CS218022B1 - Derivatives of the 2-piperazino-4-amino-6, 7-dimethoxychinazoline and method of preparation thereof - Google Patents
Derivatives of the 2-piperazino-4-amino-6, 7-dimethoxychinazoline and method of preparation thereof Download PDFInfo
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- CS218022B1 CS218022B1 CS646181A CS646181A CS218022B1 CS 218022 B1 CS218022 B1 CS 218022B1 CS 646181 A CS646181 A CS 646181A CS 646181 A CS646181 A CS 646181A CS 218022 B1 CS218022 B1 CS 218022B1
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- dimethoxyquinazoline
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- 238000000034 method Methods 0.000 title claims description 8
- 238000002360 preparation method Methods 0.000 title claims description 5
- 150000003839 salts Chemical class 0.000 claims abstract description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 5
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims abstract description 4
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims abstract description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 11
- PHTQWCKDNZKARW-UHFFFAOYSA-N isoamylol Chemical compound CC(C)CCO PHTQWCKDNZKARW-UHFFFAOYSA-N 0.000 claims description 8
- 239000011541 reaction mixture Substances 0.000 claims description 8
- APKHJGDGWQDBGM-UHFFFAOYSA-N 6,7-dimethoxy-2-piperazin-1-ylquinazolin-4-amine Chemical class N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N1CCNCC1 APKHJGDGWQDBGM-UHFFFAOYSA-N 0.000 claims description 6
- 238000009835 boiling Methods 0.000 claims description 5
- 150000001875 compounds Chemical class 0.000 claims description 5
- HWIIAAVGRHKSOJ-UHFFFAOYSA-N 2-chloro-6,7-dimethoxyquinazolin-4-amine Chemical compound ClC1=NC(N)=C2C=C(OC)C(OC)=CC2=N1 HWIIAAVGRHKSOJ-UHFFFAOYSA-N 0.000 claims description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- 150000007522 mineralic acids Chemical class 0.000 claims description 4
- 150000007524 organic acids Chemical class 0.000 claims description 4
- 235000005985 organic acids Nutrition 0.000 claims description 4
- 150000004885 piperazines Chemical class 0.000 claims description 4
- XTHPWXDJESJLNJ-UHFFFAOYSA-N sulfurochloridic acid Chemical compound OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 claims description 3
- 238000006386 neutralization reaction Methods 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims 1
- GLUUGHFHXGJENI-UHFFFAOYSA-N diethylenediamine Natural products C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims 1
- 230000003276 anti-hypertensive effect Effects 0.000 abstract description 3
- 230000000694 effects Effects 0.000 abstract 1
- 231100000053 low toxicity Toxicity 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000003756 stirring Methods 0.000 description 5
- -1 1- (4-Amino-6,7-dimethoxyquinazolin-2-yl) -4-benzenesulfonylpiperazine Chemical compound 0.000 description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 241000700159 Rattus Species 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- KXYLGVYCBLMFQO-UHFFFAOYSA-N 6,7-dimethoxy-2-(4-methylsulfonylpiperazin-1-yl)quinazolin-4-amine Chemical compound N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N1CCN(S(C)(=O)=O)CC1 KXYLGVYCBLMFQO-UHFFFAOYSA-N 0.000 description 2
- GXPSJGHGAVNKAB-UHFFFAOYSA-N 6,7-dimethoxy-2-[4-(4-methylphenyl)sulfonylpiperazin-1-yl]quinazolin-4-amine Chemical compound N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(CC1)CCN1S(=O)(=O)C1=CC=C(C)C=C1 GXPSJGHGAVNKAB-UHFFFAOYSA-N 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 2
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 229940066771 systemic antihistamines piperazine derivative Drugs 0.000 description 2
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 1
- NANQJUFFKXWVJR-UHFFFAOYSA-N 1-(benzenesulfonyl)piperazine Chemical compound C=1C=CC=CC=1S(=O)(=O)N1CCNCC1 NANQJUFFKXWVJR-UHFFFAOYSA-N 0.000 description 1
- ZZAKLGGGMWORRT-UHFFFAOYSA-N 1-methylsulfonylpiperazine Chemical compound CS(=O)(=O)N1CCNCC1 ZZAKLGGGMWORRT-UHFFFAOYSA-N 0.000 description 1
