CA1156656A - Process for the preparation of pyrimidyl-chinazolines - Google Patents
Process for the preparation of pyrimidyl-chinazolinesInfo
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- CA1156656A CA1156656A CA000373945A CA373945A CA1156656A CA 1156656 A CA1156656 A CA 1156656A CA 000373945 A CA000373945 A CA 000373945A CA 373945 A CA373945 A CA 373945A CA 1156656 A CA1156656 A CA 1156656A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
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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
- A61P7/10—Antioedematous agents; Diuretics
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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
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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
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
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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
- A61P9/08—Vasodilators for multiple indications
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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
- A61P9/12—Antihypertensives
Abstract
Process for the Preparation of Pyrimidyl-Quinazolines ABSTRACT OF THE DISCLOSURE
Pyrimidyl-quinazolines having the general formula I
(I) and pharmacologically acceptable acid addition salts thereof, wherein Rl and R2 denote hydrogen, alkyl having 1 to 6 C atoms, alkenyl having 2 to 6 C
atoms cycloalkyl having 5 to 7 C atoms, phenyl or benzyl R3 denotes hydrogen, alkyl having 1 to 6 C atoms, alkenyl having 2 to 6 C atoms, phenyl, phen-alkyl having 1 to 4 C atoms in the alkyl radical, halogen, nitro, amino, alkylcarbonylamino having 1 to 6 C atoms in the aIkyl radical, phenyl-carbonylamino or formyl are prepared by a) reacting a compound of the formula II
(II) wherein X denotes a mercapto radical or a halogen atom with a compound of the formula III
(III) or b) reacting 2-piperazinyl-4-amino-6,7-dimethoxyquinazoline with a com-pound of the formula V
wherein Hal denotes a halogen atom or c) introducing the substituent R3 into a compound of the formula VI
Pyrimidyl-quinazolines having the general formula I
(I) and pharmacologically acceptable acid addition salts thereof, wherein Rl and R2 denote hydrogen, alkyl having 1 to 6 C atoms, alkenyl having 2 to 6 C
atoms cycloalkyl having 5 to 7 C atoms, phenyl or benzyl R3 denotes hydrogen, alkyl having 1 to 6 C atoms, alkenyl having 2 to 6 C atoms, phenyl, phen-alkyl having 1 to 4 C atoms in the alkyl radical, halogen, nitro, amino, alkylcarbonylamino having 1 to 6 C atoms in the aIkyl radical, phenyl-carbonylamino or formyl are prepared by a) reacting a compound of the formula II
(II) wherein X denotes a mercapto radical or a halogen atom with a compound of the formula III
(III) or b) reacting 2-piperazinyl-4-amino-6,7-dimethoxyquinazoline with a com-pound of the formula V
wherein Hal denotes a halogen atom or c) introducing the substituent R3 into a compound of the formula VI
Description
1 1 ~G~56 The invention relates to a process for the preparation of novel pharmacologically valuable pyrimidyl-qu m azolines of the formula I
NH O
CH30 ~ N ~ ~ N l o (I) and acid addition salts, thereof, where Rl and R2 denote hydrogen, aIkyl hav-ing 1 to 6 C atoms, alkenyl having 2 to 6 C atoms, cycloaIkyl having 5 to 7 C atoms, phenyl or benzyl and R3 denotes hydrogen, alkyl having 1 to 6 C
atoms, alkenyl having 2 to 6 C atoms, phenyl, phenalkyl having 1 to 4 C
atoms in the aLkyl radical, halogen, nitro, amlno, alkylcarbonylamino having 1 to 6 C atoms in the alkyl radical, phenylcarbonylamino or formyl.
Compounds of the formula I in which Rl is the same as R~ are part-icularly preferred, as are the acid addition salts of these compounds. m e alkyl and aIkenyl groups represented by Rl, R2 and R3 can be straight-chain or branched. In the case of the cycloalkyl radical represented by Rl and R2, cyclopentyl and cyclohexyl are preferred. In the case of the phenalkyl radical, benzyl and phenethyl are preferred. Halogen denotes, in particular, chlorine, fluo~ine or bromune. In the case of the aIkylcarbonylamino radical, aoe tylamino is preferred.
The following are examples of suitable alkyl and aIkenyl radicals:
methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec.-butyl, tert.-butyl, n-pPntyl, i-pentyl, n-hexyl, allyl and methallyl. ~Iethyl, e~hyl, n propyl, n-butyl, brQmlne or amino are preferred for R3. Cbmpounds of the formula I
and/or acid addition salts thereof which æe very particularly preferred are those in which R1 = R2 = methyl and R3 denotes hydrogen or nitro.
Provided that at least one of ~he substituents Rl, R2 or R3 de-notes hydrogen, the compounds of the fon~ula I can also exist in oth~r tautcmeric forms~
~ `
5 ~ ~
The ccmpounds of the formula I can be prepared by reacting a com~
pound of the formula II
CH8 ~ (II) 3 ~N ~LX
X in formula II denoting a mercapto radical or in particular a halogen atom, preferably chlorine or bromine, with a oampound of the formula III
R ~N - R2 HN ~ ~ N ~ O ~III) R , R2 and R3, in formula III, having the meaning already indicated. This reaction is normally carried out in a sultable solvent or disparsing agent m which the reactants are dissolved or suspended, respectively, such as, for example, a hydrocarbon, for example benzene, toluene or xylene, a halogenated hydrocarbon, such as, for exa~,ple, chloroform, methylene chloride, carbon tetrachloride or chlorobenzene, an ether, such as, for e~ample, dioxane diethyl ether or tetrahydrofuran, and also water, dime-thyl sulphoxide, di-methylforn~mide, N-methylpyrrolido.ne or an alcohol, such as, for example, methanol, ethanol, amyl alcohol, isoam~l alcohol and the like. m e reaction can ke carried out at normal temFerature or at elevated temperature, for exa~,ple between 20 and 160 C. Normally, the reaction temFerature is between 80 and 140 &. At a lower boiling point of the solvent or dispersant e~ployed, the reactio~ takes place in a closed pressure vessel. In general, the molar ratio between the cc~pounds of the formMlae II and III is 1 : 1. If equi-mDlar quantities are employed, it is advisable, in the case of a compound II
wherein X denotes halogen being employed, to carry out the reaction in the presence of at least equimolar quantities of an acid-binding agent, such as, for example, potassium earbonate, sodium carbonate, triethylamine or the like.
Otherwlse, in the absence of acid-binding agents, the hydrohalides of the com-pounds of the general formula I are usually obtained. If one of the com-pounds II or III is employed in a m~lar excess, the excess of the compound can act as an acid-binding agent.
The starting compound of the formula II can be prepared in accord-ance with kncwn specifications (for example Soc. 1948, page 1764 or US Patent Specification 3,511,836).
The starting compound of the formula II in which X = Cl is kncwn, cGmpare German Offenlegungsschrift 1,620,138, column 7 and US Patent Speei-fication 3,511,836, Example 1. me starting compounds of the formula II in which X denotes a halogen atom other than chlorine, can be prepared corres-pondingly. Thus, for example, 2,4-dihydroxy-6,7-dimethoxyquinazoline, which is known, can be converted by means of phosphorus oxybromide into 2,4-dibromo- ~
6,7-dimethoxyquinazoline and the latter can be converted by means of ``
anhydrous ammonia into 2-bromD-4-amino-6,7-dimethoxyquinazoline.
me st~rting eompound of the formula II wherein X represents -SC~3 is also known, ef. Cerman Offenlegungsschrift 1,620,138, cols, 7 and 8.
m e starting ccmpaunds of the formula III can be obtaLned by reaet-ing the pyrimidines of the formula V
R3 ~ N - R
Il I (V) ~ `
Hal I O
Rl wherein Hal denotes a halogen atom, preferably ehlorine, with piperazine.
