Title: Pyrimidine A2b selective antagonist compounds, their synthesis and use
Abstract: The subject invention provides compounds having the structure: ##STR1##
wherein R1 is substituted or unsubstituted phenyl or a 5-6 membered heterocyclic or heteroaromatic ring containing from 1 to 5 heteroatoms; R2 is hydrogen, or a substituted or unsubstituted alkyl, -C(O)-alkyl, -C(O)-O-alkyl, alkoxy, cycloalkyl, alkenyl, monocyclic or bicyclic aryl, heteroaryl or heterocyclic moiety; R3 is hydrogen, or a substituted or unsubstituted alkyl, -C(O)-alkyl, -C(O)-O-alkyl, alkoxy, cycloalkyl, alkenyl, monocyclic or bicyclic aryl, heteroaryl or heterocyclic moiety, or R2 and R3 are joined to form a heterocyclic ring; wherein the dashed line represents a second bond which may be present or absent, and when present R3 is oxygen; R4 and R5 are each independently substituted or unsubstituted alkyl, -C(O)-alkyl, -C(O)-O-alkyl, alkoxy, cycloalkyl, alkenyl, monocyclic or bicyclic aryl, heteroaryl or heterocyclic moiety, or R4NR5 together form a substituted or unsubstituted monocyclic or bicyclic, heterocyclic or heteroaryl moiety containing from 1 to 6 heteroatoms; R12 is hydrogen, alkyl, halogen or cyano; and n is 0, 1, 2, 3 or 4, or an enantiomer, or a specific tautomer, or a pharmaceutically acceptable salt thereof and a method for treating a disease associated with the A2b adenosine receptor by administering a therapeutically effective amount of the compounds of the invention.
Patent Number: 6,916,804 Issued on 07/12/2005 to Castelhano, et al.
| Inventors:
|
Castelhano; Arlindo (New City, NY);
McKibben; Bryan (Hopewell Junction, NY);
Steinig; Arno (East Northport, NY);
Collington; Eric (Knebworth, GB)
|
| Assignee:
|
OSI Pharmaceuticals, Inc. (Melville, NY)
|
| Appl. No.:
|
326204 |
| Filed:
|
December 20, 2002 |
| Current U.S. Class: |
514/217.06; 544/329; 544/295; 544/296; 544/122; 540/575; 540/601; 514/256; 514/252.2; 514/252.18; 514/252.11; 514/235.8 |
| Intern'l Class: |
C07D 239/02; C07D243/08; C07D413/00; A61K031/50.5; A61K031/53.5 |
| Field of Search: |
544/329,295,296,122
514/256,217.06,252.2,252.18,252.11,235.8
540/575,601
|
References Cited [Referenced By]
U.S. Patent Documents
| 5516894 | May., 1996 | Reppert.
| |
| 5780450 | Jul., 1998 | Shade.
| |
| 5889026 | Mar., 1999 | Alanine et al.
| |
| 6117878 | Sep., 2000 | Linden.
| |
| 6465456 | Oct., 2002 | Springer et al.
| |
| Foreign Patent Documents |
| WO9747601 | Dec., 1997 | WO.
| |
| WO9942093 | Aug., 1999 | WO.
| |
| WO9962518 | Dec., 1999 | WO.
| |
| WO9964407 | Dec., 1999 | WO.
| |
| WO0139777 | Jun., 2001 | WO.
| |
| WO0257267 | Jul., 2002 | WO.
| |
Other References
Baraldi et al. Pyrazolo-triazolo-pyrimidine derivatives as adenosine receptor
antagonists: a possible template for adenosine receptor subtypes, Curr. Pharm.
Design 8: 2299-2332 ,2002.
Gao, Z. et al., "A28 Adenosine and P2Y2 Receptors Stimulate
Mitogen-activated Protein Kinase in Human Embryonic Kidney-293 Cells" J. Bio.
Chem. (1999) 274(9): 5972-5980 (Exhibit 20).
Grant, M.B. et al., "Proliferation, Migration, and ERK Activation in Human Retinal
Endothelial Cells through A2B Adenosine Receptor Stimulation" Invest.
Opthalmol. Vis. Sci. (2001) 42(9): 2068-2073 (Exhibit 21).
Haynes, J. Jr. et al., "5-(N-ethylcarboxamido)adenosine desensitizes the A2b-adenosine
receptor in lung circulation" Am. J. Physiol. (1999) 276(6):H1877-H1883
(Exhibit 22).
Linden, J. et al., "The Structure and Function of A1 and A2B
Adenosine Receptors" Life Sciences (1998) 62(17-18): 1519-1524 (Exhibit 23).
Mirabet, M. et al., "Expression of A2B adenosine receptors in human
lymphocytes: their role in T cell activation" J. Cell. Sci. (1999) 112(4):
491-502 (Exhibit 24).
Muller, C.E. and Stein, B., "Adenosine Receptor Antagonists: Structures and Potential
Therapeutic Applications" Current Pharm. Design (1996) 2:501-530 (Exhibit 25).
Muller, C.E., "A1 Adenosine receptor antagonists" Exp. Opin. Ther.
Patents (1997) 7(5):419-440 (Exhibit 26).
Nyce, J.W. and Metzger, J.W., "DNA antisense therapy for asthma in an animal
model" Nature (1997) 385: 721-725 (Exhibit 27).
Ralevic, V. and Burnstock, G., "Receptors for Purines and Pyrimidines" Pharmacol.
Rev. (1998) 50(3): 413-492 (Exhibit 28).
Regnauld, K. et al. "G-protein αolf subunit promotes cellular invasion,
survival, and neuroendocrine differentiation in digestive and urogenital epithelial
cells" Oncogene (2002) 21(25): 4020-4031 (Exhibit 29).
Strohmeier, G.R. et al., "The A2b Adenosine Receptor Mediates cAMP
Responses to Adenosine Receptor Agonists in Human Intestinal Epithelia" J. Bio.
Chem. (1995) 270: 2387-2394 (Exhibit 30).
Williams, E.F. et al., "Nucleoside transport sites in a cultured human retinal
cell line established by SV-40 T antigen gene" Current Eye Research (1994)
13: 109-118 (Exhibit 31).
Woods, C.L., and Blazynski, C., "Characterization of Adenosine A1-receptor Binding
Sites in Bovine Retinal Membranes" Exp. Eye Research (1991) 53: 325-331
(Exhibit 32); and.
