US2004053953A1PendingUtilityA1
Treatment of chemokine mediated diseases
Est. expiryMar 18, 2022(expired)· nominal 20-yr term from priority
Inventors:Arthur G. TaverasMotasim BillahDaniel LundellWilliam KreutnerJames P. JakwayJay FineLoretta A. BoberJianhua ChaoPurakkattle BijuYounong Yu
A61P 9/10A61P 7/02A61P 9/00A61P 37/08A61P 7/00A61P 37/06A61P 25/02A61P 31/16A61P 31/04A61P 25/28A61P 25/00A61P 31/12A61P 27/02A61P 27/00A61P 35/00A61P 29/00A61P 33/06A61P 3/00A61P 31/18A61P 17/02A61P 17/06A61K 45/06A61P 1/16A61P 1/00A61P 11/08A61P 11/02A61P 1/02A61P 19/10A61P 11/00A61P 17/00A61P 19/02A61P 15/00A61P 19/00A61P 1/04A61P 19/06A61P 21/00A61P 1/18A61P 11/06A61P 13/12
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Claims
Abstract
Methods of treating chemokine-mediated diseases are disclosed. The methods comprise the administration of CXC-Chemokine receptor antagonists of the formula or pharmaceutically acceptable salts or solvates thereof, in combination with other classes of pharmaceutical compounds. The chemokine-mediated diseases include acute and chronic inflammatory disorders, psoriasis, cystic fibrosis, asthma and cancer. Also disclosed are novel compounds of formula (I).
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A method of treating a CXC chemokine mediated disease comprising administering to a patient in need of such treatment, a therapeutically effective amount of:
(a) One or more compounds of the formula (I): or a pharmaceutically acceptable salt or solvate thereof; and (b) One or more drugs, agents or therapeutics useful for the treatment of chemokine mediated diseases; wherein for said compounds of formula (I):
A is selected from the group consisting of:
wherein the above rings of said A groups are substituted with 1 to 6 substituents each independently selected from the group consisting of: R 9 groups;
wherein one or both of the above rings of said A groups are substituted with 1 to 6 substituents each independently selected from the group consisting of: R 9 groups;
wherein the above phenyl rings of said A groups are substituted with 1 to 3 substituents each independently selected from the group consisting of: R 9 groups; and
B is selected from the group consisting of
n is 0 to 6; p is 1 to 5; X is O, NH, or S; Z is 1 to 3; R 2 is selected from the group consisting of: hydrogen, OH, —C(O)OH, —SH, —SO 2 NR 13 R 14 , —NHC(O)R 13 , —NHSO 2 NR 13 R 14 , —NHSO 2 R 13 , —NR 13 R 14 , —C(O)NR 13 R 14 , —C(O)NHOR 13 , —C(O)NR 13 OH, —S(O 2 )OH, —OC(O)R 13 , an unsubstituted heterocyclic acidic functional group, and a substituted heterocyclic acidic functional group; wherein there are 1 to 6 substituents on said substituted heterocyclic acidic functional group each substituent being independently selected from the group consisting of: R 9 groups; each R 3 and R 4 is independently selected from the group consisting of: hydrogen, cyano, halogen, alkyl, alkoxy, —OH, —CF 3 , —OCF 3 , —NO 2 , —C(O)R 13 , —C(O)oR 13 , —C(O)NHR 17 , —C(O)NR 13 R 14 , —SO (t) NR 13 R 14 , —SO (t) R 13 , —C(O)NR 13 OR 14 , unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, wherein there are 1 to 6 substituents on said substituted aryl group and each substituent is independently selected from the group consisting of: R 9 groups; and wherein there are 1 to 6 substituents on said substituted heteroaryl group and each substituent is independently selected from the group consisting of: R 9 groups; each R 5 and R 6 are the same or different and are independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, —CF 3 , —OCF 3 , —NO 2 , —C(O)R 13 , —C(O)OR 13 , —C(O)NR 13 R 14 , —SO (t) NR 13 R 14 , —C(O)NR 13 OR 14 , cyano, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl group; wherein there are 1 to 6 substituents on said substituted aryl group and each substituent is independently selected from the group consisting of: R 9 groups; and wherein there are 1 to 6 substituents on said substituted heteroaryl group and each substituent is independently selected from the group consisting of: R 9 groups; each R 7 and R 8 is independently selected from the group consisting of: H, unsubstituted or substituted alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkylalkyl, —CO 2 R 13 , —CONR 13 R 14 , alkynyl, alkenyl, and cycloalkenyl; and wherein there are one or more substituents on said substituted R 7 and R 8 groups, wherein each substitutent is independently selected from the group consisting of:
