U.S. patent application number 10/083836 was filed with the patent office on 2002-06-27 for a1 adenosine receptor antagonists.
Invention is credited to Neely, Constance F..
Application Number | 20020082269 10/083836 |
Document ID | / |
Family ID | 25028936 |
Filed Date | 2002-06-27 |
United States Patent
Application |
20020082269 |
Kind Code |
A1 |
Neely, Constance F. |
June 27, 2002 |
A1 adenosine receptor antagonists
Abstract
1 A compound useful as an A.sub.1 adenosine receptor antagonist
has formula (I), wherein R.sub.1 is selected from the group
consisting of C.sub.1-C.sub.8alkyl; R.sub.2 is of formula (II),
wherein n is an integer ranging from 1 to 8; R.sub.5 is H or
CH.sub.3(CH.sub.2).sub.p, wherein p is an integer ranging from 1 to
7; and R.sub.6 is H; (CH.sub.2).sub.mH; or (CH.sub.2).sub.mOH,
wherein m is an integer ranging from 1 to 8; R.sub.3 is selected
from the group consisting of: (a), (b), (c) and (d), wherein q is
an integer ranging from 1 to 8; D is selected from the group
consisting of NH, S, and O; wherein R.sub.7 is selected from the
group consisting of H, OH, NH.sub.2, R.sub.9COOH, wherein R.sub.9
is an alkylene or alkenylene group having 1 to 8 carbon atoms, and
(CH.sub.2).sub.tOH, wherein t is an integer ranging from 1 to 8;
R.sub.11 is selected from the group consisting of --CH.sub.2COOH
and --CH.sub.2--CONH(CH.sub.2).sub.wNHZ, wherein w is an integer
ranging from 1 to 2 and Z is selected from the group consisting of
hydrogen and acetate; and R.sub.4 is of formula (III), wherein
R.sub.8 is selected from the group consisting of H; OH;
(CH.sub.2).sub.fNH.sub.2 wherein f is selected from the group
consisting of 0 and an integer ranging from 1 to 8;
(CH.sub.2).sub.5OH, wherein s is an integer ranging from 1 to 8;
and R.sub.10COOH, wherein R.sub.10 is an alkylene or alkenylene
group having 1 to 8 carbon atoms; and r is an integer ranging from
1 to 8.
Inventors: |
Neely, Constance F.;
(Raleigh, NC) |
Correspondence
Address: |
MYERS BIGEL SIBLEY & SAJOVEC
PO BOX 37428
RALEIGH
NC
27627
US
|
Family ID: |
25028936 |
Appl. No.: |
10/083836 |
Filed: |
February 27, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10083836 |
Feb 27, 2002 |
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09269055 |
Mar 18, 1999 |
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09269055 |
Mar 18, 1999 |
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08753048 |
Nov 19, 1996 |
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5786360 |
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Current U.S.
Class: |
514/263.2 ;
514/263.23; 514/263.35; 544/269; 544/276 |
Current CPC
Class: |
A61P 37/08 20180101;
A61P 13/00 20180101; A61P 11/06 20180101; A61P 9/04 20180101; A61P
19/02 20180101; A61P 9/10 20180101; A61P 15/00 20180101; A61P 1/00
20180101; C07D 473/06 20130101 |
Class at
Publication: |
514/263.2 ;
514/263.23; 514/263.35; 544/269; 544/276 |
International
Class: |
A61K 031/522; C07D
473/04 |
Claims
That which is claimed is:
1. A compound of the formula: 13wherein R.sub.1 is selected from
the group consisting of C.sub.1-C.sub.8 alkyl; R.sub.2 is of the
formula: 14wherein n is an integer ranging from 1 to 8; R.sub.5 is
H or CH.sub.3 (CH.sub.2).sub.p, wherein p is an integer ranging
from 1 to 7; and R.sub.6 is H; (CH.sub.2).sub.mH; or
(CH.sub.2).sub.mOH, wherein m is an integer ranging from 1 to 8;
R.sub.3 is selected from the group consisting
of:--(CH.sub.2).sub.qC.sub.6H.sub.4--R.sub.7 15wherein q is an
integer ranging from 1 to 8; D is selected from the group
consisting of NH, S, and O; wherein R.sub.7 is selected from the
group consisting of H, OH, NH.sub.2, R.sub.9COOH, wherein R.sub.9
is an alkylene or alklenylene group having .sub.1 to 8 carbon
atoms, and (CH.sub.2).sub.tOH, wherein t is an integer ranging from
1 to 8; R.sub.11 is selected from the group consisting of,
--CH.sub.2COOH and --CH.sub.2--CONH(CH.sub.2).sub.wNHZ, wherein w
is an integer ranging from 1 to 2 and Z is selected from the group
consisting of hydrogen and acetate; and R.sub.4 is of the formula:
16wherein R.sub.8 is selected from the group consisting of H; OH;
(CH.sub.2).sub.fNH.sub.2 wherein f is selected from the group
consisting of 0 and an integer ranging from 1 to 8;
(CH.sub.2).sub.sOH, wherein s is an integer ranging from 1 to 8;
and R.sub.10COOH, wherein R.sub.10 is an alkylene or alkenylene
group having 1 to 8 carbon atoms; and r is an integer ranging from
1 to 8.
