Pyrimidine carboxamides useful as inhibitors of PDE4 isozymes

• US 6,740,655 B2
• Filed: 07/24/2002
• Issued: 05/25/2004
• Est. Priority Date: 01/31/2000
• Status: Expired due to Fees

• Current Assignee: Pfizer Inc., Pfizer Products Incorporated (Pfizer Inc.)
• Original Assignee: Pfizer Inc.
• Inventors: Chambers, Robert James, Magee, Thomas Victor, Marfat, Anthony
• Primary Examiner(s): Raymond, Richard L.
• Application Number:
  US10/181,417
• Publication Number:
  US 20030144300A1
• Time in Patent Office: 671 Days
• Field of Search: 544/319, 514/255.05, 514/269
• US Class Current: 514/255.05
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 11/08 Bronchodilators
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/04 Antipruritics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/06 Antigout agents, e.g. antihyperuricemic or uricosuric agents
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/14 : Decongestants or antiallergics
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/10 : Antimycotics
• CPC Class Codes: A61P 31/16 : for influenza or rhinoviruses
• CPC Class Codes: A61P 31/18 : for HIV
• CPC Class Codes: A61P 31/20 : for DNA viruses
• CPC Class Codes: A61P 31/22 : for herpes viruses
• CPC Class Codes: A61P 35/02 : specific for leukemia
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/02 : Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 7/04 : Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: A61P 7/10 : Antioedematous agents; Diuretics
• CPC Class Codes: A61P 7/12 : Antidiuretics, e.g. drugs for diabetes insipidus ADH A61P5/10
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/04 : Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/08 : Vasodilators for multiple indications
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 : Antihypertensives
• CPC Class Codes: A61P 9/14 : Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• CPC Class Codes: C07D 239/34 : One oxygen atom
• CPC Class Codes: C07D 405/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/14 : containing three or more hetero rings
• CPC Class Codes: C07D 409/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/14 : containing three or more hetero rings
• CPC Class Codes: C07D 417/14 : containing three or more hetero rings

Abstract

This invention is directed to compounds of the formula:

wherein j is 0 or 1; k is 0 or 1; m is 0 or 1; n is 0 or 1; W is —O—; —S(═O)_t—, where t is 0, 1, or 2; or —N(R³)—; where R³ is —H, —(C₁-C₃) alkyl, —OR¹², phenyl, or benzyl; R^C and R^D have the same meaning as R^A and R^B, except that at least one of R^C and R^D must be —H; and the other variables are defined as set forth in the specification. The invention is also directed to pharmaceutical compositions comprising the above compounds and to methods of treating a subject suffering from a disease, disorder or condition mediated by the PDE4 isozyme, the method comprising administering a therapeutically effective amount of a compound as described above. The invention is particularly directed to methods of treating inflammatory, respiratory and allergic diseases and conditions, especially asthma; chronic obstructive pulmonary disease (COPD) including chronic bronchitis, emphysema, and bronchiectasis; chronic rhinitis; and chronic sinusitis.

Claims

1. A compound of Formula (1.0.0):

or a pharmaceutically acceptable salt thereof;

wherein

2. A compound according to claim 1, wherein m is 0 or 1;

n is 1;

j and k are 0 or 1;

R is —

H, —

F, or —

Cl;

R² is —

H, —

F, or —

Cl;

R³ is —

H;

one of R^A and R⁶ is —

OH₃ and the other is —

H or —

CH₃;

one of R^C or R^D is —

H, and the other is —

H or —

CH₃;

Z^B is phenyl, pyridyl, cyclopentyl, cyclohexyl, furanyl, thienyl, thiazolyl, indolin-2-onyl, or pyrazinyl;

E is —

H, —

OR¹², —

NR¹²R¹³, —

NHS(═

O)₂CH₃, or —

S(═

O)₂NH₂;

Z^A is unsubstituted pyridyl, or phenyl substituted by R⁴ where R⁴ is taken twice and is —

F or —

Cl, or else R⁴ is a single substituent consisting of —

F, —

Cl, —

ON, —

NO₂, —

NH₂, —

CF₃, —

SCH₃, —

OCH₃, —

OCH₂CH₃, —

C(═

O)CH₃, or —

C(═

O)OCH₃;

or Z^A is phenyl where two R⁴ are taken together with the carbon atoms to which they are attached and the phenyl ring of which they are a part, to form 1,3-benzodioxolyl, 2,3-dihydrobenzofuranyl, indolinyl, chromanyl, 1,3-benzodithiolyl, or 1,4-benzodioxanyl.

