CA1138871A - Quinazol in-2-ones - Google Patents
Quinazol in-2-onesInfo
- Publication number
- CA1138871A CA1138871A CA000341352A CA341352A CA1138871A CA 1138871 A CA1138871 A CA 1138871A CA 000341352 A CA000341352 A CA 000341352A CA 341352 A CA341352 A CA 341352A CA 1138871 A CA1138871 A CA 1138871A
- Authority
- CA
- Canada
- Prior art keywords
- quinazolinone
- loweralkyl
- dimethoxy
- methoxy
- water
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
- C07D239/80—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
- C07C205/27—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups
- C07C205/35—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
- C07C205/36—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton to carbon atoms of the same non-condensed six-membered aromatic ring or to carbon atoms of six-membered aromatic rings being part of the same condensed ring system
- C07C205/37—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton to carbon atoms of the same non-condensed six-membered aromatic ring or to carbon atoms of six-membered aromatic rings being part of the same condensed ring system the oxygen atom of at least one of the etherified hydroxy groups being further bound to an acyclic carbon atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
- C07C205/45—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by at least one doubly—bound oxygen atom, not being part of a —CHO group
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C273/00—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C273/18—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas
- C07C273/1809—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas with formation of the N-C(O)-N moiety
- C07C273/1818—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas with formation of the N-C(O)-N moiety from -N=C=O and XNR'R"
- C07C273/1827—X being H
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
- C07C45/70—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form
- C07C45/71—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form being hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
- C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
Compounds of the formula wherein R1 is hydrogen; alkyl having 4-20 carbons; cyclo-alkyl, heterocycloalkyl; halo; COO loweralkyl; CN; COOH;
CH2OH; CH(O-loweralkyl)2 or nitro; and X and Y are each hydrogen; halo; nitro; loweralkyl; loweralkoxy; aryl;
arylalkyloxy; hydroxy; acyloxy; aryloxy; amino; loweralkyl-amino; diloweralkylamino; amido; loweralkylamido; diloweralkyl-amido; cyano; COOH; COO loweralkyl; CHO; CH2OH; CH2O acyl;
or CH2O aryl. The compounds find use in the treatment of hypertension and bradycardia and as a cardiotonic agent.
Compounds of the formula wherein R1 is hydrogen; alkyl having 4-20 carbons; cyclo-alkyl, heterocycloalkyl; halo; COO loweralkyl; CN; COOH;
CH2OH; CH(O-loweralkyl)2 or nitro; and X and Y are each hydrogen; halo; nitro; loweralkyl; loweralkoxy; aryl;
arylalkyloxy; hydroxy; acyloxy; aryloxy; amino; loweralkyl-amino; diloweralkylamino; amido; loweralkylamido; diloweralkyl-amido; cyano; COOH; COO loweralkyl; CHO; CH2OH; CH2O acyl;
or CH2O aryl. The compounds find use in the treatment of hypertension and bradycardia and as a cardiotonic agent.
Description
Descrip~ion of the Invention The present invention relates to the use in the treat-ment of hypertension and bradycardia and as a cardlotonic agent, of a compound of the ~ormula ~0 Y
I
wherein R1 is hydrogen; alkyl having 4-20 carbons; cyclo-alkyl 7 heterocycloalkyl; halo; COO loweralkyl; CN; COOH;
CH20H; CH(O-loweralkyl)2 or nitro; and X and Y are each hydrogen; halo; nitro; loweralkyl; loweralkoxy; aryl;
arylalkyloxy; hydroxy; acyloxyi aryloxy; amino; loweralkyl-amino; diloweralkylamino; amido; loweralkylamido; diloweralkyl-amido; cyano; COOH; COO loweralkyli CHO; CH20H; CH20 acyl; or CH20 aryl; and phar~aceutically-acceptable acid :~3~'7;~ -addi-tion salts thereof; provided that when X and Y are loweralkoxy Rl is not hydrogen.
As used herein, the terms "loweralkyl" and "loweralkoxy"
mean straight or branched chain aliphatic hydrocarbons having from 1 to about 6 carbon atoms, such as for example methyl, ethyl, isopropyl, pentyl, and the like loweralkyls, and respectively, methoxy9 ethoxy, isopropoxy, pentoxy, and the like loweralkoxys. The term "halo" includes fluoro, chloro, bromo, and iodo. The term "aryl" inclucles aromatic hydro-carbons such as naphthyl, phenyl and the like and substituted aromatic hydrocarbons such as phenyl substituted with from one to three members each selected from the group consisting of loweralkyl, loweralkoxy, halo and methylenedioxy, provided that only one such member ls methylenedioxy (called herein "substituted phenyl"); and the like. The term "acyl"
includes loweralkanoyl and aroyl radicals derived from carboxylic acids having the formula HCOO~I, loweralkyl-COOH, and aryl-COOH. Examples of the acyl groups included herein are acetyl, propionyl, n-butyryl, and the like loweralkanoyls and benzoyl, naphthoyl, 3,5-dichlorobenzoyl, and the like aroyls.
The quinazolines o~ this invention having the formula I, possess cardiovascular activity and are also useful in the treatment of hypertension and bradycardia and as cardiotonic agents.
Some of the instant compounds are novel and as such are included as part of this invention. The novel substituted quinazolinones include those compounds having the following formula:
1~3~
~o Y
H I' wherein Rl is alkyl having 4-20 carbons or cycloalkyl; and X and Y are each hydrogen; halo; nitro, loweralkyl; lower-alkoxy; aryl, arylalkyloxy; hydroxy; aGyloxy; aryloxy;
amino; loweralkylamino; diloweralkylamino; amido, loweralkyl-amido; diloweralkylamido; cyano; COOH; C00 loweralkyl, CH0;
CH20H; CH20 acyl; or CH20 aryl; and pharmaceutically-r acceptable acid addition salts thereof.
The compounds of the invent;on possess cardiovascular activities and are useful in the treatment of hypertension and bradycardia and as cardiotonic agents, as shown by their activity in the spontaneous hypertensive rat test at dosages from about 50 mg/kg to about 100 mglkg body weight. They have also been found to inhibit cyclic AMP phosphodiesterase at dosages from about 10 to about 900 mg/kg/day, thereby providing an increase in the intracellu1ar concentration of adenosine-3',5'-cyclic monophosphate, and are, therefore, useful as antiasthmatic agents. A preferred dosage range is from about 200 to about 2~0 mg/kg/day. The compounds of the invention are also useful for treatment of cardiac arrythmia as shown by their activity in eliminating chloroform-induced arrythmia in the mouse at dosages from about 30 to about 150 mg/kg.
In view of the activities of the subject ccmpounds of formula I, they are suitable for use in a method for treating a patient or subject having an ailment selected iL ~ 3 ~! 8 ~ ~
from hypertension, bradycardia, and cardiac arrythmia whichmethod comprises sys~ematically administering to said patient or subject an effective amount of said compounds for treatment of said ailment in base or acid addition salt form, preferably in admixture with a pharmaceutically-accPptable carrier. The present compounds are particularly suitable for use in treating warm-blooded animals.
To prepare the pharmaceutical compositions of this invention, a compound of formula I or salt thereof is combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending on the form of preparation desired for adminis~ration, e.g., oral or parenteral. In preparing the composit~ons in oral dosage form, any of the usual phar-maceutical media may be employed, such as, for exampleJ
water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations such as for example, suspensions, elixirs and solutions, or carriers such as starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders9 capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar-coated or enteric-coated by standard techniques. For parenterals, the carrier will usually comprise sterile water, though other ingre-dients, for example, to aid solubility or for preservative . -4-purposes may be included. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and ~he like may be employed.
The pharmaceutical composi~ions herein will generally contain, per dosage unit, e.g., tablet, capsule, powder, injections, teaspoonful and the like, from about 5 to about 500 mg and preferably from about 10 to about 25G mg.
The instant compounds may be isolated as the free base or in the form of an acid addition salt by the synthetic process normally employed. These compounds, in base form, are convertible to therapeutically active acid addition salts by treatment with an appropriate acid, such as, for example, an inorganic acid, such as, a hydrohalic acid, e.g., hydrochloric, hydrobromic, hydro-iodic acidi sulfuric or nitrtc acid; a phosphoric acicli an organic acid, such as acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, maleic, fumaric, malic, tartarlc, citric, benzoic, cinnamic, mandelic, methane-sulfonic, p-toluenesulfonic, cyclohexanesulfamic, salicylic, p-aminosalicylic, 2-phenoxybenzoic, or 2-acetoxy-benzoic acid. Conversely, the salt form can be converted in the usual manner into the free base.
Most of the substituted quinazolines of the invention, with the exception of those wherein Rl is C4-20 alkyl or cycloalkyl, are generally known ~ se or can be prepared by known procedures, as taught in the following articles and book: Schoefield, J. Chem. Soc., 1927 (1952);
Albert, J. Chem. Soc., 505 (1954); Armarego, J. Chem. Soc., (C) 234 (1966); and "Part I-Quinazolines" by W. L. F.
Ar~arego in "Fused Pyrimidines," D. J. 3rown, ed., 137~
Interscience, 1967.
The novel compounds of formula I' may be prepared by cyclizing a compound of the formula y ~ 1 NH ~ C - NH - C CH2-Rl O O
in the presence of a polyphosphoric acid. Preferably, said reaction is carried out by heating compound II in polyphosphiric acid under nitrogen to about 135C., the suspension being maintained at this temperature for about 3 hours. After cooling, the product ;s neutrallzed with a suitable base, preferahly ammonium hydroxide. Im-proved yields have also been obtained by preheating the polyphosphoric acid to about 100-120C. before adding compound II.
An alternative method of preparing novel compounds of formula I' consists in reacting a compound of the formula NHC0zEt III
~3~
with ammonia in the presence of ammonium acetate.
Pret`erably, dry ammonia gas is passed for about 3 hours through a solution of compound III with ammonium acetate in a suitable solvent such as dimethyl formamide.
The temperature is preferably ma;ntained at about 155-160C.
The intermediate used in the preparation of compound II may be prepared as indicated in the following chart:
II
IV . V
Preferably, compound Y together with the compound RlC-NH2 in a suitable solvent such as xylene or benzene are heated under n~itrogen at about 140C.
The intermediate used in the preparation of compound III may be prepared as indicated in the following chart: .
