U.S. patent application number 10/390078 was filed with the patent office on 2004-03-18 for treatment of chemokine mediated diseases.
This patent application is currently assigned to Schering Corporation. Invention is credited to Biju, Purakkattle J., Billah, Motasim, Bober, Loretta A., Chao, Jianhua, Fine, Jay S., Jakway, James, Kreutner, William, Lundell, Daniel, Taveras, Arthur G., Yu, Younong.
Application Number | 20040053953 10/390078 |
Document ID | / |
Family ID | 28454639 |
Filed Date | 2004-03-18 |
United States Patent
Application |
20040053953 |
Kind Code |
A1 |
Taveras, Arthur G. ; et
al. |
March 18, 2004 |
Treatment of chemokine mediated diseases
Abstract
Methods of treating chemokine-mediated diseases are disclosed.
The methods comprise the administration of CXC-Chemokine receptor
antagonists of the formula 1 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).
Inventors: |
Taveras, Arthur G.;
(Denville, NJ) ; Billah, Motasim; (Edison, NJ)
; Lundell, Daniel; (Flemington, NJ) ; Kreutner,
William; (West Paterson, NJ) ; Jakway, James;
(Bridgewater, NJ) ; Fine, Jay S.; (Bloomfield,
NJ) ; Bober, Loretta A.; (Linden, NJ) ; Chao,
Jianhua; (Pompton Lakes, NJ) ; Biju, Purakkattle
J.; (Scotch Plains, NJ) ; Yu, Younong; (Scotch
Plains, NJ) |
Correspondence
Address: |
SCHERING-PLOUGH CORPORATION
PATENT DEPARTMENT (K-6-1, 1990)
2000 GALLOPING HILL ROAD
KENILWORTH
NJ
07033-0530
US
|
Assignee: |
Schering Corporation
|
Family ID: |
28454639 |
Appl. No.: |
10/390078 |
Filed: |
March 17, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60365314 |
Mar 18, 2002 |
|
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Current U.S.
Class: |
514/277 ;
514/357; 514/365; 514/374; 514/400; 514/471 |
Current CPC
Class: |
A61P 1/02 20180101; A61P
15/00 20180101; A61P 19/02 20180101; A61P 37/08 20180101; A61P 7/00
20180101; A61P 9/00 20180101; A61P 31/04 20180101; A61P 25/28
20180101; A61P 9/10 20180101; A61P 27/02 20180101; A61P 13/12
20180101; A61P 19/00 20180101; A61P 11/02 20180101; A61P 29/00
20180101; A61P 33/06 20180101; A61P 1/18 20180101; A61P 31/18
20180101; A61K 45/06 20130101; A61P 27/00 20180101; A61P 31/16
20180101; A61P 35/00 20180101; A61P 11/06 20180101; A61P 11/00
20180101; A61P 17/00 20180101; A61P 3/00 20180101; A61P 17/02
20180101; A61P 17/06 20180101; A61P 25/00 20180101; A61P 19/06
20180101; A61P 25/02 20180101; A61P 1/16 20180101; A61P 21/00
20180101; A61P 37/06 20180101; A61P 11/08 20180101; A61P 1/04
20180101; A61P 7/02 20180101; A61P 19/10 20180101; A61P 1/00
20180101; A61P 31/12 20180101 |
Class at
Publication: |
514/277 ;
514/365; 514/374; 514/400; 514/357; 514/471 |
International
Class: |
A61K 031/44; A61K
031/426; A61K 031/421; A61K 031/4172; A61K 031/34 |
Claims
What 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): 435or 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: 436437438439wherein the above rings of said A groups
are substituted with 1 to 6 substituents each independently
selected from the group consisting of: R.sup.9 groups; 440wherein
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.sup.9 groups; 441wherein the above phenyl rings of
said A groups are substituted with 1 to 3 substituents each
independently selected from the group consisting of: R.sup.9
groups; and 442B is selected from the group consisting of 443n is 0
to 6; p is 1 to 5; X is O, NH, or S; Z is 1 to 3; R.sup.2 is
selected from the group consisting of: hydrogen, OH, --C(O)OH,
--SH, --SO.sub.2NR.sup.13R.sup.14, --NHC(O)R.sup.13,
--NHSO.sub.2NR.sup.13R.sup.14, --NHSO.sub.2R.sup.13,
--NR.sup.13R.sup.14, --C(O)NR.sup.13R.sup.14, --C(O)NHOR.sup.13,
--C(O)NR.sup.13OH, --S(O.sub.2)OH, --OC(O)R.sup.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.sup.9 groups; each R.sup.3 and R.sup.4
is independently selected from the group consisting of: hydrogen,
cyano, halogen, alkyl, alkoxy, --OH, --CF.sub.3, --OCF.sub.3,
--NO.sub.2, --C(O)R.sup.13, --C(O)oR.sup.13, --C(O)NHR.sup.17,
--C(O)NR.sup.13R.sup.14, --SO.sub.(t)NR.sup.13R.sup.14,
--SO.sub.(t)R.sup.13, --C(O)NR.sup.13OR.sup.14, unsubstituted or
substituted aryl, unsubstituted or substituted heteroaryl,
444wherein there are 1 to 6 substituents on said substituted aryl
group and each substituent is independently selected from the group
consisting of: R.sup.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.sup.9 groups; each R.sup.5 and R.sup.6 are the same or different
and are independently selected from the group consisting of
hydrogen, halogen, alkyl, alkoxy, --CF.sub.3, --OCF.sub.3,
--NO.sub.2, --C(O)R.sup.13, --C(O)OR.sup.13,
--C(O)NR.sup.13R.sup.14, --SO.sub.(t)NR.sup.13R.sup.14,
--C(O)NR.sup.13OR.sup.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.sup.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.sup.9 groups; each R.sup.7
and R.sup.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.sub.2R.sup.13,
--CONR.sup.13R.sup.14, alkynyl, alkenyl, and cycloalkenyl; and
wherein there are one or more substituents on said substituted
R.sup.7 and R.sup.8 groups, wherein each substitutent is
independently selected from the group consisting of: a) halogen, b)
--CF.sub.3, c) --COR.sup.13, d) --OR.sup.13, e) --NR.sup.13R.sup.14
f) --NO.sub.2, g) --CN, h) --SO.sub.2OR.sup.13, i)
--Si(alkyl).sub.3, wherein each alkyl is independently selected, j)
--Si(aryl).sub.3, wherein each alkyl is independently selected, k)
--(R.sup.13).sub.2R.sup.14Si, wherein each R.sup.13 is
independently selected, l) --CO.sub.2R.sup.13, m)
--C(O)NR.sup.13R.sup.14, n) --SO.sub.2NR.sup.13R.sup.14, o)
--SO.sub.2R.sup.13, p) --OC(O)R.sup.13, q)
--OC(O)NR.sup.13R.sup.14, r) --NR.sup.13C(O)R.sup.14, and s)
--NR.sup.13CO.sub.2R.sup.14; R.sup.8a is selected from the group
consisting of: hydrogen, alkyl, cycloalkyl and cycloalkylalkyl;
each R.sup.9 is independently selected from the group consisting
of: a) --R.sup.13, b) halogen, c) --CF.sub.3, d) --COR.sup.13, e)
--OR.sup.13, f) --NR.sup.13R.sup.14, g) --NO.sub.2, h) --CN, i)
--SO.sub.2R.sup.13, j) --SO.sub.2NR.sup.13R.sup.14, k)
--NR.sup.13COR.sup.14, l) --CONR.sup.13R.sup.14, m)
--NR.sup.13CO.sub.2R.sup.14, n) --CO.sub.2R.sup.13, o) 445p) alkyl
substituted with one or more --OH groups, q) alkyl substituted with
one or more --NR.sup.13R.sup.14 group, and r)
--N(R.sup.13)SO.sub.2R.sup.14; each R.sup.10 and R.sup.11 is
independently selected from the group consisting of R.sup.13,
halogen, --CF.sub.3, --OCF.sub.3, --NR.sup.13R.sup.14,
--NR.sup.13C(O)NR.sup.13R.sup.14, --OH, --C(O)OR.sup.13, --SH,
--SO.sub.(t)NR.sup.13R.sup.14, --SO.sub.2R.sup.13,
--NHC(O)R.sup.13, --NHSO.sub.2NR.sup.13R.sup.14,
--NHSO.sub.2R.sup.13, --C(O)NR.sup.13R.sup.14,
--C(O)NR.sup.130R.sup.14, --OC(O)R.sup.13 and cyano; R.sup.12 is
selected from the group consisting of: hydrogen, --C(O)OR.sup.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.sup.12 groups and each
substituent is independently selected from the group consisting of:
R.sup.9 groups; each R.sup.13 and R.sup.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.sup.13 and R.sup.14 groups and each substituent is
independently selected from the group consisting of: alkyl,
--CF.sub.3, --OH, alkoxy, aryl, arylalkyl, fluroalkyl, cycloalkyl,
cycloalkylalkyl, heteroaryl, heteroarylalkyl, --N(R.sup.40).sub.2,
--C(O)OR.sup.15, --C(O)NR.sup.15R.sup.16,
--S(O).sub.tNR.sup.15R.sup.16, --C(O)R.sup.15, --SO.sub.2R.sup.15
provided that R.sup.15 is not H, halogen, and
--NHC(O)NR.sup.15R.sup.16; or R.sup.13 and R.sup.14 taken together
with the nitrogen they are attached to in the groups
--C(O)NR.sup.13R.sup.14 and --SO.sub.2NR.sup.13R.sup.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.sup.18; wherein there are 1 to 3
substituents on the substituted cyclized R.sup.13 and R.sup.14
groups (i.e., there is 1 to 3 substituents on the ring formed when
the R.sup.13 and R.sup.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.sup.15, --C(O)NR.sup.15R.sup.16,
--SO.sub.tNR.sup.15R.sup.16, --C(O)R.sup.15, --SO.sub.2R.sup.15
provided that R.sup.15 is not H, --NHC(O)NR.sup.15R.sup.16,
--NHC(O)OR.sup.15, halogen, and a heterocycloalkenyl group; each
R.sup.15 and R.sup.16 is independently selected from the group
consisting of: H, alkyl, aryl, arylalkyl, cycloalkyl and
heteroaryl; R.sup.17 is selected from the group consisting of:
--SO.sub.2alkyl, --SO.sub.2aryl, --SO.sub.2cycloalkyl, and
--SO.sub.2heteroaryl; R.sup.18 is selected from the group
consisting of: H, alkyl, aryl, heteroaryl, --C(O)R.sup.19,
--SO.sub.2R.sup.19 and --C(O)NR.sup.19R.sup.20; each R.sup.19 and
R.sup.20 is independently selected from the group consisting of:
alkyl, aryl and heteroaryl; R.sup.30 is selected from the group
consisting of: alkyl, cycloalkyl, --CN, --NO.sub.2, or
--SO.sub.2R.sup.15 provided that R.sup.15 is not H; each R.sup.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.sup.31 groups and each substituent is
independently selected from the group consisting of: alkyl, halogen
and --CF.sub.3; each R.sup.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: 446and R.sup.3 for this B group is selected from the
group consisting of: --C(O)NR.sup.13R.sup.14, 447and all other
substituents are as defined in claim 1.
3. The method of claim 3 wherein substituent A is 448wherein the
furan ring is unsubstituted or substitued.
4. The method of claim 1 wherein B is: 449R.sup.2 is --OH, R.sup.13
and R.sup.14 are independently selected from the group consisting
of H and alkyl.
5. The method of claim 3 wherein wherein B is: 450R.sup.2 is --OH,
R.sup.13 and R.sup.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: 451
7. The method of claim 6 wherein B is 452
8. The method of claim 1 wherein A is selected from the group
consisting of: 453454
9. The method of claim 8 wherein A is selected from the group
consisting of: 455
10. The method of claim 9 wherein A is 456
11. The method of claim 1 wherein said compounds of formula (I) are
selected from the group consisting of:
457458459460461462463464465466467- 468469470471472473474475476
12. The method of claim 1 wherein said compounds of formula (I) are
selected from the group consisting of:
477478479480481482483484485486487- 488
13. The method of claim 1 wherein said compounds of formula (I) are
selected from the group consisting of: 489490491492
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: 493or a
pharmaceutically acceptable salt or solvate thereof.
16. The method of claim 1 wherein said compound is: 494or a
pharmaceutically acceptable salt or solvate thereof.
17. The method of claim 1 wherein said compound is: 495or a
pharmaceutically acceptable salt or solvate thereof.
18. The method of claim 1 wherein said compound is: 496or a
pharmaceutically acceptable salt or solvate thereof.
19. The method of claim 1 wherein said compound is: 497or a
pharmaceutically acceptable salt or solvate thereof.
20. The method of claim 1 wherein said compound is: 498or a
pharmaceutically acceptable salt or solvate thereof.
21. The method of claim 1 wherein said compound is: 499or a
pharmaceutically acceptable salt or solvate thereof.
22. The method of claim 1 wherein said compound is: 500or a
pharmaceutically acceptable salt or solvate thereof.
23. The method of claim 1 wherein said compound is: 501or a
pharmaceutically acceptable salt or solvate thereof.
24. The method of claim 1 wherein said compound is: 502or a
pharmaceutically acceptable salt or solvate thereof.
25. The method of claim 1 wherein said compound is: 503or a
pharmaceutically acceptable salt or solvate thereof.
26. The compound of claim 1 wherein said compound is: 504or a
pharmaceutically acceptable salt or solvate thereof.
27. The method of claim 1 wherein said compound is: 505or a
pharmaceutically acceptable salt or solvate thereof.
28. The method of claim 1 wherein said compound is: 506or a
pharmaceutically acceptable salt or solvate thereof.
29. The method of claim 1 wherein said compound is: 507or 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: 508or a
pharmaceutically acceptable salt or solvate thereof.
32. The method of claim 1 wherein said compound is: 509or a
pharmaceutically acceptable salt or solvate thereof.
33. The method of claim 1 wherein said compound is: 510or a
pharmaceutically acceptable salt or solvate thereof.
34. The method of claim 1 wherein said compound is: 511or a
pharmaceutically acceptable salt or solvate thereof.
35. The method of claim 1 wherein said compound is: 512or a
pharmaceutically acceptable salt or solvate thereof.
36. The method of claim 1 wherein said compound is: 513or a
pharmaceutically acceptable salt or solvate thereof.
37. The method of claim 1 wherein said compound is: 514or a
pharmaceutically acceptable salt or solvate thereof.
38. The method of claim 1 wherein said compound is: 515or a
pharmaceutically acceptable salt or solvate thereof.
39. The method of claim 1 wherein said compound is: 516or a
pharmaceutically acceptable salt or solvate thereof.
40. The method of claim 1 wherein said compound is: 517or a
pharmaceutically acceptable salt or solvate thereof.
41. The method of claim 1 wherein said compound is: 518or 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 .beta.-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, .beta.-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,
.beta.-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-.alpha. 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: 519or 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: 520or a
pharmaceutically acceptable salt or solvate thereof.
62. The compound of claim 58 wherein said compound is: 521or a
pharmaceutically acceptable salt or solvate thereof.
63. The compound of claim 58 wherein said compound is: 522or a
pharmaceutically acceptable salt or solvate thereof.
64. The compound of claim 58 wherein said compound is: 523or a
pharmaceutically acceptable salt or solvate thereof.
65. The compound of claim 58 wherein said compound is: 524or a
pharmaceutically acceptable salt or solvate thereof.
Description
REFERENCE TO RELATED APPLICATION
[0001] This application claims the benefit of U.S. Provisional
Application No. 60/365,314 filed Mar. 18, 2002, the disclosure of
which is incorporated herein by reference thereto.
FIELD OF THE INVENTION
[0002] This invention relates to the treatment of chemokine
mediated diseases using CXC chemokine receptor antagonists in
combination (or association) with other pharmaceutical
compounds.
BACKGROUND OF THE INVENTION
[0003] Chemokines are chemotactic cytokines that are released by a
wide variety of cells to attract macrophages, T-cells, eosinophils,
basophils, neutrophils and endothelial cells to sites of
inflammation and tumor growth. There are two main classes of
chemokines, the CXC-chemokines and the CC-- chemokines. The class
depends on whether the first two cysteines are separated by a
single amino acid (CXC-chemokines) or are adjacent (CC-chemokines).
The CXC-chemokines include interleukin-8 (IL-8),
neutrophil-activating protein-1 (NAP-1), neutrophil-activating
protein-2 (NAP-2), GRO.alpha., GRO.beta., GRO.gamma., ENA-78,
GCP-2, IP-10, MIG and PF4. CC chemokines include RANTES,
MIP-1.alpha., MIP-2.beta., monocyte chemotactic protein-1 (MCP-1),
MCP-2, MCP-3 and eotaxin. Individual members of the chemokine
families are known to be bound by at least one chemokine receptor,
with CXC-chemokines generally bound by members of the CXCR class of
receptors, and CC-chemokines by members of the CCR class of
receptors. For example, IL-8 is bound by the CXCR-1 and CXCR-2
receptors.
[0004] Since CXC-chemokines promote the accumulation and activation
of neutrophils, these chemokines have been implicated in a wide
range of acute and chronic inflammatory disorders including
psoriasis and rheumatoid arthritis. Baggiolini et al., FEBS Left.
307, 97 (1992); Miller et al., Crit. Rev. Immunol. 12, 17 (1992);
Oppenheim et al., Annu. Fev. Immunol. 9, 617 (1991); Seitz et al.,
J. Clin. Invest. 87, 463 (1991); Miller et al., Am. Rev. Respir.
Dis. 146, 427 (1992); Donnely et al., Lancet 341,643(1993).
[0005] Hence, the CXC-chemokine receptors represent promising
targets for the development of novel anti-inflammatory agents.
[0006] There remains a need for an improved method of treating
CXC-chemokine mediated diseases. For example, conditions associated
with an increase in IL-8 production (which is responsible for
chemotaxis of neutrophil and T-cell subsets into the inflammatory
site) would benefit by an improved method that inhibits IL-8
receptor binding. Such an improved method is provided by this
invention.
SUMMARY OF THE INVENTION
[0007] This invention provides a method of treating a CXC chemokine
mediated disease comprising administering to a patient (i.e., a
mammal, e.g. human) in need of such treatment, a therapeutically
effective amount of:
[0008] (a) One or more (e.g., one) compounds of the formula (I):
2
[0009] or a pharmaceutically acceptable salt or solvate thereof;
and
[0010] (b) One or more drugs, agents or therapeutics useful for the
treatment of chemokine mediated diseases.
[0011] In one embodiment, the invention provides a method of
treating a chemokine mediated disease comprising administering to a
patient (e.g., a human) in need of such treatment, an effective
amount of one or more (e.g., one) compounds of formula (I) in
combination (or association) with an effective amount of one or
more disease modifying antirheumatic drugs (DMARDs) such as, for
example, methotrexate, azathioptrine, luflunomide, penicillamine,
gold salts, mycophenolate, mofetil, cyclophosphamide and the
like.
[0012] In another embodiment, the invention provides a method of
treating a chemokine mediated disease comprising administering to a
patient (e.g., a human) in need of such treatment, an effective
amount of one or more (e.g., one) compounds of formula (I) in
combination (or association) with an effective amount of one or
more nonsteroidal anti-inflammatory drugs (NSAIDS) such as, for
example, piroxicam, ketoprofen, naproxen, indomethacin, ibuprofen
and the like.
[0013] In another embodiment the invention provides a method of
treating a chemokine mediated disease comprising administering to a
patient (e.g., a human) in need of such treatment, an effective
amount of one or more (e.g., one) compounds of formula (I) in
combination (or association) with an effective amount of one or
more compounds selected from the group consisting of:
[0014] (a) a disease modifying antirheumatic drug (such as, for
example, methotrexate, azathioptrine, luflunomide, penicillamine,
gold salts, mycophenolate, mofetil, cyclophosphamide and the
like);
[0015] (b) a nonsteroidal anitinflammatory drug (such as, for
example, piroxicam, ketoprofen, naproxen, indomethacin, ibuprofen
and the like);
[0016] (c) COX-2 selective inhibitors such as, for example,
rofecoxib and celecoxib;
[0017] (d) COX-1 inhibitors such as, for example, piroxicam;
[0018] (e) immunosuppressives such as, for example, methotrexate,
cyclosporin, leflunimide, tacrolimus, rapamycin or sulfasalazine;
and
[0019] (f) steroids such as, for example, betamethasone, cortisone,
prednisone or dexamethasone.
