JP2008056680A5 - - Google Patents

Claims (5)

Formula (1):

Or, where appropriate, a pharmaceutical composition comprising at least an effective amount of a pharmaceutically acceptable salt or solvate thereof,
In the above formula, the (CH ₂ ) _n —C (═O) Q ¹ group is present at the meta or para position,
R ¹ and R ² are independently selected from H and C ₁ -C ₄ alkyl;
n is 0, 1 or 2;
Q ¹ is

Wherein p is 1 or 2 and q is 1 or 2, optionally in a group bridged by one carbon atom,

And ^* —NR ⁸ -Q ² -A [wherein Q ² is C ₁ -C ₄ alkylene, R ⁸ is H or C ₁ -C ₄ alkyl, A is pyridyl, C ₃ -C ₁₀ cyclo Alkyl (the cycloalkyl is optionally bridged by one or more carbon atoms), tetrahydropyranyl, piperidinyl, tetrahydrothiopyranyl or

A group selected from the groups represented by:
R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are the same or different and are H, C ₁ -C ₄ alkyl, OR ⁹ , SR ⁹ , SOR ⁹ , SO ₂ R ⁹ , halo, CO _{2. ^{R 9, CF 3, CN,}} OCF 3, SO 2 NR 9 R 10, CONR 9 R 10, NR 9 R 10, NHCOR 10 and, oR ^9, 1 to 3 selected from halo and _C 1 -C ₄ alkyl Selected from phenyl optionally substituted with 1 group;
R ⁹ and R ¹⁰ are the same or different and are selected from H or C ₁ -C ₄ alkyl; ^★ represents the point of attachment to the carbonyl group;
Because
following:
Asthma regardless of type, etiology or pathogenesis, especially caused by atopic asthma, non-atopic asthma, allergic asthma, atopic bronchial IgE-mediated asthma, bronchial asthma, essential asthma, true asthma, pathophysiological disorder Endogenous asthma, extrinsic asthma caused by environmental factors, essential asthma of unknown or occult cause, non-atopic asthma, bronchitis asthma, emphysema asthma, exercise-induced asthma, allergen-induced asthma, A member selected from the group consisting of cold-induced asthma, occupational asthma, infectious asthma caused by bacterial, fungal, protozoan or viral infections, non-allergic asthma, early asthma, infant Zeyze syndrome and bronchiolitis Some asthma;
Chronic or acute bronchoconstriction, chronic bronchitis, peripheral airway obstruction, and emphysema;
Includes obstructive or inflammatory airway diseases of any type, etiology or pathology, especially dyspnea associated with or not related to chronic eosinophilic pneumonia, chronic obstructive pulmonary disease (COPD), chronic bronchitis, emphysema or COPD From the group consisting of COPD, COPD characterized by irreversible progressive airway obstruction, adult respiratory distress syndrome (ARDS), exacerbation of airway hypersensitivity resulting from other medications, and airway disease associated with pulmonary hypertension An obstructive or inflammatory airway disease that is a selected member;
Bronchitis regardless of type, etiology or pathogen, especially acute bronchitis, acute laryngeal bronchitis, arachidic acid bronchitis, catarrhal bronchitis, croup bronchitis, dry bronchitis, infectious asthmatic bronchitis, proliferative Bronchitis, a member selected from the group consisting of bronchitis, staphylococcal or streptococcal bronchitis, and alveolar bronchitis;
Acute lung injury;
Bronchiectasis regardless of type, etiology or pathogenesis, in particular columnar bronchiectasis, saccular bronchiectasis, fusiform bronchiectasis, capillary bronchiectasis, cystic bronchiectasis, dry bronchiectasis and follicles A pharmaceutical composition for use in the treatment of diseases, disorders and conditions, selected from the group consisting of bronchiectasis, which is a member selected from the group consisting of bronchiectasis. In formula (1),
R ¹ is H or CH ₃ , R ² is H or CH ₃ ,
n is 0 or 1,
Q ¹ is, ^★ in ^-NH-Q 2 -A [wherein, ^{Q 2} _{is, -CH 2 -, - (CH} 2) 2 -, - (CH 2) 3 -, - CH 2 -C (CH 3) ₂ - or -C _{(CH 3) 2} - and is,
A is