The reaction of a pyrimidine of the formula V with pipexazine is normally carried out in a suitable solvent or dispersing agent in which the reactants are dissolved or suspended, respectively, such as, for example, a hydrocarbon, : ~ :
1 1 5Q~6~B
for example benzene, toluene or xylene, a halogenated hydro Æ bon, such as, for example, chloroform, methylene chloride, carbon tetrachloride or chloro-benzene, an ether, such as, for example, dioxane, diethyl ether or tetra-hydrofuran, and also water, dimethyl sulphoxide, dimethylformamide, N-methyl-pyrrolidone or an alcohol, such as, for example, methanol, ethanol, amyl alcohol, isoamyl alcohol or the like. m e reaction can be carried out at normal temperature or at elevated temperature, for example between 20 and 140C. Normally, the reaction temperature is between 80 and 120& . At a lcwer boiling point of the solvent or dispersant used, the reaction takes pla oe in a closed pressure vessel. m e molar ratio between the pyrimidine of the formula V and piperazine can be 1:(1 to lO) and even more, if appro-priate. If equimolar quantities are em loyed, it is advisable to carry out the reaction in the presence of at least equimolar quantities of an acid-binding agent, such as, for exa~,ple, potassium carbonate, sodium carbonate, triethylamine or the like. In the absence of acid-binding agents, the hydrohalides of the compcunds of the formula III are usually obtained.
Ccmpounds of the formula I can also be prepared by reacting
NH O
CH30 ~ N ~ ~ N l o (I) and acid addition salts, thereof, where Rl and R2 denote hydrogen, aIkyl hav-ing 1 to 6 C atoms, alkenyl having 2 to 6 C atoms, cycloaIkyl having 5 to 7 C atoms, phenyl or benzyl and R3 denotes hydrogen, alkyl having 1 to 6 C
atoms, alkenyl having 2 to 6 C atoms, phenyl, phenalkyl having 1 to 4 C
atoms in the aLkyl radical, halogen, nitro, amlno, alkylcarbonylamino having 1 to 6 C atoms in the alkyl radical, phenylcarbonylamino or formyl.
Compounds of the formula I in which Rl is the same as R~ are part-icularly preferred, as are the acid addition salts of these compounds. m e alkyl and aIkenyl groups represented by Rl, R2 and R3 can be straight-chain or branched. In the case of the cycloalkyl radical represented by Rl and R2, cyclopentyl and cyclohexyl are preferred. In the case of the phenalkyl radical, benzyl and phenethyl are preferred. Halogen denotes, in particular, chlorine, fluo~ine or bromune. In the case of the aIkylcarbonylamino radical, aoe tylamino is preferred.
The following are examples of suitable alkyl and aIkenyl radicals:
methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec.-butyl, tert.-butyl, n-pPntyl, i-pentyl, n-hexyl, allyl and methallyl. ~Iethyl, e~hyl, n propyl, n-butyl, brQmlne or amino are preferred for R3. Cbmpounds of the formula I
and/or acid addition salts thereof which æe very particularly preferred are those in which R1 = R2 = methyl and R3 denotes hydrogen or nitro.
Provided that at least one of ~he substituents Rl, R2 or R3 de-notes hydrogen, the compounds of the fon~ula I can also exist in oth~r tautcmeric forms~
~ `
5 ~ ~
The ccmpounds of the formula I can be prepared by reacting a com~
pound of the formula II
CH8 ~ (II) 3 ~N ~LX
X in formula II denoting a mercapto radical or in particular a halogen atom, preferably chlorine or bromine, with a oampound of the formula III
R ~N - R2 HN ~ ~ N ~ O ~III) R , R2 and R3, in formula III, having the meaning already indicated. This reaction is normally carried out in a sultable solvent or disparsing agent m which the reactants are dissolved or suspended, respectively, such as, for example, a hydrocarbon, for example benzene, toluene or xylene, a halogenated hydrocarbon, such as, for exa~,ple, chloroform, methylene chloride, carbon tetrachloride or chlorobenzene, an ether, such as, for e~ample, dioxane diethyl ether or tetrahydrofuran, and also water, dime-thyl sulphoxide, di-methylforn~mide, N-methylpyrrolido.ne or an alcohol, such as, for example, methanol, ethanol, amyl alcohol, isoam~l alcohol and the like. m e reaction can ke carried out at normal temFerature or at elevated temperature, for exa~,ple between 20 and 160 C. Normally, the reaction temFerature is between 80 and 140 &. At a lower boiling point of the solvent or dispersant e~ployed, the reactio~ takes place in a closed pressure vessel. In general, the molar ratio between the cc~pounds of the formMlae II and III is 1 : 1. If equi-mDlar quantities are employed, it is advisable, in the case of a compound II
wherein X denotes halogen being employed, to carry out the reaction in the presence of at least equimolar quantities of an acid-binding agent, such as, for example, potassium earbonate, sodium carbonate, triethylamine or the like.
Otherwlse, in the absence of acid-binding agents, the hydrohalides of the com-pounds of the general formula I are usually obtained. If one of the com-pounds II or III is employed in a m~lar excess, the excess of the compound can act as an acid-binding agent.
The starting compound of the formula II can be prepared in accord-ance with kncwn specifications (for example Soc. 1948, page 1764 or US Patent Specification 3,511,836).
The starting compound of the formula II in which X = Cl is kncwn, cGmpare German Offenlegungsschrift 1,620,138, column 7 and US Patent Speei-fication 3,511,836, Example 1. me starting compounds of the formula II in which X denotes a halogen atom other than chlorine, can be prepared corres-pondingly. Thus, for example, 2,4-dihydroxy-6,7-dimethoxyquinazoline, which is known, can be converted by means of phosphorus oxybromide into 2,4-dibromo- ~
6,7-dimethoxyquinazoline and the latter can be converted by means of ``
anhydrous ammonia into 2-bromD-4-amino-6,7-dimethoxyquinazoline.
me st~rting eompound of the formula II wherein X represents -SC~3 is also known, ef. Cerman Offenlegungsschrift 1,620,138, cols, 7 and 8.
m e starting ccmpaunds of the formula III can be obtaLned by reaet-ing the pyrimidines of the formula V
R3 ~ N - R
Il I (V) ~ `
Hal I O
Rl wherein Hal denotes a halogen atom, preferably ehlorine, with piperazine.
The reaction of a pyrimidine of the formula V with pipexazine is normally carried out in a suitable solvent or dispersing agent in which the reactants are dissolved or suspended, respectively, such as, for example, a hydrocarbon, : ~ :
1 1 5Q~6~B
for example benzene, toluene or xylene, a halogenated hydro Æ bon, such as, for example, chloroform, methylene chloride, carbon tetrachloride or chloro-benzene, an ether, such as, for example, dioxane, diethyl ether or tetra-hydrofuran, and also water, dimethyl sulphoxide, dimethylformamide, N-methyl-pyrrolidone or an alcohol, such as, for example, methanol, ethanol, amyl alcohol, isoamyl alcohol or the like. m e reaction can be carried out at normal temperature or at elevated temperature, for example between 20 and 140C. Normally, the reaction temperature is between 80 and 120& . At a lcwer boiling point of the solvent or dispersant used, the reaction takes pla oe in a closed pressure vessel. m e molar ratio between the pyrimidine of the formula V and piperazine can be 1:(1 to lO) and even more, if appro-priate. If equimolar quantities are em loyed, it is advisable to carry out the reaction in the presence of at least equimolar quantities of an acid-binding agent, such as, for exa~,ple, potassium carbonate, sodium carbonate, triethylamine or the like. In the absence of acid-binding agents, the hydrohalides of the compcunds of the formula III are usually obtained.
