CA1097659A - Sydnonimine n-acylderivatives and method for preparing same - Google Patents
Sydnonimine n-acylderivatives and method for preparing sameInfo
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- CA1097659A CA1097659A CA284,999A CA284999A CA1097659A CA 1097659 A CA1097659 A CA 1097659A CA 284999 A CA284999 A CA 284999A CA 1097659 A CA1097659 A CA 1097659A
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- Prior art keywords
- phenylethyl
- beta
- methyl
- alpha
- sydnonimine
- Prior art date
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/04—1,2,3-Oxadiazoles; Hydrogenated 1,2,3-oxadiazoles
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Abstract Novel sydnonimine N-acyl derivatives of the formula (I):
(I) wherein R is selected from the group consisting of phenyl, .beta.-phenylethyl, d,1-.alpha.-methyl-.beta.-phenylethyl and 1-.alpha.-methyl-.beta.-phenylethyl:
R' is selected from the group consisting of hydrogen and phenyl;
X is selected from the group consisting of a lower alkyl, phenyl and a group of formula wherein R" is selected from the group consisting of hydrogen, halogen and lower fluorinated alkyl; R"' is selected from the group consisting of hydrogen, halogen and lower alkyl; with the proviso that when X is said group of formula and R', R" and R"' are hydrogen, R is 1-.alpha.-methyl-.beta.-phenylethyl;
the compounds possess a psychostimulant activity at a low toxicity and can be used as the active ingredient of medicine.
(I) wherein R is selected from the group consisting of phenyl, .beta.-phenylethyl, d,1-.alpha.-methyl-.beta.-phenylethyl and 1-.alpha.-methyl-.beta.-phenylethyl:
R' is selected from the group consisting of hydrogen and phenyl;
X is selected from the group consisting of a lower alkyl, phenyl and a group of formula wherein R" is selected from the group consisting of hydrogen, halogen and lower fluorinated alkyl; R"' is selected from the group consisting of hydrogen, halogen and lower alkyl; with the proviso that when X is said group of formula and R', R" and R"' are hydrogen, R is 1-.alpha.-methyl-.beta.-phenylethyl;
the compounds possess a psychostimulant activity at a low toxicity and can be used as the active ingredient of medicine.
Description
~7~
The present invention relates to novel sydnonimine derivatives and a method for preparing them. ~he compounds possess a pronounced psychostimulant activity and can be useful as the act.ive principle of a medicated composition.
The sydnonimine N--acyl derivatives according to the present invention are novel compounds hitherto unknown in the literature.
In accordance with the present invention, novel sydnonimine N-acyl derivatives have the formula (I):
R - N - C - R' N - C = N - C - X (I) \ / 11 O O
wherein R is selected from the group consisting of phenyl, ~-phenylethyl, d,l-~-methyl-~-phenylethyl and l-~-methyl-~-phenylethyl;
R' is selected from the group consisting of hydrogen and phenyl;
X is select~d from the group consisting of a lower alkyl, phenyl and a group of formula R"
wherein R" is selected from the group consisting of hydrogen, halogen and lower fluorinated alkyl: R"' is selected from the group consisting of hydrogen~ halogen and lower alkyl; with the proviso that when X is said group of formula -NH ~R"
R"
The present invention relates to novel sydnonimine derivatives and a method for preparing them. ~he compounds possess a pronounced psychostimulant activity and can be useful as the act.ive principle of a medicated composition.
The sydnonimine N--acyl derivatives according to the present invention are novel compounds hitherto unknown in the literature.
In accordance with the present invention, novel sydnonimine N-acyl derivatives have the formula (I):
R - N - C - R' N - C = N - C - X (I) \ / 11 O O
wherein R is selected from the group consisting of phenyl, ~-phenylethyl, d,l-~-methyl-~-phenylethyl and l-~-methyl-~-phenylethyl;
R' is selected from the group consisting of hydrogen and phenyl;
X is select~d from the group consisting of a lower alkyl, phenyl and a group of formula R"
wherein R" is selected from the group consisting of hydrogen, halogen and lower fluorinated alkyl: R"' is selected from the group consisting of hydrogen~ halogen and lower alkyl; with the proviso that when X is said group of formula -NH ~R"
R"
- 2 ~B .i , R'~ R" and R"' are hydrogen, and R is l-~-methyl-~-phenylethyl.
The compounds are white or white with a yellowish tint crystalline substances stable in the air, sparingly soluble in water, soluble in chloroform and less soluble in alcohol.
In another aspect of the invention there is provided a method of preparing an N-acyl derivative of sydnonimine of formula (I), as defined above9 which comprises reacting an N-nitroso derivative of an N-substituted nitrile of an ~-amino acid of formula (II):
R - N - CH - Rl (II) N C _ N
~0 wherein R and Rl are as defined above, with an acylation agent selected from the group consisting of haloanhydrides of carboxylic acids, anhydrides of carboxylic acids and arylisocyanates, in an organic solvent medium in the pre-sence of a basic catalyst followed by isolation of the product of formula (I).
The compounds are white or white with a yellowish tint crystalline substances stable in the air, sparingly soluble in water, soluble in chloroform and less soluble in alcohol.
In another aspect of the invention there is provided a method of preparing an N-acyl derivative of sydnonimine of formula (I), as defined above9 which comprises reacting an N-nitroso derivative of an N-substituted nitrile of an ~-amino acid of formula (II):
R - N - CH - Rl (II) N C _ N
~0 wherein R and Rl are as defined above, with an acylation agent selected from the group consisting of haloanhydrides of carboxylic acids, anhydrides of carboxylic acids and arylisocyanates, in an organic solvent medium in the pre-sence of a basic catalyst followed by isolation of the product of formula (I).
- 3 ~765~
Psychostimulating activity of the compounds according to the present invention has been tested in experiments with mice and rats.
The experiments are performed with white male mice with a weight of 18-20 g and with white rat males with a weight of 120 to 140 g with the account of parameters characterising the influence of the compounds according to the present inven-tion on the central nervous system as well as toxicity.
Following this objective, there have been studied:
(1) effect of the compounds on khe locomotory acti-vity of the animals (locomotory activity is registered using the instrument "Animex"), (2) capability of the compounds of inducing stereo-typic behaviour reactions;
(3) capability of enhancing a reflex excitability of the animals with respect to the use of tactile stimuli (air jet pointed from a syringe to an animal),
Psychostimulating activity of the compounds according to the present invention has been tested in experiments with mice and rats.
The experiments are performed with white male mice with a weight of 18-20 g and with white rat males with a weight of 120 to 140 g with the account of parameters characterising the influence of the compounds according to the present inven-tion on the central nervous system as well as toxicity.
