CA1141379A - Geminal dihalogen derivatives of condensed pyrimidine-4-one compounds, process for their preparation and pharmaceutical compositions containing them - Google Patents
Geminal dihalogen derivatives of condensed pyrimidine-4-one compounds, process for their preparation and pharmaceutical compositions containing themInfo
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- CA1141379A CA1141379A CA000351662A CA351662A CA1141379A CA 1141379 A CA1141379 A CA 1141379A CA 000351662 A CA000351662 A CA 000351662A CA 351662 A CA351662 A CA 351662A CA 1141379 A CA1141379 A CA 1141379A
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- tetrahydro
- pyrimidine
- oxo
- pyrido
- carboxylic acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
- C09B62/00—Reactive dyes, i.e. dyes which form covalent bonds with the substrates or which polymerise with themselves
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Abstract
ABSTRACT
Geminal dihalogen derivatives of condensed pyrimidine-4-one compounds of the general formula I
[wherein R represents hydrogen, lower alkyl, or lower alkoxycarbony;
R1 represents hydrogen, lower alkyl, carboxy, ester group 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 salts and optically active antipodes thereof.
The compounds I are valuable intermediates in the synthesis of compounds having antiallergic or antiasthmatic activity and some of the compounds I themselves posses pharmacological activity.
Geminal dihalogen derivatives of condensed pyrimidine-4-one compounds of the general formula I
[wherein R represents hydrogen, lower alkyl, or lower alkoxycarbony;
R1 represents hydrogen, lower alkyl, carboxy, ester group 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 salts and optically active antipodes thereof.
The compounds I are valuable intermediates in the synthesis of compounds having antiallergic or antiasthmatic activity and some of the compounds I themselves posses pharmacological activity.
Description
11~13~9 Gemln~l dihalo~en derivatives o~ condcn~ed p~rimidine-4-o~ compound~. Proces~ for their reParation and pharmaceuticsl comPo~itions containin~ them The present invention relates to geminal dihalogen derivatives of conden~ed p~rimidin-4-o~
compounds, process for their prep~ration an~
phsrmaceutical compositions co~taining them. The compounds are vsluable intermedistes in the synthesis of compounds having s~tisllergic and/or antiasthmstic properties and their certain representstives possess analgesic, antiinflammatory, plstelet-aggregation inhibiting, antistherogenic, antia~thmatic and/or antiallergic effects.
It i8 ~ell k~o~ that certain condensed pyrimidine compounds show analge~ic snd other CUS-activitie~ (British Patent Specification ~o.
1,209,946). A t~pical representative of these compounds i~ 3-(ethoxycarbonyl)-1,6-dimethyl-4-o~o-6,7,8,9-tetrahydro-4H-pyrido[1,2-a~pyrimidinium methoaulfate (PROB0~, Rimazolium) which ha~
excellent analgesic properties and is widely u~ed in the therapy (Arzneim~ttel For~chung 22 ~1972~ 815).
According to one feature of the present invention there are provided compound~ of the general formula
compounds, process for their prep~ration an~
phsrmaceutical compositions co~taining them. The compounds are vsluable intermedistes in the synthesis of compounds having s~tisllergic and/or antiasthmstic properties and their certain representstives possess analgesic, antiinflammatory, plstelet-aggregation inhibiting, antistherogenic, antia~thmatic and/or antiallergic effects.
It i8 ~ell k~o~ that certain condensed pyrimidine compounds show analge~ic snd other CUS-activitie~ (British Patent Specification ~o.
1,209,946). A t~pical representative of these compounds i~ 3-(ethoxycarbonyl)-1,6-dimethyl-4-o~o-6,7,8,9-tetrahydro-4H-pyrido[1,2-a~pyrimidinium methoaulfate (PROB0~, Rimazolium) which ha~
excellent analgesic properties and is widely u~ed in the therapy (Arzneim~ttel For~chung 22 ~1972~ 815).
According to one feature of the present invention there are provided compound~ of the general formula
- 2 -X X
~N ~ 2 ~ ~ Rl [wherein repre~ents hydrogen, lower alkyl or lower alkoxycarbonyl;
Rl represents hydrogen, lower alkyl, carbo~y, ester group or a derivati~e thereof, cyano, phenyl or halogen;
R repre~ents h~drogen, lower alkyl or phenyl;
X represents halogen;
n i8 the integer 0, 1 or 2~
snd the opticall~ active antipodes thereof.
The term "lower slkyl" used heréin for alkyl groups or al~yl containing group~, such as alkoxy group, generally sta~ds ~or Cl 6 prefer-ably Cl 4 ~traight or branched aliphat~c ~aturated hydrocarbons, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary butyl, tertiary but~l, n-pentyl, neo-pentyl, n-he~yl, etc.
~he term "derivative of the csrboxyl group"
standa for conventional carboxylir ~cid derivat~ve~, . such a~ alko~ycarbonyl e,g, lower alko~ycarbonyl, arylo~ycsrbonyl, aralkoxycarbonyl or oth2r esters, carbamoyl optionslly ~ubstituted by one or two al~l (e.g. lower alkyl), aryl or aralkyl groupa~
cya~o, csrbo~ylic acid hydrszido or hydro~amic ~1413t79 ac~d (-CO-NHOH).
The te~n 'laryl" used as sucl ~r iu aryl containing groul)s such as aryl~xy ~ay, for e~ample, stsnd for optionally sub~tituted C6 10 aromatic group~, such as phenyl or naphthyl or substituted derivati~es thereof.
The term "aralkyl" used as such or in aral~yl co~taining groups, such as arslkylo~y, may, ~or example, stand for Cl 3alkyl substituted by phenyl or naphthyl, such as benzyl, ~-phenyl-ethyl, ~,~-d~-phenyl-ethyl, ~,~,diphenyl-ethyl, etc.
~ he ter~ "halogen" stand3 for chlorine, bromine or iodine atom.
Preierred compounds o~ the present in~ention 15 include compounds of the genersl formula I wherein R represent~ hydrogen, lower slkyl, prefersbl~
methyl;
Rl represent3 carboxy) l~wer alko~y-carbonyl, preferably metho~y-carbo~yl or ethoxy-carbon~l; cysno, carbamoyl, lower alkyl, preferably methyl; phenyl;
R2 repre~ent~ hydrogen, lower alkyl, prefer~bly methyl;
~ represents chlorine or ~romine;
n i~ the integer 0, 1 or 2.
Compounds of the general formula I contain-ing carbo~y gro~p~ form salts with phsrmaceutically 11413~79 acceptable base~, ~uch as alkali metal ~alts, e.g. sodium or potas~ium salts, al~ali earth metal, such a~ cslcium or msgnesium salts, ammonium salts and ~ith organic amines, such a8 tr~ethylamine salts, ethanol amine aalts, ~c.
Optical isomer~ of the compou~ds of the general ~ormula I are also within the scope o~
the inventio~.
~ he ~ew compounds o~ the genersl formula I, pharmaceutically acceptable salts thereof and optically acti~e isomer~ thereo~ may ~or eæsmple be prepared by following proce~3es (a) or (b), which proces~e~ conætitute a ~urther ~eature of the pre~ent i~vention:
a) a monoh~logen com~o~nd of the general ~ormula R 1 f~ Il ~wherein R, Rl, R2, ~ and n are a~ hereinbe~ore de~ined~
i8 resctea with a hslogenating agent; or b) a compound o~ the ge~eral ~or~ula ~ ~ N ~ ~2 III
(C~N~Rl o 11413~9 t~herein R, Rl, R2 and n are as hereinbefore defined) i9 reacted with a ~alogenating agent and, if desired, in a compound of the general formuls I obtained a group Rl iB converted into another group Rl, and if de~ired, a rscemate o~ the general formNla I i9 re~oluted into its optically active antipode~.
According to process variant a) 8 compound of the general formula (II) - ~herein R, Rl, R2, ~
snd n are a~ hereinbefore defined - is reacted with an st least equivalent amount o~ a halogenating agent. Pre~erabl~ the halogenating agent i8 U8ed in an amount Or 1 to 1.5 molar equivalent~.
According to proces~ variant b) a compound o~ the general formula (lII) - ~herein R, Rl, R2 and n are as hereinbe~ore defined i~ rescted with at least t~o molar equivalents of a halogenating agent. The pre~erred a~ount of halogenating agent i~ 2 to 2.5 molar equi~alents calculsted for ths compound~ of formula (III).
A~ halogenating agent co~ventional halog~ating agent~ known in the art can be used.
~le~entary halogens, such a8 bromine, chlorine or iodine, halogen compound~, such as bromine-chlorine, lodine-chlorine~ etc., snd other halogen deriv~ti~es, ~uch a~ sulfur~l chloride, phosphorus pentachloride, ~-chloro-succinimide, ~-bro~o-succinimide, N-iodo-~13!79 succinimide, 1,3-dibrQmo-5,5-dimethyl-hydantoins, N-bromo-caprolsctame, tribromo-acetophe~one, tri-chloromethane sul~urylbromide and -chloride, tert.-but~l hypoc~lorite, hypobromite and hypoiodite, 1,2,4,6-tetrachloro-acetsnilide, 1,2-dibromo-tetra-chloroethane, copper~II)-bromide and chloride; snd halogen complexes, such as pyridinium bromide perbromide, phenyltrimethylammonium perbromide, tetrameth~lammonium tribromide, dio~ane dibromide, p~rrolydone-2-hydro-tribromide, etc. are pre~erably used, optionally in the pre~ence of a catalyst, for o~ample a Iewi8 acid, such as aluminium bromide and chloride, phosphorus trichloride, ~ulfur, calcium oxide, W illu~ination, dibenzo~l peroxlde, etc.
