CA1043791A - Process for preparing imidazolinylaminoquinoxalines - Google Patents
Process for preparing imidazolinylaminoquinoxalinesInfo
- Publication number
- CA1043791A CA1043791A CA234,270A CA234270A CA1043791A CA 1043791 A CA1043791 A CA 1043791A CA 234270 A CA234270 A CA 234270A CA 1043791 A CA1043791 A CA 1043791A
- Authority
- CA
- Canada
- Prior art keywords
- formula
- compound
- isothiocyanate
- group
- quinoxaline
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
This invention relates to a process for preparing derivatives of quinoxaline and quinazoline which are described and claimed in British Patent No. 1,381,979.
According to the invention there is provided an improved process for preparing a compound of the formula:
(I) where Q represents a group of the formula:
or in which the free valence may be in any one of the 5-, 6-, 7- or 8-positions in the quinoxaline or quinazoline nucleus;
(R1)x represents up to 3 optional substituents in any of the remaining 5-, 6-, 7- or 8-positions, each R1 being a halogen atom or a lower alkyl, lower alkoxy or trifluoromethyl group and x being 0 to 3;
and R2 represents an optional substituent in either of the 2- or 3-, or 2- or 4-positions of the quin-oxaline or quinazoline nucleus, respectively, R2 being a hydrogen atom or a lower alkyl or lower alkoxy group;
by reacting the corresponding isothiocyanate of the formula Q-NCS, with ethylene diamine to form a .beta.-aminoethyl thio-ureido compound of the formula Q-NH.CS.NHCH2CH2NH2, cyclizing the .beta.-aminoethyl-thioureido compound to form the compound of the formula (I), recovering the latter as the product, and optionally, converting the product into a pharmaceutically acceptable acid addition salt, the improvement which comprises preparing said isothiocyanate by heating a thiouraido compound of the formula Q-NHCSNH2, wherein Q is as defined above.
This invention relates to a process for preparing derivatives of quinoxaline and quinazoline which are described and claimed in British Patent No. 1,381,979.
According to the invention there is provided an improved process for preparing a compound of the formula:
(I) where Q represents a group of the formula:
or in which the free valence may be in any one of the 5-, 6-, 7- or 8-positions in the quinoxaline or quinazoline nucleus;
(R1)x represents up to 3 optional substituents in any of the remaining 5-, 6-, 7- or 8-positions, each R1 being a halogen atom or a lower alkyl, lower alkoxy or trifluoromethyl group and x being 0 to 3;
and R2 represents an optional substituent in either of the 2- or 3-, or 2- or 4-positions of the quin-oxaline or quinazoline nucleus, respectively, R2 being a hydrogen atom or a lower alkyl or lower alkoxy group;
by reacting the corresponding isothiocyanate of the formula Q-NCS, with ethylene diamine to form a .beta.-aminoethyl thio-ureido compound of the formula Q-NH.CS.NHCH2CH2NH2, cyclizing the .beta.-aminoethyl-thioureido compound to form the compound of the formula (I), recovering the latter as the product, and optionally, converting the product into a pharmaceutically acceptable acid addition salt, the improvement which comprises preparing said isothiocyanate by heating a thiouraido compound of the formula Q-NHCSNH2, wherein Q is as defined above.
Description
This invention relates ~o a process for preparing derivatives of quinoxaline and quinazoline which are described and claimed in British Patent No. 1,381,979.
According to the invention there is provided an improved process for preparing a compound of the formula:
~ NH-Q (I) where Q represants a group of the formula:
~ ~ ~ or ~ 2 (Rl)X (~l)x in which the free valence may be in any ona of the 5-, 6-, :1:0 7- or 8- positions in the quinoxaline or quinazoline nucleus; : :
(Rl)X represents up to 3 optional substituents in ~.