- MQIDTAUUQRHSDO-UHFFFAOYSA-N 2-[4-(4-chlorophenyl)sulfonylpiperazin-1-yl]-6,7-dimethoxyquinazolin-4-amine Chemical compound N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(CC1)CCN1S(=O)(=O)C1=CC=C(Cl)C=C1 MQIDTAUUQRHSDO-UHFFFAOYSA-N 0.000 description 1
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- VPGRYOFKCNULNK-ACXQXYJUSA-N Deoxycorticosterone acetate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)COC(=O)C)[C@@]1(C)CC2 VPGRYOFKCNULNK-ACXQXYJUSA-N 0.000 description 1
- 206010070863 Toxicity to various agents Diseases 0.000 description 1
- 102000004305 alpha Adrenergic Receptors Human genes 0.000 description 1
- 108090000861 alpha Adrenergic Receptors Proteins 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 239000002026 chloroform extract Substances 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- DZGCGKFAPXFTNM-UHFFFAOYSA-N ethanol;hydron;chloride Chemical compound Cl.CCO DZGCGKFAPXFTNM-UHFFFAOYSA-N 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 238000013059 nephrectomy Methods 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000925 very toxic Toxicity 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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Abstract
Vynález se týká derivátů 2-piperazino-4- -amino-6,7-dimethoxychinazolinu obecného vzorce I ve kterém R značí fenyl, p-tolyl, p-chlorfenyl nebo methyl a jejich adičních solí. Nové deriváty mají význačný antihypertenzní účinek a velmi nízkou toxicitu. Vynález rovněž chrání dva způsoby přípravy derivátů obecného vzorce I.This invention relates to 2-piperazino-4-derivatives. -amino-6,7-dimethoxyquinazoline of Formula I wherein R is phenyl, p-tolyl, p-chlorophenyl or methyl and addition salts thereof. New derivatives have significant antihypertensive properties effect and very low toxicity. The invention also it protects two ways of preparing derivatives of formula I.
Description
Vynález se týká derivátů 2-piperazino-4-aminoT6;7-diinethoxychlnazolinu obecného vzorce IThe present invention relates to 2-piperazino-4-amino-6,7-diinethoxyquinazoline derivatives of the general formula I
NM,NM,
CHjO ch3oCH 3 CH 3 o
II) ve kterém R značí fenyl, p-tolyl, p-chlorfenyl nebo methyl, jejich farmakologicky nezávadných solí s anorganickými nebo organickými kyselinami a způsobů jejich přípravy.(II) wherein R represents phenyl, p-tolyl, p-chlorophenyl or methyl, their pharmacologically acceptable salts with inorganic or organic acids, and processes for their preparation.
Látky obecného vzorce I vykazují při farmakologických testech pozoruhodnou antihypertenzní aktivitu, založenou pravděpodobně na blokádě α-adrenergních receptorů, a jsou tedy použitelné při léčení některých forem hypertenzní choroby. Antihypertenzní účinnost byla prokázána na krysách s experimentální hypertenzí vyvolanou podkožní implantací DOCA pelety po jednostranné nefrektomii a na opicích. Výhodné látky podle vynálezu jsou benzensulfonylderivát obecného vzorce I, v němž R značí fenyl a methansulfonylderivát obecného vzorce I, v němž R značí methyl. Benzensulfonylderivát vyvolává v dávce 5 mg/ /kg p. o. u krys již po 1 h po podání pokles tlaku krve o 10 %, který se prohlubuje mezi 3. až 4. h na 25 %.The compounds of formula I exhibit remarkable antihypertensive activity in pharmacological tests, probably based on α-adrenergic receptor blockade, and are therefore useful in the treatment of certain forms of hypertensive disease. Antihypertensive efficacy has been demonstrated in rats with experimental hypertension induced by subcutaneous DOCA pellet implantation after unilateral nephrectomy and in monkeys. Preferred compounds of the present invention are the benzenesulfonyl derivative of formula I wherein R is phenyl and the methanesulfonyl derivative of formula I wherein R is methyl. The benzenesulfonyl derivative at a dose of 5 mg / kg p.o. in rats already after 1 h after administration, a blood pressure drop of 10%, which deepens between 3 and 4 h to 25%.
