GB2171997A - 4-Amino-6,7-dimethoxy-2-Piperazin-1-ylquinazoline derivatives - Google Patents
4-Amino-6,7-dimethoxy-2-Piperazin-1-ylquinazoline derivatives Download PDFInfo
- Publication number
- GB2171997A GB2171997A GB08605551A GB8605551A GB2171997A GB 2171997 A GB2171997 A GB 2171997A GB 08605551 A GB08605551 A GB 08605551A GB 8605551 A GB8605551 A GB 8605551A GB 2171997 A GB2171997 A GB 2171997A
- Authority
- GB
- United Kingdom
- Prior art keywords
- formula
- pharmaceutically acceptable
- compound
- amino
- piperazin
- 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.)
- Withdrawn
Links
- 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 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 31
- 150000003839 salts Chemical class 0.000 claims abstract description 17
- 206010020772 Hypertension Diseases 0.000 claims abstract description 8
- 206010007559 Cardiac failure congestive Diseases 0.000 claims abstract description 7
- 206010019280 Heart failures Diseases 0.000 claims abstract description 7
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 6
- 125000001424 substituent group Chemical group 0.000 claims abstract description 3
- 239000003814 drug Substances 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- CAWNIHKSMVDTKO-UHFFFAOYSA-N [4-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperazin-1-yl]-(6-hydroxy-2,3-dihydro-1,4-benzodioxin-3-yl)methanone Chemical compound C1OC2=CC=C(O)C=C2OC1C(=O)N(CC1)CCN1C1=NC(N)=C(C=C(C(OC)=C2)OC)C2=N1 CAWNIHKSMVDTKO-UHFFFAOYSA-N 0.000 claims 1
- 125000003545 alkoxy group Chemical group 0.000 claims 1
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 abstract description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 14
- -1 chloro, bromo, iodo Chemical group 0.000 description 9
- 238000000034 method Methods 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 229910001868 water Inorganic materials 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 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 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 230000003276 anti-hypertensive effect Effects 0.000 description 2
- GGNQRNBDZQJCCN-UHFFFAOYSA-N benzene-1,2,4-triol Chemical compound OC1=CC=C(O)C(O)=C1 GGNQRNBDZQJCCN-UHFFFAOYSA-N 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- MAFQCEQWWXBUAC-UHFFFAOYSA-N methyl 6-hydroxy-2,3-dihydro-1,4-benzodioxine-2-carboxylate Chemical compound OC1=CC=C2OC(C(=O)OC)COC2=C1 MAFQCEQWWXBUAC-UHFFFAOYSA-N 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 239000003643 water by type Substances 0.000 description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- FJNCXZZQNBKEJT-UHFFFAOYSA-N 8beta-hydroxymarrubiin Natural products O1C(=O)C2(C)CCCC3(C)C2C1CC(C)(O)C3(O)CCC=1C=COC=1 FJNCXZZQNBKEJT-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 239000004150 EU approved colour Substances 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M bisulphate group Chemical group S([O-])(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 210000000748 cardiovascular system Anatomy 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- QMEZUZOCLYUADC-UHFFFAOYSA-N hydrate;dihydrochloride Chemical compound O.Cl.Cl QMEZUZOCLYUADC-UHFFFAOYSA-N 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000001631 hypertensive effect Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- ROXQOUUAPQUMLN-UHFFFAOYSA-N methyl 2,3-dibromopropanoate Chemical compound COC(=O)C(Br)CBr ROXQOUUAPQUMLN-UHFFFAOYSA-N 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 229940006093 opthalmologic coloring agent diagnostic Drugs 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 238000000053 physical method Methods 0.000 description 1
- 150000004885 piperazines Chemical class 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 238000011699 spontaneously hypertensive rat Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A compound of the formula (I). <IMAGE> wherein X is -OH, -O.CO(C1-C4 alkyl), -O.CO.Ph or -O.COCH2Ph where Ph is a phenyl group optionally substituted by 1 or 2 substituents each independently selected from F, Cl, Br, I, CF3, C1-C4 alkyl and C1-C4 alkoxy; and their pharmaceutically acceptable salts. The compounds are useful in the treatment of hypertension and congestive heart failure.