any of the remaining 5-, 6-, 7- or 8- positions, each Rl being a halogen atom or a lower alkyl, lower alkoxy.or triflu~oromethyl group and x being O to 3;
and R2 represents an optional substituent in either of the 2- or 3-, or 2- or 4- positions of the quin-- oxaline or quinazoline nucleus, respectively, R :
According to the invention there is provided an improved process for preparing a compound of the formula:
~ NH-Q (I) where Q represants a group of the formula:
~ ~ ~ or ~ 2 (Rl)X (~l)x in which the free valence may be in any ona of the 5-, 6-, :1:0 7- or 8- positions in the quinoxaline or quinazoline nucleus; : :
(Rl)X represents up to 3 optional substituents in ~.
any of the remaining 5-, 6-, 7- or 8- positions, each Rl being a halogen atom or a lower alkyl, lower alkoxy.or triflu~oromethyl group and x being O to 3;
and R2 represents an optional substituent in either of the 2- or 3-, or 2- or 4- positions of the quin-- oxaline or quinazoline nucleus, respectively, R :
-2~ ~
~4~`7~
being a hydrogen atom or a lower alkyl or lower alkoxy group:
by reac'cing the corresponding i~othiocyanate of the formula Q-NCS, with ethylane diamine to form a ~ -aminoethyl thio-ureido compound of the formula Q-NH~CS.NHCH2CH2NH2, cyclizing the ~ -aminoethyl-thioureido compound to form the compound of the formula (I), recovering the latter a~ the product, and optionally, converting the,product into a pharmaceutically acceptable acid addition salt. the improvement which comprise~
preparing said isothiocyanate by heatlng a t~oureido compound of the formula Q-NHCSNH2, wherein Q is as defined above.
The thioureido compounds of the formula Q-NHCSNH2 may be prepared a3 described in the aforesaid British patent , preferably by reacting the corre-sponding amine of the formula Q-NH2 with ~enzoyl isothiocyanate to form the corresponding N-benzoyl thioureido compound, fol- ~-lowed by hydrolysis to the thioureido compound. The benzoyl isothiocyanate may be prepared in situ from benzoyl chloride and ammonium isothiocyanate.
The process of the invention may be represented as follows:
(1) Q-NHcsNH2 > Q-~CS
~ (2) Q-NH ~ / ( _ Q-NH.CS.NHCH2CH2NH2 ~. . ' :.
~ (3) In step ~1) the reaction may be carried out by -heating the thioureido compound in a suitable inert organic solvent. High temperatures are generally nicessary, prefer-ably temperature~ of from 130 to 170C. The reaction is -'-.
~ 3~
typically carried out by refluxing the thioureido compound for a period of up to about 20 hours in a high-boiling organic solvent in which the isothiocyanate is soluble, preferably chlorobenzene or bromobenzene. It has been found that in general improved yields of the desired product of the formula (I) are obtained when the isothiocyanate intermediate is not isolated, but, if desired, the isothiocyanate can be isolated by e.g. evaporation of the solvent to dryness or by partial evaporation of the solvent followed by allowing the compound to crystallize on cooling.
In step (2) the isothiocyanate is reacted with an excess (e.g. 5 moles) of ethylene diamine in a suitable solvent~ e.g. a lower alkanol such as methanol, ethanol, or iso-propanol in which the ~-aminoethyl compound is formed in solution. The reaction is preferably carried out by adding a hot solution of the isothiocyanate in chloro- or bromo-benzene to a hot, preferably refluxing, solution of ethylene ~ ~ -diamine in the lower alkanol. Under these conditions the ~ -aminoethyl-thioureido compound automatically cyclizes to give the desired product of the formula (I), i.e. steps (2) and (3) may be carried out in one operation, viz., by adding a solution of the isothiocyanate in chloro- or bromo- benzene to a solution of ethylene diamine in a lower alkanol and heating preferably under reflux for up to about 24 hours.
In order to improve the yield of the final product, it may be necessary to carry out the cyclization in the presence of a mercuric or cupric oxide catalyst, or in the presence of an organic mercuric or cupric salt soluble in the solvent medium, as described in the aforesaid patent.
0 In the case of the preparation of the preferred compound, ' viz. 5-bromo-6-[2-imidazolin-2-ylamino]-quinoxaline, no catalys t has been found to be necessary.