3. A compound according to claim 1, wherein m is 0;

n is 1;

j is 0;

k is 0;

R¹ is —

H, —

F, or —

Cl;

R² is —

H, —

F, Cl, or —

CH₃;

R³ is —

H;

R^C is —

H;

R^D is —

H or —

CH₃;

Z^B is phenyl, cyclopentyl, cyclohexyl, furanyl, thienyl, thiazolyl, oxazolyl, indolin-2-onyl, pyridyl, or pyrazinyl, E is —

H, —

OCH₃, —

OH, —

CH(OH)CH₃, —

C(OH)(CH₃)₂, —

OC(═

O)R¹², —

NHS(═

O)₂CH₃, —

S(═

O)₂NH₂, or —

N(CH₃)₂;

Z^A is phenyl or pyridyl where R⁴ is taken twice and is —

F or —

Cl, or else R⁴ is a single substituent consisting of —

F, —

Cl, —

CN, —

NO₂, —

NH₂, —

CF₃, —

SCH₃, —

OCH₃, —

OCH₂CH₃, —

C(═

O)CH₃, or —

C(═

O)OCH₃;

or Z^A is phenyl where two R⁴ are taken together with the carbon atoms to which they are attached and the phenyl ring of which they are a part, to form 1,3-benzodioxolyl.

4. A compound according to claim 1, wherein m is 0;

n is 1;

j is 0;

k is 0;

R¹ is —

H;

R² is —

H, —

F, —

Cl, or —

CH₃;

R³ is —

H;

R^C is —

H;

R^D is —

H or —

CH₃;

Z^B is phenyl, furanyl, or thienyl;

E is —

OCH₃, —

OH, —

CH(OH)CH₃, or —

C(OH)(CH₃)₂;

Z^A is phenyl or pyridyl where R⁴ is taken twice and is —

F or —

Cl, or else R⁴ is a single substituent consisting of —

F, —

Cl, —

CN, —

OCH₃, or —

NO₂;

or Z^A is phenyl where two R⁴ are taken together with the carbon atoms to which they are attached and the phenyl ring of which they are a part, to form 1,3-benzodioxolyl.

5. A compound according to claim 1, selected from the group consisting of:

4-(Benzo[1,3]dioxol-5-yloxy)-pyrimidine-5-carboxylic acid 2-fluoro-4-(1-hydroxy-1-methyl-ethyl)-benzylamide;

4-(Benzo[1,3]dioxol-5-yloxy)-pyrimidine-5-carboxylic acid 4-(1-hydroxy-1-methyl-ethyl)-benzylamide;

2-N-(2-Chloro-benzyl)-1-[6-(2,4-difluoro-phenoxy)-pyrimidin-5-yl]-carboxamide;

1-[6-(4-Fluoro-phenoxy)-pyrimidin-5-yl]-2-N-[4-(methoxy)benzyl]-carboxamide;

1-[6-(4-Fluoro-phenoxy)-pyrimidin-5-yl]-2-N-[(thiophene-2-yl)methyl]-carboxamide;

4-(Benzo[1,3]dioxol-5-yloxy)-pyrimidine-5-carboxylic acid (thiophen-2-ylmethyl)-amide;

1-[6-(4-Fluoro-phenoxy)-pyrimidin-5-yl]-2-N-[(furan-2-yl)methyl]-carboxamide;

2-N-(2-Chloro-benzyl)-1-[6-(2,4-difluoro-phenoxy)-pyrimidin-5-yl]-carboxamide;

