Derivatives of pyrimido[6.1-a]isoquinolin-4-one

Details Derivatives of pyrimido[6.1-a]isoquinolin-4-one Derivatives of pyrimido[6.1-a]isoquinolin-4-one

2001-09-26

2004-09-21

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S230200, C514S211120, C544S252000, C544S095000, C540S547000

Reexamination Certificate

active

06794391

ABSTRACT:

The present invention relates to derivatives of pyrimido[6,1-a]isoquinolin-4-one and their application as inhibitors of phosphodiesterase (PDE) isoenzymes. More particularly the invention relates to derivatives of pyrimido[6,1-a]isoquinolin-4-one and their use in medicine for example as bronchodilators with anti-inflammatory properties.
In all cells where cyclic AMP (cAMP) is present as a secondary messenger, intracellular concentrations of cAMP are regulated by the two processes involved in its formation and degradation. Stimulation of membrane bound receptors on the external surface of the cells (e.g. by &bgr;-adrenoceptor agonists) results in activation of adenylyl cyclase to generate cAMP from ATP. Phosphodiesterases present in the cell serve to reduce the concentration of cAMP by hydrolysing it to adenosine monophosphate (AMP).
In a disease such as asthma, the principal cells involved in the associated bronchoconstriction and inflammatory processes are subject to inhibitory control by cAMP. Inhibitors of type III phosphodiesterase raise intracellular levels of cAMP, leading to relaxation of bronchial smooth muscle, whereas inhibitors of type IV phosphodiesterase inhibit the release of damaging mediators from pro-inflammatory cells. Thus, in principle, a combined PDE III/V inhibitor should have the desirable effects of a &bgr;-adrenoceptor agonist plus an inhaled anti-inflammatory steroid which are currently the mainstay of treatment in severe asthma. Moreover, a combined PDE III/IV inhibitor given by inhalation should achieve beneficial effects similar to a &bgr;-agonist plus inhaled steroid and should be an unusually effective treatment of asthma and other respiratory disorders without the undesirable glucocorticoid effects of the steroid such as osteoporosis and the stunting of growth.
The potential adverse effects of a PDE III/IV inhibitor (e.g., nausea and vomiting, gastric acid secretion, cardiovascular effects such as increase cardiac contractility, vasodilation and potential arrhythmogenic activity) should be avoidable with a compound that is directly delivered to the lungs by inhalation. It is desirable that the substance is long acting and non-irritant.
An example of a pyrimido[6,1-a]isoquinolin-4-one derivative with PDE III/IV inhibitory activity and known to possess antihypertensive vasodilator activity is trequinsin (9,10-dimethoxy-3-methyl-2-mesitylimino-2,3,6,7-tetrahydro-4H-pyrimido[6,1-a]isoquinolin-4-one), which is described by De Souza et al.,
J. Med. Chem.
27 1470-1480 (1984) and in GB-A-1597717.
As described by De Souza et al. and in GB-A-1597717, trequinsin has valuable pharmacological properties, and can be administered to human subjects suffering from, for example, respiratory disorders. However, it is unsuitable for administration by inhalation because in vitro data indicate its persistence of action is less than desirable.
It has now been found that it is possible to design certain pyrimido [6,1-A] isoquinolin-4-one derivatives which are PDE inhibitors, which have a longer duration of action relative to trequinsin.
According to a first aspect of the present invention there is provided a compound of general formula I:
wherein
each of R
1
and R
2
independently represents a C
1-6
alkyl or C
2-7
acyl group;
R
5
represents a hydrogen atom or a C
1-3
alkyl, C
2-3
alkenyl or C
2-3
alkynyl group;
R
6
represents a hydrogen atom or a C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, amino, C
1-6
alkylamino, di(C
1-6
) alkylamino or C
2-7
acylamino group; each of R
7
and le independently represents a hydrogen or halogen atom or a hydroxy, trifluoromethyl, C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, C
2-7
acyl, C
1-6
alkylthio, C
1-6
alkoxy, C
3-6
cycloalkyl; and
R
9