Van Niel, M.B. et al., "Fluorination of 3-(3-(Piperidin-1-yl)propyl)indoles and
3-(3-(Piperazin-1-yl)propyl)indoles Gives Selective Human 5-HT1D Receptor
Ligands with Improved Pharmacokinetic Profiles" J. Med. Chem. (1999) 42(12):
2087-2104 (Exhibit 33).
Blazynski, C., "Discrete Distributions of Adenosine Receptors in Mammalian Retina"
J. Neurochem. (1990) 54(2): 648-655 (Exhibit 11).
Braas, K.M. et al., "Endogenous adenosine and adenosine receptors localized to
ganglion cells of the retina" Proc. Natnl. Acad. Sci. (1987) 84: 3906-3910
(Exhibit 12).
Christofi, F.L. et al., "Differential Gene Expression of Adenosine A1, A2a, A2b,
and A3 Receptors in the Human Enteric Nervous System" J. Comp. Neurol. (2001)
439(1): 46-64 (Exhibit 13).
Corset, V. et al., "Netrin-1-mediated axon outgrowth and cAMP production requires
interaction with adenosine A2b receptor" Nature (2000) 407(6805): 747-750
(Exhibit 14).
Dubey, R.K. et al., "A2B Receptors Mediate the Antimitogenic Effects
of Adenosine in Cardiac Fibroblasts" Hypertension (2001) 37: 716-721 (Exhibit 15).
Faivre, K. et al., "Suppression of Cellular Invasion by Activated G-Protein Subunits
Gαo, Gαil, and Gαi3 and Sequestration of Gβγ" Mol.
Pharmacol. (2001) 60: 363-372 (Exhibit 16).
Feoktistov, I. and Biaggioni, I., "Adenosine A2b Receptors" Pharmacol.
Rev. (1997) 49(4): 381-402 (Exhibit 17).
Feoktistov, I. et al., "Differential Expression of Adenosine Receptors in Human
Endothelial Cells" Circulation Research (2002) 90: 531-538 (Exhibit 18).
Feoktistov, I., et al., "Adenosine A2B receptors: a novel therapeutic
target in asthma?" (1998) TiPS 19: 148-153 (Exhibit 19).
|
Primary Examiner: Raymond; Richard L.
Assistant Examiner: Liu; Hong
Attorney, Agent or Firm: White; John P., Cooper & Dunham LLP
Parent Case Text
This application claims the benefit of U.S. Provisional Application No. 60/342,595,
filed Dec. 20, 2001, the contents of which are hereby incorporated by reference.
Claims
1. A compound having the structure:
##STR88##
wherein
R
1 is substituted or unsubstituted phenyl or a 5-6 membered heterocyclic
or heteroaromatic ring containing from 1 to 5 heteroatoms;
R
2 is hydrogen, or a substituted or unsubstituted alkyl, -C(O)-alkyl,
-C(O)-O-alkyl, alkoxy, cycloalkyl, alkenyl, monocyclic or bicyclic aryl, heteroaryl
or heterocyclic moiety;
R
3 is hydrogen, or a substituted or unsubstituted alkyl, -C(O)-alkyl,
-C(O)-O-alkyl, alkoxy, cycloalkyl, alkenyl, monocyclic or bicyclic aryl, heteroaryl
or heterocyclic moiety, or R
2 and R
3 are joined to form a
heterocyclic ring;
wherein the dashed line represents a second bond which may be present or absent,
and when present R
3 is oxygen;
bicyclic aryl, heteroaryl or heterocyclic moiety, or
R
4NR
5 together form a substituted or unsubstituted monocyclic
or bicyclic, heterocyclic or heteroaryl moiety containing from 1 to 6 heteroatoms;
R
12 is hydrogen, alkyl, halogen or cyano; and
n is 0, 1,2, 3 or 4,
or an enantiomer, or a specific tautomer, or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1, wherein R
3 is hydrogen, or a substituted
or unsubstituted alkyl or aryl.
3. The compound of claim 1, having the structure:
##STR89##
wherein,
R
6 and R
9 are each, independently, hydrogen or alkyl;
R
7 is hydrogen, OH, an alkoxy, an ester, an acetal, a ketal or CN;
R
8 is a substituted or unsubstituted aryl, aryloxy, or alkylaryl;
X is C or N;
wherein when X is N, R
7 or R
8 is absent;
wherein when X is C, R
7XR
8 may form a 3-8 membered carbocyclic
or heterocyclic ring; and
m is 1 or 2.
4. The compound of claim 3, wherein,
R
7 is hydrogen, OH, or CN.
5. The compound of claim 3, wherein the compound is selected from the group consisting of:
N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(3-chlorophenoxy)-piperidin-1-yl]-acetamide;
N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(2-chlorophenoxy)-piperidin-1-yl]-acetamide;
N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(4-methoxybenzyl)-piperidin-1-yl]-acetamide;
N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(4-fluorobenzyl)-piperidin-1-yl]-acetamide;
N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(2-chlorobenzyl)-piperidin-1-yl]-acetamide;
N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(3-chlorobenzyl)-piperidin-1-yl]-acetamide;
N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(4-chlorobenzyl)-piperidin-1-yl]-acetamide;
N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-(4-benzylpiperazin-1-yl)-acetamide;
N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(4-methoxybenzyl)-piperazin-1-yl]-acetamide;
N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(2-methoxybenzyl)-piperazin-1-yl]-acetamide;
N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(3-methoxybenzyl)-piperazin-1-yl]-acetamide;
N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(4-chlorobenzyl)-piperazin-1-yl]-acetamide;
N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(3-chlorobenzyl)-piperazin-1-yl]-acetamide;
N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(2-chlorobenzyl)-piperazin-1-yl]-acetamide;
N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(3-fluorobenzyl)-piperazine-1-yl]-acetamide;
N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(2-fluorobenzyl)-piperazine-1-yl]-acetamide;
N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(3-trifluoromethylbenzyl)-piperazine-1-yl]-acetamide;
N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-(4-cyclohexylmethylpiperazin-1-yl)-acetamide;
N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-(4-phenethylpiperazin-1-yl)-acetamide;
N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-(4-phenethyl-[1,4] diazepan-1-yl)-acetamide;
N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-(4-benzyl-[1,4]diazepan-1-yl)-acetamide;
N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(2-fluorobenzyl)-[1,4]diazapan-1-yl]-acetamide;
N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(3-fluorobenzyl)-[1,4]diazapan-1-yl]-acetamide;
N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(4-fluorobenzyl)-[1,4]diazapan-1-yl]-acetamide;
N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(2-trifluoromethylbenzyl)-[1,4]diazapan-1-yl]-acetamide;
N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(3-trifluoromethylbenzyl)-[1,4]diazepan-1-yl]-acetamide;
N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(4-trifluoromethylbenzyl)-[1,4]diazapan-1-yl]-acetamide;
N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-(4-pyridin-3-ylmethyl-[1,4]diazapan-1-yl)-acetamide;
N-[5-(2-Acetylaminoethylamino)-biphenyl-3-yl]-2-[4-(3-chlorobenzyl)-[1,4]diazepan-1-yl]-acetamide;
N-[5-(2-Acetylaminoethylamino)-biphenyl-3-yl]-2-(4-pyridin-2-ylmethyl-[1,4]diazepan-1-yl)-acetamide;
N-[5-(2-Acetylaminoethylamino)-biphenyl-3-yl]-2-[4-(6-methylpyridin-2-ylmethyl)-[1,4]diazepan-1-yl]-acetamide;
N-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-{4-[2-nitro-4-(trifluoromethyl)phenyl]piperazin-1-yl}acetamide;
N-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-[4-(4-tert-butylbenzyl)piperazin-1-yl]acetamide;
N-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-{4-[(2E)-3-phenylprop-2-enyl]piperazin-1-yl}acetamide,
and
N-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-(4-benzylpiperidin-1-yl)acetamide.
