EP0157843A1 - Antihochdruck pyrrolyl-chromanen - Google Patents

Antihochdruck pyrrolyl-chromanen

Info

Publication number
EP0157843A1
EP0157843A1 EP19840903644 EP84903644A EP0157843A1 EP 0157843 A1 EP0157843 A1 EP 0157843A1 EP 19840903644 EP19840903644 EP 19840903644 EP 84903644 A EP84903644 A EP 84903644A EP 0157843 A1 EP0157843 A1 EP 0157843A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
formula
compound
cyano
hydrogen
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Withdrawn
Application number
EP19840903644
Other languages
English (en)
French (fr)
Inventor
Valerie Anne Ashwood
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Beecham Group PLC
Original Assignee
Beecham Group PLC
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Beecham Group PLC filed Critical Beecham Group PLC
Publication of EP0157843A1 publication Critical patent/EP0157843A1/de
Withdrawn legal-status Critical Current

Links

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
    • C07D405/04—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 directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to novel compounds having pharmacological activity, to a process for preparing them, to pharmaceutical compositions containing them, and to their use in the treatment of mammals.
  • U.S. Patent 4 110 347, U.S. Patent 4 251 532, U.S. Patent 4366163, European Patent Publication 9912, European Patent Publication 28064 and European Patent Publication 76075 describe classes of chromans that have blood pressure lowering activity.
  • a class of chroman derivatives has now been discovered having a 4-pyrryl substituent.
  • such derivatives have been found to have blood pressure lowering activity.
  • either one of R 1 and R 2 is hydrogen and the other is selected from the class of C 1-6 alkylcarbonyl, C 1 _ 6 alkoxycarbonyl, C 1 _ 6 alkylcarbonyloxy, C 1- 6 alkylhydroxymethyl, nitro, cyano, chloro, trifluoromethyl, C 1-6 alkylsulphinyl, C 1-6 alkylsulphonyl, C 1-6 alkoxysul ⁇ hinyl,C 1-6 C 1-6 alkoxysulphonyl, C 1-6 alkylcarbonylamino, C 1-6 alkoxycarbonylamino, C 1-6 alkyl-thiocarbonyl, C 1-6 alkoxy-thiocarbbnyl, C 1-6 alkyl-thiocarbonyloxy, C 1-6 alkyl-thiolmethyl, formyl or aminosulphinyl, aminosulphonyl or aminocarbonyl, the amino moiety being optionally substituted by one or two C 1-6 alkyl groups or
  • R 3 and R 4 is hydrogen or C 1-4 alkyl and the other is C 1-4 alkyl or R 3 and R 4 together are C 2-5 polymethylene;
  • R 5 is hydroxy, C 1-6 alkoxy or C 1-7 acyloxy and
  • R 6 is hydrogen or R 5 and R 6 together are a bond
  • R 7 is hydrogen, halogen, CF 3 , C 1-6 alkyl or C 1-6 alkoxy;
  • the pyrryl group being trans to the R 5 group when R 5 and R 6 together are not a bond; or, when one or the other of R 1 and R 2 is an amino or an amino-containing group, a pharmaceutically acceptable salt thereof.
  • R 1 and R 2 is hydrogen
  • the other is preferably selected from the class of C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonyloxy, C 1-6 alkylhydroxymethyl, nitro or cyano.
  • the other is preferably nitro, cyano or C 1-3 alkylcarbonyl, such as acetyl.
  • R 1 and R 2 When one of R 1 and R 2 is hydrogen, it is preferred that R 2 is hydrogen.
  • R 1 and R 2 When one of R 1 and R 2 is nitro, cyano or C 1-3 alkylcarbonyl the other is preferably amino optionally substituted by one or two C 1-6 alkyl or by C 2-7 alkanoyl. In particular, when one of R 1 and R 2 is nitro, cyano or C 1- 3 alkylcarbonyl, the other is amino, methylamino, dimethylamino or acetylamino. Most preferably, one of R 1 and R 2 is nitro or cyano, especially cyano, and the other is amino.
  • R 1 and R 2 are nitro, cyano or C 1-3 alkylcarbonyl, it is preferred that R 1 is nitro, cyano or C 1-3 alkylcarbonyl.
  • alkyl groups or alkyl moieties of alkyl-containing groups for R 1 or R 2 are, preferably, methyl or ethyl.
  • R 3 and R 4 are both C 1-4 alkyl. In particular, they are both methyl or ethyl, preferably both methyl.
  • R 5 is C 1-6 alkoxy and R 6 is hydrogen
  • preferred examples of R 5 include methoxy and ethoxy, of which methoxy is more preferred.
  • R 5 is C 1-7 acyloxy and R 6 is hydrogen
  • a preferred class of R 5 is unsubstituted carboxylic acyloxy, such as unsubstituted aliphatic acyloxy or bensoyloxy.
  • R 5 and R 6 together are a bond, or, more preferably, that R 5 is hydroxy and R 6 is hydrogen.
  • R 7 Suitable values for R 7 include chloro, bromo, CF 3 , methyl, ethyl, n- and iso-propyl, methoxy, ethoxy, n- and iso-propoxy.
  • R 7 is hydrogen.
  • R 1 1 and R 2 1 are hydrogen and the other is cyano or nitro
  • R 5 1 is R 5 when other than together with R 6 forms a bond and the remaining variables are as defined in formula (I).
  • R 1 2 and R 2 2 are cyano or nitro and the other is amino optionally substituted as defined and the remaining variables are as defined in formula (I).
  • R 1 2 is cyano or nitro and R 2 2 is amino. Suitable and preferred values for the remaining variables are as described under formula (I).
  • the compounds of the formula (I) are disymmetric and, therefore, can exist as stereoisomers.