C - CH
VI
..lL~ 7~
Preferably, the above reaction is carried out at room temperature in a suitable solvent such as tetrahydrofuran.
The present invention is illustrated by the following examples.
:~3~
EX~'MPLE: 1 7~Et'hQxy~6~metho-xy~4~methyl~2(1H)quinazolinone hemihydrate Dry ammonia gas is passed for -three hours thxough a solution o~ 2 ~N~car~ethoxyamino~-4-ethoxy-5-me-thoxy aceto-phenone (12.0 g, 42.6 mM~ and ammonium acetate (118.9 g) maintained at 155~160C. The reaction mixture is cooled and poured in-to an ice-water mixture (500 ml). The crude product is collected and washed well with acetone to give 7-ethoxy-6-methoxy-4-methyl-2(lH)quinazolinone hemihydrate as a -tan TFA
solid; 8.5 g (85.2%~; m.p. 262-264C; ~TMS 7.46 (s,lH,5-H), 7.15 (s,lH,8-H), 4.56 ~q,2H,J ~ 7.OHz,7-O-CH2-CH3), 41.6 (s,3H,6-OCH3~, 3.13 (s,3H,4-CE3), 1.65 (t,3H,J ~ 7.0Hz, 7-0-
I
wherein R1 is hydrogen; alkyl having 4-20 carbons; cyclo-alkyl 7 heterocycloalkyl; halo; COO loweralkyl; CN; COOH;
CH20H; CH(O-loweralkyl)2 or nitro; and X and Y are each hydrogen; halo; nitro; loweralkyl; loweralkoxy; aryl;
arylalkyloxy; hydroxy; acyloxyi aryloxy; amino; loweralkyl-amino; diloweralkylamino; amido; loweralkylamido; diloweralkyl-amido; cyano; COOH; COO loweralkyli CHO; CH20H; CH20 acyl; or CH20 aryl; and phar~aceutically-acceptable acid :~3~'7;~ -addi-tion salts thereof; provided that when X and Y are loweralkoxy Rl is not hydrogen.
As used herein, the terms "loweralkyl" and "loweralkoxy"
mean straight or branched chain aliphatic hydrocarbons having from 1 to about 6 carbon atoms, such as for example methyl, ethyl, isopropyl, pentyl, and the like loweralkyls, and respectively, methoxy9 ethoxy, isopropoxy, pentoxy, and the like loweralkoxys. The term "halo" includes fluoro, chloro, bromo, and iodo. The term "aryl" inclucles aromatic hydro-carbons such as naphthyl, phenyl and the like and substituted aromatic hydrocarbons such as phenyl substituted with from one to three members each selected from the group consisting of loweralkyl, loweralkoxy, halo and methylenedioxy, provided that only one such member ls methylenedioxy (called herein "substituted phenyl"); and the like. The term "acyl"
includes loweralkanoyl and aroyl radicals derived from carboxylic acids having the formula HCOO~I, loweralkyl-COOH, and aryl-COOH. Examples of the acyl groups included herein are acetyl, propionyl, n-butyryl, and the like loweralkanoyls and benzoyl, naphthoyl, 3,5-dichlorobenzoyl, and the like aroyls.
The quinazolines o~ this invention having the formula I, possess cardiovascular activity and are also useful in the treatment of hypertension and bradycardia and as cardiotonic agents.
Some of the instant compounds are novel and as such are included as part of this invention. The novel substituted quinazolinones include those compounds having the following formula:
1~3~
~o Y
H I' wherein Rl is alkyl having 4-20 carbons or cycloalkyl; and X and Y are each hydrogen; halo; nitro, loweralkyl; lower-alkoxy; aryl, arylalkyloxy; hydroxy; aGyloxy; aryloxy;
amino; loweralkylamino; diloweralkylamino; amido, loweralkyl-amido; diloweralkylamido; cyano; COOH; C00 loweralkyl, CH0;
CH20H; CH20 acyl; or CH20 aryl; and pharmaceutically-r acceptable acid addition salts thereof.
The compounds of the invent;on possess cardiovascular activities and are useful in the treatment of hypertension and bradycardia and as cardiotonic agents, as shown by their activity in the spontaneous hypertensive rat test at dosages from about 50 mg/kg to about 100 mglkg body weight. They have also been found to inhibit cyclic AMP phosphodiesterase at dosages from about 10 to about 900 mg/kg/day, thereby providing an increase in the intracellu1ar concentration of adenosine-3',5'-cyclic monophosphate, and are, therefore, useful as antiasthmatic agents. A preferred dosage range is from about 200 to about 2~0 mg/kg/day. The compounds of the invention are also useful for treatment of cardiac arrythmia as shown by their activity in eliminating chloroform-induced arrythmia in the mouse at dosages from about 30 to about 150 mg/kg.
In view of the activities of the subject ccmpounds of formula I, they are suitable for use in a method for treating a patient or subject having an ailment selected iL ~ 3 ~! 8 ~ ~
from hypertension, bradycardia, and cardiac arrythmia whichmethod comprises sys~ematically administering to said patient or subject an effective amount of said compounds for treatment of said ailment in base or acid addition salt form, preferably in admixture with a pharmaceutically-accPptable carrier. The present compounds are particularly suitable for use in treating warm-blooded animals.
To prepare the pharmaceutical compositions of this invention, a compound of formula I or salt thereof is combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending on the form of preparation desired for adminis~ration, e.g., oral or parenteral. In preparing the composit~ons in oral dosage form, any of the usual phar-maceutical media may be employed, such as, for exampleJ
water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations such as for example, suspensions, elixirs and solutions, or carriers such as starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders9 capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar-coated or enteric-coated by standard techniques. For parenterals, the carrier will usually comprise sterile water, though other ingre-dients, for example, to aid solubility or for preservative . -4-purposes may be included. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and ~he like may be employed.
The pharmaceutical composi~ions herein will generally contain, per dosage unit, e.g., tablet, capsule, powder, injections, teaspoonful and the like, from about 5 to about 500 mg and preferably from about 10 to about 25G mg.
The instant compounds may be isolated as the free base or in the form of an acid addition salt by the synthetic process normally employed. These compounds, in base form, are convertible to therapeutically active acid addition salts by treatment with an appropriate acid, such as, for example, an inorganic acid, such as, a hydrohalic acid, e.g., hydrochloric, hydrobromic, hydro-iodic acidi sulfuric or nitrtc acid; a phosphoric acicli an organic acid, such as acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, maleic, fumaric, malic, tartarlc, citric, benzoic, cinnamic, mandelic, methane-sulfonic, p-toluenesulfonic, cyclohexanesulfamic, salicylic, p-aminosalicylic, 2-phenoxybenzoic, or 2-acetoxy-benzoic acid. Conversely, the salt form can be converted in the usual manner into the free base.
Most of the substituted quinazolines of the invention, with the exception of those wherein Rl is C4-20 alkyl or cycloalkyl, are generally known ~ se or can be prepared by known procedures, as taught in the following articles and book: Schoefield, J. Chem. Soc., 1927 (1952);
Albert, J. Chem. Soc., 505 (1954); Armarego, J. Chem. Soc., (C) 234 (1966); and "Part I-Quinazolines" by W. L. F.
Ar~arego in "Fused Pyrimidines," D. J. 3rown, ed., 137~
Interscience, 1967.
The novel compounds of formula I' may be prepared by cyclizing a compound of the formula y ~ 1 NH ~ C - NH - C CH2-Rl O O
in the presence of a polyphosphoric acid. Preferably, said reaction is carried out by heating compound II in polyphosphiric acid under nitrogen to about 135C., the suspension being maintained at this temperature for about 3 hours. After cooling, the product ;s neutrallzed with a suitable base, preferahly ammonium hydroxide. Im-proved yields have also been obtained by preheating the polyphosphoric acid to about 100-120C. before adding compound II.
An alternative method of preparing novel compounds of formula I' consists in reacting a compound of the formula NHC0zEt III
~3~
with ammonia in the presence of ammonium acetate.
Pret`erably, dry ammonia gas is passed for about 3 hours through a solution of compound III with ammonium acetate in a suitable solvent such as dimethyl formamide.
The temperature is preferably ma;ntained at about 155-160C.
The intermediate used in the preparation of compound II may be prepared as indicated in the following chart:
II
IV . V
Preferably, compound Y together with the compound RlC-NH2 in a suitable solvent such as xylene or benzene are heated under n~itrogen at about 140C.
The intermediate used in the preparation of compound III may be prepared as indicated in the following chart: .
C - CH
VI
..lL~ 7~
Preferably, the above reaction is carried out at room temperature in a suitable solvent such as tetrahydrofuran.
The present invention is illustrated by the following examples.
:~3~
EX~'MPLE: 1 7~Et'hQxy~6~metho-xy~4~methyl~2(1H)quinazolinone hemihydrate Dry ammonia gas is passed for -three hours thxough a solution o~ 2 ~N~car~ethoxyamino~-4-ethoxy-5-me-thoxy aceto-phenone (12.0 g, 42.6 mM~ and ammonium acetate (118.9 g) maintained at 155~160C. The reaction mixture is cooled and poured in-to an ice-water mixture (500 ml). The crude product is collected and washed well with acetone to give 7-ethoxy-6-methoxy-4-methyl-2(lH)quinazolinone hemihydrate as a -tan TFA
solid; 8.5 g (85.2%~; m.p. 262-264C; ~TMS 7.46 (s,lH,5-H), 7.15 (s,lH,8-H), 4.56 ~q,2H,J ~ 7.OHz,7-O-CH2-CH3), 41.6 (s,3H,6-OCH3~, 3.13 (s,3H,4-CE3), 1.65 (t,3H,J ~ 7.0Hz, 7-0-
2 -3);
7-Benzyloxy-6-methoxy-4-m-ethyl-2_lH)quinazolinone A stream of dry ammonia gas is passed for 3 hours through a solution of 4-benzyloxy-2-~N-carbethoxyamino)-5~methoxy aceto-phenone ~16.7 g, 0.0486 m) and ammonium acetate (140 g) in dimethylformamide (75 ml) maintained at 155-160C. ~he reaction mixture is cooled and poured into an ice water mixture (1000 ml).