6. The compound of claim 3, wherein the compound is N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-acetamide.
7. The compound of claim 1, having the structure:
##STR90##
wherein
R
4NR
5 together form a substituted or unsubstituted, monocyclic
or bicyclic, heterocyclic or heteroaryl moiety containing from 1 to 6 heteroatoms.
8. The compound of claim 7, wherein
R
4NR
5 together form a substituted or unsubstituted, monocyclic
or bicyclic, heterocyclic or heteroaryl moiety containing from 1 to 6 heteroatoms.
9. The compound of claim 8, wherein any heterocyclic or heteroaryl ring, if present,
is a piperazine, piperidine, (1,4)diazepan, pyrazine, pyridine, pyrrolidine, pyrazole,
pyrimidine, thiophene, imidazole, azetidine, pyrrole, benzothiazole, benzodioxolane,
dithiolane, oxathiine, imidazolidine, quinoline, isoquinoline, dihydroisoquinoline,
indole, isoindole, triazaspiro[4.5]decane, morpholine, furan or an isothiazole ring.
10. The compound of claim 1, wherein,
R
1 is unsubstituted phenyl or phenyl substituted with Cl;
R
2 is hydrogen;
R
3 is hydrogen or oxygen;
R
4, N, R
5 together form a piperidine ring substituted with
-O(C
6H
5), -O(C
6H
4Cl), -O(C
6H
4[OCH
3]),
-(C
6H
5), -CH
2(
6H
4[OCH
3]),
-CH
2(C
6H
4F), -CH
2(C
6H
4Cl)
-(OH)(CH
2)(C
6H
5), -(CN)(C
6H
5),
-(CN)(C
6H
4Cl); a 3,5-dimethyl piperazine ring substituted
with -CH
2(C
6H
5); a piperazine ring substituted
with -CH
2(C
6H
5), -(C
6H
5),
-CH
2(C
6H
4[OCH
3]), -CH
2(C
6H
4Cl),
-CH
2(C
6H
4F), -CH
2(C
6H
4[CF
3]),
-CH
2(C
5H
4N), -CH
2(C
6H
11),
-(CH
2)
2(
6H
5); or a [1,4]diazepan ring
substituted with -(C
6H
5), -(CH
2)
2(C
6H
5),
-CH
2(C
6H
5), -CH
2(C
6H
4F),
-CH
2(C
6H
4[CF
3]), -CH
2(C
5H
4N),
-CH
2(C
6H
4Cl), or -CH
2(
5H
3N[CH
3]);
and R
12 is hydrogen.
11. The compound of any one of claims
1-
5 or
7-
11
wherein any alkyl is a straight chain (C
1-C
30)alkyl or a
branched chain (C
3-C
30)alkyl, any cycloalkyl is (C
3-C
10)cycloalkyl,
and any substituent, if present, is selected from halogen, hydroxyl, straight chain
(C
1-C
30)alkyl, branched chain (C
3-C
30)alkyl,
(C
3-C
10)cycloalkyl, straight chain(C
1-C
30)alkylcarbonyloxy,
branched chain (C
3-C
30)alkylcarbonyloxy, arylcarbonyloxy,
straight chain(C
1-C
30)alkoxycarbonyloxy, branched chain(C
3-C
30)alkoxycarbonyloxy,
aryloxycarbonyloxy, carboxylate, straight chain(C
1-C
30)alkylcarbonyl,
branched chain (C
3-C
30)alkylcarbonyl, straight chain (C
1-C
30)alkoxycarbonyl,
branched chain (C
3-C
30)alkoxycarbonyl, aminocarbonyl, straight
chain (C
1-C
30)alkylthiocarbonyl, branched chain (C
3-C
30)alkylthiocarbonyl,
straight chain (C
1-C
30)alkoxyl, branched chain (C
1-C
30)alkoxyl,
phosphate, phosphonato, cyano, amino, straight chain (C
1-C
30)alkylamino,
branched chain (C
3-C
30)alkylamino, straight chain (C
1-C
30)dialkylamino,
branched chain (C
3-C
30)dialkylamino, arylamino, diarylamino,
straight chain (C
1-C
30)alkylarylamino, branched chain (C
3-C
30)alkylarylamino,
acylamino, straight chain (C
1-C
30)alkylcarbonylamino, branched
chain (C
3-C
30)alkylcarbonylamino, arylcarbonylamino, carbamoyl,
ureido, amidino, imino, sulfhydryl, straight chain (C
1-C
30)alkylthio,
branched chain (C
3-C
30)alkylthio, arylthio, thiocarboxylate,
sulfates, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, azido, 4-10
membered heterocyclyl, straight chain (C
1-C
30)alkylaryl,
branched chain (C
3-C
30)alkylaryl, or an aromatic or 5-6 membered
heteroaromatic moiety,
which substituent may be further substituted by any of the above.
12. The pharmaceutically acceptable salt of claim 1, wherein the salt is a hydrochloride salt.
13. A pharmaceutical composition comprising the compound of 7 and a pharmaceutically
acceptable carrier.
14. The pharmaceutical composition of claim 13, formulated for oral, topical,
parenteral or nasal administration.
15. A process for the manufacture of a pharmaceutical composition comprising
admixing the compound of 7 with a pharmaceutically acceptable carrier.