The hslogenatio~ is carried out in a co~ven-tional manner. Compounds of the general formula (}I) a~d (III~, rep~ect~vely sre generally reacted with th~ su~table haloge~ating agent in an inert solvent, e.g, alkanecarbo~lic acid, halogenated hydrocarbo~, etc., prefersbl~ i~ aceti¢ acid or chloroform.
Optionall~ ac~d binding agent~, ~uch as triethy}
amine, acetamide, sodium scetate, etc. ca~ also be employed.
The reactio~ are carried out st a temperature between O C a~d 160 C, pre~ersbly at 20 C to 60 C.
Compou~ o~ the general formula ~) or the sslts thereoi eithar prec~pitate from the reaction mi~ture 1~413~79 and can be elimi~ated for e~ample by filtration, or are separated from the resction mixture by evaporating the solvent. Compounds of the genersl formula (I) can be purified by conventional technique~, ~uch a~ recry~tsllization, chromatography, etc, A compound of the general formula (I) thus obta~ned may be converted, if de~ired, to a~other compound of the general formula (I) by method~
known per se. The conversion may take place o~ the group Rl. Thus a compound of the general ~ormNla (I), in which Rl i~ carbo~y can be decarboxylated in an organic, e.g. lower alksnecarbox~lic acids, lower alkanol~, etc. or inorganic, e.g. water, solvent, at a temperature of 0 to 20~ C, optionally in the presence of a mineral acid, such as h~drogen halides, sulfuric acid, etc. The compounds of the general formula (I~ obtsined, in which Rl stands for h~drogen, R~ R2, ~ and n are a~ hereinbefore 2D defined are then i~olated or reacted with one molar equivalent of a halogenating agent. In this way compound~ o~ the general formula (I), in which i8 hibgen are o~tained The above facultative reaction ~teps sre 81~0 within the ~cope o~ the ir.vention, Compound~ of the general formula (I ) in which R i~ other than hydrogen have a centre of 11~13'79 asymmetry. Optically acti~e antipode~ of the compou~ds oi the general formula (I) can be prepared by starting from optically active compound~ of the general iormuls (II) and (III), re~pectivel~. Alternati~el~, a racemic compound Or the genersl ~ormula (I) obtained can be sub~e¢ted to re~olution in a manner known per ~e.
The in plsce o~ Rl carbo~l containi~g compound~
oi the general formula (I) may be resolved by reactin~ the racemate with a suitable optically acti~e base (for example optically active threo-l-(p-nitrophenyl)-2-amino-propane-1,3-diol) and ~eparating tho iormed members o~ t~e distereomer ~alt-pair based on their diiferent physical propertie~, ior example by cryatallization and setting free the opticall~ active antipode for, the salt by reacting it with a ~tron~ ~a~e.
Starting compound~ o~ the general formula (III) - wherein R, Rl, R2 and n are as herein-befor~ deiined - are disclosed in our earlier pat~nt~ (see ~ungarian Patent Speciiications Bo8. 156,119~ 1'i8,085; 162,384 snd 162,373; and Dutch ~atent Specification Bo. 7,212,286) and can be prepared a~ described in ~aid patents.
StartinK compounds of the general formula (II) are ~nown in the art (Arzneimittel Forsc~ung /1972J 22, 815) or can be prepared by literature ~141379 g ~orn method~.
Cortain repre~entati~es of the compounds oi the general ~ormula (I) possess anslge~ic, anti-inflammatory, platelet-aggregation inhibiting~
antiatherogenic, antiasthmati~-and/or antiallergic o~ects while othera are ~aluable intermediates i~ the s~nthesis of compounds having antiallergic and/or antiasthmatic propertie~.
~he compounds of the general fo~nula (I) ma~
be employed in the iorm of pharmaceutical composi-tions containing tho active ingredient ~n asso¢ia-tion with inert solid or liquid ¢arriers. ~he compo-sitions are prepared b~r methods knollrn ~er se.
The compoaitions can be ~ormulated in a form ~uitable for oral, parenteral admin~stration or for inspiration, more particularly, a~ tablets, dragée~, capsules, lozenges, powder mixture, aero~ol ~pray, squeou~ suspensions or solutions, in~ection ~olution~
or s~ups.
~he composition~ may contain suitable solid diluents or carrier~, sterile aqueous sol~ents or non-to~ic organic solvents. ~o the compositions ~uitsble for oral administretion the usual flavouring or ~weetening agents may be added.
Further details of the invention are ~llu~trated b~r the follow~ng Examples which are gi~cn for illuatration and not for l~mitation.
111i137g ~sm~le 1 1~4 g. ~0.005 mole~) of 9-bromo-6-meth~l-4-o~o-6,7,8,9-tetrsh~dro-4H-pyridotl,2-s~pyri~idine-
~N ~ 2 ~ ~ Rl [wherein repre~ents hydrogen, lower alkyl or lower alkoxycarbonyl;
Rl represents hydrogen, lower alkyl, carbo~y, ester group or a derivati~e thereof, cyano, phenyl or halogen;
R repre~ents h~drogen, lower alkyl or phenyl;
X represents halogen;
n i8 the integer 0, 1 or 2~
snd the opticall~ active antipodes thereof.
The term "lower slkyl" used heréin for alkyl groups or al~yl containing group~, such as alkoxy group, generally sta~ds ~or Cl 6 prefer-ably Cl 4 ~traight or branched aliphat~c ~aturated hydrocarbons, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary butyl, tertiary but~l, n-pentyl, neo-pentyl, n-he~yl, etc.
~he term "derivative of the csrboxyl group"
standa for conventional carboxylir ~cid derivat~ve~, . such a~ alko~ycarbonyl e,g, lower alko~ycarbonyl, arylo~ycsrbonyl, aralkoxycarbonyl or oth2r esters, carbamoyl optionslly ~ubstituted by one or two al~l (e.g. lower alkyl), aryl or aralkyl groupa~
cya~o, csrbo~ylic acid hydrszido or hydro~amic ~1413t79 ac~d (-CO-NHOH).
The te~n 'laryl" used as sucl ~r iu aryl containing groul)s such as aryl~xy ~ay, for e~ample, stsnd for optionally sub~tituted C6 10 aromatic group~, such as phenyl or naphthyl or substituted derivati~es thereof.
The term "aralkyl" used as such or in aral~yl co~taining groups, such as arslkylo~y, may, ~or example, stand for Cl 3alkyl substituted by phenyl or naphthyl, such as benzyl, ~-phenyl-ethyl, ~,~-d~-phenyl-ethyl, ~,~,diphenyl-ethyl, etc.
~ he ter~ "halogen" stand3 for chlorine, bromine or iodine atom.
Preierred compounds o~ the present in~ention 15 include compounds of the genersl formula I wherein R represent~ hydrogen, lower slkyl, prefersbl~
methyl;
Rl represent3 carboxy) l~wer alko~y-carbonyl, preferably metho~y-carbo~yl or ethoxy-carbon~l; cysno, carbamoyl, lower alkyl, preferably methyl; phenyl;
R2 repre~ent~ hydrogen, lower alkyl, prefer~bly methyl;
~ represents chlorine or ~romine;
n i~ the integer 0, 1 or 2.
Compounds of the general formula I contain-ing carbo~y gro~p~ form salts with phsrmaceutically 11413~79 acceptable base~, ~uch as alkali metal ~alts, e.g. sodium or potas~ium salts, al~ali earth metal, such a~ cslcium or msgnesium salts, ammonium salts and ~ith organic amines, such a8 tr~ethylamine salts, ethanol amine aalts, ~c.
Optical isomer~ of the compou~ds of the general ~ormula I are also within the scope o~
the inventio~.
~ he ~ew compounds o~ the genersl formula I, pharmaceutically acceptable salts thereof and optically acti~e isomer~ thereo~ may ~or eæsmple be prepared by following proce~3es (a) or (b), which proces~e~ conætitute a ~urther ~eature of the pre~ent i~vention:
a) a monoh~logen com~o~nd of the general ~ormula R 1 f~ Il ~wherein R, Rl, R2, ~ and n are a~ hereinbe~ore de~ined~
i8 resctea with a hslogenating agent; or b) a compound o~ the ge~eral ~or~ula ~ ~ N ~ ~2 III
(C~N~Rl o 11413~9 t~herein R, Rl, R2 and n are as hereinbefore defined) i9 reacted with a ~alogenating agent and, if desired, in a compound of the general formuls I obtained a group Rl iB converted into another group Rl, and if de~ired, a rscemate o~ the general formNla I i9 re~oluted into its optically active antipode~.
According to process variant a) 8 compound of the general formula (II) - ~herein R, Rl, R2, ~
snd n are a~ hereinbefore defined - is reacted with an st least equivalent amount o~ a halogenating agent. Pre~erabl~ the halogenating agent i8 U8ed in an amount Or 1 to 1.5 molar equivalent~.
