A1 adenosine receptor antagonists

Details A1 adenosine receptor antagonists A1 adenosine receptor antagonists

2000-05-03

2002-12-17

Riley, Jezia (Department: 1637)

Organic compounds -- part of the class 532-570 series

Organic compounds

Chalcogen bonded directly to ring carbon of the purine ring...

C544S272000

Reexamination Certificate

active

06495687

ABSTRACT:

FIELD AND BACKGROUND OF THE INVENTION
The present invention relates to novel compounds useful as A
1
adenosine receptor antagonists.
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.
In general, adenosine receptors can be divided into two main classes, A
1
receptors which can inhibit, and A
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., Müller 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
1
receptors. It is also stated that substitutions at the 7-position are typically not favorable.
It is an object of the present invention to therefore provide compounds useful as A
1
adenosine receptor antagonists which display high potency and affinity levels, along with water solubility.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides a compound of the general formula:
wherein R
1
is selected from the group consisting of C
1
-C
8
alkyl;
R
2
is of the formula:
 wherein n is an integer ranging from 1 to 8; R
5
is H or (CH
2
)
p
, wherein p is an integer-ranging from 1 to 7; and R
5
is H or (CH
2
)
m
OH, wherein m is an integer ranging from 1 to 8;
R
3
is of the formula:
—(CH
2
)
q
C
6
H
4
—R
7
 wherein q is an integer ranging from 1 to 8; and wherein R
7
is selected from the group consisting of H, NH
2
, R
9
COOH, wherein R
9
is an alkylene or alkenylene group having 1 to 8 carbon atoms, and (CH
2
)
t
OH, wherein t is an integer ranging from 1 to 8; and
R
4
is of the formula:
 wherein R
8
is selected from the group consisting of H; NH
2
; (CH
2
)
s
OH, wherein s is an integer ranging from 1 to 8; and R
10
COOH, wherein R
10
is an alkylene or alkenylene group having 1 to 8 carbon atoms; and r is an integer ranging from 1 to 8.
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.
In a third aspect, the invention provides a pharmaceutically acceptable salt of the above compound.
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
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.
The present invention is directed to a compound of the formula (I):
R
1
is selected from the group consisting of C
1
-C
8
alkyl, preferably C
1
to C
4
alkyl. For the purposes of the invention, R
1
is more preferably C
1
or C
3
alkyl, and is most preferably C
3
alkyl.
R
2
is of the formula:
wherein n is an integer ranging from 1 to 8, more preferably 1 to 4; R
5
is H or (CH
2
)
p
, wherein p is an integer ranging from 1 to 7, more preferably 1 to 4; and R
6
is H or (CH
2
)
m
OH, wherein m is an integer ranging from 1 to 8, more preferably 1 to 4.
R
3
is of the formula:
—(CH
2
)
q
C
6
H
4
—R
7
wherein q is an integer ranging from 1 to 8, more preferably 1 to 4; and wherein R
7
is selected from the group consisting of H, NH
2
, R
9
COOH, wherein R
9
is an alkylene or alkenylene group having 1 to 8 carbon atoms, and (CH
2
)
t
H, wherein t is an integer ranging from 1 to 8. The alkylene or alkenylene groups may be substituted or unsubstituted. R
9
is preferably CH═CH.
R
4
is of the formula:
wherein R
8
is selected from the group consisting of H; NH
2
; (CH
2
)
s
OH, wherein s is an integer ranging from 1 to 8, more preferably 1 to 4; and R
10
COOH, wherein R
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
9
and R
10
are preferably CH═CH.
In one preferred embodiment, R
1
is C
3
alkyl; R
5
is (CH
2
)
p
wherein p is 2; R
6
is (CH
2
)
m
OH wherein m is 2; R
7
is H; R
8
is NH
2
; n is 2; m is 2; q is 1; and r is 2.
In another preferred embodiment, R
1
is C
3
alkyl; R
5
is (CH
2
)
p
wherein p is 1; R
6
is H; R
7
is NH
2
; R
8
is NH
2
; n is 2; q is 1; and r is 2.
In another preferred embodiment, R
1
is C
3
alkyl; R
5
is (CH
2
)
p
wherein p is 1, R
6
is H; R
7
is H; R
8
is NH
2
; is 2; q is 1; and r is 2.
In another preferred embodiment, R
1
is C
3
alkyl; R
5
is (CH
2
)
p
wherein p is 2; R
6
is H; R
7
is H; R
8
is selected from the group consisting of (CH
2
)
s
OH, wherein s is 2 and R
10
COOH, wherein R
10
is CH═CH; n is 2; q is 1; and r is 2.
In another preferred embodiment, R
1
is C
3
alkyl; R
5
is (CH
2
)
p
wherein p is 1; R
6
is H; R
7
is selected from the group consisting of R
9
COOH, wherein R
9
is CH═CH and (CH
2
)
t
OH, wherein t is 1; R
8
is NH
2
; n is 2; q is 1; and r is 2.
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.
The invention also provides A
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
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
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 disclosur

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