GB2051048A - Geminal Dihalogen Derivatives of Condensed Pyrimidin-4-one Compounds their Preparation and Pharmaceutical Compositions Containing them - Google Patents
Geminal Dihalogen Derivatives of Condensed Pyrimidin-4-one Compounds their Preparation and Pharmaceutical Compositions Containing them Download PDFInfo
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Abstract
Geminal dihalogen derivatives of condensed pyrimidine-4-one compounds of the general formula <IMAGE> [wherein R represents hydrogen, lower alkyl, or lower alkoxycarbonyl; R<1> represents hydrogen, lower alkyl, ester group, carboxy or a derivative thereof, cyano, phenyl or halogen; R<2> represents hydrogen, lower alkyl or phenyl; X represents halogen; n is the integer 0, 1 or 2] and the salts and optically active antipodes thereof are of interest as chemical intermediates; some also exhibit a variety of physiological activities and may be formulated into pharmaceutical compositions in conventional manner. The novel compounds can be made by halogenating a corresponding starting material wherein one or both X-substituents are hydrogen.
Description
SPECIFICATION
Geminal Dihalogen Derivatives of Condensed Pyrimidin-4-one Compounds, Their Preparation and Pharmaceutical Compositions Containing Them
The present invention relates to geminal halogen derivatives of condensed pyrimidin-4-one compounds, process for their preparation and pharmaceutical compositions containing them. The compounds are valuable intermediates in the synthesis of compounds having antiallergic and/or antiasthmatic properties and a proportion of them possess analgesic, antiinflammatory, plateletaggregation inhibiting, antiatherogenic, antiasthmatic and/or antiallergic effects.
It is well known that certain condensed pyrimidine compounds show analgesic and other CNSactivities (British Patent Specification No. 1,209,946). A typical representative of these compounds is 3-(ethoxywarbonyl)-1 ,6-dimethyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1 ,2-a]pyrimidinium methosulfate (ProbonR, Rimazolium) which has excellent analgesic properties and is widely used in therapy [Arzneimittel Forschung 22 (1972 81 5)].
According to one feature of the present invention there are provided compounds of the general formula I and their salts:
[wherein
R represents hydrogen, lower alkyl or lower alkoxycarbonyl;
R1 represents hydrogen, lower alkyl, ester group, carboxy or a derivative thereof, cyano, phenyl or halogen;
R2 represents hydrogen, lower alkyl or phenyl;
X represents halogen;
n is the integer 0, 1 or 2] and the optically active antipodes thereof.
The term "lower alkyl" used herein for alkyl groups or alkyl containing groups, such as alkoxy group, generally stands for C16 preferably C14 straight or branched aliphatic saturated hydrocarbons, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary butyl, tertiary butyl, n-pentyl, neo-pentyl, n-hexyl, etc.
The term "derivative of the carboxyl group" stands for conventional carboxylic acid derivatives, such as alkoxycarbonyl e.g. lower alkoxycarbonyl, aryloxycarbonyl aralkoxycarbonyl or other esters, carbamoyl optionally substituted by one or two alkyl (e.g. lower alkyl), aryl or aralkyl groups; cyano, carboxylic acid hydrazido or hydroxamic acid (--COO-NHOH).
The term "aryl" used as such or in aryl containing groups such as aryloxy may, for example, stand for optionally substituted C6~10 aromatic groups, such as phenyl or naphthyl or substituted derivatives thereof.
The term "aralkyl" used as such or in aralkyl containing groups, such as aralkyloxy, may, for example, stand for C13 alkyl substituted by phenyl or naphthyl, such as benzyl, P-phenyl-ethyl, a,P- diphenyl-ethyl, P,P-diphenyl-ethyl, etc.
The term "halogen" stands for chlorine, bromine or iodine.
Preferred compounds of the present invention include compounds of the general formula I wherein
R represents hydrogen, lower alkyl, preferably methyl;
R1 represents carboxy, lower alkoxy-carbonyl, preferably methoxy-carbonyl or ethoxy-carbonyl; cyano, carbamoyl, lower alkyl, preferably methyl; phenyl;
R2 represents hydrogen, lower alkyl, preferably methyl;
X represents chlorine or bromine;
n is the integer 0, 1 or 2.
Compounds of the general formula I containing carboxy groups form salts with pharmaceutically acceptable bases, such as alkali metal salts, e.g. sodium or potassium salts, alkaline earth metal, such as calcium or magnesium salts, ammonium salts and with organic amines, such as triethylamine salts, ethanol amine salts, etc.
Optical isomers of the compounds of the general formula I are also within the scope of the invention.
The new compounds of the general formula I, pharmaceutically acceptable salts thereof and optically active isomers thereof may for example be prepared by following processes (a) or (b), which processes constitute a further feature of the present invention: (a) a monohalogen compound of the general formula
Wherein R, R1, R2, X and n are as hereinbefore defined] is reacted with a haiogenating agent; or
b) a compound of the general formula
[wherein
R, R1, R2 and n are as hereinbefore defined]
is reacted with a halogenating agent and, if desired, in a compound of the general formula I obtained a
group R1 is converted into another group R1, and if desired, a racemate of the general formula I is
resoluted into its optically active antipodes.
According to process variant a) a compound of the general formula (Il)--wherein R, R1, R2, X and
n are as hereinbefore defined-is reacted with e.g. an at least equivalent amount of a halogenating
agent. Preferably the halogenating agent is used in an amount of 1 to 1.5 molar equivalents.
According to process variant b) compound of the general formula (Ill)--wherein R, R1, R2 and n
are as hereinbefore defined is reacted with e.g. at least two molar equivalents of a halogenating agent.