Ccmpounds of the formula I can also be prepared by reacting
2-piperazinyl-4-am mo-6,7-dlmethoxyquinazoline of the formula rv CH3O ~ N
CH3O ~ N ~ ~ (IV) with a compound of the formula V. m e reaction of the quinazoline derivative of the formula IV with a pyrimidine of the formula V is normally carried out in a suitable solvent or dispersing a~ent in which the reactants are dis-solved or suspanded, respectively, such as, for example, a hydrocarbon, for exa~ple benzene, toluene or xylene, a halogenated hydrocarbon, such as, for example, chloroform, methylene chloride, carbon tetrachloride or chloro-banzene, an ether, such as, for example, dioxane, diethyl e-ther or te-tra-hydrofuran, and also water, dimethyl sulphoxide, dimethylformamide, N-methyl-pyrrolidone or an alcohol, such as, for example, methanol, e~hanol, amyl alcohol, isoamyl alcohol or the like. m e reaction can be carried out at normal temperature or at elevated temperature, or example between 20 and 160C. Normally, tbe reaction temperature is between 80 and 140C. At a lcwer boiling point of the solvent or dispersant used, the reaction takes place in a closed pressure vessel.
In general, the molar ratio between the two compounds is 1:1. If equimolar quantities are employed, it is advisable to carry out the reaction in the presence of at least equimolar quantities of an acid-binding agent, such as, for example, potassium c æbonate, sodium carbonate, triethylamine or the like. Gtherwise, in the absence of acid~binding agents, tbe hy~ro-halides of the compounds of the formula I are usually obtained. If a molar excess of the formula IV is employed, this exoe ss can act as the acid-binding agent.
The quinazoline of the formula IV can be prepared in accordance with known specifications (for example Germ~n Offenlegungsschrift 1,620,138).
A further process for the preparation of the compounds, accordlng to the invention, of the formula I in which R3 is not hydrogen, consists in using as starting material the compounds of the formula Vl NH2 o C~301~NJ--N/~ ~J~
which are unsubstituted in the 5-position of the pyrimidine ring and introduc-ing, in a manner which is in itself known, the substituents R into the .
5-position, for example introducing the formyl group by reacting VI with acetic acid/formic anhydride, the nitro group by careful nitration with nitric acid, the amino group and the aLkylcæbonylamino or phenylcarbonyl-1 1 5~G5~
amino group by reducing the nitro group and, if necessary, acylating with acylating agents which introduce the aIkylcarbonyl or phenylcarbonyl, respect-ively, and the bromine radical by careful bromination and so on.
Inorganic and organic acids are suitable for the formation of acid addition salts with the ccmpounds of the formula I, for example hydrogen chloride, hydrogen bromide, naphthalene-1,5-disulphonic acid, phosphoric acid, nitric acid, sulphuric acid, oxalic acid, lactic acid, tartaric ad d, acetic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, m~lonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulphamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, methanesulphonic acid, p-toluenesulphonic acid, citric acid or adipic acid. Pharmaceutically acceptable acid addition salts are preferred. The acid addition salts can be obtained in the customary manner by combining the ccmponents, appropriately in a suitable diluent or dispersing agent. Examples of suitable diluents and dispersing agents are ether, water, alcohols, hydrocarbons and the like.
The com~ounds, according to the invention, of the formu~a I and their pharmaceutically acceptable acid addition salts possess valuable pharmacological properties. In particular, they possess a strongly marked action for the reduction of blood pressure and are therefore suitable for the treatment of hypertension. Surprisingly, the campounds of the formula I are markedly superior to the known ccmpounds of similar structure of US Patent Specification 3,511,836. The quinazolyl-pyrimidines according to the inven-tion can, therefore, be administered to humans on their own, in mixtures with one another or in pharmaceutical formulations which contain, as the active constituent, an effective dose of at least one quinazolyl-pyrimidine accord-ing to the invention or an acid addition salt thereof together with customary pharmaceutically acceptable excipients and additives. Examples of suitable excipients are water, vegetable oils, starch, gelatine, lactose, magnesium stearate, waxes, petroleum jelly and the like. Examples of additives which can be used are wetting agents, disintegrants, preservatives and the like.
The pharma oeutical formulations can be present in the form of, for example, tablets, capsules, aqueous or oily solutions or suspensions, emulsions, injectable aqueous or oily solutions or suspensions, dispersible powders or aerosol mixtures. Besides the compcunds of the formula I, the pharmaceutical formulations can also ~ontain, in addition, one or more other pharmaceutic-ally active substances, for example tranquillisers, such as, for example, luminal, meprobamate, chlorpromazine and benzodiazepine sedatives, such as, ~ -for example, diazepam or chlordiazepoxide, vasodilators, such as, for example, glycerol trinitrate, pentaerythritol tetranitrate and carbochrQmene, agents which tonicise the heart, such as, for example, digitalis formulations, ~-blockers, such as, for example, propranolol, bronchodilators and sympathomi-metic agents, such as, for example, isoprenaline, orciprenaline and the like ~-adrenergic block.~ng agents, such as, or example, phentolamine, and diuretics, such as, or example, furosemide.
The preparation of the co~pounds of the formula I is illustrated by means of the follcwing examples:
Example 1 2.9 g of 2-piperaz.inyl-4-am~lo-6,7-dimethoxyquinazoline are stirred for 24 hours at room temperature in 50 ml of ethanol to which are added 4 g of potassium carbonate and 2.2 g of 1,3-di~.ethyl-5-nitro-6-chloropyrimidine-2,4-dione. The mixture is then filtered and the residue is digested in 20 ml of 0.5 N aqueous hydrochloric acid.
The mixture is filtered again and the residue is suspended in ..
aqueous sodium carbonate solution and filtered off and recrystallised fron aqueous dimethylformamide.
This gives 4-~4-amino-6,7-dimethoxyquinazolin-2-yl)-1-~1,3-dimethyl-2,4-dioxo-5-nitro-pyrimidin-6-yl~-piperazine of the formula .. .
~ 15~6~6 CH30 ~ ~ ~ 3 CH30 N ~ N 1 0 Melting point 300&.
Analysis: (C20H24N8&) calculated: 50.8 5~1 23.7 20.3 found: 50.9 5.1 23.5 20.4 Yield: 87% of theory.
The 1,3-d~nethyl-5-nitro-6-chloropyrimidine-2,4-dione used as the starting material can be prepared as follows:
17 g of 1,3-d~nethyl-6-chloropyrimidine-2,4-dione are added in por-tions at 15C to 50 ml of concentrated sulphuric acid. The m~xture is then cooled to 3 to 5C and 17 ml of fuming nitric acid are added dropwise slowly to the mixture, while stirring. The solution is then poured onto ice, while stirring, whereupon a semi-solid precipitate is deposited. The mixture is extracted with methylene chloride, the organic phasa is dried with magnesium sulphate and the solution is concentrated at 25C under a water-pump vacuum.
This leaves as rasidue an oil which solidifies after a short t~ne. The sub, stance is racrystallised onca from ligroin/ethyl acetate. This givas 1,3-dimethyl-5-nitro-6-chloropyrimidine-2,4-dione in a yield of 95% of theory. `;
Melting point: 92&.
The 2-piperazinyl-4-amino-6,7-dimethoxyquinazoline used as the starting material can be prepared as follows:
2.5 g of 2 chloro-4-amino-6,7-dime~hoxyquinazoline are added to a solution of 5 g of anhydrous piperazine in 50 ml of dio~ane and the mixture is then heated at 95& for 12 hours. It is then concentrated, the residue is dissolved in water and the pH of the solution is adjus-ted -to 2.5 with hydro-"~
1 1~6~56 chloric acid. The acid aqueous solution is extracted with methylene chloride and the aqueous phase is then rendered aIkaline with sodium hydroxide solu-tion. A precipitate is deposited and is recrystallised frcm ethanol. This gives 2-piperazinyl-4-amino-6,7-di~thoxyquinazoline in a yield of 83% of theory.