Following this objective, there have been studied:
(1) effect of the compounds on khe locomotory acti-vity of the animals (locomotory activity is registered using the instrument "Animex"), (2) capability of the compounds of inducing stereo-typic behaviour reactions;
(3) capability of enhancing a reflex excitability of the animals with respect to the use of tactile stimuli (air jet pointed from a syringe to an animal),
(4) acute (24-hours) toxicity of the compounds in individually kept mice and mice placed into standard cages by 10 animals in each cage, l.e. so-called "group toxicity", To quantitatively evaluake the central stimulant activity of the compounds in the:testson mice the values of ED200 (locomotion) are determined, l.e. doses in which the compounds cause a two-fold potentiakion of locomotory acti-vity of the animals; in the tesks performed wikh rats there are determined values of ED50 (stereotypy~, i.eO doses in : which the compour-ds, one hour after their administration, cause, in 5~/O of the test rats, stereotypic behaviour reactions (ED 0 doses are calculated by the Litchfield and Wilkoxsons method), The compounds according to the present invention _ 4 --~7~
are sparingly soluble in water. They were administered to the animals in the form of a suspension prepared with the use of a 1% solution of carboxymethylcellulose with the addition of Twin-80 as an emulsifying agent. Since molecular weights of the test compounds differ from each other, their doses are calculated in mcM/kg.
The compounds according to the present invention provide an exciting effect in the central nervous system which is demonstrated in mice and rats by an enhanced locomotory acitivity thereof. Thus, minimal doses, which permanently cause a pronounced locomotory hyperactivity in the animals, of the above-mentioned compounds of the formula (1), wherein R is PhCH2CH2 or R is d,l -PhCH2(C~3)CH; with Rt = H and X ~ NHC6H4Cl - para, or X = NHC6H3C12-meta, para - are 7 to 10 mcM/Xg, while for the compounds of the formula (1) with R = d,1 -PhCH2(CH3)CH, R' = H, at X = NH-C6H4CF3-meta or X = NH-C6H4CH3-para and for the compounds of the formula (1) 6 5 2 2' H, X = NH-C6H4CF3-meta, minimal active doses are 15 to 20 mcM/kg. The simulant effect of these doses is observed after 10-15 rninutes after administra-tion reaching its maximum after 30-50 minutes at a total duration of the effect of 1.5-2 hours. when these doses are increased by 3-4 times (with mice) and 1~5-2 times Iwlth rats), the intensity and duration of the locomotory hyperactivity is also increased. Further increase in doses results in the origination of stereotypic behaviour reactions with the animals which is manifested by swing motions of the head and fore limbs, smelling and licking the case floor. The stereo-typy duration at high-doses is 6 to 8 hours.
In a special series of experiments there has been made a quantitative comparison of the central stimulant effect ~71~
of the compounds according to the present invention as deter-mined by tests of locomotory activity with rnice and stereotypy with rats. Certain results of these experiments are presented in the following Table.
Table Activity of the compounds of the formula (1): R=d,l C6H5CH2 (CH3)CH RT=H, as by tests for locomotory excitation with mice (ED200) and stereotypic behaviour with rats (ED50).
.. . ... , _ . . . ........... _ Compounds of the present ED2oo(locomo- ED50 (stereotypy), invention tion)for mice, for rats, mcM/kg mcM~kg of the formula ~1), wherein:
X = NH-C6H4Cl - para 18.2 20.0 X iS NH-C6H~-CF3 - meta 32.3 39.9 , The compound of the formula (1) according to the present invention, wherein R is 1 -PhCH2(CH3)CH, R' = H, X =NHC6H5 in doses of from 3 to 5 mcM/kg causes a moderate tactile hyperreflexia and in doses of from 6 to 8 mcM~kg ~ an acute tactile hyperreflexia. The latter is clearly pronounced with mice-by a series of strong sudden jumps occurring right at the moment of contact with the air jet, Within the doses range of from 9 to 80 mcM/kg this compound increase the locomotory activity of mice in the direct relationship be-tween this effect value and dose logarythm~ The locomotory activity value is doubled upon administration of the dose of ED200 within the range of from 30 to 35 mcM/kg. With the dose of ~0 mcM/kg, the increase in the locomotory activity reaches - its ma~imum within 20 to 30 minutes after the compound administration and is maintained at this level during the next
are sparingly soluble in water. They were administered to the animals in the form of a suspension prepared with the use of a 1% solution of carboxymethylcellulose with the addition of Twin-80 as an emulsifying agent. Since molecular weights of the test compounds differ from each other, their doses are calculated in mcM/kg.
The compounds according to the present invention provide an exciting effect in the central nervous system which is demonstrated in mice and rats by an enhanced locomotory acitivity thereof. Thus, minimal doses, which permanently cause a pronounced locomotory hyperactivity in the animals, of the above-mentioned compounds of the formula (1), wherein R is PhCH2CH2 or R is d,l -PhCH2(C~3)CH; with Rt = H and X ~ NHC6H4Cl - para, or X = NHC6H3C12-meta, para - are 7 to 10 mcM/Xg, while for the compounds of the formula (1) with R = d,1 -PhCH2(CH3)CH, R' = H, at X = NH-C6H4CF3-meta or X = NH-C6H4CH3-para and for the compounds of the formula (1) 6 5 2 2' H, X = NH-C6H4CF3-meta, minimal active doses are 15 to 20 mcM/kg. The simulant effect of these doses is observed after 10-15 rninutes after administra-tion reaching its maximum after 30-50 minutes at a total duration of the effect of 1.5-2 hours. when these doses are increased by 3-4 times (with mice) and 1~5-2 times Iwlth rats), the intensity and duration of the locomotory hyperactivity is also increased. Further increase in doses results in the origination of stereotypic behaviour reactions with the animals which is manifested by swing motions of the head and fore limbs, smelling and licking the case floor. The stereo-typy duration at high-doses is 6 to 8 hours.
In a special series of experiments there has been made a quantitative comparison of the central stimulant effect ~71~
of the compounds according to the present invention as deter-mined by tests of locomotory activity with rnice and stereotypy with rats. Certain results of these experiments are presented in the following Table.
Table Activity of the compounds of the formula (1): R=d,l C6H5CH2 (CH3)CH RT=H, as by tests for locomotory excitation with mice (ED200) and stereotypic behaviour with rats (ED50).