16. A process for manufacturing the compound of claim 3, comprising reacting
a compound having the structure:
##STR91##
wherein R
a is Cl or Br, with
##STR92##
under suitable conditions to provide:
##STR93##
wherein,
R
6 and R
9 are each independently hydrogen or alkyl;
R
7 is hydrogen, OH, an alkoxy, an ester, an acetal, a ketal or CN;
R
8 is substituted or unsubstituted aryl, aryloxy, or alkylaryl;
X is C or N;
wherein when X is N, R
7 may be absent;
wherein when X is C,R
7XR
8 may form a 3-8 membered carbocyclic
or heterocyclic ring; and
m is 1 or 2.
17. The process of claim 16, wherein in the solvent is acetonitrile and THF.
18. A method for treating a disease associated with the A
2b adenosine
receptor in a subject in need of such treatment comprising administering to the
subject a therapeutically effective amount of the compound of claim 1 so as to
thereby treat the disease associated with the A
2b adenosine receptor
is asthma, urticaria, scleroderm arthritis, myocardial infarction, myocardial reperfusion
after ischemia, diabetic retinopathy of prematurity, diabetes, diarrhea, inflammatory
bowel disease, or is associated with mast cell degranulation, vasodilation, hypertension,
hypersensitivity or the release of allergic mediators.
19. The method of claim 18, wherein the disease associated with the A
2b
adenosine receptor is diabetes.
20. The method of claim 18, wherein the disease associated with the A
2b
adenosine receptor is asthma.
21. The method of claim 18, wherein the disease associated with the A
2b
adenosine receptor is associated with mast cell degranulation.
22. An article of manufacture comprising:
packaging material;
the pharmaceutical composition of claim 13; and
instructions for use of the pharmaceutical composition in the treatment of a
disease associated with the A
2b adenosine receptor.
Description
Throughout this application, various publications are referenced by full
citations. The disclosures of these publications in their entireties are hereby
incorporated by reference into this application in order to more fully describe
the state of the art as known to those skilled therein as of the date of the invention
described and claimed herein.
BACKGROUND OF THE INVENTION
Adenosine is an ubiquitous modulator of numerous physiological activities,
particularly within the cardiovascular and nervous systems. The effects of adenosine
appear to be mediated by specific cell surface receptor proteins. Adenosine modulates
diverse physiological functions including induction of sedation, vasodilation,
suppression of cardiac rate and contractility, inhibition of platelet aggregability,
stimulation of gluconeogenesis and inhibition of lipolysis. In addition to its
effects on adenylate cyclase, adenosine has been shown to open potassium channels,
reduce flux through calcium channels, and inhibit or stimulate phosphoinositide
turnover through receptor-mediated mechanisms (See for example, C. E. Muller and
B. Stein "Adenosine Receptor Antagonists: Structures and Potential Therapeutic
Applications,"
Current Pharmaceutical Design, 2:501 (1996) and C. E. Muller
"A
1-Adenosine Receptor Antagonists,"
Exp. Opin. Ther. Patents 7(5):419 (1997)).
Adenosine receptors belong to the superfamily of purine receptors which
are currently subdivided into P
1 (adenosine) and P
2 (ATP,
ADP, and other nucleotides) receptors. Four receptor subtypes for the nucleoside
adenosine have been cloned so far from various species including humans. Two receptor
subtypes (A
1 and A
2a) exhibit affinity for adenosine in the
nanomolar range while two other known subtypes A
2b and A
3 are
low-affinity receptors, with affinity for adenosine in the low-micromolar range.
A
1 and A
3 adenosine receptor activation can lead to an inhibition
of adenylate cyclase activity, while A
2a and A
2b activation
causes a stimulation of adenylate cyclase.
A few A
1 antagonists have been developed for the treatment of cognitive
disease, renal failure, and cardiac arrhythmias. It has been suggested that A
2a
antagonists may be beneficial for patients suffering from Morbus Parkinson
(Parkinson's disease). Particularly in view of the potential for local delivery,
adenosine receptor antagonists may be valuable for treatment of allergic inflammation
and asthma. Available information (for example, Nyce & Metzger "DNA antisense Therapy
for Asthma in an Animal Model"
Nature (1997) 385: 721-5)indicates that in
this pathophysiologic context, A
1 antagonists may block contraction
of smooth muscle underlying respiratory epithelia, while A
2b or A
3
receptor antagonists may block mast cell degranulation, mitigating the release
of histamine and other inflammatory mediators. A
2b receptors have been
discovered throughout the gastrointestinal tract, especially in the colon and the
intestinal epithelia. It has been suggested that A
2b receptors mediate
cAMP response (Strohmeier et al.,
J. Bio. Chem. (1995) 270:2387-94).
A
2b receptors have also been implicated in wide variety
of physiological activities, thereby suggesting that treatment of associated disorders
can be effected by blocking the A
2b receptor. For example, A
2b
receptor sites play a role in the degranulation of mast cells and hence in
the treatment of asthma, myocardial reperfusion injury, allergic reactions including
but not limited to rhinitis, poison ivy induced responses, urticaria, scleroderm
arthritis, other autoimmune diseases and inflammatory bowel diseases (Gao, Z. et
al.,
J. Biol. Chem. (1999), 274(9):5972-5980, Linden, J. et al.,
Life
Sciences (1998), 62(17-18):1519-1524 and U.S. Pat. No. 6,117,878, issued Sep.
12, 2000). A
2b receptors have also been shown to inhibit the growth
of cardiac fibroblasts, thereby suggesting that they may prevent cardiac remodeling
associated with hypertension, myocardial infarction and myocardial reperfusion
after ischemia (Dubey, R. K. et al.,
Hypertension (2001), 37:716-721), mediate
the role of adenosine in lymphocyte activation (Mirabet, M. et al.,
J. Cell.
Sci. (1999), 112(4):491-502), regulate vasodilation and growth (Ralevic, V.
and Burnstock, G.,
Pharmacol. Rev. (1998), 50(3):413-492, Corset, V. et
al.,
Nature (2000), 407(6805):747-750, and Haynes, J. Jr. et al.,
Am.
J. Physiol. (1999), 276(6):H1877-83), participate in neural reflexes in the
human gut (Christofi, F. L. et al.,
J. Comp. Neurol. (2001), 439(1):46-64),
and regulate retinal angiogenesis-thereby suggesting the use of A
2b antagonists
in treating diseases associated with abberant neovascularization such as diabetic
retinopathy and retinopathy of prematurity (Grant, M. B. et al.,
Invest. Opthalmol.