Description
SPECIFICATION 4-Amino-6, 7-dimethoxy-2-piperazin-l-ylquinazoline derivatives
The invention relates to therapeutic agents which are derivatives of 4amino-6,7-dimethoxy-2-piperazin-1 -V1 quinazoline. Such compounds are useful as regulators of the cardiovascular system, and, in particular, in the treatment of hypertension and congestive heart failure.
The novel compounds according to the invention are those having the general formula:
where Xis -OH, -O.CO(C1-C4 alkyl), -O.CO.Ph or -O.COCH2Ph
where Ph is a phenyl group optionally substituted by 1 or 2 substituents each independently selected from
F,
CI, Br, I, CF3, C1-C4 alkyl and C1-C4 alkoxy; and their pharmaceutically acceptable salts.
Pharmaceutically acceptable acid addition salts of the compounds of the invention are those formed from acids which form non-toxic acid addition salts containing pharmaceutically acceptable anions, such as the hydrochloride, hydrobromide, sulphate or bisulphate, phosphate or acid phosphate, acetate, maleate, fumarate, succinate, lactate, tartrate, citrate, gluconate, mesylate and p-toluene sulphonate salts.
Additionally when Xis OH, the alkali and alkaline earth metal salts form a part of the invention.
The preferred group of compounds has the formula:
The most preferred compounds are 4-amino-6,7-dimethoxy-2-[4-(6-hydroxybenzo-1 ,4-dioxan-2-carbonyl)pi perazin-1 -yl]-qui nazoline and 4-am ino-6,7-dimethoxy-2-[4-7dimethoxy-2-[4-)7-hydroxybenzo-1 ,4-dioxan-2 carbonyl)-piperazi -yljquinazoline.
The compounds of the invention containing one or more asymmetric centres will exist as one or more pairs of enantiomers, and such pairs or individual isomers may be separable by physical methods, e.g. by fractional crystallisation of suitable salts. The invention includes the separated pairs as well as mixtures thereof, as racemic mixtures or as separated d-and I-optically-active isomericforms.
The hydroxy-substituted compounds of the formula (IA) may be prepared by methods analogous to those of the prior art by reacting a quinazoline of the formula:
wherein Q represents a leaving group such as chloro, bromo, iodo, or (C1 -C4 alkyl)thio, with a piperazine derivative of the formula:
with resultant elimination of HO. O is preferably chloro.
The reaction is typically carried out by heating the reactants, e.g. at a temperature of from 80 to 1 500C, e.g.
under reflux, in an inert organic solvent, e.g. n-butanol. When the reaction is substantially complete, the product may be isolated and purified by conventional. For example, in a typical procedure the reaction mixture is cooled, and the resulting solid product collected, washed with e.g. cold ethanol and then with ether and dried.
The intermediates of the formula (II) are either known compounds or may be prepared by methods analogous to those of the prior art. The intermediates of the formula (III) may be prepared conventionally according to the follow reaction procedure wherein Y is chloro or (preferably) methoxy:
The intermediates of the formula (IV) may be prepared by conventional procedures, for example according to the following reaction procedure:
wherein Y is a leaving group such as methoxy.
This method produces a mixture of isomers (i.e. the 6-and 7-hydroxy, or the 5-and 8-hydroxy derivatives of the formula IV) which can then be separated chromatographically (see Preparation 1).
The intermediates of the formula (V) are known compounds.
The hydroxy-containing compounds of the formula (I) can also be prepared as follows :
where Y is a suitable leaving group.
The reaction can be carried out at room temperature in a suitable solvent such as methyiene chloride. The compound of the formula (VI) is a known compound. It may be necessary to protect the -OH group in the compounds (IV) in the above reaction.
The compounds of the formula (I) in which Xis -O.CO(C1-C4alkyI), -O.COPh or -O,COCH2Ph can be prepared by the acylation of the corresponding compounds in which Xis -OH according to conventional techniques, e.g. using an appropriate acid chloride or anhydride.
The pharmaceutically acceptable acid addition salts ofthe compounds of the invention may be prepared by conventional procedures, e.g. by reacting the free base with the appropriate acid in an inert organic solvent, and collecting the resulting precipitate of the salt by filtration. If necessary, the product may then be recrystallised to purify it. Often, however, the product obtained by the routes outlined above will be in an acid-addition salt form. Additionally, when Xis OH, salts may also be formed by reaction with an alkali or alkaline earth metal hydroxide in a suitable solvent.