2. The compound according to claim 1, wherein R.sub.1 is C.sub.3
alkyl; R.sub.3 is:--(CH.sub.2).sub.qC.sub.6H.sub.4--R.sub.7R.sub.5
is CH.sub.3 (CH.sub.2).sub.p wherein p is 1; R.sub.6 is
(CH.sub.2).sub.mOH wherein m is 2; R.sub.7 is H; R.sub.8 is
NH.sub.2; f is 0; n is 2; m is 2; q is 1; and r is 2.
3. The compound according to claim 1, wherein R.sub.1 is C.sub.3
alkyl; R.sub.3 is:--(CH.sub.2).sub.qC.sub.6H.sub.4--R.sub.7R.sub.5
is CH.sub.3 (CH.sub.2).sub.p wherein p is 1; R.sub.6 is H; R.sub.7
is NH.sub.2; R.sub.8 is NH.sub.2; f is 0; n is 2; q is 1; and r is
2.
4. The compound according to claim 1, wherein R.sub.1 is C.sub.3
alkyl; R.sub.3 is:--(CH.sub.2).sub.qC.sub.6H.sub.4--R.sub.7R.sub.5
is CH.sub.3 (CH.sub.2).sub.p wherein p is 1; R.sub.6 is H; R.sub.7
is H; R.sub.8 is NH.sub.2; f is 0; n is 2; q is 1; and r is 2.
5. The compound according to claim 1, wherein R.sub.1 is C.sub.3
alkyl; R.sub.3 is:--(CH.sub.2).sub.qC.sub.6H.sub.4--R.sub.7R.sub.5
is CH.sub.3 (CH.sub.2).sub.p wherein p is 1; R.sub.6 is H; R.sub.7
is H; R.sub.8 is selected from the group consisting of
(CH.sub.2).sub.sOH wherein s is 2 and R.sub.10COOH, wherein
R.sub.10 is CH.dbd.CH; n is 2; q is 1; and r is 2.
6. The compound according to claim 1, wherein R.sub.1 is C.sub.3
alkyl; R.sub.3 is:--(CH.sub.2).sub.qC.sub.6H.sub.4--R.sub.7R.sub.5
is CH.sub.3 (CH.sub.2).sub.p wherein p is 1; R.sub.6 is H; R.sub.7
is selected from the group consisting of (CH.sub.2).sub.tOH wherein
t is 2 and R.sub.9COOH, wherein R.sub.9 is CH.dbd.CH; R.sub.8 is
NH.sub.2 ; f is 0; n is 2; q is 1; and r is 2.
7. An assay-type probe of the compound defined in claim 1, wherein
said assay-type probe is labeled with non-radioactive material.
8. The assay-type probe: according to claim 7, wherein said
non-radioactive material is a fluorescent dye.
9. The assay-type probe according to claim 7, wherein said
non-radioactive material is biotin.
10. The assay-type probe according to claim 7, wherein R.sub.1 is
C.sub.3 alkyl; R.sub.3
is:--(CH.sub.2).sub.qC.sub.6H.sub.4--R.sub.7R.sub.5 is CH.sub.3
(CH.sub.2).sub.p wherein p is 1; R.sub.7 is H; R.sub.8is NH.sub.2;
f is 0; n is 2; q is 1; r is 2; and R.sub.6 is (CH.sub.2).sub.mOH
wherein m is 2; wherein said non-radioactive material is biotin
bonded to the hydroxyl group present on R.sub.6.