The preferred amount of halogenating agent is 2 to 2.5 molar equivalents calculated from the
compounds of formula (III).
As halogenating agent conventional halogenating agents known in the art can be used.
Elementary halogens, such as bromine, chlorine or iodine, halogen compounds, such as brominechlorine, iodine-chlorine, etc., and other halogen derivatives, e.g. inorganic acid halides such as sulfuryl chloride, phosphorus pentachloride; halogenated acid imides, such as N-chloro-succinimide, N-bromosuccinimide, N-iodo-succinimide, 1 ,3-dibromo-5,5-dimethyl-hydantoin; N-bromo-caprolactam; tribromo-acetophenone, trichloromethane sulfurylbromide and -chloride, tert.-butyl hypochlorite, hypobromite and hypoiodite, 1 ,2,4,6-tetrachloro-acetanilide, 1 ,2-dibromo-tetrachloroethane, copper(ll)-bromide and chloride; and halogen complexes, such as pyridinium bromide perbromide, phenyltrimethylammonium perbromide, tetramethylammonium tribromide, dioxane dibromide, pyrrolydone-2-hydro-tribromide, etc. are preferably used, optionally in the presence of a catalyst, for example a Lewis acid, such as aluminium bromide and chloride, phosphorus trichloride, sulfur, calcium oxide, UV illumination, dibenzoyl peroxide, etc.
The halogenation is carried out in a conventional manner. Compounds of the general formula (II) and (III), respectively are generally reacted with the suitable halogenating agent in an inert solvent, e.g.
alkanecarboxylic acid, halogenated hydrocarbon, etc., preferably in acetic acid or chloroform.
Optionally acid binding agents, such as triethyl amine, acetamide, sodium acetate, etc, can also be employed.
The reactions are carried out at a temperature e.g. between OOC and 1 600 C, preferably at 200C to 600C. Compounds of the general formula (I) or the salts thereof either precipitate from the reaction mixture and can be eliminated for example by filtration, or are separated from the reaction mixture by evaporating the solvent. Compounds of the general formula (I) can be purified by conventional techniques, such as recrystallization, chromatography, etc.
A compound of the general formula (I) thus obtained may be converted, if desired, to another compound of the general formula (I) by methods known per se. The conversion may take place on the group R1. Thus a compound of the general formula (I), in which R1 is carboxy can be decarboxylated in an organic, e.g. lower alkanecarboxylic acids, lower alkanols, etc. or inorganic, e.g. water, solvent, at a temperature of O to 2000 C, optionally in the presence of a mineral acid, such as hydrogen halides, sulfuric acid, etc. The compounds of the general formula (I) obtained, in which R1 stands for hydrogen,
R, R2, X and n are as hereinbefore defined are then isolated or reacted with one molar equivalent of a halogenating agent. In this way compounds of the general formula (I), in which R1 is halogen are obtained.
The above facultative reaction steps are also within the scope of the invention.
Compounds of the general formula (I) in which R is other than hydrogen have a centre of asymmetry. Optically active antipodes of the compounds of the general formula (I) can be prepared by starting from optically active compounds of the general formula (II) and (III), respectively, Alternatively, a racemic compound of the general formula (I) obtained can be subjected to resolution in a manner known per se.Those compounds of the general formula (I) wherein R1 is carboxyl may be resolved be reacting the racemate with a suitable optically active base (for example optically active threo-1-(p nitrophenyl)-2-amino-propane-1 ,3-diol) and separating the two resulting distereomeric salts on the basis of their different physical properties, for example by crystallization, and setting free the optically active antipode from the salt by reacting it with a strong base.
Starting compounds of the general formula (Ill)--wherein R, R1, R2 and n are as hereinbefore defined-are disclosed in our earlier patents (see Hungarian Patent Specifications Nos. 156,119; 158,085; 162,384 and 162,373; and Dutch Patent Specification No. 7,212,286) and can be prepared as described in said patents.
Starting compounds of the general formula (II) are known in the art [Arzneimittel Forschung (1 972) 22, 815] or can be prepared by literature methods.
Certain representatives of the compounds of the general formula (I) possess analgesic, antiinflammatory, platelet-aggregation inhibiting, antiatherogenic, antiasthmatic and/or antiallergic effects while others are valuabie intermediates in the synthesis of compounds having antiallergic and/or antiasthmatic properties.
The compounds of the general formula (I) may be employed in the form of pharmaceutical compositions containing the active ingredient in association with inert solid or liquid carriers. The compositions are prepared by methods known per se.
The compositions can be formulated in a form suitable for oral or parenteral administration or for inspiration, more particularly, as tablets, dragées, capsules, lozenges, powder mixture, aerosol sprays, aqueous suspensions or solutions, injection solutions or syrups.
The compositions may contain suitable solid diluents or carriers, sterile aqueous solvents or nontoxic organic solvents. To the compositions suitable for oral administration the usual flavouring or sweetening agents may be added.
Further details of the invention are illustrated by the following Examples which are given for illustration and not for limitation.
Example 1 1.4 g (0.005 moles) of 9-bromo-6-methyl-4-oxo-6,7,8,9-tetrahyd ,2-a]pyrimidine- 3-carboxylic acid are dissolved in 1 5 ml of chloroform dried over sodium sulfate. To the solution a solution of 0.3 ml (0.005 moles) of bromine in 5 ml of chloroform is added dropwise, under stirring at room temperature. The reaction mixture is then stirred at room temperature for half an hour and allowed to stand overnight. The precipitated crystals are filtered off and washed with a small amount of chloroform.