1-[6-(4-Fluoro-phenoxy)-pyrimidin-5-yl]-2-N-[1-methyl-1-(4-methoxy)benzyl]-carboxamide;

1-[6-(4-Fluoro-phenoxy)-pyrimidin-5-yl]-2-N-[1-methyl-1-(thiophene-2-yl)methyl]-carboxamide;

2-N-[1-Methyl-1-(thiophene-2-yl)methyl]-1-[6-(pyridin-3-yl)-oxy-pyrimidin-5-yl]-carboxamide;

4-(Benzo[1,3]dioxol-5-yloxy)-pyrimidine-5-carboxylic acid (1-thiophen-2-yl-ethyl)-amide;

1-[6-(5-Chloro-pyridin-3-yl)-oxy-pyrimidin-5-yl]-2-N-[(3-methyl)thiophene-2-yl)methyl]-carboxamide;

2-N-[(4-Methoxy)phenyl)methyl]-1-[6-(pyridin-3-yl)-oxy-pyrimidin-5-yl]-carboxamide;

2-N-[(4-Chloro-thiophene-2-yl)methyl]-1-[6-(4-fluoro-phenoxy)-pyrimidin-5-yl]-carboxamide;

4-(Benzo[1,3]dioxol-5-yloxy)-pyrimidine-5-carboxylic acid (4-chloro-thiophen-2-ylmethyl)-amide;

2-N-[(5-Chloro-furan-2-yl)methyl]-1-[6-(4-fluoro-phenoxy)-pyrimidin-5-yl]-carboxamide;

1-[6-(5-Chloro-pyridin-3-yl)-oxy-pyrimidin-5-yl]-2-N-[thiazol-2-yl)methyl]-carboxamide;

1-[6-(4-Fluoro-phenoxy)-pyrimidin-5-yl]-2-N-[4-(1-hydroxy-iso-propyl)benzyl]-carboxamide;

4-(Benzo[1,3]dioxol-5-yloxy)-pyrimidine-5-carboxylic acid 4-(1-hydroxy-ethyl)-benzylamide;

2-N-(2,3-Difluoro-benzyl)-1-[6-(4-fluoro-phenoxy)-pyrimidin-5-yl]-carboxamide;

1-[6-(4-Fluoro-phenoxy)-pyrimidin-5-yl]-2-N-(4-hydroxy-benzyl)-carboxamide;

2-N-(2-Chloro-benzyl)-1-{6-[3-(N,N-dimethylamino)-phenoxy]-pyrimidin-5-yl}-carboxamide;

2-N-(2-Chloro-benzyl)-1-[6-(4-cyano-phenoxy)-pyrimidin-5-yl]-carboxamide;

4-(Benzo[1,3]dioxol-5-yloxy)-pyrimidine-5-carboxylic acid 2-chloro-benzylamide;

1-[6-(4-Fluoro-phenoxy)-pyrimidin-5-yl]-2-N-(4-methylsulfoamino-benzyl)-carboxamide;

1-[6-(4-Fluoro-phenoxy)-pyrimidin-5-yl]-2-N-[1-methyl-1-(5-chloro-2-thiopheneyl)methyl]-carboxamide;

4-(Benzo(1,3]dioxol-5-yloxy)-pyrimidine-5-carboxylic acid [1-(5-chloro-thiophen-2-yl)-ethyl]-amide;

2-N-[4-(1-Hydroxy-iso-propyl)-benzyl]-1-[6-(3-nitro-phenoxy)-pyrimidin-5-yl]-carboxamide;

1-[6-(3-Cyano-phenoxy)-pyrimidin-5-yl]-2-N-[4-(1-hydroxy-iso-propyl)-benzyl]-carboxamide;

1-[6-(4-Fluoro-phenoxy)-pyrimidin-5-yl]-2-N-[4-(1-hydroxy-iso-propyl)-benzyl]-carboxamide;

2-N-[4-(1-Hydroxy-iso-propyl)-benzyl]-1-[6-(3-trifluoromethyl-phenoxy)-pyrimidin-5-yl]-carboxamide;