11. The assay-type probe according to claim 7, wherein R.sub.1 is
C.sub.3 alkyl; R.sub.3
is:--(CH.sub.2).sub.qC.sub.6H.sub.4--R.sub.7R.sub.5 is CH.sub.3
(CH.sub.2).sub.p wherein p is 1; R.sub.6 is H; R.sub.7 is NH.sub.2;
n is 2; q is 1; r is 2; and R.sub.8 is NH.sub.2; f is 0; wherein
said non-radioactive material is biotin bonded to the amino group
present on R.sub.8.
12. The assay-type probe according to claim 7, wherein R.sub.1 is
C.sub.3 alkyl; R.sub.3
is:--(CH.sub.2).sub.qC.sub.6H.sub.4--R.sub.7R.sub.5 is CH.sub.3
(CH.sub.2).sub.p wherein p is 1; R.sub.6 is H; R.sub.7is H; n is 2;
q is 1; r is 2; and R.sub.8 is R.sub.10COOH, wherein R.sub.10 is an
alkylene or alkenylene group having 1 to 8 carbon atoms; wherein
said non-radioactive,e material is biotin bonded to the carboxyl
group present on R.sub.8.
13. An assay-type probe of the compound defined in claim 1, wherein
said assay-type probe is labeled with radioactive material.
14. The assay-type probe according to claim 13, wherein said
radioactive material is a radioactive isotope selected from the
group consisting of .sup.18F, .sup.19F, tritium, and .sup.125I.
15. A pharmaceutically,y acceptable salt of compound defined by the
formula: 17wherein R.sub.1 is selected from the group consisting of
C.sub.1-C.sub.8 alkyl; R.sub.2 is of the formula: 18wherein n is an
integer ranging from 1 to 8; R.sub.5 is H or CH.sub.3
(CH.sub.2).sub.p, wherein p is an integer ranging from 1 to 7; and
R.sub.6 is H; (CH.sub.2).sub.mH; or (CH.sub.2).sub.mOH, wherein m
is an integer ranging from 1 to 8; R.sub.3 is selected from the
group consisting of:--(CH.sub.2).sub.qC.sup.6H.sub.4--R.sub.7
19wherein q is an integer ranging from 1 to 8; D is selected from
the group consisting of NH, S, and O; wherein R.sub.7 is selected
from the group consisting of H, OH, NH.sub.2, R.sub.9COOH, wherein
R.sub.9 is an alkylene or alkenylene group having 1 to 8 carbon
atoms, and (CH.sub.2).sub.tOH, wherein t is an integer ranging from
1 to 8; R.sub.11 is selected from the group consisting of
--CH.sub.2COOH and --CH.sub.2--CONH(CH.sub.2).sub.wMHZ, wherein w
is an integer ranging from 1 to 2 and Z is selected from the group
consisting of hydrogen and acetate; and R.sub.4 is of the formula:
20wherein R.sub.8 is selected from the group consisting of H; OH;
(CH.sub.2).sub.fNH.sub.2 wherein f is selected from the group
consisting of 0 and an integer ranging from 1 to 8;
(CH.sub.2).sub.sOH, wherein s is an integer ranging from 1 to 8;
and R.sub.10COOH, wherein R.sub.10 is an alkylene or alkenylene
group having 1 to 8 carbon atoms; and r is an integer ranging from
1 to 8.
16. The compound according to claim 15, wherein R.sub.1 is C.sub.3
alkyl; R.sub.3 is:--(CH.sub.2).sub.qC.sub.6H.sub.4--R.sub.7R.sub.5
is CH.sub.3 (CH.sub.2).sub.p wherein p is 1; R.sub.6 is
(CH.sub.2).sub.mOH wherein m is 2; R.sub.7 is H; R.sub.8 is
NH.sub.2; f is 0; n is 2; m is 2; q is 1; and r is 2.
17. The compound according to claim 15, wherein R.sub.1 is C.sub.3
alkyl; R.sub.3 is:--(CH.sub.2).sub.q C.sub.6H.sub.4--R.sub.7R.sub.5
is CH.sub.3 (CH.sub.2).sub.p wherein p is 1; R.sub.6 is H; R.sub.7
is NH.sub.2; R.sub.8 is NH.sub.2; f is 0; n is 2; q is 1; and r is
2.
18. The compound according to claim 15, wherein R.sub.1 is C.sub.3
alkyl; R.sub.3 is:--(CH.sub.2).sub.qC.sub.6H.sub.4--R.sub.7R.sub.5
is CH.sub.3 (CH.sub.2).sub.p wherein p is 1; R.sub.6 is H; R.sub.7
is H; R.sub.8 is NH.sub.2; f is 0; n is 2; q is 1; and r is 2.