According to proces~ variant b) a compound o~ the general formula (lII) - ~herein R, Rl, R2 and n are as hereinbe~ore defined i~ rescted with at least t~o molar equivalents of a halogenating agent. The pre~erred a~ount of halogenating agent i~ 2 to 2.5 molar equi~alents calculsted for ths compound~ of formula (III).
A~ halogenating agent co~ventional halog~ating agent~ known in the art can be used.
~le~entary halogens, such a8 bromine, chlorine or iodine, halogen compound~, such as bromine-chlorine, lodine-chlorine~ etc., snd other halogen deriv~ti~es, ~uch a~ sulfur~l chloride, phosphorus pentachloride, ~-chloro-succinimide, ~-bro~o-succinimide, N-iodo-~13!79 succinimide, 1,3-dibrQmo-5,5-dimethyl-hydantoins, N-bromo-caprolsctame, tribromo-acetophe~one, tri-chloromethane sul~urylbromide and -chloride, tert.-but~l hypoc~lorite, hypobromite and hypoiodite, 1,2,4,6-tetrachloro-acetsnilide, 1,2-dibromo-tetra-chloroethane, copper~II)-bromide and chloride; snd halogen complexes, such as pyridinium bromide perbromide, phenyltrimethylammonium perbromide, tetrameth~lammonium tribromide, dio~ane dibromide, p~rrolydone-2-hydro-tribromide, etc. are pre~erably used, optionally in the pre~ence of a catalyst, for o~ample a Iewi8 acid, such as aluminium bromide and chloride, phosphorus trichloride, ~ulfur, calcium oxide, W illu~ination, dibenzo~l peroxlde, etc.
The hslogenatio~ is carried out in a co~ven-tional manner. Compounds of the general formula (}I) a~d (III~, rep~ect~vely sre generally reacted with th~ su~table haloge~ating agent in an inert solvent, e.g, alkanecarbo~lic acid, halogenated hydrocarbo~, etc., prefersbl~ i~ aceti¢ acid or chloroform.
Optionall~ ac~d binding agent~, ~uch as triethy}
amine, acetamide, sodium scetate, etc. ca~ also be employed.
The reactio~ are carried out st a temperature between O C a~d 160 C, pre~ersbly at 20 C to 60 C.
Compou~ o~ the general formula ~) or the sslts thereoi eithar prec~pitate from the reaction mi~ture 1~413~79 and can be elimi~ated for e~ample by filtration, or are separated from the resction mixture by evaporating the solvent. Compounds of the genersl formula (I) can be purified by conventional technique~, ~uch a~ recry~tsllization, chromatography, etc, A compound of the general formula (I) thus obta~ned may be converted, if de~ired, to a~other compound of the general formula (I) by method~
known per se. The conversion may take place o~ the group Rl. Thus a compound of the general ~ormNla (I), in which Rl i~ carbo~y can be decarboxylated in an organic, e.g. lower alksnecarbox~lic acids, lower alkanol~, etc. or inorganic, e.g. water, solvent, at a temperature of 0 to 20~ C, optionally in the presence of a mineral acid, such as h~drogen halides, sulfuric acid, etc. The compounds of the general formula (I~ obtsined, in which Rl stands for h~drogen, R~ R2, ~ and n are a~ hereinbefore 2D defined are then i~olated or reacted with one molar equivalent of a halogenating agent. In this way compound~ o~ the general formula (I), in which i8 hibgen are o~tained The above facultative reaction ~teps sre 81~0 within the ~cope o~ the ir.vention, Compound~ of the general formula (I ) in which R i~ other than hydrogen have a centre of 11~13'79 asymmetry. Optically acti~e antipode~ of the compou~ds oi the general formula (I) can be prepared by starting from optically active compound~ of the general iormuls (II) and (III), re~pectivel~. Alternati~el~, a racemic compound Or the genersl ~ormula (I) obtained can be sub~e¢ted to re~olution in a manner known per ~e.
The in plsce o~ Rl carbo~l containi~g compound~
oi the general formula (I) may be resolved by reactin~ the racemate with a suitable optically acti~e base (for example optically active threo-l-(p-nitrophenyl)-2-amino-propane-1,3-diol) and ~eparating tho iormed members o~ t~e distereomer ~alt-pair based on their diiferent physical propertie~, ior example by cryatallization and setting free the opticall~ active antipode for, the salt by reacting it with a ~tron~ ~a~e.
Starting compound~ o~ the general formula (III) - wherein R, Rl, R2 and n are as herein-befor~ deiined - are disclosed in our earlier pat~nt~ (see ~ungarian Patent Speciiications Bo8. 156,119~ 1'i8,085; 162,384 snd 162,373; and Dutch ~atent Specification Bo. 7,212,286) and can be prepared a~ described in ~aid patents.
StartinK compounds of the general formula (II) are ~nown in the art (Arzneimittel Forsc~ung /1972J 22, 815) or can be prepared by literature ~141379 g ~orn method~.
Cortain repre~entati~es of the compounds oi the general ~ormula (I) possess anslge~ic, anti-inflammatory, platelet-aggregation inhibiting~
antiatherogenic, antiasthmati~-and/or antiallergic o~ects while othera are ~aluable intermediates i~ the s~nthesis of compounds having antiallergic and/or antiasthmatic propertie~.
~he compounds of the general fo~nula (I) ma~
be employed in the iorm of pharmaceutical composi-tions containing tho active ingredient ~n asso¢ia-tion with inert solid or liquid ¢arriers. ~he compo-sitions are prepared b~r methods knollrn ~er se.
The compoaitions can be ~ormulated in a form ~uitable for oral, parenteral admin~stration or for inspiration, more particularly, a~ tablets, dragée~, capsules, lozenges, powder mixture, aero~ol ~pray, squeou~ suspensions or solutions, in~ection ~olution~
or s~ups.
~he composition~ may contain suitable solid diluents or carrier~, sterile aqueous sol~ents or non-to~ic organic solvents. ~o the compositions ~uitsble for oral administretion the usual flavouring or ~weetening agents may be added.
Further details of the invention are ~llu~trated b~r the follow~ng Examples which are gi~cn for illuatration and not for l~mitation.
111i137g ~sm~le 1 1~4 g. ~0.005 mole~) of 9-bromo-6-meth~l-4-o~o-6,7,8,9-tetrsh~dro-4H-pyridotl,2-s~pyri~idine-
3-carbo~ylic acid are dis~olved in 15 ml. of chloro-form dried o~er ~odium ~ulfate. To the solution a eolution of 0.3 ml. tO.005 moles) of bromi~e in 5 ml. o~ chloroform i8 added dropwise, under etirring st room temperature. The reaction m~ture i8 then ~tirred at room temperature for half an hour and allowed to ~tand overnight. The precipitated cry8tal8 Br~
f~l~ered of~ and washed with a small amount o~ chloroiorm.
To the precipitate 10 ml. of ~ater and 10 ml.
o~ chloroform are added, and the pH of the aqueous ph~se i~ ad~u~ted to 2 with a 5 % by weight sodium hydrogen carbonate ~olution, under ~tirring. ~he organic phase is ~eparated, the aqueous phase is shaken with t~o lOLml portions of chloroform. ~he com~ined organic pha~e~ are dried over snhydrous sodium ~ul~ste and the sol~ent i9 di~tilled ofi under reduced pressure. ~he residue i9 re-cry~tallized irom methanol. 0.3 g. (16.4 %) o~ 9,9-dibromo-6-methyl-4-o~o-6,7,8,9-tetrahydro-4~-pyrido[l,2-a]p~ri~idine-3-carboxglic acid are obtained, melting at 165 to 166 a.
Analy~i8 for C10~1 ~23~ 2 calculated: C 32.81 %, ~ 2.75 %, ~ 7.65 %, ~r 43.6~ ~;
~ound: C 33.22 %, ~ 2.78 %, N 7.65 %, Br 43 58 %.
11413!79 ExamPle 2 1.4 g. ~0.005 mole~) of 9-bromo-6-methyl-
f~l~ered of~ and washed with a small amount o~ chloroiorm.
To the precipitate 10 ml. of ~ater and 10 ml.
o~ chloroform are added, and the pH of the aqueous ph~se i~ ad~u~ted to 2 with a 5 % by weight sodium hydrogen carbonate ~olution, under ~tirring. ~he organic phase is ~eparated, the aqueous phase is shaken with t~o lOLml portions of chloroform. ~he com~ined organic pha~e~ are dried over snhydrous sodium ~ul~ste and the sol~ent i9 di~tilled ofi under reduced pressure. ~he residue i9 re-cry~tallized irom methanol. 0.3 g. (16.4 %) o~ 9,9-dibromo-6-methyl-4-o~o-6,7,8,9-tetrahydro-4~-pyrido[l,2-a]p~ri~idine-3-carboxglic acid are obtained, melting at 165 to 166 a.
Analy~i8 for C10~1 ~23~ 2 calculated: C 32.81 %, ~ 2.75 %, ~ 7.65 %, ~r 43.6~ ~;
~ound: C 33.22 %, ~ 2.78 %, N 7.65 %, Br 43 58 %.