Melting point: 235 C.
Example 2 2.4 g of 2-chloro-4-amino-6,7-dimethoxyquinazoline, together with 4.5 y of 1,3-~imethyl-6-piperazinylpyrimidine-2,4~io~e and 50 ml of ethanol are heated in an autoclave for 8 hours at 130C. me mixture is then cooled and concentrated under a water-pump vacuum. The residue is digested with water and is then recrystallised from dimethylformamide. ~his gives 4-(4-a~ino-6,7-dimethoxyquinazolin-2-yl)-1-(1,3-dimethyl-2,4-dioxo-pyrimidin-6-yl)-piperazine.
NH O
CH3O ~ N ~ ~ (IV) with a compound of the formula V. m e reaction of the quinazoline derivative of the formula IV with a pyrimidine of the formula V is normally carried out in a suitable solvent or dispersing a~ent in which the reactants are dis-solved or suspanded, respectively, such as, for example, a hydrocarbon, for exa~ple benzene, toluene or xylene, a halogenated hydrocarbon, such as, for example, chloroform, methylene chloride, carbon tetrachloride or chloro-banzene, an ether, such as, for example, dioxane, diethyl e-ther or te-tra-hydrofuran, and also water, dimethyl sulphoxide, dimethylformamide, N-methyl-pyrrolidone or an alcohol, such as, for example, methanol, e~hanol, amyl alcohol, isoamyl alcohol or the like. m e reaction can be carried out at normal temperature or at elevated temperature, or example between 20 and 160C. Normally, tbe reaction temperature is between 80 and 140C. At a lcwer boiling point of the solvent or dispersant used, the reaction takes place in a closed pressure vessel.
In general, the molar ratio between the two compounds is 1:1. If equimolar quantities are employed, it is advisable to carry out the reaction in the presence of at least equimolar quantities of an acid-binding agent, such as, for example, potassium c æbonate, sodium carbonate, triethylamine or the like. Gtherwise, in the absence of acid~binding agents, tbe hy~ro-halides of the compounds of the formula I are usually obtained. If a molar excess of the formula IV is employed, this exoe ss can act as the acid-binding agent.
The quinazoline of the formula IV can be prepared in accordance with known specifications (for example Germ~n Offenlegungsschrift 1,620,138).
A further process for the preparation of the compounds, accordlng to the invention, of the formula I in which R3 is not hydrogen, consists in using as starting material the compounds of the formula Vl NH2 o C~301~NJ--N/~ ~J~
which are unsubstituted in the 5-position of the pyrimidine ring and introduc-ing, in a manner which is in itself known, the substituents R into the .
5-position, for example introducing the formyl group by reacting VI with acetic acid/formic anhydride, the nitro group by careful nitration with nitric acid, the amino group and the aLkylcæbonylamino or phenylcarbonyl-1 1 5~G5~
amino group by reducing the nitro group and, if necessary, acylating with acylating agents which introduce the aIkylcarbonyl or phenylcarbonyl, respect-ively, and the bromine radical by careful bromination and so on.
Inorganic and organic acids are suitable for the formation of acid addition salts with the ccmpounds of the formula I, for example hydrogen chloride, hydrogen bromide, naphthalene-1,5-disulphonic acid, phosphoric acid, nitric acid, sulphuric acid, oxalic acid, lactic acid, tartaric ad d, acetic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, m~lonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulphamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, methanesulphonic acid, p-toluenesulphonic acid, citric acid or adipic acid. Pharmaceutically acceptable acid addition salts are preferred. The acid addition salts can be obtained in the customary manner by combining the ccmponents, appropriately in a suitable diluent or dispersing agent. Examples of suitable diluents and dispersing agents are ether, water, alcohols, hydrocarbons and the like.
The com~ounds, according to the invention, of the formu~a I and their pharmaceutically acceptable acid addition salts possess valuable pharmacological properties. In particular, they possess a strongly marked action for the reduction of blood pressure and are therefore suitable for the treatment of hypertension. Surprisingly, the campounds of the formula I are markedly superior to the known ccmpounds of similar structure of US Patent Specification 3,511,836. The quinazolyl-pyrimidines according to the inven-tion can, therefore, be administered to humans on their own, in mixtures with one another or in pharmaceutical formulations which contain, as the active constituent, an effective dose of at least one quinazolyl-pyrimidine accord-ing to the invention or an acid addition salt thereof together with customary pharmaceutically acceptable excipients and additives. Examples of suitable excipients are water, vegetable oils, starch, gelatine, lactose, magnesium stearate, waxes, petroleum jelly and the like. Examples of additives which can be used are wetting agents, disintegrants, preservatives and the like.
The pharma oeutical formulations can be present in the form of, for example, tablets, capsules, aqueous or oily solutions or suspensions, emulsions, injectable aqueous or oily solutions or suspensions, dispersible powders or aerosol mixtures. Besides the compcunds of the formula I, the pharmaceutical formulations can also ~ontain, in addition, one or more other pharmaceutic-ally active substances, for example tranquillisers, such as, for example, luminal, meprobamate, chlorpromazine and benzodiazepine sedatives, such as, ~ -for example, diazepam or chlordiazepoxide, vasodilators, such as, for example, glycerol trinitrate, pentaerythritol tetranitrate and carbochrQmene, agents which tonicise the heart, such as, for example, digitalis formulations, ~-blockers, such as, for example, propranolol, bronchodilators and sympathomi-metic agents, such as, for example, isoprenaline, orciprenaline and the like ~-adrenergic block.~ng agents, such as, or example, phentolamine, and diuretics, such as, or example, furosemide.
The preparation of the co~pounds of the formula I is illustrated by means of the follcwing examples:
Example 1 2.9 g of 2-piperaz.inyl-4-am~lo-6,7-dimethoxyquinazoline are stirred for 24 hours at room temperature in 50 ml of ethanol to which are added 4 g of potassium carbonate and 2.2 g of 1,3-di~.ethyl-5-nitro-6-chloropyrimidine-2,4-dione. The mixture is then filtered and the residue is digested in 20 ml of 0.5 N aqueous hydrochloric acid.
The mixture is filtered again and the residue is suspended in ..
aqueous sodium carbonate solution and filtered off and recrystallised fron aqueous dimethylformamide.
This gives 4-~4-amino-6,7-dimethoxyquinazolin-2-yl)-1-~1,3-dimethyl-2,4-dioxo-5-nitro-pyrimidin-6-yl~-piperazine of the formula .. .
~ 15~6~6 CH30 ~ ~ ~ 3 CH30 N ~ N 1 0 Melting point 300&.
Analysis: (C20H24N8&) calculated: 50.8 5~1 23.7 20.3 found: 50.9 5.1 23.5 20.4 Yield: 87% of theory.
The 1,3-d~nethyl-5-nitro-6-chloropyrimidine-2,4-dione used as the starting material can be prepared as follows:
17 g of 1,3-d~nethyl-6-chloropyrimidine-2,4-dione are added in por-tions at 15C to 50 ml of concentrated sulphuric acid. The m~xture is then cooled to 3 to 5C and 17 ml of fuming nitric acid are added dropwise slowly to the mixture, while stirring. The solution is then poured onto ice, while stirring, whereupon a semi-solid precipitate is deposited. The mixture is extracted with methylene chloride, the organic phasa is dried with magnesium sulphate and the solution is concentrated at 25C under a water-pump vacuum.
This leaves as rasidue an oil which solidifies after a short t~ne. The sub, stance is racrystallised onca from ligroin/ethyl acetate. This givas 1,3-dimethyl-5-nitro-6-chloropyrimidine-2,4-dione in a yield of 95% of theory. `;
Melting point: 92&.