19. The compound according to claim 15, wherein R.sub.1 is C.sub.3
alkyl; R.sub.3 is:--(CH.sub.2).sub.qC.sub.6H.sub.4--R.sub.7R.sub.5
is CH.sub.3 (CH.sub.2).sub.p wherein p is 1; R.sub.6 is H; R.sub.7
is H; R.sub.8 is selected from the group consisting of
(CH.sub.2).sub.sOH wherein s is 2 and R.sub.10COOH, wherein
R.sub.10 is CH.dbd.CH; n is 2; q is 1; and r is 2.
20. The compound according to claim 15, wherein R.sub.1 is C.sub.3
alkyl; R.sub.3 is:--(CH.sub.2).sub.qC.sub.6H.sub.4--R.sub.7R.sub.5
is CH.sub.3 (CH.sub.2).sub.p wherein p is 1; R.sub.6 is H; R.sub.7
is selected from the group consisting of (CH.sub.2).sub.tOH wherein
t is 2 and R.sub.9COOH, wherein R.sub.9 is CH.dbd.CH; R.sub.8 is
NH.sub.2; f is 0; n is 2; q is 1; and r is 2.
21. A pharmaceutical composition which comprises a compound of
claim 1 and a pharmaceutically acceptable carrier.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The instant application is a continuation-in-part
application of U.S. patent application Ser. No. 08/753,048 filed
Nov. 19, 1996.
FIELD AND BACKGROUND OF THE INVENTION
[0002] The present invention relates to novel compounds useful as
A.sub.1 adenosine receptor antagonists.
[0003] Adenosine receptors are involved in a vast number of
peripheral and central regulatory mechanisms such as, for example,
vasodilation, cardiac depression, inhibition of lipolysis,
inhibition of insulin release and potentiation glucagon release in
the pancreas, and inhibition of neurotransmitter release from nerve
endings.
[0004] In general, adenosine: receptors can be divided into two
main classes, A.sub.1 receptors which (,an inhibit, and A.sub.2
receptors which can stimulate adenylate cyclase activity. One of
the best known classes of adenosine receptor antagonists are the
xanthines which include caffeine and theophylline. See e.g., Muller
et al., J. Med. Chem. 33: 2822-2828 (1990). In general, many of
these antagonists often suffer from poor water solubility, and low
potency or lack of selectivity for adenosine receptors.
Additionally, selective analogues of adenosine receptor antagonists
have been developed through the "functionalized congener" approach.
Analogues of adenosine receptor ligands bearing functionalized
chains have been synthesized and attached covalently to various
organic moieties such as amines and peptides. Attachment of the
polar groups to xanthine congeners has been found to increase water
solubility. Nonetheless, such developments have yet to fully
address problems associated with potency and selectivity. More
recently Jacobson et al. J. Med. Chem. 35: 408-422 (1992) has
proposed various derivatives of adenosine and theophylline for use
as receptor antagonists. The article discloses that hydrophobic
substituents are able to potentially enhance affinity. However, it
is also acknowledged that such substituents may result in a
decrease in solubility thus rendering the antagonists less soluble
in vivo. In confronting these problems, Jacobson et al. indicates
that a dipropyl substitution at the 1 and 3 positions of
theophylline allows desirable affinity at A.sub.1 receptors. It is
also stated that substitutions at the 7-position are typically not
favorable.
[0005] It is an object of the present invention to therefore
provide compounds useful as Al adenosine receptor antagonists which
display high potency and affinity levels, along with water
solubility.