To the precipitate 10 ml of water and 10 ml of chloroform are added, and the pH of the aqueous phase is adjusted to 2 with a 5% by weight sodium hydrogen carbonate solution, under stirring. The organic phase is separated, the aqueous phase is shaken with two 10 ml portions of chloroform. The combined organic phases are dried over anhydrous sodium sulfate and the solvent is distilled off under reduced pressure. The residue is recrystallized from methanol. 0.3 g (1 6.4%) of 9,9-dibromo-6-methyl 4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1 ,2-a]pyrimidine-3-carboxylic acid are obtained, melting at 1 65 to 1660C.
Analysis for C1oH1oN203BR2 calculated: C 32.81%, H 2.75%, N 7.65%, Br 43.65%;
found: C 33.22%, H 2.78%, N 7.65%, Br 43.58%.
Example 2
1.4 g (0.005 moles) of 9-bromo-6-methyl-4-oxo-6,7 ,8,9-tetrahydro-4H-pyrido[ 1 ,2-a]pyrimidine- 3-carboxylic acid are dissolved in 30 ml of glacial acetic acid. To the solution a solution of 0.3 ml (0.05 moles) of bromine in 2 ml of glacial acetic acid is added dropwise, under stirring, at room temperature.
The reaction mixture is then stirred at 40 to 600C for half an hour, whereupon the acetic acid is distilled off under reduced pressure. To the residue 10 ml of water and 10 ml of chloroform are added, and the pH of the aqueous phase is adjusted to 2 with a 10% by weight solution of sodium hydrogen carbonate, under stirring. The organic phase is separated, the aqueous phase is shaken with two 10 ml portions of chloroform. The combined organic phases are dried over anhydrous sodium sulfate and the solvent is distilled off under reduced pressure. The residue is recrystallized from methanol.
0.8 g (53.8%) of 9,9-dibromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a] pyrimidine-3- carboxylic acid are obtained, melting at 164 to 1 660C. The product does not give any melting point depression when admixed with the product of Example 1.
Example 3
14 g of crystalline sodium acetate and 10.4 g (0.05 moles) of 6-methyl-4-oxo-6,7,8,9 tetrahydro-4H-pyrido[ 1 ,2-a] pyrimidine-3-carboxylic acid are dissolved in 100 ml of glacial acetic acid.
To the solution 5.4 ml (0.1 moles) of bromine are added dropwise at a slow rate, at room temperature with stirring. The reaction mixture is then stirred at room temperature for two hours, whereupon the solvent is distilled off under reduced pressure. To the residue 50 ml of water and 50 ml of chloroform are added, and the pH of the aqueous phase is adjusted to 2 with a 5% by weight solution of sodium carbonate under stirring. The organic phase is separated, the aqueous phase is shaken with two 50 ml portions of chloroform. The combined organic phases are dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. The residue is recrystallized from methanol.
9.4 g (51.3%) of 9,9-dibromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1.2-a]pyrimidine-3carboxylic acid are obtained, melting at 165 to 1660 C. The product does not give any melting point depression when admixed with the product of any of Examples 1 and 2.
Example 4
Following the procedure described in Example 2 but replacing racemic (+)-9-brnmo-6-methyl-4- oxo-6,7,8,9-tetrahydro-4H-pyrido[l ,2-a]pyrimidine-3-carboxylic acid by optically active (+)-9-bromo6-methyl-4-oxo-6,7,8,9-tetra hydro-4H-pyrido [1,2-a] pyrimidine-3-carboxylic acid, (+)-9,9-dibromo-6methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid is obtained, melting at 157 to 1 590C. Yield: 49.0%, [α]D20=+47.5 (c=1, methanol).
Analysis for C1ON1ON2o3Br: calculated: C 32.81%, H 2.75%, N 7.65%, Br 43.66%;
found: C 33.11%, H 2.60%, N 7.56%, Br 43.44%.
Example 5
Following the procedure described in Example 3 but replacing racemic (+)-6-methyl-4-oxo S,7,8,9-tetrahydro-4H-pyrido[l ,2-a]pyrimidine-3-carboxylic acid by optically active (-)-6-methyl-4- oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a] pyrimidi ne-3-carboxylic acid, (+)-9,9-dibromo-6-methyl-4oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid is obtained, melting at 157 to
158 C. The product does not give any melting point depression when admixed with the product of
Example 4. Yield: 51.2%, [a]20=+47.50 (c=1, methanol).
Example 6
Following the procedure described in Example 2 but replacing racemic (#)-9-bromo-6-methyl-4- oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-3-carboxylic acid by optically active (-)-9-bromo-6- methyl-4-oxo-6,7,8,9-tetra hydro-4H-pyrido[1 ,2-a] pyrimidine-3-carboxylic acid, (-)-9,9-dibromo-6- methyl-4-oxo-6,7,8,9-tetra hydro-4H-pyrido[l ,2-a]pyrimidine-3-carboxylic acid is obtained, melting at
157 to 1 590C. Yield: 49.5%, []DO=~ 47.5O (c=1, methanol).
Analysis for CroH1oN2o3Br2 calculated: C 32.81%, H 2.75%, N 7.65%, Br 43.65%; found: C 33.21%, H 2.72%, N 7.60%, Br 43.62%.
Example 7
Following the procedure described in Example 3 but replacing racemic (+)-6-methyl-4-oxo6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid by optically active (+)-6-methyC4- oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid (-)-9,9-dibromo-6-methyl-4oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid is obtained, melting at 157 to 159 C. Yield: 51.5%; [a]020=-47.50 (c=1, methanol). The product does not give any melting point depression when admixed with the product of Example 6.