The 2-piperazinyl-4-amino-6,7-dimethoxyquinazoline used as the starting material can be prepared as follows:
2.5 g of 2 chloro-4-amino-6,7-dime~hoxyquinazoline are added to a solution of 5 g of anhydrous piperazine in 50 ml of dio~ane and the mixture is then heated at 95& for 12 hours. It is then concentrated, the residue is dissolved in water and the pH of the solution is adjus-ted -to 2.5 with hydro-"~
1 1~6~56 chloric acid. The acid aqueous solution is extracted with methylene chloride and the aqueous phase is then rendered aIkaline with sodium hydroxide solu-tion. A precipitate is deposited and is recrystallised frcm ethanol. This gives 2-piperazinyl-4-amino-6,7-di~thoxyquinazoline in a yield of 83% of theory.
Melting point: 235 C.
Example 2 2.4 g of 2-chloro-4-amino-6,7-dimethoxyquinazoline, together with 4.5 y of 1,3-~imethyl-6-piperazinylpyrimidine-2,4~io~e and 50 ml of ethanol are heated in an autoclave for 8 hours at 130C. me mixture is then cooled and concentrated under a water-pump vacuum. The residue is digested with water and is then recrystallised from dimethylformamide. ~his gives 4-(4-a~ino-6,7-dimethoxyquinazolin-2-yl)-1-(1,3-dimethyl-2,4-dioxo-pyrimidin-6-yl)-piperazine.
NH O
3 ~ N ~ N - CH
C 3 ~ N ~ ~ ~ N 1 O
Melting point: 273C.
Analys~S: (C2oH25N7 4) C H N o calculated: 56.2 5.9 23.0 15.0 found: 56.0 6.0 23.0 14.7 Yield: 81% of theory.
The 1,3-dimethyl-6-piperazinylpyrimidine-2,4-dione used as the starting material can be prepared as follows:
20 g of 1,3-di~ethyl-6-chloropyrimidine-2,4-dione are added to a mlxture of 30 g of piperazine and 500 ml of toluene and the mixture is boiled under reflux for 3 hours. It is then filtered and the filtrate is concen-11~8~5~
trated under a water-pump vacuum. The residue which remains after concentra-tion is recrystallised from ethyl acetate. This gives 1,3-dimethyl-6-piperazinylpyrimidine-2,4-dione ~\N ~N ~0 in a yield of 75% of theory.
Melting point: 117 C.
E ~
5.2 g of 4-(4-amino-6,7-dimethoxyquinazolin-2-yl)-1-(1,3-dibutyl-2,4-dioxo-pyrimidin-6-yl)-piperazine NH~ 0 3 ~ N ~ N - C4Hg CH30 ~ ~ N ~ N 1 o c4Hg are dissolved in 20 ml of glacial acetic acid. A mixture of 1.7 g of bromlne and 20 ml of glacial aoe tic acid is then added dropwise, while chilling, and cooling with ice. me mixture is then stirred for a further 2 hours at room te~perature. me product is then filtered off and recrystallised from ethanol. This gives 1-(4-amino-6,7_dimethoxyquinazolLn-2-yl)-1-(1,3-dibutyl-2,4-dioxo-5-brcmopyrimidin-6-yl)-piperazine hydrobromide ~ O
CH30 ~ N ~ ~ - C4H9 CH30 ~ ~ --"`N 0 . HBr C~Hg Melting point: above 300C, de ~ ~position.
~ 10 ~
'.~
Analysis: (C26H37Br2N704) C H Br N O
calculated: 46.5 5.5 23.8 14.6 9.5 found: 46.7 5.3 23.5 14.7 9.8 Yield: 61% of theory.
Example 4 5.6 g of 4-(4-amino-6,7-dimethoxyquinazolin-2-yl)-1-(1,3-dicyclo-hexyl-2,4-dioxo-pyrlmidin-6-yl)-piperazine NH2 o 3 ~ ~ ~ ~ - C6Hll C6 11 ;
are added to a mixture of 24 ml of acetic anhydride and 12 ml of formic acid and the mix*ure is stirred for 5 hours at 80C. It is then concentrated under a water-pump vacuum. me residue is treated wlth 0.5 N aqueous sodium hydroxide solution and is filtered off and recrystallised from dimethylform~
amide. This gives 4-(4-amino-6,7-dimethoxyquinazolin-2-yl)-1-(1,3-dihexyl- , 2,4-dioxo-5-formyl-pyrimidin-6-yl)-piperazine CH3 ~ ~ ~ N - C6H
3 ~ I O
Melting point: 314 C, decomposition.
Analysis: (C31H41N705) C H N O
calculated: 62.96.9 16.6 13.5 found: 62.8 6.6 16.5 13.2 Yield: 81% of theory.
Example 5
C 3 ~ N ~ ~ ~ N 1 O
Melting point: 273C.
Analys~S: (C2oH25N7 4) C H N o calculated: 56.2 5.9 23.0 15.0 found: 56.0 6.0 23.0 14.7 Yield: 81% of theory.
The 1,3-dimethyl-6-piperazinylpyrimidine-2,4-dione used as the starting material can be prepared as follows:
20 g of 1,3-di~ethyl-6-chloropyrimidine-2,4-dione are added to a mlxture of 30 g of piperazine and 500 ml of toluene and the mixture is boiled under reflux for 3 hours. It is then filtered and the filtrate is concen-11~8~5~
trated under a water-pump vacuum. The residue which remains after concentra-tion is recrystallised from ethyl acetate. This gives 1,3-dimethyl-6-piperazinylpyrimidine-2,4-dione ~\N ~N ~0 in a yield of 75% of theory.
Melting point: 117 C.
E ~
5.2 g of 4-(4-amino-6,7-dimethoxyquinazolin-2-yl)-1-(1,3-dibutyl-2,4-dioxo-pyrimidin-6-yl)-piperazine NH~ 0 3 ~ N ~ N - C4Hg CH30 ~ ~ N ~ N 1 o c4Hg are dissolved in 20 ml of glacial acetic acid. A mixture of 1.7 g of bromlne and 20 ml of glacial aoe tic acid is then added dropwise, while chilling, and cooling with ice. me mixture is then stirred for a further 2 hours at room te~perature. me product is then filtered off and recrystallised from ethanol. This gives 1-(4-amino-6,7_dimethoxyquinazolLn-2-yl)-1-(1,3-dibutyl-2,4-dioxo-5-brcmopyrimidin-6-yl)-piperazine hydrobromide ~ O
CH30 ~ N ~ ~ - C4H9 CH30 ~ ~ --"`N 0 . HBr C~Hg Melting point: above 300C, de ~ ~position.
~ 10 ~
'.~
Analysis: (C26H37Br2N704) C H Br N O
calculated: 46.5 5.5 23.8 14.6 9.5 found: 46.7 5.3 23.5 14.7 9.8 Yield: 61% of theory.
Example 4 5.6 g of 4-(4-amino-6,7-dimethoxyquinazolin-2-yl)-1-(1,3-dicyclo-hexyl-2,4-dioxo-pyrlmidin-6-yl)-piperazine NH2 o 3 ~ ~ ~ ~ - C6Hll C6 11 ;
are added to a mixture of 24 ml of acetic anhydride and 12 ml of formic acid and the mix*ure is stirred for 5 hours at 80C. It is then concentrated under a water-pump vacuum. me residue is treated wlth 0.5 N aqueous sodium hydroxide solution and is filtered off and recrystallised from dimethylform~
amide. This gives 4-(4-amino-6,7-dimethoxyquinazolin-2-yl)-1-(1,3-dihexyl- , 2,4-dioxo-5-formyl-pyrimidin-6-yl)-piperazine CH3 ~ ~ ~ N - C6H
3 ~ I O
Melting point: 314 C, decomposition.
Analysis: (C31H41N705) C H N O
calculated: 62.96.9 16.6 13.5 found: 62.8 6.6 16.5 13.2 Yield: 81% of theory.
