Hypoxathine compounds

Details Hypoxathine compounds Hypoxathine compounds

1999-01-26

2001-10-30

Berch, Mark L. (Department: 1611)

Organic compounds -- part of the class 532-570 series

Organic compounds

Chalcogen bonded directly to ring carbon of the purine ring...

C544S276000

Reexamination Certificate

active

06310205

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to novel and improved methods for preparing adenine and purine derivatives and in particular the present invention relates to improved methods for preparing 3-substituted adenines and 3,8-di-substituted 6-aminopurine derivatives for use as phosphodiesterase inhibitors. The methods according to the invention provide a surprising and unexpectedly improved process that eliminates the need for thionation steps, and further helps avoid reactions under pressure with volatile aminating reagents in the preparation of cyclic nucleotide phosphodiesterase inhibitors.
Cyclic nucleotide phosphodiesterases (PDE's) have received considerable attention as molecular targets for anti-asthmatic agents. Cyclic 3′,5′-adenosine monophosphate (cAMP) and cyclic 3′,5′-guanosine monophosphate (cGMP) are known second messengers that mediate the functional responses of cells to a multitude of hormones, neurotransmitters and autocoids. At least two therapeutically important effects could result from phosphodiesterase inhibition, and the consequent rise in intracellular adenosine 3′,5′-cyclic monophosphate (cAMP) or guanosine 3′,5′-cyclic monophosphate (cGMP) in key cells in the pathophysiology of asthma. These are smooth muscle relaxation (resulting in bronchodilation) and anti-inflammatory activity.
It has become known that there are multiple, distinct PDE isoezymes which differ in their cellular distribution. A variety of inhibitors possessing a marked degree of selectivity for one isoenzyme or the other have been synthesized.
The structure-activity relationships (SAR) of isozyme-selective inhibitors has been discussed in detail, e.g., in the article by Theodore J. Torphy, et al., “Novel Phosphodiesterases Inhibitors For The Therapy Of Asthma”, Drug News & Prospectives, 6(4) May 1993, pages 203-214. The PDE enzymes can be grouped into five or more families according to their specificity toward hydrolysis of cAMP or cGMP, their sensitivity to regulation by calcium, calmodulin or cGMP, and their selective inhibition by various compounds. PDE I is stimulated by Ca
2+
/calmodulin. PDE II is cGMP-stimulated, and is found in the heart and adrenals. PDE III is cGMP-inhiibited, and possesses positive inotropic activity. PDE IV is cAMP specific, and possesses airway relaxation, antiinflammatory and antidepressant activity. PDE V appears to be important in regulating cGMP content in vascular smooth muscle, and therefore PDE V inhibitors may have cardiovascular activity.
While there are compounds derived from numerous structure activity relationship studies which provide PDE III inhibition, the number of structural classes of PDE IV inhibitors is relatively limited.
It has previously been shown that the 3,8-di-substituted 6-thioxanthine derivatives as described in EP-A-0256692 exhibit enhanced bronchodilator and anti-inflammatory activity compared to the corresponding xanthine derivatives. Transformation of these 6-thioxanthine derivatives to the corresponding isoguanines substantially reduces the bronchodilator and anti-inflammatory activity in certain tests.
A different preparation of 3-methyl-6-dimethyl amino-3H-purine, 3-benzyl-6-methyl amino-3H-purine and 3-benzyl-6-isopropyl amino-3H-purine was reported in J. Org. Chem., 55, 5761-5766 (1990). No biological activity was disclosed for these compounds.