Vis. Sci. (2001), 42(9):2068-2073). They are also involved in the modulation
of intestinal tone and secretion and neurotransmission and neurosecretion (Feoktistov,
I. and Biaggioni, I.,
Pharmacol. Rev. (1997), 49(4):381-402).
A
2b receptors are also coupled to Gs/Gq signaling which
has been shown to be involved in cellular transformations such as cellular invasion
(Faivre, K. et al.,
Molecular Pharmacology (2001), 60:363-372 and Regnauld,
K. et al.,
Oncogene (2002), 21(25):4020-4031), thereby suggesting that treatment
of cancer can be effected with A
2b antagonists.
Adenosine receptors have also been shown to exist on the retinas of various
mammalian species including bovine, porcine, monkey, rat, guinea pig, mouse, rabbit
and human (See, Blazynski et al., "Discrete Distributions of Adenosine Receptors
in Mammalian Retina,"
Journal of Neurochemistry, volume 54, pages 648-655
(1990); Woods et al., "Characterization of Adenosine A
1-Receptor Binding
Sites in Bovine Retinal Membranes,"
Experimental Eye Research, volume 53,
pages 325-331 (1991); and Braas et al., "Endogenous adenosine and adenosine receptors
localized to ganglion cells of the retina,"
Proceedings of the National Academy
of Science, volume 84, pages 3906-3910 (1987)). Recently, Williams reported
the observation of adenosine transport sites in a cultured human retinal cell line
(Williams et al., "Nucleoside Transport Sites in a Cultured Human Retinal Cell
Line Established By SV-40 T Antigen Gene,"
Current Eye Research, volume
13, pages 109-118 (1994)).
Compounds which regulate the uptake of adenosine have previously been suggested
as potential therapeutic agents for the treatment of retinal and optic nerve head
damage. In U.S. Pat. No. 5,780,450 to Shade, Shade discusses the use of adenosine
uptake inhibitors for treating eye disorders. Shade does not disclose the use of
specific A
3 receptor inhibitors. The entire contents of U.S. Pat. No.
5,780,450 are hereby incorporated herein by reference.
Compounds specific to the adenosine A
1, A
2a and A
3
receptors and their uses thereof have been previously disclosed in PCT International
Publication Nos. WO 99/62518 and WO 01/39777 A1. The entire contents of PCT International
Publication Nos. WO 99/62518 and WO 01/39777 A1 are hereby incorporated herein
by reference.
PCT International Publication No. WO 99/64407 generically discloses α-(1-piperazinyl)acetamido
arenecarboxylic acid derivatives as antidaibetic agents. However, the compounds
disclosed differ from the compounds of the present invention in that they have
a carboxylic acid group rather than an amino group attached to the central ring.
In addition, the cited application does not exemplify any compounds in which the
central ring is pyrimidine or any compounds which have a phenyl ring or a heterocyclic
ring attached to the central aryl ring.
PCT International Publication No. WO 97/47601 discloses fused heterocyclic compounds
having D
4 and D
2 receptor activity. The disclosed compounds
differ from the compounds of the present invention in that the central ring structure
is bicyclic in WO 97/47601 rather than monocyclic as in the compounds of the present
invention, and the central ring structure in WO 97/47601 does not allow for an
additional aminoalkyl substituent.
Additional adenosine receptor antagonists are needed as pharmacological
tools and are of considerable interest as drugs for the above-referenced disease
states and/or conditions.
SUMMARY OF THE INVENTION
The subject invention provides compounds having the structure:
##STR2##
wherein
- R1 is substituted or unsubstituted phenyl or a 5-6 membered
heterocyclic or heteroaromatic ring containing from 1 to 5 heteroatoms;
- R2 is hydrogen, or a substituted or unsubstituted alkyl,
-C(O)-alkyl, -C(O)-O-alkyl, alkoxy, cycloalkyl, alkenyl, monocyclic or bicyclic
aryl, heteroaryl or heterocyclic moiety;
- R3 is hydrogen, or a substituted or unsubstituted alkyl,
-C(O)-alkyl, -C(O)-O-alkyl, alkoxy, cycloalkyl, alkenyl, monocyclic or bicyclic
aryl, heteroaryl or heterocyclic moiety, or R2 and R3 are
joined to form a heterocyclic ring;
- wherein the dashed line represents a second bond which may be present
or absent, and when present R3 is oxygen;
- R4 and R5 are each independently substituted or
unsubstituted alkyl, -C(O)-alkyl, -C(O)-O-alkyl, alkoxy, cycloalkyl, alkenyl, monocyclic
or bicyclic aryl, heteroaryl or heterocyclic moiety, or
- R4NR5 together form a substituted or unsubstituted
monocyclic or bicyclic, heterocyclic or heteroaryl moiety containing from 1 to
6 heteroatoms;
- R12 is hydrogen, alkyl, halogen or cyano; and
- n is 0, 1, 2, 3 or 4,
or an enantiomer, or a specific tautomer, or a pharmaceutically acceptable salt thereof.
The subject invention also provides compounds having the structure:
##STR3##
wherein
- R10 is substituted or unsubstituted alkyl, -C(O)-alkyl, -C(O)-O-alkyl,
alkoxy, cycloalkyl, alkenyl, or a substituted or unsubstituted, monocyclic or bicyclic
aryl, heterocyclic or heteroaryl moiety containing from 1 to 6 heteroatoms; and
- R11 is a hydrogen or halogen atom.
The subject invention further provided compounds having the structure:
##STR4##
wherein,
- R10 is substituted or unsubstituted alkyl, -C(O)-alkyl, -C(O)-O-alkyl,
alkoxy, cycloalkyl, alkenyl, or a substituted or unsubstituted monocyclic or bicyclic
aryl, heterocyclic or heteroaryl moiety containing from 1 to 6 heteroatoms;
- R11 is a hydrogen or halogen atom; and
- R12 is hydrogen, alkyl, halogen or cyano.
The subject invention further provides compounds having the structure:
##STR5##
wherein R
a is Cl, Br or I; and
- R12 is hydrogen, alkyl, halogen or cyano.
The subject invention further provides compounds having the structure:
##STR6##
wherein R
b is hydrogen or methyl.
The subject invention further provides compounds having the structure:
##STR7##
wherein,
- Rc is a halogen atom;
- R11 is a hydrogen or halogen atom; and
- R12 is hydrogen, alkyl, halogen or cyano.