If it is desired to isolate the ~ -aminoethyl-thioureido compound~ then step (2) may be carried out by reacting the isothiocyanate with ethylene diamine at room tem-perature for up to a few hours in a solvent such as diethyl ether, benzene, chloroform or dioxan from which the compound precipitates and may be recovered by filtration, the cycliza-tion of step ~3) then being carried out by refluxing the -isolated ~ -aminoethyl-thioureido compound in a lower alkanol.
Typically, the product of formula (I) is recovered by allowing the reaction mixture to cool and stirring, the -~
product precipitating from the reaction mixture. It may how-ever be necessary to partially evaporate the solvent before crystallization will occur, or even to completely evaporate the reaction mixture ln vacuo to obtain the desired product. `
When a cyalization catalyst is usled, the reaction mixture should be fiItered prior to crystallization or evaporation to .
remove any mercuric or cupric sulphide formed as a by-product.
:
The product may be recrystallized as the free base or c~nverted to an acid addition salt by reaction with a ~uitable acid by conventional means.
; ~ Preferred compounds of the formula (I) preparable ` ~ ;~
by the method of the present invention include those whereln 25 (Rl)X includes a halogen atomr more preferably a bromine atom, ;
and/or those wherein the 2-imidazolin-2-ylamino group is in -the 6- or 7-po ition in the qulnoxaline or quinazoline nucleus.
More preferably, when the 2-imidazolin-2-ylamino group i9 in the 6 -position, (Rl)X is a single halogen in the S- position, and when the imidazolin group is in the 7- position, (Rl)X i8 .
. . ' ~ .
:. , ' ,. . .. ' - ' ,, :
a single halogen atom in the 8- position.
As previously stated, the most preferred compound of the formula (I) is 5-bromo-6[2-imidazolin-2-ylamino]quinoxaline.
As stated in the aforementioned patent, S the compounds of the formula (I) are of value as antihyper~
tensive agents.
The method of the invention is illustrated by the following Example, in which all temperatures are given in C.
EXAMPLE
Part A
Preparation of 5-~romo-6-thioureidoquinoxal_ne.
A mixture of 6-amino-5~bromoquinoxaline hydrobromide -(2.09 kg.) and deionized water (14 1.) was stirred at 50, filtered warm, and thff solids washed with warm water (2 x 3.45 l.) and discarded. Anhydrous sodium acetate (g.843 kg.) was then added to the combined filtrate and washings and the cooled mixture was extracted with methylene chloride (5 x 15 1.). The combined methylene chloride extracts were evaporated to dryness and the residual 6-amino-5-bromo-quinoxaline was dissolve~ in acetone (22 1.).
A mixture of benzoyl chloride (0.950 kg.), ammonium thiocyanate (0.565 kg.) and acetone (13 l.) was stirred under reflux for 15 minutes. The mixture was cooled slightly and ~ ;
stirred as the acetone solution of 6-amino-5-bro~oquinoxaline ~ -~
was added over 20 minutes. The resulting suspension was heat-ed under reflux for 45 minutes and the acetone was then distil-10d off as deionized water (35 1.) was added. The aqueous ~uspension was chilled to 10C. and the solids were filtered and washed with water (lO 1).
The collected solids were stirred with a mixture .:,, . . ,:
- ` :
of 40~ aqueous sodium hydroxide solution (2.95 1.) and de-ionized water (27 1.), and heated at 90 for 30 minutes. The ;
reaction solution was chilled, adjusted to pH 8 with concen~
trated hydrochloric acid, and stirred at 10~ for 30 minutes to ensure complete prPcipitatîon of the product. Filtration and washing with water (2 x 3 lo ) gave 5-bromo-6-thioureido-quinoxaline (1.59 kg., 82.0~) as a yellow solid m.p. 193-197 (decomp.).
Analysis:
Found: C, 38.22; H, 2.55; N, 20.00%;
Required for CgH7BrN4S C, 38.18; H, 2.49; N, 19.79%
Part B
Preparation of 5-Bromo-6-[2-imidazolin-2-ylamino]quinoxaline.