[0020] In another embodiment the invention provides a method of
treating a chemokine mediated disease comprising administering to a
patient (e.g., a human) in need of such treatment, an effective
amount of one or more (e.g., one) compounds of formula (I) in
combination (or association) with an effective amount of one or
more compounds selected from the group consisting of:
[0021] (a) a disease modifying antirheumatic drug (such as, for
example, methotrexate, azathioptrine, luflunomide, penicillamine,
gold salts, mycophenolate, mofetil, cyclophosphamide and the
like);
[0022] (b) a nonsteroidal anitinflammatory drug (such as, for
example, piroxicam, ketoprofen, naproxen, indomethacin, ibuprofen
and the like);
[0023] (c) COX-2 selective inhibitors such as, for example,
rofecoxib and celecoxib;
[0024] (d) COX-1 inhibitors such as, for example, piroxicam;
[0025] (e) immunosuppressives such as, for example, methotrexate,
cyclosporin, leflunimide, tacrolimus, rapamycin or
sulfasalazine;
[0026] (f) steroids such as, for example, betamethasone, cortisone,
prednisone or dexamethasone;
[0027] (g) a biological response modifier and
[0028] (h) other anti-inflammatory agents or therapeutics useful
for the treatment of chemokine mediated diseases.
[0029] In another embodiment, the invention provides a method of
treating a chemokine mediated disease comprising administering to a
patient (e.g., a human) in need of such treatment, an effective
amount of one or more (e.g., one) compounds of formula (I), in
combination (or association) with an effective amount of one or
more biological response modifiers (BRMs) such as, for example,
anti-TNF antagonists including antibodies and/or receptors/receptor
fragments, IL-1 antagonists, anti-CD40, anti-CD28, IL-10,
anti-adhesion molecules and the like.
[0030] In another embodiment, the invention provides a method of
treating a chemokine mediated disease comprising administering to a
patient (e.g., a human) in need of such treatment, an effective
amount of one or more (e.g., one) compounds of formula (I) in
combination (or association) with an effective amount of one or
more compounds selected from the group consisting of:
[0031] a) anti-inflammatory agents such as, for example, p38 kinase
inhibitors, PDE4 inhibitors, and TACE inhibitors;
[0032] b) chemokine receptor antagonists such as, for example,
thalidomide;
[0033] c) leukotriene inhibitors; and
[0034] d) other small molecule inhibitors of pro-inflammatory
cytokine production.
[0035] In another embodiment, the invention provides a method of
treating a chemokine mediated disease, said disease being a
pulmonary disease (e.g., COPD, asthma, or cystic fibrosis)
comprising administering to a patient (e.g., a human) in need of
such treatment, an effective amount of one or more (e.g., one)
compounds of formula (I) in combination (or association) with an
effective amount of one or more compounds selected from the group
consisting of: glucocorticoids, 5-lipoxygenase inhibitors, .beta.-2
adrenoceptor agonists, muscarinic M1 antagonists, muscarinic 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. Agents
that belong to these classes include, but are not limited to,
beclomethasone, mometasone, ciclesonide, budesonide, fluticasone,
albuterol, salmeterol, formoterol, loratadine, desloratadine,
tiotropium bromide, MSI-ipratropium bromide, montelukast,
theophilline, cilomilast, roflumilast, cromolyn, ZD-4407,
talnetant, LTB-019, revatropate, pumafentrine, CP955, AR-C-89855,
BAY-19-8004, GW-328267, QAB-149, DNK-333, YM-40461 and TH-9506 (or
pharmaceutically acceptable formulations thereof).
[0036] In another embodiment, the invention provides a method of
treating a chemokine mediated disease, said disease being multiple
sclerosis comprising administering to a patient in need of such
treatment a therapeutically effective amount of one or more (e.g.,
one) compounds of formula (I) in combination (or association) with
an effective amount of one or more compounds selected from the
group consisting of methotrexate, cyclosporin, leflunimide,
sulfasalazine, .beta.-methasone, .beta.-interferon, glatiramer
acetate, prednisone, etonercept, infliximab, and formulations
thereof.
[0037] In another embodiment, the invention provides a method of
treating a chemokine mediated disease, said disease being
rheumatoid arthritis comprising administering to a patient in need
of such treatment an effective amount of one or more (e.g., one)
compounds of formula (I) in combination (or association) with an
effective amount of one or more compounds selected from the group
consisting of a COX-2 inhibitor, a COX inhibitor, an
immunosuppressive, a steroid, a PDE IV inhibitor, an
anti-TNF-.alpha. compound, MMP inhibitors, glucocorticoids,
chemokine inhibitors, CB2-selective inhibiitors, other classes of
compounds indicated for the treatment of rheumatoid arthritis, and
formulations thereof.
[0038] In another embodiment, the invention provides a method of
treating a chemokine mediated disease, said disease being
rheumatoid arthritis comprising administering to a patient in need
of such treatment an effective amount of one or more (e.g., one)
compounds of formula (I) in combination (or association) with an
effective amount of one or more compounds selected from the group
consisting of a COX-2 inhibitor, a COX inhibitor, an
immunosuppressive, a steroid, a PDE IV inhibitor, an
anti-TNF-.alpha. compound, MMP inhibitors, glucocorticoids,
chemokine inhibitors, and CB2-selective inhibitors.
[0039] In another embodiment, the invention provides a method of
treating a chemokine mediated disease, said disease being stroke
and cardiac reperfusion injury comprising administering to a
patient in need of such treatment an effective amount of one or
more (e.g., one) compounds of formula (I) in combination (or
association) with an effective amount of one or more compounds
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.
[0040] In another embodiment, the invention provides a method of
treating a chemokine mediated disease, said disease being stroke
and cardiac reperfusion injury comprising administering to a
patient in need of such treatment an effective amount of one or
more (e.g., one) compounds of formula (I) in combination (or
association) with an effective amount of one or more compounds
selected from the group consisting of thrombolitics, antiplatelet
agents, gpIIb/IIIa antagonist, and anticoagulants.
[0041] In another embodiment, the invention provides a method of
treating a chemokine mediated disease, said disease being stroke
and cardiac reperfusion injury comprising administering to a
patient in need of such treatment an effective amount of one or
more (e.g., one) compounds of formula (I) in combination (or
association) with an effective amount of one or more compounds
selected from the group consisting of an effective amount of one or
more compounds selected from the group consisting of tenecteplase,
TPA, alteplase, abciximab, eftiifbatide, heparin and formulations
thereof.
[0042] This invention also provides novel compounds of formula (I),
wherein said novel compounds are selected from the group consisting
of: 3
[0043] or the pharmaceutically acceptable salts or solvates
thereof.
DETAILED DESCRIPTION OF THE INVENTION
[0044] Unless indicated otherwise, the following definitions apply
throughout the present specification and claims. These definitions
apply regardless of whether a term is used by itself or in
combination with other terms. Hence the definition of "alkyl"
applies to "alkyl" as well as to the "alkyl" portions of "alkoxy",
etc.
[0045] When any variable (e.g., aryl, R.sup.2) occurs more than one
time in any constituent, its definition on each occurrence is
independent of its definition at every other occurrence. Also,
combinations of substituents and/or variables are permissible only
if such combinations result in stable compounds.
[0046] "An effective amount" means a therapeutically effective
amount, e.g., an amount that provides a clinical response to the
disease being treated.
[0047] Examples of "one or more" include (a) 1, 2 or 3, (b) 1 or 2,
or (c) 1.
[0048] Examples of "at least one" include (a) 1, 2 or 3, (b) 1 or
2, or (c) 1.
[0049] "Bn" represents benzyl.
[0050] "Alkyl" means a straight or branched saturated hydrocarbon
chain having the designated number of carbon atoms. Where the
number of carbon atoms is not specified, 1 to 20 carbons are
intended. Preferred alkyl groups contain 1 to 12 carbon atoms in
the chain. More preferred alkyl groups contain 1 to 6 carbon atoms
in the chain.
[0051] "Alkoxy" means an alkyl-0 group in which alkyl is as
previously defined. Non-limiting examples of alkoxy groups include
methoxy, ethoxy, n-propoxy, iso-propoxy and n-butoxy. The bond to
the parent moiety is through the ether oxygen.
[0052] "Alkenyl" means an aliphatic hydrocarbon group containing at
least one carbon-carbon double bond and which may be straight or
branched. Where the number of carbon atoms is not specified, 2 to
20 carbons are intended. Preferred alkenyl groups have 2 to 12
carbon atoms in the chain; and more preferably 2 to 6 carbon atoms
in the chain. Non-limiting examples of suitable alkenyl groups
include ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl,
n-pentenyl, octenyl and decenyl. Alkenylalkyl means that the
alkenyl group is attached to the parent moiety through an alkyl
group.
[0053] "Alkynyl" means an aliphatic hydrocarbon group containing at
least one carbon-carbon triple bond and which may be straight or
branched. Where the number of carbon atoms is not specified, 2 to
15 carbons are intended. Preferred alkynyl groups have 2 to 12
carbon atoms in the chain; and more preferably 2 to 4 carbon atoms
in the chain. Non-limiting examples of suitable alkynyl groups
include ethynyl, propynyl, 2-butynyl, 3-methylbutynyl, n-pentynyl,
and decynyl. Alkynylalkyl means that the alkynyl group is attached
to the parent moiety through an alkyl group.
[0054] "Aryl" means an aromatic monocyclic or multicyclic ring
system comprising about 6 to about 14 carbon atoms, preferably
about 6 to about 10 carbon atoms. Non-limiting examples of suitable
aryl groups include phenyl, naphthyl, indenyl, tetrahydronaphthyl,
indanyl, anthracenyl, fluorenyl and the like.
[0055] "Arylalkyl" means an aryl-alkyl group in which the aryl and
alkyl groups are as defined. Non-limiting examples of suitable
alkylaryl groups include o-tolyl, p-tolyl and xylyl. The bond to
the parent moiety is through the alkyl group.
[0056] "Cycloalkyl" means a non-aromatic ring system having 3 to 10
carbon atoms and one to three rings, preferably 5 to 10 carbon
atoms. Preferred cycloalkyl rings contain 5 to 7 ring atoms.
Non-limiting examples of cycloalkyl groups include cyclopropyl,
cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, adamantyl and the
like.
[0057] "Cycloalkylalkyl" means a cycloalkyl group attached to the
parent moiety through an alkyl group. Non-limiting examples include
cyclopropylmethyl, cyclohexylmethyl and the like.
[0058] "Cycloalkenyl" means a non-aromatic mono or multicyclic ring
system comprising 3 to 10 carbon atoms, preferably 5 to 10 carbon
atoms which contains at least one carbon-carbon double bond.
Preferred cycloalkenyl rings contain 5 to 7 ring atoms.
Non-limiting examples of cycloalkyl groups include cyclopentenyl,
cyclohexenyl, cycloheptenyl, norbornenyl and the like.
[0059] "Halo" means fluoro, chloro, bromo, or iodo groups.
Preferred are fluoro, chloro or bromo, and more preferred are
fluoro and chloro.
[0060] "Halogen" means fluorine, chlorine, bromine, or iodine.
Preferred are fluorine, chlorine or bromine, and more preferred are
fluorine and chlorine.
[0061] "Haloalkyl" means an alkyl group as defined above wherein
one or more hydrogen atoms on the alkyl is replaced by a halo group
defined above.
[0062] "Heterocyclyl" or "heterocyclic" means a non-aromatic
saturated monocyclic or multicyclic ring system comprising 3 to 10
ring atoms, preferably 5 to 10 ring atoms, in which one or more of
the atoms in the ring system is an element other than carbon, for
example nitrogen, oxygen or sulfur, alone or in combination. There
are no adjacent oxygen and/or sulfur atoms present in the ring
system. Preferred heterocyclyls contain 5 to 6 ring atoms. The
prefix aza, oxa or thia before the heterocyclyl root name means
that at least a nitrogen, oxygen or sulfur atom respectively is
present as a ring atom. The nitrogen or sulfur atom of the
heterocyclyl can be optionally oxidized to the corresponding
N-oxide, S-oxide or S,S-dioxide. Non-limiting examples of suitable
monocyclic heterocyclyl rings include piperidyl, pyrrolidinyl,
piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl,
1,3-dioxolanyl, 1,4-dioxanyl, tetrahydrofuranyl,
tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.
[0063] The term heterocyclic acidic functional group is intended to
include groups such as, pyrrole, imidazole, triazole, tetrazole,
and the like.
[0064] "Heteroaryl" means an aromatic monocyclic or multicyclic
ring system comprising 5 to 14 ring atoms, preferably 5 to 10 ring
atoms, in which one or more of the ring atoms is an element other
than carbon, for example nitrogen, oxygen or sulfur, alone or in
combination. Preferred heteroaryls contain 5 to 6 ring atoms. The
prefix aza, oxa or thia before the heteroaryl root name means that
at least a nitrogen, oxygen or sulfur atom respectively, is present
as a ring atom. A nitrogen atom of a heteroaryl can be optionally
oxidized to the corresponding N-oxide. Non-limiting examples of
suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl,
pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl,
pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl,
1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl,
phthalazinyl, imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl,
benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl,
quinolinyl, imidazolyl, thienopyridyl, quinazolinyl,
thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl,
benzoazaindolyl, 1,2,4-triazinyl, benzothiazolyl and the like.
[0065] "Heteroarylalkyl" means a heteroaryl-alkyl group where the
bond to the parent moiety is through an alkyl group.
[0066] N-oxides can form on a tertiary nitrogen present in an R
substituent, or on .dbd.N-- in a heteroaryl ring substituent and
are included in the compounds of formula I.
[0067] As used herein, the term "composition" is intended to
encompass a product comprising the specified ingredients in the
specified amounts, as well as any product which results, directly
or indirectly, from combination of the specified ingredients in the
specified amounts.
[0068] Compounds of formula (I) are described in WO 02/076926
published Oct. 3, 2002, and WO 02/083624 published Oct. 24, 2002,
the disclosures of each being incorporated herein by reference
thereto.
[0069] Examples of chemokine mediated diseases include: 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 (e.g., AIDS),
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, transplant reperfusion injury and
early transplantation.
[0070] Examples of anti-adhesion molecules include anti-CD11a
(efalizumab), CD58-Fc (alefacept), anti-VLA (natalizumab), as well
as small molecule antagonists of LFA-1 (such as IC-747), VLA-4
(such as GW559090), and LFA-3. Examples of leukotriene inhibitors
include LTD4 receptor antagonists (e.g., Singulair), Zileuton, and
inhibitors of 5-lipoxygenase. Examples of inhibitors of cytokine
production include inhibitors of TNF-.alpha. such as thalidomide.
Examples of other classes of compounds indicated for the treatment
of rheumatoid arthritis include inhibitors of p38 kinase,
TNF-.alpha. converting enzyme (TACE), nitiric oxide synthase and
methotrexate.
[0071] For the compounds of formula (I):
[0072] A is selected from the group consisting of: 4567
[0073] wherein the above rings of said A groups are substituted
with 1 to 6 substituents each independently selected from the group
consisting of: R.sup.9 groups; 8
[0074] 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.sup.9 groups; 9
[0075] 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.sup.9 groups; and 10
[0076] B is selected from the group consisting of 11
[0077] n is 0 to 6;
[0078] p is 1 to 5;
[0079] X is 1 to 3;
[0080] R.sup.2 is selected from the group consisting of: hydrogen,
OH, --C(O)OH, --SH, --SO.sub.2NR.sup.13R.sup.14, --NHC(O)R.sup.13,
--NHSO.sub.2NR.sup.13R.sup.14, --NHSO.sub.2R.sup.13,
--NR.sup.13R.sup.14, --C(O)NR.sup.13R.sup.14, --C(O)NHOR.sup.13,
--C(O)NR.sup.13OH, --S(O.sub.2)OH, --OC(O)R.sup.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.sup.9 groups;
[0081] each R.sup.3 and R.sup.4 is independently selected from the
group consisting of: hydrogen, cyano, halogen, alkyl, alkoxy, --OH,
--CF.sub.3, --OCF.sub.3, --NO.sub.2, --C(O)R.sup.13,
--C(O)OR.sup.13, --C(O)NHR.sup.17, --C(O)NR.sup.13R.sup.14,
--SO.sub.(t)NR.sup.13R.sup.14, --SO.sub.(t)R.sup.13,
--C(O)NR.sup.13OR.sup.14, unsubstituted or substituted aryl,
unsubstituted or substituted heteroaryl, 12
[0082] wherein there are 1 to 6 substituents on said substituted
aryl group and each substituent is independently selected from the
group consisting of: R.sup.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.sup.9 groups;
[0083] each R.sup.5 and R.sup.6 are the same or different and are
independently selected from the group consisting of hydrogen,
halogen, alkyl, alkoxy, --CF.sub.3, --OCF.sub.3, --NO.sub.2,
--C(O)R.sup.13, --C(O)OR.sup.13, --C(O)NR.sup.13R.sup.14,
--SO.sub.(t)NR.sup.13R.sup.14, --C(O)NR.sup.13OR.sup.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.sup.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.sup.9 groups;
[0084] each R.sup.7 and R.sup.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.sub.2R.sup.13, --CONR.sup.13R.sup.14, alkynyl, alkenyl, and
cycloalkenyl; and wherein there are one or more (e.g., 1 to 6)
substituents on said substituted R.sup.7 and R.sup.8 groups,
wherein each substitutent is independently selected from the group
consisting of:
[0085] a) halogen,
[0086] b) --CF.sub.3,
[0087] c) --COR.sup.13,
[0088] d) --OR.sup.13,
[0089] e) --NR.sup.13R.sup.14
[0090] f) --NO.sub.2,
[0091] g) --CN,
[0092] h) --SO.sub.2OR.sup.14,
[0093] i) --Si(alkyl).sub.3, wherein each alkyl is independently
selected,
[0094] j) --Si(aryl).sub.3, wherein each alkyl is independently
selected,
[0095] k) --(R.sup.13).sub.2R.sup.14Si, wherein each R.sup.13 is
independently selected,
[0096] l) --CO.sub.2R.sup.13,
[0097] m) --C(O)NR.sup.3R.sup.14,
[0098] n) --SO.sub.2NR.sup.13R.sup.14,
[0099] o) --SO.sub.2R.sup.13,
[0100] p) --OC(O)R.sup.13,
[0101] q) --OC(O)NR.sup.13R.sup.14,
[0102] r) --NR.sup.13C(O)R.sup.14, and
[0103] s) --NR.sup.13CO.sub.2R.sup.14;
[0104] (fluoroalkyl is one non-limiting example of an alkyl group
that is substituted with halogen);
[0105] R.sup.8a is selected from the group consisting of: hydrogen,
alkyl, cycloalkyl and cycloalkylalkyl;
[0106] each R.sup.9 is independently selected from the group
consisting of:
[0107] a) --R.sup.13,
[0108] b) halogen,
[0109] c) --CF.sub.3,
[0110] d) --COR.sup.13,
[0111] e) --OR.sup.13,
[0112] f) --NR.sup.13R.sup.14,
[0113] g) --NO.sub.2,
[0114] h) --CN,
[0115] i) --SO.sub.2R.sup.13,
[0116] j) --SO.sub.2NR.sup.13R.sup.14,
[0117] k) --NR.sup.13COR.sup.14,
[0118] l) --CONR.sup.13R.sup.14,
[0119] m) --NR.sup.13CO.sub.2R.sup.14,
[0120] n) --CO.sub.2R.sup.13,
[0121] o) 13
[0122] p) alkyl substituted with one or more (e.g., one) --OH
groups (e.g., --(CH.sub.2).sub.qOH, wherein q is 1-6, usually 1 to
2, and preferably 1),
[0123] q) alkyl substituted with one or more (e.g., one)
--NR.sup.13R.sup.14 group (e.g.,
--(CH.sub.2).sub.qNR.sup.13R.sup.14, wherein q is 1-6, usually 1 to
2, and preferably 1), and
[0124] r) --N(R.sup.13)SO.sub.2R.sup.14 (e.g., R.sup.13 is H and
R.sup.14 is alkyl, such as methyl);
[0125] each R.sup.10 and R.sup.11 is independently selected from
the group consisting of R.sup.13, (e.g., hydrogen and alkyl (e.g.,
C.sub.1 to C.sub.6 alkyl, such as methyl)), halogen, --CF.sub.3,
--OCF.sub.3, --NR.sup.13R.sup.14, --NR.sup.13C(O)NR.sup.13R.sup.14,
--OH, --C(O)OR.sup.13, --SH, --SO.sub.(t)NR.sup.13R.sup.14,
--SO.sub.2R.sup.13, --NHC(O)R.sup.13,
--NHSO.sub.2NR.sup.13R.sup.14, --NHSO.sub.2R.sup.13,
--C(O)NR.sup.13R.sup.14, --C(O)NR.sup.13OR.sup.14, --OC(O)R.sup.13
and cyano;
[0126] R.sup.12 is selected from the group consisting of: hydrogen,
--C(O)OR.sup.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.sup.12 groups
and each substituent is independently selected from the group
consisting of: R.sup.9 groups;
[0127] each R.sup.13 and R.sup.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.sup.13 and R.sup.14 groups and each substituent is
independently selected from the group consisting of: alkyl,
--CF.sub.3, --OH, alkoxy, aryl, arylalkyl, fluroalkyl, cycloalkyl,
cycloalkylalkyl, heteroaryl, heteroarylalkyl, --N(R.sup.40).sub.2,
--C(O)OR.sup.15, --C(O)NR.sup.15R.sup.16,
--S(O).sub.tNR.sup.15R.sup.16, --C(O)R.sup.15, --SO.sub.2R.sup.15
provided that R.sup.15 is not H, halogen, and
--NHC(O)NR.sup.15R.sup.16; or
[0128] R.sup.13 and R.sup.14 taken together with the nitrogen they
are attached to in the groups --C(O)NR.sup.13R.sup.14 and
--SO.sub.2NR.sup.13R.sup.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.sup.18; wherein there are 1 to 3 substituents on the substituted
cyclized R.sup.13 and R.sup.14 groups (i.e., there is 1 to 3
substituents on the ring formed when the R.sup.13 and R.sup.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.sup.15,
--C(O)NR.sup.15R.sup.16, --SO.sub.tNR.sup.15R.sup.16,
--C(O)R.sup.15, --SO.sub.2R.sup.15 provided that R.sup.15 is not H,
--NHC(O)NR.sup.15R.sup.16, --NHC(O)OR.sup.15, halogen, and a
heterocycloalkenyl group (i.e., a heterocyclic group that has at
least one, and preferably one, double bond in a ring, e.g., 14
[0129] each R.sup.15 and R.sup.16 is independently selected from
the group consisting of: H, alkyl, aryl, arylalkyl, cycloalkyl and
heteroaryl;
[0130] R.sup.17 is selected from the group consisting of:
--SO.sub.2alkyl, --SO.sub.2aryl, --SO.sub.2cycloalkyl, and
--SO.sub.2heteroaryl;
[0131] R.sup.18 is selected from the group consisting of: H, alkyl,
aryl, heteroaryl, --C(O)R.sup.19, --SO.sub.2R.sup.19 and
--C(O)NR.sup.19R.sup.20;
[0132] each R.sup.19 and R.sup.20 is independently selected from
the group consisting of: alkyl, aryl and heteroaryl;
[0133] R.sup.30 is selected from the group consisting of: alkyl,
cycloalkyl, --CN, --NO.sub.2, or --SO.sub.2R.sup.15 provided that
R.sup.15 is not H;
[0134] each R.sup.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.sup.31 groups and each substituent is
independently selected from the group consisting of: alkyl, halogen
and --CF.sub.3;
[0135] each R.sup.40 is independently selected from the group
consisting of: H, alkyl and cycloalkyl;
[0136] g is 1 or 2; and
[0137] t is 0, 1 or 2.