The subject invention also provides the use of the compound of any one of Structures
I-VIII for manufacturing a medicament useful for treating a disease associated
with the A
2b adenosine receptor in a subject, wherein the disease associated
with the A
2b adenosine receptor is asthma, urticaria, scleroderm arthritis,
myocardial infarction, myocardial reperfusion after ischemia, diabetic retinopathy,
retinopathy of prematurity, diabetes, diarrhea, inflammatory bowel disease, proliferating
tumor or is associated with mast cell degranulation, vasodilation, hypertension,
hypersensitivity or the release of allergic mediators.
DETAILED DESCRIPTION
The subject invention provides compounds having the structure:
##STR8##
wherein
- R1 is substituted or unsubstituted phenyl or a 5-6 membered
heterocyclic or heteroaromatic ring containing from 1 to 5 heteroatoms;
- R2 is hydrogen, or a substituted or unsubstituted alkyl,
-C(O)-alkyl, -C(O)-O-alkyl, alkoxy, cycloalkyl, alkenyl, monocyclic or bicyclic
aryl, heteroaryl or heterocyclic moiety;
- R3 is hydrogen, or a substituted or unsubstituted alkyl,
-C(O)-alkyl, -C(O)-O-alkyl, alkoxy, cycloalkyl, alkenyl, monocyclic or bicyclic
aryl, heteroaryl or heterocyclic moiety, or R2 and R3 are
joined to form a heterocyclic ring;
- wherein the dashed line represents a second bond which may be present
or absent, and when present R3 is oxygen;
- R4 and R5 are each independently substituted or
unsubstituted alkyl, -C(O)-alkyl, -C(O)-O-alkyl, alkoxy, cycloalkyl, alkenyl, monocyclic
or bicyclic aryl, heteroaryl or heterocyclic moiety, or
- R4NR5 together form a substituted or unsubstituted
monocyclic or bicyclic, heterocyclic or heteroaryl moiety containing from 1 to
6 heteroatoms;
- R12 is hydrogen, alkyl, halogen or cyano; and
- n is 0, 1, 2, 3 or 4,
or an enantiomer, or a specific tautomer, or a pharmaceutically acceptable salt thereof.
In one embodiment of Structure I, R
3 is hydrogen, or a substituted
or unsubstituted alkyl or aryl.
In another embodiment of Structure I, any heterocyclic or heteroaryl ring, if
present, is a piperazine, piperidine, (1,4)diazepan, pyrazine, pyridine, pyrrolidine,
pyrazole, pyrimidine, thiophene, imidazole, azetidine, pyrrole, benzothiazole,
benzodioxolane, dithiolane, oxathiine, imidazolidine, quinoline, isoquinoline,
dihydroisoquinoline, indole, isoindole, triazaspiro[4.5]decane, morpholine, furan
or an isothiazole ring.
In another embodiment, the subject invention provides compounds having the structure:
##STR9##
wherein,
- R6 and R9 are each, independently, hydrogen or alkyl;
- R7 is hydrogen, OH, an alkoxy, an ester, an acetal, a ketal
or CN;
R
8 is a substituted or unsubstituted aryl, aryloxy, or alkylaryl;
- X is C or N;
- wherein when X is N, R7 or R8 is absent;
- wherein when X is C, R7XR8 may form a 3-8 membered
carbocyclic or heterocyclic ring; and
- m is 1 or 2.
In one embodiment of Structure II, R
7 is hydrogen, OH, or CN.
In another embodiment, the compound is selected from the group consisting of:
- N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(3-chlorophenoxy)-piperidin-1-yl]-acetamide;
- N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(2-chlorophenoxy)-piperidin-1-yl]-acetamide;
- N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(4-methoxybenzyl)-piperidin-1-yl]-acetamide;
- N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(4-fluorobenzyl)-piperidin-1-yl]-acetamide;
- N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(2-chlorobenzyl)-piperidin-1-yl]-acetamide;
- N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(3-chlorobenzyl)-piperidin-1-yl]-acetamide;
- N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(4-chlorobenzyl)-piperidin-1-yl]-acetamide;
- N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-(4-benzylpiperazin-1-yl)-acetamide;
- N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(4-methoxybenzyl)-piperazin-1-yl]-acetamide;
- N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(2-methoxybenzyl)-piperazin-1-yl]-acetamide;
- N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(3-methoxybenzyl)-piperazin-1-yl]-acetamide;
- N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(4-chlorobenzyl)-piperazin-1-yl]-acetamide;
- N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(3-chlorobenzyl)-piperazin-1-yl]-acetamide;
- N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(2-chlorobenzyl)-piperazin-1-yl]-acetamide;
- N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(3-fluorobenzyl)-piperazine-1-yl]-acetamide;
- N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(2-fluorobenzyl)-piperazine-1-yl]-acetamide;
- N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(3-trifluoromethylbenzyl)-piperazine-1-yl]-acetamide;
- N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-(4-cyclohexylmethylpiperazin-1-yl)-acetamide;
- N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-(4-phenethylpiperazin-1-yl)-acetamide;
- N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-(4-phenethyl-[1,4]diazepan-1-yl)-acetamide;
- N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-(4-benzyl-[1,4]diazepan-1-yl)-acetamide;
- N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(2-fluorobenzyl)-[1,4]diazapan-1-yl]-acetamide;
- N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(3-fluorobenzyl)-[1,4]diazapan-1-yl]-acetamide;
- N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(4-fluorobenzyl)-[1,4]diazapan-1-yl]-acetamide;
- N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(2-trifluoromethylbenzyl)-[1,4] diazapan-1-yl]-acetamide;
- N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(3-trifluoromethylbenzyl)-[1,4]diazepan-1-yl]-acetamide;
- N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(4-trifluoromethylbenzyl)-[1,4]diazapan-1-yl]-acetamide;
- N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-(4-pyridin-3-ylmethyl-[1,4]diazapan-1-yl)-acetamide;
- N-[5-(2-Acetylaminoethylamino)-biphenyl-3-yl]-2-[4-(3-chlorobenzyl)-[1,4]diazepan-1-yl]-acetamide;
- N-[5-(2-Acetylaminoethylamino)-biphenyl-3-yl]-2-(4-pyridin-2-ylmethyl-[1,4]diazepan-1-yl)-acetamide;
- N-[5-(2-Acetylaminoethylamino)-biphenyl-3-yl]-2-[4-(6-methylpyridin-2-ylmethyl)-[1,4]diazepan-1-yl]-acetamide;
- N-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-{4-[2-nitro-4-(trifluoromethyl)phenyl]piperazin-1-yl}acetamide;
- N-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-[4-(4-tert-butylbenzyl)piperazin-1-yl]acetamide;
- N-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-{4-[(2E)-3-phenylprop-2-enyl]piperazin-1-yl}acetamide, and
- N-(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)-2-(4-benzylpiperidin-1-yl)acetamide.