11413!79 ExamPle 2 1.4 g. ~0.005 mole~) of 9-bromo-6-methyl-
4-oxo-6,7,8,q-tetrahydro-4~-pyrido~1~2-a~pyr~midine-3-carboxylic acid sre dissolved in 3Q ml. of glscial acetic acid. To the solution a ~olution of 0.3 ml. (0.05 moles) of bromine ~n 2 ml. of glacial scetic acid is added dropwise, under stirring, at room temperature. The re~ction m~xture i~ then stirred at 40 to 60 ~ ~or hal~
a~ hour, ~hereupon the acetic acid is di~tilled off under reduced pres~ure. ~o the residue 10 ml.
o~ ~ater and 10 ml. o~ chloro~orm are zdded, and the pH o~ the aqueoua ph~se i8 ad3u~ted to 2 with a 10 % by weight solution o~ aodium hydrogen car~onate, under ~tirring~ The or~anic ph~se ~
separated, the a~ueous phase is sha~en wiuh ~wo 10-ml portions o~ chlorofo~m. The co~Qbined organic phases are dried over a~hydrou~ sodium sul~ate and the solvent ia distilled o~f under reduced pressure.
The residue ~a recrystallized from methanol.
0.8 g. (53.8 %) o~ 9,9-dibromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4E-pyrido~1,2-s~pyrimidine-3-csrbox~lic acid are obtained, melting st 164 to 166 C. The product doea not give any melting poi~t depre~sion when admixed with the product o~
E~ample 1.
13~g E~amDle 3 14 g. oi crystalline sodium acetate and 10.4 g. (0.05 mole~) oi 6-methyl-4-o~o-6,7,8,9-tetrahydro-4H-pyrido~1,2-a]pyrimidine-3-carboxylic acid are di~olved in 100 ml. of glaclsl scetic acid. To the solution 5.4 ml. (0.1 moles) pf bromine are added dropwi~e at a ~low rate, st room temperature with ~tirring. The reaction mixture is then stirred at room temperature ior two hours, whereupon the solvent i~ distilled Or~ under reduced pressure. To the residue 50 ml. oi water and 50 ml. oi chloroiorm are added, and the pH
oi the aqueous phase i~ ad~usted to 2 with a 5 %
by weight solut~on oi sodium carbonate under stirring. The organic phase is separated, the aqueous phase is shaken with two 50~ml portions oi chloro-~orm. The combined organlc pha~es are dried over snh~drous sodium suliate, and the sol~ent is distilled of~ under reduced pres~ure. The residue i~ recr~atallized irom methanol.
9.4 g. (51.3 %) o~ 9,9-dibromo-6-meth~1-4-oxo-6,7,8,9-tetrahydro-4H-pyridoll,2-a3pyrimidine-3-¢arbo~ylia acid are obtained, melting at 165 to 166 C. The product does not give any melt~ng point depre~sion whe~ admixed with the product Or ~ny oi E~ample~ 1 and 2.
3~g E~mple 4 Following the procedure de~cribed in Example 2 but replacing racemic (+)-9-bromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido~1,2-a3 pyrimidine-3-carboxylic acid by optically active (+)-9-bromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido~l,2-a3pyrimidine-3-carbo~ylic acid, (+)-9,9-dibromo-6-methyl-4-oxo-697,8,9-tetrahydro-4~-pyrido~1,2-a~pyrimidine-3-carboxylic acid i9 obtained, melting at 157 to 159 C~ Yield: 49.0 %, ~D0 = +47-5 (c = 1, methanol).
Analy~i~ for Cl ~lO~T23Br calculated: C 32.81 %, H 2.75 $~ N 7.65 %, ~r 43.66 %~
~ound: C 33.11 %, H 2.60 %, ~ 7.56 %, Br 43.44 %.
~
~ollowing the procedure described in Example 3 but replacing rscemic (+)-6-methyl-4-ogo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a~pyrimidine-3-carboxylic acid by optically acti~e (-~-6-methyl-4-o~o-6t7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carbo~ylic acid, (+)-9,9-dibromo-6-methy~4-ox~-6,7,8,9-tetra-hydro 4H-pyrido{1,2-a3pyrimid~ne-3-carbo~ylic acid i~ obtained, melting at 157 to 15~ ~. The product doe~ not gi~e any melting point depression when admi~ed with the product of E~ample 4. Yield:
51.2 %, ~]20 z +47.5 (c = 1, methanol)~
1~41379 ~amPle 6 Follo~ing the procedure de~cribed in E~ampl 2 but replacing racemic (+)~9-bromo-6-methy1~4-o~o-6,7,8,9-tetrahydro-4H-pyrido~1,2-a3 pyrimidin-3-oarboxylic acid by optically active (-)-9-bromo-6-methyl-4-o~o-6,7,8,9-tetrahydro-4H-p~rido~1,2-aJpyrimidine-3-carbox~lic acid, (-)-9,9-dibromo 6-methyl-4-o~o-6,7,8,9-tetrahydro-4H-pyrldo~1,2_a¦pyrimidine-3-csrbo~ylic acid i8 obtsined, melting at 157 to 159 C. Yield: 49.5 ~, 20 ~ _47.5 (c - 1, methanol).
Ansly9i8 for C10~1 ~23Br2S
calculated~ C 32.81 %, H 2.75 %, ~ 7.65 %, Br 43.65 %~
~ou~d: C 33.21 %, H 2.72 %, ~ 7.60 %, ~r 43.62 %.
Exam~le 7 ~ollowing the procedure described in EYample 3 but replacing racemic (+)-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido~1,2-a3pyrimidine-3-carboxylic acid b~ opticall~ sctive (+)-6-methyl-4_oxo-6,7,8,9-tetrahydro-4~-p~r~do~1,2-a]pyrimidine-3-carboxylic acld, (-)-9,9-dibromo-6-methy1-4-oxo-6,7,8,9-tetrahy<lro-4H-pyrido~1,2-a]pyrimidine-3-carboxylic acia ~9 obtained, melting at 157 to l59 C.
Ylelds 51.5 %; ~]20 ~ _47 5 (c ~ 1, methsnol). The product does not give any melting point depress~on when admi~ed with the product of E~ample 6.
li~l379 E~amples 8 to 11 1.4 g. of crystalline sodium acetate and 0.005 moles of a ~tarting compou~d ~ho~n in Table I are dis~ol~ed i~ 10 ml. of glacial ~cetic acid.
To the solution 0.54 ml. tO.Ol moles) of bromine are sdded dropwi~e at 810w rate, under stirring at room temperst~re. The reaction mixture is then ~tirred for t~o hours at room temperature whereupon acetic acid i8 distilled o~ under reduced pressure.
~o the residue 10 ml. of chloroform are added, and the suspension i9 stirred ~or 15 minute~ at room temperature. The crystal~ are filtered of~ and washed with chloroform. The filtrate is eva~orated.
The re~idue i8 recrystallized from the 801vent 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 Tsble II are dissol~ed in 10 ml. of glacial acetic ac~d.
To the ~olution 3.2 g. (0.01 mole~) of pyridinium bromide perbromide are added portionwise, under stirr~ng at roo~ temperature, The reaction mi~ture 18 then ~tirred at room tempersture for two hours and acetic acid i~ distilled off under reduced pres~ure. To the re~idue 10 ml. o~ water are added and it is sha~en with three 10-ml. porti~ns of chloroform. The oombined organic pha~es are dried 11413~79 o~er anhydrous ~odium sulfste snd the solvent i~
distilled off in vacuo. The residue i8 re-crystallized from methanol.
E~8mple 18 to 20 0.05 moles of a starting compound shown ln Table III are dissolved (suspended) in 80 ml. Or dichloromethane and to the aolulon (suspe~aion~
obtained a solution of 13.5 g. (0.1 moles) o~
sulfuryl chloride in 20 ml~ of dichloromethane i~ added at room temperature. The reaction mixture i8 boiled until t~e gas e~olution term~nstes (3 to 4 hour~), the solvent is di~tilled o~f and the residue is recrystallized from ethanol. Yield: 70 to 80 %. The compounds obtained are listed in Table III.
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a~ hour, ~hereupon the acetic acid is di~tilled off under reduced pres~ure. ~o the residue 10 ml.
o~ ~ater and 10 ml. o~ chloro~orm are zdded, and the pH o~ the aqueoua ph~se i8 ad3u~ted to 2 with a 10 % by weight solution o~ aodium hydrogen car~onate, under ~tirring~ The or~anic ph~se ~
separated, the a~ueous phase is sha~en wiuh ~wo 10-ml portions o~ chlorofo~m. The co~Qbined organic phases are dried over a~hydrou~ sodium sul~ate and the solvent ia distilled o~f under reduced pressure.
The residue ~a recrystallized from methanol.
0.8 g. (53.8 %) o~ 9,9-dibromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4E-pyrido~1,2-s~pyrimidine-3-csrbox~lic acid are obtained, melting st 164 to 166 C. The product doea not give any melting poi~t depre~sion when admixed with the product o~
E~ample 1.