[0138] For compounds of formula (I), when R.sup.3 is
--SO.sub.(t)NR.sup.13R.sup.14 (e.g., --SO.sub.2NR.sup.13R.sup.14),
preferably R.sup.13 and R.sup.14 are independently selected from
the group consisting of: H and alkyl (e.g., methyl, ethyl,
isopropyl and t-butyl). Examples include, but are not limited to
(1) --SO.sub.2NH.sub.2 and (2) --SO.sub.2NR.sup.13R.sup.14 wherein
R.sup.13 and R.sup.14 are the same or different alkyl group (e.g.,
methyl, ethyl, isopropyl and t-butyl), e.g., the same alkyl group,
such as, for example --SO.sub.2N(CH.sub.3).sub.2.
[0139] For compounds of formula (I), when R.sup.3 is
--C(O)NR.sup.13R.sup.14, preferably R.sup.13 and R.sup.14 are
independently selected from the group consisting of: H and alkyl
(e.g., methyl, ethyl, isopropyl and t-butyl). Examples include, but
are not limited to --C(O)NR.sup.13R.sup.14 wherein each R.sup.13
and R.sup.14 are the same or different alkyl group, e.g., the same
alkyl group, such as, for example --C(O)N(CH.sub.3).sub.2.
[0140] For the compounds of formula (I) substituent A is preferably
selected from the group consisting of:
[0141] (1) unsubstituted or substituted: 15
[0142] wherein all substitutents are as defined for formula
(I).
[0143] Examples of substituent A in formula (I) include, but are
not limited to: 16171819
[0144] Substituent A in formula (I) is most preferably selected
from the group consisting of: 2021
[0145] Substituent A in formula (I) is more preferably selected
from the group consisting of: 22
[0146] Substituent B in formula (I) is preferably selected from the
group consisting of: 23
[0147] wherein all substituents are as defined for formula (I).
[0148] Substituent B in formula (I) is most preferably selected
from the group consisting of: 24
[0149] Substituent B in Formula (I) is more preferably selected
from the group consisting of: 25
[0150] Compounds of formula (I) useful in the methods of this
invention are described in the embodiments below. The embodiments
have been numbered for purposes of reference thereto.
[0151] Embodiment No. 1 is directed to the methods of this
invention using compounds of formula (I) wherein B is: 26
[0152] and all other substitutents are as defined for of formula
(I).
[0153] Embodiment No. 2 is directed to the methods of this
invention using compounds of formula (I) wherein B is: 27
[0154] and all other substitutents are as defined for of formula
(I).
[0155] Embodiment No. 3 is directed to the methods of this
invention using compounds of formula (I) wherein B is: 28
[0156] and all other substitutents are as defined for of formula
(I).
[0157] Embodiment No. 4 is is directed to the methods of this
invention using compounds of formula (I) wherein B is: 29
[0158] and all other substitutents are as defined for of formula
(I).
[0159] Embodiment No. 5 is directed to the methods of this
invention using compounds of formula (I) wherein B is: 30
[0160] and all other substitutents are as defined for of formula
(I).
[0161] Embodiment No. 6 is directed to the methods of this
invention using compounds of formula (I) wherein B is: 31
[0162] and all other substitutents are as defined for of formula
(I).
[0163] Embodiment No. 7 is directed to the methods of this
invention using compounds of formula (I) wherein B is: 32
[0164] and all other substitutents are as defined for of formula
(I).
[0165] Embodiment No. 8 is directed to the methods of this
invention using compounds of formula (I) wherein B is: 33
[0166] and all other substitutents are as defined for of formula
(I).
[0167] Embodiment No. 9 is directed to the methods of this
invention using compounds of formula (I) wherein B is: 34
[0168] and all other substitutents are as defined for of formula
(I).
[0169] Embodiment No. 10 is directed to the methods of this
invention using compounds of formula (I) wherein B is: 35
[0170] and all other substitutents are as defined for of formula
(I).
[0171] Embodiment No. 11 is directed to the methods of this
invention using compounds of formula (I) wherein B is: 36
[0172] and all other substitutents are as defined for of formula
(I).
[0173] Embodiment No. 12 is directed to the methods of this
invention using compounds of formula (I) wherein B is: 37
[0174] and all other substitutents are as defined for of formula
(I).
[0175] Embodiment No. 13 is directed to the methods of this
invention using compounds of formula (I) wherein B is: 38
[0176] and all other substitutents are as defined for of formula
(I).
[0177] Embodiment No. 14 is directed to the methods of this
invention using compounds of formula (I) wherein B is: 39
[0178] and all other substitutents are as defined for of formula
(I).
[0179] Embodiment No. 15 is directed to the methods of this
invention using compounds of formula (I) wherein B is: 40
[0180] and all other substitutents are as defined for of formula
(I).
[0181] Embodiment No. 16 is directed to the methods of this
invention using compounds of formula (I) wherein B is: 41
[0182] and all other substitutents are as defined for of formula
(I).
[0183] Embodiment No. 17 is directed to the methods of this
invention using compounds of formula (I) wherein B is: 42
[0184] and all other substitutents are as defined for of formula
(I).
[0185] Embodiment No. 18 is directed to the methods of this
invention using compounds of formula (I) wherein B is: 43
[0186] and all other substitutents are as defined for of formula
(I).
[0187] Embodiment No. 19 is directed to the methods of this
invention using compounds of formula (I) wherein B is selected from
the group consisting of: 44
[0188] and R.sup.3 for this B group is selected from the group
consisting of: --C(O)NR.sup.13R.sup.14, 45
[0189] and all other substituents are as defined for formula
(I).
[0190] Embodiment No. 20 is directed to the methods of this
invention using compounds of formula (I) wherein B is: 46
[0191] and all other substituents are as defined in formula
(I).
[0192] Embodiment No. 21 is directed to the methods of this
invention using compounds of formula (I) wherein B is 47
[0193] R.sup.13 and R.sup.14 are independently selected from the
group consisting of H and alkyl (e.g., methyl, ethyl, isopropyl and
t-butyl), and all other substituents are as defined in formula
(I).
[0194] Embodiment No. 22 is directed to the methods of this
invention using compounds of formula (I) wherein B is 48
[0195] wherein:
[0196] (1) R.sup.2 is --OH and all other substituents are as
defined in formula (I), or
[0197] (2) R.sup.2 is --OH, and R.sup.13 and R.sup.14 are
independently selected from the group, consisting of: H and alkyl
(e.g., methyl, ethyl, isopropyl and t-butyl), or
[0198] (3) R.sup.2 is --OH, and R.sup.13 and R.sup.14 are the same
or different and alkyl group (e.g., methyl, ethyl, isopropyl and
t-butyl), for example the same alkyl group, for example methyl,
and
[0199] (4) and all other substituents are as defined in formula
(I).
[0200] Embodiment No. 23 is directed to the methods of this
invention using compounds of formula (I) wherein B is 49
[0201] R.sup.3 is selected from the group consisting of: 50
[0202] and all other substituents are as defined in formula
(I).
[0203] Embodiment No. 24 is directed to the methods of this
invention using compounds of formula (I) wherein B is 51
[0204] R.sup.3 is selected from the group consisting of: 52
[0205] R.sup.2 is --OH, and all other substituents are as defined
in formula (I).
[0206] Embodiment No. 25 is directed to the methods of this
invention using compounds of formula (I) wherein B is: 53
[0207] and all other substituents are as defined in formula (I)
[0208] Embodiment No. 26 is directed to the methods of this
invention using compounds of formula (I) wherein B is: 54
[0209] R.sup.2 is --OH, and all other substituents are as defined
in formula (I).
[0210] Embodiment No. 27 is directed to the methods of this
invention using compounds of formula (I) wherein B is: 55
[0211] R.sup.2 is as defined for compounds of formula (I), R.sup.13
and R.sup.14 are independently selected from the group consisting
of H and alkyl (e.g., methyl, ethyl, isopropyl and t-butyl), and
all other substituents areas defined for compounds of formula (I).
For example, R.sup.13 and R.sup.14 are the same or different alkyl
group. Also, for example, R.sup.13 and R.sup.14 are the same alkyl
group. Also, for example, R.sup.13 and R.sup.14 are methyl.
[0212] Embodiment No. 28 is directed to the methods of this
invention using compounds of formula (I) wherein B is: 56
[0213] R.sup.2 is --OH, R.sup.13 and R.sup.14 are independently
selected from the group consisting of H and alkyl (e.g., methyl,
ethyl, isopropyl and t-butyl), and all other substituents areas
defined for compounds of formula (I). For example, R.sup.13 and
R.sup.14 are the same or different alkyl group. Also, for example,
R.sup.13 and R.sup.14 are the same alkyl group. Also, for example,
R.sup.13 and R.sup.14 are methyl.
[0214] Embodiment No. 29 is directed to the methods of this
invention using compounds of formula (I) wherein B is as described
in Embodiment No. 23, R.sup.4 is H, R.sup.5 is H, R.sup.6 is H, and
all other substituents are as defined for compounds of formula
(I).
[0215] Embodiment No. 30 is directed to the methods of this
invention using compounds of formula (I) wherein B is as described
in Embodiment No. 24, R.sup.4 is H, R.sup.5 is H, R.sup.6 is H, and
all other substituents areas defined for compounds of formula
(I).
[0216] Embodiment No. 31 is directed to the methods of this
invention using compounds of formula (I) wherein B is as described
in Embodiments Nos. 21, 22, 25 and 26, except that R.sup.13 and
R.sup.14 are each methyl, and all other substituents are as defined
in formula (I).
[0217] Embodiment No. 32 is directed to the methods of this
invention using compounds of formula (I) wherein B is: 57
[0218] R.sup.11 is H, and all other substituents are as defined in
formula (I).
[0219] Embodiment No. 33 is directed to the methods of this
invention using compounds of formula (I) wherein B is: 58
[0220] R.sup.2 is --OH, and all other substituents are as defined
in formula (I).
[0221] Embodiment No. 34 is directed to the methods of this
invention using compounds of formula (I) wherein B is: 59
[0222] R.sup.3 is --C(O)NR.sup.13R.sup.14, and all other
substituents are as defined in formula (I).
[0223] Embodiment No. 35 is directed to the methods of this
invention using compounds of formula (I) wherein B is: 60
[0224] R.sup.3 is --S(O).sub.tNR.sup.13R.sup.14 (e.g., t is 2), and
all other substituents are as defined in formula (I).
[0225] Embodiment No. 36 is directed to the methods of this
invention using compounds of formula (I) wherein B is: 61
[0226] R.sup.2 is --OH, R.sup.3 is --C(O)NR.sup.13R.sup.14, and all
other substituents are as defined in formula (I).
[0227] Embodiment No. 37 of this invention is directed to the
methods of this invention using compounds of formula (I) wherein B
is: 62
[0228] R.sup.2 is --OH, and R.sup.3 is
--S(O).sub.tNR.sup.13R.sup.14 (e.g., t is 2), and all other
substituents are as defined in formula (I).
[0229] Embodiment No. 38 is directed to the methods of this
invention using compounds of formula (I) wherein B is: 63
[0230] R.sup.2 is --OH, R.sup.3 is --C(O)NR.sup.13R.sup.14,
R.sup.11 is H, and all other substituents are as defined in formula
(I).
[0231] Embodiment No. 39 is directed to the methods of this
invention using compounds of formula (I) wherein B is: 64
[0232] R.sup.2 is --OH, R.sup.3 is --S(O).sub.tNR.sup.13R.sup.14
(e.g., t is 2), R.sup.11 is H, and all other substituents are as
defined in formula (I).
[0233] Embodiment No. 40 is directed to the methods of this
invention using compounds of formula (I) wherein B is: 65
[0234] R.sup.2 is --OH, R.sup.3 is --C(O)NR.sup.13R.sup.14,
R.sup.11 is H, and R.sup.13 and R.sup.14 are independently selected
from the group consisting of: H, alkyl (e.g., methyl, ethyl,
isopropyl and t-butyl), unsubstituted heteroaryl and substituted
heteroaryl, and all other substituents are as defined in formula
(I). For example, one of R.sup.13 or R.sup.14 is alkyl (e.g.,
methyl). An example of a substituted heteroaryl group is 66
[0235] Embodiment No. 41 is directed to the methods of this
invention using compounds of formula (I) wherein B is: 67
[0236] R.sup.2 is --OH, R.sup.3 is --S(O).sub.tNR.sup.13R.sup.14
(e.g., t is 2), R.sup.11 is H, and R.sup.13 and R.sup.14 are
independently selected from the group consisting of: H and alkyl
(e.g., methyl, ethyl, isopropyl, and t-butyl), and all other
substituents are as defined in formula (I). For example R.sup.3 is
(1) --SO.sub.2NH.sub.2 and (2) --SO.sub.2NR.sup.13R.sup.14 wherein
R.sup.13 and R.sup.14 are the same or different alkyl group (e.g.,
methyl, ethyl, isopropyl and t-butyl), e.g., the same alkyl group,
such as, for example --SO.sub.2N(CH.sub.3).sub.2.
[0237] Embodiment No. 42 is directed to the methods of this
invention using compounds of formula (I) wherein B is: 68
[0238] R.sup.11 is H, and all other substituents are as defined in
formula (I).
[0239] Embodiment No. 43 is directed to the methods of this
invention using compounds of formula (I) wherein B is: 69
[0240] R.sup.2 is --OH, and all other substituents are as defined
in formula (I).
[0241] Embodiment No. 44 is directed to the methods of this
invention using compounds of formula (I) wherein B is: 70
[0242] R.sup.3 is --C(O)NR.sup.13R.sup.14, and all other
substituents are as defined in formula (I).
[0243] Embodiment No. 45 is directed to the methods of this
invention using compounds of formula (I) wherein B is: 71
[0244] R.sup.3 is --S(O).sub.tNR.sup.13R.sup.14 (e.g., t is 2), and
all other substituents are as defined in formula (I).
[0245] Embodiment No. 46 is directed to the methods of this
invention using compounds of formula (I) wherein B is: 72
[0246] R.sup.2 is --OH, R.sup.3 is --C(O)NR.sup.13R.sup.14, and all
other substituents are as defined in formula (I).
[0247] Embodiment No. 47 is directed to the methods of this
invention using compounds of formula (I) wherein B is: 73
[0248] R.sup.2 is --OH, and R.sup.3 is
--S(O).sub.tNR.sup.13R.sup.14 (e.g., t is 2), and all other
substituents are as defined in formula (I).
[0249] Embodiment No. 48 is directed to the methods of this
invention using compounds of formula (I) wherein B is: 74
[0250] R.sup.2 is --OH, R.sup.3 is --C(O)NR.sup.13R.sup.14,
R.sup.11 is H, and all other substituents are as defined in formula
(I).
[0251] Embodiment No. 49 is directed to the methods of this
invention using compounds of formula (I) wherein B is: 75
[0252] R.sup.2 is --OH, R.sup.3 is --S(O).sub.tNR.sup.13R.sup.14
(e.g., t is 2), R.sup.11 is H, and all other substituents are as
defined in formula (I).
[0253] Embodiment No. 50 is directed to the methods of this
invention using compounds of formula (I) wherein B is: 76
[0254] R.sup.2 is --OH, R.sup.3 is --C(O)NR.sup.13R.sup.14,
R.sup.11 is H, and R.sup.13 and R.sup.14 are independently selected
from the group consisting of: alkyl, unsubstituted heteroaryl and
substituted heteroaryl, and all other substituents are as defined
in formula (I). For example, one of R.sup.13 or R.sup.14 is alkyl
(e.g., methyl). An example of a substituted heteroaryl group is
77
[0255] Embodiment No. 51 is directed to the methods of this
invention using compounds of formula (I) wherein B is: 78
[0256] R.sup.2 is --OH, R.sup.3 is --S(O).sub.tNR.sup.13R.sup.14
(e.g., t is 2), R.sup.11 is H, R.sup.13 and R.sup.14 are
independently selected from the group consisting of: H and alkyl
(e.g., methyl, ethyl, isopropyl, and tbutyl), and all other
substituents are as defined in formula (I). For example R.sup.3 is
(1) --SO.sub.2NH.sub.2 and (2) --SO.sub.2NR.sup.13R.sup.14 wherein
R.sup.13 and R.sup.14 are the same or different alkyl group (e.g.,
methyl, ethyl, isopropyl and t-butyl), e.g., the same alkyl group,
such as, for example --SO.sub.2N(CH.sub.3).sub.2.
[0257] Embodiment No. 52 is directed to the methods of this
invention using compounds of formula (I) wherein substituent B is
selected from the group consisting of: 79
[0258] wherein R.sup.2 to R.sup.6 and R.sup.10 to R.sup.14 are as
defined above for the compounds of formula (I).
[0259] Embodiment No. 53 is directed to the methods of this
invention using compounds of formula (I) wherein substituent B is
selected from the group consisting of: 80
[0260] wherein
[0261] R.sup.2 is selected from the group consisting of: H, OH,
--NHC(O)R.sup.13 or and --NHSO.sub.2R.sup.13;
[0262] R.sup.3 is selected from the group consisting of:
--SO.sub.2NR.sup.13R.sup.14, --NO.sub.2, cyano,
--C(O)NR.sup.13R.sup.14, --SO.sub.2R.sup.13; and
--C(O)OR.sup.13;
[0263] R.sup.4 is selected from the group consisting of: H,
--NO.sub.2, cyano, --CH.sub.3, halogen, and --CF.sub.3;
[0264] R.sup.5 is selected from the group consisting of: H,
--CF.sub.3, --NO.sub.2, halogen and cyano;
[0265] R.sup.6 is selected from the group consisting of: H, alkyl
and --CF.sub.3;
[0266] each R.sup.10 and R.sup.11 is independently selected from
the group consisting of: R.sup.13, hydrogen, halogen, --CF.sub.3,
--NR.sup.13R.sup.14, --NR.sup.13C(O)NR.sup.13R.sup.14,
--C(O)OR.sup.13, --SH, --SO.sub.(t)NR.sup.13R.sup.14,
--SO.sub.2R.sup.13, --NHC(O)R.sup.13,
--NHSO.sub.2NR.sup.13R.sup.14, --NHSO.sub.2R.sup.13,
--C(O)NR.sup.13R.sup.14, --C(O)NR.sup.13OR.sup.14, --OC(O)R.sup.13,
--COR.sup.13, --OR.sup.13, and cyano;
[0267] each R.sup.13 and R.sup.14 is independently selected from
the group consisting of: H, methyl, ethyl and isopropyl; or
[0268] R.sup.13 and R.sup.14 when taken together with the nitrogen
they are attached to in the groups --NR.sup.13R.sup.14,
--C(O)NR.sup.13R.sup.14, --SO.sub.2NR.sup.13R.sup.14,
--OC(O)NR.sup.13R.sup.14, --CONR.sup.13R.sup.14,
--NR.sup.13C(O)NR.sup.13- R.sup.14, --SO.sub.tNR.sup.13R.sup.14,
--NHSO.sub.2NR.sup.13R.sup.14 form an unsubstituted or substituted
saturated heterocyclic ring (preferably a 3 to 7 membered ring)
optionally having one additional heteroatom selected from the group
consisting of: O, S or NR.sup.18; wherein R.sup.18 is selected from
the group consisting of: H, alkyl, aryl, heteroaryl,
--C(O)R.sup.19, --SO.sub.2R.sup.19 and --C(O)NR.sup.19R.sup.20;
wherein each R.sup.19 and R.sup.20 is independently selected from
the group consisting of: alkyl, aryl and heteroaryl; wherein there
are 1 to 3 substituents on the substituted cyclized R.sup.13 and
R.sup.14 groups (i.e., the substituents on the ring formed when
R.sup.13 and R.sup.14 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.sup.15, --C(O)NR.sup.15R.sup.16,
--SO.sub.tNR.sup.15R.sup.16, --C(O)R.sup.15, --SO.sub.2R.sup.15
provided that R.sup.15 is not H, --NHC(O)NR.sup.15R.sup.16 and
halogen; and wherein each R.sup.15 and R.sup.16 is independently
selected from the group consisting: of H, alkyl, aryl, arylalkyl,
cycloalkyl and heteroaryl.