The antihypertensive activity of the compounds of the invention is shown by their ability to lower the blood pressure of conscious spontaneously hypertensive rats and conscious renally hypertensive dogs when administered orally.
The compounds of the invention can be administered alone, but will generally be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice. For example, they may be administered orally in the form of tablets containing such excipients as starch or lactose, or in capsules either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavouring or colouring agents. They may be injected parenterally, for example, intramuscularly, intravenously or subcutaneously. For parenteral administration, they are best used in the form of a sterile aqueous solution which may contain other solutes, for example, enough salt or glucose to make the solution isotonic.
The compounds of the invention can be administered to humans for the treatment of hypertension and congestive heart failure by either the oral or parenteral routes, and may be administered orally at dosage levels approximately within the range 1 to 20 mg/day for an average adult patient (70 kg), given in a single dose or up to 3 divided doses. Intravenous dosage levels would be expected to be about 1/5th to 1/10th of a single oral dose. Thus for an average adult patient, individual oral doses in tablet or capsule form will be approximately in the range from 1 to 20 mg of the active compound. Variations will necessarily occur depending on the weight and condition of the subject being treated and the particular route of administration chosen as will be known to those skilled in the art.
Thus the invention also provides a pharmaceutical composition comprising a compound of the formula (I) or pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable diluent or carrier.
The invention also provides a compound of the formula (I) or a pharmaceutically acceptable salt thereof, for use as a medicament, in particular for use in the treatment of hypertension or congestive heart failure.
The invention also provides for the use of a compound of the formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of hypertension and congestive heart failure.
The invention further provides a method of treating a human being having hypertension or congestive heart failure, which comprises administering to the human an antihypertensive amount of a compound of the formula (I) or pharmaceutically acceptable salt thereof or pharmaceutical composition as defined above.
The following Example illustrate the invention:
EXAMPLE 1
2-[4-(6-Hydroxybenzo-1 ,4-dioxan-2-carbonyl )-piperazin-i-yl]-4-amino-6,7-di methoxyquinazoline hydrochloride hemihydrate 1 -(6-Hydroxybenzo-1 ,4-dioxan-2-carbonyl)-piperazine (0.8 g; 0.003 moles) and 4-amino-2-chloro-6,7dimethoxyquinazoline (0.73 g, 0.003 moles) were dissolved in boiling butan-1-ol (250 ml.) and the solution was heated under reflux for 1.5 hours during which time a solid precipitated.
After cooling the reaction in ice, the precipitate was collected, washed with cold ethanol, then with ether and dried in vacuo over silica gel to yield the product as a crystalline hydrochloride hemihydrate (0.3 g), m.p.
329-330"C.
Analysis %:
Found: C,53.54; H,5.17; N,13.36; Calculated for C23H25N5O6.HCI.H2O: C,53.85; H,5.1 1; N,13.65
EXAMPLE2
2-[4-(7-Hydroxybenzo-1 ,4-dioxan-2-carbonyl)-piperazin-1 -yl]-4-amino-6,7-di methoxyquinazoline hydrochloride 1 -(7-Hydroxybenzo-1 ,4-dioxan-2-carbonyl)-piperazine (0.73 g, 0.0028 moles) and 4-amino-2-chloro-6,7dimethoxy-quinazoline (0.66 g; 0.0028 moles) were reacted together under the conditions described for
Example 1 to yield the title compound as a crystalline hydrochloride (0.5 g), m.p. 324-325"C.
Analysis%:- Found: C,54.47; H,5.33; N,13.94; Calculated for C23H25NO6.HCl: C,54.81; H,5.20; N,13.90.
The following Preparations illustrate the preparation of certain starting materials:
Preparation 1 6-Hydroxy-2-methoxyca rbonyl-benzo-1 4-dioxa n a n d and 7-hydroxy-2-methoxycarbonyl-benzo-1 ,4-dioxan A mixture of 1,2,4-trihydroxybenzene (3 g; 0.024 moles) and anhydrous potassium carbonate (3.5 g; 0.25 moles) in dry acetonitrile (80 ml) was stirred for 5 minutes at 50or, and then methyl 2,3-dibromopropanoate (5.85 g; 3.02 ml, 0.024 moles) was added. The reaction mixture was heated under reflux for 6 hours, then cooled and the solvent removed under reduced pressure. The residue was partitioned between dichloromethane and water. The phases were separated and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were washed with saturated brine, dried with sodium sulphate and the solvent removed under reduced pressure to yield a brown oil. This oil was purified by chromatography over silica gel (eluting with 50.90% CH2Cl2/hexane) to yield, after collection and evaporation of appropriate fractions, the product as a crystalline solid (4 g). The product was a mixture of 6-hydroxy-2-methoxycarbonyl-benzo-1 ,4-dioxan and 7-hydroxy-2-methoxycarbonyl-benzo-1 ,4-dioxan.
