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
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- United Kingdom
- Prior art keywords
- formula
- pharmaceutically acceptable
- compound
- amino
- piperazin
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- 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
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 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| WAP | Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1) |