Examples 8 to 11
1.4 g of crystalline sodium acetate and 0.005 moles of a starting compound shown in Table I are dissolved in 10 ml of glacial acetic acid. To the solution 0.54 ml (0.01 moles) of bromine are added dropwise at slow rate, under stirring at room temperature. The reaction mixture is then stirred for two
hours at room temperature whereupon acetic acid is distilled off under reduced pressure. To the
residue 10 ml of chloroform are added, and the suspension is stirred for 1 5 minutes at room temperature. The crystals are filtered off and washed with chloroform. The filtrate is evaporated. The
residue is recrystallized from the solvent indicated in Table I.
Examples 12 to 17
1.4 g of crystalline sodium acetate and 0.005 moles of a starting compound shown in Table II are
dissolved in 10 ml of glacial acetic acid. To the solution 3.2 g (0.01 moles) of pyridinium bromide
perbromide are added portionwise, under stirring at room temperature. The reaction mixture is then
stirred at room temperature for two hours and acetic acid is distilled off under reduced pressure. To the
residue 10 ml of water are added and it is shaken with three 10 ml portions of chloroform. The
combined organic phases are dried over anhydrous sodium sulfate and the solvent is distilled off in
vacuo. The residue is recrystallized from methanol.
Examples 18 to 20
0.05 moles of a starting compound shown in Table Ill are dissolved (suspended) in 80 ml of
dichloromethane and to the solution (suspension) obtained a solution of 13.5 g (0.1 moles) of sulfuryl
chloride in 20 ml of dichloromethane is added at room temperature. The reaction mixture is boiled until
the gas evolution terminates (3 to 4 hours), the solvent is distilled off and the residue is recrystallized
from ethanol. Yield: 70 to 80%. The compounds obtained are listed in Table Ill.
Tabl3 I
Solvent
Used for Analysis (%)
Example Starting Yield M.p. Recrystal- Calculated Found
No. Compound Product (%) ( C) lization Formula C H N Br 8 6-methyl-4- 9,9-dibromo-6
oxo-6,7,8,9- methyl-4-oxo
tetrahydro- 6,7,8,9-tetra
4H-pyrido- hydro-4H-pyrido
[1,2-a]pyri- [1,2-a]pyrimidine
midine-3-car- 3-carboxylic acid 31.81 2.75 7.65 43.65
boxylic acid 38.8 165-6 methanol C10H10N2O3BR2 33.12 2.60 7.59 43.62 9 6-methyl-4- 9,9-dibromo-6
oxo-6,7,8,9- methyl-4-oxo
tetrahydro- 6,7,8,9-tetra
4H-pyrido- hydro-4H-pyrido
[1,2-a]pyri- [1,2-a]pyrimidine
midine-3-car- 3-carboxylic acid
boxylic acid ethyl ester 36.57 3.58 7.10 40.55
ethyl ester 90.0 oil C12H14N2O3BR2 36.84 3.54 7.06 40.38 10 6-methyl-4- 9,9-dibromo-6
oxo-6,7,8,9- methyl-4-oxo
tetrahydro- 6,7,8,9-tetra
4H-pyrido- hydro-4H-pyrido
[1,2-a]pyri- [1,2-a]pyrimidine
midine-3- 3-carboxamide 32.90 3.03 11.51 43.78
carboxamid 82.2 156-7 methanol C10H11N3O2BR2 33.03 3.21 11.40 43.88 11 6-methyl-4- 9,9-dibromo-6
oxo-6,7,8,9- methyl-4-oxo
tetrahydro- 6,7,8,9-tetra
4H-pyrido- Hydro-4H-pyrido
[1,2-a]pyri- [1,2-a]pyrimidine
midine-3- 3-carbonitrile 34.61 2.61 12.11 46.05
carbonitrile 81.0 164-5 methanol C10H9N3OBr2 34.77 2.86 12.09 46.26 Table II
Analysis (%)
Example Starting Yield M.p. Calculated Found
No.Compound Product (%) ( C) Formula C H N Br 12 (+)-6-methyl- (#)-9,9-dibromo
4-oxo-6,7,8,9- 6-methyl-4-oxo
tetrahydro- 6,7,8,9-tetrahydro
4H-pyrido- 4H-pyrido
[1,2-a]pyri- [1,2-a]pyrimidine
midine-3-car- 3-carboxylic acid 32.81 2.75 7.65 43.66
boxylic acid 50.7 165-166 C10H10N2O3Br2 32.71 2.80 7.78 43.72 13 (-)-6-methyl- (+)-9,9-dibromo-6
4-oxo-6,7,8,9- methyl-4-oxo
tetrahydro- 6,7,8,9-tetrahydro
4H-pyrido- 4H-pyrido
[1,2-a]pyri- [1,2-a]pyrimidine
midine-3-car- 3-carboxylic acid
boxylic acid [α20=+47.5 (c=1, 32.81 2.75 7.65 43.66
methanol) 50.0 157-158 C10H10N2O3Br2 32.99 2.80 7.72 43.79 14 (+)-6-methyl- (-)-9,9-dibromo-ss
4-oxo-6,7,8,9- methyl-4-oxo
tetrahydro- 6,7,8,9-tetrahydro
4H-pyrido- 4H-pyrido
[1,2-a]pyri- [1,2-a]pyrimidine
midine-3-car- 3-carboxylic acid
boxylic acid [α;20=-47.5 (c=1, 32.81 2.75 7.65 43.66
methanol) 50.1 157-158 C10H10N2O3Br2 32.60 2.67 7.42 43.45 15 4-oxo-6,7,8,9- 9,9-dibromo-4-oxo
tetrahydro-4H- 6,7,8,9-tetrahydro
pyrido[1,2-a] 4H-pyrido[1,2-a]
pyrimidine-3- pyrimidine-3- 30.71 2.29 7.96 45.40
carboxylic acid carboxylic acid 45.5 136-138 C9H8N2O3Br2 30.59 2.46 8.06 45.60 16 7-methyl-4- 9,9-dibromo-7