1-[6-(3-Chloro-phenoxy)-pyrimidin-5-yl]-2-N-[4-(1-hydroxy-iso-propyl)-benzyl]-carboxamide;

2-N-(2-Fluoro-benzyl)-1-[6-(pyridin-3-yl)-oxy-pyrimidin-5-yl]-carboxamide;

1-[6-(4-Fluoro-phenoxy)-pyrimidin-5-yl]-2-N-(4-imino-benzyl)-carboxamide;

4-(Benzo[1,3]dioxol-5-yloxy)-pyrimidine-5-carboxylic acid 4-amino-benzylamide;

2-N-[5-(1-Hydroxyethyl)-thiophene-2-yl]-1-[6-(pyridin-3-yl)-oxy-pyrimidin-5-yl]-carboxamide;

4-(Benzo[1,3]dioxol-5-yloxy)-pyrimidine-5-carboxylic acid [5-(1-hydroxy-ethyl)-thiophen-2-ylmethyl]-amide;

2-N-[5-(1-Hydroxy-iso-propyl)-thiophene-2-yl]-1-[6-(pyridin-3-yl)-oxy-pyrimidin-5-yl]-carboxamide;

4-(Benzo[1,3]dioxol-5-yloxy)-pyrimidine-5-carboxylic acid [5-(1-hydroxy-1-methyl-ethyl)-thiophen-2-ylmethyl]-amide;

2-N-[4-(1-Hydroxy-iso-propyl)-benzyl]-1-[6-(3-methylthio-phenoxy)-pyrimidin-5-yl]-carboxamide;

1-[6-(4-Fluoro-phenoxy)-pyrimidin-5-yl]-2-N-{4-[(1-hydroxy-iso-propyl)-cylcohexyl]methyl}-carboxamide;

1-[6-(4-Fluoro-phenoxy)-pyrimidin-5-yl]-2-N-[(5-methyl-pyrazin-2-yl)methyl]-carboxamide;

4-(Benzo[1,3]dioxol-5-yloxy)-pyrimidine-5-carboxylic acid (5-methyl-pyrazin-2-ylmethyl)-amide;

2-N-(4-N,N-Dimethyl-benzyl)-1-[6-(4-fluoro-phenoxy)-pyrimidin-5-yl]-carboxamide;

4-(Benzo[1,3]dioxol-5-yloxy)-pyrimidine-5-carboxylic acid 4-dimethylamino-benzylamide;

2-N-[(4-Aminosulfonyl)-benzyl]-1-[6-(4-fluoro-phenoxy)-pyrimidin-5-yl]-carboxamide;

4-(Benzo[1,3]dioxol-5-yloxy)-pyrimidine-5-carboxylic acid 4-sulfamoyl-benzylamide;

2-N-[4-(1-Hydroxy-iso-propyl)-benzyl]-1-[6-(3-methylcarbonyl-phenoxy)-pyrimidin-5-yl]-carboxamide;

1-[6-(3-Cyano-phenoxy)-pyrimidin-5-yl]-2-N-{4-[(1-hydroxy-iso-propyl)-cylcohexyl]methyl}-carboxamide;

2-N-[4-(1-Hydroxy-iso-propyl)-benzyl]1-[6-(3-methoxycarbonyl-phenoxy)-pyrimidin-5-yl]-carboxamide; and

2-N-(2-Chloro-benzyl)1-[6-(3-methylcarbonyl-phenoxy)-pyrimidin-5-yl]-carboxamide.