In another embodiment, the compound is N-[6-(2-Acetylaminoethylamino)-2-phenylpyrimidin-4-yl]-2-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-acetamide.
In a further embodiment, the subject invention provides compounds having the
structure:
##STR10##
wherein
- R4 and R5 are each independently substituted or
unsubstituted alkyl, -C(O)-alkyl, -C(O)-O-alkyl, alkoxy, cycloalkyl, alkenyl, monocyclic
or bicyclic aryl, heteroaryl or heterocyclic moiety, or
- R4NR5 together form a substituted or unsubstituted,
monocyclic or bicyclic, heterocyclic or heteroaryl moiety containing from 1 to
6 heteroatoms.
In one embodiment of Structure III,
- R4 and R5 are each independently substituted or
unsubstituted alkyl, -C(O)-alkyl, -C(O)-O-alkyl, cycloalkyl, alkenyl, monocyclic
or bicyclic aryl, heteroaryl or heterocyclic moiety, or
- R4NR5 together form a substituted or unsubstituted,
monocyclic or bicyclic, heterocyclic or heteroaryl moiety containing from 1 to
6 heteroatoms.
In another embodiment of Structure III, R
4 and R
5 are each
independently substituted or unsubstituted alkyl, -C(O)-alkyl, -C(O)-O-alkyl, cycloalkyl,
alkenyl, monocyclic or bicyclic aryl, heteroaryl or heterocyclic moiety.
In another embodiment, R
4 and R
5 are each independently
substituted or unsubstituted alkyl, -C(O)-alkyl, -C(O)-O-alkyl, cycloalkyl, alkenyl,
monocyclic or bicyclic aryl, heteroaryl or heterocyclic moiety.
In another embodiment, any heterocyclic or heteroaryl ring, if present, is a
piperazine,
piperidine, (1,4)diazepan, pyrazine, pyridine, pyrrolidine, pyrazole, pyrimidine,
thiophene, imidazole, azetidine, pyrrole, benzothiazole, benzodioxolane, dithiolane,
oxathiine, imidazolidine, quinoline, isoquinoline, dihydroisoquinoline, indole,
isoindole, triazaspiro[4.5]decane, morpholine, furan or an isothiazole ring.
The subject invention also provides compounds having the structure:
##STR11##
wherein
- R10 is substituted or unsubstituted alkyl, -C(O)-alkyl, -C(O)-O-alkyl,
alkoxy, cycloalkyl, alkenyl, or a substituted or unsubstituted, monocyclic or bicyclic
aryl, heterocyclic or heteroaryl moiety containing from 1 to 6 heteroatoms; and
- R11 is a hydrogen or halogen atom.
In one embodiment of Structure IV, R
10 is a substituted or unsubstituted
alkyl, -C(O)-alkyl, -C(O)-O-alkyl, cycloalkyl, alkenyl, or a substituted or unsubstituted,
monocyclic or bicyclic aryl, heterocyclic or heteroaryl moiety containing from
1 to 6 heteroatoms.
In a further embodiment, R
11 is hydrogen.
In a further embodiment, R
11 is a halogen atom.
In a further embodiment of Structure W, any heterocyclic or heteroaryl ring,
if
present, is a piperazine, piperidine, (1,4)diazepan, pyrazine, pyridine, pyrrolidine,
pyrazole, pyrimidine, thiophene, imidazole, azetidine, pyrrole, benzothiazole,
benzodioxolane, dithiolane, oxathiine, imidazolidine, quinoline, isoquinoline,
dihydroisoquinoline, indole, isoindole, triazaspiro[4.5]decane, morpholine, furan
or an isothiazole ring.
The subject invention further provided compounds having the structure:
##STR12##
wherein,
- R10 is substituted or unsubstituted alkyl, -C(O)-alkyl, -C(O)-O-alkyl,
alkoxy, cycloalkyl, alkenyl, or a substituted or unsubstituted monocyclic or bicyclic
aryl, heterocyclic or heteroaryl moiety containing from 1 to 6 heteroatoms;
- R11 is a hydrogen or halogen atom; and
- R12 is hydrogen, alkyl, halogen or cyano.
In one embodiment of Structure V, R
10 is substituted or unsubstituted
alkyl, -C(O)-alkyl, -C(O)-O-alkyl, cycloalkyl, alkenyl, or a substituted or unsubstituted
monocyclic or bicyclic aryl, heterocyclic or heteroaryl moiety containing from
1 to 6 heteroatoms and R
12 is hydrogen or methyl.
In a further embodiment, R
11 is hydrogen.
In a further embodiment, R
12 is hydrogen.
In a further embodiment, R
12 is methyl.
In a further embodiment, R
11 is a halogen atom.
In a further embodiment, R
12 is hydrogen.
In a further embodiment, R
12 is methyl.
In a further embodiment, any heterocyclic or heteroaryl ring, if present, is a
piperazine, piperidine, (1,4)diazepan, pyrazine, pyridine, pyrrolidine, pyrazole,
pyrimidine, thiophene, imidazole, azetidine, pyrrole, benzothiazole, benzodioxolane,
dithiolane, oxathiine, imidazolidine, quinoline, isoquinoline, dihydroisoquinoline,
indole, isoindole, triazaspiro[4.5]decane, morpholine, furan or an isothiazole ring.
The subject invention further provides compounds having the structure:
##STR13##
wherein R
a is Cl, Br or I; and
- R12 is hydrogen, alkyl, halogen or cyano.
In one embodiment, R
a is Cl.
In another embodiment, R
a is Br.
The subject invention further provides compounds having the structure:
##STR14##
wherein R
b is hydrogen or methyl.
In one embodiment, R
b is hydrogen.
In another embodiment, R
b is methyl.
The subject invention further provides compounds having the structure:
##STR15##
wherein,
- Rc is a halogen atom;
- R11 is a hydrogen or halogen atom; and
- R12 is hydrogen, alkyl, halogen or cyano.
In one embodiment, R, is Cl.
In a further embodiment, R
11 is hydrogen.
In another embodiment, R
12 is hydrogen.
In another embodiment, R
12 is methyl.
In another embodiment, R
11 is Cl.
In a further embodiment, R
12 is hydrogen.
In another embodiment, R
12 is methyl.