oxo-6,7,8,9- methyl-4-oxo
tetrahydro-4H- 6,7,8,9-tetrahydro
pyrido[1,2-a]- 4H-pyrido[1,2-a]
pyrimidine-3- pyrimidine-3- 32.81 2.75 7.65 43.66
carboxylic acid carboxylic acid 65.5 264-265 C10H10N2O3Br2 32.73 2.80 7.77 43.49 17 8-methyl-4- 9,9-dibromo-8
oxo-6,7,8,9- methyl-4-oxo
tetrahydro-4H- 6,7,8,9-tetrahydro
pyrido[1,2-a]- 4H-pyrido[1,2-a]
pyrimidine-3- pyrimidine-3- 32.81 2.75 7.65 43.66
carboxylic acid carboxylic acid 64.9 235-237 C10H10N2O3Br2 32.72 2.81 7.72 43.55 Table III
Analysis (%)
Example Starting M.p. Calculated Found
No. Compound Product ( C) Formula C H N Cl 18 6-methyl-4-oxo- 9,9-dichloro-6-methyl
6,7,8,9-tetra- 4-oxo-6,7,8,9-tetra
hydro-4H-pyri- hydro-4H-pyrido[1,2-a]
do[1,2-a]pyrimi- pyrimidine-3-carboxylic
dine-3-carboxylic acid 43.34 3.60 10.11 25.58
acid 194 C10H10N2O3Cl2 43.20 3.65 10.05 25.63 19 6-methyl-4-oxo- 9,9-dichloro-6-methyl
6,7,8,9-tetra- 4-oxo-6,7,8,9-tetra
hydro-4H-pyri- hydro-4H-pyrido[1,2-a]
do[1,2-a]pyrimi- pyrimidine-3-carboxylic
dine-3-carboxylic acid ethyl ester 47.23 4.62 9.18 23.58
acid ethyl ester 82-84 C12H14N2O3Cl2 47.02 4.65 9.08 23.16 20 6-methyl-4-oxo- 9,9-dichloro-6-methyl
6,7,8,9-tetra- 4-oxo-6,7,8,9-tetra
hydro-4H-pyri- hydro-4H-pyrido[1,2-a]
do[1,2-a]pyri- pyrimidine-3-carbox
midine-3-carbox- amide 43,48 4.01 15.21 25.67
amid 122 C10H11N3O2Cl2 43,27 4.02 15.31 25.78 Example 21
2.2 g of crystalline sodium acetate and 0.8 g (0.005 moles) of 6-methyl-6,7,8,9-tetrahydro-4H pyrido[1 ,2-a]pyrimidine-4-one are dissolved in 10 ml of glacial acetic acid. To the solution 1.0 ml (0.018 moles) of bromine are added dropwise, at room temperature, under stirring. The reaction mixture is then stirred at 50 to 600C for half an nour whereupon acetic acid is distilled off under reduced pressure. To the residue 10 ml of chloroform are added and the suspension is stirred at room temperature for 1 5 minutes. The crystals are filtered off and washed with chloroform. The filtrate is evaporated in vacuo. Recrystallization of the residue from methanol yields 1.5 g (74.8%) of 3,9,9 tribromo-6-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-4-one, melting at 1 57 to 1 59 0 C.
Analysis for CgHgN2OBr3: calculated: C 26.96%, H 2.26%, N 6.98%, Br 59.79%;
found: C 26.80%, H 2.06%, N 7.00%, Br 59.00%.
Example 22
Following the procedure described in Example 8 but starting from 3,6-dimethyl-6,7,8,9tetrahydro-4H-pyrido[1,2-a]pyrimidine-4-one, 9,9-dibromo-3,6-dimethyl-6,7,8,9-tetrahydro-4H pyrido[1 ,2-a]pyrimidine-4-one is obtained, melting 114 to 11 50C. Yield: 30.0%.
Analysis for C'OHt2N20Br2: calculated: C 35.74%, H 3.59%, N 8.34%, Br 47.56%;
found: C 35.74%, H 3.72%, N 8.22%, Br 47.85%.
Example 23
To a solution of 2.1 g (0.01 moles) of 6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1 2- a]pyrimidine-3-carboxylic acid in 20 ml of chloroform 3.6 g (0.02 moles) of N-bromo-succinimide are added portionwise, with stirring. The reaction mixture is refluxed for five hours and chloroform is distilled off under reduced pressure. To the residue 20 ml of water are added and the suspension is stirred at room temperature for 15 minutes. The insoluble crystals are filtered off, dried and recrystallized from methanol. 1.5 g (41.0%) of 9,9-dibromo-6-methyl-4-oxo-6,7,8,9-tetrahydro- 4H-pyrido[1 ,2-a]pyrimidine-3-carboxylic acid are obtained, melting at 1 63 to 1 64 OC.
The product does not give any melting point depression when admixed with the product of
Example 1.
Example 24
To a solution of 1.04 g (0.005 moles) of 6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1 ,2- a]pyrimidine-3-carboxylic acid in 10 ml of chloroform 1.33 g (0.01 moles) of N-chloro-succinimide are added in small portions, under stirring. The reaction mixture is then refluxed for five hours, whereupon chloroform is distilled off under reduced pressure. To the residue 10 ml of water are added and the suspension is stirred at room temperature for 15 minutes.The crystals are filtered off, dried and recrystallized from methanol. 0.7 g (50.5%) of 9,9-dichloro-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H- pyrido[l ,2-a]pyrimidine-3-ca rboxylic acid are obtained, melting at 190 to 191 OC. The product does not give any melting point depression when admixed with the product of Example 1 8.