The greyish precipitate is fi~tered and crystallized from methanol (after treatment with charcoal) to give 7-benzyloxy-6-methoxy-4-methyl-2(1H)quinazolinone as an off-white solid;
11.4 g (80.0%); m.p. 250-252 C; CF3COOH 7.46 (s,5H, 2' 3', TMS
4', 5', 6'-H), 7.43 (S. lH, 5-H), 7.23 (s, lH, 8-H), 5.46 (s, 2H, 7-O-CH -), 4.11 (s, 3H, 6-OCH3), 3.13 (s,3H, 4-CH ).
~L~L3~3~7~L
EX~MpLE 3 7-n~ButQxy~6~methoxy~4~methyl 2(`lH~quinazolinone hydrate A stream of dry ammonia ~as is passed for three hours through a solution of 4-n~butoxy-2-(N-carbethoxyamino)-5-methoxy acetophenone (21.97 g, 71 mM~ and ammonium acetate (196 g) maintained at 155-160C. The reaction mixture is cooled and poured into an ice-water mixture (500 ml~. A tan solid forms.
Filtration, washing with watex (50 ml), and drying affords 7-n-Butoxy-6-methoxy-4-methyl-2(1H)quinazolinone hydrate as a tan solid, 15.77 g(79.2~); m.p.=138-140C; ~CF3COOH 7.40 (s,lH,5-H), TMS
7.10 (s,lH,8-H), 4.40 (t,2H,J - 6.0Hz,l'-H), 4.13 (s,3H,6-OCH3),
7-Benzyloxy-6-methoxy-4-m-ethyl-2_lH)quinazolinone A stream of dry ammonia gas is passed for 3 hours through a solution of 4-benzyloxy-2-~N-carbethoxyamino)-5~methoxy aceto-phenone ~16.7 g, 0.0486 m) and ammonium acetate (140 g) in dimethylformamide (75 ml) maintained at 155-160C. ~he reaction mixture is cooled and poured into an ice water mixture (1000 ml).
The greyish precipitate is fi~tered and crystallized from methanol (after treatment with charcoal) to give 7-benzyloxy-6-methoxy-4-methyl-2(1H)quinazolinone as an off-white solid;
11.4 g (80.0%); m.p. 250-252 C; CF3COOH 7.46 (s,5H, 2' 3', TMS
4', 5', 6'-H), 7.43 (S. lH, 5-H), 7.23 (s, lH, 8-H), 5.46 (s, 2H, 7-O-CH -), 4.11 (s, 3H, 6-OCH3), 3.13 (s,3H, 4-CH ).
~L~L3~3~7~L
EX~MpLE 3 7-n~ButQxy~6~methoxy~4~methyl 2(`lH~quinazolinone hydrate A stream of dry ammonia ~as is passed for three hours through a solution of 4-n~butoxy-2-(N-carbethoxyamino)-5-methoxy acetophenone (21.97 g, 71 mM~ and ammonium acetate (196 g) maintained at 155-160C. The reaction mixture is cooled and poured into an ice-water mixture (500 ml~. A tan solid forms.
Filtration, washing with watex (50 ml), and drying affords 7-n-Butoxy-6-methoxy-4-methyl-2(1H)quinazolinone hydrate as a tan solid, 15.77 g(79.2~); m.p.=138-140C; ~CF3COOH 7.40 (s,lH,5-H), TMS
7.10 (s,lH,8-H), 4.40 (t,2H,J - 6.0Hz,l'-H), 4.13 (s,3H,6-OCH3),
3.10 ~s,3H,4-CH3~, 0.80-2.38 ~m,7H2l-H,3'-H,4'-H); M~ 262.
7-(2',6l-Dichlorobenzyloxy)-6-methoxy-4-methyl-2(1H) quinazolinone A stream of dry ammonia ~as is passed for three hours through a solution of 2-(N-carbethoxyamino)-4-(2',6l-dichloro-benzyloxy)-5-methoxy acetophenone and ammonium acetate (200 g) in dimethylformamide (125 ml) maintained at 160-165C. The reaction mixture is cooled and poured into methanol-water ~500 ml). The tan precipitate which forms i5 filtered, washed with cold water (50 ml) and triturated with acetone (250 ml) to give 7-(2',6'-dichlorobenzyloxy)-6-methoxy-4-methyl-2(lH) quinazolinone as a tan solid; 15.33 g (76.3%); m.p. ~ 286-288C.
CF3COOH 7.55 (s,lH,5-H), 7.30-7.65 (M,4H,8-H,3'H~ 4'H, TMS
~3~
5~H~, 5-8~ (~,2~CH2~O~, 4.15 (s,3H, 6-OCH3~, 3.15 (s,3H,4-CH3~ M 365 EXAMPLE S
7-(2',6l-Dichlorobenzyloxy)-6-methoxy-4-methyl-2(1H) quinazolinone A stream of dry ammonia ~as is passed for three hours through a solution of 2-(N-carbethoxyamino)-4-(2',6l-dichloro-benzyloxy)-5-methoxy acetophenone and ammonium acetate (200 g) in dimethylformamide (125 ml) maintained at 160-165C. The reaction mixture is cooled and poured into methanol-water ~500 ml). The tan precipitate which forms i5 filtered, washed with cold water (50 ml) and triturated with acetone (250 ml) to give 7-(2',6'-dichlorobenzyloxy)-6-methoxy-4-methyl-2(lH) quinazolinone as a tan solid; 15.33 g (76.3%); m.p. ~ 286-288C.
CF3COOH 7.55 (s,lH,5-H), 7.30-7.65 (M,4H,8-H,3'H~ 4'H, TMS
~3~
5~H~, 5-8~ (~,2~CH2~O~, 4.15 (s,3H, 6-OCH3~, 3.15 (s,3H,4-CH3~ M 365 EXAMPLE S
4-n-Decxl-6,7-dimethoxy-2~1H~quinazolinone A suspension of N-~3,4-dimethoxyphenyl)-N'-undecanoyl urea ~10.0 g, 0.02~ m~ in excess polyphosphoric acid (80 g) is heated under nitrogen to 135C. The suspension is maintained at 135C or three hours with stirring. The reaction mixture is cooled and quenched on ice water (200 g~ and the resulting gummy mixture is warmed and neutralized with conc.ammonium hydroxide to~ pH 8.Q. The resulting precipitate is isolated, washed wit~ water and dried in air to give 4-n-decyl-6,7-di-methoxy-2~1Hlquinazolinone (6.1 g; 63.2%). Upon recrystalliza-tion from ethanol (200 ml) yellow flakes are obtained (M.P.
166-167C).
6,7-Dimethoxy-4-n-hexyl-2~1H~guinazolinone A mixture of N-(3,4-dimethoxyphenyl)-N'-heptanoyl urea ~21.1 g, 68.8 mM~ and polyphosphoric acid (254.4 g, 753 mM) is heated to 130C. for three hours under nitrogen. After cooling, ice water (~ 200 ml) is added followed by the addition of conc.
ammonium hydroxide until the pH is'~7Ø The precipitate is isolat~d, washed with water, and dried to give a light green solid (4.4 g). Recrystallization from ethyl acetate/isopropanol (1:1) gives 6,7-dimethoxy-4-n-hexyl-2(lH)quinazolinone (1.6 g, TMS
8.0%~; m.p. 120-123C; NMR DMSO-6 ~0.60-2.00 (m,llH,-(CH2)4-CH3), 2.80-3.20 (m,2H,-CH2-C-N), 3.87 ~ ., . ~ ~
1~3~
(s, 6H~ ~CH3s~ 6.8Q and 7.3Q C2 s, 2H, C5-C8~H~sli M~ 290.
4~C~c`lopent~lmethy'l-6,7-dime'thoxy-2(1H)qu'inazolin~one A suspension of N-(3,4-dimethoxyphenyl)~N'-cyclopentyl-acetyl urea (6.~5 g, 0.024 m~ in polyphosphoric acid (200 g) is heated for 3 hours under nitrogen at 130-140C. After cooling, the reaction mixture is quenched on 1000 g ice and ~rou~ht to~ pH 10 with conc. ammonium hydroxide. The precipi-tate which forms is isolated, washed with water and dried to give 4-cyclopentylmethyl-6,7-dimethoxy-2(lH)-quinazolinone (0.97 g, 15.4%) as a dark solid, m.p.>240C dec.
4-n-Bu-toxy-3-methoxyacetophenone A solution of acetovanillone (40.0 g, 241 mM), sodium hydroxide (10.12 g, 253 mM) and iodobutane (56.60 g, 308 mM) in ethanol ~800 ml) is heated at reflux for 16 hours. The xeaction mixture is cooled and the solvent removed in vacuo to give a brown syrup. Crystallization from methanol/water affords 4-n-butoxy-3-methoxy-acetophenone as an off-white solid; (47.61 g, 88.9%); m.p. ~ 46-47 C; ~TMS 7.58 (dd, lH, J6 5 = 9 Hz~ J6,2 ~ 2 Hz, 6-H), 7.50 (d, lH, J2 6 = 2 Hz, 2-H), 6.85 (d, lH, J5 6 = 9 Hz, 5-H), 4.10 (t, 2H, J ~ 6 Hz, l'-H), 3.95 (s, 3H, o 3-OCH3), 2.55 (s, 3H, -C-CH3), 0.75-2.10 (m, 7H, 2'-H, 3'-H, 4'-H), M~ 222.
;1~
EXAMPLE ~
6~m~no-3-methoxy-4~enzyloxyacetophelione A solution of 4-benzyloxy-3-methoxy-6-nitroacetophenone C24~5 gr 0.0813 m~ in ~lacial acetic acid (140 ml) and water n40 ml~ is treated at 90-95C with iron powder (19.5 g), added in portions during 1 hour; water is added at the start of the reaction and at successive quarter hour intervals (total of 5 times/5 ml each). After a further 30 minutes, the mixture is diluted with water and the precipitated solid is filtered.
Crystallization from ethanol (150 ml) and subsequent recrystal-lization from methanol ~200 ml) gives 6-amino-3-methoxy-4-benzyloxyacetophenone as a light brown solid; (15.5 g, 70.8%~;
DMSO
m.p. 124-126 C; ~TMS 6.6-7.6 ~m, 9H, 2, 5, 2', 3', 4', 5', 6l-H and NH2~, 5O06 ~s, 2H, 0-CH2-O-), 3.73 (s, 3H, -OCH3), 2.46 (s,3H, C-CH )..