.. . ... , _ . . . ........... _ Compounds of the present ED2oo(locomo- ED50 (stereotypy), invention tion)for mice, for rats, mcM/kg mcM~kg of the formula ~1), wherein:
X = NH-C6H4Cl - para 18.2 20.0 X iS NH-C6H~-CF3 - meta 32.3 39.9 , The compound of the formula (1) according to the present invention, wherein R is 1 -PhCH2(CH3)CH, R' = H, X =NHC6H5 in doses of from 3 to 5 mcM/kg causes a moderate tactile hyperreflexia and in doses of from 6 to 8 mcM~kg ~ an acute tactile hyperreflexia. The latter is clearly pronounced with mice-by a series of strong sudden jumps occurring right at the moment of contact with the air jet, Within the doses range of from 9 to 80 mcM/kg this compound increase the locomotory activity of mice in the direct relationship be-tween this effect value and dose logarythm~ The locomotory activity value is doubled upon administration of the dose of ED200 within the range of from 30 to 35 mcM/kg. With the dose of ~0 mcM/kg, the increase in the locomotory activity reaches - its ma~imum within 20 to 30 minutes after the compound administration and is maintained at this level during the next
5 hour.
In tests on mice, minimal lethal doses (i.e. doses killing 10 to 200/o of the test animals) of the compounds accord-ing to the present invention are within the range of from 200 to 2,000 mcM/kg which is by 25-100 times higher than the dosage causing a clearly pronounced pharmacological activity -locomotory hyperractivity-of mice. It should be noted that toxicity of the compounds is not increased upon administration of the test compounds to the group-housing animals, i.e. there is no phenomenon of "group toxicity" which is characteristic for a series of known psychostimulant compounds such as amphetamine or dextramphetamine.
Therefore, the compounds according to the present invention are low-toxic and in small doses cause an intensive excitation of animals which is characteristic of psychostimu-lant preparations.
Known in the art is a derivative of sydnonimine, i.e. d,l-N-phenylcarbamoyl-3-(~-methyl- ~-phenylethyl) syndo-nimine which also possesses a psychostimulant activity. Com-parison of this prior art compound with those of the present -invention shows however, that the novel compounds according to the present invention are 2-4 times as active as those of the prior art in experiments with animals. Thus, a known compound, i.e. d,l-~-phenylcarbamoyl-3-(~-methyl- ~- phenyl-ethyl) sydnonimine is characterised by values of ED200 of 7~.6 mcM/kg (for locomotion3 and ED50 of 107.1 mcM/~g (for stereotypy), thls means that to achieve the same pharmacologi-cal effect, it is necessary to administer doses 2-4 times as high as those of the compounds according to the present invention.
Most active among the compounds according to the present invention are:
N-para-chlorophenylcarbamoyl-3-( ~ -phenylethyl) sydnonimine of the formula:
-CH2 - CH2 - N - fH
N + C = N - C - NH - ~ -Cl O O
and d,l-N-para-chlorophenylcarbamoyl-3-( ~ -methyl- ~- phenyl-ethyl)-sydnonimine of the formula:
CH3 N + C = N - C - NH - ~ - Cl O O
The novel compounds, viz. N~acylderivatives of sydnonimine according to the present invention are prepared by reacting N-nitrosoderivatives of N-substituted nitriles of ~- aminoacids of the formula:
R - N - CH - R' N~ C - N (lI) wherein R is phenyl, ~ -phenylethyl, d,l - ~ -methyl- ~ -phenylethyl, 1- ~ -methyl~ phenylethyl; R' is H, phenyl, when Rl is phenyl, R is phenyl only, with an acylation agent in a solvent medium in the presence of a basic-character catalyst, followed by isolation of the desired product~ As the acylation agent it is advisable to use haloanhydrides, anhydrides of carboxylic acids or arylisocyanates. It is preferable to use, as the solvent, benzene, toluene, di-chloroethane. As the catalyst use can be made of various bases, however, it is better to use, as the catalyst, triethylamine, dimethylbenzylamine, N-methylmorpholine. The réaction is conducted both at room temperature and upon heating, dependiny on the acylation agent activity. It is preferable to conduct the reaction at a temperature within the range of between 40 to 60C.
The method according to the present invention is performed in the following manner.
To a solution of N-nitrosoderivatives of ~-sub-stituted nitriles of ~ -aminoacids of the formula (II) there are added a basic-character catalyst and an acylation agent.
The reaction mixture is preferably heated to a temperature within the range of from 40 to 60C to accelerate the process.
On completion of the reaction the desired product is recovered from the reaction mass by conventional methods.
As the acylation agents in the reaction according to the present invention varlous electrophylic reagents can be used such as anhydrides and chloroanhydrides of carboxylic acids, arylisocyanates. As the catalyst use can be made of various bases; it has been found that most suitable for the acceleration of the reaction is triethylamine; slightly slower the reaction proceeds in the presence of dimethylbenzylamine, N-methylmorphoIine; use can be also made of other bases such as imidazole, pyridine, quinoxaline and the like. The reaction speed substantially depends on the solvent employed while being increased (in the aase of triethylamine as the catalyst) in the serieso chloroform >hexane ~toluene > benzene >chloro benzene > O-dichlorobenze > 1,2-dichloroethane >nitrobenzene.
It is preferred to use toluene or benzene, since the starting compounds are well soluble in these solvents, whereas the reaction products, i.e~ corresponding N-acylderivatives of sydnonimine, are not soluble, as a rule, in these particular solvents, wherefore they are precipitated in their pure form.
The reaction can occur in water, but in this case the acylation agent vigorously reacts with water, for ~ ~ 7$~
this reason~ it is more suitab~e ~o conduct the reaction in orga~ic hydroxyl-frae solvents.
~he reaction can be per~orm~d a-t room tempera-ture, espe-cially in the case o-~ active acylation agents; however, the process rate is rapidly increased with increasing ternperature.
At high temporatures there may occur a thermal decomposition of the starting nitrosoderivative, wherefora it is pre~era~le to carry out the process at a temperature within an optimal range o~ ~rom 40 to 60C. The desired product yie~d ranges from 80 to 90~0 o~ the theoretical~
~or a ~etter ùnderstanding o~ the present inven~ion9 some specific ~xamples illu~trating the method ~or preparing the nove~ N-acylderivative~ o~ sydnonimine are given herein-be~ow.