represents a hydrogen or halogen atom or a hydroxy, trifluoromethyl, C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, C
2-7
acyl, C
1-6
alkylthio, C
1-6
alkoxy or C
3-6
cycloalkyl group;
X represents OCH
2
or a group CR
3
R
4
, wherein each of R
3
and R
4
independently represents a hydrogen atom or a C
1-3
alkyl group;
each of R
10
and R
11
independently represents a hydrogen atom, a C
1-3
alkyl, C
3-6
cycloalkyl or phenyl group;
Y represents an oxygen atom or a group CHNO
2
, NCN, NH or NNO
2
;
n is an integer from 2 to 4;
or a salt thereof.
As used herein the term “halogen” or its abbreviation “halo” means fluoro, chloro, bromo or iodo.
As used herein the term “C
1-6
alkyl” refers to straight chain or branched chain alkyl groups having from one to six carbon atoms. Illustrative of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl and hexyl. C
1-4
alkyl groups are preferred.
As used herein the term “C
2-3
alkenyl” refers to straight chain or branched chain hydrocarbon groups having from two to three carbon atoms and having in addition one double bond, of either E or Z stereochemistry where applicable. This term would include for example, vinyl and 1-propenyl.
As used herein the term “C
2-3
alkynyl” refers to straight chain hydrocarbon groups having from two to three carbon atoms and having in addition one triple bond. This term would include for example, ethynyl and 1-propynyl.
As used herein the term “C
2-6
alkenyl” refers to straight chain or branched chain hydrocarbon groups having from two to six carbon atoms and having in addition one double bond, of either E or Z stereochemistry where applicable. This term would include for example, vinyl, 1-propenyl, 1- and 2-butenyl and 2-methyl-2-propenyl. C
2-3
alkenyl groups are preferred.
As used herein the term “C
2-6
alkynyl” refers to straight chain or branched chain hydrocarbon groups having from two to six carbon atoms and having in addition one triple bond. This term would include for example, ethynyl, 1-propynyl, 1- and 2-butynyl, 2-methyl-2-propynyl, 2-pentanyl, 3-pentanyl, 4-pentanyl, 2-hexanyl, 3-hexanyl, 4-hexanyl and 5-hexanyl. C
2-3
alkynyl groups are preferred.
As used herein the term “C
1-6
alkoxy” refers to straight chain or branched chain alkoxy groups having from one to six carbon atoms. Illustrative of such alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, neopentoxy and hexoxy. C
1-4
a alkoxy groups are preferred.
As used herein the term “C
2-7
acyl” refers to straight chain or branched chain acyl groups having from two to seven carbon atoms. Illustrative of such acyl groups are acetyl, propionyl (or propiono or propanoyl), isopropionyl (or isopropiono or isopropanoyl), butyryl (or butanoyl), isobutyryl (or isobutanoyl), pentanoyl (or valeryl), hexanoyl (or capronyl) and heptanoyl.
As used herein the term “C
2-7
acyloxy” refers to straight chain or branched chain acyloxy groups having from two to seven carbon atoms. Illustrative of such acyloxy groups are acetyloxy, propionyl (or propiono or propanoyl)oxy, isopropionyl (or isopropiono or isopropanoyl)oxy, butyryl (or butanoyl)oxy, isobutyryl (or isobutanoyl)oxy, pentanoyl (or valeryl)oxy, hexanoyl (or capronyl)oxy and heptanoyloxy. C
2-4
acyloxy groups are preferred.
As used herein the term “C
3-6
cycloalkyl” refers to an alicyclic group having from three to six carbon atoms. Illustrative of such cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Cyclopentyl and cyclohexyl groups are preferred.
As used herein the term “C
1-6
alkylthio” refers to straight chain or branched chain alkylthio groups having from one to six carbon atoms. Illustrative of such alkylthio groups are methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, neopentylthio and hexylthio. C
1-4
alkylthio groups are preferred.
As used herein the term “C
1-6
alkylamino” refers to straight chain or branched chain alkylamino groups having from one to six carbon atoms. Illustrative of such alkylamino groups are methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, sec-butylamino, tert-butylamin

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