Po 24 h lze ještě zaznamenat tlak asi o 10 % nižší než výchozí. V dávce 3 mg/kg p. o. byly uvedené poklesy tlaku poněkud nižší. Tato látka je velice málo toxická. Perorální aplikace dávky 2 g/kg myším nevyvolává žádné toxické příznaky. Methansulfonylderivát je poněkud toxičtější, jeho LD 50 na myších je asi 1800 mg/kg p. o. Jeho· perorální aplikace krysám v dávce 5 mg/kg a 3 mg/kg však vede k hlubším poklesům tlaku, až o 40 %.After 24 hours, the pressure can still be about 10% lower than the initial pressure. At a dose of 3 mg / kg p.o., these pressure drops were somewhat lower. This substance is very toxic. Oral administration of 2 g / kg to mice does not produce any toxic symptoms. The methanesulfonyl derivative is somewhat more toxic, its LD 50 in mice being about 1800 mg / kg p.o. Its oral administration to rats at doses of 5 mg / kg and 3 mg / kg, however, results in deeper pressure drops of up to 40%.
Deriváty obecného vzorce I lze podle vynálezu připravit dvěma způsoby. Podle prvního způsobu se nechá reagovat 2-chlor-4-amino-6,7-dimethoxychinazolin (USA pat. spis č. 3 511 836) s derivátem piperazinu obecného vzorce IIThe derivatives of the formula I according to the invention can be prepared in two ways. According to a first method, 2-chloro-4-amino-6,7-dimethoxyquinazoline (U.S. Pat. No. 3,511,836) is reacted with a piperazine derivative of the formula II
HN^N-SO^R (//) v němž R značí totéž jako ve vzorci I. Reakce se provádí v butanolu nebo isoamylalkoholu při teplotě varu reakční směsi po dobu 4 až 6 h. Ochlazením reakční směsi vykrystaluje hydrochlorid produktu vzorce I, který se buď překrystaluje z vodného methanolu nebo vodného ethanolu, nebo se může převést alkalizací vodné suspenze, například vodným amoniakem na bázi, která se izoluje vytřepáním do vhodného, s vodou nemísitelného rozpouštědla, například chloroformu a odpařením rozpouštědla. Získaná surová báze se dá překrystalovat z methanolu, ethanolu nebo vodného ethanolu. Neutralizací farmakologicky nezávadnými anorganickými nebo· organickými kyselinami v bezvodém nebo vodném alifatickém alkoholu, např. vodném ethanolu, se mohou získat adiční soli. Deriváty piperazinu vzorce Π jsou látky známé [R = fenyl: USA pat. spis č. 2 507 408; R = p-tolyl: F. S. Moore se sp., J. Chem. Soc. 1929, 39; R = -p-chlorfenyl: A. Lespagnol a sp., Chim. Ther, 2, 125 (1967); R = methyl: Britský pat. spis č. 674 325).The reaction is carried out in butanol or isoamyl alcohol at the boiling point of the reaction mixture for 4 to 6 h. By cooling the reaction mixture, the hydrochloride of the product of formula I crystallizes, which It can either be recrystallized from aqueous methanol or aqueous ethanol, or it can be converted by alkalinizing an aqueous suspension, for example aqueous ammonia, on a base which is isolated by shaking it into a suitable water-immiscible solvent, for example chloroform and evaporating the solvent. The crude base obtained can be recrystallized from methanol, ethanol or aqueous ethanol. Addition salts can be obtained by neutralization of pharmacologically acceptable inorganic or organic acids in anhydrous or aqueous aliphatic alcohol, e.g. aqueous ethanol. Piperazine derivatives of formula Π are known [R = phenyl: US Pat. No. 2,507,408; R = p-tolyl: F.S. Moore et al., J. Chem. Soc. 1929, 39; R = -p-chlorophenyl: A. Lespagnol et al., Chim. Ther., 2, 125 (1967); R = methyl: British Pat. No. 674,325).