4-Benzyloxy-2-(N-carbethoxyamino)-5-methoxyacetophenone Ethyl chloroformate (18.5 g, 0.125 m) is added cautiously with stirring to 5-amino-3-methoxy-4-benzyloxyacetophenone (20.5 g, 0.0755 m) in tetrahydrofuran (200 ml~ is added slowly.
Removal of the solvent in vacuo yields a light brown semi-solid.
The crude product is extracted with chloroform (3X200 ml), dried (sodium sulfate), filtered, and the solvent removed ln vacuo to give a pale brown residue (19.2 g). Recrystallization from isopropanol affords 4-benzyloxy-2-(N-carbethoxyamino)-:
;
,~g ~3~
166-167C).
6,7-Dimethoxy-4-n-hexyl-2~1H~guinazolinone A mixture of N-(3,4-dimethoxyphenyl)-N'-heptanoyl urea ~21.1 g, 68.8 mM~ and polyphosphoric acid (254.4 g, 753 mM) is heated to 130C. for three hours under nitrogen. After cooling, ice water (~ 200 ml) is added followed by the addition of conc.
ammonium hydroxide until the pH is'~7Ø The precipitate is isolat~d, washed with water, and dried to give a light green solid (4.4 g). Recrystallization from ethyl acetate/isopropanol (1:1) gives 6,7-dimethoxy-4-n-hexyl-2(lH)quinazolinone (1.6 g, TMS
8.0%~; m.p. 120-123C; NMR DMSO-6 ~0.60-2.00 (m,llH,-(CH2)4-CH3), 2.80-3.20 (m,2H,-CH2-C-N), 3.87 ~ ., . ~ ~
1~3~
(s, 6H~ ~CH3s~ 6.8Q and 7.3Q C2 s, 2H, C5-C8~H~sli M~ 290.
4~C~c`lopent~lmethy'l-6,7-dime'thoxy-2(1H)qu'inazolin~one A suspension of N-(3,4-dimethoxyphenyl)~N'-cyclopentyl-acetyl urea (6.~5 g, 0.024 m~ in polyphosphoric acid (200 g) is heated for 3 hours under nitrogen at 130-140C. After cooling, the reaction mixture is quenched on 1000 g ice and ~rou~ht to~ pH 10 with conc. ammonium hydroxide. The precipi-tate which forms is isolated, washed with water and dried to give 4-cyclopentylmethyl-6,7-dimethoxy-2(lH)-quinazolinone (0.97 g, 15.4%) as a dark solid, m.p.>240C dec.
4-n-Bu-toxy-3-methoxyacetophenone A solution of acetovanillone (40.0 g, 241 mM), sodium hydroxide (10.12 g, 253 mM) and iodobutane (56.60 g, 308 mM) in ethanol ~800 ml) is heated at reflux for 16 hours. The xeaction mixture is cooled and the solvent removed in vacuo to give a brown syrup. Crystallization from methanol/water affords 4-n-butoxy-3-methoxy-acetophenone as an off-white solid; (47.61 g, 88.9%); m.p. ~ 46-47 C; ~TMS 7.58 (dd, lH, J6 5 = 9 Hz~ J6,2 ~ 2 Hz, 6-H), 7.50 (d, lH, J2 6 = 2 Hz, 2-H), 6.85 (d, lH, J5 6 = 9 Hz, 5-H), 4.10 (t, 2H, J ~ 6 Hz, l'-H), 3.95 (s, 3H, o 3-OCH3), 2.55 (s, 3H, -C-CH3), 0.75-2.10 (m, 7H, 2'-H, 3'-H, 4'-H), M~ 222.
;1~
EXAMPLE ~
6~m~no-3-methoxy-4~enzyloxyacetophelione A solution of 4-benzyloxy-3-methoxy-6-nitroacetophenone C24~5 gr 0.0813 m~ in ~lacial acetic acid (140 ml) and water n40 ml~ is treated at 90-95C with iron powder (19.5 g), added in portions during 1 hour; water is added at the start of the reaction and at successive quarter hour intervals (total of 5 times/5 ml each). After a further 30 minutes, the mixture is diluted with water and the precipitated solid is filtered.
Crystallization from ethanol (150 ml) and subsequent recrystal-lization from methanol ~200 ml) gives 6-amino-3-methoxy-4-benzyloxyacetophenone as a light brown solid; (15.5 g, 70.8%~;
DMSO
m.p. 124-126 C; ~TMS 6.6-7.6 ~m, 9H, 2, 5, 2', 3', 4', 5', 6l-H and NH2~, 5O06 ~s, 2H, 0-CH2-O-), 3.73 (s, 3H, -OCH3), 2.46 (s,3H, C-CH )..
4-Benzyloxy-2-(N-carbethoxyamino)-5-methoxyacetophenone Ethyl chloroformate (18.5 g, 0.125 m) is added cautiously with stirring to 5-amino-3-methoxy-4-benzyloxyacetophenone (20.5 g, 0.0755 m) in tetrahydrofuran (200 ml~ is added slowly.
Removal of the solvent in vacuo yields a light brown semi-solid.
The crude product is extracted with chloroform (3X200 ml), dried (sodium sulfate), filtered, and the solvent removed ln vacuo to give a pale brown residue (19.2 g). Recrystallization from isopropanol affords 4-benzyloxy-2-(N-carbethoxyamino)-:
;
,~g ~3~
5~metho~yacetophenone as~ an of~-white solid; ~18.1 ~, 7Q.0 CDCl mp 88~QC; ~TMS 3 11~33 Chroad s, lH, NH~, 8.23 (s, lH, 6-H~, 7.2Q 7.4Q Cm, 6H, 2', 3', 4', 5', 6~, 3-H~, 5.16 (s, 2H, 4-O-CH2~, 4.16 Cq, 2H, J-7.0 Hz, -O-CH2-CH3~, 3~83 (s, 3H, 5-OCH3), 2.53 ~s, 3H, -~-CH3), 1.32 (t, 3H, J~7.0 Hz, -O-CH2-CH3).
Undecanoylamide A mixture of undecanoic acid (150 g), thionyl chloride ~100 g~ and benzene (lS0 ml~ is refluxed with stirring for 6 hours. The reaction mixture is concentrated in vacuo to a dark oil. The oil is dissolved in tetrahydrofuran (150 ml), cooled to 0C and concentrated ammonium hydroxide (150 ml) is added dropwise with stirrïng. After aging for 1 hour at 0C~ the pre-cipitate which forms is isolated, washed with water and dried in air to give undecanoylamide (61.0 g, 61%)l m.p. 88-89C.
N-3,4-Dimethoxyphenyl-N'-undecanoyl urea A mixture of 3,4-dimethoxyphenylisocyanate (19.69 g, 0.11 m~ and undecanoylamide ~18.5 g, 0.1 m) in xylene (15 ml) is heated to 140C under nitrogen. After 2.5 hours, the reaction mixture is cooled to 70C and acetone is added (50 ml). After cooling to about 10 C, the crystalline product which forms is isolated and dried in vacuo to give N-3,4-dimethoxyphenyl-N'-undecanoyl urea (22.5 g, 55.2%), m.p. 112-113C.
~L3~7~
4~n-Decyl~6,7~dime-thoxy~2(1H~quinazolinone A suspension of N 3,4-dimethoxyphenyl-N'~undecanoyl urea (10.0 g, 0~024 m~ in polyphosphoric acid (80 ~, x's) is heated under nitrogen for 3 hours at 135C. The reaction is quenched on ice water (200 g) and adjusted to pH 8 with conc.
ammonium hydroxide. The yellow precipitate is isolated, washed with water and air dried to give 4-n-decyl-6,7-dimethoxy-2(lEI)-quinazolinone (6.1 g, 64~). The product is recrystallized from ethanol (m.p. 166-67Cl.
When in the above~procedures heptadecanamide is employed in place of und~canoylamide, 4-hexadecyl-6,7-dimethoxy-2(1~)quinazolinone is obtained.
When in the above procedures 3-piperidylpropionamide is employed in place of undecanoylamide, 4-~3-piperidylethyl)-
Undecanoylamide A mixture of undecanoic acid (150 g), thionyl chloride ~100 g~ and benzene (lS0 ml~ is refluxed with stirring for 6 hours. The reaction mixture is concentrated in vacuo to a dark oil. The oil is dissolved in tetrahydrofuran (150 ml), cooled to 0C and concentrated ammonium hydroxide (150 ml) is added dropwise with stirrïng. After aging for 1 hour at 0C~ the pre-cipitate which forms is isolated, washed with water and dried in air to give undecanoylamide (61.0 g, 61%)l m.p. 88-89C.
N-3,4-Dimethoxyphenyl-N'-undecanoyl urea A mixture of 3,4-dimethoxyphenylisocyanate (19.69 g, 0.11 m~ and undecanoylamide ~18.5 g, 0.1 m) in xylene (15 ml) is heated to 140C under nitrogen. After 2.5 hours, the reaction mixture is cooled to 70C and acetone is added (50 ml). After cooling to about 10 C, the crystalline product which forms is isolated and dried in vacuo to give N-3,4-dimethoxyphenyl-N'-undecanoyl urea (22.5 g, 55.2%), m.p. 112-113C.
~L3~7~
4~n-Decyl~6,7~dime-thoxy~2(1H~quinazolinone A suspension of N 3,4-dimethoxyphenyl-N'~undecanoyl urea (10.0 g, 0~024 m~ in polyphosphoric acid (80 ~, x's) is heated under nitrogen for 3 hours at 135C. The reaction is quenched on ice water (200 g) and adjusted to pH 8 with conc.
ammonium hydroxide. The yellow precipitate is isolated, washed with water and air dried to give 4-n-decyl-6,7-dimethoxy-2(lEI)-quinazolinone (6.1 g, 64~). The product is recrystallized from ethanol (m.p. 166-67Cl.
When in the above~procedures heptadecanamide is employed in place of und~canoylamide, 4-hexadecyl-6,7-dimethoxy-2(1~)quinazolinone is obtained.
When in the above procedures 3-piperidylpropionamide is employed in place of undecanoylamide, 4-~3-piperidylethyl)-
6,7-dimethoxy-2(1Hlquinazolinone is obtained.
~hen in the above procedures 2-chloroacetamide is employed in place of undecanoylamide, 4-chloromethyl-6,7-di-methoxy-2(lH)quinazolinone is obtained.