~amp~.e 1 c;~ /
B To a so~utio~ of 5 g o~ ~ N-n~troso-N-~c~-methy~
ph~ny~ethy~)-aminoaceto~itri~e in 70 m~ o~ dr~ benzene thsre are added 6.7 ml o~ triethy:Lami:~e and 5095 m~ of acetic an-hydride. ~ter heatixlg :e02 3 ho~s ~ the temparatslra o~
50C the xeaction mass is avapora~ed to dr~e~s; the residue is ground with et:he:r; the preclpitate is filtered-off,washad with water to give 5~3 g (83.5%) o~ acet7~-3~(cC~
met~ pheny~et~l)s~dno~ a m~lti~s a~ 98 99~C. ~olmd, %: C 63,46; H 6018; N 17~040 C,~3~15~302~ CalU~ateds %:
C 63.60; H 6.16 ~ 17c12, ~7~5~
Example 2 To a solution of 1 g of d,l-N-nitroso-N-phenyl-~-aminophenylacetonitrile in 10 mllof dry benzene there are added 1.15 ml of triethylamine and 0.49 ml of benzoyl chloride.
r~he mixture is stirred for 3 hours at the temperature of 50C, the residue is treated with dry ether, the precipitate is filtered-off and washed with water. The yield of N-benzoyl-3,4-diphenylsydnonimine is 0.87 g, melting point is le5-187C
(with decomposition). Found, %: C 73.75 H 4.46 N 11.73.
C21H15N302. Calculated, %: C 73.gO H 4.44 N 12.31.
Example 3 To a solution of 0.70 g of l-N-nitroso-N-(~-methyl--phenylethyl)aminoacetonitrile in 7 ml of dry benzene there are added 0.65 ml of triethylamine and 0.42 ml of phenyliso-cyanate; after 3 hours, the reaction mass is heated, to the temperature of 50C, then it is cooled, the precipitate is filtered-off, washed with benzene, dried and recrystallized from isopropanol to gi~e 0.96 g (86.5%) of the desired product i.e. 1-3-(~-methyl- ~ -phenylethyl)-N-phenylcarbamoylsydnoni-mine comprising a white powder with a yellowish tint sub-stantially insoluble in water but soluble in fats, acetone, chloroform: its melting point is 150 152C (with decomposi-tion), specific rotation ~= -254~5 (acetone,c=l~; it has three maximum points in UV-spectrum: ~max = 204 mn, 259 nm, 341 nm (ethanol). Found,%: C 67~41 H 5.74 ~ 17.23.
C18H18~402. Calculated,%: C 67.06 H 5.63 N 17.38.
Example 4 A solution o~ 2003 g (0.01 mo~) of` ~7~(T~ ~itroso-~--( oC methy~- ~ pheny~ethyl) aminoacetonitril~, 1.54 g (0.01 mol) of paxa-chlorophenylisoc~anate and 1041 ml (0.01 mol~
o~ tri~thylamin0 in 20 m~ o~ dry benzene is heated for 4 hours a-t the temperature o~ 50QC; then the so~ution is coolod, the precipitate is6~ ~ter~d-o~9 wash0d with benze~e to give 3.0 g (85.4%) o~ N-para-chloro~hen~lcarbamo~l-3-( ~ -methy~ phenyle~hyl)sydnonimineg melting at 128-130C
(decompositionj. ~ou~d, %: C 6Q60 H 4.92 N 15.47.
C1gH17ClN402~ CaLculat0dg 50 C 60o59 l:I 4 79 N '15 70 IR-spectrum, cm ~: 1,64~; 1,590, 1,530; 3~140~ ~R-spectrum (in CDCl2 relative to ~S)~ ~8.10 ppm; 9.30 ppm.
Examp~ 5 r~he process is conducted inz.~anner similar to that described in the foregoing E~ample 49 e~cept that as the cat~st use is made o~ 5 m~ o~ dimethy~b~nzylamine (instead o~ triethy~ami~e); th~ ~ield o~ thc dasired pro~uct is 85~o by weight of th~ theoretical va~ue~
E~ampl~ 6 The proc3~ ~s conducted i~ a ma~ner simi~ar to that described i~ ~xamp~e 4 hsreLnbe~ore~ e~cept that as ths cata-lyst u~e is made o~ 6 m~ o~ N-m~thylmorpho~i~o ~i~stsad of triethylamine~; th~ ~ield o~ th~ desired product is 85% o~
the theoretical valuQ.
: - 13 -.. . . ...
- . : . , ' ' ' ~ , '' .. - , . : . .. .. :
. . . ... . .. . .. . . . . . ..
"
.
.
~LQ'a7~i59 Example 7 d,l-~-nitroso~ methyl- ~ -phenylethyl)amino-acetonitrile is reacted with meta-, para-dichlorophenyliso-cyanate following the procedure described in the foregoing Example 4 at the temperature of 40C. There is obtained d,l-meta, para-dichlorophenylcarbamoyl-3-(~-methyl- ~ -phenyl-ethyl)sydnonimine; the yield is 88% of the theory, melting point is 128-129C (with decomposition). Found, %: C54.92, 18 16 2 4 2- Calculated, % C 55.20, H 4.13 N 14.31 IR-spectrum, cm : 1,645; 1,580; 1,515. PMR-spectrum (in CDC13 relative to TMS)~ 8.12, 9.52 ppm.
Example 8 d,l-N-nitroso-N-(~-methyl- ~ -phenylethyl)amino-acetonitrile is reacted with meta -trifluoromethylphenyl-isocyanate in a manner similar to that described in Example 4 hereinbefore. There is obtained d,l-N-meta -trifluoromethyl-phenylcarbamoyl-3-( ~-methyl- ~ -phenylethyl)sydnonimine;
the yield is 81.5% of the theory; melting point is 150-152C (with decomposition). Found, %: C 58.22; H 4.10, N 14.26. ClgH17F3N4O2. Calculated, %: C 58.50, H 4.39;
N 14.37. IR-spectrum, cm : 1,642, 1,595; 1,540: 3,168. PMR-spectrum (in CDC13, relative to TMS) ~: 8.14, 9.56 ppm.
Example 9 N-nitroso-N-( ~ -phenylethyl)aminoacetonitrile is reacted with meta-para-dichlorophenylisocyanate following the procedure described in Example 4 hereinbefore. There is obtained N-meta-, para-dichlorophenylcarbamoyl-3-( ~-phenyl-'' . .' ' ' .. : .
~C~7~9 ethyl)sydnonimine, the yield is 85.5% of the theory, melting point is 137-138C (with decomposition). Found, %- C 54.26, ; 17 14 2 4 2 H 3.74, N 14.85. IR-spectrum, cm : 1,653, 1,580; 1,510.
PMR-spectrum (in CDC13 relative to TMS),~: 8.08, 9,52 ppm.
Example 10 N-nitroso-N- ( ~-phenylethyl)aminoacetonitrile is reacted with meta-trimfluoromethylphenylisocy~nate following the procedure described in the foregoing Example 4 to give N-meta-trifluorophenylcarbamoyl-3~ phenylethyl)-sydnoni-mine; the yield is 82.2% of the theoretical value; melting point is 143-14SC (with decomposition). Found, %: C 57.50;
18H15F3N402. Calculated, %: C 57 30;
H 4.02; N 14.89. IR-spectrum, cm : 1,640; 1,595, L,538;
3,165. iPMR-spectrum (in CDC13 relative to TMS), ~ 8.12;
9.52 ppm.