A suspension of 5-bromo 6-thioureidoquinoxaline (50 g.) prepared as in Part A in bromobenzene (500 ml.) was re~luxed for 2 hours and cooled to ambient temperature. The mix~ure was then filtered and the filtrate was added over 40 minutes to a refluxing solution o ethylene diamine (42.5 g.) in ethanol (300 ml.). The mixture was refluxed for 2 hours and then distilled at atmospheric pressure to remove the ethanol. S~irring of the residual solution at 10 for 30 minutes followed by filtration and washing with ethanol (50 ml.), gave 5-bromo-6-[2-imidazolin-2-ylamino]quinoxaline (39.Q8 g., 75.8~) as yellow crystals, m.p. 252.
Part C
Preparation of 5-Bromo-6-[2-imidazolin-2-ylamino]~uinoxaline tartrate.
A mixture of 5-bromo-6-[2-imidazolin-2-ylamino~-quinoxaline ~65.4 g.) prepared as in Part B~ tartaric acid (33.59 g.), charcoal (6.54 g.) and deionized water (280 ml.) '7~
was heated at 95 for 50 minutes. The mixture was then filter-ed hot and the solids were washed with hot water (47 ml.) and discarded. The combined filtrate and washings were stirred and heated as acetone (1308 ml.) was added at a rate which maintained a gentle reflux. The mixture was cooled and stirred at 10C. to ensure complete precipitation of the product. Filtration and washing with acetone (2 x 125 ml.) gave 5~bromo-6~2-imidazolin-2-ylamino]quinoxaline tartrate (92.80 g., 93.7%) as white crystals m.p. 207.5.
~
Found: C, 40.56; H, 3.60; N, 16.14%;
Required for C15H16BrN506 C, 40.74; H, 3.65; N, 15.84%
' " ':' ,.:
~4~`7~
being a hydrogen atom or a lower alkyl or lower alkoxy group:
by reac'cing the corresponding i~othiocyanate of the formula Q-NCS, with ethylane diamine to form a ~ -aminoethyl thio-ureido compound of the formula Q-NH~CS.NHCH2CH2NH2, cyclizing the ~ -aminoethyl-thioureido compound to form the compound of the formula (I), recovering the latter a~ the product, and optionally, converting the,product into a pharmaceutically acceptable acid addition salt. the improvement which comprise~
preparing said isothiocyanate by heatlng a t~oureido compound of the formula Q-NHCSNH2, wherein Q is as defined above.
The thioureido compounds of the formula Q-NHCSNH2 may be prepared a3 described in the aforesaid British patent , preferably by reacting the corre-sponding amine of the formula Q-NH2 with ~enzoyl isothiocyanate to form the corresponding N-benzoyl thioureido compound, fol- ~-lowed by hydrolysis to the thioureido compound. The benzoyl isothiocyanate may be prepared in situ from benzoyl chloride and ammonium isothiocyanate.
The process of the invention may be represented as follows:
(1) Q-NHcsNH2 > Q-~CS
~ (2) Q-NH ~ / ( _ Q-NH.CS.NHCH2CH2NH2 ~. . ' :.
~ (3) In step ~1) the reaction may be carried out by -heating the thioureido compound in a suitable inert organic solvent. High temperatures are generally nicessary, prefer-ably temperature~ of from 130 to 170C. The reaction is -'-.
~ 3~
typically carried out by refluxing the thioureido compound for a period of up to about 20 hours in a high-boiling organic solvent in which the isothiocyanate is soluble, preferably chlorobenzene or bromobenzene. It has been found that in general improved yields of the desired product of the formula (I) are obtained when the isothiocyanate intermediate is not isolated, but, if desired, the isothiocyanate can be isolated by e.g. evaporation of the solvent to dryness or by partial evaporation of the solvent followed by allowing the compound to crystallize on cooling.