SUMMARY OF THE INVENTION
[0006] In one aspect, the present invention provides a compound of
the general formula: 2
[0007] wherein
[0008] R.sub.1 is selected from the group consisting of
C.sub.1-C.sub.8 alkyl;
[0009] R.sub.2 is of the formula: 3
[0010] wherein n is an integer ranging from 1 to 8; R.sub.5 is H or
CH.sub.3(CH.sub.2).sub.p, wherein p is an integer ranging from 1 to
7; and R.sub.6 is H, (CH.sub.2).sub.mH, or (CH.sub.2).sub.mOH,
wherein m is an integer ranging from 1 to 8;
[0011] R.sub.3 is selected from the group consisting of:
--(CH.sub.2).sub.qC.sub.6H.sub.4--R.sub.7 4
[0012] wherein q is an integer ranging from 1 to 8; D is selected
from the group consisting of S, NH, and O; and wherein R.sub.7 is
selected from the group consisting of H, OH, NH.sub.2, R.sub.9COOH,
wherein R.sub.9 is an alkylene or alkenylene group having 1 to 8
carbon atoms, and (CH.sub.2).sub.tOH, wherein t is an integer
ranging from 1 to 8; wherein R.sub.11 is selected from the group
consisting of --CH.sub.2COOH and
--CH.sub.2--CONH(CH.sub.2).sub.wNHZ, wherein w is an integer
ranging from 1 to 2 and Z is selected from the group consisting of
hydrogen and acetate; and
[0013] R.sub.4 is of the formula: 5
[0014] wherein R.sub.8 is selected from the group consisting of H;
OH; (CH.sub.2).sub.fNH.sub.2 wherein f is selected from the group
consisting of 0 and an integer ranging from 1 to 8;
(CH.sub.2).sub.sOH, wherein s is an integer ranging from 1 to 8;
and R.sub.10COOH, wherein R.sub.10 is an alkylene or alkenylene
group having 1 to 8 carbon atoms; and r is an integer ranging from
1 to 8.
[0015] In a second aspect, the invention provides for assay-type
probes of the above compound, wherein the probes are marked or
conjugated with radioactive or non-radioactive material.
[0016] In a third aspect, the invention provides a pharmaceutically
acceptable salt of the above compound.
[0017] In a fourth aspect, the invention provides a pharmaceutical
composition which comprises the above compound and a
pharmaceutically acceptable carrier.
DETAILED DESCRIPTION OF THE INVENTION
[0018] The present invention will now be described more fully
hereinafter, in which preferred embodiments of the invention are
shown. This invention may, however, be embodied in different forms
and should not be construed as limited to the embodiments set forth
herein. Rather, these embodiments are provided so that this
disclosure will be thorough and complete, and will fully convey the
scope of the invention to those skilled in the art.
[0019] The present invention is directed to a compound of the
formula (I): 6
[0020] R.sub.1 is selected from the group consisting of
C.sub.1-C.sub.8 alkyl, preferably C.sub.1 to C.sub.4 alkyl. For the
purposes of the invention, R.sub.1 is more preferably C.sub.1 or
C.sub.3 alkyl, and is most preferably C.sub.3 alkyl.
[0021] R.sub.2 is of the formula: 7
[0022] wherein n is an integer ranging from 1 to 8, more preferably
1 to 4; R.sub.5 is H or CH.sub.3(CH.sub.2).sub.p, wherein p is an
integer ranging from 1 to 7, more preferably 1 to 4; and R.sub.6 is
H, (CH.sub.2).sub.mH, or (CH.sub.2).sub.mOH, wherein m is an
integer ranging from 1 to 8, more preferably 1 to 4.
[0023] R.sub.3 is selected from the group consisting of:
--(CH.sub.2).sub.qC.sub.6H.sub.4--R.sub.7 8
[0024] wherein q is an integer ranging from 1 to 8; D is selected
from the group consisting of S, O, and NH; and wherein R.sub.7 is
selected from the group consisting of H, OH, NH.sub.2, R.sub.9COOH,
wherein R.sub.9 is an alkylene or alkenylene group having 1 to 8
carbon atoms, and (CH.sub.2).sub.tOH, wherein t is an integer
ranging from 1 to 8. The alkylene or alkenylene groups may be
substituted or unsubstituted. R.sub.9 is preferably CH.dbd.CH.
R.sub.11 is selected from the group consisting of --CH.sub.2COOH
and --CH.sub.2--CONH(CH.sub.2).sub.wNHZ, wherein w is an integer
ranging from 1 to 2 and Z is selected from the group consisting of
hydrogen and acetate.
[0025] R.sub.4 is of the formula: 9
[0026] wherein R.sub.8 is selected from the group consisting of H;
OH; (CH.sub.2).sub.fNH.sub.2, wherein f is selected from the group
consisting of 0 and an integer ranging from 1 to 8;
(CH.sub.2).sub.sOH, wherein s is an integer ranging from 1 to 8,
more preferably 1 to 4; and R.sub.10COOH, wherein R.sub.10 is an
alkylene or alkenylene group having 1 to 8 carbon atoms; and r is
an integer ranging from 1 to 8, more preferably 1 to 4. In the
above, R.sub.9 and R.sub.10 are preferably CH.dbd.CH.