13~g E~amDle 3 14 g. oi crystalline sodium acetate and 10.4 g. (0.05 mole~) oi 6-methyl-4-o~o-6,7,8,9-tetrahydro-4H-pyrido~1,2-a]pyrimidine-3-carboxylic acid are di~olved in 100 ml. of glaclsl scetic acid. To the solution 5.4 ml. (0.1 moles) pf bromine are added dropwi~e at a ~low rate, st room temperature with ~tirring. The reaction mixture is then stirred at room temperature ior two hours, whereupon the solvent i~ distilled Or~ under reduced pressure. To the residue 50 ml. oi water and 50 ml. oi chloroiorm are added, and the pH
oi the aqueous phase i~ ad~usted to 2 with a 5 %
by weight solut~on oi sodium carbonate under stirring. The organic phase is separated, the aqueous phase is shaken with two 50~ml portions oi chloro-~orm. The combined organlc pha~es are dried over snh~drous sodium suliate, and the sol~ent is distilled of~ under reduced pres~ure. The residue i~ recr~atallized irom methanol.
9.4 g. (51.3 %) o~ 9,9-dibromo-6-meth~1-4-oxo-6,7,8,9-tetrahydro-4H-pyridoll,2-a3pyrimidine-3-¢arbo~ylia acid are obtained, melting at 165 to 166 C. The product does not give any melt~ng point depre~sion whe~ admixed with the product Or ~ny oi E~ample~ 1 and 2.
3~g E~mple 4 Following the procedure de~cribed in Example 2 but replacing racemic (+)-9-bromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido~1,2-a3 pyrimidine-3-carboxylic acid by optically active (+)-9-bromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido~l,2-a3pyrimidine-3-carbo~ylic acid, (+)-9,9-dibromo-6-methyl-4-oxo-697,8,9-tetrahydro-4~-pyrido~1,2-a~pyrimidine-3-carboxylic acid i9 obtained, melting at 157 to 159 C~ Yield: 49.0 %, ~D0 = +47-5 (c = 1, methanol).
Analy~i~ for Cl ~lO~T23Br calculated: C 32.81 %, H 2.75 $~ N 7.65 %, ~r 43.66 %~
~ound: C 33.11 %, H 2.60 %, ~ 7.56 %, Br 43.44 %.
~
~ollowing the procedure described in Example 3 but replacing rscemic (+)-6-methyl-4-ogo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a~pyrimidine-3-carboxylic acid by optically acti~e (-~-6-methyl-4-o~o-6t7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carbo~ylic acid, (+)-9,9-dibromo-6-methy~4-ox~-6,7,8,9-tetra-hydro 4H-pyrido{1,2-a3pyrimid~ne-3-carbo~ylic acid i~ obtained, melting at 157 to 15~ ~. The product doe~ not gi~e any melting point depression when admi~ed with the product of E~ample 4. Yield:
51.2 %, ~]20 z +47.5 (c = 1, methanol)~
1~41379 ~amPle 6 Follo~ing the procedure de~cribed in E~ampl 2 but replacing racemic (+)~9-bromo-6-methy1~4-o~o-6,7,8,9-tetrahydro-4H-pyrido~1,2-a3 pyrimidin-3-oarboxylic acid by optically active (-)-9-bromo-6-methyl-4-o~o-6,7,8,9-tetrahydro-4H-p~rido~1,2-aJpyrimidine-3-carbox~lic acid, (-)-9,9-dibromo 6-methyl-4-o~o-6,7,8,9-tetrahydro-4H-pyrldo~1,2_a¦pyrimidine-3-csrbo~ylic acid i8 obtsined, melting at 157 to 159 C. Yield: 49.5 ~, 20 ~ _47.5 (c - 1, methanol).
Ansly9i8 for C10~1 ~23Br2S
calculated~ C 32.81 %, H 2.75 %, ~ 7.65 %, Br 43.65 %~
~ou~d: C 33.21 %, H 2.72 %, ~ 7.60 %, ~r 43.62 %.
Exam~le 7 ~ollowing the procedure described in EYample 3 but replacing racemic (+)-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido~1,2-a3pyrimidine-3-carboxylic acid b~ opticall~ sctive (+)-6-methyl-4_oxo-6,7,8,9-tetrahydro-4~-p~r~do~1,2-a]pyrimidine-3-carboxylic acld, (-)-9,9-dibromo-6-methy1-4-oxo-6,7,8,9-tetrahy<lro-4H-pyrido~1,2-a]pyrimidine-3-carboxylic acia ~9 obtained, melting at 157 to l59 C.
Ylelds 51.5 %; ~]20 ~ _47 5 (c ~ 1, methsnol). The product does not give any melting point depress~on when admi~ed with the product of E~ample 6.
li~l379 E~amples 8 to 11 1.4 g. of crystalline sodium acetate and 0.005 moles of a ~tarting compou~d ~ho~n in Table I are dis~ol~ed i~ 10 ml. of glacial ~cetic acid.
To the solution 0.54 ml. tO.Ol moles) of bromine are sdded dropwi~e at 810w rate, under stirring at room temperst~re. The reaction mixture is then ~tirred for t~o hours at room temperature whereupon acetic acid i8 distilled o~ under reduced pressure.
~o the residue 10 ml. of chloroform are added, and the suspension i9 stirred ~or 15 minute~ at room temperature. The crystal~ are filtered of~ and washed with chloroform. The filtrate is eva~orated.
The re~idue i8 recrystallized from the 801vent 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 Tsble II are dissol~ed in 10 ml. of glacial acetic ac~d.
To the ~olution 3.2 g. (0.01 mole~) of pyridinium bromide perbromide are added portionwise, under stirr~ng at roo~ temperature, The reaction mi~ture 18 then ~tirred at room tempersture for two hours and acetic acid i~ distilled off under reduced pres~ure. To the re~idue 10 ml. o~ water are added and it is sha~en with three 10-ml. porti~ns of chloroform. The oombined organic pha~es are dried 11413~79 o~er anhydrous ~odium sulfste snd the solvent i~
distilled off in vacuo. The residue i8 re-crystallized from methanol.
E~8mple 18 to 20 0.05 moles of a starting compound shown ln Table III are dissolved (suspended) in 80 ml. Or dichloromethane and to the aolulon (suspe~aion~
obtained a solution of 13.5 g. (0.1 moles) o~
sulfuryl chloride in 20 ml~ of dichloromethane i~ added at room temperature. The reaction mixture i8 boiled until t~e gas e~olution term~nstes (3 to 4 hour~), the solvent is di~tilled o~f and the residue is recrystallized from ethanol. Yield: 70 to 80 %. The compounds obtained are listed in Table III.
3~ 77 ..
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~14~379 Exam~le 21 2.2 g. of cry~talline ~odium acetata and 0.8 g. (0.005 moles) of 6-methyl-6,7,8,9-tetra-hydro-4H-pyrido~1,2-a~pyrimidine-4-one ~re dissol~ed in 10 ml. of glacial acetic acid. To the eolution 1.0 ml. (0.018 mole~) of bromine are added dropwi~e, at room temperature, under stirring~
The reaction mixture i~ then ~tirred st 50 to 60 C
for half an hour ~hereupon acetic ac~d is distilled off under red~ced preasure. ~o the re~idue 10 ml.
of chlorororm sre added and the su~pen~ion i8 ~tirred at room temperature for 15 minutes. The cry~tal~ are filtered of~ and washed with chloro-form. The filtrate i8 e~aporated in vacuo. Re-cry~tallization of the re~idue from methanol yielde 1~5 g. ~74.8 %) of 3,9,9-tribromo-6-meth~1-6,7,8,9-tetrahydro-4H-pyrido~1,2-a~pyrimldine-4-one, melt~ng at 157 to 159 C.
Analy~i~ for CgH9~20Br3s calculateds C 26.96 %, H 2.26 %, ~ 6.98 %, Br 59.79 %;
~ound: C 26.80 %, ~ 2.06 %, ~ 7.00 %, Br 59.00 %.
Exa~Ple 22 Followi~g the procedure descrlbed in Example 8 b~t ~tarting from 3,6~d~methyl-6,7,8,9-tetra-hydro-4~-pyrido~1,2-a3p~rimidine-4-one, 9,9-di-bromo-3~6-dimethyl-6~7,8,9-tetrahydro-4H-pyridoC1,2-a]pyrimidine-4-one i~ obtained, melting 1~13qg 114 to 115 C. Yields 30.0 %.
Analy~i8 for C10~12N2Br2 calculated: C 35.74 %, H 3~59 %, ~ 8.34 %, Br 47.56 %;
iound~ C 35.74 %, H 3.72 %, ~ 8.22 %, Br 47.85 %.