Example 5
4.7 g of 4-(4-amino-6,7-dimethoxyquinazolin-2-yl)-1-(1,3-dimethyl-2,4-dioxo-5-nitro~yrimidin-6-yl)-piperazine CH30 ~ N 2 ~ N - CH3 3 ~ N ~ ~ ~ N 1 0 are suspended in 300 ml of etha~ol, 0.4 g of 10% strength Pd-on-charcoal are added and the mixture is hydrogenated by shaking with hydrogen for 20 hours at room temperature and normal pressure. m e mixture is then filtered, the residue is immediately digested under hot conditions with dimethylformamide and the catalyst is filtered off while the dimethylformamide solution is still hot. The dimethylformamide solution is then con oentrated under a water-pump vacuum and the residue is recrystallised from aqu~ous dimethylformamide.
This gives 4-(4-amino-6,7-dimethoxyquinazolin-2-yl)-1-(1,3-dimethyl-2,4-dioxs-5-amino-pyrimidin-6-yl)-piperazine C~I30 ~ M ~ ~ - CH
C1130~NJ_ ~ Nlo ~lelting point: 327C.
Analysis: (C20H26N7 4) calculated: 54.3 5.9 25.3 14.5 found: 54.0 6.1 25~0 14~7 Yield: 78% of theory.
m e following substances were prepared analogously to Examples 1 to
This gives 4-(4-amino-6,7-dimethoxyquinazolin-2-yl)-1-(1,3-dimethyl-2,4-dioxs-5-amino-pyrimidin-6-yl)-piperazine C~I30 ~ M ~ ~ - CH
C1130~NJ_ ~ Nlo ~lelting point: 327C.
Analysis: (C20H26N7 4) calculated: 54.3 5.9 25.3 14.5 found: 54.0 6.1 25~0 14~7 Yield: 78% of theory.
m e following substances were prepared analogously to Examples 1 to
5:
`~.
`~.
6 ~ ~
CH3~ ~ 2N R3 ~ N - R2 CH30 ~ N ~ ~ ~ N ~ o Rl :
Rl = R2 R3 p~L~t.
.
C~I3 -C4H9 325 C
-CH3 -N~I-C0 C2H5 314C
-C3H7 -CH2 ~ 331C
CH -CH-CH2- ~ 319 &
n 6 13 322C
-c~3 -C~2-CH-CH2 328 C
-CH2 ~ H 324 &
-C4Hg H 309C
cyclohexyl H 323 &
Rl R2 R3Meltin . .
~;~
1 ~56~6 The pharmacological efficacy of the compounds of the invention was tested as follows:
1. Measurement of Blood Pressure in normotonic anesthetlzed Rats Male IV~NOV~S rats (300 - 340 g) of the SIV 50 phylum were anesthetized by administering 66 mg/kg of ~-chloralose (1.1 percent solution, 0.6 ml/
100 g) and 20 mg/kg of aprobarbital into the tail vein. The trachea was cannulated in order to facilitate the spontaneous respiration. The blood pressure was measured conventionally by a surgical method via a PE tube inserted into the right carotid artery. A three way cock per~itted the use of this PE tube for the intraarterial administration of the test sub-stan oes, a volume of 0.1 ml having been injected in each case. By rinsing with 0.9 percent NaCl the test substan oe s were also transferred towards the central nervous system via the vertebral artery before distribution in the general circulation started.
The maximum systolic and diastolic lowering of the blood pressure as well as the maximIm change of the cardiac rate were evaluated quantitatively.
The time passed between the beginning of the change and the reaching of the initial value was regarded as the duration of efficacy. The values given in the following Table 1 were obtained:
5 ~
T a b 1 e Formulation BPs - BPd CR
and Dose ~ mmHg min Q ni~Ig ~ s/mln (mg~kg) x x x 0.01 - 30 36 - 27 + 5 Prazosin _ - 20 60 . .... .. _ . . .
BPS = systoLic blood pressure BPd = diastolic blood pressure DE = duration of efficacy CR = cardiac rate x = mean value * = 4-(4-amino-6,7-dimethaxychinazoline-2-yl)-1-(1,3-dimethyl-2,4-dioxo-5-nitro-pyrimidine-6-yl)-piperazine Prazosin = camparison formulation according to US Patent 3,511,836 2. Effect of Blood Pressure in normotonic anesthetized Dogs :
The investigations were carried out on mongrel dogs of both sexes under pentobarb.ital anesthesia (30 - 40 mg/kg administered intravenously).
Ar~ificial respiration of the animals was effected by means of a Bird Mark
CH3~ ~ 2N R3 ~ N - R2 CH30 ~ N ~ ~ ~ N ~ o Rl :
Rl = R2 R3 p~L~t.
.
C~I3 -C4H9 325 C
-CH3 -N~I-C0 C2H5 314C
-C3H7 -CH2 ~ 331C
CH -CH-CH2- ~ 319 &
n 6 13 322C
-c~3 -C~2-CH-CH2 328 C
-CH2 ~ H 324 &
-C4Hg H 309C
cyclohexyl H 323 &
Rl R2 R3Meltin . .
~;~
1 ~56~6 The pharmacological efficacy of the compounds of the invention was tested as follows:
1. Measurement of Blood Pressure in normotonic anesthetlzed Rats Male IV~NOV~S rats (300 - 340 g) of the SIV 50 phylum were anesthetized by administering 66 mg/kg of ~-chloralose (1.1 percent solution, 0.6 ml/
100 g) and 20 mg/kg of aprobarbital into the tail vein. The trachea was cannulated in order to facilitate the spontaneous respiration. The blood pressure was measured conventionally by a surgical method via a PE tube inserted into the right carotid artery. A three way cock per~itted the use of this PE tube for the intraarterial administration of the test sub-stan oes, a volume of 0.1 ml having been injected in each case. By rinsing with 0.9 percent NaCl the test substan oe s were also transferred towards the central nervous system via the vertebral artery before distribution in the general circulation started.
The maximum systolic and diastolic lowering of the blood pressure as well as the maximIm change of the cardiac rate were evaluated quantitatively.
The time passed between the beginning of the change and the reaching of the initial value was regarded as the duration of efficacy. The values given in the following Table 1 were obtained:
5 ~
T a b 1 e Formulation BPs - BPd CR
and Dose ~ mmHg min Q ni~Ig ~ s/mln (mg~kg) x x x 0.01 - 30 36 - 27 + 5 Prazosin _ - 20 60 . .... .. _ . . .
BPS = systoLic blood pressure BPd = diastolic blood pressure DE = duration of efficacy CR = cardiac rate x = mean value * = 4-(4-amino-6,7-dimethaxychinazoline-2-yl)-1-(1,3-dimethyl-2,4-dioxo-5-nitro-pyrimidine-6-yl)-piperazine Prazosin = camparison formulation according to US Patent 3,511,836 2. Effect of Blood Pressure in normotonic anesthetized Dogs :
The investigations were carried out on mongrel dogs of both sexes under pentobarb.ital anesthesia (30 - 40 mg/kg administered intravenously).
Ar~ificial respiration of the animals was effected by means of a Bird Mark
7 respirator. me final expiratory carbon dioxide content (measured with ~;
a Uras machine was between 4.5 and 5% by volum~.
In order to ensure a constant depth of the narcosis -the animals we~e given a continuous intravenous infusion of pentobarbital = 4 m~/kg/6 ml/h during the entire experiment.
The systolic and diastolic blood pressure were measured peripherally in the femoral artery via a Statham pressure recorder.
5 0~
The parameters were continuously recorded on a Brush Mark 6 direct re-corder via preamplifiers.
The test substances were injected intravenously in the form of boluses.