Druhý způsob přípravy derivátů piperazinu obecného vzorce I spočívá v reakci 2-piperazino-4-amino-6,7-dimethoxychinazolinu [T. H. Althuis a H. J. Mess, ). Med. Chem. 20, 148 (1977)] se sulfochloridem obecného vzorce IIIA second method for preparing piperazine derivatives of formula (I) is by reacting 2-piperazino-4-amino-6,7-dimethoxyquinazoline [T. H. Althuis and H. J. Mess. Copper. Chem. 20, 148 (1977)] with a sulfochloride of formula III
R.SCLCl , it-?· (III), v němž R značí totéž jako ve vzorci I. Reakce se provádí tak, že se k roztoku 2-piperazino-4-amino-6,7-dimethoxychinazolinu ve vhodném organickém rozpouštědle, např. chloroformu, přikape za míchání roztok sulfochloridu v témže rozpouštědle a reakce se dokončí zahřátím rekční směsi k varu. Reakční směs se álkalizuje např. rozmícháním s vodným amoniakem. Surová báze I se získá odpařením rozpouštědla z odděleného roztoku a převádí se na adiční soli dříve zmíněným postupem.(III), wherein R is the same as in Formula I. The reaction is carried out by reacting to a solution of 2-piperazino-4-amino-6,7-dimethoxyquinazoline in a suitable organic solvent, e.g. of chloroform, a solution of the sulfochloride in the same solvent is added dropwise with stirring, and the reaction is completed by heating the reaction mixture to boiling. The reaction mixture is basified, for example, by stirring with aqueous ammonia. The crude base I is obtained by evaporation of the solvent from the separated solution and converted into the addition salts by the aforementioned procedure.
Podrobnosti způsobů přípravy sloučenin vzorce I podle vynálezu jšou uvedeny v následujících příkladech provedení, které jsou ovšem jen ilustrací možností vynálezu, aniž by bylo jejich účelem tyto možnosti vyčerpávajícím způsobem popisovat.The details of the processes for the preparation of the compounds of the formula I according to the invention are given in the following examples, which, however, are merely illustrative of the possibilities of the invention, without being intended to fully describe them.
Příklad 1 l-(4-Amino-6,7-dimethoxychinazolin-2-ylj-4-benzensulfonylpiperazinExample 1 1- (4-Amino-6,7-dimethoxyquinazolin-2-yl) -4-benzenesulfonylpiperazine
Směs 4,8 g 2-chlor-4-amino-6,7-dimethoxychinazolinu a 4,6 g 1-benzensulfonylpiperazinu ve 100 ml isoamylalkoholu se zahřívá 4 h k varu. Ochlazením se vyloučí hydrochlorid produktu, který se dsaje. Po vysušení se získá 7,3 g (78,4 % teorie) hydrochloridu l-(4-amino-6,7-dimethoxychinazolin-2-yl j-4-benzensulf onylpiperazinu, který po překrystalování z vodného ethanolu máA mixture of 4.8 g of 2-chloro-4-amino-6,7-dimethoxyquinazoline and 4.6 g of 1-benzenesulfonylpiperazine in 100 ml of isoamyl alcohol is heated at reflux for 4 hours. On cooling, the hydrochloride of the product precipitates. After drying, 7.3 g (78.4% of theory) of 1- (4-amino-6,7-dimethoxyquinazolin-2-yl) -4-benzenesulfonylpiperazine hydrochloride, which after recrystallization from aqueous ethanol, is obtained
t. t. 243 až 247 °C. Krystaluje ve formě hydrátu.mp 243-247 ° C. Crystallizes as a hydrate.