~3~37~
E~YAMpLE 14 Heptanamide A mi~xture oE heptanoyl chloride ~52 ~, a . 3514 m~ and tetrahydrofuran (laO ml~ is cooled to 0C and stirred under nitrogen. After cooling, -the reaction mixture is made basic by adding conc. ammonium hydroxide dropwise. A tan solid precipi-tates and is collected by filtra-tion and dried ln vacuo over phosphorous pentoxide to give heptanamide (13.68 g, 30.1~). m.p.
87-110C, ~ 12~.
lQ
N~C3,4-Dimethoxyphenyl)-N'-heptanoyl urea A mixture of 3,4-dimethoxyphenyl isocyanate ~18.98 g, 0.106 m~ and heptanamide (13.68 g, 0.106 m) is fused under nitrogen at 125C for 3 hours. After cooling to room temperature, acetone is added and the solid which forms is filtered, washed with acetone and dried ln vacuo over phosphorous pentoxide to give N-~3,4-dimethoxyphenyl)-N'-heptanoyl urea (31.2 g, 95.5%);
m.p. 168-172C, ~ 308.
EXAMPLE_16 Cyclopentylacetamide A solutlon of cyclopentyl acetic acid (50 g, 0.38 m) in benzene (100 ml) is treated with thionyl chloride (100 ml) and the resulting mixture is refluxed with stirring for 16 hours.
The reaction mixture is then concentrated ln vacuo to a tan oil.
The oil is dissolved in tetrahydrofuran (200 ml) and cooled to OC ~
~L~3~
Concent~ated a~monium hydroxide (200 ml~ is added ovex 1 hour w~th sti~rr~ng. A$ter a~ng at room temperature overnight, the reaction mi~xture is concentrated in ~acuo to 100 ml and chilled at 0 C for 12 hours. The resulting preclpitate is isolated, washed with watex and dried in vacuo to give cyclopentylacetamide (21.7 g, 28%~ as a colorless solid ~m.p. 137-39 C).
EXAMPL~ 17 N~C3,4 dimethoxyphenyl)-N'-cyclopentylacetyl urea lQ A mixture of 3,4-dimethoxyphenyl-isocyanate (5.0 g, 0~028 m) and cyclopentylacetamide (3.81 g, 0.028 m~ is fused neat at 130-140C for 3 hours. The solid mass is cooled and tri-turated with acetone (30 ml) to give N-(3,4-dimethoxyphenyl~-N'-cyclopentylacetyl urea (6.95 g, 78.9%), m.p. 180-210C dec.
3~Methoxy~n-butoxynitrobenzene Sodium hydride (mineral oil) ~50%, 1.44 g, 0.03 m) is added to a solution of 3-methoxy-4-hydroxynitrobenzene (3.78 g;
Q.02 m) in anhydrous dimethylformamide (25 ml) at-5C. ~fter aging for 15 minutes at room temperature, n-butylbromide t4.11 g) is added all at once and the mixture is aged for 2 hours at room temperature and then 2.5 hours at 80C. After cooling, 8~L
the reaction is ~uenched on ice (lOQ g~ and extracted with ether (3XlQ~ ml~. The et~er ~s w~shed with water ~2X75 ml~ and dried over magnesi~um sulfate. Evaporation of the ether yields a tan oil which is crystallized ~rom hot hexane to give 3-methoxy-4-n-butoxynitrofienzene tl.72 g, 38~5%~, m.p. 53-54C.
3-Methoxy~4-n-butoxyaniline hydroGhloride A solution of 3-methoxy-4-n-~utoxynitrobenzene (1.1 g, 0.004 m) in ethanol (50 ml) and conc. aqueous hydrochloric acid (2 ml) is treated with 10~ Pd/C (0.2 g). The mixture is shaken with hydrogen for 2 hours at a~out 45 psi., filtered through celite and conc. in vacuo to give 3-methoxy-4-n-butoxyaniline hydrochloride (1.0 g, 88%) as a ~ray solid, (m.p. dec 250 C).
4~Ethoxy-3-methoxy-2-nitroacetophenone Nitric acid (180 ml) is cooled in ice water. 4-Ethoxy-3-methoxy-acetophenone (30 ~, 0.154 m) is added portion wise and à light brown solution forms. After standing for 10 minutes, the reaction mixture is poured over ice water. The solid yellow product which forms is filtered and crystallized from isopropyl alcohol to yield 4-ethoxy-3-methoxy-2-nitroacetophenone (30.1 g, 81.9%), m.p. 105-109C).
~3E~
2-Amino-4-e-thoxy-5-methoxyacetophenone .
A mixture of 4-ethoxy-5-methoxy-2-nitroacetophenone (20.1 g, 84 mM) in glacial acetic acid (144.2 ml) and water (144.2 ml) is -treated at 90-95C with iron powder (20.1 g) (added in portions over one hour). Wa-ter is added at the start of the reaction and a-t successive quarter hour intervals (five ti~es/5 ml each). After two hours, the mixture is diluted with water and the light green precipitate which forms is filtered. ~ecyrstallization from isopropanol gives 2-amino-4-ethoxy-5-methoxyacetophenone as a yellow solid (13.5 g, 76.8~), m.p. 154-15~C.
_X PLE 22 2-(N-Carbethoxyamino)-4-ethoxy~5-methoxyacetophenone Ethyl chloroformate (12 g, 117 mM) is added with stirring to 2-amino-4-ethoxy-5-methoxyacetophenone - (11.4 g, 59.5 mM) dissolved in tetrahydrofuran (200 ml).
A solution of sodium hydroxide in water (3.7 g in 10 ml water) is added and the solution is refluxed for -two hours and then concentrated in vacuo. The light brown residue which forms is extracted with chloroform (2 x 125 ml), dried over sodium sulfate, filtered, and the solvent removed _ vacuo. The crude product is recrys-tallized from _-hexane (200 ml~ to afford 2-(N-carbethoxyamino)-4-ethoxy-5-methoxyacetophenone (14.5 g, 94.7%), m.p.
91-93C.
~3~38~7~
~-n-Butoxy-5-methoxy-2-nitroacetophenone 4-n-Butoxy-5-methoxyacetophenone (45.33 g, 204 mM) is added during five minutes to nitric acid ~280 ml, speciic gravity 1.42) at 0. After an additional ten minutes at the same temperature, the dark brown solu-tion is poured into ice water (l liter). The crude pro-duct is collected by filtration. Recrystallization from methanol (200 ml) affords 4-n-butoxy-5-methoxy-2-nitro-acetophenone as a yellow solid, (32.76 g, 60.1%); m.p.
76-77C.
2-Amino-4-n-butoxy-S-methoxyacetophenone A mixture of 4-n-butoxy-5-methoxy-2-nitroacetoph~none (30.66 g, llS mM) in glacial acetic acid (205 ml) and water (205 ml) is treated at 90-95C with iron powder (64.4 g, 40 mesh), added in portions over one hour; water is added at the start of the reaction and at successive quarter hour intervals (total of five times/5 ml each). After two hours at 90-95C, the mixture is diluted with water (lO00 ml) and the precipitate filtered. The dark brown solid which forms is washed with chloroform (2 liters). The chloroform is dried (Na2SO4), filtered, and the solvent removed in vacuo to give the product as a light brown syrup that crystallizes on standing. Recyr~tallization of a portion (3.10 g) from isopropanol (30 ml) affords 2-amino-4-_-butoxy-5-methoxy-acetophenone as a yellow solid (1~90 g); m.p. 88-89~C.
, ' ~L~31~37~
4-n-sutoxy-2-(N-carbethoxyamino)-5-methoxyacetophenone Ethyl chloroformate (23.6 ml, 0.247 m) is added cautiously with stirring to 2-amino-4-_-butoxy-5- methoxy-acetophenone (23.10 g, 0.097 m) dissolved in tetra-hydrofuran ~500 ml). A solution of sodium hydroxide (7.84 g, 0.196 m) in water (24 ml) is added slowly and the resulting solution is heated at reflux for two hours.
The tetrahydrofuran is removed ln vacuo from the reaction mixture and the resulting brown aqueous mixture is extracted with chloroform (4 x 150 ml), dried (Na2SO4) and the chloroform i5 removed ln vacuo to give a brown syrup that crystallizes on standing. ~ecrystallization from hexane yields 4-_-butoxy-2-(N-carbethoxyamino)-5-methoxyacetophenone as a pale yellow solid (m.p. 64-66C).
EXAMPI.E 26 -4-(2',6'-Dichlorobenzyloxy)-5-methoxy 2-nitroacetophenone To HNO3 (specific gravity 1.42, 285 ml) cooled in ice water is added portion wise 4-(2',6'-dichloro-20 benzyloxy)-5-methoxyacetophenone (56.27 g, 0.173 m). A red solid forms. The reaction mixture is removed from the ice bath and heated to 30C in an oil bath. The tempera-ture is maintained at 30C for ten minutes. During this time, the red solid turns yellow. The reaction mixture is then poured over ice water (1 liter~ and the resulting yellow solid is filtered, washed with water (100 ml), and dried to give 4-(2',6'-dichlorobenzyloxy)-5-methoxy-2-nitroacetophenone as a yellow solid (m.p. 148-151C).
~31~
2-Amino-4-(2',6'-dichlorobenzyloxy)-5-metnoxyacetophenone -A mixture of 4-(2',6'-dichlorobenzyloxy)-5-methoxy-2-nitroacetophenone (60.98 g, 0.165 m) in glacial acetic acid t428.5 ml) and water (428.5 ml) at 90-95C is treated with iron powder (134.4 g) added in 10-12 portions over 0.5 hours with vigorous stirring. When the addition is com-plete, the suspension is heated at 90-95C for two hours.
The reaction mixture is then heated at 90-95C for an additional four hours and then cooled. Water (1 liter) is added and the dark brown solid material is filtered and washed with chloroform (2 liters). The chlor-form is dried (Na2SO4), filtered, and the solvent removed _ vacuo to give a brown solid. Recrystallization from methanol (500 ml) treated with chaxcoal gives 2-amino-4-t2'.6`-dichlorobenzyloxy)-5-methoxyacetophenone as a yellow solid (22.71 g); m.p. 86-88C.