  • the present invention extends to all such stereoisomers individually and as mixtures, such as racemic modifications.
  • the present invention also provides a process for the preparation of a compound of formula (I), which process comprises the reaction of a compound of formula (VI):
  • the reaction is preferably carried out in an inert solvent such as dimethylsulphoxide in the presence of a base, such as sodium hydride.
  • a base such as sodium hydride.
  • Conversions of an aromatic group or atom into one of the class of substituents as defined hereinbefore are generally known.
  • protecting agents include acyl groups, such as acetyl. Removal of the acyl protecting agent is carried out by base hydrolysis.
  • a more suitable method is to use a trifluoroacetyl protecting group which may be removed by mild hydrolysis.
  • a further suitable method of deprotection of a protected amino group in the presence of a cyano group is to utilise a benzyloxycarbonyl or p-nitrobenzyloxycarbonyl protecting group which groups may be removed by mild catalytic hydrogenolysis. Benzyloxycarbonyl amino and p-nitrobenzyloxycarbonylamino groups may be formed by reaction of the appropriate chloride with the free amine function.
  • a hydrogen atom may be replaced by a nitro group by nitrating in a known manner a compound,wherein one of R 1 ' and R 2 ' is hydrogen and the other is acetamido, followed by hydrolysing the compound, converting the resulting amine into a diazonium salt, and finally decomposing it, leaving a compound of formula (I), wherein one of R 1 and R 2 is hydrogen and the other is nitro.
  • any of these conversions are carried out at an earlier stage as mentioned hereafter.
  • the replacement of a hydrogen atom by a nitro group is carried out on the chromene before Stage (c) or (d) in the Scheme hereinafter.
  • R 5 in a compound of formula (I) into another R 5 examples are generally known in the art.
  • R5 when R5 is hydroxy, it may be alkylated using an alkyl ioide in an inert solvent, such as toluene, in the presence of a base, such as potassium hydroxide, or it may be acylated using a carboxylic acid chloride or anhydride in a non-hydroxylic solvent in the presence of a condensation promoting agent, such as dicy ⁇ lohexylcarbodiimide.
  • R 5 when R 5 is C 1-7 acyloxy or C 1-6 alkoxy it may be converted into hydroxy by conventional hydrolysis with for example, dilute mineral acid.
  • R 1 ', R 2 ', R 3 and R 4 are as hereinbefore defined a base, such as potassium hydroxide, in a solvent, such as ether or aqueous dioxan.
  • reaction (b) may produce mixtures of compounds during reaction (b) owing to the two sites available for ring formation. It is therefore advisable to remove any of the undesired compound by, for example, chromatography, before reaction (c) or (d).
  • the compounds of formula (I) exist in optically active forms, and the processes of the present invention produce mixtures of such forms.
  • the individual isomers may be separated one from the other by, for example, chromatography using a chiral phase.
  • the compounds of formula (I) have been found to have blood-pressure lowering activity. They are therefore useful in the treatment of hypertension.
  • the present invention accordingly provides a pharmaceutical composition which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • the present invention provides an anti-hypertensive pharmaceutical composition which comprises an anti-hypertensive effective amount of a compound of this invention and a pharmaceutically acceptable carrier.
  • compositions are preferably adapted for oral administration. However, they may be adapted for other administration for patients suffering from heart failure.
  • a composition of the invention is in the form of a unit-dose.
  • Suitable unit dose forms include tablets, capsules and powders in sachets or vials.
  • Such unit dose forms may contain from 1 to 100 mg of a compound of the invention and more usually from 2 to 50 mg, for example 5 to 25 mg such as 6, 10, 15 or 20 mg.
  • Such compositions may be administered from 1 to 6 times a day, more usually from 2 to 4 times a day, in a manner such that the daily dose is from 5 to 200 mg for a 70 kg human adult and more particularly from 10 to 100 mg.
  • compositions of the invention may be formulated with conventional excipients, such as a filler, a disintegrating agent, a binder, a lubricant, a flavouring agent and the like. They are formulated in conventional manner, for example in a manner similar to that used for known anti-hypertensive agents, diuretics and ⁇ -blocking agents.
  • the present invention further provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of hypertension.
  • the present invention yet further provides a method of treating hypertension in mammals including man, which comprises administering to the suffering mammal an anti-hypertensive effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the invention.
  • W+W BP recorder model 8005