Example 11 d,l-N-nitroso-N~ methyl~ ~-phenylethyl)aminoaceto-nitrile lS reacted with para-tolylisocyanate following the proced~re described in Example 4 hereinbefore-at~the tempera-ture of 60CC. There is obtained d,l-N-para-tolylcarbamoyl-3-(~-methyl- G~phenylethyl)sydnonimine, the yield is 85% of the theoretical value; melting point is 128-130C (with decomposi-tion). Found, %: C 67,67, H 5.91; ~ 16.62. ClgH20N4O2.
Calculated, %: C 67.91; H 5.93; ~ 16.63. IR-spectrum, cm 1 1,645; 1,595; 1,540. PMR-spectrum (in CDC13 relative to TMS) ~ 8.10; 9.07 pp~.
.
5~
Example 12 The -orocess is conductsd in a manner simi~ar to tha~
described i~ Exa~ple 4~ 0xcept that toluene is used as a sol-vent. ~ho yield of the dasired product is 86~ of the theore-tical value.
Ex~nple 13 ~ h~ process is conducted in a manner similar to that described in the foregoing Examp~e 4, e~cept that dry dichlo-roetha~e is used as a so~vent. On co~pletion of the reaction the reactio~ mass is ev~porated to dryness; the residue is ground in ether, ~i~tered-o~X and recr~sta~lized from iso-propano~. ~he yield of the desired product is 80% of the theoretical value.
~ 16 -~ ., ' ' - ' ' , : -, , ,. ,,:
In tests on mice, minimal lethal doses (i.e. doses killing 10 to 200/o of the test animals) of the compounds accord-ing to the present invention are within the range of from 200 to 2,000 mcM/kg which is by 25-100 times higher than the dosage causing a clearly pronounced pharmacological activity -locomotory hyperractivity-of mice. It should be noted that toxicity of the compounds is not increased upon administration of the test compounds to the group-housing animals, i.e. there is no phenomenon of "group toxicity" which is characteristic for a series of known psychostimulant compounds such as amphetamine or dextramphetamine.
Therefore, the compounds according to the present invention are low-toxic and in small doses cause an intensive excitation of animals which is characteristic of psychostimu-lant preparations.
Known in the art is a derivative of sydnonimine, i.e. d,l-N-phenylcarbamoyl-3-(~-methyl- ~-phenylethyl) syndo-nimine which also possesses a psychostimulant activity. Com-parison of this prior art compound with those of the present -invention shows however, that the novel compounds according to the present invention are 2-4 times as active as those of the prior art in experiments with animals. Thus, a known compound, i.e. d,l-~-phenylcarbamoyl-3-(~-methyl- ~- phenyl-ethyl) sydnonimine is characterised by values of ED200 of 7~.6 mcM/kg (for locomotion3 and ED50 of 107.1 mcM/~g (for stereotypy), thls means that to achieve the same pharmacologi-cal effect, it is necessary to administer doses 2-4 times as high as those of the compounds according to the present invention.
Most active among the compounds according to the present invention are:
N-para-chlorophenylcarbamoyl-3-( ~ -phenylethyl) sydnonimine of the formula:
-CH2 - CH2 - N - fH
N + C = N - C - NH - ~ -Cl O O
and d,l-N-para-chlorophenylcarbamoyl-3-( ~ -methyl- ~- phenyl-ethyl)-sydnonimine of the formula:
CH3 N + C = N - C - NH - ~ - Cl O O
The novel compounds, viz. N~acylderivatives of sydnonimine according to the present invention are prepared by reacting N-nitrosoderivatives of N-substituted nitriles of ~- aminoacids of the formula:
R - N - CH - R' N~ C - N (lI) wherein R is phenyl, ~ -phenylethyl, d,l - ~ -methyl- ~ -phenylethyl, 1- ~ -methyl~ phenylethyl; R' is H, phenyl, when Rl is phenyl, R is phenyl only, with an acylation agent in a solvent medium in the presence of a basic-character catalyst, followed by isolation of the desired product~ As the acylation agent it is advisable to use haloanhydrides, anhydrides of carboxylic acids or arylisocyanates. It is preferable to use, as the solvent, benzene, toluene, di-chloroethane. As the catalyst use can be made of various bases, however, it is better to use, as the catalyst, triethylamine, dimethylbenzylamine, N-methylmorpholine. The réaction is conducted both at room temperature and upon heating, dependiny on the acylation agent activity. It is preferable to conduct the reaction at a temperature within the range of between 40 to 60C.
The method according to the present invention is performed in the following manner.
To a solution of N-nitrosoderivatives of ~-sub-stituted nitriles of ~ -aminoacids of the formula (II) there are added a basic-character catalyst and an acylation agent.
The reaction mixture is preferably heated to a temperature within the range of from 40 to 60C to accelerate the process.
On completion of the reaction the desired product is recovered from the reaction mass by conventional methods.
As the acylation agents in the reaction according to the present invention varlous electrophylic reagents can be used such as anhydrides and chloroanhydrides of carboxylic acids, arylisocyanates. As the catalyst use can be made of various bases; it has been found that most suitable for the acceleration of the reaction is triethylamine; slightly slower the reaction proceeds in the presence of dimethylbenzylamine, N-methylmorphoIine; use can be also made of other bases such as imidazole, pyridine, quinoxaline and the like. The reaction speed substantially depends on the solvent employed while being increased (in the aase of triethylamine as the catalyst) in the serieso chloroform >hexane ~toluene > benzene >chloro benzene > O-dichlorobenze > 1,2-dichloroethane >nitrobenzene.
It is preferred to use toluene or benzene, since the starting compounds are well soluble in these solvents, whereas the reaction products, i.e~ corresponding N-acylderivatives of sydnonimine, are not soluble, as a rule, in these particular solvents, wherefore they are precipitated in their pure form.
The reaction can occur in water, but in this case the acylation agent vigorously reacts with water, for ~ ~ 7$~
this reason~ it is more suitab~e ~o conduct the reaction in orga~ic hydroxyl-frae solvents.
~he reaction can be per~orm~d a-t room tempera-ture, espe-cially in the case o-~ active acylation agents; however, the process rate is rapidly increased with increasing ternperature.
At high temporatures there may occur a thermal decomposition of the starting nitrosoderivative, wherefora it is pre~era~le to carry out the process at a temperature within an optimal range o~ ~rom 40 to 60C. The desired product yie~d ranges from 80 to 90~0 o~ the theoretical~
~or a ~etter ùnderstanding o~ the present inven~ion9 some specific ~xamples illu~trating the method ~or preparing the nove~ N-acylderivative~ o~ sydnonimine are given herein-be~ow.