[0027] The invention may be illustrated below with respect to
preferred embodiments. In these embodiments, R.sub.3 is of the
formula:
--(CH.sub.2).sub.qC.sub.6H.sub.4--R.sub.7
[0028] In one preferred embodiment, R.sub.1 is C.sub.3 alkyl;
R.sub.5 is CH.sub.3 (CH.sub.2).sub.p wherein p is 1; R.sub.6 is
(CH.sub.2).sub.mOH wherein m is 2; R.sub.7 is H; R.sub.8 is
NH.sub.2; f is 0; n is 2; m is 2; q is 1; and r is 2.
[0029] In another preferred embodiment, R.sub.1 is C.sub.3 alkyl;
R.sub.5 is CH.sub.3 (CH.sub.2).sub.p. wherein p is 1; R.sub.6 is H;
R.sub.7 is NH.sub.2; R.sub.8 is NH.sub.2; f is 0; n is 2; q is 1;
and r is 2.
[0030] In another preferred embodiment, R.sub.1 is C.sub.3 alkyl;
R.sub.5 is CH.sub.3 (CH.sub.2).sub.p wherein p is 1; R.sub.6 is H;
R.sub.7 is H; R.sub.8 is NH.sub.2; f is 0; n is 2; q is 1; and r is
2.
[0031] In another preferred embodiment, R.sub.1 is C.sub.3 alkyl;
R.sub.5 is CH.sub.3 (CH.sub.2).sub.p wherein p is 1; R.sub.6 is H;
R.sub.7 is H; R.sub.8 is selected from the group consisting of
(CH.sub.2).sub.sOH, wherein s is 2 and R.sub.10COOH, wherein
R.sub.10 is CH.dbd.CH; n is 2; q is 1; and r is 2.
[0032] In another preferred embodiment, R.sub.1 is C.sub.3 alkyl;
R.sub.5 is CH.sub.3 (CH.sub.2).sub.p wherein p is 1; R.sub.6 is H;
R.sub.7 is selected from the group consisting of R.sub.9COOH,
wherein R.sub.9 is CH.dbd.CH and (CH.sub.2).sub.tOH, wherein t is
2; R.sub.8 is NH.sub.2; f is 0;n is 2; q is 1; and r is 2.
[0033] The compound of the present invention may form
pharmaceutically acceptable salts with both organic and inorganic
acid and bases. Examples of suitable acids for salt formation are
hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic,
malonic, salicylic, ascorbic, maleic, methanesulfonic, and the
like. Any of the amine acid addition salts may also be used. The
salts are prepared by contacting the free base form of the compound
with an appropriate amount of the desired acid in a manner known to
one skilled in the art. Examples of suitable bases for salt
formation are sodium hydroxide, sodium carbonate, sodium
bicarbonate, potassium hydroxide, calcium hydroxide, ammonia,
organic amines, and the like. The salts may be prepared by
contacting the free acid form of the compound with an appropriate
amount of the desired base in a manner known to one skilled in the
art.
[0034] The invention also provides A.sub.1 adenosine receptor
antagonist compounds with radioactive or non-radioactive labels.
Such labelled compounds are useful as assay-type probes or
conjugates, and may be used to obtain quantitative binding
measurements of the A.sub.1 adenosine receptor antagonist
compounds. For the purposes of the invention, "assay-type probes"
refers to those materials which are useful for enhancing the
selectivity of the quantitative analysis of the A.sub.1 adenosine
receptor compounds of the invention. Examples of such assay-type
probes are described in U.S. Pat. No. 5,248,770 to Jacobson et al.,
the disclosure of which is incorporated herein by reference in its
entirety. The probes are highly useful in that they have little
adverse effect on the affinity of the compounds of the present
invention. Radioactive markers include, but are not limited to, an
electric spin marker, a .sup.19F NMR probe, a radioactive .sup.18F
isotope marker, a radioactive iodine marker (e.g., .sup.1251I), a
radioactive .sup.3H marker, tritium, and a complex of a metal atom
or a metal ion and a chelating agent. An exemplary metal ion is a
radioactive isotope of technetium or indium. An exemplary chelating
agent is diethylene pentacetic anhydride.
[0035] Various non-radioactive materials may be used in labelling
the present A.sub.1 adenosine receptor compounds. Numerous examples
are presented in U.S. Pat. No. 5,248,770 to Jacobson et al. Biotin
is used-as a common non-radioactive label for such probes, as
described in R. W. Old et al. Principals of Gene Manipulation, 4th
ed: 328-331 (1989). To facilitate labelling the compounds with
biotin or any other appropriate material, a spacer component may be
added to the compound according to an accepted method. Such a
method is described in the Jacobson et al. '770 patent. Exemplary
spacer components include, but are not limited to, an oligopeptide,
triglycidyl, and N-hydroxysuccinimide ester.