[0269] Embodiment No. 54 is directed to the methods of this
invention using compounds of formula (I) wherein substituent B is
selected from the group consisting of: R.sup.5 81
[0270] wherein:
[0271] R.sup.2 is selected from the group consisting of: H, OH,
--NHC(O)R.sup.13 and --NHSO.sub.2R.sup.13;
[0272] R.sup.3 is selected from the group consisting of:
--C(O)NR.sup.13R.sup.14, --SO.sub.2NR.sup.13R.sup.14, --NO.sub.2,
cyano, --SO.sub.2R.sup.13; and --C(O)OR.sup.13;
[0273] R.sup.4 is selected from the group consisting of: H,
--NO.sub.2, cyano, --CH.sub.3 or --CF.sub.3;
[0274] R.sup.5 is selected from the group consisting of: H,
--CF.sub.3, --NO.sub.2, halogen and cyano; and
[0275] R.sup.6 is selected from the group consisting of: H, alkyl
and --CF.sub.3;
[0276] R.sup.11 is selected from the group consisting of: H,
halogen and alkyl; and
[0277] each R.sup.13 and R.sup.14 is independently selected from
the group consisting of: H, methyl, ethyl and isopropyl; or
[0278] R.sup.13 and R.sup.14 when taken together with the nitrogen
they are attached to in the groups --NR.sup.13R.sup.14,
--C(O)NR.sup.13R.sup.14, --SO.sub.2NR.sup.13R.sup.14,
--OC(O)NR.sup.13R.sup.14, --CONR.sup.13R.sup.14,
--NR.sup.13C(O)NR.sup.13- R.sup.14, --SO.sub.tNR.sup.13R.sup.14,
--NHSO.sub.2NR.sup.13R.sup.14 form an unsubstituted or substituted
saturated heterocyclic ring (preferably a 3 to 7 membered ring)
optionally having one additional heteroatom selected from O, S or
NR.sup.18 wherein R.sup.18 is selected from H, alkyl, aryl,
heteroaryl, --C(O)R.sup.19, --SO.sub.2R.sup.19 and
--C(O)NR.sup.19R.sup.20, wherein each R.sup.19 and R.sup.20 is
independently selected from alkyl, aryl and heteroaryl, wherein
there are 1 to 3 substituents on the substituted cyclized R.sup.13
and R.sup.14 groups (i.e., on the ring formed when R.sup.13 and
R.sup.14 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.sup.15,
--C(O)NR.sup.15R.sup.16, --SO.sub.tNR.sup.15R.sup.16,
--C(O)R.sup.15, --SO.sub.2R.sup.15 provided that R.sup.15 is not H,
--NHC(O)NR.sup.15R.sup.16 and halogen; and wherein each R.sup.15
and R.sup.16 is independently selected from the group consisting
of: H, alkyl, aryl, arylalkyl, cycloalkyl and heteroaryl.
[0279] Embodiment No. 55 is directed to the methods of this
invention using compounds of formula (I) wherein substituent B is
selected from the group consisting of: 82
[0280] wherein:
[0281] R.sup.2 is selected from the group consisting of: H, OH,
--NHC(O)R.sup.13 and --NHSO.sub.2R.sup.13;
[0282] R.sup.3 is selected from the group consisting of:
--C(O)NR.sup.13R.sup.14--SO.sub.2NR.sup.13R.sup.14, --NO.sub.2,
cyano, and --SO.sub.2R.sup.13;
[0283] R.sup.4 is selected from the group consisting of: H,
--NO.sub.2, cyano, --CH.sub.3 or --CF.sub.3;
[0284] R.sup.5 is selected from the group consisting of: H,
--CF.sub.3, --NO.sub.2, halogen and cyano; and
[0285] R.sup.6 is selected from the group consisting of: H, alkyl
and --CF.sub.3;
[0286] R.sup.11 is selected from the group consisting of: H,
halogen and alkyl; and
[0287] each R.sup.13 and R.sup.14 is independently selected from
the group consisting of: H, methyl and ethyl.
[0288] Embodiment No. 56 is directed to the methods of this
invention using compounds of formula (I) wherein substituent B is
selected from the group consisting of: 83
[0289] wherein:
[0290] R.sup.2 is --OH;
[0291] R.sup.3 is selected from the group consisting of:
--SO.sub.2NR.sup.13R.sup.14 and --CONR.sup.13R.sup.14;
[0292] R.sup.4 is selected form the group consisting of: H,
--CH.sub.3 and --CF.sub.3;
[0293] R.sup.5 is selected from the group consisting of: H and
cyano;
[0294] R.sup.6 is selected from the group consisting of: H,
--CH.sub.3 and --CF.sub.3;
[0295] R.sup.11 is H; and
[0296] R.sup.13 and R.sup.14 are independently selected from the
group consisting of H and methyl (e.g., for
--SO.sub.2NR.sup.13R.sup.14 both R.sup.13 and R.sup.14 are H, or
both R.sup.13 and R.sup.14 are methyl, also, for example, for
--CONR.sup.13R.sup.14 both R.sup.13 and R.sup.14 are methyl).
[0297] Embodiment No. 57 is directed to the methods of this
invention using compounds of formula (I) wherein substituent B is
selected from the group consisting of: 84
[0298] wherein all substituents are as defined for formula (I).
[0299] Embodiment No. 58 is directed to the methods of this
invention using compounds of formula (I) wherein substituent B is
selected from the group consisting of: 85
[0300] Embodiment No. 59 is directed to the methods of this
invention using compounds of formula (I) wherein substituent B is
selected from the group consisting of: 86
[0301] Embodiment No. 60 is directed to the methods of this
invention using compounds of formula (I) wherein substituent A is
selected from the group consisting of: 87
[0302] wherein the above rings are unsubstituted or substituted, as
described for formula (I); and 88
[0303] wherein in (a) and (b): each R.sup.7 and R.sup.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.sub.2R.sup.13,
--CONR.sup.13R.sup.14, fluoroalkyl, alkynyl, alkenyl, and
cycloalkenyl, wherein said substituents on said R.sup.7 and R.sup.8
substituted groups are selected from the group consisting of: a)
cyano, b) --CO.sub.2R.sup.13, c) --C(O)NR.sup.13R.sup.14, d)
--SO.sub.2NR.sup.13R.sup.14, e) --NO.sub.2, f) --CF.sub.3, g)
--OR.sup.13, h) --NR.sup.13R.sup.14, i) --OC(O)R.sup.13, j)
--OC(O)NR.sup.13R.sup.14, and k) halogen; and R.sup.8a and R.sup.9
are as defined in formula (I).
[0304] Embodiment No. 61 is directed to the methods of this
invention using compounds of formula (I) wherein substituent A is
selected from the group consisting of: 89
[0305] wherein the above rings are unsubstituted, or the above
rings are substituted with 1 to 3 substituents independently
selected from the group consisting of: halogen, alkyl, cycloalkyl,
--CF.sub.3, cyano, --OCH.sub.3, and --NO.sub.2; each R.sup.7 and
R.sup.8 is independently selected from the group consisting of: H,
alkyl (e.g., methyl, ethyl, t-butyl, and isopropyl), fluoroalkyl
(such as, --CF.sub.3 and --CF.sub.2CH.sub.3), cycloalkyl (e.g.,
cyclopropyl, and cyclohexyl), and cycloalkylalkyl (e.g.,
cyclopropylmethyl); and R.sup.9 is selected from the group
consisting of: H, halogen, alkyl, cycloalkyl, --CF.sub.3, cyano,
--OCH.sub.3, and --NO.sub.2; and 90
[0306] wherein each R.sup.7 and R.sup.8 is independently selected
from the group consisting of: H, alkyl (e.g., methyl, ethyl,
t-butyl, and isopropyl), fluoroalkyl (such as, --CF.sub.3 and
--CF.sub.2CH.sub.3), cycloalkyl (e.g., cyclopropyl, and
cyclohexyl), and cycloalkylalkyl (e.g., cyclopropylmethyl); wherein
R.sup.8, is as defined in formula (I), and wherein R.sup.9 is
selected from the group consisting of: H, halogen, alkyl,
cycloalkyl, --CF.sub.3, cyano, --OCH.sub.3, and --NO.sub.2; each
R.sup.7 and R.sup.8 is independently selected from the group
consisting of: H, alkyl (e.g., methyl, ethyl, t-butyl, and
isopropyl), fluoroalkyl (such as, --CF.sub.3 and
--CF.sub.2CH.sub.3), cycloalkyl (e.g., cyclopropyl, and
cyclohexyl), and cycloalkylalkyl (e.g., cyclopropylmethyl).
[0307] Embodiment No. 62 is directed to the methods of this
invention using compounds of formula (I) wherein substituent A is
selected from the group consisting of: 91
[0308] wherein the above rings are unsubstituted, or the above
rings are substituted with 1 to 3 substituents independently
selected from the group consisting of: H, F, Cl, Br, alkyl,
cycloalkyl, and --CF.sub.3; R.sup.7 is selected from the group
consisting of: H, fluoroalkyl, alkyl and cycloalkyl; R.sup.8 is
selected form the group consisting of: H, alkyl, --CF.sub.2CH.sub.3
and --CF.sub.3; and R.sup.9 is selected from the group consisting
of: H, F, Cl, Br, alkyl or --CF.sub.3; and 92
[0309] wherein R.sup.7 is selected from the group consisting of: H,
fluoroalkyl, alkyl and cycloalkyl; R.sup.8 is selected form the
group consisting of: H, alkyl, --CF.sub.2CH.sub.3 and --CF.sub.3;
and R.sup.8a is as defined for formula (I).
[0310] Embodiment No. 63 is directed to the methods of this
invention using compounds of formula (I) wherein substituent A is
selected from the group consisting of: 93
[0311] wherein the above rings are unsubstituted, or the above
rings are substituted with 1 to 3 substituents independently
selected from the group consisting of: H, F, Cl, Br, alkyl,
cycloalkyl, and --CF.sub.3; R.sup.7 is selected from the group
consisting of: H, --CF.sub.3, --CF.sub.2CH.sub.3, methyl, ethyl,
isopropyl, cyclopropyl and t-butyl; and R.sup.8 is H; and 94
[0312] wherein R.sup.7 is selected from the group consisting of: H,
--CF.sub.3, --CF.sub.2CH.sub.3, methyl, ethyl, isopropyl,
cyclopropyl and t-butyl; and R.sup.8 is H; and R.sup.8a is as
defined for formula (I).
[0313] Embodiment No. 64 is directed to the methods of this
invention using compounds of formula (I) wherein substituent A is
selected from the group consisting of: 95
[0314] wherein the above rings are unsubstituted, or the above
rings are substituted with 1 to 3 substituents independently
selected from the group consisting of: F, Cl, Br, alkyl,
cycloalkyl, and --CF.sub.3; R.sup.7 is selected from the group
consisting of: H, --CF.sub.3, --CF.sub.2CH.sub.3, methyl, ethyl,
isopropyl, cyclopropyl and t-butyl; and R.sup.8 is H; and 96
[0315] wherein R.sup.7 is selected from the group consisting of: H,
--CF.sub.3, --CF.sub.2CH.sub.3, methyl, ethyl, isopropyl,
cyclopropyl and t-butyl; and R.sup.8 is H; and R.sup.8a is as
defined for formula IA;
[0316] Embodiment No. 65 is directed compounds of formula (1)
wherein substituent A is selected from the group consisting of:
[0317] (1) unsubstituted or substituted: 97
[0318] wherein all substitutents are as defined for formula
(I).
[0319] Embodiment No. 66 is directed to the methods of this
invention using compounds of formula (I) wherein substituent A is
selected from the group consisting of: 9899100101
[0320] Embodiment No. 67 is directed to the methods of this
invention using compounds of formula (I) wherein substituent A is
selected from the group consisting of: 102103
[0321] Embodiment No. 68 is directed to the methods of this
invention using compounds of formula (I) wherein substituent A is
selected from the group consisting of: 104
[0322] Embodiment No. 69 is directed to the methods of this
invention using compounds of formula (I) wherein B is as described
in any one of the Embodiment Nos. 1 to 59, and A is as defined in
any one of the Embodiment Nos. 60 to 68.
[0323] Embodiment No. 70 is directed to the methods of this
invention using compounds of formula (I) wherein B is as described
in any one of the Embodiment Nos. 1 to 59, and A is: 105
[0324] and all other substituents are as defined for formula
(I).
[0325] Embodiment No. 71 is directed to the methods of this
invention using compounds of formula (I) wherein B is as described
in any one of the Embodiment Nos. 1 to 59, and A is: 106
[0326] wherein R.sup.7 is H, and R.sup.8 is alkyl (e.g., methyl,
ethyl, isopropyl, cyclopropyl and t-butyl), and all other
substituents are as defined for formula (I).
[0327] Embodiment No. 72 is directed to the methods of this
invention using compounds of formula (I) wherein B is as described
in any one of the Embodiment Nos. 1 to 59, and A is: 107
[0328] and all other substituents are as defined for formula
(I).
[0329] Embodiment No. 73 is directed to the methods of this
invention using compounds of formula (I) wherein B is as described
in any one of the Embodiment Nos. 1 to 59, and A is: 108
[0330] wherein the furan ring is unsubstituted or substituted as
described in the definition of A for formula (I), and all other
substituents are as defined for formula (I).
[0331] Embodiment No. 74 is directed to the methods of this
invention using compounds of formula (I) wherein B is described in
any one of the Embodiment Nos. 1 to 59, and A is 109
[0332] wherein the furan ring is substituted and all other
substituents are as defined for formula (I).
[0333] Embodiment No. 75 is directed to the methods of this
invention using compounds of formula (I) wherein B is as described
in any one of the Embodiment Nos. 1 to 59, and A is 110
[0334] wherein the furan ring is substituted with at least one
(e.g., 1 to 3, or 1 to 2) alkyl group and all other substituents
are as defined for formula (I).
[0335] Embodiment No. 76 is directed to the methods of this
invention using compounds of formula (I) wherein B is as described
in any one of the Embodiment Nos. 1 to 59, A is 111
[0336] wherein the furan ring is substituted with one alkyl group
and all other substituents are as defined for formula (I).
[0337] Embodiment No. 77 is directed to the methods of this
invention using compounds of formula (I) wherein B is as described
in any one of the Embodiment Nos. 1 to 59, and A is 112
[0338] wherein the furan ring is substituted with one C.sub.1 to
C.sub.3 alkyl group (e.g., methyl or isopropyl), and all other
substituents are as defined for formula (I).
[0339] Embodiment No. 78 is directed to the methods of this
invention using compounds of formula (I) wherein B is as described
in any one of the Embodiment Nos. 1 to 59, and A is as defined in
any one of the Embodiment Nos. 73 to 77, except that R.sup.7 and
R.sup.8 are the same or different and each is selected from the
group consisting of: H and alkyl.
[0340] Embodiment No. 79 is directed to the methods of this
invention using compounds of formula (I) wherein B is as described
in any one of the Embodiment Nos. 1 to 59, and A is as defined in
any one of the Embodiment Nos. 73 to 77, except that R.sup.7 is H,
and R.sup.8 is alkyl (e.g., ethyl or t-butyl).
[0341] Embodiment No. 80 is directed to the methods of this
invention using compounds of formula (I) wherein:
[0342] (1) substituent A in formula (I) is selected from the group
consisting of: 113
[0343] wherein the above rings are unsubstituted or substituted, as
described for formula (I); and 114
[0344] wherein in (a) and (b) above: each R.sup.7 and R.sup.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.sub.2R.sup.13,
--CONR.sup.13R.sup.14, fluoroalkyl, alkynyl, alkenyl, and
cycloalkenyl, wherein said substituents on said R.sup.7 and R.sup.8
substituted groups are selected from the group consisting of: a)
cyano, b) --CO.sub.2R.sup.13, c) --C(O)NR.sup.13R.sup.14, d)
--SO.sub.2NR.sup.13R.sup.14, e) --NO.sub.2, f) --CF.sub.3, g)
--OR.sup.13, h) --NR.sup.13R.sup.14, i) --OC(O)R.sup.13, j)
--OC(O)NR.sup.13R.sup.14, and k) halogen; and R.sup.8a and R.sup.9
are as defined in formula (I); and
[0345] (2) substituent B in formula (I) is selected from the group
consisting of: 115
[0346] wherein R.sup.2 to R.sup.6 and R.sup.10 to R.sup.14 are as
defined above for the compounds of formula (I).
[0347] Embodiment No. 81 is directed to the methods of this
invention using compounds of formula (I) wherein:
[0348] (1) substituent A in formula (I) is selected from the group
consisting of: 116
[0349] wherein the above rings are unsubstituted, or the above
rings are substituted with 1 to 3 substituents independently
selected from the group consisting of: halogen, alkyl, cycloalkyl,
--CF.sub.3, cyano, --OCH.sub.3, and --NO.sub.2; each R.sup.7 and
R.sup.8 is independently selected from the group consisting of: H,
alkyl (e.g., methyl, ethyl, t-butyl, and isopropyl), fluoroalkyl
(such as, --CF.sub.3 and --CF.sub.2CH.sub.3), cycloalkyl (e.g.,
cyclopropyl, and cyclohexyl), and cycloalkylalkyl (e.g.,
cyclopropylmethyl); and R.sup.9 is selected from the group
consisting of: H, halogen, alkyl, cycloalkyl, --CF.sub.3, cyano,
--OCH.sub.3, and --NO.sub.2; and 117
[0350] wherein each R.sup.7 and R.sup.8 is independently selected
from the group consisting of: H, alkyl (e.g., methyl, ethyl,
t-butyl, and isopropyl), fluoroalkyl (such as, --CF.sub.3 and
--CF.sub.2CH.sub.3), cycloalkyl (e.g., cyclopropyl, and
cyclohexyl), and cycloalkylalkyl (e.g., cyclopropylmethyl); wherein
R.sup.8a is as defined in formula (1), and wherein R.sup.9 is
selected from the group consisting of: H, halogen, alkyl,
cycloalkyl, --CF.sub.3, cyano, --OCH.sub.3, and --NO.sub.2; each
R.sup.7 and R.sup.8 is independently selected from the group
consisting of: H, alkyl (e.g., methyl, ethyl, t-butyl, and
isopropyl), fluoroalkyl (such as, --CF.sub.3 and
--CF.sub.2CH.sub.3), cycloalkyl (e.g., cyclopropyl, and
cyclohexyl), and cycloalkylalkyl (e.g., cyclopropylmethyl); and
[0351] (2) substituent B in formula (I) is selected from the group
consisting of: 118
[0352] wherein
[0353] R.sup.2 is selected from the group consisting of: H, OH,
--NHC(O)R.sup.13 or and --NHSO.sub.2R.sup.13;
[0354] R.sup.3 is selected from the group consisting of:
--SO.sub.2NR.sup.13R.sup.14, --NO.sub.2, cyano,
--C(O)NR.sup.13R.sup.14, --SO.sub.2R.sup.13; and
--C(O)OR.sup.13;
[0355] R.sup.4 is selected from the group consisting of: H,
--NO.sub.2, cyano, --CH.sub.3, halogen, and --CF.sub.3;
[0356] R.sup.5 is selected from the group consisting of: H,
--CF.sub.3, --NO.sub.2, halogen and cyano;
[0357] R.sup.6 is selected from the group consisting of: H, alkyl
and --CF.sub.3;
[0358] each R.sup.10 and R.sup.11 is independently selected from
the group consisting of: R.sup.13, hydrogen, halogen, --CF.sub.3,
--NR.sup.13R.sup.14, --NR.sup.13C(O)NR.sup.13R.sup.14,
--C(O)OR.sup.13, --SH, --SO.sub.(t)NR.sup.13R.sup.14,
--SO.sub.2R.sup.13, --NHC(O)R.sup.13,
--NHSO.sub.2NR.sup.13R.sup.14, --NHSO.sub.2R.sup.13,
--C(O)NR.sup.13R.sup.14, --C(O)NR.sup.13OR.sup.14, --OC(O)R.sup.13,
--COR.sup.13, --OR.sup.13, and cyano;
[0359] each R.sup.13 and R.sup.14 is independently selected from
the group consisting of: H, methyl, ethyl and isopropyl; or
[0360] R.sup.13 and R.sup.14 when taken together with the nitrogen
they are attached to in the groups --NR.sup.13R.sup.14,
--C(O)NR.sup.13R.sup.14, --SO.sub.2NR.sup.13R.sup.14,
--OC(O)NR.sup.13R.sup.14, --CONR.sup.13R.sup.14,
--NR.sup.13C(O)NR.sup.13- R.sup.14, --SO.sub.tNR.sup.13R.sup.14,
--NHSO.sub.2NR.sup.13R.sup.14 form an unsubstituted or substituted
saturated heterocyclic ring (preferably a 3 to 7 membered ring)
optionally having one additional heteroatom selected from the group
consisting of: O, S or NR.sup.18; wherein R.sup.18 is selected from
the group consisting of: H, alkyl, aryl, heteroaryl,
--C(O)R.sup.19, --SO.sub.2R.sup.19 and --C(O)NR.sup.19R.sup.20;
wherein each R.sup.19 and R.sup.20 is independently selected from
the group consisting of: alkyl, aryl and heteroaryl; wherein there
are 1 to 3 substituents on the substituted cyclized R.sup.13 and
R.sup.14 groups (i.e., the substituents on the ring formed when
R.sup.13 and R.sup.14 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.sup.15,
--C(O)NR.sup.15R.sup.16--SO.sub.tNR.sup.15R.sup.16,
--C(O)R.sup.15--SO.sub.2R.sup.15 provided that R.sup.15 is not H,
--NHC(O)NR.sup.15R.sup.16 and halogen; and wherein each R.sup.15
and R.sup.16 is independently selected from the group consisting:
of H, alkyl, aryl, arylalkyl, cycloalkyl and heteroaryl.