Example 25
Following the procedure described in Example 8 but replacing 6-methyl-4-oxo-6,7,8,9tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid by 3-ethyl-2,6-di methyl-6,7,8,9-tetrahydro- 4H-pyrido[1 ,2-a]pyrimidine-4-one and recrystallizing the crude product from a 50% aqueous ethanol solution, 9,9-dibromo-3-ethyl-2,6-dimethyl-6,7,8,9-tetrahydro-4H-pyrido[1 ,2-a]pyrimidine-4-one are obtained, melting at 90 to 920C. Yield: 57.2%.
Analysis for C,2H,6N20Br2: calculated: C 39.59%, H 4.43%, N 7.69%, Br 43.9%; found: C 39.21%, H 4.25%, N 7.59%, Br 43.76%.
Example 26
Following the procedure described in Example 8 but replacing 6-methyl-4-oxo-6,7,8,9tetrahydro-4H-pyrido[1,2-a] pyrimidine-3-carboxylic acid by 3-phenyl-6-methyl-6,7,8,9-tetrahydro-4H- pyrido[1 ,2-a]pyrimidine-4-one and recrystallizing the crude product from ethanol, 9,9-dibromo-3phenyl-6-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-4-one is obtained, melting at 1 54 to 1 560C. Yield: 70.4%.
Analysis for C,5H,4N2OBr2: calculated: C 45.26%, H 3.54%, N 7.04%, Br 40.14%;
found: C 45.26%, H 3.54%, N 7.21%, Br 40.25%.
Example 27
2.08 g (0.01 moles) of ethyl-4-oxo-4,6,7,8-tetrnhydrn-pyrrnlo[1 '2-a]pyrimidine-3-carboxylate are dissolved in 10 ml of a 75% (v/v) aqueous acetic acid solution and 2.72 g (0.02 moles) of sodium acetate are added. Thereafter a solution of 3.2 g (0.02 moles) of bromine in 10 ml of a 75% (v/v) acetic acid solution is added dropwise. The reaction mixture is then stirred at 600C for half an hour, and it is diluted with 1 50 ml of water and shaken with three 4 ml portions of chloroform. The combined chloroform phases are dried over sodium sulfate and evaporated. The yellow oily residue turns crystalline upon standing.Recrystallization of the crude product from ethanol yields 2.2 g (60%) of ethyl 8,8-dibromo-4-oxo-6,7 ,8,9-tetrahydro-pyrrolo[1 ,2-a]pyrimidine-3-carboxylate, melting at 97 to 1000C.
Analysis for C,OHa0N203Br: calculated: C 32.81%, H 2.75%, N 7.65%, Br 43.66%;
found: C 33.28%, H 2.62%, N 7.52%, Br 43.27%.
Example 28
Following the procedure described in Example 27 but replacing ethyl 4-oxo-4,6,7,8-tetrahydro pyrrolo [1 2-a] pyrimidine-3-carboxylate by ethyl 4-oxo-5,6,7,8,9,10-hexahydro-4H-pyri mido[1,2- a]azepine-3-carboxylate and conducting the reaction at 900 C for one hour, 2.1 g (53%) of ethyl 10,10 dibromo-5,6,7,8,9,1 0-hexahydro-4H-pyrido[1 ,2-a]azepine-3-carboxylate are obtained.
R,0.8 (a 4:1 mixture of benzene and methanol, Kieselgel 60 F254).
Analysis for C,2H,4N203Br2: calculated: C 36.57%, H 3.58%, N 7.10%, Br 40.55%;
found: C 36.32%, H 3.49%, N 7.02%, Br 41.02%.
Claims (32)
1. Compounds of the general formula
[wherein
R represents hydrogen, lower alkyl or lower alkoxycarbonyl;
R' represents hydrogen, lower alkyl, ester group, carboxy or a derivative thereof, cyano, phenyl or halogen;
R2 represents hydrogen, lower alkyl or phenyl;
X represents halogen;
n is the integer 1 or 2] and the optically active antipodes and salts thereof.
2. Compounds as claimed in Claim 1 wherein:
R represents hydrogen or methyl;
R1 represents carboxy, methoxycarbonyl, ethoxycarbonyl, cyano, carbamoyl, methyl or phenyl;
R2 represents hydrogen or methyl; and
X represents chlorine or bromine.
3. Compounds as claimed in Claim 1 or 2 wherein R1 represents carboxy.
4. 9,9-dibromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[ 1 ,2-a]pyrimidine-3-carboxylic acid.
5. (+)-9,9-dibromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1 2-a] pyrimidine-3-carboxylic acid.
6. (-)-9,9-dibromo-6-methyl-4-oxo-6,7,B,9-tetrahydro-4H-pyrido[1 ,2-a]pyrimidine-3-carboxylic acid.
7. 9,9-dibromo-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1 2-a] pyrimidine-3-carboxylic acid.
8. 9,9-dichloro-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1 ,2-a]pyrimidine-3-carboxylic acid.
9. 9,9-dibromo-7-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1 ,2-a]pyrimidine-3-carboxylic acid.
10. 9,9-dibromo-8-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1 ,2-a]pyrimidine-3-carboxylic acid.
11. Physiologically compatible salts of the compounds of Claims 4 to 1 0.
12. Compounds as claimed in Claim 1, other than as claimed in Claims 4 to 10, as herein specifically disclosed.
13. A process for the preparation of compounds as claimed in Claim 1, the salts and optically active antipodes thereof, which comprises reacting
a) a racemic or optically active monohalogen derivative of the general formula
b) a racemic or optically active compound of the general formula
(wherein R, R', R2 and n are as defined in Claim 1) with a halogenating agent, and if desired, converting an R' group in a compound of the general formula I obtained into another R1 group and/or, if desired, separating a racemate of the general formula I obtained into optically active antipodes thereof.