Exam~le 23 To a ~olution of 2.1 g. (0.01 moles) of
~h -o ~ h ^o +~ h ^o a) ~ ~1 ~ a) +, ~1 ~ a) +, ~1 ~2 El a)~-l h E3 0IJ h h E a~--~ h 1~ o ~S I ~ o ~ a) 1~ 0 ~
O~D 1 ~5 C~ ~O I ~ O +' ~ ~ ~ O
I ~-1~1 1 ~ I ~-rl I ~ I a~-rl I
3O ~h~-rl O ^h~ O I tl~
h0 ~ I O h0 ~ I h0 ?7 1 o ^ ~ a) ~s O ^ ~ ~> ~ o ^ C:L a ~ I ~ ~1 ~ I r? ~1~ 1 ~
O~ ^ J:~ rl ~ rl ,sl ~ ^:~ rl O~D ~ ~ O~ V~D
h ~ rl rl I I rl 0 rl I I rl O o E ~ o 0 8 ~ o o E
~4I ~ h rl I ~ h ~ ~ I ~ h ~
o~ o ~ h O~ O ~ h rl cr~ o ~:1 h rl I ~ ;;~ ^ I ~ o .~ . O~ Cb n~ cr~
O I I E ~ ~ rl rt~ h O I J I O
~; 0 r-l r~ ~ aJ rl ri ~ 1~ ~c c~ r~ rl ~
O h h h O O h h h O r> O S-l h h h bO ~I ~ ;~7 ~,Q I ~ ~7 ~7~ I ~ -7 ?7 G~
~:d- 0 ~ O h d- 0 ~ r:L ~ r-l ~ a>
r :~~ 0 r~ r~~ I X ~d V .~ ~1 ~
h s:~. ~ ~ ~q N t~ a) ~ J 0 ~ o~ co o ~ l ~ 0 o - l ~ c~ o ^ s::
cn O a) ^ h r-~ a) a) ~ h ~~ 0 ~ 0 ^ h ~ I rl ~
F~ ~ ~L~ ~ ~ J !;: rl El C~ ~ ~ rl I ^ ;~> O r~ ~ ^ ~ O-r~ ~ ~ 0-~
Q) ~D ~ ~ ~ ~D ~ ~ ~ ca ~D~D ~ ~ a o æ Oo ~ ON
r~
~14~379 Exam~le 21 2.2 g. of cry~talline ~odium acetata and 0.8 g. (0.005 moles) of 6-methyl-6,7,8,9-tetra-hydro-4H-pyrido~1,2-a~pyrimidine-4-one ~re dissol~ed in 10 ml. of glacial acetic acid. To the eolution 1.0 ml. (0.018 mole~) of bromine are added dropwi~e, at room temperature, under stirring~
The reaction mixture i~ then ~tirred st 50 to 60 C
for half an hour ~hereupon acetic ac~d is distilled off under red~ced preasure. ~o the re~idue 10 ml.
of chlorororm sre added and the su~pen~ion i8 ~tirred at room temperature for 15 minutes. The cry~tal~ are filtered of~ and washed with chloro-form. The filtrate i8 e~aporated in vacuo. Re-cry~tallization of the re~idue from methanol yielde 1~5 g. ~74.8 %) of 3,9,9-tribromo-6-meth~1-6,7,8,9-tetrahydro-4H-pyrido~1,2-a~pyrimldine-4-one, melt~ng at 157 to 159 C.
Analy~i~ for CgH9~20Br3s calculateds C 26.96 %, H 2.26 %, ~ 6.98 %, Br 59.79 %;
~ound: C 26.80 %, ~ 2.06 %, ~ 7.00 %, Br 59.00 %.
Exa~Ple 22 Followi~g the procedure descrlbed in Example 8 b~t ~tarting from 3,6~d~methyl-6,7,8,9-tetra-hydro-4~-pyrido~1,2-a3p~rimidine-4-one, 9,9-di-bromo-3~6-dimethyl-6~7,8,9-tetrahydro-4H-pyridoC1,2-a]pyrimidine-4-one i~ obtained, melting 1~13qg 114 to 115 C. Yields 30.0 %.
Analy~i8 for C10~12N2Br2 calculated: C 35.74 %, H 3~59 %, ~ 8.34 %, Br 47.56 %;
iound~ C 35.74 %, H 3.72 %, ~ 8.22 %, Br 47.85 %.
Exam~le 23 To a ~olution of 2.1 g. (0.01 moles) of
6-meth~1-4-oxo-6,7~8~9-tetrahydro-4H-pyrido~1~2-a]
pgrimidine-3-carboxylic acid in 20 ~1. of chloro-form 3.6 g. (0.02 mole~) of N-bromo-succini~d~
are added portionw~e, with stixring. The reaction mi~ture i8 re~lu~ed for five hour~ and chloroform i8 distilled o~f under reduced pre~sure, ~o the re~idue 20 ml. of water are sdded and the ~uspensions i~ ~tirred st room te~perature ~or 15 minutea. The ~5 in~oluble crystals are filtered off, dried and recry~tallized from metha~ol. 1.5 g. (41.0 %) of 9,9-dibromo-6-methyl-4_o~o-6,7,8,9-tetrahydro-4H-~rido~1,2-a~pyrimidine-3-carboxylic acid are obtained, me}ting at 163 to 164 C.
The product doe~ not give any melting point depre~s~o~ when admi~ed with the produet of Example 1.
ExampLe 24 To a ~olution of 1.04 g. (0.005 mole~) of 6-~ethyl-4-o~o-6,7,8,9-tetrshgdro-4H-pyrido{1,2-a]
p~rimidine-3-carboxyliG acid in 10 ml. of chloro-form 1.33 g. (0.01 moles) of N-chloro-succinimiae are added i~ 8m811 portions, under ~tirring. The ~413~9 reaction mi~ture i8 then refluxed for ~iYe hour~, ~hereupon chloroform i9 distilled off under reduced pressure. To the residue 10 ml. of water are sdded and the su~pension i~ stirred at room temper~ture for 15 minute~. ~he cry~t~ls are filtered of~, dried snd recrystalli~d ~ro~
methanol. 0.7 g. (50.5 %) of 9,9-d~ohloro-6-methyl-4-o20-6, 7,8,9-tetrahydro-4H-p~ridoC1,2-a~pyrimidine-3-carboxylic acid are obtai~ed, melting at 190 to 191 C. The product doe~ ~ot give any melting point depression when sdmixed with the product o~ Example 18.
Example 25 Following the procedure described in ~xampl 8 but replacing 6-methyl-4-o~o-6,7,8,9-te~rahydro-4~-pyrido~1,2-a~p~rimidine-3-carbo~ylic acid by 3-ethyl-2,6-dimethyl-6,7,8,9-tetrahydro-4~-pyrido~1,2-a]pyrimidine-4-one and recrystallizing the crude product from a 50 % aqueous etha~ol ~olu-tion, 9,9-dibromo-3-ethyl-2,6-dimethyl-6,7,~,9-tetrahydro-4H-pyrido~1,2-a]pyrimidine-4-one sre obtai~ed, melting at 90 to 92 C. Yield: 57.2 %.
A~al~sis ~or C12 ~ 20Br2:
cslcul~ted: C 39.59 %, H 4.43 %, ~ 7.69 %, Br 43.9 %;
founds C 39.21 %, R 4.25 %, N 7.59 %, Br 43.76 %.
Example 26 Following the procedure de~cribed in Example _ 24 8 but replacing 6-methyl-4-oxo-6,7,8,9-tetra-hydro-4R-p~rido-[1,2-a~pyrimidine-3-carboxylic acid by 3-phenyl-6-meth~1_6,7,8,9-tetrsh~dro-4H-pyrido~1,2-a~pyri~idine-4-one and recrystslliz-ing the ¢rude product from ethanol, 9,9-dibromo-3-phenyl-6-meth~1-6,7,8,9-tetrah~dro-4~ p~rido-tl,2-a3pyrimidi~e-4-one iR obtainod, melting at 154 to 156 C. Yleld~ 70.4 %.
Anal~sis ~or C15 ~4N20 Br2 calculated: C 45.26 %, H 3,54 %~ ~ 7.04 %, Br 40.14 %~
foundI C 45.26 %, H 3.54 %, J 7.21 %, Br 40.25 %.
E~ample 27 2.08 g. (0.01 moles) oi ethyl-4-oxo-4,6,7,8-tetrahydro-p~rrolo~1,2-a~pyrimidine-3-carboxylat~
are dissol~ed in 10 ml. oi a 75 % (~/~) aqueous acetic acid 801ution and 2.72 g. to-o2 moles) Or sodium acetste are s~ded. ~herea~b~r 8 solution Or 3.2 g. (0.02 mole~) of bromine in 10 ml. of 8 75 (v/v) acetic acid eolution i8 sdd~d dropwise. Tho reaction mixture is then stirred ar 60 C for half an hour, and it is diluted with 150 ml. Or water snd ~hsk~n with three 4-ml ~ortions of chloroform. ~he combined chloroiorm phsse~ sre dried o~er sodium ~ulfate and evaporated. ~he ~ellow oily residue turns cry~talline upon ~tandi~g. R~cry~tallization of the crude product fro~ ethanol ~ields 2.2 g. t60 ~0) Or ethyl 8,8-di-11~13qg _ ~,5 _ bromo-4-o~o-6,7~8,9-tetrahydro-pyrrolo~1,2-s3-pyrimidine-3-carboxylate, melting at 97 to 100 C.
Ansly~i~ for ClOHlON203Br cslculated: C 32.81 %, H 2.75 %, ~ 7.65 %, Br 43,66 %;
f~und: C 33.28 %, H 2.62 %, ~ 7.52 %, Br 43.27 %.