[0361] Embodiment No. 82 is directed to the methods of this
invention using compounds of formula (I) wherein substituent A is
even more preferably selected from the group consisting of: 119
[0362] wherein the above rings are unsubstituted, or the above
rings are substituted with 1 to 3 substituents independently
selected from the group consisting of: H, F, Cl, Br, alkyl,
cycloalkyl, and --CF.sub.3; R.sup.7 is selected from the group
consisting of: H, fluoroalkyl, alkyl and cycloalkyl; R.sup.8 is
selected form the group consisting of: H, alkyl, --CF.sub.2CH.sub.3
and --CF.sub.3; and R.sup.9 is selected from the group consisting
of: H, F, Cl, Br, alkyl or --CF.sub.3; and 120
[0363] wherein R.sup.7 is selected from the group consisting of: H,
fluoroalkyl, alkyl and cycloalkyl; R.sup.8 is selected form the
group consisting of: H, alkyl, --CF.sub.2CH.sub.3 and --CF.sub.3;
and R.sup.8a is as defined for formula (1).
[0364] Embodiment No. 83 is directed to the methods of this
invention using compounds of formula (1) wherein:
[0365] (1) substituent A is selected from the group consisting of:
121
[0366] wherein the above rings are unsubstituted, or the above
rings are substituted with 1 to 3 substituents independently
selected from the group consisting of: H, F, Cl, Br, alkyl,
cycloalkyl, and --CF.sub.3; R.sup.7 is selected from the group
consisting of: H, --CF.sub.3, --CF.sub.2CH.sub.3, methyl, ethyl,
isopropyl, cyclopropyl and t-butyl; and R.sup.8 is H; and 122
[0367] wherein R.sup.7 is selected from the group consisting of: H,
--CF.sub.3, --CF.sub.2CH.sub.3, methyl, ethyl, isopropyl,
cyclopropyl and t-butyl; and R.sup.8 is H; and R.sup.8a is as
defined for formula (I); and
[0368] (2) substituent B is selected from the group consisting of:
123
[0369] wherein:
[0370] R.sup.2 is selected from the group consisting of: H, OH,
--NHC(O)R.sup.13 and --NHSO.sub.2R.sup.13;
[0371] R.sup.3 is selected from the group consisting of:
--C(O)NR.sup.13R.sup.14, --SO.sub.2NR.sup.13R.sup.14, --NO.sub.2,
cyano, --SO.sub.2R.sup.13; and --C(O)OR.sup.13;
[0372] R.sup.4 is selected from the group consisting of: H,
--NO.sub.2, cyano, --CH.sub.3 or --CF.sub.3;
[0373] R.sup.5 is selected from the group consisting of: H,
--CF.sub.3, --NO.sub.2, halogen and cyano; and
[0374] R.sup.6 is selected from the group consisting of: H, alkyl
and --CF.sub.3;
[0375] R.sup.11 is selected from the group consisting of: H,
halogen and alkyl; and
[0376] each R.sup.13 and R.sup.14 is independently selected from
the group consisting of: H, methyl, ethyl and isopropyl; or
[0377] R.sup.13 and R.sup.14 when taken together with the nitrogen
they are attached to in the groups --NR.sup.13R.sup.4,
--C(O)NR.sup.13R.sup.14- , --SO.sub.2NR.sup.3R.sup.4,
--QC(O)NR.sup.3R.sup.4, --CONR.sup.3R.sup.14,
--NR.sup.13C(O)NR.sup.13R.sup.14, --SO.sub.tNR.sup.13R.sup.14,
--NHSO.sub.2NR.sup.13R.sup.14 form an unsubstituted or substituted
saturated heterocyclic ring (preferably a 3 to 7 membered ring)
optionally having one additional heteroatom selected from O, S or
NR.sup.18 wherein R.sup.18 is selected from H, alkyl, aryl,
heteroaryl, --C(O)R.sup.19, --SO.sub.2R.sup.19 and
--C(O)NR.sup.19R.sup.20, wherein each R.sup.19 and R.sup.20 is
independently selected from alkyl, aryl and heteroaryl, wherein
there are 1 to 3 substituents on the substituted cyclized R.sup.13
and R.sup.14 groups (i.e., on the ring formed when R.sup.13 and
R.sup.14 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.sup.15,
--C(O)NR.sup.15R.sup.16, --SO.sub.tNR.sup.15R.sup.16,
--C(O)R.sup.15, --SO.sub.2R.sup.15 provided that R.sup.15 is not H,
--NHC(O)NR.sup.15R.sup.16 and halogen; and wherein each R.sup.15
and R.sup.16 is independently selected from the group consisting
of: H, alkyl, aryl, arylalkyl, cycloalkyl and heteroaryl.
[0378] Embodiment No. 84 is directed to the methods of this
invention using compounds of formula (I) wherein:
[0379] (1) substituent A is selected from the group consisting of:
124
[0380] wherein the above rings are unsubstituted, or the above
rings are substituted with 1 to 3 substituents independently
selected from the group consisting of: F, Cl, Br, alkyl,
cycloalkyl, and --CF.sub.3; R.sup.7 is selected from the group
consisting of: H, --CF.sub.3, --CF.sub.2CH.sub.3, methyl, ethyl,
isopropyl, cyclopropyl and t-butyl; and R.sup.8 is H; and 125
[0381] wherein R.sup.7 is selected from the group consisting of: H,
--CF.sub.3, --CF.sub.2CH.sub.3, methyl, ethyl, isopropyl,
cyclopropyl and t-butyl; and R.sup.8 is H; and R.sup.8a is as
defined for formula (I);
[0382] (2) substituent B is selected from the group consisting of:
126
[0383] wherein:
[0384] R.sup.2 is selected from the group consisting of: H, OH,
--NHC(O)R.sup.13 and --NHSO.sub.2R.sup.13;
[0385] R.sup.3 is selected from the group consisting of:
--C(O)NR.sup.13R.sup.14--SO.sub.2NR.sup.13R.sup.14, --NO.sub.2,
cyano, and --SO.sub.2R.sup.13;
[0386] R.sup.4 is selected from the group consisting of: H,
--NO.sub.2, cyano, --CH.sub.3 or --CF.sub.3;
[0387] R.sup.5 is selected from the group consisting of: H,
--CF.sub.3, --NO.sub.2, halogen and cyano; and
[0388] R.sup.6 is selected from the group consisting of: H, alkyl
and --CF.sub.3;
[0389] R.sup.11 is selected from the group consisting of: H,
halogen and alkyl; and
[0390] each R.sup.13 and R.sup.14 is independently selected from
the group consisting of: H, methyl and ethyl.
[0391] Embodiment No. 85 is directed to the methods of this
invention using compounds of formula (I) wherein:
[0392] (1) substituent A is selected from the group consisting of:
127
[0393] (2) substituent B is selected from the group consisting of:
128
[0394] wherein:
[0395] R.sup.2 is --OH;
[0396] R.sup.3 is selected from the group consisting of:
--SO.sub.2NR.sup.13R.sup.14 and --CONR.sup.13R.sup.14;
[0397] R.sup.4 is selected form the group consisting of: H,
--CH.sub.3 and --CF.sub.3;
[0398] R.sup.5 is selected from the group consisting of: H and
cyano;
[0399] R.sup.6 is selected from the group consisting of: H,
--CH.sub.3 and --CF.sub.3;
[0400] R.sup.11 is H; and
[0401] R.sup.13 and R.sup.14 are independently selected from the
group consisting of H and methyl (e.g., for
--SO.sub.2NR.sup.13R.sup.14 both R.sup.13 and R.sup.14 are H, or
both R.sup.13 and R.sup.14 are methyl, also, for example, for
--CONR.sup.13R.sup.14 both R.sup.13 and R.sup.14 are methyl).
[0402] Embodiment No. 86 is directed to the methods of this
invention using compounds of formula (I) wherein substituent A is
as defined in Embodiment No. 65 and substituent B is as defined in
Embodiment No. 57.
[0403] Embodiment No. 87 is directed to the methods of this
invention using compounds of formula (I) wherein substituent A is
as defined in Embodiment No. 65 and substituent B is as defined in
Embodiment No. 58.
[0404] Embodiment No. 88 is directed to the methods of this
invention using compounds of formula (I) wherein substituent A is
as defined in Embodiment No. 65 and substituent B is as defined in
Embodiment No. 59.
[0405] Embodiment No. 89 is directed to the methods of this
invention using compounds of formula (I) wherein substituent A is
as defined in Embodiment No. 66 and substituent B is as defined in
Embodiment No. 57.
[0406] Embodiment No. 90 is directed to the methods of this
invention using compounds of formula (I) wherein substituent A is
as defined in Embodiment No. 66 and substituent B is as defined in
Embodiment No. 58.
[0407] Embodiment No. 91 is directed to the methods of this
invention using compounds of formula (I) wherein substituent A is
as defined in Embodiment No. 66 and substituent B is as defined in
Embodiment No. 59.
[0408] Embodiment No. 92 is directed to the methods of this
invention using compounds of formula (I) wherein substituent A is
as defined in Embodiment No. 67 and substituent B is as defined in
Embodiment No. 57.
[0409] Embodiment No. 93 is directed to the methods of this
invention using compounds of formula (I) wherein substituent A is
as defined in Embodiment No. 67 and substituent B is as defined in
Embodiment No. 58.
[0410] Embodiment No. 94 is directed to the methods of this
invention using compounds of formula (I) wherein substituent A is
as defined in Embodiment No. 67 and substituent B is as defined in
Embodiment No. 59.
[0411] Embodiment No. 95 is directed to the methods of this
invention using compounds of formula (I) wherein substituent A is
as defined in Embodiment No. 68 and substituent B is as defined in
Embodiment No. 57.
[0412] Embodiment No. 96 is directed to the methods of this
invention using compounds of formula (I) wherein substituent A is
as defined in Embodiment No. 68 and substituent B is as defined in
Embodiment No. 58.
[0413] Embodiment No. 97 is directed to the methods of this
invention using compounds of formula (I) wherein substituent A is
as defined in Embodiment No. 68 and substituent B is as defined in
Embodiment No. 59.
[0414] Embodiment No. 98 is directed to the methods of this
invention using compounds of formula (I) as defined in any one of
the Embodiment Nos. 1 to 97 wherein the compound of formula (I) is
a pharmaceutically acceptable salt.
[0415] Embodiment No. 99 is directed to the methods of this
invention using compounds of formula (I) as defined in any one of
the Embodiment Nos. 1 to 97 wherein the compound of formula (I) is
a sodium salt.
[0416] Embodiment No. 100 is directed to the methods of this
invention using compounds of formula (I) as defined in any one of
the Embodiment Nos. 1 to 97 wherein the compound of formula (I) is
a calcium salt.
[0417] Embodiment No. 101 is directed to the methods of this
invention using a pharmaceutically acceptable salt of any one of
the representative compounds of formula (I) described below.
[0418] Embodiment No. 102 is directed to the methods of this
invention using a sodium salt of any one of the representative
compounds of formula (I) described below.
[0419] Embodiment No. 103 is directed to the methods of this
invention using a calcium salt of any one of the representative
compounds of formula (I) described below.
[0420] Embodiment No. 104 is directed to the methods of this
invention using a pharmaceutical composition comprising at least
one (e.g., 1 to 3, usually 1) compound of formula (I) as described
in any one of the Embodiment Nos. 1 to 103 in combination with a
pharmaceutically acceptable carrier (or diluent).
[0421] Embodiment No. 105 is directed to a pharmaceutically
acceptable salt of a novel compound of formula (I), wherein said
compound is selected from the group consisting of: 129
[0422] Embodiment No. 106 is directed to a calcium salt of any one
of the novel compounds of formula (I) described in Embodiment No.
105.
[0423] Embodiment No. 107 is directed to a sodium salt of any one
of the novel compounds of formula (I) described in Embodiment No.
105.
[0424] Embodiment No. 108 is directed to a pharmaceutical
composition comprising at least one (e.g., 1 to 3, usually 1) novel
compound of formula (I) as described in Embodiment No. 105 in
combination with a pharmaceutically acceptable carrier (or
diluent).
[0425] Representative compounds of formula (I) useful in the
methods of this invention include but are not limited to:
1301311321331341351361371- 38139140141142143144145146147148149
[0426] Preferred compounds of formula (I) useful in the methods of
this invention include: 150151152153154155156157158159160
[0427] A more preferred group of compounds of formula (I) useful in
the methods of this invention include: 161162163164165166
[0428] A most preferred group of compounds of formula (I) useful in
the methods of this invention include: 167168169170171
[0429] Certain compounds of formula (I) may exist in different
stereoisomeric forms (e.g., enantiomers, diastereoisomers and
atropisomers). The invention contemplates all such stereoisomers
both in pure form and in admixture, including racemic mixtures.
Isomers can be prepared using conventional methods.
[0430] Certain compounds will be acidic in nature, e.g. those
compounds which possess a carboxyl or phenolic hydroxyl group.
These compounds may form pharmaceutically acceptable salts.
Examples of such salts may include sodium, potassium, calcium,
aluminum, gold and silver salts. Also contemplated are salts formed
with pharmaceutically acceptable amines such as ammonia, alkyl
amines, hydroxyalkylamines, N-methylglucamine and the like.
[0431] Certain basic compounds also form pharmaceutically
acceptable salts, e.g., acid addition salts. For example, the
pyrido-nitrogen atoms may form salts with strong acid, while
compounds having basic substituents such as amino groups also form
salts with weaker acids. Examples of suitable acids for salt
formation are hydrochloric, sulfuric, phosphoric, acetic, citric,
oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic,
maleic, methanesulfonic and other mineral and carboxylic acids well
known to those skilled in the art. The salts are prepared by
contacting the free base form with a sufficient amount of the
desired acid to produce a salt in the conventional manner. The free
base forms may be regenerated by treating the salt with a suitable
dilute aqueous base solution such as dilute aqueous NaOH, potassium
carbonate, ammonia and sodium bicarbonate. The free base forms
differ from their respective salt forms somewhat in certain
physical properties, such as solubility in polar solvents, but the
acid and base salts are otherwise equivalent to their respective
free base forms for purposes of the invention.
[0432] All such acid and base salts are intended to be
pharmaceutically acceptable salts within the scope of the invention
and all acid and base salts are considered equivalent to the free
forms of the corresponding compounds for purposes of the
invention.
[0433] Compounds of formula (I) can exist in unsolvated and
solvated forms, including hydrated forms. In general, the solvated
forms, with pharmaceutically acceptable solvents such as water,
ethanol and the like, are equivalent to the unsolvated forms for
the purposes of this invention.
[0434] This invention also includes Prodrugs of the novel compounds
of this invention, and of the compounds of formula (I) useful in
the methods of this invention. The term "prodrug," as used herein,
represents compounds which are rapidly transformed in vivo to the
parent compound of the above formula, for example, by hydrolysis in
blood. A thorough discussion is provided in T. Higuchi and V.
Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S.
Symposium Series, and in Edward B. Roche, ed., Bioreversible
Carriers in Drug Design, American Pharmaceutical Association and
Pergamon Press, 1987, both of which are incorporated herein by
reference.
[0435] For preparing pharmaceutical compositions from the compounds
of formula (I), inert, pharmaceutically acceptable carriers can be
either solid or liquid. Solid form preparations include powders,
tablets, dispersible granules, capsules, cachets and suppositories.
The powders and tablets may be comprised of from about 5 to about
95 percent active ingredient. Suitable solid carriers are known in
the art, e.g., magnesium carbonate, magnesium stearate, talc, sugar
or lactose. Tablets, powders, cachets and capsules can be used as
solid dosage forms suitable for oral administration. Examples of
pharmaceutically acceptable carriers and methods of manufacture for
various compositions may be found in A. Gennaro (ed.), Remington:
The Science and Practice of Pharmacy, 20.sup.th Edition, (2000),
Lippincott Williams & Wilkins, Baltimore, Md.
[0436] Liquid form preparations include solutions, suspensions and
emulsions. As an example may be mentioned water or water-propylene
glycol solutions for parenteral injection or addition of sweeteners
and opacifiers for oral solutions, suspensions and emulsions.
Liquid form preparations may also include solutions for intranasal
administration.
[0437] Aerosol preparations suitable for inhalation may include
solutions and solids in powder form, which may be in combination
with a pharmaceutically acceptable carrier, such as an inert
compressed gas, e.g. nitrogen.
[0438] Also included are solid form preparations which are intended
to be converted, shortly before use, to liquid form preparations
for either oral or parenteral administration. Such liquid forms
include solutions, suspensions and emulsions.
[0439] The compounds of formula (I) may also be deliverable
transdermally. The transdermal composition can take the form of
creams, lotions, aerosols and/or emulsions and can be included in a
transdermal patch of the matrix or reservoir type as are
conventional in the art for this purpose.
[0440] Preferably the compound of formula (I) is administered
orally.
[0441] Preferably, the pharmaceutical preparation is in a unit
dosage form. In such form, the preparation is subdivided into
suitably sized unit doses containing appropriate quantities of the
active component, e.g., an effective amount to achieve the desired
purpose.
[0442] The quantity of active compound in a unit dose of
preparation may be varied or adjusted from about 0.01 mg to about
1000 mg, preferably from about 0.01 mg to about 750 mg, more
preferably from about 0.01 mg to about 500 mg, and most preferably
from about 0.01 mg to about 250 mg, according to the particular
application.
[0443] The actual dosage employed may be varied depending upon the
requirements of the patient and the severity of the condition being
treated. Determination of the proper dosage regimen for a
particular situation is within the skill of the art. For
convenience, the total dosage may be divided and administered in
portions during the day as required.
[0444] The amount and frequency of administration of the compounds
of formula (I) and/or the pharmaceutically acceptable salts thereof
will be regulated according to the judgment of the attending
clinician considering such factors as age, condition and size of
the patient as well as severity of the symptoms being treated. A
typical recommended daily dosage regimen for oral administration
can range from about 0.04 mg/day to about 4000 mg/day, in two to
four divided doses.
[0445] The compounds used in combination with the compounds of
formula (I) can be administered in their normally prescribed
amounts as know by the skilled clinician (see, for example, the
Physicians' Desk Reference, 56.sup.th edition, 2002, published by
Medical Economics company, Inc. at Montvale, NJ 07645-1742, the
disclosure of which is incorporated herein by reference thereto).