a) halogen,
b) —CF 3 ,
c) —COR 13 ,
d) —OR 13 ,
e) —NR 13 R 14
f) —NO 2 ,
g) —CN,
h) —SO 2 OR 13 ,
i) —Si(alkyl) 3 , wherein each alkyl is independently selected,
j) —Si(aryl) 3 , wherein each alkyl is independently selected,
k) —(R 13 ) 2 R 14 Si, wherein each R 13 is independently selected,
l) —CO 2 R 13 ,
m) —C(O)NR 13 R 14 ,
n) —SO 2 NR 13 R 14 ,
o) —SO 2 R 13 ,
p) —OC(O)R 13 ,
q) —OC(O)NR 13 R 14 ,
r) —NR 13 C(O)R 14 , and
s) —NR 13 CO 2 R 14 ;
R 8a is selected from the group consisting of: hydrogen, alkyl, cycloalkyl and cycloalkylalkyl; each R 9 is independently selected from the group consisting of:
a) —R 13 ,
b) halogen,
c) —CF 3 ,
d) —COR 13 ,
e) —OR 13 ,
f) —NR 13 R 14 ,
g) —NO 2 ,
h) —CN,
i) —SO 2 R 13 ,
j) —SO 2 NR 13 R 14 ,
k) —NR 13 COR 14 ,
l) —CONR 13 R 14 ,
m) —NR 13 CO 2 R 14 ,
n) —CO 2 R 13 ,
o)
p) alkyl substituted with one or more —OH groups,
q) alkyl substituted with one or more —NR 13 R 14 group, and
r) —N(R 13 )SO 2 R 14 ;
each R 10 and R 11 is independently selected from the group consisting of R 13 , halogen, —CF 3 , —OCF 3 , —NR 13 R 14 , —NR 13 C(O)NR 13 R 14 , —OH, —C(O)OR 13 , —SH, —SO (t) NR 13 R 14 , —SO 2 R 13 , —NHC(O)R 13 , —NHSO 2 NR 13 R 14 , —NHSO 2 R 13 , —C(O)NR 13 R 14 , —C(O)NR 13 0R 14 , —OC(O)R 13 and cyano; R 12 is selected from the group consisting of: hydrogen, —C(O)OR 13 , unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkylalkyl, and unsubstituted or substituted heteroarylalkyl group; wherein there are 1 to 6 substituents on the substituted R 12 groups and each substituent is independently selected from the group consisting of: R 9 groups; each R 13 and R 14 is independently selected from the group consisting of: H, unsubstituted or substituted alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted fluoroalkyl, and unsubstituted or substituted heterocycloalkylalkyl (wherein “heterocyloalkyl” means heterocyclic); wherein there are 1 to 6 substituents on said substituted R 13 and R 14 groups and each substituent is independently selected from the group consisting of: alkyl, —CF 3 , —OH, alkoxy, aryl, arylalkyl, fluroalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, —N(R 40 ) 2 , —C(O)OR 15 , —C(O)NR 15 R 16 , —S(O) t NR 15 R 16 , —C(O)R 15 , —SO 2 R 15 provided that R 15 is not H, halogen, and —NHC(O)NR 15 R 16 ; or R 13 and R 14 taken together with the nitrogen they are attached to in the groups —C(O)NR 13 R 14 and —SO 2 NR 13 R 14 form an unsubstituted or substituted saturated heterocyclic ring (preferably a 3 to 7 membered heterocyclic ring), said ring optionally containing one additional heteroatom selected from the group consisting of: O, S and NR 18 ; wherein there are 1 to 3 substituents on the substituted cyclized R 13 and R 14 groups (i.e., there is 1 to 3 substituents on the ring formed when the R 13 and R 14 groups are taken together with the nitrogen to which they are bound) and each substituent is independently selected from the group consisting of: alkyl, aryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, arylalkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, amino, —C(O)OR 15 , —C(O)NR 15 R 16 , —SO t NR 15 R 16 , —C(O)R 15 , —SO 2 R 15 provided that R 15 is not H, —NHC(O)NR 15 R 16 , —NHC(O)OR 15 , halogen, and a heterocycloalkenyl group; each R 15 and R 16 is independently selected from the group consisting of: H, alkyl, aryl, arylalkyl, cycloalkyl and heteroaryl; R 17 is selected from the group consisting of: —SO 2 alkyl, —SO 2 aryl, —SO 2 cycloalkyl, and —SO 2 heteroaryl; R 18 is selected from the group consisting of: H, alkyl, aryl, heteroaryl, —C(O)R 19 , —SO 2 R 19 and —C(O)NR 19 R 20 ; each R 19 and R 20 is independently selected from the group consisting of: alkyl, aryl and heteroaryl; R 30 is selected from the group consisting of: alkyl, cycloalkyl, —CN, —NO 2 , or —SO 2 R 15 provided that R 15 is not H; each R 31 is independently selected from the group consisting of: unsubstituted alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl and unsubstituted or substituted cycloalkyl; wherein there are 1 to 6 substituents on said substituted R 31 groups and each substituent is independently selected from the group consisting of: alkyl, halogen and —CF 3 ; each R 40 is independently selected from the group consisting of: H, alkyl and cycloalkyl; g is 1 or 2; and t is 0, 1 or 2.