In the above formula, R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are the same or different, and H, OH, CH ₃ , OCH ₃ , OCF ₃ , OCH ₂ — CH ₃ , SCH ₃ , N (CH ₃ ) ₂ , N (C═O) CH ₃ , C (═O) NH ₂ , COOCH ₃ , SO ₂ CH ₃ , SO ₂ NH ₂ , CN, halo, CF _{3 and} Wherein R is selected from phenyl optionally substituted with OH]. A pharmaceutical composition comprising at least an effective amount of a compound of formula (1) according to claim 1. A compound of formula (1) according to claim 1 and:
(A) a 5-lipoxygenase (5-LO) inhibitor or a 5-lipoxygenase activating protein (FLAP) antagonist,
(B) Leukotriene antagonists (LTRAs), including antagonists of LTB ₄ , LTC ₄ , LTD ₄ and LTE ₄ ;
(C) histamine receptor antagonists, including H1 and H3 antagonists,
(D) α ₁ -and α ₂ -adrenergic receptor agonist vasoconstrictor sympathomimetic drugs for decongestants,
(E) a muscarinic M3 receptor antagonist or anticholinergic agent;
(F) PDE inhibitors, such as PDE3, PDE4 and PDE5 inhibitors,
(G) theophylline,
(H) sodium cromoglycate,
(I) COX inhibitors, both non-selective and selective COX-1 or COX-2 inhibitors (NSAIDs),
(J) oral and inhaled glucocorticosteroids,
(K) a monoclonal antibody active against the endogenous inflammatory entity,
(L) an anti-tumor necrosis factor (anti-TNF-α) agent,
(M) an adhesion molecule inhibitor comprising a VLA-4 antagonist;
(N) kinin-B ₁ -and B ₂ -receptor antagonists,
(O) an immunosuppressant,
(P) inhibitors of matrix metalloproteases (MMPs),
(Q) tachykinin NK ₁ , NK ₂ and NK ₃ receptor antagonists,
(R) an elastase inhibitor,
(S) an adenosine A2a receptor agonist,
(T) an inhibitor of urokinase,
(U) a compound acting on a dopamine receptor, such as a D2 agonist,
(V) a modulator of the NFκβ pathway, such as an IKK inhibitor,
(W) modulators of cytokine signaling pathways, such as p38 MAP kinase or syk kinase,
(X) agents that can be classified as mucolytics or antitussives (y) antibiotics,
A medicament that is a combination with (z) an HDAC inhibitor and (aa) other therapeutic agent (s) selected from PI3 kinase inhibitors. Other therapeutic agents include:
An H3 antagonist,
Muscarinic M3 receptor antagonist,
A PDE4 inhibitor,
Glucocorticosteroids,
An adenosine A2a receptor agonist,
Selected from the group consisting of leukotriene antagonists (LTRAs), including modulators of cytokine signaling pathways, such as p38 MAP kinase or syk kinase, or antagonists of LTB ₄ , LTC ₄ , LTD ₄ and LTE ₄ ,
The medicament according to claim 3. In the compound of formula (1):
R ¹ is H or CH ₃ , R ² is H or CH ₃ ,
n is 0 or 1,
Q ¹ is ^* -NH-Q ² -A [wherein Q ² is —CH ₂ —, — (CH ₂ ) ₂ —, — (CH ₂ ) ₃ —, —CH ₂ —C (CH ₃ ). ₂ - or -C _{(CH 3) 2} - and is,
A is

In the above formula, R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are the same or different, and H, OH, CH ₃ , OCH ₃ , OCF ₃ , OCH ₂ — CH ₃ , SCH ₃ , N (CH ₃ ) ₂ , N (C═O) CH ₃ , C (═O) NH ₂ , COOCH ₃ , SO ₂ CH ₃ , SO ₂ NH ₂ , CN, halo, CF _{3 and} , Selected from phenyl optionally substituted with OH]. The pharmaceutical according to claim 3 or 4.