[0036] Biotin may be bonded to any suitable linkage provided by
substituents on the compound structure in accordance with any
accepted and suitable technique. For example, referring to compound
(I) as defined herein, biotin may be bonded to the hydroxy group on
R.sub.6 when the compound contains (CH.sub.2).sub.mOH at R.sub.6
with m defined herein; to the amino group present on either of
R.sub.7 or R.sub.8 when (CH.sub.2).sub.fNH.sub.2 is contained at
the R.sub.8 position, wherein f is defined herein; to the hydroxyl
group present as R.sub.7 or R.sub.8; or to the carboxyl group
present when R.sub.7 and R.sub.8 are R.sub.9COOH or R.sub.10COOH
respectively, with R.sub.9 and R.sub.10 defined herein.
Additionally, the biotin may be bonded to a hydroxyl group present
on R.sub.8, when R.sub.8 is (CH.sub.2).sub.sOH with s being defined
herein. Biotin may also be bonded to R.sub.7, when R.sub.7 is
(CH.sub.2).sub.tOH with t being defined herein. The biotin-labeled
probes may be detected through appropriate and known analytical
techniques.
[0037] Fluorescent dyes may also be employed as a non-radioactive
labels and are applied to appropriate locations on the compounds of
the invention. Such dyes include, but are not limited to,
tetramethylrhodamine, fluorescein isothiocyanate, and mixtures
thereof. Other non-radioactive materials include for example,
nitrobenzoxadiazole;
2,2,6,6-tetramethyl-piperindinyloxy-4-isothiocyanate; and mixtures
thereof.
[0038] The invention is also directed to a pharmaceutical
composition which includes the compound of the present invention
and a pharmaceutically acceptable carrier. The pharmaceutical
composition is particularly useful in applications relating to
organ preservation in vivo or in situ, perfusion of an isolated
organ either removed or contained within the body (e.g., when an
organ is transported for transplantation), cardiopulmonary bypass,
perfusion of an extremity or limb, and the like. The compounds may
be used in intra-articular, intra-thecal, gastrointestinal, and
genital urinary applications, as well as in any cavity or lumen
such as, for example, the thoracic cavity or ear canal.
[0039] The pharmaceutical composition may be employed, as an
example, in oral dosage form as a liquid composition. Such liquid
compositions can include suspension compositions or syrup
compositions and can be prepared with such carriers as water; a
saccharide such as sucrose, sorbitol, fructose, and the like; a
glycol such as polyethyleneglycol, polypropyleneglycol, and the
like; an oil such as sesame oil, olive oil, soybean oil, and the
like; an antiseptic such as p-hydroxy-benzoic acid esters and the
like; and a flavor component such as a fruit flavor or a mint
flavor. The pharmaceutical composition may also be in the form of
powder, pills, capsules, and tablets and can be prepared with
various carriers. Suitable carriers include, but are not limited
to, lactose, glucose, sucrose, mannitol, and the like;
disintegrators such as starch, sodium alginate, and the like;
binders such as polyvinyl alcohol, hydroxypropyl cellulose,
gelatin, and the like; surfactants such as, for example, fatty acid
esters; and plasticizers such as, for example, glycerins. The
composition of the present invention is especially useful when
applied sublingually. It should be noted that in the preparation of
the tablets and capsules, a solid pharmaceutical carrier is used.
Advantageously, the pharmaceutical composition may be used in the
form of, for example, eye drops or an aerosol.
[0040] Other types of pharmaceutical compositions may be employed
in the form of a suppository, a nasel spray, and an injectable
solution. These compositions are prepared using appropriate aqueous
solutions which may include, but are not limited to, distilled
water, and saline and buffer additives. Other components may be
employed such as organic materials including neutral fatty bases.
Additionally, the pharmaceutical composition may be utilized in a
transdermal application.
[0041] Biopolymers may be used as carriers in the above
pharmaceutical compositions. Exemplary biopolymers may include, for
example, proteins, sugars, or lipids.
[0042] The A.sub.1 receptor antagonists of the present invention
are particularly useful as, for example, anti-allergenics, CNS
stimulants, diuretics, anti-asthmatics, and cardiotonics.