Example 28 Following the procedure de~cribed in Example 27 but replacing ethyl 4-oxo-4,6,7,8-tetra-hydro-pyrrolo~1,2-a]pyri~idine-3-carboxylate by ethyl 4-oxo-5~6,7,8,9,10-hexahydro-4H-pyrimidotl~2-~ -azepine-3-csrbo~ylate and conducting the reaction st 90 C for one hour, 2.1 g. (53 %~ of ethyl 10,10-dibrDmo-5,6,7,8,9,10-hexahydro-4H-pyrido~1,2-a3-azepine-3-carbox~ate are obtained~
R~ = 0.8 (a 4:1 ~ixture o~bbenzene and methanol, Kie~elgel 60 F254) Analy~ or C12H14N23Br2 calculated: C 36.57 %, H 3.58 %, ~ 7.10 %, Br 40.55 %;
found: C 36.32 %, H 3.49 %, N 7.02 %, Br 41.02 %.
pgrimidine-3-carboxylic acid in 20 ~1. of chloro-form 3.6 g. (0.02 mole~) of N-bromo-succini~d~
are added portionw~e, with stixring. The reaction mi~ture i8 re~lu~ed for five hour~ and chloroform i8 distilled o~f under reduced pre~sure, ~o the re~idue 20 ml. of water are sdded and the ~uspensions i~ ~tirred st room te~perature ~or 15 minutea. The ~5 in~oluble crystals are filtered off, dried and recry~tallized from metha~ol. 1.5 g. (41.0 %) of 9,9-dibromo-6-methyl-4_o~o-6,7,8,9-tetrahydro-4H-~rido~1,2-a~pyrimidine-3-carboxylic acid are obtained, me}ting at 163 to 164 C.
The product doe~ not give any melting point depre~s~o~ when admi~ed with the produet of Example 1.
ExampLe 24 To a ~olution of 1.04 g. (0.005 mole~) of 6-~ethyl-4-o~o-6,7,8,9-tetrshgdro-4H-pyrido{1,2-a]
p~rimidine-3-carboxyliG acid in 10 ml. of chloro-form 1.33 g. (0.01 moles) of N-chloro-succinimiae are added i~ 8m811 portions, under ~tirring. The ~413~9 reaction mi~ture i8 then refluxed for ~iYe hour~, ~hereupon chloroform i9 distilled off under reduced pressure. To the residue 10 ml. of water are sdded and the su~pension i~ stirred at room temper~ture for 15 minute~. ~he cry~t~ls are filtered of~, dried snd recrystalli~d ~ro~
methanol. 0.7 g. (50.5 %) of 9,9-d~ohloro-6-methyl-4-o20-6, 7,8,9-tetrahydro-4H-p~ridoC1,2-a~pyrimidine-3-carboxylic acid are obtai~ed, melting at 190 to 191 C. The product doe~ ~ot give any melting point depression when sdmixed with the product o~ Example 18.
Example 25 Following the procedure described in ~xampl 8 but replacing 6-methyl-4-o~o-6,7,8,9-te~rahydro-4~-pyrido~1,2-a~p~rimidine-3-carbo~ylic acid by 3-ethyl-2,6-dimethyl-6,7,8,9-tetrahydro-4~-pyrido~1,2-a]pyrimidine-4-one and recrystallizing the crude product from a 50 % aqueous etha~ol ~olu-tion, 9,9-dibromo-3-ethyl-2,6-dimethyl-6,7,~,9-tetrahydro-4H-pyrido~1,2-a]pyrimidine-4-one sre obtai~ed, melting at 90 to 92 C. Yield: 57.2 %.
A~al~sis ~or C12 ~ 20Br2:
cslcul~ted: C 39.59 %, H 4.43 %, ~ 7.69 %, Br 43.9 %;
founds C 39.21 %, R 4.25 %, N 7.59 %, Br 43.76 %.
Example 26 Following the procedure de~cribed in Example _ 24 8 but replacing 6-methyl-4-oxo-6,7,8,9-tetra-hydro-4R-p~rido-[1,2-a~pyrimidine-3-carboxylic acid by 3-phenyl-6-meth~1_6,7,8,9-tetrsh~dro-4H-pyrido~1,2-a~pyri~idine-4-one and recrystslliz-ing the ¢rude product from ethanol, 9,9-dibromo-3-phenyl-6-meth~1-6,7,8,9-tetrah~dro-4~ p~rido-tl,2-a3pyrimidi~e-4-one iR obtainod, melting at 154 to 156 C. Yleld~ 70.4 %.
Anal~sis ~or C15 ~4N20 Br2 calculated: C 45.26 %, H 3,54 %~ ~ 7.04 %, Br 40.14 %~
foundI C 45.26 %, H 3.54 %, J 7.21 %, Br 40.25 %.
E~ample 27 2.08 g. (0.01 moles) oi ethyl-4-oxo-4,6,7,8-tetrahydro-p~rrolo~1,2-a~pyrimidine-3-carboxylat~
are dissol~ed in 10 ml. oi a 75 % (~/~) aqueous acetic acid 801ution and 2.72 g. to-o2 moles) Or sodium acetste are s~ded. ~herea~b~r 8 solution Or 3.2 g. (0.02 mole~) of bromine in 10 ml. of 8 75 (v/v) acetic acid eolution i8 sdd~d dropwise. Tho reaction mixture is then stirred ar 60 C for half an hour, and it is diluted with 150 ml. Or water snd ~hsk~n with three 4-ml ~ortions of chloroform. ~he combined chloroiorm phsse~ sre dried o~er sodium ~ulfate and evaporated. ~he ~ellow oily residue turns cry~talline upon ~tandi~g. R~cry~tallization of the crude product fro~ ethanol ~ields 2.2 g. t60 ~0) Or ethyl 8,8-di-11~13qg _ ~,5 _ bromo-4-o~o-6,7~8,9-tetrahydro-pyrrolo~1,2-s3-pyrimidine-3-carboxylate, melting at 97 to 100 C.
Ansly~i~ for ClOHlON203Br cslculated: C 32.81 %, H 2.75 %, ~ 7.65 %, Br 43,66 %;
f~und: C 33.28 %, H 2.62 %, ~ 7.52 %, Br 43.27 %.
Example 28 Following the procedure de~cribed in Example 27 but replacing ethyl 4-oxo-4,6,7,8-tetra-hydro-pyrrolo~1,2-a]pyri~idine-3-carboxylate by ethyl 4-oxo-5~6,7,8,9,10-hexahydro-4H-pyrimidotl~2-~ -azepine-3-csrbo~ylate and conducting the reaction st 90 C for one hour, 2.1 g. (53 %~ of ethyl 10,10-dibrDmo-5,6,7,8,9,10-hexahydro-4H-pyrido~1,2-a3-azepine-3-carbox~ate are obtained~
R~ = 0.8 (a 4:1 ~ixture o~bbenzene and methanol, Kie~elgel 60 F254) Analy~ or C12H14N23Br2 calculated: C 36.57 %, H 3.58 %, ~ 7.10 %, Br 40.55 %;
found: C 36.32 %, H 3.49 %, N 7.02 %, Br 41.02 %.
Claims (29)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing a compound of the general formula I
[wherein R represents hydrogen, lower alkyl or lower alkoxycarbonyl;
R1 represents hydrogen, lower alkyl, carboxy, ester group or a derivative thereof, cyano, phenyl or halogen;
R2 represents hydrogen, lower alkyl or phenyl;
X represents halogen; and n is the integer 0, 1 or 2]
or an optically active antipode or a pharmaceutically acceptable salt thereof, (a) reacting a racemic or optically active monohalogen derivative of the general formula II
(wherein R, R1, R2 and n are as defined above) with a halogenating agent;
(b) reacting a racemic or optically active compound of the general formula III
(wherein R, R1, R2 and n are as defined) above with a halogenating agent;
(c) decarboxylating a compound of general formula I, wherein R1 represents carboxyl, so as to prepare a compound of general formula I in which R1 is hydrogen;
(d) reacting a compound of general formula I, in which R1 is carboxyl with a halogenating agent, to prepare a compound of general formula I, in which R1 is halogen; or (e) reacting a compound of general formula I, in which R1 is hydrogen, with a halogenating agent to prepare a compound of general formula I, in which R1 is halogen, and if necessary, separating a racemate of the general formula I obtained into the optically active antipodes thereof, and, if necessary, converting a compound I to a pharmaceutically acceptable salt thereof.
[wherein R represents hydrogen, lower alkyl or lower alkoxycarbonyl;
R1 represents hydrogen, lower alkyl, carboxy, ester group or a derivative thereof, cyano, phenyl or halogen;
R2 represents hydrogen, lower alkyl or phenyl;
X represents halogen; and n is the integer 0, 1 or 2]
or an optically active antipode or a pharmaceutically acceptable salt thereof, (a) reacting a racemic or optically active monohalogen derivative of the general formula II
(wherein R, R1, R2 and n are as defined above) with a halogenating agent;
(b) reacting a racemic or optically active compound of the general formula III
(wherein R, R1, R2 and n are as defined) above with a halogenating agent;
(c) decarboxylating a compound of general formula I, wherein R1 represents carboxyl, so as to prepare a compound of general formula I in which R1 is hydrogen;
(d) reacting a compound of general formula I, in which R1 is carboxyl with a halogenating agent, to prepare a compound of general formula I, in which R1 is halogen; or (e) reacting a compound of general formula I, in which R1 is hydrogen, with a halogenating agent to prepare a compound of general formula I, in which R1 is halogen, and if necessary, separating a racemate of the general formula I obtained into the optically active antipodes thereof, and, if necessary, converting a compound I to a pharmaceutically acceptable salt thereof.
2. A process as claimed in claim 1 in which process variant (a) at least one molar equivalent of a halogenating agent is used.
3. A process as claimed in claim 1 in which in process variant (b) at least two molar equivalents of a halogenation agent are used.
