US 2003O144300A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2003/0144300 A1 Magee et al. (43) Pub. Date: Jul. 31, 2003 (54) PYRIMIDINE CARBOXAMIDES USEFUL AS Related U.S. Application Data INHIBITORS OF PDE4 ISOZYMES (60) Provisional application No. 60/179,282, filed on Jan. (76) Inventors: Thomas Victor Magee, Mystic, CT 31, 2000. (US); Anthony Marfat, Mystic, CT (US); Robert James Chambers, Publication Classification Mystic, CT (US) (51) Int. Cl." ...................... A61K 31/513; A61K 31/506 Correspondence Address: (52) U.S. Cl. ......................... 514/256; 514/269; 544/314; PFIZER INC. 544/326; 544/328 PATENT DEPARTMENT, MS8260-1611 EASTERN POINT ROAD (57) ABSTRACT GROTON, CT 06340 (US 9 (US) Compounds of formula (1.0.0) are described, as well as the (21) Appl. No.: 10/181,417 usefulness of a pharmaceutical composition for treating inflammatory, respiratory and allergic diseases and condi (22) PCT Filed: Jan. 30, 2001 tions, especially asthma, chronic obstructive pulmonary disease (COPD) including chronic bronchitis, emphysema, (86) PCT No.: PCT/IB01/00125 and bronchiectasis, chronic rhinitis, and chronic sinusitis. US 2003/O144300 A1 Jul. 31, 2003 PYRIMIDINE CARBOXAMIDES USEFULAS al., J. Med. Chem. 39 120-125, 1996; Schneider et al., INHIBITORS OF PDE4 ISOZYMES Pharmacol. Biochem. Behav: 50 211-217, 1995; Banner and Page, Br. J. Pharmacol. 11493-98, 1995; Barnette et al., J. 1.O REFERENCE TO COPENDING Pharmacol. Exp. Ther. 273 674-679, 1995; Wright et al. APPLICATIONS “Differential in vivo and in vitro bronchorelaxant activities 0001 Reference is made to copending International of CP-80633, a selective phosphodiesterase 4 inhibitor, application and US application based thereon, Serial No. "Can. J. Physiol. Pharmacol. 75 1001-1008, 1997; Manabe PCT/IB98/00315, both filed Mar. 10, 1998 (Attorney Docket et al. "Anti-inflammatory and bronchodilator properties of No. PC9762A), and published as WO 98/45268 on Oct. 15, KF19514, a phosphodiesterase 4 and 1 inhibitor, Eur: J. 1998; claiming priority from application Ser. No. 60/043, Pharmacol. 332 97-107, 1997; and Ukita et al. “Novel, 403 filed Apr. 4, 1997 (Attorney Docket No. PC9762), now potent, and Selective phosphodiesterase-4 inhibitors as anti abandoned; which discloses nicotinamide derivatives having asthmatic agents: Synthesis and biological activities of a biological activity as inhibitors of the PDE4 isozyme, and series of 1-pyridylnaphthalene derivatives.J. Med. Chem. thus useful in the treatment of inflammatory, respiratory and 42 1088-1099, 1999. Accordingly, there continues to be allergic diseases and conditions. Nothing that is disclosed in considerable interest in the art with regard to the discovery the above-mentioned applications would teach the perSon of of further Selective inhibitors of PDE4S. ordinary skill in the pertinent art the novel compounds of the 0006 The present invention is also concerned with the present invention or their unexpectedly high level of inhibi use of selective PDE4 inhibitors for the improved therapeu tory activity for the PDE4 isozyme. tic treatment of a number of inflammatory, respiratory and allergic diseases and conditions, but especially for the treat 0002 Reference is also made to copending application ment of asthma, chronic obstructive pulmonary disease Ser. No. 09/345,185 filed Jun. 30, 1999 (Attorney Docket (COPD) including chronic bronchitis, emphysema, and No. PC10096A); claiming priority from application Ser. No. bronchiectasis, chronic rhinitis, and chronic Sinusitis. Here 60/105,120 filed Oct. 21, 1998 (Attorney Docket No. tofore in the art, however, the first-line therapy for treatment PC10096), which discloses compounds and processes for of asthma and other obstructive airway diseases has been the preparing N-Substituted nicotinamide derivatives. However, nonselective PDE inhibitor theophylline, as well as pentoxi the disclosed compounds and processes are not the same as fylline and IBMX, which may be represented by Formulas those of the present invention. (0.0.1), (0,0.2), and (0.0.3), respectively: 0.003 Reference is further made to copending applica tions filed of even date with the instant application, Attorney Docket Nos. PC10523; PC10546; PC10657; PC10690; and (0.0.1) PC10691, which involve other classes of nicotinamide derivatives useful as selective inhibitors of the PDE4 isozyme. 