2-(N-Carbethoxyamino)-4-(2',6'-dichlorobenzyloxy)-5-methoxy-acetophenone Ethyl chloroformate (16.28 g, 0.150 m) is added cautiously with stirring to 2-amino-4-(2',6:-dichloro-benzyloxy)-5- methoxyacetophenone(20.41 g, 0.058 m) dissolved in tetrahydrofuran (500 ml). A solution of sodium hydroxide (4.84 g, 0.121 m) in water (20 ml) is added slowly and the resulting solution is heated at xeflux for two and one half hours. The tetrahydrofuran ~L~3~
is removed in vacuo from the reaction mixture to give a ligi~t brown solid. Water (50 ml) is added an`d the resulting mixture is extracted with chloroform (3 x 150 ml) and dried (~a2SO4). The chloroform is then removed ln vacuo to give a yellow solid. Recrystalliæation from isopropanol gives 2-(N-carbethoxyamino)-4-(2',6'-dichloro-benzyloxy)-5-methoxyacetophenone as an off-white solid ~m.p.. 160-162C), 7.80 g.
4-Benzyloxy-3-methoxy~6-nitroacetophenone .
4-Benzyloxy-3-methoxyacetophenone (61.0 g, 0.234 m) is added to nitric acid (110 ml, speeifie gravity 1~42) at 0-20C. A~ter 2-5 minutes, a vigorous reaction occurs dissolving all solids. The dark brown solution which forms is poured onto ice water (1 liter) and the crude product is collected by filtration. Two reerystallizations from methanol give 4-benzyloxy-3-methoxy-6-nitroaeetophenone as a pale yellow solid (40.0 g, 57.3%); m.p. 141-143~C.
EXAMP~E 30 6,7-Dihydroxy-4-methyl-2-(lH)quinazolinone hydrate A solution of 6,7-dimethoxy-4-methyl-2(lH) quinazolinone (12.4 g, 0.057 M) in acetic acid (300 ml) and hydrobromic acid (240 ml, 48% aqueous) is refluxed for 19 hours. The solution is cooled in an ice-water bath and the precipitated hydrobromide salt (8.0 g) is collected by filtration and then washed with excess acetone. The salt is dissolved in water (75 ml) and saturated aqueous sodi~m bicarbonate is added until the pH is neutral. The precipitated free base is collected by filtration and washed with acetone to yield 6,7-dihydroxy-4-methyl-2(1H)quinazolinone hydra-te (4.S g, 41.0%) as a pale yellow solid, m.p. 320C dec.
~hen in the above procedures 2-chloroacetamide is employed in place of undecanoylamide, 4-chloromethyl-6,7-di-methoxy-2(lH)quinazolinone is obtained.
~3~37~
E~YAMpLE 14 Heptanamide A mi~xture oE heptanoyl chloride ~52 ~, a . 3514 m~ and tetrahydrofuran (laO ml~ is cooled to 0C and stirred under nitrogen. After cooling, -the reaction mixture is made basic by adding conc. ammonium hydroxide dropwise. A tan solid precipi-tates and is collected by filtra-tion and dried ln vacuo over phosphorous pentoxide to give heptanamide (13.68 g, 30.1~). m.p.
87-110C, ~ 12~.
lQ
N~C3,4-Dimethoxyphenyl)-N'-heptanoyl urea A mixture of 3,4-dimethoxyphenyl isocyanate ~18.98 g, 0.106 m~ and heptanamide (13.68 g, 0.106 m) is fused under nitrogen at 125C for 3 hours. After cooling to room temperature, acetone is added and the solid which forms is filtered, washed with acetone and dried ln vacuo over phosphorous pentoxide to give N-~3,4-dimethoxyphenyl)-N'-heptanoyl urea (31.2 g, 95.5%);
m.p. 168-172C, ~ 308.
EXAMPLE_16 Cyclopentylacetamide A solutlon of cyclopentyl acetic acid (50 g, 0.38 m) in benzene (100 ml) is treated with thionyl chloride (100 ml) and the resulting mixture is refluxed with stirring for 16 hours.
The reaction mixture is then concentrated ln vacuo to a tan oil.
The oil is dissolved in tetrahydrofuran (200 ml) and cooled to OC ~
~L~3~
Concent~ated a~monium hydroxide (200 ml~ is added ovex 1 hour w~th sti~rr~ng. A$ter a~ng at room temperature overnight, the reaction mi~xture is concentrated in ~acuo to 100 ml and chilled at 0 C for 12 hours. The resulting preclpitate is isolated, washed with watex and dried in vacuo to give cyclopentylacetamide (21.7 g, 28%~ as a colorless solid ~m.p. 137-39 C).
EXAMPL~ 17 N~C3,4 dimethoxyphenyl)-N'-cyclopentylacetyl urea lQ A mixture of 3,4-dimethoxyphenyl-isocyanate (5.0 g, 0~028 m) and cyclopentylacetamide (3.81 g, 0.028 m~ is fused neat at 130-140C for 3 hours. The solid mass is cooled and tri-turated with acetone (30 ml) to give N-(3,4-dimethoxyphenyl~-N'-cyclopentylacetyl urea (6.95 g, 78.9%), m.p. 180-210C dec.
3~Methoxy~n-butoxynitrobenzene Sodium hydride (mineral oil) ~50%, 1.44 g, 0.03 m) is added to a solution of 3-methoxy-4-hydroxynitrobenzene (3.78 g;
Q.02 m) in anhydrous dimethylformamide (25 ml) at-5C. ~fter aging for 15 minutes at room temperature, n-butylbromide t4.11 g) is added all at once and the mixture is aged for 2 hours at room temperature and then 2.5 hours at 80C. After cooling, 8~L
the reaction is ~uenched on ice (lOQ g~ and extracted with ether (3XlQ~ ml~. The et~er ~s w~shed with water ~2X75 ml~ and dried over magnesi~um sulfate. Evaporation of the ether yields a tan oil which is crystallized ~rom hot hexane to give 3-methoxy-4-n-butoxynitrofienzene tl.72 g, 38~5%~, m.p. 53-54C.
3-Methoxy~4-n-butoxyaniline hydroGhloride A solution of 3-methoxy-4-n-~utoxynitrobenzene (1.1 g, 0.004 m) in ethanol (50 ml) and conc. aqueous hydrochloric acid (2 ml) is treated with 10~ Pd/C (0.2 g). The mixture is shaken with hydrogen for 2 hours at a~out 45 psi., filtered through celite and conc. in vacuo to give 3-methoxy-4-n-butoxyaniline hydrochloride (1.0 g, 88%) as a ~ray solid, (m.p. dec 250 C).
4~Ethoxy-3-methoxy-2-nitroacetophenone Nitric acid (180 ml) is cooled in ice water. 4-Ethoxy-3-methoxy-acetophenone (30 ~, 0.154 m) is added portion wise and à light brown solution forms. After standing for 10 minutes, the reaction mixture is poured over ice water. The solid yellow product which forms is filtered and crystallized from isopropyl alcohol to yield 4-ethoxy-3-methoxy-2-nitroacetophenone (30.1 g, 81.9%), m.p. 105-109C).
~3E~
2-Amino-4-e-thoxy-5-methoxyacetophenone .
A mixture of 4-ethoxy-5-methoxy-2-nitroacetophenone (20.1 g, 84 mM) in glacial acetic acid (144.2 ml) and water (144.2 ml) is -treated at 90-95C with iron powder (20.1 g) (added in portions over one hour). Wa-ter is added at the start of the reaction and a-t successive quarter hour intervals (five ti~es/5 ml each). After two hours, the mixture is diluted with water and the light green precipitate which forms is filtered. ~ecyrstallization from isopropanol gives 2-amino-4-ethoxy-5-methoxyacetophenone as a yellow solid (13.5 g, 76.8~), m.p. 154-15~C.
_X PLE 22 2-(N-Carbethoxyamino)-4-ethoxy~5-methoxyacetophenone Ethyl chloroformate (12 g, 117 mM) is added with stirring to 2-amino-4-ethoxy-5-methoxyacetophenone - (11.4 g, 59.5 mM) dissolved in tetrahydrofuran (200 ml).
A solution of sodium hydroxide in water (3.7 g in 10 ml water) is added and the solution is refluxed for -two hours and then concentrated in vacuo. The light brown residue which forms is extracted with chloroform (2 x 125 ml), dried over sodium sulfate, filtered, and the solvent removed _ vacuo. The crude product is recrys-tallized from _-hexane (200 ml~ to afford 2-(N-carbethoxyamino)-4-ethoxy-5-methoxyacetophenone (14.5 g, 94.7%), m.p.
91-93C.
~3~38~7~
~-n-Butoxy-5-methoxy-2-nitroacetophenone 4-n-Butoxy-5-methoxyacetophenone (45.33 g, 204 mM) is added during five minutes to nitric acid ~280 ml, speciic gravity 1.42) at 0. After an additional ten minutes at the same temperature, the dark brown solu-tion is poured into ice water (l liter). The crude pro-duct is collected by filtration. Recrystallization from methanol (200 ml) affords 4-n-butoxy-5-methoxy-2-nitro-acetophenone as a yellow solid, (32.76 g, 60.1%); m.p.
76-77C.
2-Amino-4-n-butoxy-S-methoxyacetophenone A mixture of 4-n-butoxy-5-methoxy-2-nitroacetoph~none (30.66 g, llS mM) in glacial acetic acid (205 ml) and water (205 ml) is treated at 90-95C with iron powder (64.4 g, 40 mesh), added in portions over one hour; water is added at the start of the reaction and at successive quarter hour intervals (total of five times/5 ml each). After two hours at 90-95C, the mixture is diluted with water (lO00 ml) and the precipitate filtered. The dark brown solid which forms is washed with chloroform (2 liters). The chloroform is dried (Na2SO4), filtered, and the solvent removed in vacuo to give the product as a light brown syrup that crystallizes on standing. Recyr~tallization of a portion (3.10 g) from isopropanol (30 ml) affords 2-amino-4-_-butoxy-5-methoxy-acetophenone as a yellow solid (1~90 g); m.p. 88-89~C.
, ' ~L~31~37~
4-n-sutoxy-2-(N-carbethoxyamino)-5-methoxyacetophenone Ethyl chloroformate (23.6 ml, 0.247 m) is added cautiously with stirring to 2-amino-4-_-butoxy-5- methoxy-acetophenone (23.10 g, 0.097 m) dissolved in tetra-hydrofuran ~500 ml). A solution of sodium hydroxide (7.84 g, 0.196 m) in water (24 ml) is added slowly and the resulting solution is heated at reflux for two hours.