Analogickým postupem se připraví:In an analogous manner, prepare:
1- (4-amino-6,7-dimethoxychinazolin-2-yl) 2180221- (4-Amino-6,7-dimethoxyquinazolin-2-yl) 218022
-4-(4-chlorbenzensulfonyl)piperazin, jehož hydrochlorid krystalující z 80°/o' vodného ethanolu ve formě hydrátu má t. t. 255 až 260 °C a l-(4-amino-6,7-dimethoxychinazolin-2-yl)-4-(p-toluensulfonyl)piperazin, jehož hydrochlorid krystalující z 90% vodného ethanolu ve formě hydrátu má t. t. 232 až 236 °C.-4- (4-chlorobenzenesulfonyl) piperazine, the hydrochloride of which crystallizes from 80% aqueous ethanol as a hydrate, mp 255-260 ° C, and 1- (4-amino-6,7-dimethoxyquinazolin-2-yl) - 4- (p-toluenesulfonyl) piperazine, the hydrochloride of which crystallizes from 90% aqueous ethanol as a hydrate, mp 232-236 ° C.
Příklad 2Example 2
1-(4-Amino-6,7-dimethoxychinazolin-2-yl)-4-methansulfonylpiperazin1- (4-Amino-6,7-dimethoxyquinazolin-2-yl) -4-methanesulfonylpiperazine
Směs 7,2 g 2-chlor-4-amino-6,7-dimethoxychinazolinu a 4,9 g 1-methansulfonylpiperazinu ve 100 ml isoamylalkoholu se zahřívá za míchání 6 h k varu. Ochlazením na teplotu místnosti a několikahodinovým stáním se z reakční směsi vyloučí hydrochlorid produktu, který se suspenduje ve 100 ml vody a alkalizací vodným amoniakem se uvolní báze, která se vytřepe do chloroformu.A mixture of 7.2 g of 2-chloro-4-amino-6,7-dimethoxyquinazoline and 4.9 g of 1-methanesulfonylpiperazine in 100 ml of isoamyl alcohol is heated to boiling under stirring for 6 hours. By cooling to room temperature and standing for several hours, the hydrochloride of the product precipitates from the reaction mixture, which is suspended in 100 ml of water and basified with aqueous ammonia to liberate the base, which is taken up in chloroform.
Chloroformový extrakt se vysuší bezvodým uhličitanem draselným a chloroform se oddestiluje za sníženého tlaku. Získá se 6,7 gramu (60,7 %' teorie] báze s t. t. 243 až 246 °C. Analyticky čistá látka překrystalovaná ž 50% vodného ethanolu má t. t. 245 až 246 °C. Hydrochlorid připravený okyselením roztoku báze v 50% ethanolu kyselinou chlorovodíkovou krystaluje z vodného ethanolu ve formě hemihydrátu a má t. t. 254 až 260 °C (za rozkladu).The chloroform extract was dried over anhydrous potassium carbonate and the chloroform was distilled off under reduced pressure. 6.7 g (60.7% of theory) of the base are obtained having a melting point of 243-246 [deg.] C. An analytically pure substance recrystallized in 50% aqueous ethanol has a melting point of 245-246 [deg.] C. Hydrochloride prepared by acidifying a base solution in 50% ethanol hydrochloride crystallized from aqueous ethanol as a hemihydrate and had mp 254-260 ° C (dec.).