~amp~.e 1 c;~ /
B To a so~utio~ of 5 g o~ ~ N-n~troso-N-~c~-methy~
ph~ny~ethy~)-aminoaceto~itri~e in 70 m~ o~ dr~ benzene thsre are added 6.7 ml o~ triethy:Lami:~e and 5095 m~ of acetic an-hydride. ~ter heatixlg :e02 3 ho~s ~ the temparatslra o~
50C the xeaction mass is avapora~ed to dr~e~s; the residue is ground with et:he:r; the preclpitate is filtered-off,washad with water to give 5~3 g (83.5%) o~ acet7~-3~(cC~
met~ pheny~et~l)s~dno~ a m~lti~s a~ 98 99~C. ~olmd, %: C 63,46; H 6018; N 17~040 C,~3~15~302~ CalU~ateds %:
C 63.60; H 6.16 ~ 17c12, ~7~5~
Example 2 To a solution of 1 g of d,l-N-nitroso-N-phenyl-~-aminophenylacetonitrile in 10 mllof dry benzene there are added 1.15 ml of triethylamine and 0.49 ml of benzoyl chloride.
r~he mixture is stirred for 3 hours at the temperature of 50C, the residue is treated with dry ether, the precipitate is filtered-off and washed with water. The yield of N-benzoyl-3,4-diphenylsydnonimine is 0.87 g, melting point is le5-187C
(with decomposition). Found, %: C 73.75 H 4.46 N 11.73.
C21H15N302. Calculated, %: C 73.gO H 4.44 N 12.31.
Example 3 To a solution of 0.70 g of l-N-nitroso-N-(~-methyl--phenylethyl)aminoacetonitrile in 7 ml of dry benzene there are added 0.65 ml of triethylamine and 0.42 ml of phenyliso-cyanate; after 3 hours, the reaction mass is heated, to the temperature of 50C, then it is cooled, the precipitate is filtered-off, washed with benzene, dried and recrystallized from isopropanol to gi~e 0.96 g (86.5%) of the desired product i.e. 1-3-(~-methyl- ~ -phenylethyl)-N-phenylcarbamoylsydnoni-mine comprising a white powder with a yellowish tint sub-stantially insoluble in water but soluble in fats, acetone, chloroform: its melting point is 150 152C (with decomposi-tion), specific rotation ~= -254~5 (acetone,c=l~; it has three maximum points in UV-spectrum: ~max = 204 mn, 259 nm, 341 nm (ethanol). Found,%: C 67~41 H 5.74 ~ 17.23.
C18H18~402. Calculated,%: C 67.06 H 5.63 N 17.38.
Example 4 A solution o~ 2003 g (0.01 mo~) of` ~7~(T~ ~itroso-~--( oC methy~- ~ pheny~ethyl) aminoacetonitril~, 1.54 g (0.01 mol) of paxa-chlorophenylisoc~anate and 1041 ml (0.01 mol~
o~ tri~thylamin0 in 20 m~ o~ dry benzene is heated for 4 hours a-t the temperature o~ 50QC; then the so~ution is coolod, the precipitate is6~ ~ter~d-o~9 wash0d with benze~e to give 3.0 g (85.4%) o~ N-para-chloro~hen~lcarbamo~l-3-( ~ -methy~ phenyle~hyl)sydnonimineg melting at 128-130C
(decompositionj. ~ou~d, %: C 6Q60 H 4.92 N 15.47.
C1gH17ClN402~ CaLculat0dg 50 C 60o59 l:I 4 79 N '15 70 IR-spectrum, cm ~: 1,64~; 1,590, 1,530; 3~140~ ~R-spectrum (in CDCl2 relative to ~S)~ ~8.10 ppm; 9.30 ppm.
Examp~ 5 r~he process is conducted inz.~anner similar to that described in the foregoing E~ample 49 e~cept that as the cat~st use is made o~ 5 m~ o~ dimethy~b~nzylamine (instead o~ triethy~ami~e); th~ ~ield o~ thc dasired pro~uct is 85~o by weight of th~ theoretical va~ue~
E~ampl~ 6 The proc3~ ~s conducted i~ a ma~ner simi~ar to that described i~ ~xamp~e 4 hsreLnbe~ore~ e~cept that as ths cata-lyst u~e is made o~ 6 m~ o~ N-m~thylmorpho~i~o ~i~stsad of triethylamine~; th~ ~ield o~ th~ desired product is 85% o~
the theoretical valuQ.
: - 13 -.. . . ...
- . : . , ' ' ' ~ , '' .. - , . : . .. .. :
. . . ... . .. . .. . . . . . ..
"
.
.
~LQ'a7~i59 Example 7 d,l-~-nitroso~ methyl- ~ -phenylethyl)amino-acetonitrile is reacted with meta-, para-dichlorophenyliso-cyanate following the procedure described in the foregoing Example 4 at the temperature of 40C. There is obtained d,l-meta, para-dichlorophenylcarbamoyl-3-(~-methyl- ~ -phenyl-ethyl)sydnonimine; the yield is 88% of the theory, melting point is 128-129C (with decomposition). Found, %: C54.92, 18 16 2 4 2- Calculated, % C 55.20, H 4.13 N 14.31 IR-spectrum, cm : 1,645; 1,580; 1,515. PMR-spectrum (in CDC13 relative to TMS)~ 8.12, 9.52 ppm.
Example 8 d,l-N-nitroso-N-(~-methyl- ~ -phenylethyl)amino-acetonitrile is reacted with meta -trifluoromethylphenyl-isocyanate in a manner similar to that described in Example 4 hereinbefore. There is obtained d,l-N-meta -trifluoromethyl-phenylcarbamoyl-3-( ~-methyl- ~ -phenylethyl)sydnonimine;
the yield is 81.5% of the theory; melting point is 150-152C (with decomposition). Found, %: C 58.22; H 4.10, N 14.26. ClgH17F3N4O2. Calculated, %: C 58.50, H 4.39;
N 14.37. IR-spectrum, cm : 1,642, 1,595; 1,540: 3,168. PMR-spectrum (in CDC13, relative to TMS) ~: 8.14, 9.56 ppm.
Example 9 N-nitroso-N-( ~ -phenylethyl)aminoacetonitrile is reacted with meta-para-dichlorophenylisocyanate following the procedure described in Example 4 hereinbefore. There is obtained N-meta-, para-dichlorophenylcarbamoyl-3-( ~-phenyl-'' . .' ' ' .. : .