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP19840903644 1983-09-14 1984-09-13 Antihochdruck pyrrolyl-chromanen Withdrawn EP0157843A1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB8324547 1983-09-14
GB838324547A GB8324547D0 (en) 1983-09-14 1983-09-14 Compounds

Publications (1)

Publication Number Publication Date
EP0157843A1 true EP0157843A1 (de) 1985-10-16

Family

ID=10548742

Family Applications (1)

Application Number Title Priority Date Filing Date
EP19840903644 Withdrawn EP0157843A1 (de) 1983-09-14 1984-09-13 Antihochdruck pyrrolyl-chromanen

Country Status (3)

Country Link
EP (1) EP0157843A1 (de)
GB (1) GB8324547D0 (de)
WO (1) WO1985001290A1 (de)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
LT4578B (lt) 1996-07-26 1999-11-25 Nissan Chemical Industries, Ltd. Chromano dariniai

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NZ230711A (en) * 1988-09-23 1990-10-26 Ortho Pharma Corp Substituted thienopyrans as antihypertensive agents
US4997846A (en) * 1988-12-09 1991-03-05 Researche Syntex France, S.A. Novel benzopyranylpyrrolinone derivatives
US5072006A (en) * 1988-12-09 1991-12-10 Recherche Syntex France S.A. Novel benzopyranylpyrrolinone derivatives
WO1997023209A1 (en) * 1995-12-25 1997-07-03 Nissan Chemical Industries, Ltd. Therapeutic agent for cardiac failure

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1548221A (en) * 1976-01-27 1979-07-04 Beecham Group Ltd Trans-4-heterocycyl-3,4-dihydro-2h-benzo pyran-3-ol esters
EP0009912B1 (de) * 1978-10-04 1983-06-22 Beecham Group Plc Chromanol-Derivate, Verfahren zu ihrer Herstellung und diese enthaltende pharmazeutische Zusammensetzungen

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO8501290A1 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
LT4578B (lt) 1996-07-26 1999-11-25 Nissan Chemical Industries, Ltd. Chromano dariniai

Also Published As

Publication number Publication date
GB8324547D0 (en) 1983-10-19
WO1985001290A1 (en) 1985-03-28

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Effective date: 19850815

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Inventor name: ASHWOOD, VALERIE, ANNE