2 (en) | 1978-10-05 |
| ATA687976A (en) | 1978-04-15 |
| AU1715576A (en) | 1978-03-02 |
| FR2361390A1 (en) | 1978-03-10 |
| GB1513980A (en) | 1978-06-14 |
| SE7609357L (en) | 1977-03-20 |
| NZ181870A (en) | 1978-11-13 |
| PT65547B (en) | 1978-03-24 |
| BE845755A (en) | 1977-03-01 |
| AR210612A1 (en) | 1977-08-31 |
| SE7907106L (en) | 1979-08-27 |
| FR2362128A1 (en) | 1978-03-17 |
| FR2361388A1 (en) | 1978-03-10 |
| CH617195A5 (en) | 1980-05-14 |
| SU650506A3 (en) | 1979-02-28 |
| AT347051B (en) | 1978-12-11 |
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