~C~7~9 ethyl)sydnonimine, the yield is 85.5% of the theory, melting point is 137-138C (with decomposition). Found, %- C 54.26, ; 17 14 2 4 2 H 3.74, N 14.85. IR-spectrum, cm : 1,653, 1,580; 1,510.
PMR-spectrum (in CDC13 relative to TMS),~: 8.08, 9,52 ppm.
Example 10 N-nitroso-N- ( ~-phenylethyl)aminoacetonitrile is reacted with meta-trimfluoromethylphenylisocy~nate following the procedure described in the foregoing Example 4 to give N-meta-trifluorophenylcarbamoyl-3~ phenylethyl)-sydnoni-mine; the yield is 82.2% of the theoretical value; melting point is 143-14SC (with decomposition). Found, %: C 57.50;
18H15F3N402. Calculated, %: C 57 30;
H 4.02; N 14.89. IR-spectrum, cm : 1,640; 1,595, L,538;
3,165. iPMR-spectrum (in CDC13 relative to TMS), ~ 8.12;
9.52 ppm.
Example 11 d,l-N-nitroso-N~ methyl~ ~-phenylethyl)aminoaceto-nitrile lS reacted with para-tolylisocyanate following the proced~re described in Example 4 hereinbefore-at~the tempera-ture of 60CC. There is obtained d,l-N-para-tolylcarbamoyl-3-(~-methyl- G~phenylethyl)sydnonimine, the yield is 85% of the theoretical value; melting point is 128-130C (with decomposi-tion). Found, %: C 67,67, H 5.91; ~ 16.62. ClgH20N4O2.
Calculated, %: C 67.91; H 5.93; ~ 16.63. IR-spectrum, cm 1 1,645; 1,595; 1,540. PMR-spectrum (in CDC13 relative to TMS) ~ 8.10; 9.07 pp~.
.
5~
Example 12 The -orocess is conductsd in a manner simi~ar to tha~
described i~ Exa~ple 4~ 0xcept that toluene is used as a sol-vent. ~ho yield of the dasired product is 86~ of the theore-tical value.
Ex~nple 13 ~ h~ process is conducted in a manner similar to that described in the foregoing Examp~e 4, e~cept that dry dichlo-roetha~e is used as a so~vent. On co~pletion of the reaction the reactio~ mass is ev~porated to dryness; the residue is ground in ether, ~i~tered-o~X and recr~sta~lized from iso-propano~. ~he yield of the desired product is 80% of the theoretical value.
~ 16 -~ ., ' ' - ' ' , : -, , ,. ,,:
Claims (24)
1. A method for preparing an N-acyl derivative of sydnon-imine of the formula (I):
(I) wherein R is selected from the group consisting of phenyl, .beta.-phenylethyl, d,1-.alpha.-methyl-.beta.-phenylethyl and 1-.alpha.-methyl-.beta.-phenylethyl;
R' is selected from the group consisting of hydrogen and phenyl;
X is selected from the group consisting of a lower alkyl, phenyl and a group of formula wherein R" is selected from the group consisting of hydrogen, halogen and lower fluorinated alkyl; R"' is selected from the group consisting of hydrogen, halogen and lower alkyl, with the proviso that when X is said group of formula and R', R" and R"' are hydrogen, R is 1-.alpha.-methyl-.beta.-phenylethyl.
comprising reacting an N-nitroso derivative of an N-substituted nitrile of an .alpha.-aminoacid of the formula (II):
(II) wherein R and R' are as defined above, with an acylation agent selected from the group consisting of haloanhydrides of carboxylic acids, anhydrides of carboxylic acids and arylisocyanates, in an organic solvent medium in the presence of a basic catalyst followed by isolation of the product of formula (I).
(I) wherein R is selected from the group consisting of phenyl, .beta.-phenylethyl, d,1-.alpha.-methyl-.beta.-phenylethyl and 1-.alpha.-methyl-.beta.-phenylethyl;
R' is selected from the group consisting of hydrogen and phenyl;
X is selected from the group consisting of a lower alkyl, phenyl and a group of formula wherein R" is selected from the group consisting of hydrogen, halogen and lower fluorinated alkyl; R"' is selected from the group consisting of hydrogen, halogen and lower alkyl, with the proviso that when X is said group of formula and R', R" and R"' are hydrogen, R is 1-.alpha.-methyl-.beta.-phenylethyl.
comprising reacting an N-nitroso derivative of an N-substituted nitrile of an .alpha.-aminoacid of the formula (II):
(II) wherein R and R' are as defined above, with an acylation agent selected from the group consisting of haloanhydrides of carboxylic acids, anhydrides of carboxylic acids and arylisocyanates, in an organic solvent medium in the presence of a basic catalyst followed by isolation of the product of formula (I).
2. A method as claimed in claim 1, wherein the organic solvent is selected from the group consisting of benzene, toluene and dichloroethane.
3. A method as claimed in claim 1, wherein the catalyst is selected from the group consisting of triethylamine, dimethylbenzylamine and N-methylmorpholine.
4. A method as claimed in claim 1, wherein the process is carried out at a temperature within the range of 40 to 60°C.
5. A method as claimed in claim 1, wherein R is selected from the group consisting of .beta.-phenylethyl, d,1-.alpha.-methyl-.beta.-phenylethyl and 1-.alpha.-methyl-.beta.-phenylethyl; R' is hydrogen or phenyl, and X is selected from the group consisting of methyl and wherein R" is hydrogen, halogen or fluorinated methyl and R"' is hydrogen, halogen or methyl.
6. A method according to claim 1, wherein, in said derivative (II), R is .beta.-phenylethyl and R' is hydrogen, and said acylating agent is p-chlorophenylisocyanate.
7. A method according to claim 1, wherein, in said derivative (II), R is .alpha.-methyl-.beta.-phenylethyl and R' is hydrogen, and said acylating agent is p-chlorophenylisocyanate.
8. A method according to claim 1 for preparing N-p-chlorophenylcarbamoyl-3-(.beta.-phenylethyl)-sydnonimine comprising reacting N-nitroso-N-(.beta.-phenylethyl)-aminoacetonitrile with p-chlorophenylisocyanate.
9. A method according to claim 1 for preparing d,1-N-p-chlorophenylcarbamoyl-3-(.alpha.-methyl-.beta.-phenylethyl)-sydnonimine comprising reacting d,1-N-nitroso-(.alpha.-methyl-.beta.-phenylethyl)-aminoacetonitrile with p-chlorophenylisocyanate.