14. A process as claimed in Claim 13 in which in process variant a) at least one molar equivalent of a halogenating agent is used.
1 5. A process as claimed in Claim 13 in which in process variant b) at least two molar equivalents of a halogenation agent are used.
1 6. A process as claimed in any of Claims 1 3 to 1 5 wherein elementary halogen, a halogenated acid imide or an inorganic acid halide is used as a halogenating agent.
1 7. A process as claimed in Claim 1 5 in which bromine, N-bromo-succinimide or sulfuryl chloride is used as a halogenating agent.
1 8. A process as claimed in any of Claims 13 to 1 7 wherein said process is carried out in an inert organic solvent.
1 9. A process as claimed in Claim 1 8 wherein said organic solvent is an alkanecarboxylic acid or halogenated hydrocarbon.
20. A process as claimed in any of Claims 13 to 1 9 wherein said process is carried out in the presence of an acid binding agent.
21. A process as claimed in Claim 20 wherein said acid binding agent is an alkali metal acetate.
22. A process as claimed in any of Claims 13 to 21 which comprises decarboxylating an initial product of the general formula I, wherein R' represents carboxyl, R, R2, X and n are as defined in Claim 1, to prepare a compound of the general formula I in which R' is hydrogen.
23. A process as claimed in any of Claims 13 to 21 which comprises reacting an initial product of the general formula I, in which R1 is carboxyl and R, R2, X and n are as defined in Claim 1, with a halogenating agent, to prepare a compound of the general formula I, in which R' is halogen.
24. A process as claimed in Claim 23 which comprises using an elementary halogen as a halogenating agent.
25. A process as claimed in any of Claims 13 to 22 which comprises reacting a compound of the general formula I, in which R' is hydrogen, R, R2, X and n are as defined in Claim 1, with a halogenating agent to prepare a compound of the general formula I, in which R' is halogen.
26. A process as claimed in any of Claims 1 3 to 23 wherein are used compounds of the general formula II or Ill, in which R1 is carboxy, R, R2, X and n are as defined in Claim 1, to prepare compounds of the general formula I, in which R' is carboxy.
27. A process as claimed in any of Claims 13 to 26, substantially as herein described.
28. A process as claimed in any of Claims 13 to 26, substantially as herein described with reference to the Examples.
29. Pharmaceutical compositions comprising as active ingredient at least one compound of formula I as defined in Claim 1, 2, 3 or 12 or a physiologically compatible salt thereof in association with a pharmaceutical carrier or excipient.
30. Pharmaceutical compositions as claimed in Claim 29 comprising the compound of Claim 4 or a physiologically compatible salt thereof.
31. Pharmaceutical compositions as claimed in Claim 29 comprising a compound of any of
Claims 5 to 11.
32. Compounds of Claims 1 to 12 for use as analgesic, antiinflammatory, antiatherogenic, antiasthmatic or antiallergic agents, or for inhibiting platelet aggregation, in human therapy.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU79CI1932A HU179443B (en) | 1979-05-11 | 1979-05-11 | Process for producing substituted geminal dihalogeno-derivatives of pyrido-square bracket-1,2-a-square closed-pyrimidines,pyrrolo-square bracket-1,2-a-square bracket closed-pyrimidines and pyrimido-square bracket-1,2,-a-square bracket closed-asepines |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB2051048A true GB2051048A (en) | 1981-01-14 |
| GB2051048B GB2051048B (en) | 1983-01-19 |
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| Application Number | Title | Priority Date | Filing Date |
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| GB8015469A Expired GB2051048B (en) | 1979-05-11 | 1980-05-09 | Geminal dihalogen derivatives of condensed pyrimidin-4-one compounds their preparation and pharmaceutical compositions containing them |
Country Status (24)
| Country | Link |
|---|---|
| JP (1) | JPS5615286A (en) |
| AT (1) | AT377261B (en) |
| BE (1) | BE883217A (en) |
| CA (1) | CA1141379A (en) |
| CH (1) | CH646971A5 (en) |
| CS (1) | CS241025B2 (en) |
| DD (1) | DD150605A5 (en) |
| DE (1) | DE3017564A1 (en) |
| DK (1) | DK204680A (en) |
| ES (1) | ES491896A0 (en) |
| FI (1) | FI68825C (en) |
| FR (1) | FR2456101A1 (en) |
| GB (1) | GB2051048B (en) |
| GR (1) | GR68518B (en) |
| HU (1) | HU179443B (en) |
| IL (1) | IL59967A (en) |
| IT (1) | IT1133085B (en) |
| LU (1) | LU82437A1 (en) |
| NL (1) | NL8002678A (en) |
| NO (1) | NO152607C (en) |
| PL (1) | PL124035B1 (en) |
| PT (1) | PT71213A (en) |
| SE (1) | SE441747B (en) |