[0043] Selective analogues of adenosine receptor antagonists have
been developed through the "functionalized congener" approach. See
e.g., U.S. Pat. No. 4,968,672 to Jacobson et al.; and Jacobson et
al., Mol. Pharmacol. 29: 126-133 (1985). In terms of pharmacology,
the compounds advantageously display increased affinity at A.sub.1
receptor sites relative to former A.sub.1 receptor antagonists
while simultaneously exhibiting good water solubility.
[0044] The foregoing example is illustrative of the present
invention, and is not to be construed as limiting thereof.
EXAMPLE
Synthesis of A.sub.1 Adenosine Receptor Antagonists
[0045] A.sub.1 adenosine receptor antagonists of the present
invention may be synthesized according to the process illustrated
below: 10
[0046] In the above reaction pathway, R' may be C.sub.1-C.sub.8
alkyl; R" may be selected from the group consisting of H, OH,
(CH.sub.3).sub.eNO.sub.2 wherein e is selected from the group
consisting of 0 and an integer ranging from 1 to 8;
(CH.sub.2).sub.sOH, wherein s is an integer ranging from 1 to 8;
and R.sub.10COOH, wherein R.sub.10 is an alkylene or alkenylene
group having 1 to 8 carbon atom; R.sup.x may be selected from the
group consisting of:
(CH.sub.2).sub.qC.sub.6H.sub.4R'" 11
[0047] wherein R'" may be selected from the group consisting of H,
OH, NO.sub.2, R.sub.9COOH, wherein R.sub.9 is an alkylene or
alkenylene group having 1 to 8 carbon atoms, and
(CH.sub.2).sub.tOH, wherein t is an integer ranging from 1 to 8; D
may be selected from the group consisting of O, S, and NH; q is an
integer ranging from 1 to 8; R.sub.11 is selected from the group
consisting of --CH.sub.2COOH and
--CH.sub.2--CONH(CH.sub.2).sub.wNHZ, wherein w is an integer
ranging from 1 to 2 and Z is selected from the group consisting of
hydrogen and acetate; and R.sup.iv may be selected from the group
consisting of H, (CH.sub.2).sub.mH, and (CH.sub.2).sub.mOH, wherein
m is an integer ranging from 1 to 8. As identified in formula
(VII), R.sup.v may be selected from the group consisting of H; OH;
(CH.sub.2).sub.fNH.sub.2 wherein f is selected from the group
consisting of 0 and an integer ranging from 1 to 8;
(CH.sub.2).sub.sOH, wherein s is an integer ranging from 1 to 8;
and R.sub.10COOH, wherein R.sub.10 is an alkylene or alkenylene
group having 1 to 8 carbon atoms. R.sup.xi may be selected from the
group consisting of:
(CH.sup.2).sub.qC.sub.6H.sub.4R.sup.vi
[0048] 12
[0049] wherein D may be selected from the group consisting of O, S,
and NH; q is an integer ranging from 1 to 8; R.sup.vi may be
selected from the group consisting of H, OH, NH.sub.2, R.sub.9COOH,
wherein R.sub.9 is an alkylene or alkenylene group having 1 to 8
carbon atoms, and (CH.sub.2).sub.tOH, wherein t is an integer
ranging from 1 to 8. R.sub.11 is selected from the group consisting
of --CH.sub.2COOH and --CH.sub.2--CONH(CH.sub.2).sub.wNHZ, wherein
w is an integer ranging from 1 to 2 and Z is selected from the
group consisting of hydrogen and acetate. In general, the above
synthesis steps may be carried out at standard temperature and
pressure conditions, optionally under reflux. An exception to this
pertains to the reaction involving intermediates (VI) and (VII)
which is preferably performed at a temperature ranging from about
25.degree. C. to about 50.degree. C and at atmospheric pressure. In
the reaction step involving intermediate (V) becoming intermediate
(VI), it is desired to employ an oxidation step with FeCl.sub.3 or
NaIO.sub.4 subsequent to the nitrobenzene reflux. Moreover, it
should be noted that when R" and/or R'" contain nitro groups, a
reaction step which involves applying H.sub.2 over a Pd/C catalyst
is employed prior to the reaction with CH.sub.3OH/HCl. The
resulting product (VII) may be further processed and purified
according to accepted procedures.
[0050] In the specification and example, there have been disclosed
typical preferred embodiments of the invention and, although
specific terms are employed, they are used in a generic and
descriptive sense only and not for purposes of limitation of the
scope of the invention being set forth in the following claims.
* * * * *