Benzylated PDE4 inhibitors

Details Benzylated PDE4 inhibitors Benzylated PDE4 inhibitors

2001-03-16

2003-04-29

Shah, Mukund J. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C548S543000

Reexamination Certificate

active

06555572

ABSTRACT:

TECHNICAL FIELD
The present invention is directed to a method for reducing the emetogenic effects of PDE inhibitors, and more particularly is directed to compounds having PDE4 inhibition activity with little or no emetogenic side-effects, and chemical methods including benzylation for preparing such compounds.
BACKGROUND OF THE INVENTION
Enzymes known as phosphodiesterases (PDEs) function in vivo to hydrolytically cleave the 3′-phosphodiester bond of cyclic nucleotides to thereby form the corresponding 5′-monophosphate. For instance, certain PDEs can hydroylze the 3′-phosphodiester bond of adenosine 3′,5′-cyclic monophosphate (cAMP) so as to form 5′-adenosine monophosphate (5′-AMP), and/or can hydrolyze the 3′-phosphodiester bond of guanosine 3′,5′-cyclic monophosphate (cGMP) so as to form 5′-guanosine monophosphate (5′-GMP). These cyclic nucleotides exert a significant impact on cellular processes by, for example, converting inactive protein kinase enzymes into an active form. The active form of the protein kinase catalyzes various phosphorylation processes that impact on fundamental cellular processes including transcriptional regulation, ion channel function, and signaling protein activity.
Researchers investigating PDEs generally agree that there are at least eleven distinct PDE families, differentiated on the basis of amino acid sequence, substrate specificity and sensitivity to endogenous and exogenous regulators. These families are commonly known as PDE1 through PDE11. In addition, researchers found that cyclic nucleotide concentration is a significant factor in the course of the in vivo inflammatory response. Accordingly, much research has been directed to methods for influencing the concentration of cyclic nucleotides as a means to influence the inflammatory response, and particular attention has been directed at PDE4 activity. One promising area of research is the development of small organic molecules that inhibit PDE activity. By inhibiting PDE activity, these small molecules reduce the amount of cyclic nucleotide that is converted into the (inactive) corresponding 5′-monophosphate, thereby elevating cyclic nucleotide concentration, and indirectly increasing protein kinase activity within the cell.
Many major pharmaceutical companies are working to develop specific small organic molecules into pharmaceutical compositions that function as PDE inhibitors. ROLIPRAM™ (Schering AG) is an example of an early attempt to develop such a composition directed to PDE4. However, while ROLIPRAM™ exhibited marked anti-inflammatory activity, it was also found to demonstrate unwanted side effects including emesis (also known as nausea and vomiting) and potentiation of gastric acid secretion. These undesired side effects caused ROLIPRAM™ to be withdrawn from development as an anti-inflammatory pharmaceutical. An understanding of the cause of these side-effects, and approaches to mitigate them, subsequently became topics of intense study.
It is now recognized that PDE4 exists in two distinct forms, i.e., two conformers. One conformer, known variously as HPDE4 or HARB, is particularly prevalent in the gastrointestinal tract and central nervous system, has a high affinity for ROLIPRAM™ (i.e., has a High Affinity ROLIPRAM™ Binding Site, “HARBS”), and is considered responsible for the unwanted side-effects. The other conformer is known variously as LPDE4 or LARB, is found in immunocompetent cells, and has a low affinity for ROLIPRAM™. Researchers are seeking to develop small molecules that inhibit the catalytic activity of LPDE4 rather than bind to HPDE4, i.e., molecules that have a low LPDE4:HPDE4 ratio where the numerator and denominator are the appropriate IC
50
values. In other words, researchers are seeking so-called “second generation” inhibitor molecules that interact with the LPDE4 catalytic site of PDE4, rather than the HPDE4 ROLIPRAM™ binding site, to provide desirable anti-inflammatory effect without unwanted side-effects such as emesis.