In step (2) the isothiocyanate is reacted with an excess (e.g. 5 moles) of ethylene diamine in a suitable solvent~ e.g. a lower alkanol such as methanol, ethanol, or iso-propanol in which the ~-aminoethyl compound is formed in solution. The reaction is preferably carried out by adding a hot solution of the isothiocyanate in chloro- or bromo-benzene to a hot, preferably refluxing, solution of ethylene ~ ~ -diamine in the lower alkanol. Under these conditions the ~ -aminoethyl-thioureido compound automatically cyclizes to give the desired product of the formula (I), i.e. steps (2) and (3) may be carried out in one operation, viz., by adding a solution of the isothiocyanate in chloro- or bromo- benzene to a solution of ethylene diamine in a lower alkanol and heating preferably under reflux for up to about 24 hours.
In order to improve the yield of the final product, it may be necessary to carry out the cyclization in the presence of a mercuric or cupric oxide catalyst, or in the presence of an organic mercuric or cupric salt soluble in the solvent medium, as described in the aforesaid patent.
0 In the case of the preparation of the preferred compound, ' viz. 5-bromo-6-[2-imidazolin-2-ylamino]-quinoxaline, no catalys t has been found to be necessary.
If it is desired to isolate the ~ -aminoethyl-thioureido compound~ then step (2) may be carried out by reacting the isothiocyanate with ethylene diamine at room tem-perature for up to a few hours in a solvent such as diethyl ether, benzene, chloroform or dioxan from which the compound precipitates and may be recovered by filtration, the cycliza-tion of step ~3) then being carried out by refluxing the -isolated ~ -aminoethyl-thioureido compound in a lower alkanol.
Typically, the product of formula (I) is recovered by allowing the reaction mixture to cool and stirring, the -~
product precipitating from the reaction mixture. It may how-ever be necessary to partially evaporate the solvent before crystallization will occur, or even to completely evaporate the reaction mixture ln vacuo to obtain the desired product. `
When a cyalization catalyst is usled, the reaction mixture should be fiItered prior to crystallization or evaporation to .
remove any mercuric or cupric sulphide formed as a by-product.
:
The product may be recrystallized as the free base or c~nverted to an acid addition salt by reaction with a ~uitable acid by conventional means.
; ~ Preferred compounds of the formula (I) preparable ` ~ ;~
by the method of the present invention include those whereln 25 (Rl)X includes a halogen atomr more preferably a bromine atom, ;
and/or those wherein the 2-imidazolin-2-ylamino group is in -the 6- or 7-po ition in the qulnoxaline or quinazoline nucleus.
More preferably, when the 2-imidazolin-2-ylamino group i9 in the 6 -position, (Rl)X is a single halogen in the S- position, and when the imidazolin group is in the 7- position, (Rl)X i8 .
. . ' ~ .
:. , ' ,. . .. ' - ' ,, :
a single halogen atom in the 8- position.
As previously stated, the most preferred compound of the formula (I) is 5-bromo-6[2-imidazolin-2-ylamino]quinoxaline.
As stated in the aforementioned patent, S the compounds of the formula (I) are of value as antihyper~
tensive agents.
The method of the invention is illustrated by the following Example, in which all temperatures are given in C.
EXAMPLE
Part A
Preparation of 5-~romo-6-thioureidoquinoxal_ne.
A mixture of 6-amino-5~bromoquinoxaline hydrobromide -(2.09 kg.) and deionized water (14 1.) was stirred at 50, filtered warm, and thff solids washed with warm water (2 x 3.45 l.) and discarded. Anhydrous sodium acetate (g.843 kg.) was then added to the combined filtrate and washings and the cooled mixture was extracted with methylene chloride (5 x 15 1.). The combined methylene chloride extracts were evaporated to dryness and the residual 6-amino-5-bromo-quinoxaline was dissolve~ in acetone (22 1.).
A mixture of benzoyl chloride (0.950 kg.), ammonium thiocyanate (0.565 kg.) and acetone (13 l.) was stirred under reflux for 15 minutes. The mixture was cooled slightly and ~ ;
stirred as the acetone solution of 6-amino-5-bro~oquinoxaline ~ -~
was added over 20 minutes. The resulting suspension was heat-ed under reflux for 45 minutes and the acetone was then distil-10d off as deionized water (35 1.) was added. The aqueous ~uspension was chilled to 10C. and the solids were filtered and washed with water (lO 1).