10. A method according to claim 9, wherein the catalyst is trimethylamine.
11. A method according to claim 9, wherein the catalyst is dimethylbenzylamine.
12. A method according to claim 9, wherein the catalyst is N-methylmorpholine.
13. A method according to claim 1 for preparing 1-N-phenylcarbamoyl-3-(.alpha.-methyl-.beta.-phenylethyl)-sydnonimine comprising reacting 1-N-nitroso-N-(.alpha.-methyl-.beta.-phenylethyl)-aminoacetonitrile with phenylisocyanate.
14. A method according to claim 1 for preparing 1-N-p-chlorophenylcarbamoyl-3-(.alpha.-methyl-.beta.-phenylethyl)-sydnonimine comprising reacting 1-N-nitroso-N-(.alpha.-methyl-.beta.-phenylethyl)-aminoacetonitrile with p-chlorophenylisocyanate.
15. An N-acyl derivative of sydnonimine of formula (I), as defined in claim 1, whenever prepared by the method of claim 1, 2 or 3 or by an obvious chemical equivalent.
16. An N-acyl derivative of sydnonimine of formula (I), as defined in claim 1, whenever prepared by the method of claim 4 or by an ohvious chemical equivalent.
17. An N-acyl derivative of sydnonimine of formula (I), as defined in claim 1, wherein R is selected from the group consisting of .beta.-phenylethyl, d,1-.alpha.-methyl-.beta.-phenylethyl and 1-.alpha.-methyl-.beta.-phenylethyl; R1 is hydrogen or phenyl; and X
is selected from the group consisting of methyl and wherein R" is hydrogen, halogen or fluorinated methyl and R"' is hydrogen, halogen or methyl, whenever prepared by the method of claim 5 or by an obvious chemical equivalent.
is selected from the group consisting of methyl and wherein R" is hydrogen, halogen or fluorinated methyl and R"' is hydrogen, halogen or methyl, whenever prepared by the method of claim 5 or by an obvious chemical equivalent.
18. An N-acyl derivative of sydnonimine of formula (I), as defined in claim 1, wherein R is .beta.-phenylethyl, R' is hydrogen and X is p-chlorophenylamino, whenever prepared by the method of claim 6 or by an obvious chemical equivalent.
19. An N-acyl derivative of sydnonimine of formula (I), as defined in claim 1, wherein R is .alpha.-methyl-.beta.-phenylethyl, R' is hydrogen and X is p-chlorophenylamino, whenever prepared by the method of claim 7 or by an obvious chemical equivalent.
20. N-p-Chlorophenylcarbamoyl-3-(.beta.-phenylethyl)-sydnonimine, whenever prepared by the method of claim 8 or by an obvious chemical equivalent.
21. d,1-N-p-Chlorophenylcarbamoyl-3-(.alpha.-methyl-.beta.-phenylethyl)-sydnonimine, whenever prepared by the method of claim 9, 10 or 11, or by an obvious chemical equivalent.
22. d,1-N-p-Chlorophenylcarbamoyl-3-(.alpha.-methyl-.beta.-phenylethyl)-sydnonimine, whenever prepared by the method of claim 12, or by an obvious chemical equivalent.
23. 1-N-Phenylcarbamoyl-3-(.alpha.-methyl-.beta.-phenylethyl)-sydnonimine, whenever prepared by the method of claim 13 or by an obvious chemical equivalent.
24. 1-N-p-Chlorophenylcarbamoyl-3-(.alpha.-methyl-.beta.-phenylethyl)-sydnonimine, whenever prepared by the method of claim 14 or by an obvious chemical equivalent.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SU762423787A SU715575A1 (en) | 1976-11-25 | 1976-11-25 | L-3-(beta-phenylisopropyl)-n-phenylcarbamoylsidnoimine possessing psychostimulating activity |
| SU2423787 | 1976-11-25 | ||
| SU2425985 | 1976-11-30 | ||
| SU2425985 | 1978-11-30 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1097659A true CA1097659A (en) | 1981-03-17 |
Family
ID=26665602
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA284,999A Expired CA1097659A (en) | 1976-11-25 | 1977-08-18 | Sydnonimine n-acylderivatives and method for preparing same |
Country Status (4)
| Country | Link |
|---|---|
| JP (1) | JPS5365880A (en) |
| CA (1) | CA1097659A (en) |
| DE (1) | DE2738022A1 (en) |
| FR (1) | FR2372160A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2121785A1 (en) * | 2007-03-14 | 2009-11-25 | Caliper Life Sciences, Inc. | Sydnonimines - specific dopamine reuptake inhibitors and their use in treating dopamine related disorders |
| US10188651B2 (en) | 2013-03-15 | 2019-01-29 | Melior Pharmaceuticals Ii, Llc | Methods of treating sleep disorders |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4277609A (en) * | 1979-08-31 | 1981-07-07 | American Home Products Corporation | Sydnone imines |
| US4324897A (en) * | 1980-10-02 | 1982-04-13 | American Home Products Corporation | 1,2,3 Oxadiazolium salts |
| EP4282862A1 (en) * | 2022-05-25 | 2023-11-29 | Irbm S.P.A. | Flavivirus inhibitors |
-
1977
- 1977-08-18 CA CA284,999A patent/CA1097659A/en not_active Expired
- 1977-08-23 DE DE19772738022 patent/DE2738022A1/en not_active Withdrawn
- 1977-08-26 FR FR7726079A patent/FR2372160A1/en active Granted
- 1977-09-16 JP JP11063877A patent/JPS5365880A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2121785A1 (en) * | 2007-03-14 | 2009-11-25 | Caliper Life Sciences, Inc. | Sydnonimines - specific dopamine reuptake inhibitors and their use in treating dopamine related disorders |
| EP2121785A4 (en) * | 2007-03-14 | 2011-01-12 | Caliper Life Sciences Inc | Sydnonimines - specific dopamine reuptake inhibitors and their use in treating dopamine related disorders |
| US9604945B2 (en) | 2007-03-14 | 2017-03-28 | Caliper Life Sciences, Inc. | Sydnonimines-specific dopamine reuptake inhibitors and their use in treating dopamine related disorders |
| US10188651B2 (en) | 2013-03-15 | 2019-01-29 | Melior Pharmaceuticals Ii, Llc | Methods of treating sleep disorders |
| US11351169B2 (en) | 2013-03-15 | 2022-06-07 | Melior Pharmaceuticals Ii, Llc | Methods of treating dyskinesia and related disorders |
| US12048697B2 (en) | 2013-03-15 | 2024-07-30 | Melior Pharmaceuticals Ii, Llc | Methods of treating dyskinesia and related disorders |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5365880A (en) | 1978-06-12 |
| FR2372160A1 (en) | 1978-06-23 |
| FR2372160B1 (en) | 1980-06-20 |
| DE2738022A1 (en) | 1978-06-01 |
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