The tetrahydrofuran is removed ln vacuo from the reaction mixture and the resulting brown aqueous mixture is extracted with chloroform (4 x 150 ml), dried (Na2SO4) and the chloroform i5 removed ln vacuo to give a brown syrup that crystallizes on standing. ~ecrystallization from hexane yields 4-_-butoxy-2-(N-carbethoxyamino)-5-methoxyacetophenone as a pale yellow solid (m.p. 64-66C).
EXAMPI.E 26 -4-(2',6'-Dichlorobenzyloxy)-5-methoxy 2-nitroacetophenone To HNO3 (specific gravity 1.42, 285 ml) cooled in ice water is added portion wise 4-(2',6'-dichloro-20 benzyloxy)-5-methoxyacetophenone (56.27 g, 0.173 m). A red solid forms. The reaction mixture is removed from the ice bath and heated to 30C in an oil bath. The tempera-ture is maintained at 30C for ten minutes. During this time, the red solid turns yellow. The reaction mixture is then poured over ice water (1 liter~ and the resulting yellow solid is filtered, washed with water (100 ml), and dried to give 4-(2',6'-dichlorobenzyloxy)-5-methoxy-2-nitroacetophenone as a yellow solid (m.p. 148-151C).
~31~
2-Amino-4-(2',6'-dichlorobenzyloxy)-5-metnoxyacetophenone -A mixture of 4-(2',6'-dichlorobenzyloxy)-5-methoxy-2-nitroacetophenone (60.98 g, 0.165 m) in glacial acetic acid t428.5 ml) and water (428.5 ml) at 90-95C is treated with iron powder (134.4 g) added in 10-12 portions over 0.5 hours with vigorous stirring. When the addition is com-plete, the suspension is heated at 90-95C for two hours.
The reaction mixture is then heated at 90-95C for an additional four hours and then cooled. Water (1 liter) is added and the dark brown solid material is filtered and washed with chloroform (2 liters). The chlor-form is dried (Na2SO4), filtered, and the solvent removed _ vacuo to give a brown solid. Recrystallization from methanol (500 ml) treated with chaxcoal gives 2-amino-4-t2'.6`-dichlorobenzyloxy)-5-methoxyacetophenone as a yellow solid (22.71 g); m.p. 86-88C.
2-(N-Carbethoxyamino)-4-(2',6'-dichlorobenzyloxy)-5-methoxy-acetophenone Ethyl chloroformate (16.28 g, 0.150 m) is added cautiously with stirring to 2-amino-4-(2',6:-dichloro-benzyloxy)-5- methoxyacetophenone(20.41 g, 0.058 m) dissolved in tetrahydrofuran (500 ml). A solution of sodium hydroxide (4.84 g, 0.121 m) in water (20 ml) is added slowly and the resulting solution is heated at xeflux for two and one half hours. The tetrahydrofuran ~L~3~
is removed in vacuo from the reaction mixture to give a ligi~t brown solid. Water (50 ml) is added an`d the resulting mixture is extracted with chloroform (3 x 150 ml) and dried (~a2SO4). The chloroform is then removed ln vacuo to give a yellow solid. Recrystalliæation from isopropanol gives 2-(N-carbethoxyamino)-4-(2',6'-dichloro-benzyloxy)-5-methoxyacetophenone as an off-white solid ~m.p.. 160-162C), 7.80 g.
4-Benzyloxy-3-methoxy~6-nitroacetophenone .
4-Benzyloxy-3-methoxyacetophenone (61.0 g, 0.234 m) is added to nitric acid (110 ml, speeifie gravity 1~42) at 0-20C. A~ter 2-5 minutes, a vigorous reaction occurs dissolving all solids. The dark brown solution which forms is poured onto ice water (1 liter) and the crude product is collected by filtration. Two reerystallizations from methanol give 4-benzyloxy-3-methoxy-6-nitroaeetophenone as a pale yellow solid (40.0 g, 57.3%); m.p. 141-143~C.
EXAMP~E 30 6,7-Dihydroxy-4-methyl-2-(lH)quinazolinone hydrate A solution of 6,7-dimethoxy-4-methyl-2(lH) quinazolinone (12.4 g, 0.057 M) in acetic acid (300 ml) and hydrobromic acid (240 ml, 48% aqueous) is refluxed for 19 hours. The solution is cooled in an ice-water bath and the precipitated hydrobromide salt (8.0 g) is collected by filtration and then washed with excess acetone. The salt is dissolved in water (75 ml) and saturated aqueous sodi~m bicarbonate is added until the pH is neutral. The precipitated free base is collected by filtration and washed with acetone to yield 6,7-dihydroxy-4-methyl-2(1H)quinazolinone hydra-te (4.S g, 41.0%) as a pale yellow solid, m.p. 320C dec.
7-Hydroxy-6-methoxy-4-methyl-2(lH)quinazolinone hydrobromide A solution of 7-benzyloxy-6-methoxy-4-methyl-2(1H) quinazolinone (20.0 g, O.Q675 m) in acetic acid (350 ml) and hydrobromic acid (325 ml, 48% aqueous) is refluxed for 4 hours. The solution is cooled in an ice-water bath and the solid (10.1 ~) which precipitates is collected by filtration, washed with hot methanol and then recrystallized from water (150 ml) to afford pure 7-hydroxy~6-methoxy-4-methyl-2(lH)quinazolinone hydrobromide as a yellowish-green 15 solid (9.0 g, 46.4%); m.p. 303-305C.
6-Hydroxy-7-methoxy-4-methyl-2(lH)quinazolinone hydrobromide hemihydrate 6,7-Dimethoxy-4-methyl-2(lH)quinazolinone (6.2 g, 20 0.0285 m) in acetic acid (150 ml) and hydrobromic acid (120 ml, 48% aqueous) is refluxed for 19 hours. The solution is cooled in an ice-water bath and the solid (5.1 g) which precipitates is collected by filtration.
Removal of the solvent from the filtrate gives an oily residue (1.95 g) which is crystallized from water and then twice from methanol to afford pure 6-hydroxy-7-methoxy-4-2(lH)quinazolinone hydrobromide hemihydrate as a yellowish-green solid (0.6 g, 7.1%); m.p. 230-232C.
~"
~38~7~
The following pharmacological data i6 provided:
TABLE I
-R
R~ ~
R'~ ~ O
v _ B.P.(SHR) R R' R" ORF lowering (mm) Dose (MPK) _ _ _ . __ _ _ ~
n ClOH2 ¦ CH3 CH315757 12 100 _ .
_ _ . n-~6H13 CH3CH3 15643 18 100 CH3 C2H5CH315710 27.5 40 _ _ . _ __ CH3 n~C~Hg CH3 15724 17 10 _ ~ _ .. . _ _ . . ~ _ ~ _ ~ H CH3 l54l7 6 1OO
... ~ __ _ _ _ TABL~ -II
~ _ , ~_I
Increase ln ~RF RBF t%) Dose (MPK?
_ 15757 NA 13.9 _ _ _ . _ 15643 +~4 13.9 _ 15710 NA 13.9 _ __ 15724 ~26 _ 13 9 _ 15417 +lÇ _ 13.9 15615 +49 13.9 15403 _ _+~9 . 13.9 -~5-- -,f ' 3~æ 7~
The following procedure of the SHR (spontaneously hypertensive rats) is as follows: Groups of 4 male SHR rats with systolic pressures greater than 170 mm. mercury were used to evaluate compounds for antihypertensive activity.
Systolic blood pressure is recorded via the tail-cuff method (which is indirect). Compounds are administered by various routes in graded doses. Blood pressure is reeorded at various time intervals following each dose.
There are two references regarding this procedure- Okamoto and his co-author Aoki. Japanese Clrculation Journal Volume 27, Page 282 (1963).
Roper Laborat~ of Animal Science, Volume 26, 305 (1976).
:
The Renal Vasodilator Procedure .... . .. _.
Adult mongrel dogs are anesthesized and surgically prepared for electromagnetic measurement of renal artery blood flow.
A carotid artery is cannulated for measuring arterial blood pressure and drugs are administered intravenously.
Heart rate is monitored by a cardio tachometer. Renal vascular resistance is calculated as the ratio of the mean arterial blood pressure over renal artery blood flow. Cumulative dose response data is obtained by infusing the test drug at progressively increasing infusion rates, each dose being infused for five minu~es.
The maximum percentage increase from pre-drug control in renal artery blood flow (or decrease in renal vascular resistance) is quantitated for each infusion dose.
Reference Goldberg and coworkers, Journal of Pharmacology and Experimental Therapeutics, Vol. 163 (1968).
~38~
The examples contained herein have been provided by way of illustration and not to limit the scope of the present invention which is defined by the appended claims~
:
6-Hydroxy-7-methoxy-4-methyl-2(lH)quinazolinone hydrobromide hemihydrate 6,7-Dimethoxy-4-methyl-2(lH)quinazolinone (6.2 g, 20 0.0285 m) in acetic acid (150 ml) and hydrobromic acid (120 ml, 48% aqueous) is refluxed for 19 hours. The solution is cooled in an ice-water bath and the solid (5.1 g) which precipitates is collected by filtration.
Removal of the solvent from the filtrate gives an oily residue (1.95 g) which is crystallized from water and then twice from methanol to afford pure 6-hydroxy-7-methoxy-4-2(lH)quinazolinone hydrobromide hemihydrate as a yellowish-green solid (0.6 g, 7.1%); m.p. 230-232C.
~"
~38~7~
The following pharmacological data i6 provided:
TABLE I
-R
R~ ~
R'~ ~ O
v _ B.P.(SHR) R R' R" ORF lowering (mm) Dose (MPK) _ _ _ . __ _ _ ~
n ClOH2 ¦ CH3 CH315757 12 100 _ .
_ _ . n-~6H13 CH3CH3 15643 18 100 CH3 C2H5CH315710 27.5 40 _ _ . _ __ CH3 n~C~Hg CH3 15724 17 10 _ ~ _ .. . _ _ . . ~ _ ~ _ ~ H CH3 l54l7 6 1OO
... ~ __ _ _ _ TABL~ -II
~ _ , ~_I
Increase ln ~RF RBF t%) Dose (MPK?
_ 15757 NA 13.9 _ _ _ . _ 15643 +~4 13.9 _ 15710 NA 13.9 _ __ 15724 ~26 _ 13 9 _ 15417 +lÇ _ 13.9 15615 +49 13.9 15403 _ _+~9 . 13.9 -~5-- -,f ' 3~æ 7~
The following procedure of the SHR (spontaneously hypertensive rats) is as follows: Groups of 4 male SHR rats with systolic pressures greater than 170 mm. mercury were used to evaluate compounds for antihypertensive activity.