6. A combination of a compound of claim 1 together with one or more members selected from the group consisting of the following:

(a) Leukotriene biosynthesis inhibitors, 5-lipoxygenase (5-LO) inhibitors, and 5-lipoxygenase activating protein (FLAP) antagonists selected from the group consisting of zileuton;

ABT-761;

fenleuton;

tepoxalin;

Abbott-79175;

Abbott-85761;

N-(5-substituted)-thiophene-2-alkylsulfonamides of Formula (5.2.8);

2,6-di-tert-butylphenol hydrazones of Formula (5.2.10);

Zeneca ZD-2138 of Formula (5.2.11);

SB-210661 of Formula (5.2.12);

pyridinyl-substituted 2-cyanonaphthalene compound L-739,010;

2-cyanoquinoline compound L-746,530;

indole and quinoline compounds MK-591, MK-886, and BAY x 1005;

(b) Receptor antagonists for leukotrienes LTB₄, LTC₄, LTD₄, and LTE₄ selected from the group consisting of phenothiazin-3-one compound L-651,392;

amidino compound CGS-25019c;

benzoxazolamine compound ontazolast;

benzenecarboximidamide compound BIIL 284/260;

compounds zafirlukast, ablukast, montelukast, pranlukast, verlukast (MK-679), RG-12525, Ro-245913, iralukast (CGP 45715A), and BAY x 7195;

(c) PDE4 inhibitors;

(d) 5-Lipoxygenase (5-LO) inhibitors; and

5-lipoxygenase activating protein (FLAP) antagonists;

(e) Dual inhibitors of 5-lipoxygenase (5-LO) and antagonists of platelet activating factor (PAF);

(f) Leukotriene antagonists (LTRAs) of LTB₄, LTC₄, LTD₄, and LTE₄;

(g) Antihistaminic H₁ receptor antagonists cetirizine, loratadine, desloratadine, fexofenadine, astemizole, azelastine, and chlorpheniramine;

(h) Gastroprotective H₂ receptor antagonists;

(i) α

₁- and α

₂-adrenoceptor agonist vasoconstrictor sympathomimetic agents administered orally or topically for decongestant use, selected from the group consisting of propylhexedrine, phenylephrine, phenylpropanolamine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride, and ethylnorepinephrine hydrochloride;

(j) one or more α

₁- and α

₂-adrenoceptor agonists as recited in (i) above in combination with one or more inhibitors of 5-lipoxygenase (5-LO) as recited in (a) above;

(k) Anticholinergic agents ipratropium bromide;

tiotropium bromide;

oxitropium bromide;

pirenzepine; and

telenzepine;

(l) β

₁- to β

₄-adrenoceptor agonists selected from the group consisting of metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol, and pirbuterol;

(m) Theophylline and aminophylline;

(n) Sodium cromoglycate;

(o) Muscarinic receptor (M1, M2, and M3) antagonists;

(p) COX-1 inhibitors (NSAIDs); and

nitric oxide NSAIDs;

(q) COX-2 selective inhibitor rofecoxib;

(r) insulin-like growth factor type I (IGF-1) mimetics;

(s) Ciclesonide;

(t) Inhaled glucocorticoids with reduced systemic side effects selected from the group consisting of prednisone, prednisolone, flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, and mometasone furoate;

(u) Tryptase inhibitors;

(v) Platelet activating factor (PAF) antagonists;

(w) Monoclonal antibodies active against endogenous inflammatory entities;

(x) IPL 576;

(y) Anti-tumor necrosis factor (TNFα

) agents selected from the group consisting of etanercept, infliximab, and D2E7;

(z) DMARDs selected from the group consisting of leflunomide;

(aa) TCR peptides;

(bb) Interleukin converting enzyme (ICE) inhibitors;

(cc) IMPDH inhibitors;

(dd) Adhesion molecule inhibitors including VLA-4 antagonists;

(ee) Cathepsins;

(ff) MAP kinase inhibitors;

(gg) Glucose-6 phosphate dehydrogenase inhibitors;

(hh) Kinin-B₁- and B₂-receptor antagonists;

(ii) Gold in the form of an aurothio group in combination with hydrophilic groups;

(jj) Immunosuppressive agents selected from the group consisting of cyclosporine, azathioprine, and methotrexate;

(kk) Anti-gout agents selected from the group consisting of colchicine;

(ll) Xanthine oxidase inhibitors selected from the group consisting of allopurinol;

(mm) Uricosuric agents selected from the group consisting of probenecid, sulfinpyrazone, and benzbromarone;