The values obtamed are disclosed in the following Table 2:
T a b 1 e 2 Formulation BPS BPd and Dose ~ m~g min Q mmH~ ~ s/mln (m~/kg) x ~ x x _ 0.1 - 40 60 - 42 - 17 Prazosin 0.5 - 15 10 - 10 0 (m e abbreviations are identical with those used in Table 1) The pharmaceutical formulations can contain, for example, 0.1 to 50 mg, pre~
ferably 0.5 to 40 m~, per dose of the active substance. Per kg of body weight, for example, 0.002 to 1 mg, preferably 0.02 to 0.5 mg of the active substance can ke administered daily.
Example 6 Pills can ke prepared according to ~he following formulation:
4-(4-amino-6,7-dimetho~ychinazoline-2-yl)-1-(1,3_dimethyl-2,4-dioxo-5-nitro-pyrimidine-6-yl)-piperazine 2 m~
Co m starch 100 m~
Lactose 60 m~
Sec. calcium phosphate 30 m~
Soluble starch 2 mg ~agnesium stearate 2 m~
Colloidal silicic acid 4 mg ~ . .
200 m~
~ ,..
, ~ . . :
1 15~
Example 7 Tablets can be prepared according to the following formulation:
4-(4-amino-6,7-dimethoxychinazoline-2-yl)-1-(1,3-dimethyl-2,4-dioxo-pyrimidine-6-yl)-pipera2ine 2 mg Lactose 60 mg Cornstarch 30 ~g ~`
Soluble starch 4 mg Magnesium stearate 4 m~
~.~
a Uras machine was between 4.5 and 5% by volum~.
In order to ensure a constant depth of the narcosis -the animals we~e given a continuous intravenous infusion of pentobarbital = 4 m~/kg/6 ml/h during the entire experiment.
The systolic and diastolic blood pressure were measured peripherally in the femoral artery via a Statham pressure recorder.
5 0~
The parameters were continuously recorded on a Brush Mark 6 direct re-corder via preamplifiers.
The test substances were injected intravenously in the form of boluses.
The values obtamed are disclosed in the following Table 2:
T a b 1 e 2 Formulation BPS BPd and Dose ~ m~g min Q mmH~ ~ s/mln (m~/kg) x ~ x x _ 0.1 - 40 60 - 42 - 17 Prazosin 0.5 - 15 10 - 10 0 (m e abbreviations are identical with those used in Table 1) The pharmaceutical formulations can contain, for example, 0.1 to 50 mg, pre~
ferably 0.5 to 40 m~, per dose of the active substance. Per kg of body weight, for example, 0.002 to 1 mg, preferably 0.02 to 0.5 mg of the active substance can ke administered daily.
Example 6 Pills can ke prepared according to ~he following formulation:
4-(4-amino-6,7-dimetho~ychinazoline-2-yl)-1-(1,3_dimethyl-2,4-dioxo-5-nitro-pyrimidine-6-yl)-piperazine 2 m~
Co m starch 100 m~
Lactose 60 m~
Sec. calcium phosphate 30 m~
Soluble starch 2 mg ~agnesium stearate 2 m~
Colloidal silicic acid 4 mg ~ . .
200 m~
~ ,..
, ~ . . :
1 15~
Example 7 Tablets can be prepared according to the following formulation:
4-(4-amino-6,7-dimethoxychinazoline-2-yl)-1-(1,3-dimethyl-2,4-dioxo-pyrimidine-6-yl)-pipera2ine 2 mg Lactose 60 mg Cornstarch 30 ~g ~`
Soluble starch 4 mg Magnesium stearate 4 m~
~.~
Claims (18)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing pyrimidyl-quinazolines having the general formula I
(I) and pharmacologically acceptable acid addition salts thereof, wherein R1 and R2 denote hydrogen, alkyl having 1 to 6 C atoms, alkenyl having 2 to 6 C atoms, cycloalkyl having 5 to 7 C atoms, phenyl or benzyl, R3 denotes hydrogen, alkyl having 1 to 6 C
atoms, alkenyl having 2 to 6 C atoms, phenyl, phenalkyl having 1 to 4 C atoms in the alkyl radical, halogen, nitro, amino, alkylcarbonylamino having 1 to 6 C atoms in the alkyl radical, phenylcarbonylamino or formyl are prepared by a) reacting a compound of the formula II
(II) wherein X denotes a mercapto radical or a halogen atom, with a compound of the formula III
(III) wherein Rl, R2 and R3 have the meanings given above or b) reacting 2-piperazinyl-4-amino-6,7-dimethoxyquinazoline with a compound of the formula V
(V) wherein Hal denotes a halogen atom, and wherein Rl, R2 and R3 have the meanings given above or c) introducing the substituent R3 into a compound of the formula VI
(VI) in the 5-position of the pyrimidinedione nucleus, Rl, R2 and R3 having the meanings given above and optionally converting the resulting compound of the formula I into an acid addition salt.
(I) and pharmacologically acceptable acid addition salts thereof, wherein R1 and R2 denote hydrogen, alkyl having 1 to 6 C atoms, alkenyl having 2 to 6 C atoms, cycloalkyl having 5 to 7 C atoms, phenyl or benzyl, R3 denotes hydrogen, alkyl having 1 to 6 C
atoms, alkenyl having 2 to 6 C atoms, phenyl, phenalkyl having 1 to 4 C atoms in the alkyl radical, halogen, nitro, amino, alkylcarbonylamino having 1 to 6 C atoms in the alkyl radical, phenylcarbonylamino or formyl are prepared by a) reacting a compound of the formula II
(II) wherein X denotes a mercapto radical or a halogen atom, with a compound of the formula III
(III) wherein Rl, R2 and R3 have the meanings given above or b) reacting 2-piperazinyl-4-amino-6,7-dimethoxyquinazoline with a compound of the formula V
(V) wherein Hal denotes a halogen atom, and wherein Rl, R2 and R3 have the meanings given above or c) introducing the substituent R3 into a compound of the formula VI
(VI) in the 5-position of the pyrimidinedione nucleus, Rl, R2 and R3 having the meanings given above and optionally converting the resulting compound of the formula I into an acid addition salt.
2. Pyrimidyl-quinazolines having the general formula I
(I) and pharmacologically acceptable acid addition salts thereof, wherein Rl and R2 denote hydrogen, alkyl having 1 to 6 C atoms, alkenyl having 2 to 6 C atoms, cycloalkyl having 5 to 7 C atoms phenyl or benzyl, R3 denotes hydrogen, alkyl having 1 to 6 C atoms, alkenyl having 2 to 6 C atoms, phenyl, phenalkyl having 1 to 4 C
atoms in the alkyl radical, halogen, nitro, amino, alkylcarbonyl-amino having 1 to 6 C atoms in the alkyl radical, phenylcarbonylamino or formyl whenever prepared by the process of claim 1 or by an obvious chemical equivalent thereof.
(I) and pharmacologically acceptable acid addition salts thereof, wherein Rl and R2 denote hydrogen, alkyl having 1 to 6 C atoms, alkenyl having 2 to 6 C atoms, cycloalkyl having 5 to 7 C atoms phenyl or benzyl, R3 denotes hydrogen, alkyl having 1 to 6 C atoms, alkenyl having 2 to 6 C atoms, phenyl, phenalkyl having 1 to 4 C
atoms in the alkyl radical, halogen, nitro, amino, alkylcarbonyl-amino having 1 to 6 C atoms in the alkyl radical, phenylcarbonylamino or formyl whenever prepared by the process of claim 1 or by an obvious chemical equivalent thereof.
3. A process according to claim 1, wherein R1 is the same as R2.
4. A process according to claim 1, wherein R1 and R2 are methyl.
5. A process according to claim 1, wherein R3 is hydrogen.
6. A process according to claim 1, wherein R3 is nitro.
7. A process according to claim 1, wherein X is chlorine or bromine.
8. A process according to claim 1, wherein Hal is chlorine.
9. A process according to claim 1, wherein the reaction is carried out in a suitable solvent or dispersant.
10. A process according to claim 1, wherein the reaction is carried out at roam temperature or at elevated temperature.
11. A process according to claim 1, wherein the compound II is reacted with compound III, or 2-piperazinyl-4-amino-6,7-dimethoxychinazoline is reacted with compound V, at temperatures between 80 and 140°C.