2 . The method of claim 1 wherein B is selected from the group consisting of:
and R 3 for this B group is selected from the group consisting of: —C(O)NR 13 R 14 ,
and all other substituents are as defined in claim 1 .
3 . The method of claim 3 wherein substituent A is
wherein the furan ring is unsubstituted or substitued.
4 . The method of claim 1 wherein B is:
R 2 is —OH, R 13 and R 14 are independently selected from the group consisting of H and alkyl.
5 . The method of claim 3 wherein wherein B is:
R 2 is —OH, R 13 and R 14 are independently selected from the group consisting of H and alkyl.
6 . The method of claim 1 wherein B is selected from the group consisting of:
7 . The method of claim 6 wherein B is
8 . The method of claim 1 wherein A is selected from the group consisting of:
9 . The method of claim 8 wherein A is selected from the group consisting of:
10 . The method of claim 9 wherein A is
11 . The method of claim 1 wherein said compounds of formula (I) are selected from the group consisting of:
12 . The method of claim 1 wherein said compounds of formula (I) are selected from the group consisting of:
13 . The method of claim 1 wherein said compounds of formula (I) are selected from the group consisting of:
14 . The method of claim 13 wherein said compound is a calcium or sodium salt.
15 . The method of claim 1 wherein said compound is:
or a pharmaceutically acceptable salt or solvate thereof.
16 . The method of claim 1 wherein said compound is:
or a pharmaceutically acceptable salt or solvate thereof.
17 . The method of claim 1 wherein said compound is:
or a pharmaceutically acceptable salt or solvate thereof.
18 . The method of claim 1 wherein said compound is:
or a pharmaceutically acceptable salt or solvate thereof.
19 . The method of claim 1 wherein said compound is:
or a pharmaceutically acceptable salt or solvate thereof.
20 . The method of claim 1 wherein said compound is:
or a pharmaceutically acceptable salt or solvate thereof.
21 . The method of claim 1 wherein said compound is:
or a pharmaceutically acceptable salt or solvate thereof.
22 . The method of claim 1 wherein said compound is:
or a pharmaceutically acceptable salt or solvate thereof.
23 . The method of claim 1 wherein said compound is:
or a pharmaceutically acceptable salt or solvate thereof.
24 . The method of claim 1 wherein said compound is:
or a pharmaceutically acceptable salt or solvate thereof.
25 . The method of claim 1 wherein said compound is:
or a pharmaceutically acceptable salt or solvate thereof.
26 . The compound of claim 1 wherein said compound is:
or a pharmaceutically acceptable salt or solvate thereof.
27 . The method of claim 1 wherein said compound is:
or a pharmaceutically acceptable salt or solvate thereof.
28 . The method of claim 1 wherein said compound is:
or a pharmaceutically acceptable salt or solvate thereof.
29 . The method of claim 1 wherein said compound is:
or a pharmaceutically acceptable salt or solvate thereof.
30 . The method of claim 25 wherein said compound is a calcium or sodium salt.
31 . The method of claim 1 wherein said compound is:
or a pharmaceutically acceptable salt or solvate thereof.