4. A process as claimed in claim 1 in which elementary halogen, a halogenated acid imide or an inorganic acid halide is used as the halo-genating agent.
5. A process as claimed in claim 4 in which bromine, N-bromo-succinimide or sulfuryl chloride is used as the halogenating agent.
6. A process as claimed in claim 1 which comprises carrying out process variant (a) or (b) in an inert organic solvent, alkanecarboxylic acid or halogenated hydrocarbon.
7. A process as claimed in claim 6, wherein the solvent is an alkanecarboxylic acid or halogenated hydrocarbon.
8. A process as claimed in claim 1 which comprises carrying out process variant (a) or (b) in the presence of an acid binding agent.
9. A process as claimed in claim 8, wherein the acid binding agent is an alkali metal acetate.
10. A process as claimed in claim 1, wherein a starting compound of formula II or III is used in which R represents carboxy or derivatives thereof.
11. A process for preparing 9,9-dibromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a] pyrimidine-3-carboxylic acid, which comprises reacting 9-bromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a] pyrimidine-3-carboxylic acid with bromine.
12. A process for preparing 9,9-dibromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyridotl,2-a] pyrimidine-3-carboxylic acid, which comprises reacting 6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid with bromine.
13. A process for preparing (+)-9,9-dibromo-6-methy1-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a]pyrimidine-3-carboxylic acid, which comprises reacting (+)-9-bromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]
pyrimidine-3-carboxylic acid with bromine.
pyrimidine-3-carboxylic acid with bromine.
14. A process for preparing (+)-9,9-dibromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxylic acid, which comprises reacting (-)-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid with bromine.
15. A process for preparing (-)-9,9-dibromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid, which comprises reacting (-)-9-bromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]
pyrimidine-3-carboxylic acid with bromine.
pyrimidine-3-carboxylic acid with bromine.
16. A process for preparing (-)-9,9-dibromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidine-3-carboxylic acid, which comprises reacting (+)-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]
pyrimidine-3-carboxylic acid with bromine.
pyrimidine-3-carboxylic acid with bromine.
17. A process for preparing 9,9-dibromo-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidine-3-carboxylic acid, which comprises reacting 4-oxo-6,7,8,9-tetrahydro-4H-pyridol1,2-a]pyrimidine-3-carboxylic acid with pyridinium bromide perbromide.
18. A process for preparing 9,9-dichloro-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid, which comprises reacting 6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid with sulfuryl chloride.
19. A process for preparing 9,9-dibromo-7-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid, which comprises reacting 7-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid with pyridinium bromide perbromide.
20. A process for preparing 9,9-dibromo-8-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid, which comprises reacting 8-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid with pyridinium bromide perbromide.
21. A compound of the general formula I
[wherein R represents hydrogen, lower alkyl or lower alkoxycarbonyl;
R1 represents hydrogen, lower alkyl, carboxy, ester group or a derivative thereof, cyano, phenyl or halogen R2 represents hydrogen, lower alkyl or phenyl X represents halogen; and n is the integer 0, 1 or 23 or an optically active antipode or pharmaceutically acceptable salt thereof, whenever prepared by the process claimed in claim 1, or by an obvious chemical equivalent thereof.
[wherein R represents hydrogen, lower alkyl or lower alkoxycarbonyl;
R1 represents hydrogen, lower alkyl, carboxy, ester group or a derivative thereof, cyano, phenyl or halogen R2 represents hydrogen, lower alkyl or phenyl X represents halogen; and n is the integer 0, 1 or 23 or an optically active antipode or pharmaceutically acceptable salt thereof, whenever prepared by the process claimed in claim 1, or by an obvious chemical equivalent thereof.
22. A compound as claimed in claim 21, wherein R1 represents carboxy, whenever prepared by the process claimed in claim 10, or by an obvious chemical equivalent thereof.
23. 9,9-Dibromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]
pyrimidine-3-carboxylic acid; whenever prepared by the process claimed in claim 11 or 12, or by an obvious chemical equivalent thereof.
pyrimidine-3-carboxylic acid; whenever prepared by the process claimed in claim 11 or 12, or by an obvious chemical equivalent thereof.
24. (+)-9,9-Dibromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a]pyrimidine-3-carboxylic acid; whenever prepared by the process claimed in claim 13 or 14, or by an obvious chemical equivalent thereof.
25. (-)-9,9-Dibromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a]pyrimidine-3-carboxylic acid; whenever prepared by the process claimed in claim 15 or 16, or by an obvious chemical equivalent thereof.
26. 9,9-Dibromo-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a?pyrimidine-3-carboxylic acid; whenever prepared by the process claimed in claim 17, or by an obvious chemical equivalent thereof.
27. 9,9-Dichloro-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2-a]
pyrimidine-3-carboxylic acid; whenever prepared by the process claimed in claim 18, or by an obvious chemical equivalent thereof.
pyrimidine-3-carboxylic acid; whenever prepared by the process claimed in claim 18, or by an obvious chemical equivalent thereof.
28. 9,9-Dibromo-7-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a]pyrimidine-3-carboxylic acid; whenever prepared by the process claimed in claim 19, or by an obvious chemical equivalent thereof.
29. 9,9-Dibromo-8-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]
pyrimidine-3-carboxylic acid, whenever prepared by the process claimed in claim 20, or by an obvious chemical equivalent thereof.
pyrimidine-3-carboxylic acid, whenever prepared by the process claimed in claim 20, or by an obvious chemical equivalent thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HUCI-1932 | 1979-05-11 | ||
| 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 (1)
| Publication Number | Publication Date |
|---|---|
| CA1141379A true CA1141379A (en) | 1983-02-15 |
Family
ID=10994747
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000351662A Expired CA1141379A (en) | 1979-05-11 | 1980-05-09 | Geminal dihalogen derivatives of condensed pyrimidine-4-one compounds, process for 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) |
Families Citing this family (5)
| 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 |
| 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 |
| 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 DE DE19803017564 patent/DE3017564A1/en not_active Withdrawn
- 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 SU SU802920002A patent/SU1151210A3/en active
- 1980-05-09 DK DK204680A patent/DK204680A/en not_active Application Discontinuation
- 1980-05-09 CH CH366380A patent/CH646971A5/en not_active IP Right Cessation
- 1980-05-09 NL NL8002678A patent/NL8002678A/en not_active Application Discontinuation
- 1980-05-09 FR FR8010481A patent/FR2456101A1/en active Granted
- 1980-05-09 JP JP6161680A patent/JPS5615286A/en active Pending
- 1980-05-09 AT AT0247580A patent/AT377261B/en not_active IP Right Cessation
- 1980-05-09 IT IT67719/80A patent/IT1133085B/en active
- 1980-05-09 CA CA000351662A patent/CA1141379A/en not_active Expired
- 1980-05-09 PT PT71213A patent/PT71213A/en unknown
- 1980-05-09 FI FI801512A patent/FI68825C/en not_active IP Right Cessation
- 1980-05-09 NO NO801378A patent/NO152607C/en unknown
- 1980-05-09 BE BE0/200550A patent/BE883217A/en not_active IP Right Cessation
- 1980-05-09 LU LU82437A patent/LU82437A1/en unknown
- 1980-05-09 GB GB8015469A patent/GB2051048B/en not_active Expired
- 1980-05-10 PL PL1980224163A patent/PL124035B1/en unknown
- 1980-05-12 DD DD80221053A patent/DD150605A5/en unknown
- 1980-05-12 ES ES491896A patent/ES491896A0/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| IL59967A (en) | 1984-05-31 |
| SU1151210A3 (en) | 1985-04-15 |
| NO801378L (en) | 1980-11-12 |
| SE8003479L (en) | 1980-11-12 |
| ES8102570A1 (en) | 1981-02-16 |
| PT71213A (en) | 1980-06-01 |
| BE883217A (en) | 1980-09-01 |
| DD150605A5 (en) | 1981-09-09 |
| CS241025B2 (en) | 1986-03-13 |
| CS325880A2 (en) | 1985-06-13 |
| AT377261B (en) | 1985-02-25 |
| PL224163A1 (en) | 1981-02-13 |
| IL59967A0 (en) | 1980-07-31 |
| HU179443B (en) | 1982-10-28 |
| FI68825B (en) | 1985-07-31 |
| NL8002678A (en) | 1980-11-13 |
| LU82437A1 (en) | 1980-07-31 |
| GR68518B (en) | 1982-01-11 |
| GB2051048A (en) | 1981-01-14 |
| GB2051048B (en) | 1983-01-19 |
| FR2456101A1 (en) | 1980-12-05 |
| FI801512A (en) | 1980-11-12 |
| IT1133085B (en) | 1986-07-09 |
| DK204680A (en) | 1980-11-12 |
| JPS5615286A (en) | 1981-02-14 |
| FI68825C (en) | 1985-11-11 |
| CH646971A5 (en) | 1984-12-28 |
| SE441747B (en) | 1985-11-04 |
| NO152607B (en) | 1985-07-15 |
| ES491896A0 (en) | 1981-02-16 |
| IT8067719A0 (en) | 1980-05-09 |
| DE3017564A1 (en) | 1980-11-13 |
| PL124035B1 (en) | 1982-12-31 |
| NO152607C (en) | 1985-10-23 |
| ATA247580A (en) | 1984-07-15 |
| FR2456101B1 (en) | 1985-04-05 |
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