2O BACKGROUND OF THE INVENTION 0004. The 3',5'-cyclic nucleotide phosphodiesterases ---CH (PDES) comprise a large class of enzymes divided into at least eleven different families which are structurally, bio Theophylline chemically and pharmacologically distinct from one another. (0.0.2) The enzymes within each family are commonly referred to O as isoenzymes, or isozymes. A total of more than fifteen gene N products is included within this class, and further diversity HC --~~ N r y H. results from differential Splicing and post-translational pro cessing of those gene products. The present invention is primarily concerned with the four gene products of the 1-2CH fourth family of PDEs, i.e., PDE4A, PDE4B, PDE4C, and PDE4D. These enzymes are collectively referred to as being Pentoxifylline isoforms or subtypes of the PDE4 isozyme family. Further (0.0.3) below will be found a more detailed discussion of the CH genomic organization, molecular structure and enzymatic activity, differential Splicing, transcriptional regulation and O l O phosphorylation, distribution and expression, and Selective CH N inhibition of the PDE4 isozyme subtypes. N 0005. The PDE4s are characterized by selective, high H3-N- C. affinity hydrolytic degradation of the Second messenger Ns/ cyclic nucleotide, adenosine 3',5'-cyclic monophosphate IBMX (cAMP), and by sensitivity to inhibition by rolipram. A number of selective inhibitors of the PDE4s have been discovered in recent years, and beneficial pharmacological 0007. Theophylline, which has the PDEs as one of its effects resulting from that inhibition have been shown in a biochemical targets, in addition to its well characterized variety of disease models. See, e.g., Torphy et al., Environ. bronchodilatory activity, affects the vasculature of patients Health Perspect 102 Suppl. 10, 79-84, 1994; Duplantier et with increased pulmonary artery pressure, Suppresses US 2003/O144300 A1 Jul. 31, 2003 inflammatory cell responses, and induces apoptosis of eosi 0009. However, benafentrine results in bronchodilation nophils. Theophylline's adverse events, most commonly only when administered by inhalation, and Zardaverine cardiac dysrhythmias and nausea, are also mediated by PDE produces only a modest and short-lived bronchodilation. inhibition, however, leading to the Search for more Selective Milrinone, a cardiotonic agent, induces short-lived bron inhibitors of PDEs that are able to suppress both immune chodilation and a slight degree of protection against induced cell functions in vitro and allergic pulmonary inflammation in Vivo, while at the same time having improved side-effect bronchoconstriction, but has marked adverse events, e.g., profiles. Within the airways of patients suffering from tachycardia and hypotension. Unsatisfactory results have asthma and other obstructive airway diseases, PDE4 is the also been obtained with a weakly selective PDE4 inhibitor, most important of the PDE isozymes as a target for drug tibenelast, and a selective PDE5 inhibitor, Zaprinast, which discovery because of its distribution in airway Smooth may be represented by Formulas (0.0.7) and (0,0.8): muscle and inflammatory cells. Several PDE4 inhibitors introduced to the art thus far have been designed to have an improved therapeutic indeX concerning the cardiovascular, (0.0.7) gastrointestinal, and central nervous System Side effects of the above-mentioned nonselective Xanthines. c C OH 0008 Airflow obstruction and airway inflammation are He1 No O features of asthma as well as COPD. While bronchial asthma Tibenelast is predominantly characterized by an eosinophilic inflam (0.0.8) mation, neutrophils appear to play a major role in the O pathogenesis of COPD. Thus, PDEs that are involved in H Smooth muscle relaxation and are also found in eosinophils N as well as neutrophils probably constitute an essential ele ment of the progress of both diseases. The PDEs involved \N / include PDE3s as well as PDE4s, and bronchodilating inhibitors have been discovered which are selective PDE3 O N-N inhibitors and dual PDE3/4 selective inhibitors. Examples of c1\1 H these are milrinone, a selective PDE3 inhibitor, as well as Zaprinast Zardaverine and benafentrine, both dual PDE3/4 selective inhibitors, which may be represented by Formulas (0.0.4), (0.0.5), and (0.0.6), respectively: 0010 More relative success has been obtained in the art with the discovery and development of selective PDE4 inhibitors. (0.0.4) 0011. In vivo, PDE4 inhibitors reduce the influx of eosi nophils to the lungs of allergen-challenged animals while also reducing the bronchoconstriction and elevated bron chial responsiveness occurring after allergen challenge. PDE4 inhibitors also suppress the activity of immune cells, Millrinone including CD4 T-lymphocytes, monocytes, mast cells, and (0.0.5) basophils; reduce pulmonary edema; inhibit excitatory FHC nonadrenergic noncholinergic neurotransmission (eNANC); potentiate inhibitory nonadrenergic noncholinergic neu O rotransmission (iNANC); reduce airway smooth muscle mitogenesis; and induce bronchodilation. PDE4 inhibitors N O a nY NH also SuppreSS the activity of a number of inflammatory cells