32 . The method of claim 1 wherein said compound is:
or a pharmaceutically acceptable salt or solvate thereof.
33 . The method of claim 1 wherein said compound is:
or a pharmaceutically acceptable salt or solvate thereof.
34 . The method of claim 1 wherein said compound is:
or a pharmaceutically acceptable salt or solvate thereof.
35 . The method of claim 1 wherein said compound is:
or a pharmaceutically acceptable salt or solvate thereof.
36 . The method of claim 1 wherein said compound is:
or a pharmaceutically acceptable salt or solvate thereof.
37 . The method of claim 1 wherein said compound is:
or a pharmaceutically acceptable salt or solvate thereof.
38 . The method of claim 1 wherein said compound is:
or a pharmaceutically acceptable salt or solvate thereof.
39 . The method of claim 1 wherein said compound is:
or a pharmaceutically acceptable salt or solvate thereof.
40 . The method of claim 1 wherein said compound is:
or a pharmaceutically acceptable salt or solvate thereof.
41 . The method of claim 1 wherein said compound is:
or a pharmaceutically acceptable salt or solvate thereof.
42 . The method of claim 1 wherein said drug, agent or therapeutic used in combination with said compounds of formula (I) is selected from the group consisting of
(a) a disease modifying antirheumatic drug;
(b) a nonsteroidal anitinflammatory drug;
(c) a COX-2 selective inhibitor;
(d) a COX-1 inhibitor;
(e) an immunosuppressive;
(f) a steroid;
(g) a biological response modifier and
(h) other anti-inflammatory agents or therapeutics useful for the treatment of chemokine mediated diseases.
43 . The method of claim 42 wherein said disease modifying antirheumatic drug is selected from the group consisting of methotrexate, azathioptrine luflunomide, penicillamine, gold salts, mycophenolate, mofetil and cyclophosphamide.
44 . The method of claim 42 wherein said nonsteroidal anitinflammatory drug is selected from the group consisting of piroxicam, ketoprofen, naproxen, indomethacin, and ibuprofen.
45 . The method of claim 42 wherein said COX-2 selective inhibitor is selected from the group consisting of rofecoxib and celecoxib.
46 . The method of claim 42 wherein said COX-1 inhibitor is piroxicam.
47 . The method of claim 42 wherein said immunosuppressive is selected from the group consisting of methotrexate, cyclosporin, leflunimide, tacrolimus, rapamycin and sulfasalazine.
48 . The method of claim 42 wherein said steroid is selected from the group consisting of β-methasone, prednisone, cortisone, prednisolone and dexamethasone.
49 . The method of claim 42 wherein said biological response modifier is selected from the group consisting of anti-TNF antagonists, IL-1 antagonists, anti-CD40, anti-CD28, IL-10 and anti-adhesion molecules.
50 . The method of claim 42 wherein said other anti-inflammatory agents or therapeutics are selected from the group consisting of p38 kinase inhibitors, PDE4 inhibitors, TACE inhibitors, chemokine receptor antagonists, thalidomide, leukotriene inhibitors and other small molecule inhibitors of pro-inflammatory cytokine production.
51 . The method of claim 1 wherein said chemokine mediated disease is selected from the group consisting of psoriasis, atopic dermatitis, asthma, COPD, adult respiratory disease, arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, stroke, cardiac and renal reperfusion injury, glomerulonephritis, thrombosis, Alzheimer's disease, graft vs. host reaction, allograft rejections, malaria, acute respiratory distress syndrome, delayed type hypersensitivity reaction, atherosclerosis, cerebral and cardiac ischemia, osteoarthritis, multiple sclerosis, restinosis, angiogenesis, osteoporosis, gingivitis, respiratory viruses, herpes viruses, hepatitis viruses, HIV, Kaposi's sarcoma associated virus, meningitis, cystic fibrosis, pre-term labor, cough, pruritis, multi-organ dysfunction, trauma, strains, sprains, contusions, psoriatic arthritis, herpes, encephalitis, CNS vasculitis, traumatic brain injury, CNS tumors, subarachnoid hemorrhage, post surgical trauma, interstitial pneumonitis, hypersensitivity, crystal induced arthritis, acute and chronic pancreatitis, acute alcoholic hepatitis, necrotizing enterocolitis, chronic sinusitis, angiogenic ocular disease, ocular inflammation, retinopathy of prematurity, diabetic retinopathy, macular degeneration with the wet type preferred and corneal neovascularization, polymyositis, vasculitis, acne, gastric and duodenal ulcers, celiac disease, esophagitis, glossitis, airflow obstruction, airway hyperresponsiveness, bronchiectasis, bronchiolitis, bronchiolitis obliterans, chronic bronchitis, cor pulmonae, cough, dyspnea, emphysema, hypercapnea, hyperinflation, hypoxemia, hyperoxia-induced inflammations, hypoxia, surgical lung volume reduction, pulmonary fibrosis, pulmonary hypertension, right ventricular hypertrophy, peritonitis associated with continuous ambulatory peritoneal dialysis (CAPD), granulocytic ehrlichiosis, sarcoidosis, small airway disease, ventilation-perfusion mismatching, wheeze, colds, gout, alcoholic liver disease, lupus, burn therapy, periodontitis and early transplantation.