The amount and frequency of administration of the compounds used in
combination with the compounds of formula (I) will be regulated
according to the judgment of the attending clinician considering
such factors as age, condition and size of the patient as well as
severity of the symptoms being treated.
Biological Assays
[0446] The compounds of formula (I) are useful in the treatment of
CXC-chemokine mediated conditions and diseases. This utility is
manifested in their ability to inhibit IL8 and GRO-.alpha.
chemokine as demonstrated by the following in vitro assays.
[0447] Receptor Binding Assays:
[0448] CXCR1 SPA Assay
[0449] For each well of a 96 well plate, a reaction mixture of 10
pg hCXCR1-CHO overexpressing membranes (Biosignal) and 200
.mu.g/well WGA-SPA beads (Amersham) in 100 .mu.l was prepared in
CXCR1 assay buffer (25 mM HEPES, pH 7.8, 2 mM CaCl.sub.2, 1 mM
MgCl.sub.2, 125 mM NaCl, 0.1% BSA) (Sigma). A 0.4 nM stock of
ligand, [125I]-IL-8 (NEN) was prepared in the CXCR1 assay buffer.
20.times. stock solutions of test compounds were prepared in DMSO
(Sigma). A 6.times. stock solution of IL-8 (R&D) was prepared
in CXCR2 assay buffer. The above solutions were added to a 96-well
assay plate (PerkinElmer) as follows: 10 .mu.l test compound or
DMSO, 40 .mu.l CXCR1 assay buffer or IL-8 stock, 100 .mu.l of
reaction mixture, 50 .mu.l of ligand stock (Final [Ligand]=0.1 nM).
The assay plates were shaken for 5 minutes on plate shaker, then
incubated for 8 hours before cpm/well were determined in Microbeta
Trilux counter (PerkinElmer). % Inhibition of Total binding-NSB
(250 nM IL-8) was determined for IC.sub.50 values.
[0450] Alternative CXCR1 SPA Assay
[0451] Protocol using CXCR1-expressing membranes from Biosignal
Packard
[0452] For each 50 .mu.l reaction, a working stock of 0.25
.mu.g/.mu.l hCXCR1-CHO over-expressing membranes with a specific
activity of 0.05 pmol/mg (Biosignal Packard) and 25 .mu.g/.mu.l
WGA-SPA beads (Perkin Elmer Life Sciences) was prepared in CXCR1
assay buffer (25 mM HEPES, pH 7.8, 0.1 mM CaCl.sub.2, 1 mM
MgCl.sub.2, 100 mM NaCl) (Sigma). This mixture was incubated on ice
for 30 minutes and then centrifuged at 2500 rpm for 5 minutes. The
beads and membranes were resuspended in CXCR1 assay buffer to the
same concentrations as in the original mixture. A 0.125 nM stock of
ligand, [.sup.125I]-IL-8 (Perkin Elmer Life Sciences), was prepared
in the CXCR1 assay buffer. Test compounds were first serially
diluted by half-logs in DMSO (Sigma) and then diluted 20-fold in
CXCR1 assay buffer. The above solutions were added to a Corning NBS
(non-binding surface) 96-well assay plate as follows: 20 .mu.l test
compound or 5% DMSO (final [DMSO]=2%), 20 .mu.l of membranes and
SPA bead mixture (Final [membrane]=5 .mu.g/reaction; Final [SPA
bead]=500 .mu.g/reaction), 10 .mu.l of ligand stock (Final
[.sup.125I-IL-8]=0.025 nM). The assay plates were incubated for 4
hours before cpm/well were determined in a Microbeta Trilux counter
(Perkin Elmer Life Sciences). IC.sub.50 values were quantified
using nonlinear regression analysis in GraphPad Prism.
[0453] Alternative CXCR1 SPA Assay
[0454] Protocol Using CXCR1-Expressing Membranes from
Euroscreen
[0455] For each 50 .mu.l reaction, a working stock of 0.025
.mu.g/[l hCXCR1-CHO overexpressing membranes with a specific
activity of 3.47 pmol/mg (Euroscreen) and 5 .mu.g/.mu.l WGA-SPA
beads (Perkin Elmer Life Sciences) was prepared in CXCR1 assay
buffer (25 mM HEPES, pH 7.8, 2.0 mM CaCl.sub.2, 1 mM MgCl.sub.2,
125 mM NaCl) (Sigma). This mixture was incubated on ice for 5
minutes. A 0.125 nM stock of ligand, [.sup.125I]-IL-8 (Perkin Elmer
Life Sciences), was prepared in the CXCR1 assay buffer. Test
compounds were first serially diluted by half-logs in DMSO (Sigma)
and then diluted 13.3-fold in CXCR1 assay buffer. The above
solutions were added to a Corning NBS (non-binding surface) 96-well
assay plate as follows: 20 .mu.l test compound or 7.5% DMSO (final
[DMSO]=3%), 20 .mu.l of membranes and SPA bead mixture (Final
[membrane]=0.5 .mu.g/reaction; Final [SPA bead]=100
.mu.g/reaction), 10 .mu.l of ligand stock (Final
[.sup.125I-IL-8]=0.025 nM). The assay plates were incubated for 4
hours before cpm/well were determined in a Microbeta Trilux counter
(Perkin Elmer Life Sciences). IC.sub.50 values were quantified
using nonlinear regression analysis in GraphPad Prism.
[0456] For the CXCR1 assay, compounds of formula (I) had an
IC.sub.50 of <20 .mu.M
[0457] CXCR2 SPA Assay
[0458] For each well of a 96 well plate, a reaction mixture of 4
.mu.g hCXCR2-CHO overexpressing membranes (Biosignal) and 200
.mu.g/well WGA-SPA beads (Amersham) in 100 .mu.l was prepared in
CXCR2 assay buffer (25 mM HEPES, pH 7.4, 2 mM CaCl.sub.2, 1 mM
MgCl.sub.2). A 0.4 nM stock of ligand, [125I]-IL-8 (NEN), was
prepared in the CXCR2 assay buffer. 20.times. stock solutions of
test compounds were prepared in DMSO (Sigma). A 6.times. stock
solution of GRO-.alpha. (R&D) was prepared in CXCR2 assay
buffer. The above solutions were added to a 96-well assay plate
(PerkinElmer or Corning) as follows: 10 .mu.l test compound or
DMSO, 40 .mu.l CXCR2 assay buffer or GRO-.alpha. stock, 100 .mu.l
of reaction mixture, 50 .mu.l of ligand stock (Final [Ligand]=0.1
nM). When 40.times. stock solutions of test compounds in DMSO were
prepared, then the above protocol was used except instead 5 .mu.l
test compound or DMSO and 45 .mu.l CXCR2 assay buffer were used.
The assay plates were shaken for 5 minutes on a plate shaker, then
incubated for 2-8 hours before cpm/well were determined in
Microbeta Trilux counter (PerkinElmer). % Inhibition of total
binding minus non-specific binding (250 nM Gro-.alpha. or 50 .mu.M
antagonist) was determined and IC50 values calculated. Compounds of
formula (I) had an IC.sub.50 of <5 .mu.M.
[0459] Alternative CXCR2 SPA Assay
[0460] Protocol Using the CXCR2 50 .mu.l Assay
[0461] For each 50 .mu.l reaction, a working stock of 0.031
.mu.g/.mu.l hCXCR2-CHO over-expressing membranes with a specific
activity of 0.4 pmol/mg (Biosignal Packard) and 2.5 .mu.g/.mu.l
WGA-SPA beads (Perkin Elmer Life Sciences) was prepared in CXCR2
assay buffer (25 mM HEPES, pH 7.4, 2.0 mM CaCl.sub.2, 1 mM
MgCl.sub.2) (Sigma). This mixture was incubated on ice for 5
minutes. A 0.50 nM stock of ligand, [.sup.125I]-IL-8 (Perkin Elmer
Life Sciences), was prepared in the CXCR2 assay buffer. Test
compounds were first serially diluted by half-logs in DMSO (Sigma)
and then diluted 13.3-fold in CXCR2 assay buffer. The above
solutions were added to a Corning NBS (non-binding surface) 96-well
assay plate as follows: 20 .mu.l test compound or 7.5% DMSO (final
[DMSO]=3%), 20 .mu.l of membranes and SPA bead mixture (final
[membrane]=0.625 .mu.g/reaction; final [SPA bead]=50
.mu.g/reaction), 10 .mu.l of ligand stock (final
[.sup.125I-IL-8]=0.10 nM). The assay plates were incubated for 2
hours before cpm/well were determined in a Microbeta Trilux counter
(Perkin Elmer Life Sciences). IC.sub.50 values were quantified
using nonlinear regression analysis in GraphPad Prism.
[0462] Alternative CXCR2 SPA Assay
[0463] Protocol Using the CXCR2 200 .mu.l Assay
[0464] For each 200 .mu.l reaction, a working stock of 0.02
.mu.g/.mu.l hCXCR2-CHO overexpressing membranes with a specific
activity of 0.6 pmol/mg (Biosignal Packard) and 2 .mu.g/.mu.l
WGA-SPA beads (Perkin Elmer Life Sciences) was prepared in CXCR2
assay buffer (25 mM HEPES, pH 7.4, 2.0 mM CaCl.sub.2, 1 mM
MgCl.sub.2) (Sigma). This mixture was incubated on ice for 5
minutes. A 0.40 nM stock of ligand, [.sup.125I]-IL-8 (Perkin Elmer
Life Sciences), was prepared in the CXCR2 assay buffer. Test
compounds were first serially diluted by half-logs in DMSO (Sigma)
and then diluted 20-fold in CXCR2 assay buffer. The above solutions
were added to a Corning NBS (non-binding surface) 96-well assay
plate as follows: 50 111 test compound or 10% DMSO (final
[DMSO]=2.5%), 100 .mu.l of membranes and SPA bead mixture (final
[membrane]=2 .mu.g/reaction; final [SPA bead]=200 .mu.g/reaction),
50 .mu.l of ligand stock (final [.sup.125I-IL-8]=0.10 nM). The
assay plates were incubated for 2 hours before cpm/well were
determined in a Microbeta Trilux counter (Perkin Elmer Life
Sciences). IC.sub.50 values were quantified using nonlinear
regression analysis in GraphPad Prism.
[0465] For the CXCR2 assay, compounds of formula (I) had a
K.sub.t<20 .mu.M.
[0466] Carrageenan-Induced Rat Paw Edema Model
[0467] Carrageenan (0.05 ml of an 1% solution in saline) was
injected into one hindpaw of male Sprague-Dawley rats. Paw volumes
(ml) were measured by a water displacement plethysmometer prior to
and 3 h after the injection of carrageenan. The increase in paw
volume that occurred between the two timepoints was determined for
each group. Rats received Compound A: 172
[0468] (see Example 405 of WO 02/083624) or standard drugs in
methylcellulose vehicle by the oral route, 1 hr before carrageenan
injection. The percentage by which the edematous response was
inhibited was calculated by comparing the increase in paw edema of
drug-treated rats to that of vehicle-treated controls. To determine
neutrophil accumulation in the paws, rats were sacrificed at 3 hrs
and myeloperoxidase (MPO) activity was measured from inflammatory
fluid expressed from the hindpaw using a calorimetric assay
(Bradley et al., 1982). PGE.sub.2 production in the hindpaw was
assessed by ELISA (R&D Systems, Minneapolis, Minn.).
[0469] Combination studies were performed with Compound A and the
following standard anti-inflammatory agents--the non-selective
anti-inflammatory drug indomethacin, and the steroid betamethasone.
The combination of suboptimal doses of compound A at 1 mg/kg (20%
inhibition) and indomethacin at 0.5 mg/kg (0% inhibition) caused a
significant 41% reduction of paw edema, suggesting that this
combination results in greater efficacy than either agent alone.
This combination did not cause a further reduction in MPO activity
in the hindpaw compared to compound A alone (Compound A=67%
inhibition; indomethacin=-58% inhibition; combination=55%
inhibition). The combination of suboptimal doses of Compound A at 1
mg/kg and betamethasone at 0.05 mg/kg (32% inhibition) also
demonstrated greater efficacy in inhibiting edema (61% inhibition).
An additive inhibition of paw PGE.sub.2 levels was also observed
(31% inhibition by either betamethasone or Compound A alone, versus
78% inhibition with the combination).
[0470] Streptococcal Cell Wall-Induced Mouse Knee Swelling
Model
[0471] The method described by Lubberts et al, 1998 was used for
these studies, with some modifications. Female 8-12 week old
C57BL/6J animals were fasted overnight and dosed orally with
Compound A, indomethacin, or a combination of these agents
suspended in methylcellulose one hour prior to a single
intra-articular injection of 6 .mu.l containing 25 .mu.g of
bacterial SCW (4.32 mg/ml rhammose; Lee Laboratories, Grayson, Ga.)
in saline into the right knee joint. The left knee joint received
an injection of 6 .mu.l of saline at the same time. In other
experiments, a neutralizing rat anti-mouse TNF.alpha. antibody or
matched rat IgG isotype control was administered intraperitoneally
two hours prior to SCW injection and Compound A or methylcellulose
vehicle was orally administered one hour prior to SCW injection.
Knee swelling measurements were performed 2 hours after SCW
injection using a dial-gauge caliper (Starret, Athol, Mass.) by
measuring the difference in swelling between the right and left
knee joints. Patellar organ cultures for assessment of synovial
cytokine and chemokine and prostaglandin levels were prepared at 2
hours after SCW injection and established as described (Lubberts et
al, 1998), using ELISA kits obtained from R&D Systems
(Minneapolis, Minn.). Statistical analysis was performed using the
Student's t-test, with p<0.05 considered to be indicative of
statistical significant differences between groups.
[0472] Combination therapy with Compound A (10 mg/kg=46%
inhibition; 25 mg/kg=70% inhibition) and indomethacin (2 mg/kg=42%
inhibition) resulted in significantly greater reduction of knee
swelling compared to either agent alone in all instances. Thus, the
combination of Compound A at 10 mg/kg with indomethacin resulted in
a 74% inhibition of the response, while Compound A at 25 mg/kg in
combination with indomethacin led to a 93% inhibition of the
swelling response. Compound A administered alone significantly
inhibited IL-1.beta. production by ex vivo patellar organ culture
(49% inhibition at 10 mg/kg; 64% inhibition at 25 mg/kg) while
indomethacin treatment resulted in a 11% inhibition. Combination
treatment resulted in a 71% (10 mg/kg Compound A+indomethacin) and
57% inhibition (25 mg/kg Compound A+indomethacin) of IL-1.beta.
production, consistent with the concept that the effect on
IL-1.beta. was attributable to the pharmacological action of
Compound A. In comparison, the effect of combination therapy on
PGE.sub.2 levels (86% and 85% inhibition, respectively) in patellar
organ culture was accounted for by the activity of indomethacin
alone (89% inhibition) while Compound A alone had mild activity
(34-40% inhibition at 10-25 mg/kg).
REFERENCES
[0473] Bradley, P. P., D. A. Priebat, R. D. Christensen and G.
Rothstein. 1982. Measurement of cutaneous inflammation: Estimation
of neutrophil content with an enzyme marker. J. Invest. Dermatol.
78:206-209.
[0474] Lubberts, E., L. A. B. Joosten, M. M. A. Helsen and W. B.
van den Berg. 1998. Regulatory role of interleukin 10 in joint
inflammation and cartilage destruction in murine streptococcal cell
wall (SCW) arthritis. More therapeutic benefit with IL-4/IL-10
combination therapy than with IL-10 treatment alone. Cytokine
10:361-369.
[0475] Compounds of formula (I) may be produced by processes known
to those skilled in the art, in the following reaction schemes, and
in the preparations and examples below. Specific procedures for the
preparation of many of the compounds of formula (I) may be found in
in WO 02/076926 published Oct. 3, 2002, and WO 02/083624 published
Oct. 24, 2002.
[0476] A general procedure for the preparation of compounds of
formula (I) is as follows: 173 174
[0477] Scheme 1
[0478] An amine is condensed (Step A) with a nitrosalicylic acid
under standard coupling conditions and the resulting nitrobenzamide
is reduced (Step B) under hydrogen atmosphere in the presence of a
suitable catalyst. The remaining partner required for the synthesis
of the final target is prepared by condensing an aryl amine with
the commercially available diethylsquarate to give the
aminoethoxysquarate product. Subsequent condensation of this
intermediate with the aminobenzamide prepared earlier provides the
desired chemokine antagonist (Scheme 1).
[0479] Scheme 2
[0480] Alternatively, the aminobenzamide of Scheme 1 is first
condensed with commercially available diethylsquarate to give an
alternate monoethoxy intermediate. Condensation of this
intermediate with an amine gives the desired chemokine antagonist.
175 176
[0481] Scheme 3
[0482] Benztriazole compounds of Formula (I) are prepared by
stirring nitrophenylenediamines with sodium nitrite in acetic acid
at 60.degree. C. to afford the nitrobenzotriazole intermediate
(Scheme 3). Reduction of the nitro group in the presence of
palladium catalyst and hydrogen atmosphere provides the amine
compound. Subsequent condensation of this intermediate with the
aminooethoxysquarate prepared earlier (Scheme 1) provides the
desired chemokine antagonist.
[0483] Scheme 4
[0484] Condensation of nitrophenylenediamines with anhydrides or
activated acids at reflux (Scheme 4) affords benzimidazole
intermediates which after reduction with hydrogen gas and palladium
catalyst and condensation with the aminoethoxysquarate previously
prepared (Scheme 1) affords benzimidazole chemokine antagonists.
177 178
[0485] Scheme 5
[0486] Indazole structures of Formula (I) can be prepared according
to Scheme 5 by reduction of nitroindazole A (J. Am. Chem Soc. 1943,
65, 1804-1805) to give aminoindazole B and subsequent condensation
with the aminoethoxysquarate prepared earlier (Scheme 1).
[0487] Scheme 6
[0488] Indole structures of Formula (I) can be prepared according
to Scheme 6 by reduction of nitroindole A (J. Med. Chem. 1995, 38,
1942-1954) to give aminoindole B and subsequent condensation with
the aminoethoxysquarate prepared earlier (Scheme 1).
[0489] The invention disclosed herein is exemplified by the
following preparations and examples which should not be construed
to limit the scope of the disclosure. Alternative mechanistic
pathways and analogous structures may be apparent to those skilled
in the art.
PREPARATIVE EXAMPLES 13.17A-13.17B
[0490] Following the procedure set forth in Preparative Example
13.13 in WO 02/083624, but using the prepared or commercially
available aldehydes, the optically pure amine products in the Table
below were obtained.
1 Prep Ex. Aldehyde Amine Product Yield (%) 13.17A 179 180 181 38
13.17B 182 183 184 31
PREPARATIVE EXAMPLE 13.29
[0491] 185
[0492] Step A
[0493] To a solution of 3-methoxythiophene (3 g) in dichloromethane
(175 mL) at -78.degree. C. was added chlorosulfonic acid (8.5 mL)
dropwise. The mixture was stirred for 15 min at -78.degree. C. and
1.5 h at room temp. Afterwards, the mixture was poured carefully
into crushed ice, and extracted with dichloromethane. The extracts
were washed with brine, dried over magnesium sulfate, filtered
through a 1-in silica gel pad.
[0494] The filtrate was concentrated in vacuo to give the desired
compound (4.2 g).
[0495] Step B
[0496] The product from Step A above (4.5 g) was dissolved in
dichloromethane (140 mL) and added with triethylamine (8.8 mL)
followed by diethyl amine in THF (2M, 21 mL). The resulting mixture
was stirred at room temperature overnight. The mixture was washed
with brine and saturated bicarbonate (aq) and brine again, dried
over sodium sulfate, filtered through a 1-in silica gel pad. The
filtrate was concentrated in vacuo to give the desired compound
(4.4 g).
[0497] Step C
[0498] The product from Step B above (4.3 g) was dissolved in
dichloromethane (125 mL) and cooled in a -78.degree. C. bath. A
solution of boron tribromide (1.0 M in dichloromethane, 24.3 mL)
was added. The mixture was stirred for 4 h while the temperature
was increased slowly from -78.degree. C. to 10.degree. C. H.sub.2O
was added, the two layers were separated, and the aqueous layer was
extracted with dichloro-methane.
[0499] The combined organic layer and extracts were washed with
brine, dried over magnesium sulfate, filtered, and concentrated in
vacuo to give 3.96 g of the desired hydroxy-compound.
[0500] Step D
[0501] The product from step C above (3.96 g) was dissolved in 125
mL of dichloromethane, and added with potassium carbonate (6.6 g)
followed by bromine (2 mL). The mixture was stirred for 5 h at room
temperature, quenched with 100 mL of H.sub.2O. The aqueous mixture
was addjusted to pH .about.5 using a 0.5N hydrogen chloride aqueous
solution, and extracted with dichloromethane. The extracts were
washed with a 10% Na.sub.2S.sub.2O.sub.3 aqueous solution and
brine, dried over sodium sulfate, and filtered through a celite
pad. The filtrate was concentrated in vacuo to afford 4.2 g of the
desired bromo-compound.