(nn) Antineoplastic agents that are antimitotic drugs selected from the group consisting of vinblastine and vincristine;

(oo) Growth hormone secretagogues;

(pp) Inhibitors of matrix metalloproteases (MMPs) that are selected from the group consisting of the stromelysins, the collagenases, the gelatinases, aggrecanase, collagenase-1 (MMP-1), collagenase-2 (MMP-8), collagenase-3 (MMP-13), stromelysin-1 (MMP-3), stromelysin-2 (MMP-10), and stromelysin-3 (MMP-11);

(qq) Transforming growth factor (TGFβ

);

(rr) Platelet-derived growth factor (PDGF);

(ss) Fibroblast growth factor selected from the group consisting of basic fibroblast growth factor (bFGF);

(tt) Granulocyte macrophage colony stimulating factor (GM-CSF);

(uu) Capsaicin;

(vv) Tachykinin NK₁ and NK₃ receptor antagonists selected from the group consisting of NKP-608C;

SB-233412 (talnetant); and

D-4418;

(ww) Elastase inhibitors selected from the group consisting of UT-77 and ZD-0892; and

(xx) Adenosine A2a receptor agonists.

7. A method of treating a disease, disorder or condition mediated by the PDE4 isozyme in a mammal, said method comprising administering to said mammal in need of such mediation, a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

9. A method of claim 7 wherein said disease, disorder or condition is atopic asthma;

non-atopic asthma;

allergic asthma;

bronchial asthma;

essential asthma;

true asthma;

intrinsic asthma caused by pathophysiologic disturbances;

extrinsic asthma caused by environmental factors;

essential asthma of unknown or inapparent cause;

bronchitic asthma;

emphysematous asthma;

exercise-induced asthma;

occupational asthma;

infective asthma caused by bacterial, fungal, protozoal or viral infection;

non-allergic asthma;

incipient asthma;

or wheezy infant syndrome.

10. A method of claim 7 wherein said disease, disorder or condition is chronic or acute bronchoconstriction;

chronic bronchitis;

small airways obstruction;

emphysema;

pneumoconiosis;

chronic eosinophilic pneumonia;

chronic obstructive pulmonary disease;

adult respiratory distress syndrome;

or exacerbation of airways hyper-reactivity consequent to other drug therapy.

11. A method of claim 10 wherein said chronic obstructive pulmonary disease is characterized by irreversible, progressive airways obstruction.

12. A method of claim 10 wherein said pneumonconiosis is aluminosis;

bauxite workers'"'"' disease;

anthracosis;

miners'"'"' disease;

asbestosis;

steam-fitters asthma;

chalicosis;

flint disease;

ptilosis caused by inhaling the dust from ostrich feathers;

siderosis caused by the inhalation of iron particles;

silicosis;

grinders'"'"' disease;

byssinosis;

cotton-dust asthma;

or talc pneumoconiosis.

13. A method of claim 7 wherein said disease, disorder or condition is bronchitis;

acute bronchitis;

chronic bronchitis;

acute laryngotracheal bronchitis;

arachidic bronchitis;

catarrhal bronchitis;

croupus bronchitis;

dry bronchitis;

infectious asthmatic bronchitis;

productive bronchitis;

staphylococcus bronchitis;

streptococcal bronchitis;

or vesicular bronchitis.

14. A method of claim 7 wherein said disease, disorder or condition is bronchiectasis;

cylindric bronchiectasis;

sacculated bronchiectasis;

fusiform brochiectasis;

capillary bronchiectasis;

cystic bronchiectasis;

dry bronchiectasis or follicular bronchiectasis.

15. A method of claim 7 wherein said disease, disorder or condition is seasonal allergic rhinitis;

perennial allergic rhinitis;

sinusitis;

purulent sinusitis;

nonpurulent sinusitis;

acute sinusitis;

chronic sinusitis;

ethmoid sinusitis;

frontal sinusitis;

or sphenoid sinusitis.

8. A method of claim/wherein said PDE4 isozyme is the PDE4-D subtype isozyme.