12. A process according to claim 1, wherein the reaction is carried out in the presence of an acid-binding agent.
13. A process according to claim 1, wherein X in the compound of formula II denotes chlorine or bromine.
14. A process according to claim 1, wherein Hal in the compound of formula V denotes chlorine.
15. A process according to claim 1, wherein 4-(4-amino-6,7-dimethoxyquinazolin-2-yl)-1-(1,3-dimethyl-2,4-dioxo-5-nitro-pyrimidin-6-yl)-piperazine is prepared by reacting 2-piperazinyl-4-amino-6,7-dimethoxyquinazoline with 1,3-dimethyl-5-nitro-6-chloropyrimidine-2,4-dione.
16. 4-(4-amino-6,7-dimethoxyquinazolin-2-yl)-1-(1,3-dimethyl-2,4-dioxo-5-nitro-pyrimidin-6-yl)-piperazine whenever prepared by the process of claim 15 or by an obvious chemical equivalent thereof.
17. A process according to claim lc, wherein 1-(4-amino-6,7-dimethoxyquinazolin-2-y1)-1-(1,3-dibutyl-2,4-dioxo-5-bromo-pyrimidin-6-yl)-piperazine hydrobromide by bromating 4-(4-amino-6,7-dimethoxyquinazolin-2-y1)-1-(1,3-dibutyl-2,4-dioxopyrimidin-6-y1)piperazine.
18. 1-(4-amino-6,7-dimethoxyquinazolin-2-y1)-1-(1,3-dibutyl-2,4-dioxo-5-bromopyrimidin-6-yl)-piperazine hydrobromide whenever prepared by the process of claim 17 or by an obvious chemical equivalent thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19803011809 DE3011809A1 (en) | 1980-03-27 | 1980-03-27 | PYRIMIDYL-CHINAZOLINE, METHOD FOR THE PRODUCTION THEREOF, PHARMACEUTICAL PREPARATIONS CONTAINING IT AND THEIR USE |
| DEP3011809,3 | 1980-03-27 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1156656A true CA1156656A (en) | 1983-11-08 |
Family
ID=6098481
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000373945A Expired CA1156656A (en) | 1980-03-27 | 1981-03-26 | Process for the preparation of pyrimidyl-chinazolines |
Country Status (18)
| Country | Link |
|---|---|
| EP (1) | EP0037495A1 (en) |
| JP (1) | JPS56150088A (en) |
| AR (1) | AR227542A1 (en) |
| AU (1) | AU6877481A (en) |
| CA (1) | CA1156656A (en) |
| CS (1) | CS219898B2 (en) |
| DD (1) | DD157614A5 (en) |
| DE (1) | DE3011809A1 (en) |
| DK (1) | DK115581A (en) |
| ES (1) | ES500738A0 (en) |
| FI (1) | FI810778L (en) |
| GR (1) | GR71870B (en) |
| IL (1) | IL62495A0 (en) |
| NO (1) | NO810870L (en) |
| PL (2) | PL230320A1 (en) |
| PT (1) | PT72724B (en) |
| SU (1) | SU1052158A3 (en) |
| ZA (1) | ZA812034B (en) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6267077A (en) * | 1985-09-18 | 1987-03-26 | Mitsui Petrochem Ind Ltd | Quinazoline derivative and pharmaceutical |
| JPS61140568A (en) * | 1984-12-14 | 1986-06-27 | Mitsui Petrochem Ind Ltd | Quinazoline derivative, and hypotensor containing said derivative as active component |
| CN102140090A (en) * | 2004-03-15 | 2011-08-03 | 武田药品工业株式会社 | Dipeptidyl peptidase inhibitors |
| CA2572544C (en) * | 2004-07-02 | 2013-02-26 | Corcept Therapeutics, Inc. | Modified pyrimidine glucocorticoid receptor modulators |
| CN103596431B (en) | 2011-03-18 | 2016-06-22 | 科赛普特治疗公司 | Pyrimidine ring hexyl glucocorticoid receptor modulator |
| CN112236416B (en) | 2018-06-04 | 2024-03-01 | 科赛普特治疗公司 | Pyrimidine cyclohexenyl glucocorticoid receptor modulators |
| CA3158745A1 (en) | 2019-12-11 | 2021-06-17 | Corcept Therapeutics Incorporated | Methods of treating antipsychotic-induced weight gain with miricorilant |
| EP4146631A1 (en) | 2020-05-06 | 2023-03-15 | Corcept Therapeutics Incorporated | Polymorphs of pyrimidine cyclohexyl glucocorticoid receptor modulators |
| CA3202353A1 (en) | 2020-12-21 | 2022-06-30 | Jeffrey Mark Dener | Method of preparing pyrimidine cyclohexyl glucocorticoid receptor modulators |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2007656B (en) * | 1977-11-05 | 1982-05-19 | Pfizer Ltd | Therapeutic agents |
-
1980
- 1980-03-27 DE DE19803011809 patent/DE3011809A1/en not_active Withdrawn
- 1980-12-15 GR GR64485A patent/GR71870B/el unknown
-
1981
- 1981-03-13 NO NO810870A patent/NO810870L/en unknown
- 1981-03-13 DK DK115581A patent/DK115581A/en not_active Application Discontinuation
- 1981-03-13 FI FI810778A patent/FI810778L/en not_active Application Discontinuation
- 1981-03-20 EP EP81102088A patent/EP0037495A1/en not_active Ceased
- 1981-03-24 PT PT72724A patent/PT72724B/en unknown
- 1981-03-25 PL PL23032081A patent/PL230320A1/xx unknown
- 1981-03-25 DD DD81228589A patent/DD157614A5/en unknown
- 1981-03-25 PL PL23388281A patent/PL233882A1/xx unknown
- 1981-03-25 SU SU813261941A patent/SU1052158A3/en active
- 1981-03-25 JP JP4257181A patent/JPS56150088A/en active Pending
- 1981-03-25 CS CS812182A patent/CS219898B2/en unknown
- 1981-03-26 AR AR284752A patent/AR227542A1/en active
- 1981-03-26 IL IL62495A patent/IL62495A0/en unknown
- 1981-03-26 ES ES500738A patent/ES500738A0/en active Granted
- 1981-03-26 AU AU68774/81A patent/AU6877481A/en not_active Abandoned
- 1981-03-26 CA CA000373945A patent/CA1156656A/en not_active Expired
- 1981-03-26 ZA ZA00812034A patent/ZA812034B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| IL62495A0 (en) | 1981-05-20 |
| PL233882A1 (en) | 1982-05-10 |
| CS219898B2 (en) | 1983-03-25 |
| PL230320A1 (en) | 1982-03-29 |
| DD157614A5 (en) | 1982-11-24 |
| ES8202000A1 (en) | 1982-01-16 |
| JPS56150088A (en) | 1981-11-20 |
| ES500738A0 (en) | 1982-01-16 |
| SU1052158A3 (en) | 1983-10-30 |
| GR71870B (en) | 1983-07-08 |
| PT72724A (en) | 1981-04-01 |
| DE3011809A1 (en) | 1981-10-01 |
| AU6877481A (en) | 1981-10-01 |
| FI810778L (en) | 1981-09-28 |
| EP0037495A1 (en) | 1981-10-14 |
| NO810870L (en) | 1981-09-28 |
| AR227542A1 (en) | 1982-11-15 |
| DK115581A (en) | 1981-09-28 |
| PT72724B (en) | 1982-03-24 |
| ZA812034B (en) | 1982-05-26 |
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