The present invention is directed to fulfilling this need in the art, and providing further related advantages as set forth more completely herein.
For additional and more detailed discussion of PDE enzymes, including the history of their discovery, their characterization and classification, their in vivo activity, their inhibition by small organic molecules, and current clinical efforts directed to providing pharmaceutical compositions containing these small molecules, see, e.g., Bumouf, C. et al. “Phosphodiesterase 4 Inhibitors”
Annual Reports in Medicinal Chemistry,
Vol. 33, Chap. 10, pp 91-109, 1998 (Bristol, J. A., ed.); Essayan, D. M. “Cyclic Nucleotide Phosphodiesterase (PDE) Inhibitors and Immunomodulation”
Biochemical Pharmacology
57:965-973, 1999; Souness, J. E. and Foster, M. “Potential of phospodiesterase type IV inhibitors in the treatment of rheumatoid arthritis”
Idrugs
1(5):541-553, 1998; Souness, J. E. et al. “Immunosuppressive and anti-inflammatory effect of cAMP phosphodiesterase (PDE) type 4 inhibitors” Immunopharmacology 47: 127-162, 2000; and Torphy, T. J. “Phosphodiesterase Isozymes”
Am J. Respir. Crit. Care Med.
157:351-370, 1998, as well as the numerous references cited in these articles.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides a method for improving the therapeutic ratio of PDE4 inhibitors through reduction or elimination of emetogenic properties while allowing retention of PDE activity. In one aspect, the method comprises benzylation of a PDE4 inhibitor, wherein the benzylation places a benzyl group on a carbon atom of a PDE4 inhibitor, to provide a benzylated PDE4 inhibitor. In one aspect, the PDE4 inhibitor is ROLIPRAM™, while in another aspect the PDE4 inhibitor is ARIFLO™. The benzylation may replace an extractable hydrogen of the PDE4 inhibitor with a benzyl group. For instance, the PDE4 inhibitor may be reacted with a base in order to extract the extractable hydrogen, followed by reaction with a benzylating agent. In one aspect, the PDE4 inhibitor has a carbonyl group and the extractable hydrogen is located alpha to (i.e., next to) the carbonyl group. In another aspect, the PDE4 inhibitor has a carbonyl group and benzyl group is located beta to (i.e., with one intervening atom between) the carbonyl group. In another aspect, the PDE4 inhibitor has a carbonyl group and benzyl group is located gamma to (i.e., with two intervening atoms between) the carbonyl group. The extractable hydrogen may be removed under chemical conditions and replaced with a benzyl group.
In one aspect, the benzylated PDE4 inhibitor comprises at least one benzyl group (Bzl) of the formula
wherein each of the numerals 1, 2, 3, 4 and 5 may be carbon or nitrogen, with the proviso that the ring is aromatic and contains at least 3 carbon atoms;
n is 5 and R
1
at each occurrence is independently selected from halogen, nitro, R
2
, NR
2
(m)
, and OR
2
wherein m=0, 1, 2, or 3 and R
2
at each occurrence is independently selected from H, C
1
-C
8
alkyl, alkoxyalkyl having 3-7 carbons in the alkoxy portion and 2-4 carbons in the alkyl portion, phenoxyalkyl having 2-6 carbons in the alkyl portion, C
3
-C
7
cycloalkyl, C
6
-C
9
polycycloalkyl, alkylcycloalkyl, hydroxyalkyl, carboxyl, alkylcarboxylate, carboxylate, alkyl carboxyl, amide, alkylamide, aryl, heteroaryl, heteroalkyl, heterocycloalkyl, phenylalkyl having 1-8 carbons in the alkyl portion, phenylaminoalkyl having 2-6 carbons in the alkyl portion and the amino may be optionally substituted with C
1
-C
4
alkyl and indanyl; wherein the alkyl portion of an R
2
group may be optionally substituted with one or more fluorine atoms, hydroxyl or C
1
-C
8
alkoxy; and the aryl portion of an R
2
group may be optionally substituted with C
1
-C
8
alkyl, C
1
-C
8
alkoxy or halogen.
In another aspect, the benzylated PDE4 inhibitor comprises at least one benzyl group (Bzl) of the formula
wherein each of the numerals 1, 2, 3, 4 and 5 may be carbon or nitrogen, with the proviso that t

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