Příklad 3Example 3
1- (4-Amino-6,7-dimethoxychinazolin-2-yI) -4-p-toluensulfonylpiperazin ' K roztoku 2,5 g 2-piperazino-4-amino-6,7-dimethoxychinazolinu v 80 ml chloroformu se přikape za míchání roztok 1,9 g p-toluensulfochloridu v 10 ml chloroformu a směs se za míchání zahřívá 2 h k varu. Po ochlazení na teplotu místnosti se reakční směs rozmíchá s vodným amoniakem a chloroformový roztok se oddělí, vysuší bezvodým uhličitanem draselným a chloroform se oddestiluje za sníženého tlaku. V prakticky kvantitativním výtěžku se získá surová báze produktu, která po překrystalování z 80% vodného ethanolu má t. t. 245 až 247 stupňů Celsia. Okyselením roztoku báze v 80% vodném ethanolu kyselinou chlorovodíkovou se získá hydrochlorid, který krystaluje ve formě hydrátu a má t. t. 232 až 236 °C.1- (4-Amino-6,7-dimethoxyquinazolin-2-yl) -4-p-toluenesulfonylpiperazine To a solution of 2.5 g of 2-piperazino-4-amino-6,7-dimethoxyquinazoline in 80 ml of chloroform is added dropwise with stirring a solution of 1.9 g of p-toluenesulfochloride in 10 ml of chloroform and the mixture is heated to boiling under stirring for 2 h. After cooling to room temperature, the reaction mixture was stirred with aqueous ammonia and the chloroform solution was separated, dried over anhydrous potassium carbonate, and the chloroform was distilled off under reduced pressure. In practically quantitative yield, a crude product base is obtained which, after recrystallization from 80% aqueous ethanol, has a melting point of 245 to 247 degrees Celsius. Acidification of the solution of the base in 80% aqueous ethanol with hydrochloric acid gives the hydrochloride, which crystallizes as a hydrate, m.p. 232-236 ° C.
Analogickým způsobem se připraví:In an analogous manner, prepare:
1- (4-amino-6,7-dimethoxychinazolin-2-yl )-4-benzensulfonylpiperazin, t. t. hydrochloridu hydrátu 243 až 247 °C,1- (4-amino-6,7-dimethoxyquinazolin-2-yl) -4-benzenesulfonylpiperazine, m.p.
1- (4-amino-6,7-dimethoxychinazolin-2-yl) -4-(4-chlorbenzensulfonyl jpiperazin, t. t. hydrochloridu hydrátu 255 až 260 °C a1- (4-Amino-6,7-dimethoxyquinazolin-2-yl) -4- (4-chlorobenzenesulfonyl) piperazine, m.p. 255-260 ° C; and
1- (4-amino-6,7-dimethoxychinazolin-2-yl) -4-methansulfonylpiperazin, t. t. báze 243 až 246 °C.1- (4-amino-6,7-dimethoxyquinazolin-2-yl) -4-methanesulfonylpiperazine, mp 243-246 ° C.
Claims (3)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS646181A CS218022B1 (en) | 1981-09-01 | 1981-09-01 | Derivatives of the 2-piperazino-4-amino-6, 7-dimethoxychinazoline and method of preparation thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS646181A CS218022B1 (en) | 1981-09-01 | 1981-09-01 | Derivatives of the 2-piperazino-4-amino-6, 7-dimethoxychinazoline and method of preparation thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CS218022B1 true CS218022B1 (en) | 1983-02-25 |
Family
ID=5411699
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS646181A CS218022B1 (en) | 1981-09-01 | 1981-09-01 | Derivatives of the 2-piperazino-4-amino-6, 7-dimethoxychinazoline and method of preparation thereof |
Country Status (1)
| Country | Link |
|---|---|
| CS (1) | CS218022B1 (en) |
-
1981
- 1981-09-01 CS CS646181A patent/CS218022B1/en unknown
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