Systolic blood pressure is recorded via the tail-cuff method (which is indirect). Compounds are administered by various routes in graded doses. Blood pressure is reeorded at various time intervals following each dose.
There are two references regarding this procedure- Okamoto and his co-author Aoki. Japanese Clrculation Journal Volume 27, Page 282 (1963).
Roper Laborat~ of Animal Science, Volume 26, 305 (1976).
:
The Renal Vasodilator Procedure .... . .. _.
Adult mongrel dogs are anesthesized and surgically prepared for electromagnetic measurement of renal artery blood flow.
A carotid artery is cannulated for measuring arterial blood pressure and drugs are administered intravenously.
Heart rate is monitored by a cardio tachometer. Renal vascular resistance is calculated as the ratio of the mean arterial blood pressure over renal artery blood flow. Cumulative dose response data is obtained by infusing the test drug at progressively increasing infusion rates, each dose being infused for five minu~es.
The maximum percentage increase from pre-drug control in renal artery blood flow (or decrease in renal vascular resistance) is quantitated for each infusion dose.
Reference Goldberg and coworkers, Journal of Pharmacology and Experimental Therapeutics, Vol. 163 (1968).
~38~
The examples contained herein have been provided by way of illustration and not to limit the scope of the present invention which is defined by the appended claims~
:
Claims (8)
1. A process for preparing a compound of the formula I' wherein R1 is alkyl having 4-20 carbons; or cycloalkyl; and X and Y are each hydrogen; halo; nitro; loweralkyl; lower-alkoxy; aryl; arylalkyloxy, hydroxy; acyloxy, aryloxy; amino;
loweralkylamino; diloweralkylamino; amido; loweralkylamido;
diloweralkylamido; cyano; COOH; COO loweralkyl; CHO; CH2OH;
CH2O acyl; or CH2O aryl; and pharmaceutically-acceptable acid addition salts thereof, characterized by a) heating a compound of the formula (II) in the presence of polyphosphoric acid; or b) heating a compound of the formula III) with ammonia in the presence of ammonium acetate and, if desired, preparing pharmaceutically-acceptable acid addition salts of the products thereof.
loweralkylamino; diloweralkylamino; amido; loweralkylamido;
diloweralkylamido; cyano; COOH; COO loweralkyl; CHO; CH2OH;
CH2O acyl; or CH2O aryl; and pharmaceutically-acceptable acid addition salts thereof, characterized by a) heating a compound of the formula (II) in the presence of polyphosphoric acid; or b) heating a compound of the formula III) with ammonia in the presence of ammonium acetate and, if desired, preparing pharmaceutically-acceptable acid addition salts of the products thereof.
2. A process for preparing 4-n-decyl-6,7-dimethoxy-2(1H)quinazolinone, characterized by cyclizing N-(3,4-dimethoxyphenyl)-N'-undecanoyl urea in the presence of polyphosphoric acid.
3. A process for preparing 6,7-dimethoxy-4-n-hexyl-2(1H)quinazolinone, characterized by cyclizing N-(3,4-dimethoxyphenyl)-N'-heptanoyl urea in the presence of polyphosphoric acid.
4. A process for preparing 6,7-dimethoxy-4-n-hexadecyl-2(1H)quinazolinone, characterized by cyclizing N-(3,4-dimethoxyphenyl)-N'-heptadecanoyl urea in the presence of polyphosphoric acid.
5. A compound of the formula I' wherein R1 is alkyl having 4-20 carbons; or cycloalkyl;
and X and Y are each hydrogen; halo; nitro; loweralkyl;
loweralkoxy; aryl; arylalkyloxy; hydroxy; acyloxy; aryloxy;
amino; loweralkylamino; diloweralkylamino; amido; loweralkylamido;
diloweralkylamido; cyano; COOH; COO loweralkyl; CHO; CH2OH;
CH2O acyl; or CH2O aryl; or pharmaceutically-acceptable acid addition salts thereof whenever prepared or produced by the process of claim 1 or by their obvious chemical equivalent.
and X and Y are each hydrogen; halo; nitro; loweralkyl;
loweralkoxy; aryl; arylalkyloxy; hydroxy; acyloxy; aryloxy;
amino; loweralkylamino; diloweralkylamino; amido; loweralkylamido;
diloweralkylamido; cyano; COOH; COO loweralkyl; CHO; CH2OH;
CH2O acyl; or CH2O aryl; or pharmaceutically-acceptable acid addition salts thereof whenever prepared or produced by the process of claim 1 or by their obvious chemical equivalent.
6. 4-n-decyl-6,7-dimethoxy-2 (1H) quinazolinone whenever prepared or produced by the process of claim 2 or by their obvious chemical equivalent.
7. 6,7-dimethoxy-4-n-hexyl-2 (1H) quinazolinone whenever prepared or produced by the process of claim 3 or by their obvious chemical equivalent.
8. 6,7-dimethoxy-4-n-hexadecyl-2 (1H) quinazolinone whenever prepared or produced by the process of claim 4 or by their obvious chemical equivalent.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA374,116A CA1125170A (en) | 1978-12-07 | 1981-03-27 | Quinazol in -2-ones |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US96717378A | 1978-12-07 | 1978-12-07 | |
| US967,173 | 1978-12-07 | ||
| US6836779A | 1979-08-21 | 1979-08-21 | |
| US68,367 | 1979-08-21 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1138871A true CA1138871A (en) | 1983-01-04 |
Family
ID=26748897
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000341352A Expired CA1138871A (en) | 1978-12-07 | 1979-12-06 | Quinazol in-2-ones |
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| Country | Link |
|---|---|
| AT (1) | AT374468B (en) |
| AU (1) | AU533427B2 (en) |
| CA (1) | CA1138871A (en) |
| CH (1) | CH645106A5 (en) |
| DE (1) | DE2949395A1 (en) |
| ES (1) | ES486696A0 (en) |
| FR (1) | FR2443462A1 (en) |
| GB (1) | GB2088874B (en) |
| IE (1) | IE49469B1 (en) |
| IL (1) | IL58898A (en) |
| IT (1) | IT1164812B (en) |
| NL (1) | NL7908849A (en) |
| PH (1) | PH16910A (en) |
| PT (1) | PT70559A (en) |
| SE (1) | SE446181B (en) |
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| US4490374A (en) * | 1982-09-30 | 1984-12-25 | Ortho Pharmaceutical Corporation | 5,6-Dialkoxy-3,4-optionally substituted-2(1H)quinazolinones, composition and method of use |
| US4631283A (en) * | 1982-09-30 | 1986-12-23 | Ortho Pharmaceutical Corporation | Ortho substituted dihydroxy-2(1H)quinazolinone-1-alkanoic acids |
| US4751304A (en) * | 1984-09-26 | 1988-06-14 | Ortho Pharmaceutical Corporation | Process for preparing 5,6-dialkoxy-4-alkyl-2(1H)-quinazolinones |
| GB0015228D0 (en) * | 2000-06-21 | 2000-08-16 | Portela & Ca Sa | Substituted nitrated catechols, their use in the treatment of some central and peripheral nervous system disorders |
| USD966133S1 (en) * | 2020-09-21 | 2022-10-11 | Aileen Martin | Sanitizer dispenser |
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| DE2118315C3 (en) * | 1970-04-20 | 1975-04-03 | Sumitomo Chemical Co., Ltd., Osaka (Japan) | 2- (1H) -quinazolinone derivatives, processes for their preparation and pharmaceuticals containing these compounds |
| US4129653A (en) * | 1977-01-05 | 1978-12-12 | Ortho Pharmaceutical Corporation | Substituted pyrrolo [1,2-c] quinazolines and pharmaceutical compositions and methods employing them |
-
1979
- 1979-12-05 AU AU53470/79A patent/AU533427B2/en not_active Ceased
- 1979-12-06 CA CA000341352A patent/CA1138871A/en not_active Expired
- 1979-12-07 SE SE7910105A patent/SE446181B/en not_active IP Right Cessation
- 1979-12-07 DE DE19792949395 patent/DE2949395A1/en not_active Ceased
- 1979-12-07 IE IE2364/79A patent/IE49469B1/en unknown
- 1979-12-07 PH PH23380A patent/PH16910A/en unknown
- 1979-12-07 ES ES486696A patent/ES486696A0/en active Granted
- 1979-12-07 IT IT51025/79A patent/IT1164812B/en active
- 1979-12-07 FR FR7930116A patent/FR2443462A1/en active Granted
- 1979-12-07 PT PT70559A patent/PT70559A/en unknown
- 1979-12-07 IL IL58898A patent/IL58898A/en unknown
- 1979-12-07 CH CH1090079A patent/CH645106A5/en not_active IP Right Cessation
- 1979-12-07 AT AT0776379A patent/AT374468B/en not_active IP Right Cessation
- 1979-12-07 GB GB8138698A patent/GB2088874B/en not_active Expired
- 1979-12-07 NL NL7908849A patent/NL7908849A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| NL7908849A (en) | 1980-06-10 |
| FR2443462A1 (en) | 1980-07-04 |
| AT374468B (en) | 1984-04-25 |
| IE49469B1 (en) | 1985-10-16 |
| DE2949395A1 (en) | 1980-06-19 |
| ES8104253A1 (en) | 1981-04-16 |
| IE792364L (en) | 1980-06-07 |
| IT1164812B (en) | 1987-04-15 |
| GB2088874B (en) | 1983-09-28 |
| CH645106A5 (en) | 1984-09-14 |
| AU5347079A (en) | 1980-06-12 |
| IL58898A0 (en) | 1980-03-31 |
| SE7910105L (en) | 1980-06-08 |
| GB2088874A (en) | 1982-06-16 |
| FR2443462B1 (en) | 1983-09-23 |
| AU533427B2 (en) | 1983-11-24 |
| PH16910A (en) | 1984-04-10 |
| SE446181B (en) | 1986-08-18 |
| IT7951025A0 (en) | 1979-12-07 |
| ES486696A0 (en) | 1981-04-16 |
| PT70559A (en) | 1980-01-01 |
| ATA776379A (en) | 1983-09-15 |
| IL58898A (en) | 1984-03-30 |
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