[0502] Step E
[0503] The product from Step D (4.2 g) was dissolved in 100 mL of
acetone and added with potassium carbonate (10 g) followed by
iodomethane (9 mL). The mixture was heated to reflux and continued
for 3.5 h. After cooled to room temperature, the mixture was
filtered through a Celite pad. The filtrate was concentrated in
vacuo to a dark brown residue, which was purified by flash column
chromatography eluting with dichloromethane-hexanes (1:1, v/v) to
give 2.7 g of the desired product.
[0504] Step F
[0505] The product from step E (2.7 g) was converted to the desired
imine compound (3 g), following the similar procedure to that of
Preparative Example 13.19 step D.
[0506] Step G
[0507] The imine product from step F (3 g) was dissolved in 80 mL
of dichloromethane and cooled in a -78.degree. C. bath. A solution
of boron tribromide (1.0 M in dichloromethane, 9.2 mL) was added
dropwise. The mixture was stirred for 4.25 h from -78.degree. C. to
5.degree. C. H.sub.2O (50 mL) was added, and the layers were
separated. The aqueous layer was extracted with dichloromethane.
The organic layer and extracts were combined, washed with brine,
and concentrated to an oily residue. The residue was dissolved in
80 mL of methanol, stirred with sodium acetate (1.5 g) and
hydroxyamine hydrochloride (0.95 g) at room temperature for 2 h.
The mixture was poured into an aqueous mixture of sodium hydroxide
(1.0 M aq, 50 mL) and ether (100 mL). The two layers were
separated. The aqueous layer was washed with ether three times. The
combined ether washings were re-extracted with H.sub.2O once. The
aqueous layers were combined, washed once with dichloromethane,
adjusted to pH .about.6 using 3.0 M and 0.5 M hydrogen chloride
aqueous solutions, and extracted with dichloromethane. The organic
extracts were combined, washed with brine, dried over sodium
sulfate, and concentrated in vacuo to give 1.2 g of desired amine
compound.
PREPARATIVE EXAMPLES 13.30-13.32-A
[0508] Following the procedures set forth in Example 13.29, but
using commercially available amines, hydroxy-amino-thiophene
products in the Table below were obtained.
2 Yield Prep Ex. Amine Product MH.sup.+ 13.30 (Bn).sub.2NH 186 10%
375.1 13.31 Me(Bn)NH 187 14% 299.0 13.32 Et(Bn)NH 188 22% 13.32A
(Et).sub.2NH 189 25%
PREPARATIVE EXAMPLE 13.33
[0509] 190
[0510] Step A
[0511] 2-Chlorosulfonyl-3-methoxy-thiophene (4.0 g, 18.8 mmol), the
product from Step A of Preparative Example 13.29 was converted to
3-methoxy-2-ethylbenzylsulfonyl-thiophene (5.5 g, 94%,
MH.sup.+=312.1) by using ethylbenzyl-amine, following the procedure
set forth in Preparative Example 13.29, Step B.
[0512] Step B
[0513] 10 The product from Step A above (5.5 g, 17.70 mmol) was
demethylated following the procedure set forth in Preparative
Example 13.29, Step C. The alcohol product was obtained in 4.55 g
(87%, MH.sup.+=298.0).
[0514] Step C
[0515] The product from Step B above (4.55 g, 15.30 mmol) was
brominated using the procedure set forth in Preparative Example
13.29, Step D. The corresponding bromide was obtained in 4.85 g
(84%).
[0516] Step D
[0517] The bromo-alcohol from Step C above (4.84 g, 12.86 mmol) was
methylated using the procedure set forth in Preparative Example
13.29, Step E. The product was obtained in 4.82 g (96%).
[0518] Step E
[0519] The product from Step D above (4.82 g, 12.36 mmol) was
stirred with concentrated sulfuric acid (5 mL) at room temperature
ro 3 h. Ice water (30 mL) was added to the mixture followed by
CH.sub.2Cl.sub.2 (50 mL). The aqueous mixture was adjusted to pH
.about.6 using a 1.0 M NaOH aqueous solution. The layers were
separated. The aqueous layer was extracted with CH.sub.2Cl.sub.2
(50 mL.times.3). The combined organic layers were washed with
brine, dried over Na.sub.2SO.sub.4, and concentrated to a dark
brown oil, which was purified by flash column chromatography,
eluting with CH.sub.2Cl.sub.2-hexanes (1:1, v/v). Removal of
solvents afforded 3.03 g (82%) of the debenzylated product
(M.sup.+=300.0, M+2=302.0).
[0520] Step F
[0521] The product from Step E (1.34 g, 4.45 mmol) was methylated
using the procedure set forth in Preparative Example 13.29, Step E.
The desired product was obtained in 1.36 g (97%, M.sup.+=314.1,
M+2=316.0).
[0522] Step G
[0523] The product from Step F (1.36 g, 4.33 mmol) was converted to
imine product (1.06 g, 55%, MH.sup.+=415.1) using the procedure set
forth in Preparative Example 13.29, Step F.
[0524] Step H
[0525] The imine product from Step G (1.06 g, 2.56 mmol) was
converted to the desired hydroxy-amino thiophene compound (0.26 g,
43%) using the procedure set forth in Preparative Example 13.29,
Step G.
[0526] PREPARATIVE EXAMPLE 13.34 191
[0527] Step A
[0528] 2-Chlorosulfonyl-3-methoxy-thiophene (3.8 g, 17.87 mmol),
the product from step A of Preparative Example 13. 29, was
dissolved in 100 mL of CH.sub.2Cl.sub.2 and 20 mL of pyridine.
3-Amino-5-methyl-isoxazole (3.5 g, 35.68 mmol) was added. The
mixture was stirred for 20 h at room temperature, diluted with 100
mL of CH.sub.2Cl.sub.2, and washed with a 0.5 N HCl aqueous
solution (50 mL.times.2), H.sub.2O (50 mL), and brine (50 mL). The
organic solution was dried with Na.sub.2SO.sub.4, and conentrated
in vacuo to a brown oil. This oil was dissolved in 100 mL of
CH.sub.2Cl.sub.2, washed again with a 0.5 M HCl aqueous solution
(30 mL.times.3) and brine. After dried over Na.sub.2SO.sub.4, the
organic solution was concentrated in vacuo to a yellow solid, 4.48
g (91%, MH.sup.+=275.0) of the desired product.
[0529] Step B
[0530] The product from Step A above (4.48 g, 16.33 mmol) was
dissolved in acetone (100 mL), added with potassium carbonate (5.63
g, 40.80 mmol) and iodomethane (10.1 mL, 163.84 mmol). The mixture
was stirred at room temperature for 1.5 h, diluted with 100 mL of
hexanes and 50 mL of CH.sub.2Cl.sub.2, and filtered through a 1-in
silica gel pad, rinsing with CH.sub.2Cl.sub.2. The filtrate was
concentrated under reduced pressure to give 4.23 g (90%,
MH.sup.+=289.0) of the desired product as a light yellow solid.
[0531] Step C
[0532] To a stirred suspension of sodium hydride (130 mg, 95%, 5.4
mmol) in 8 mL of N,N'-dimethylforamide at room temperature was
added ethanethio](0.45 mL, 6.0 mmol) dropwise. After 5 min, the
mixture became a clear solution, and was added to a stirred
solution of the product obtained from Step B above (0.45 g, 1.56
mmol) in 2 mL of N,N'-dimethylforamide in a round bottom flask. The
flask was sealed with a ground glass stopper, and the mixture was
heated at 90-95.degree. C. for 4 h. After cooled to room
temperature, the mixture was poured into 20 mL of a 1.0 M NaOH
aqueous solution, further rinsed with 20 mL of H.sub.2O. The
aqueous mixture was washed with diethyl ether (30 mL.times.2),
adjusted to PH .about.5 using a 0.5 M HCl aqueous solution, and
extracted with CH.sub.2Cl.sub.2 (50 mL x4). The combined extracts
were washed with brine, dried (Na.sub.2SO.sub.4), and concentrated
to a dark yellow solution. This was dissolved in 50 mL of ethyl
acetate, washed with H.sub.2O (30 mL x2) and brine (30 mL), dried
over Na.sub.2SO.sub.4. Evaporation of solvent gave 0.422 g of the
alcohol product (99%, MH.sup.+=275.0).
[0533] Step D
[0534] The alcohol obtained from Step C above (0.467 g, 1.70 mmol)
was brominated using the procedure set forth in Preparative Example
13.29, Step D, to afford the corresponding bromide in 0.607 g
(100%).
[0535] Step E
[0536] The bromide obtained from Step D above (0.607 g, 1.72 mmol)
was methylated using the procedure set forth in Preparative Example
13.29, Step E, to give the desired product in 0.408 g (65%,
M.sup.+=367, M+2=369.1).
[0537] Step F
[0538] The product (0.405 g, 1.103 mmol) from Step E above was
converted to the imine compound (0.29 g, 56%) using the procedure
set forth in Preparative Example 13.29, Step F.
[0539] Step G
[0540] The imine product obtained from Step F above (0.29 g, 0.61
mmol) was demethylated using the procedure set forth in Step C
above to give the corresponding alcohol as a dark yellow oil, which
was dissolved in 5 mL methanol and added with sodium acetate (0.12
g, 1.46 mmol) and hydroxyamine hydrochloride (0.075 g, 1.08 mmol).
The resulting mixture was stirred at room temperature for 3 h, and
poured into 10 mL of 1.0 M NaOH aqueous solution. 30 mL of H.sub.2O
was used as rinsing and combined to the aqueous layer. The aqueous
mixture was washed with diethyl ether (40 mL.times.3), adjusted to
pH .about.6 using a 1.0 M HCl aqueous solution, and extracted with
ethyl acetate (40 mL.times.3). The organic extracts were washed
with H.sub.2O (20 mL.times.2), brine (20 mL), dried over
Na.sub.2SO.sub.4, and concentrated in vacuo to give 0.112 g of the
desired hydroxy-amino thiophene sulfonamide (64%,
MH.sup.+=290).
PREPARATIVE EXAMPLE 13.35
[0541] 192
[0542] Step A
[0543] To a solution of 2-methyl furan (1.72 g) in ether was added
BuLi (8.38 mL) at -78.degree. C. and stirred at room temperature
for half an hour. The reaction mixture again cooled to -78.degree.
C. and quenched with cyclopropyl amide 1 and stirred for two hours
at -78.degree. C. and slowly warmed to room temperature. The
reaction mixture stirred for three hours at room temperature and
quenched with the addition of saturated ammonium chloride solution.
The mixture was taken to a separatory funnel, washed with water,
brine and dried over anhydrous sodium sulfate. Filtration and
removal of solvent afforded the crude ketone, which was purified by
using column chromatography to afford the ketone 3.0 g (87%) as a
pale yellow oil.
[0544] Step B
[0545] To a solution of ketone (1.0 g) in THF (5.0 mL) at 0.degree.
C. was added R-methyl oxazoborolidine (1.2 mL, 1 M in toluene)
dropwise followed by addition of a solution of borane complexed
with dimethyl sulfide (1.85 mL, 2M in THF). The reaction mixture
was stirred for 30 minutes at 0.degree. C. and than at room
temperature for one hour. The reaction mixture was cooled to
0.degree. C. and MeOH was added carefully. The mixture was stirred
for 20 minutes and was concentrated under reduced pressure. The
residue was extracted with ether, washed with water, 1 M HCl (10
mL), saturated sodium bicarbonate (10.0 mL) water and brine. The
organic layer was dried over anhydrous sodium sulfate, filtered and
removal of solvent afforded the crude alcohol which was purified by
silica gel chromatography to afford the pure alcohol 0.91 g (91%)
as yellow oil.
PREPARATIVE EXAMPLE 13.36
[0546] 193
[0547] Step A
[0548] An equimolar mixture of 2-methylfuran (1.0 g) and anhydride
(2.6 g) was mixed with SnCl.sub.4 (0.05 mL) and heated at
100.degree. C. for 3 hours. After cooling the reaction mixture,
water (10 mL) was added, followed by saturated sodium carbonate
solution until it becomes alkaline. The reaction mixture was
extracted with ether several times and the combined ether layer was
washed with water, brine and dried over anhydrous sodium sulfate.
Filtration and removal of solvent afforded the crude ketone, which
was purified by using silica gel chromatography to afford the
ketone 0.9 g (43%) as a yellow oil.
[0549] Step B
[0550] The step B alcohol was obtained following a similar
procedure set forth in the preparative example 13.35 Step B.
PREPARATIVE EXAMPLE 13.37
[0551] 194
[0552] Step A
[0553] To a solution of 5-methyl furan-2-aldehyde (1.0 g) and
3-bromo-3,3-difluoropropene (2.24 g) in DMF (30 mL) was added
indium powder (1.66 g) and lithium iodide (50.0 mg). The reaction
mixture was stirred over night, diluted with water and extracted
with ether. The ether layer was washed with water, brine and
purified by silicagel chromatography to afford the pure alcohol 2.8
g (92%).
PREPARATIVE EXAMPLES 13.38-13.45
[0554] Following a similar procedure set forth in Preparative
Examples 13.25 and 13.35, and using the indicated Furan and
Electrophile, the following Alcohols in the Table below were
prepared.
3 Prep. Ex Furan Electrophile Alcohol Yield 13.38 195 196 197 86%
13.39 198 199 200 69% 13.40 201 202 203 84% 13.41 204 205 206 82%
13.42 207 208 209 60% 13.43 210 211 212 65% 13.44 213 214 215 82%
13.45 216 217 218 89%
PREPARATIVE EXAMPLES 13.50-13.61
[0555] Following a similar procedure set forth in WO 02/083624,
Preparative Example 13.25, and using the indicated Alcohol, the
Amines in the Table below were prepared.
4 PREP. EX. ALCOHOL AMINE YIELD 13.50 13.45 219 28% 13.51 13.38 220
58% 13.52 13.36 221 69% 13.53 13.35 222 81% 13.54 13.37 223 82%
13.55 13.39 224 45% 13.56 13.41 225 57% 13.57 13.40 226 58% 13.58
13.44 227 54% 13.59 13.42 228 53% 13.60 13.43 229 50% 13.61 13.37
230 82%
PREPARATIVE EXAMPLE 13.70
[0556] 231
[0557] Step A
[0558] The imine was prepared following the procedure set forth in
WO 02/083624 Preparative Example 13.19 from the known bromoester
(1.0 g) as a yellow solid, Step A to yield 1.1 g (79%).
[0559] Step B
[0560] The Step A product (0.6 g) was reacted following the
procedure set forth in the preparative example 13.19 to give the
amine product 0.19 g (64%).
[0561] Step C
[0562] The Step B product (1.0 g) was reacted following the
procedure set forth in WO 02/083624 Preparative Example 13.19 to
give the acid as yellow solid 0.9 g (94%).
[0563] Step D
[0564] The Step C product (0.35 g) was reacted following the
procedure set forth in WO 02/083624 Preparative Example 13.19 to
give the amino acid as yellow solid 0.167 g (93%).
PREPARATIVE EXAMPLE 13.71
[0565] 232
[0566] Following a similar procedure set forth in Preparative
Example 13.33 Step E, but using the product from WO 02/083624
Preparative Example 13.32, the title compound was obtained (121 mg,
69% yield, MH+=223.0).
PREPARATIVE EXAMPLE 23.15A-23.15E
[0567] Following the procedures set forth in WO 02/083624
Preparative Example 19.2 but using the amines from the Preparative
Example indicated in the Table below, the corresponding
cyclobutenedione intermediates were prepared.
5 Amine from Prep Prep 1. Yield Ex. Ex. Product 2. MH.sup.+ 23.15F
13.32A 233 1. 68% 2. 375.1
PREPARATIVE EXAMPLE 24
[0568] Following the procedures set forth in WO 02/083624
Preparative Example 13.23 (but instead using
5-bromo-6-methoxybenzoic acid in Step A) and in WO 02/083624
Preparative Example 23.14, the corresponding cyclobutenedione
intermediate could be prepared. 234
PREPARATIVE EXAMPLE 25
[0569] Following the procedures set forth in Preparative Example
13.24 (but instead using 2-aminopyridine) and in WO 02/083624
Preparative Example 23.14, the corresponding cyclobutenedione
intermediate could be prepared. 235
PREPARATIVE EXAMPLE 26
[0570] Following the procedures set forth in WO 02/083624
Preparative Example 23.14 (but instead the title compound from WO
02/083624 Preparative Example 135), the corresponding
cyclobutenedione intermediate could be prepared. 236
PREPARATIVE EXAMPLE 34.15-34.16
[0571] Following the procedures set forth in Preparative Example
34.8 in WO 02/083624 but using the nitroalkanes indicated in the
table below, the aldehydes were prepared.
6 YIELD PREP. Ex. NITROALKANE ALDEHYDE (%) 34.15 237 238 17 34.16
239 240 21
PREPARATIVE EXAMPLE 34.17
[0572] 241
[0573] Step A
[0574] To a stirred suspension of 5-bromo-2-furoic acid (15.0 g,
78.54 mmol) in 225 mL of CH.sub.2Cl.sub.2 at room temperature was
added oxalyl chloride followed by a catalytic amount of
N,N'-dimethylforamide. After 1 h, ethanol (20 mL) was added
followed by triethylamine (22 mL). Reaction was continued for 15 h.
The mixture was concentrated under reduced pressure to a residue,
which was extracted with excess volume of hexanes, and
hexanes-CH.sub.2Cl.sub.2 (3:1, v/v). The extracts were filtered,
the filtrated was concentrated to a yellow oil, dried on high
vacuum, yielding 17.2 g (93%) of the desired ester.
[0575] Step B
[0576] The ester product obtained from Step A above (17.2 g, 73.18
mmol) was converted to 2-ethyl-4-tertbutyl-5-bromo-furoate (7.9 g,
37%) using the literature procedure: J. Am. Chem.Soc., 1939, 61,
473-478 (the disclosure of which is incorporated herein by
reference thereto).
[0577] Step C
[0578] The ester product obtained from Step B above (7.9 g, 27.13
mol) was reduced to the alcohol (6.32 g) using the procedure set
forth in WO 02/083624 Preparative Example 34.8, Step C.
[0579] Step D
[0580] The product obtained from Step C above (6.32 g) was
dissolved in 140 mL of THF and cooled in a -78.degree. C. bath. A
2.5 M solution of n-butyllithium in hexanes (22 mL, 55.0 mmol) was
added dropwise along the side wall of the flask. After 15 min,
H.sub.2O (.about.70 mL) was added. Cooling bath was removed, the
mixture was stirred for an additional 1 h. Brine (50 mL) and
CH.sub.2Cl.sub.2 (300 mL) were added, the two layers were
separated, the aqueous layer was extracted with CH.sub.2Cl.sub.2
(100 mL), and the combined organic layers ere dried by
Na.sub.2SO.sub.4. Evaporation of solvents afforded 5.33 g (crude)
of the debrominated product as a reddish brown oil.
[0581] Step E
[0582] The alcohol product obtained from Step D above (5.33 g) was
oxidized to the corresponding aldehyde (3.06 g, 74% over three
steps) using the procedure set forth in WO 02/083624 Preparative
Example 34.8, Step D.
[0583] PREPARATIVE EXAMPLE 34.18 242
[0584] Step A
[0585] To a stirred solution of cyclopropyl bromide (4.0 mL, 50
mmol) in 120 mL of ether at -78.degree. C. was added dropwise a
1.7M solution of t-butyllithium in pentane (44.5 mL, 75.7 mmol).
After 10 min, cooling bath was removed, stirring was continued for
1.5 h. The mixture was cooled again in a -78.degree. C. bath, and
3-furaldehyde (3.5 mL, 41.9 mmol) was added. Reaction was continued
for 1 h, and quenched with a saturated NH4Cl aqueous solution. The
aqueous mixture was extracted with CH.sub.2Cl.sub.2 (100
mL.times.3). The organic extracts were washed with brine, dried by
Na.sub.2SO.sub.4, filtered, and concentrated in vacuo to give 5.3 g
(91%) of the alcohol product as a yellow oil.
[0586] Step B
[0587] Chloro trimethylsilane (27.2 mL, 214.2 mmol) was added
dropwise to a vigorously stirred suspension of sodium iodide (32 g,
213.5 mmol) in 100 mL of acetonitrile. After 5 min, a solution of
the alcohol obtained from Step A above (4.93 g, 35.68 mmol) in 100
mL of acetonitrile was added dropwise. Stirring was continued for 5
min. H.sub.2O (100 mL) was added, the layers were separated, and
the aqueous layer was extracted with ether (100 mL.times.2). The
organic layers were combined, washed with a 10%
Na.sub.2S.sub.2O.sub.3 aqueous solution and brine, and dried over
Na.sub.2SO.sub.4. Evaporation of solvents gave a dark brown oil,
which was filtered through a 5-in silica gel column, eluting with
CH.sub.2Cl.sub.2-hexanes (1:3.5, v/v). Removal of solvents afforded
4.22 g (47%) of the iodo product as a light yellow oil.