In a further embodiment of Structure I,
- R1 is unsubstituted phenyl or phenyl substituted with Cl;
- R2 is hydrogen;
- R3 is hydrogen or oxygen;
- R4, N, R5 together form a piperidine ring substituted
with -O(C6H5), -O(C6H4Cl), -O(C6H4[OCH3]),
-(C6H5), -CH2(C6H4[OCH3]),
-CH2(C6H4F), -CH2(C6H4Cl),
-(OH)(CH2)(C6H5), -(CN)(C6H5),
-(CN)(C6H4Cl); a 3,5-dimethyl piperazine ring substituted
with -CH2(C6H5); a piperazine ring substituted
with -CH2(C6H5), -(C6H5),
-CH2(C6H4[OCH3]), -CH2(C6H4Cl),
-CH2(C6H4F), -CH2(C6H4[CF3]),
-CH2(C5H4N), -CH2(C6H11),
-(CH2)2(C6H5); or a [1′,4]diazepan
ring substituted with -(C6H5), -(CH2)2(C6H5),
-CH2(C6H5), -CH2(C6H4F),
-CH2(C6H4[CF3]), -CH2(C5H4N),
-CH2(C6H4CI), or -CH2(C5H3N[CH3]); and
- R12 is hydrogen.
The subject invention also provides a method for treating a disease associated
with the A
2b adenosine receptor in a subject in need of such treatment
comprising administering to the subject a therapeutically effective amount of the
compound of Structure I so as to thereby treat the disease associated with the
A
2b adenosine receptor in the subject, wherein the disease associated
with the A
2b adenosine receptor is asthma, urticaria, scleroderm arthritis,
myocardial infarction, myocardial reperfusion after ischemia, diabetic retinopathy,
retinopathy of prematurity, diabetes, diarrhea, inflammatory bowel disease, proliferating
tumor or is associated with mast cell degranulation, vasodilation, hypertension,
hypersensitivity or the release of allergic mediators.
In one embodiment, the disease associated with the A
2b adenosine receptor
is diabetes.
In another embodiment, the disease associated with the A
2b adenosine
receptor is asthma.
In another embodiment, the disease associated with the A
2b adenosine
receptor is associated with mast cell degranulation.
In another embodiment, the disease associated with the A
2b adenosine
receptor is a proliferating tumor.
The subject invention also provides a pharmaceutical composition comprising the
compound of any of Structures I-V and a pharmaceutically acceptable carrier.
In one embodiment, the pharmaceutical composition is formulated for oral, topical,
parenteral or nasal administration.
The subject invention also provides a process for the manufacture of a pharmaceutical
composition comprising admixing the compound of any of Structures I-V with a pharmaceutically
acceptable carrier.
The subject invention also provides a package comprising the above pharmaceutical
composition and instructions for use of the pharmaceutical composition in the treatment
of a disease associated with the A
2b adenosine receptor.
The subject invention also provides the pharmaceutically acceptable salt of Structure
I, wherein the salt is a hydrochloride salt.
The subject invention also provides a process of manufacturing the compound of
Structure VI, comprising the steps of:
- (a) reacting
##STR16##
with a 2-substituted diethyl malonate in the presence of a base in a solvent
under suitable conditions to provide:
##STR17##
- (b) reacting the product of step (a) with a chlorinating agent to provide:
##STR18##
- (c) reacting the product of step (b) with an aminating agent in the
presence of solvent to provide:
##STR19##
- (d) reacting the product of step (c) with N-acetylethylenediamine to
provide:
##STR20##
- (e) reacting the product with
##STR21##
- in the presence of base in solvent to provide:
##STR22##
wherein Ra is Cl or Br; and
- R12 is hydrogen, alkyl, halogen or cyano.
In one embodiment of the above process, the solvent in step (a) is DMF and the
base is DBU.
In another embodiment, the chlorinating agent in step (b) is POCl
3.
In a further embodiment, the aminating agent of step (c) is ammonia and the solvent
is DMSO.
In a further embodiment, the base is 2,6-lutidine and the solvent is CH
2Cl
2/DMF.
In a further embodiment, the subject invention provides a compound produced by
the above process.
The subject invention also provides a process for manufacturing the compound
of Structure II, comprising reacting a compound having the structure:
##STR23##
wherein R
a is Cl or Br,
- with
##STR24##
- under suitable conditions to provide:
##STR25##
wherein,
- R6 and R9 are each independently hydrogen or alkyl;
- R7 is hydrogen, OH, an alkoxy, an ester, an acetal, a ketal
or CN;
- R8 is a substituted or unsubstituted aryl, aryloxy, or alkylaryl;
- X is C or N;
- wherein when X is N, R7 or R8 is absent;
- wherein when X is C, R7XR8 may form a 3-8 membered
carbocyclic or heterocyclic ring; and
- m is 1 or 2.
The subject invention also provides a compound produced by the above process.
The subject invention also provides a compound having the structure:
##STR26##
wherein,
- R13 is a substituted or unsubstituted (C1-C4)alkyl,
branched alkyl or (C3-C7)cycloalkyl, wherein the substituent
is -OH, OR, -NH2, -NR18R19, -R20NOCR21,
R22R23NCO-, carboxyl, carbamoyl (-R20NOCNR22R23),
carbamate (-R20NOCOR), or a heterocyclic ring; or a substituted or unsubstituted
aryl or heterocyclic ring wherein any substituent, if present, is OH, OR, halogen,
NH2, or NHR; -wherein R is alkyl, cycloalkyl, aryl, heteroaryl, susbtituted
alkyl, aryl, arylalkyl, or heterocyclic;
- R14 is substituted or unsubstituted phenyl, wherein the substituent,
if present, is halogen, OH, NH2, OR, NHR or a 5-6 membered heterocyclic ring;
- R15 is H, or alkyl;
- R16 is H, substituted or unsubstituted alkyl or aryl, or
R15 and R16 are joined to form a heterocyclic ring;
- X is CHR17, CR24R25, O or NR;
- R17 is H, substituted or unsubstituted alkyl, aryl, arylalkyl,
heterocyclic, heterocyclic alkyl, OH, OR, NH2, NR18R19,
R20NOCR21, R22R23NCO-, carboxyl, carbamoyl
(-R20NOCNR22R23), carbamate (-R20NOCOR),
or (C3-C7)cycloalkyl;
- R18 and R19 are each independently hydrogen, substituted
or unsubstituted alkyl or aryl or R18NR19 together form a
heterocyclic ring of between 4 and 8 members;
- R20 and R2, are each independently a substituted
or unsubsti