PDE IV (and possibly PDE V) is present in all the major inflammatory cells in asthma including eosinophils, neutrophils, T-lymphocytes, macrophages and endothelial cells. Its inhibition causes down regulation of cellular activation and relaxes smooth muscle cells in the trachea and bronchus. On the other hand, inhibition of PDE III, which is present in myocardium, causes an increase in both the force and rate of cardiac contractility. These are undesirable side effects for an anti-inflammatory agent. Theophylline, a non-selective PDE inhibitor, inhibits both PDE III and PDE IV, resulting in both desirable anti-asthmatic effects and undesirable cardiovascular stimulation. With this well-known distinction between PDE isozymes, the opportunity for concomitant anti-inflammation and bronchodilation without many of the side effects associated with theophylline therapy is apparent. The increased incidence of morbidity and mortality due to asthma in many Western countries over the last decade has focused the clinical emphasis on the inflammatory nature of this disease and the benefit of inhaled steroids. Development of an agent that possesses both bronchodilatory and antiinflammatory properties would be most advantageous. It appears that selective PDE IV inhibitors should be more effective with fewer side effects than theophylline. Clinical support has been shown for this hypothesis. Attempts have therefore been made to find new compounds having more selective and improved PDE IV inhibition.
It has been shown in published international patent application WO 95/00516 (assigned to Euro-Celtique, S.A. and incorporated by reference in its entirety herein) that the analogous transformation of 3 and 3,8-di-substituted thiohypoxanthines into the corresponding purine derivatives gives compounds having PDE IV inhibitory activity comparable to or in some cases greater than 6-thioxanthine derivatives of EP-A-0256692.
WO 95/00516 discloses that 3- and 3,8-substituted 6-aminopurine derivatives possess potent PDE IV inhibitory and related antiinflammatory activity. However, the synthetic methods reported in that publication for the preparation of the 3- and 3,8-substituted 6-aminopurine derivatives of interest require a thionation step and require that the reaction be conducted under pressure in order to contain the necessary low boiling amines, both of which requirements create economic and processing inefficiencies during synthesis of these desirable compounds on a larger scale.
SUMMARY OF THE INVENTION
A primary object of the present invention is to provide new methods for the synthesis of compounds which are PDE IV inhibitors.
Another object of the present invention is to provide an improved method of synthesizing compounds which are PDE IV inhibitors without the need for a thionation step and without the need for a pressure reactor.
Further objects of this invention will become apparent from a reading of the following description.
With the above and other objects in view, the present invention relates in part to a novel group of 3-substituted and 3,8-di-substituted 6-amino purine derivatives having bronchodilator and/or anti-inflammatory activity, and hypoxanthine intermediate compounds.
DETAILED DESCRIPTION OF THE INVENTION
The instant invention involves the preparation of compounds of Formula IV from compounds of Formula I in three steps with a marked improvement in the ease of carrying out the reactions. The process is best illustrated in the following reaction scheme (Scheme A):
wherein:
R
6
is N(R
6a
)(R
6b
) or a C
3
-C
8
ring containing from one to three nitrogen atoms, from zero to two oxygen atoms, up to two sulfur atoms, optionally substituted with hydroxy, alkoxy, CO
2
H, CONH
2
, ═NOH, ═NOCONH
2
, (hydroxy) carbamido, ═O R
3
represents an C
2-8
alkyl which is unbranched or branched and unsubstituted or substituted with OH, alkoxy, halogen, ═NOH, ═NOCONH
2
, (hydroxy)carbamido or ═O; C
3-8
cycloalky which is unsubstituted or substituted with OH, alkoxy, halogen, ═NOH, ═NOCONH
2
, (hydroxy)carbamido or ═O; C
4-8
cycloalkylalkyl wherein the cycloalkyl portion is unsubstituted or substituted with OH, alkoxy, halogen, ═NOH, ═NOCONH
2
, or ═O; aryl or benzyl which is optionally unsubstituted or substituted with OH, alkoxy, halogen, ═NOH, ═NOCONH
2
, (hydroxy)carbamido or ═O; C
4-8
cycloalkylalkyl wherein the cycloalkyl portion is unsubstituted or substituted with OH, alkoxy, halogen, ═NOH, ═NOCONH, or ═O; aryl or benzyl which is optionally unsubstituted or substituted with halogen, —NH
2
, alkylamino, dialkylamin

Affiliated with

Also associated with

Rating

Hypoxathine compounds does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Hypoxathine compounds, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Hypoxathine compounds will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2551042