[0588] Step C
[0589] The iodo-product obtained from Step B above (2.2 g, 8.8
mmol) was dissolved in 60 mL of ether, and stirred in a -78.degree.
C. bath. A 1.7 M solution of t-butyllithium in pentane (10.4 mL,
17.7 mmol) was added dropwise. After 20 min, cooling bath was
removed. Reaction was continued for 2.5 h, and quenched with
H.sub.2O (20 mL). The aqueous mixture was stirred overnight and
separated. The aqueous layer was extracted with ether (30 mL). The
combined organic layers were washed with brine, dried by
Na.sub.2SO.sub.4, and filtered through a Celite pad. Removal of
solvent gave 1.10 g (100%) of 3-butylfuran as a reddish-yellow
oil.
[0590] Step D
[0591] 3-Butylfuran (1.1 g, 8.8 mmol), obtained from Step C above,
was dissolved in 60 mL of ether, and stirred in a -78.degree. C.
bath. A 1.7 M solution of t-butyllithium in pentane (6.0 mL, 10.2
mmol) was added dropwise along the side wall of the flask. The
mixture was stirred for 3 h from -78.degree. C. to 0.degree. C.,
and continued for 1 h at room temperature. A solution of
N,N'-dimethylforamide (1.1 mL, 14.23 mmol) was added. Reaction was
continued overnight, and quenched with a saturated NH.sub.4Cl
aqueous solution. The two layers were separated, the aqueous layer
was extracted with CH.sub.2Cl.sub.2 (30 mL.times.2). The combined
organic layers were washed with brine, dried with Na.sub.2SO.sub.4,
and concentrated to an oil, which was purified by preparative TLC
(CH.sub.2Cl.sub.2-- hexanes=1:1.5, v/v) to give 0.48 g (36%) of the
aldehyde (contaminated by some 3-butyl-2-furaldehyde).
PREPARATIVE EXAMPLE 34.19
[0592] 243
[0593] Step A
[0594] 3-Ethylfuran was prepared from 3-hydroxymethylfuran
according to literature procedure: J. Org. Chem., 1983, 48,
1106-1107 (the disclosure of which is incorporated herein by
reference thereto).
[0595] Step B
[0596] 3-Ethylfuran obtained from Step A above was converted to
4-ethyl-2-furaldehyde using the procedure set forth in WO 02/083624
Preparative Example 34.18, Step D.
PREPARATIVE EXAMPLES 65-75.10J
[0597] Following the procedure set forth in WO 02/083624
Preparative Example 64 but using the aldehydes, amino alcohols, and
organolithium reagents in the Table below (prepared according to
the Preparative Examples indicated from WO 02/083624), the
optically pure amine products in the Table below were obtained.
7 Prep Amino Organo 1. Yield (%) Ex. Aldehyde Alcohol lithium
Product 2. MH.sup.+ 75.10A 244 245 246 247 1. 61 2. 135 [M -
NH.sub.2].sup.+ 75.10B 248 249 EtLi 250 1. 24 2. 154 75.10C 251 252
EtLi 253 1. 32 2. 165 [M - NH.sub.2].sup.+ 75.10D 254 255 MeLi 256
1. 47 2. 137 [M - NH.sub.2].sup.+ 75.10E 257 258 iPrLi 259 1. 30 2.
165 [M - NH.sub.2].sup.+ 75.10F 260 261 262 263 1. 67 2. 163.0 [M -
NH.sub.2].sup.+ 75.10G 264 265 EtLi 266 1. 24 2. 165 [M -
NH.sub.2].sup.+ 75.10H 267 268 EtLi 269 1. 70 2. 194 75.10J 270 271
EtLi 272 1. 54 2. 208
PREPARATIVE EXAMPLES 75.11-75.59
[0598] Following the procedure set forth in WO 02/083624
Preparative Example 64 but using the prepared or commercially
available aldehydes, amino alcohols, and organolithium reagents in
the Table below and carrying the amine on crude, the optically pure
amine products in the Table below were obtained.
8 Prep Amino Organo Yield Ex. Aldehyde Alcohol lithium Product (%)
75.60 273 274 t-BuLi 275 60
PREPARATIVE EXAMPLE 500.7
[0599] 276
[0600] Step A
[0601] If one were to use a similar procedure to that used in WO
02/083624 Preparative Example 13.3 Step B, except using the hydroxy
acid from Bioorg. Med. Chem. Lett. 6(9), 1996,1043 (the disclosure
of which is incorporated herein by reference thereto), one would
obtain the desired methoxy compound.
[0602] Step B
[0603] If one were to use a similar procedure to that used in WO
02/083624 Preparative Example 13.19 Step B, except using the
product from Step A above, one would obtain the desired
compound.
[0604] Step C
[0605] If one were to use a similar procedure to that used in
Synth. Commun. 1980, 10, p. 107 (the disclosure of which is
incorporated herein by reference thereto), except using the product
from Step B above and t-butanol, one would obtain the desired
compound.
[0606] Step D
[0607] If one were to use a similar procedure to that used in
Synthesis, 1986,1031 (the disclosure of which is incorporated
herein by reference thereto), except using the product from Step C
above, one would obtain the desired sulfonamide compound.
[0608] Step E
[0609] If one were to use a similar procedure to that used in WO
02/083624 Preparative Example 13.19 Step E, except using the
product from Step D above, one would obtain the desired
compound.
PREPARATIVE EXAMPLE 500.8
[0610] 277
[0611] Step A
[0612] If one were to treat the product from Step C of WO 02/083624
Example 1125 with BuLi (2.2 eq.) in THF followed by quenching of
the reaction mixture with N,N,-dimethylsulfamoyl chloride (1.1 eq.)
then one would obtain the title compound.
[0613] Step B
[0614] If one were to use the product of Step A above and follow
Step E of Preparative Example 500.7, then one would obtain the
title compound.
PREPARATIVE EXAMPLE 500.9
[0615] 278
[0616] Step A
[0617] To a solution of 3-methoxythiophene (3 g) in dichloromethane
(175 mL) at -78.degree. C. was added chlorosulfonic acid (8.5 mL)
dropwise. The mixture was stirred for 15 min at -78.degree. C. and
1.5 h at room temp. Afterwards, the mixture was poured carefully
into crushed ice, and extracted with dichloromethane. The extracts
were washed with brine, dried over magnesium sulfate, filtered
through a 1-in silica gel pad. The filtrate was concentrated in
vacuo to give the desired compound (4.2 g).
[0618] Step B
[0619] The product from Step A above (4.5 g) was dissolved in
dichloromethane (140 mL) and added with triethylamine (8.8 mL)
followed by diethyl amine in THF (2M, 21 mL). The resulting mixture
was stirred at room temperature overnight. The mixture was washed
with brine and saturated bicarbonate (aq) and brine again, dried
over sodium sulfate, filtered through a 1-in silica gel pad. The
filtrate was concentrated in vacuo to give the desired compound
(4.4 g).
[0620] Step C
[0621] The product from Step B above (4.3 g) was dissolved in
dichloromethane (125 mL) and cooled in a -78.degree. C. bath. A
solution of boron tribromide (1.0 M in dichloromethane, 24.3 mL)
was added. The mixture was stirred for 4 h while the temperature
was increased slowly from -78.degree. C. to 10.degree. C. H.sub.2O
was added, the two layers were separated, and the aqueous layer was
extracted with dichloro-methane. The combined organic layer and
extracts were wahed with brine, dried over magnesium sulfate,
filtered, and concentrated in vacuo to give 3.96 g of the desired
hydroxy-compound.
[0622] Step D
[0623] The product from step C above (3.96 g) was dissolved in 125
mL of dichloromethane, and added with potassium carbonate (6.6 g)
followed by bromine (2 mL). The mixture was stirred for 5 h at room
temperature, quenched with 100 mL of H.sub.2O. The aqueous mixture
was addjusted to pH .about.5 using a 0.5N hydrogen chloride aqueous
solution, and extracted with dichloromethane. The extracts were
washed with brine, dried over sodium sulfate, and filtered through
a celite pad. The filtrate was concentrated in vacuo to afford 4.2
g of the desired bromo-compound.
[0624] Step E
[0625] The product from Step D (4.2 g) was dissolved in 100 mL of
acetone and added with potassium carbonate (10 g) followed by
iodomethane (9 mL). The mixture was heated to reflux and continued
for 3.5 h. After cooled to room temperature, the mixture was
filtered through a Celite pad. The filtrate was concentrated in
vacuo to a dark brown residue, which was purified by flash column
chromatography eluting with dichloromethane-hexanes (1:1, v/v) to
give 2.7 g of the desired product.
[0626] Step F
[0627] The product from step E (2.7 g) was converted to the desired
imine compound (3 g), following the similar procedure to that of WO
02/083624 Preparative Example 513.19step D.
[0628] Step G
[0629] The imine product from step F (3 g) was dissolved in 80 mL
of dichloromethane and cooled in a -78.degree. C. bath. A solution
of boron tribromide (1.0 M in dichloromethane, 9.2 mL) was added
dropwise. The mixture was stirred for 4.25 h from -78.degree. C. to
5.degree. C. H.sub.2O (50 mL) was added, and the layers were
separated. The aqueous layer was extracted with dichloromethane.
The organic layer and extracts were combined, washed with brine,
and concentrated to an oily residue. The residue was dissolved in
80 mL of methanol, stirred with sodium acetate (1.5 g) and
hydroxyamine hydrochloride (0.95 g) at room temperature for 2 h.
The mixture was poured into an aqueous mixture of sodium hydroxide
(1.0 M aq, 50 mL) and ether (100 mL). The two layers were
separated. The aqueous layer was washed with ether three times. The
combined ether washings were re-extracted with H.sub.2O once. The
aqueous layers were combined, washed once with dichloromethane,
adjusted to pH .about.6 using 3.0 M and 0.5 M hydrogen chloride
aqueous solutions, and extracted with dichloromethane. The organic
extracts were combined, washed with brine, dried over sodium
sulfate, and concentrated in vacuo to give 1.2 g of desired amine
compound.
PREPARATIVE EXAMPLE 600
[0630] 279
[0631] Step A
[0632] Following the procedure set forth in WO 02/083624
Preparative Example 13.19 Step D, the imine was prepared from the
known bromoester (1.0 g) to yield 1.1 g (79%) as a yellow
solid.
[0633] Step B
[0634] The product of Step A (0.6 g) was reacted following the
procedure set forth in WO 02/083624 Preparative Example 13.19 Step
E to give the amine product 0.19 g (64%).
[0635] Step C
[0636] The product of Step B (1.0 g) was reacted following the
procedure set forth in WO 02/083624 Preparative Example 13.19 Step
B to give the acid as yellow solid 0.9 g (94%).
[0637] Step D
[0638] The product of Step C (0.35 g) was reacted following the
procedure set forth in WO 02/083624 Preparative Example 13.19 Step
E to give the amino acid as yellow solid 0.167 g (93%).
PREPARATIVE EXAMPLE 601
[0639] 280
[0640] Step A
[0641] To a solution of 2-methyl furan (1.72 g) in ether was added
BuLi (8.38 mL) at -78.degree. C. and stirred at room temperature
for half an hour. The reaction mixture again cooled to -78.degree.
C. and quenched with cyclopropyl amide 1 and stirred for two hours
at -78.degree. C. and slowly warmed to room temperature. The
reaction mixture stirred for three hours at room temperature and
quenched with the addition of saturated ammonium chloride solution.
The mixture was taken to a separatory funnel, washed with water,
brine and dried over anhydrous sodium sulfate. Filtration and
removal of solvent afforded the crude ketone, which was purified by
using column chromatography to afford the ketone 3.0 g (87%) as a
pale yellow oil.
[0642] Step B
[0643] To a solution of ketone (1.0 g) from Step A above in THF
(5.0 mL) at 0.degree. C. was added R-methyl oxazoborolidine (1.2
mL, 1 M in toluene) dropwise followed by addition of a solution of
borane complexed with dimethyl sulfide (1.85 mL, 2M in THF). The
reaction mixture was stirred for 30 minutes at 0.degree. C. and
than at room temperature for one hour. The reaction mixture was
cooled to 0.degree. C. and MeOH was added carefully. The mixture
was stirred for 20 minutes and was concentrated under reduced
pressure. The residue was extracted with ether, washed with water,
1 M HCl (10 mL), saturated sodium bicarbonate (10.0 mL) water and
brine. The organic layer was dried over anhydrous sodium sulfate,
filtered and removal of solvent afforded the crude alcohol which
was purified by silica gel chromatography to afford the pure
alcohol 0.91 g (91%) as yellow oil.
PREPARATIVE EXAMPLE 602
[0644] 281
[0645] Step A
[0646] An equimolar mixture of 2-methylfuran (1.0 g) and anhydride
(2.6 g) was mixed with SnCl.sub.4 (0.05 mL) and heated at
100.degree. C. for 3 hours. After cooling the reaction mixture,
water (10 mL) was added, followed by saturated sodium carbonate
solution until it becomes alkaline. The reaction mixture was
extracted with ether several times and the combined ether layer was
washed with water, brine and dried over anhydrous sodium sulfate.
Filtration and removal of solvent afforded the crude ketone, which
was purified by using silica gel chromatography to afford the
ketone 0.9 g (43%) as a yellow oil.
[0647] Step B
[0648] The title alcohol was obtained following a similar procedure
set forth in Preparative Example 601.
PREPARATIVE EXAMPLE 603
[0649] 282
[0650] To a solution of 5-methyl furan-2-aldehyde (1.0 g) and
3-bromo-3,3-difluoropropene (2.24 g) in DMF (30 mL) was added
indium powder (1.66 g) and lithium iodide (50.0 mg). The reaction
mixture was stirred over night, diluted with water and extracted
with ether. The ether layer was washed with water, brine and
purified by silica gel chromatography to afford the pure alcohol
2.8 g (92%).
PREPARATIVE EXAMPLES 604-611
[0651] Following a similar procedure set forth in WO 02/083624
Preparative Examples 13.25 or 601 the following Alcohols were
prepared.
9 Prep Ex Furan Electrophile Alcohol Yield 604 283 284 285 86% 605
286 287 288 69% 606 289 290 291 84% 607 292 293 294 82% 608 295 296
297 60% 609 298 299 300 65% 610 301 302 303 82% 611 304 305 306
89%
PREPARATIVE EXAMPLES 620-631
[0652] Following a similar procedure to that set forth in WO
02/083624 Preparative Example 13.25 the following Amines were
prepared from the corresponding Alcohols.
10 Prep % Ex ALCOHOL AMINE YIELD 620 307 308 28 621 309 310 58 622
311 312 69 623 313 314 81 624 315 316 82 625 317 318 45 626 319 320
57 627 321 322 58 628 323 324 54 629 325 326 53 630 327 328 50 631
329 330 82%
PREPARATIVE EXAMPLE 640-641
[0653] Following the procedures set forth in WO 02/083624
Preparative Example 19 but using the amine from the Preparative
Example indicated in the Table below, the cyclobutenedione
intermediates were obtained.
11 Amine from 1. Yield Prep Ex. Prep Ex. Product 2. MH.sup.+ 640
600 Step B 331 1. 60% 2. 138 641 600 Step D 332 1. 65% 2. 138
EXAMPLES 360.109-360.117
[0654] Following the procedure set forth in WO 02/083524 Example
261 but using the 5 amine from the Preparative Example indicated in
the table below, the following cyclobutenedione products were
obtained.
12 1. Yield 2. MH.sup.+ Ex. Amine Product 3. mp (.degree. C.)
360.109 75.10A 333 334 1. 67% 2. 410.1 3. 119-121 360.110 75.10B
335 336 1. 71% 2. 412 3. 102 360.111 75.10C 337 338 1. 64% 2. 440.1
3. 91-93 360.112 75.10D 339 340 1. 79% 3. 412 3. 111-113 360.113
75.10E 341 342 1. 20% 2. 440.1 3. 130 (DEC) 360.114 75.10F 343 344
1. 61% 2. 438.1 3. 117-119 360.115 75.10G 345 346 1. 61% 2. 440.1
3. 117-119 360.116 75.10H 347 348 1. 81% 2. 452 3. 118 360.117
75.10J 349 350 1. 65% 2. 466 3. 109
EXAMPLES 368.32-368.45
[0655] Following the procedure set forth in WO 02/083624 Example
261 but using the amine in the table below and the cyclobutenedione
intermediate from the Preparative Example indicated, the following
cyclobutenedione products were obtained.
13 1. Yield Prep. 2. MH.sup.+ Ex. Amine Ex. Product 3. mp (.degree.
C.) 368.32 75.49 351 23.14 352 1. 58% 2. 471.1 3. 149 368.33 75.1
353 23.15A 354 1. 33% 2. 440.1 3. 181 368.34 75.9 355 23.15A 356 1.
56% 2. 468 3. 180 368.35 75.N6 357 23.15A 358 1. 28% 2. 480 3. 186
368.36 75.N8 359 23.15A 360 1. 48% 2. 494 3. 112.5 368.37 75.1 361
23.15B 362 1. 58% 2. 592 3. 177-179 368.38 75.49 363 23.15C 364 1.
69% 2. 516 3. 88-90 368.39 75.49 365 23.15D 366 1. 80% 2. 530 3.
134-137 368.40 75.49 367 23.15E 368 1. 57% 2. 454 3. 138-140 368.41
75.49 369 19.2 370 1. 26% 2. 507 3. 162-164 368.42 3 23.25 371 1.
82% 2. 466 3. 141-143 368.43 3 23.26 372 1. 67% 2. 480 3. 139 dec
368.44 13.29 23.16 373 1. 29% 2. 480 3. 112-114 368.45 13.29 23.26
374 1. 88% 2. 508 3. 190 dec
EXAMPLES 1200-1212
[0656] Following the procedure set forth in WO 02/083624 Example
261 but using the prepared amine indicated in the table below, the
following cyclobutenedione products were obtained.
14 1. Yield 2. MH.sup.+ Ex. Amine Product 3. mp (.degree. C.) 1200
375 376 1. 61.3% 2. 451.4 3. 108.6 1201 377 378 1. 54% 2. 439.5 3.
117.8 1202 379 380 1. 80% 2. 439.5 3. 128-131.8 1203 381 382 1. 75%
2. 423.4 3. 118-119 1204 383 384 1. 74% 2. 447.4 3. 108-111 1205
385 386 1. 42% 2. 415.42 3. 136-140 1206 387 388 1. 46% 2. 423.4 3.
114-117 1207 389 390 1. 35% 2. 433.1 3. 123-128 1208 391 392 1. 42%
2. 423.4 3. 118-121 1209 393 394 1. 51% 2. 415.4 3. 112-117 1210
395 396 1. 44% 2. 415.4 3. 115-120 1211 397 398 1. 48% 2. 445.4 3.
105-110
EXAMPLES 1300-1309
[0657] Following the procedure set forth in WO 02/083624 Example
261 but using the prepared amine in the table below and the
cyclobutenedione intermediate from the Preparative Example
indicated (from either this Application of from WO 02/083624), the
following cyclobutenedione products were obtained.
15 1. Yield Prep. 2. MH.sup.+ Ex. Amine Ex. Product 3. mp
(20.degree. C.) 1300 399 640 400 1. 35% 2. 390.4 3. 100 1301 401
641 402 1. 78% 2. 390.4 3. 130 1302 403 23.9 404 1. 48% 2. 483.4 3.
116 1303 405 23.9 406 1. 46% 2. 443.5 3. 106 1304 407 23.9 408 1.
40% 2. 445.54 3. 102 1305 409 23.9 410 1. 51% 2. 413.4 3. 98 1306
411 23.9 412 1. 78% 2. 405.5 3. 246 1307 413 23.9 414 1. 83% 2.
439.5 3. 129 1308 415 23.15A 416 1. 11% 2. 519.47 3. 123 1309 417
23.15A 418 1. 47% 2. 475 3. 113 1310 419 23.15F 420 1. 55% 2. 496.1
3. 123-125 1311 421 23.15F 422 1. 74% 2. 468.1 3. 116-118
EXAMPLES 1500-1503
[0658] If one were to follow the procedure set forth in WO
02/083624 Example 261 but using the prepared amine and the
cyclobutenedione intermediate in the table below from the
Preparative Example indicated, the following cyclobutenedione
products could be obtained.
16 Cyclobutenedione Amine from intermediate Ex. Prep Ex. from Prep
Ex Product 1500 423 26 424 1501 425 23.15F 426 1502 427 24 428 1503
429 24 430 1504 431 25 432 1505 433 25 434
[0659] While the present invention has been described in
conjunction with specific embodiments set forth above, many
alternatives, modifications and variations thereof will be apparent
to those of ordinary skill in the art. All such alternatives,
modifications and variations are intended to fall within the spirit
and scope of the present invention.
* * * * *