The collected solids were stirred with a mixture .:,, . . ,:
- ` :
of 40~ aqueous sodium hydroxide solution (2.95 1.) and de-ionized water (27 1.), and heated at 90 for 30 minutes. The ;
reaction solution was chilled, adjusted to pH 8 with concen~
trated hydrochloric acid, and stirred at 10~ for 30 minutes to ensure complete prPcipitatîon of the product. Filtration and washing with water (2 x 3 lo ) gave 5-bromo-6-thioureido-quinoxaline (1.59 kg., 82.0~) as a yellow solid m.p. 193-197 (decomp.).
Analysis:
Found: C, 38.22; H, 2.55; N, 20.00%;
Required for CgH7BrN4S C, 38.18; H, 2.49; N, 19.79%
Part B
Preparation of 5-Bromo-6-[2-imidazolin-2-ylamino]quinoxaline.
A suspension of 5-bromo 6-thioureidoquinoxaline (50 g.) prepared as in Part A in bromobenzene (500 ml.) was re~luxed for 2 hours and cooled to ambient temperature. The mix~ure was then filtered and the filtrate was added over 40 minutes to a refluxing solution o ethylene diamine (42.5 g.) in ethanol (300 ml.). The mixture was refluxed for 2 hours and then distilled at atmospheric pressure to remove the ethanol. S~irring of the residual solution at 10 for 30 minutes followed by filtration and washing with ethanol (50 ml.), gave 5-bromo-6-[2-imidazolin-2-ylamino]quinoxaline (39.Q8 g., 75.8~) as yellow crystals, m.p. 252.
Part C
Preparation of 5-Bromo-6-[2-imidazolin-2-ylamino]~uinoxaline tartrate.
A mixture of 5-bromo-6-[2-imidazolin-2-ylamino~-quinoxaline ~65.4 g.) prepared as in Part B~ tartaric acid (33.59 g.), charcoal (6.54 g.) and deionized water (280 ml.) '7~
was heated at 95 for 50 minutes. The mixture was then filter-ed hot and the solids were washed with hot water (47 ml.) and discarded. The combined filtrate and washings were stirred and heated as acetone (1308 ml.) was added at a rate which maintained a gentle reflux. The mixture was cooled and stirred at 10C. to ensure complete precipitation of the product. Filtration and washing with acetone (2 x 125 ml.) gave 5~bromo-6~2-imidazolin-2-ylamino]quinoxaline tartrate (92.80 g., 93.7%) as white crystals m.p. 207.5.
~
Found: C, 40.56; H, 3.60; N, 16.14%;
Required for C15H16BrN506 C, 40.74; H, 3.65; N, 15.84%
' " ':' ,.:
Claims (7)
1. An improved process for preparing a compound of the formula:
.... (I) where Q represents a group of the formula:
or in which the free valence may be in any one of the 5-, 6-, 7- or 8 positions in the quinoxaline or quinazoline nucleus;
(R1)x represents up to 3 optional substituents in any of the remaining 5-, 6-, 7- or 8-positions, each R1 being a halogen atom or a lower alkyl, lower alkoxy or trifluoro-methyl group and x being 0 to 3;
and R2 represents an optional substituent in either of the 2-or 3-, or 2- or 4 -positions of the quinoxaline or quinazoline nucleus, respectively, R2 being a hydrogen atom or a lower alkyl or lower alkoxy group;
by reacting the corresponding isothiocyanate of the formula Q-NCS
with ethylene diamine to form a .beta.-aminoethyl thioureido compound of the formula Q-NH.CS.NHCH2CH2NH2, cyclizing the .beta.-aminoethyl-thioureido compound to form the compound of the Formula (I), re-covering the latter as the product, and, optionally, converting the product into a pharmaceutically acceptable acid addition salt, the improvements which comprises preparing said isocyanate by heating a thioureido compound of the formula Q-NHCSNH2, wherein Q is as defined above.