A small amount was then recrystallised from ethyl acetate, m.p.134-138 C.
Analysis %:
Found: C,57.02; H,4.80; CalculatedforC10H1005: C,57.14; H,4.79; The pure mixture was separated by multiple passes on a Waters Prep. 500 (Trade Mark) HPLC machine, using 2 Waters Prep-Pak (Trade Mark) C18 columns in series, eluting with 80:20 water: methanoi, flow rate 100 mls. min.- and detection by i.r. The structures of the isomers were assigned by spectroscopic correlation with related analogues of known structure:
6-Hydroxy compound N.m.r.8 (CDCI3) = 6.37 (1H,dd,J9,3Hz,7-ArH), 6.42 (1H,d,J 3Hz,5-Ar) 6.85 (1H,d,J 9Hz,8Ar-H).
7-Hydroxy compound N.m.r.8 (CDCI3) = 6.38 (1 H,dd,J 9,3Hz,6-ArH),6.51 H, H, d,J 3Hz,8-ArH), 6.37 (1 H,d,J 9Hz,5-ArH).
Preparation 2 1 -(6-Hydroxybenzo-1 ,4-dioxan-2-carbonyl )-piperazine 1/4 hydrate
A solution of 6-hydroxy-2-methoxycarbonyl-benzo-1,4-dioxan (1.0 g; 0.0048 moles) in 1,2dimethoxyethane (10 ml) was added dropwise to a slowly distilling solution of piperazine (1.23 g; 0.14 moles) in 1,2-dimethoxyethane, at such a rate that the volume of the reaction mixture remained constant.
After the addition was complete (45 min.) the distillation was continued until no further distillate appeared, and a thick brown oil remained. This residue was dissolved in a methanol/dichloromethane mixture (1:14), pre-adsorbed onto silica gel, and eluted with methanol/dichloromethane mixtures (3-15%) to yield, after collection and evaporation of appropriate fractions, the product as a crystalline quarter hydrate (0.88 g), m.p.
90-94"C.
Analysis %:
Found: C,58.15; H,6.14; N,10.86;
Calcuiated for C13H16N204.(H20)114 requires: C,58.09; H,6.29; N,10.42.
Preparation 3 1 -(7-Hydroxybenzo-1 ,4-dioxan-2-carbonyl )-piperazine 1/4 hydrate
7-Hydroxy-2-methoxycarbonyl-benzo-1,4-dioxan (1.04 g; 0.005 moles) and piperazine (1.28 g; 0.015 moles) were reacted together under the same conditions as described for Preparation 2 to yield the product as a crystalline quarter hydrate (0.77 g) m.p. 211-212"C.
Analysis %
Found: C,57.76; H,6.03; N,10.42; CalculatedforC13Hf6N204.(H2O)1l4: C,58.09; H,6.29; N,10.42.
Claims (7)
1. Acompound oftheformula (I):
wherein X is -OH, -O.CO(C1-C4 alkyl), -O.CO.Ph or -O.COCH2Ph where Ph is a phenyi group optionally substituted by 1 or 2 substituents each independently selected from F, C-, Br, I, CF3, C1-C4 alkyl and Ca-C4 alkoxy; or a pharmaceutically acceptable salt thereof.
2. A compound as claimed in claim 1 wherein Xis OH.
3. 4-Amino-6,7-dimethoxy-2-[4-(6-hydroxybenzo-1 ,4-dioxan-2-carbonyl)-piperazin-1 -yI]quinazoline.
4. 4-Amino-6,7-dimethoxy-2-[4-(7-hydroxybenzo-1 ,4-dioxan-2-carbonyl)-piperazin-1 -yl]quinazoline.
5. A pharmaceutical composition comprising a compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable sale thereof together with a pharmaceutically acceptable diluent or carrier.
6. A compound of the formula (I) as defined in any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, for use as a medicament.