52 . The method of claim 1 wherein said chemokine mediated disease is a pulmonary disease and said one or more drugs, agents or therapeutics are selected from the group consisting of: glucocorticoids, 5-lipoxygenase inhibitors, β-2 adrenoceptor agonists, muscarinic M1 and M3 antagonists, muscarinic M2 agonists, NK3 antagonists, LTB4 antagonists, cysteinyl leukotriene antagonists, bronchodilators, PDE4 inhibitors, PDE inhibitors, elastase inhibitors, MMP inhibitors, phospholipase A2 inhibitors, phospholipase D inhibitors, histamine H1 antagonists, histamine H3 antagonists, dopamine agonists, adenosine A2 agonists, NK1 and NK2 antagonists, GABA-b agonists, nociceptin agonists, expectorants, mucolytic agents, decongestants, antioxidants, anti-IL-8 anti-bodies, anti-IL-5 antibodies, anti-IgE antibodies, anti-TNF antibodies, IL-10, adhesion molecule inhibitors, and growth hormones.
53 . The method of claim 52 wherein said pulmonary disease is COPD, asthma or cystic fibrosis.
54 . The method of claim 1 wherein said chemokine mediated disease is multiple sclerosis and said one or more drugs, agents or therapeutics are selected from the group consisting of methotrexate, cyclosporin, leflunimide, sulfasalazine, β-methasone, interferon, glatiramer acetate, prednisone, etonercept, and infliximab.
55 . The method of claim 1 wherein said chemokine mediated disease is rheumatoid arthritis and said one or more drugs, agents or therapeutics are selected from the group consisting of a COX-2 inhibitor, a COX inhibitor, an immunosuppressive, a steroid, a PDE IV inhibitor, an anti-TNF-α compound, MMP inhibitors, glucocorticoids, chemokine inhibitors, CB2-selective inhibiitors, and other classes of compounds indicated for the treatment of rheumatoid arthritis.
56 . The method of claim 1 wherein said chemokine mediated disease is stroke and cardiac reperfusion injury and said one or more drugs, agents or therapeutics are selected from the group consisting of thrombolitics, antiplatelet agents, gpIIb/IIIa antagonist, anticoagulants, other compounds indicated for the treatment of rheumatoid arthritis and formulations thereof.
57 . The method of claim 1 wherein said chemokine mediated disease is stroke and cardiac reperfusion injury and said one or more drugs, agents or therapeutics are selected from the group consisting of tenecteplase, TPA, alteplase, abciximab, eftiifbatide, heparin and formulations thereof.
58 . A compound of selected from the group consisting of:
or a pharmaceutically acceptable salt or solvate thereof.
59 . The compound of claim 58 wherein said compound is a sodium salt.
60 . The compound of claim 58 wherein said compound is a calcium salt.
61 . The compound of claim 58 wherein said compound is:
or a pharmaceutically acceptable salt or solvate thereof.
62 . The compound of claim 58 wherein said compound is:
or a pharmaceutically acceptable salt or solvate thereof.
63 . The compound of claim 58 wherein said compound is:
or a pharmaceutically acceptable salt or solvate thereof.
64 . The compound of claim 58 wherein said compound is:
or a pharmaceutically acceptable salt or solvate thereof.
65 . The compound of claim 58 wherein said compound is:
or a pharmaceutically acceptable salt or solvate thereof.Join the waitlist — get patent alerts
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