| SU (1) | SU1151210A3 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5158952A (en) * | 1988-11-07 | 1992-10-27 | Janssen Pharmaceutica N.V. | 3-[2-[4-(6-fluoro-1,2-benzisoxozol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9 tetrahydro-9-hydroxy-2-methyl-4H-pyrido [1,2-a]pyrimidin-4-one, compositions and method of use |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HU178453B (en) * | 1979-05-11 | 1982-05-28 | Chinoin Gyogyszer Es Vegyeszet | Process for producing 9-hydrazino-4-oxo-6,7,8,9-tetrahydro-4h-p-pyrido-square bracket-1,2-a-square bracket closed-pyrimidine derivatives |
| US4395549A (en) | 1981-10-02 | 1983-07-26 | Chinoin Gyogyszer Es Vegyeszeti Termekek Gyara Rt. | 6-Hydrazono-pyrido[2,1-b] quinazoline-11 ones |
| IL69274A (en) * | 1982-08-05 | 1986-08-31 | Erba Farmitalia | (substituted amino)derivatives of 3-benzylidene-pyrrolo(2,1-b)quinazolin-9-ones and 6-benzylidene-pyrido(2,1-b)quinazolin-11-ones,their preparation and pharmaceutical compositions containing them |
| UA72189C2 (en) | 1997-11-17 | 2005-02-15 | Янссен Фармацевтика Н.В. | Aqueous suspensions of 9-hydroxy-risperidone fatty acid esters provided in submicron form |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH538494A (en) * | 1966-11-02 | 1973-06-30 | Chinoin Gyogyszer Es Vegyeszet | Process for the preparation of new homopyrimidazole derivatives |
| HU178496B (en) * | 1977-12-29 | 1982-05-28 | Chinoin Gyogyszer Es Vegyeszet | Process for preparing 6,7,8,9-tetrahydro-4h-pyrido/1,2-a/pyrimidine derivatives with antiallergic activity |
-
1979
- 1979-05-11 HU HU79CI1932A patent/HU179443B/en unknown
-
1980
- 1980-05-01 IL IL59967A patent/IL59967A/en unknown
- 1980-05-03 GR GR61852A patent/GR68518B/el unknown
- 1980-05-08 SU SU802920002A patent/SU1151210A3/en active
- 1980-05-08 CS CS803258A patent/CS241025B2/en unknown
- 1980-05-08 SE SE8003479A patent/SE441747B/en not_active IP Right Cessation
- 1980-05-08 DE DE19803017564 patent/DE3017564A1/en not_active Withdrawn
- 1980-05-09 CA CA000351662A patent/CA1141379A/en not_active Expired
- 1980-05-09 PT PT71213A patent/PT71213A/en unknown
- 1980-05-09 LU LU82437A patent/LU82437A1/en unknown
- 1980-05-09 JP JP6161680A patent/JPS5615286A/en active Pending
- 1980-05-09 DK DK204680A patent/DK204680A/en not_active Application Discontinuation
- 1980-05-09 NL NL8002678A patent/NL8002678A/en not_active Application Discontinuation
- 1980-05-09 BE BE0/200550A patent/BE883217A/en not_active IP Right Cessation
- 1980-05-09 NO NO801378A patent/NO152607C/en unknown
- 1980-05-09 IT IT67719/80A patent/IT1133085B/en active
- 1980-05-09 FI FI801512A patent/FI68825C/en not_active IP Right Cessation
- 1980-05-09 AT AT0247580A patent/AT377261B/en not_active IP Right Cessation
- 1980-05-09 FR FR8010481A patent/FR2456101A1/en active Granted
- 1980-05-09 GB GB8015469A patent/GB2051048B/en not_active Expired
- 1980-05-09 CH CH366380A patent/CH646971A5/en not_active IP Right Cessation
- 1980-05-10 PL PL1980224163A patent/PL124035B1/en unknown
- 1980-05-12 ES ES491896A patent/ES491896A0/en active Granted
- 1980-05-12 DD DD80221053A patent/DD150605A5/en unknown
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5158952A (en) * | 1988-11-07 | 1992-10-27 | Janssen Pharmaceutica N.V. | 3-[2-[4-(6-fluoro-1,2-benzisoxozol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9 tetrahydro-9-hydroxy-2-methyl-4H-pyrido [1,2-a]pyrimidin-4-one, compositions and method of use |
Also Published As
| Publication number | Publication date |
|---|---|
| SU1151210A3 (en) | 1985-04-15 |
| GR68518B (en) | 1982-01-11 |
| FI68825C (en) | 1985-11-11 |
| SE8003479L (en) | 1980-11-12 |
| LU82437A1 (en) | 1980-07-31 |
| DE3017564A1 (en) | 1980-11-13 |
| FI801512A (en) | 1980-11-12 |
| AT377261B (en) | 1985-02-25 |
| HU179443B (en) | 1982-10-28 |
| PT71213A (en) | 1980-06-01 |
| IT8067719A0 (en) | 1980-05-09 |
| NL8002678A (en) | 1980-11-13 |
| NO152607C (en) | 1985-10-23 |
| FR2456101A1 (en) | 1980-12-05 |
| BE883217A (en) | 1980-09-01 |
| DD150605A5 (en) | 1981-09-09 |
| PL124035B1 (en) | 1982-12-31 |
| IL59967A (en) | 1984-05-31 |
| IL59967A0 (en) | 1980-07-31 |
| FI68825B (en) | 1985-07-31 |
| FR2456101B1 (en) | 1985-04-05 |
| CH646971A5 (en) | 1984-12-28 |
| CA1141379A (en) | 1983-02-15 |
| ES8102570A1 (en) | 1981-02-16 |
| CS325880A2 (en) | 1985-06-13 |
| ATA247580A (en) | 1984-07-15 |
| DK204680A (en) | 1980-11-12 |
| SE441747B (en) | 1985-11-04 |
| PL224163A1 (en) | 1981-02-13 |
| CS241025B2 (en) | 1986-03-13 |
| NO801378L (en) | 1980-11-12 |
| IT1133085B (en) | 1986-07-09 |
| JPS5615286A (en) | 1981-02-14 |
| ES491896A0 (en) | 1981-02-16 |
| GB2051048B (en) | 1983-01-19 |
| NO152607B (en) | 1985-07-15 |
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