7. Use of a compound of formula (I) as defined in any one of claims 1-4 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of hypertension and congestive heart failure.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB858506174A GB8506174D0 (en) | 1985-03-09 | 1985-03-09 | 4-amino-6 7-dimethoxy-2-piperazin-1-ylquinazoline derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB8605551D0 GB8605551D0 (en) | 1986-04-09 |
| GB2171997A true GB2171997A (en) | 1986-09-10 |
Family
ID=10575759
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB858506174A Pending GB8506174D0 (en) | 1985-03-09 | 1985-03-09 | 4-amino-6 7-dimethoxy-2-piperazin-1-ylquinazoline derivatives |
| GB08605551A Withdrawn GB2171997A (en) | 1985-03-09 | 1986-03-06 | 4-Amino-6,7-dimethoxy-2-Piperazin-1-ylquinazoline derivatives |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB858506174A Pending GB8506174D0 (en) | 1985-03-09 | 1985-03-09 | 4-amino-6 7-dimethoxy-2-piperazin-1-ylquinazoline derivatives |
Country Status (1)
| Country | Link |
|---|---|
| GB (2) | GB8506174D0 (en) |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0564093A1 (en) * | 1992-04-01 | 1993-10-06 | Pfizer Inc. | Hydroxylated metabolites and derivatives of doxazosin as anti-atherosclerosis agents |
| FR2724383A1 (en) * | 1994-09-13 | 1996-03-15 | Synthelabo | 2-Amino-pyrimidine-4-carboxamide derivs. are alpha 1 adrenergic receptor antagonists for urinary system |
| WO1997023462A1 (en) * | 1995-12-23 | 1997-07-03 | Pfizer Research And Development Company, N.V./S.A. | Quinoline and quinazoline compounds useful in therapy |
| WO1998030560A1 (en) * | 1997-01-11 | 1998-07-16 | Pfizer Limited | Quinoline and quinazoline compounds useful in therapy, particularly in the treatment of begnin prostatic hyperplasia |
| EP0875506A1 (en) * | 1997-05-01 | 1998-11-04 | Pfizer Limited | Quinoline and quinazoline compounds useful in therapy |
| EP0887344A1 (en) * | 1997-06-05 | 1998-12-30 | Pfizer Limited | Quinolines and quinazolines useful in therapy |
| US5919931A (en) * | 1996-04-03 | 1999-07-06 | Brantford Chemicals Inc. | Process for the manufacture of intermediates suitable to make doxazosin, terazosin, prazosin, tiodazosin and related antihypertensive medicines |
| US6608200B1 (en) * | 2002-10-07 | 2003-08-19 | Council Of Scientific & Industrial Research | Process for the preparation of N-(2,3-Dihydrobenzo[1,4]dioxin-2-carbonyl)piperazine |
-
1985
- 1985-03-09 GB GB858506174A patent/GB8506174D0/en active Pending
-
1986
- 1986-03-06 GB GB08605551A patent/GB2171997A/en not_active Withdrawn
Cited By (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0564093A1 (en) * | 1992-04-01 | 1993-10-06 | Pfizer Inc. | Hydroxylated metabolites and derivatives of doxazosin as anti-atherosclerosis agents |
| AU660359B2 (en) * | 1992-04-01 | 1995-06-22 | Pfizer Inc. | Hydroxylated metabolites and derivatives of doxazosin as anti-atherosclerosis agents |
| FR2724383A1 (en) * | 1994-09-13 | 1996-03-15 | Synthelabo | 2-Amino-pyrimidine-4-carboxamide derivs. are alpha 1 adrenergic receptor antagonists for urinary system |
| US6103738A (en) * | 1995-12-23 | 2000-08-15 | Pfizer Inc. | Quinoline and quinazoline compounds useful in therapy |
| WO1997023462A1 (en) * | 1995-12-23 | 1997-07-03 | Pfizer Research And Development Company, N.V./S.A. | Quinoline and quinazoline compounds useful in therapy |
| US6642242B2 (en) | 1995-12-23 | 2003-11-04 | Pfizer Inc. | Quinoline and quinazoline compounds useful in therapy |
| US6750214B2 (en) | 1995-12-23 | 2004-06-15 | Alan John Collis | Quinoline and quinazoline compounds useful in therapy |