.... (I) where Q represents a group of the formula:
or in which the free valence may be in any one of the 5-, 6-, 7- or 8 positions in the quinoxaline or quinazoline nucleus;
(R1)x represents up to 3 optional substituents in any of the remaining 5-, 6-, 7- or 8-positions, each R1 being a halogen atom or a lower alkyl, lower alkoxy or trifluoro-methyl group and x being 0 to 3;
and R2 represents an optional substituent in either of the 2-or 3-, or 2- or 4 -positions of the quinoxaline or quinazoline nucleus, respectively, R2 being a hydrogen atom or a lower alkyl or lower alkoxy group;
by reacting the corresponding isothiocyanate of the formula Q-NCS
with ethylene diamine to form a .beta.-aminoethyl thioureido compound of the formula Q-NH.CS.NHCH2CH2NH2, cyclizing the .beta.-aminoethyl-thioureido compound to form the compound of the Formula (I), re-covering the latter as the product, and, optionally, converting the product into a pharmaceutically acceptable acid addition salt, the improvements which comprises preparing said isocyanate by heating a thioureido compound of the formula Q-NHCSNH2, wherein Q is as defined above.
2. A process as claimed in claim 1, wherein (R1)x includes a halogen atom and/or wherein the 2-imidazoline-2-ylamino group is in the 6- or 7-position in the quinoxaline or quin-azoline nucleus.
3. A process as claimed in claim 2, wherein the 2-imidazolin-2-ylamino group is in the 6-position and (R1) is a single halogen atom in the 5-position.
4. A process as claimed in claim 2, wherein the 2-imidazolin-2-ylamino group is in the 7-position and (R1)X is a single halogen atom in the 8-position.
5. A process as claimed in any one of claims 2, 3 and 4, wherein the halogen atom is a bromine atom.
6. A process as claimed in any one of claims 2, 3 and 4, wherein the thioureido compound is converted to the corresponding isothiocyanate by heating at a temperature of from 130° to 170°C. in a high-boiling organic solvent in which the isothiocyanate is soluble.
7. A process as claimed in any one of claims 2, 3 and 4, wherein the thioureido group of said thioureido compound is in the 6-position of said quinoxaline or quinazoline nucleus and (R1)X is a single halogen atom in the 5-position and said thioureido compound is converted to the correspond-ing isothiocyanate by heating at a temperature of from 130° to 170°C. in a high boiling organic solvent in which the isothiocyanate is soluble.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB3914374A GB1463520A (en) | 1974-09-06 | 1974-09-06 | Process for the production of imidazolines |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1043791A true CA1043791A (en) | 1978-12-05 |
Family
ID=10407882
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA234,270A Expired CA1043791A (en) | 1974-09-06 | 1975-08-27 | Process for preparing imidazolinylaminoquinoxalines |
Country Status (12)
| Country | Link |
|---|---|
| JP (1) | JPS51149291A (en) |
| BE (1) | BE833135A (en) |
| CA (1) | CA1043791A (en) |
| DE (1) | DE2538620A1 (en) |
| DK (1) | DK398775A (en) |
| ES (1) | ES440760A1 (en) |
| FI (1) | FI752487A (en) |
| FR (1) | FR2283899A1 (en) |
| GB (1) | GB1463520A (en) |
| LU (1) | LU73327A1 (en) |
| NL (1) | NL7510473A (en) |
| SE (1) | SE7509271L (en) |
Families Citing this family (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5077292A (en) * | 1989-10-12 | 1991-12-31 | Allergan, Inc. | (2-imidazolin-2-ylamino) tetrahydroquinoxalines and methods for using same |