| US5919931A (en) * | 1996-04-03 | 1999-07-06 | Brantford Chemicals Inc. | Process for the manufacture of intermediates suitable to make doxazosin, terazosin, prazosin, tiodazosin and related antihypertensive medicines |
| WO1998030560A1 (en) * | 1997-01-11 | 1998-07-16 | Pfizer Limited | Quinoline and quinazoline compounds useful in therapy, particularly in the treatment of begnin prostatic hyperplasia |
| AP819A (en) * | 1997-01-11 | 2000-04-03 | Pfizer | Quinoline and quinazoline compounds useful in therapy. |
| US6169093B1 (en) | 1997-01-11 | 2001-01-02 | Pfizer Inc. | Quinoline and quinazoline compounds useful in therapy, particularly in the treatment of benign prostatic hyperplasia |
| US6365599B1 (en) | 1997-01-11 | 2002-04-02 | Pfizer, Inc. | Quinoline and quinazoline compounds useful in therapy |
| EP0875506A1 (en) * | 1997-05-01 | 1998-11-04 | Pfizer Limited | Quinoline and quinazoline compounds useful in therapy |
| EP0887344A1 (en) * | 1997-06-05 | 1998-12-30 | Pfizer Limited | Quinolines and quinazolines useful in therapy |
| US6608200B1 (en) * | 2002-10-07 | 2003-08-19 | Council Of Scientific & Industrial Research | Process for the preparation of N-(2,3-Dihydrobenzo[1,4]dioxin-2-carbonyl)piperazine |
Also Published As
| Publication number | Publication date |
|---|---|
| GB8605551D0 (en) | 1986-04-09 |
| GB8506174D0 (en) | 1985-04-11 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP0100200B1 (en) | 2-substituted 4-amino-6,7-dimethoxyquinolines | |
| JPH05208957A (en) | New r-and s-carbazole derivatives | |
| US4408047A (en) | Imidazodiazines | |
| EP0104614B1 (en) | Phenylpiperazine derivatives and process for producing the same | |
| US4243666A (en) | 4-Amino-2-piperidino-quinazolines | |
| EP0816338B1 (en) | 3-(bis-substituted-phenylmethylene)oxindole derivatives | |
| US4134991A (en) | Derivatives of 2-(3-phenyl-2-aminopropionyloxy)-acetic acid | |
| JPS63290868A (en) | Diketopiperazine derivative and salts thereof | |
| GB2171997A (en) | 4-Amino-6,7-dimethoxy-2-Piperazin-1-ylquinazoline derivatives | |
| JPH0473432B2 (en) | ||
| PT91783B (en) | PROCESS FOR THE PREPARATION OF {(DIARYMETHYL) ALKYL} -1-PYRROLIDINS AND PIPERIDINES | |
| JPH0434549B2 (en) | ||
| JP2632877B2 (en) | Substituted 1H-imidazole compounds | |
| JPH05246980A (en) | β-oxo-β-benzenepropanethioamide derivative | |
| US4550111A (en) | Alkanolamine derivatives | |
| JPH03106875A (en) | 1-(3-pyridylmethyl)phthalazine derivative | |
| SK158692A3 (en) | 2-amino-5-cyano-1,4-dihydropyridines, method of their preparation and their use in medicines | |
| US4775673A (en) | Substituted acylpiperazinoquinazolines and pharmaceutical compositions containing same | |
| US4616023A (en) | Pharmaceutical compositions of 4-(dibenzo-[a,d]cycloalkenyl)piperazine compounds and methods | |
| US4929616A (en) | Novel basic-substituted 5-halo-thienoisothiazol-3(2H)-one 1,1-dioxides, a process for the preparation thereof, and pharmaceutical preparations containing these compounds | |
| KR100571945B1 (en) | 2- ｛3- [4- (2-ｔ-butyl-6-trifluoromethylpyrimidin-4-yl) piperazin-1-yl] propylmercaptopyrimidin-4-ol-fumarate | |
| SU900808A3 (en) | Process for preparing aminopropanol derivatives of 6-hydroxy-2,3,4,5-tetrahydro-1h-1-benzaszepine-2-one or their salts | |
| CA1088068A (en) | Piperidino-quinazolines | |
| SU895291A3 (en) | Method of preparing derivatives of 4-amino-2-piperidinoquinazoline or their salts with pharamacetically adopted acids | |
| HU199813B (en) | Process for producing new benzothiazinone derivatives and pharmaceutical compositions comprising such active ingredient |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| WAP | Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1) |