| US5198442A (en) * | 1989-10-12 | 1993-03-30 | Allergan, Inc. | (2-imidazolin-2-ylamino) quinoxaline derivatives and methods for using same |
| US5204347A (en) * | 1989-10-12 | 1993-04-20 | Allergan, Inc. | Methods for using (2-imidazolin-2-ylamino) tetrahydroquinoxalines |
| US5112822A (en) * | 1989-10-12 | 1992-05-12 | Allergan, Inc. | (2-imidazolin-2-ylamino) quinoxaline derivatives and methods for using same |
| US5326763A (en) * | 1989-10-12 | 1994-07-05 | Allergan, Inc. | Methods for using (2-imidazolin-2-ylamino) quinoxaline derivatives |
| US5021416A (en) * | 1989-10-31 | 1991-06-04 | Allergan, Inc. | Method for using (2-imidazolin-2-ylamino) quinoxalines to reduce or maintain intraocular pressure |
| US5237072A (en) * | 1990-02-06 | 1993-08-17 | Allergan, Inc. | Method for producing amino-2-imidazoline derivatives |
| US5130441A (en) * | 1990-02-06 | 1992-07-14 | Allergan, Inc. | Method for producing amino-2-imidazoline derivatives |
| JP3683908B2 (en) * | 1993-10-13 | 2005-08-17 | アラーガン、インコーポレイテッド | Method of using (2-imidazolin-2-ylamino) quinoxaline derivative |
| US6323204B1 (en) | 1993-10-13 | 2001-11-27 | Allergan | Methods for using (2-imidazolin-2-ylamino) quinoxaline derivatives |
| CA2505836C (en) | 2004-05-06 | 2013-08-27 | Alcon Inc. | Topical brimonidine tartrate formulations that lack chlorine dioxide |
| US10517869B2 (en) | 2013-12-24 | 2019-12-31 | Sentiss Pharma Private Limited | Topical brimonidine tartrate ophthalmic solution |
| JP6339364B2 (en) * | 2013-12-27 | 2018-06-06 | カズマパートナーズ株式会社 | Amorphous brimonidine tartrate and method for producing the same |
| JP6270603B2 (en) * | 2014-04-14 | 2018-01-31 | カズマパートナーズ株式会社 | Novel polymorph of brimonidine tartrate and process for producing the same |
| US20230218611A1 (en) | 2020-04-29 | 2023-07-13 | Sentiss Pharma Private Limited | Ophthalmic compositions comprising a combination of brinzolamide and brimonidine |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BE795970A (en) * | 1972-02-29 | 1973-08-27 | Pfizer | NEW DERIVATIVES OF QUINOLEINE, QUINOXALINE AND QUINAZOLINE ER PHARMACEUTICAL COMPOSITION CONTAINING THEM |
-
1974
- 1974-09-06 GB GB3914374A patent/GB1463520A/en not_active Expired
-
1975
- 1975-08-25 SE SE7509271A patent/SE7509271L/en unknown
- 1975-08-27 CA CA234,270A patent/CA1043791A/en not_active Expired
- 1975-08-29 DE DE19752538620 patent/DE2538620A1/en active Pending
- 1975-09-01 JP JP50105862A patent/JPS51149291A/en active Pending
- 1975-09-04 FI FI752487A patent/FI752487A/fi not_active Application Discontinuation
- 1975-09-04 LU LU73327A patent/LU73327A1/xx unknown
- 1975-09-05 DK DK398775A patent/DK398775A/en unknown
- 1975-09-05 ES ES440760A patent/ES440760A1/en not_active Expired
- 1975-09-05 NL NL7510473A patent/NL7510473A/en unknown
- 1975-09-05 FR FR7527324A patent/FR2283899A1/en not_active Withdrawn
- 1975-09-05 BE BE159796A patent/BE833135A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| NL7510473A (en) | 1976-03-09 |
| JPS51149291A (en) | 1976-12-22 |
| DE2538620A1 (en) | 1976-03-18 |
| BE833135A (en) | 1976-03-05 |
| FR2283899A1 (en) | 1976-04-02 |
| SE7509271L (en) | 1975-12-29 |
| GB1463520A (en) | 1977-02-02 |
| LU73327A1 (en) | 1977-05-11 |
| DK398775A (en) | 1976-03-07 |
| AU8430575A (en) | 1977-03-03 |
| ES440760A1 (en) | 1977-04-01 |
| FI752487A (en) | 1976-03-07 |
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