Pharmaceutical administration of adenosine agonists

Details Pharmaceutical administration of adenosine agonists Pharmaceutical administration of adenosine agonists

2001-02-14

2004-09-14

Wilson, James O. (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C514S081000

Reexamination Certificate

active

06790839

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to drugs for use in cancer therapy. More specifically, the present invention concerns drugs which induce proliferation of cells of the hematopoietic system.
1. Prior Art
The following is a list of prior art references considered to be relevant as background to the invention:
1. Daly, J. W., Adenosine receptors: Targets for future drugs.
J. Med. Chem.,
25:197-207, 1982.
2. Stiles, G. L., Adenosine receptors and beyond: Molecular mechanisms of physiological regulation,
Clin. Res.,
38:10-18, 1990.
3. Collis, M. G., The vasodilator role of adenosine,
Pharmacol. Ther,
41:143-162, 1989.
4. Fishman et al., Extracellular adenosine acts as a chemoprotective agent,
Proceeding of the American Association for Cancer Research,
39:470, 1998.
5. Moos, W. H., et al., N
6
-cycloalkyladenosines. Potent A
1
selective adenosine agonists,
J. Medicinal Chemistry
28:1383-1384, 1985.
6. Jacobson, K. A et al., Functionalized congeners of adenosine,
J. Medicinal Chemistry
28:1341-1346, 1985.
7. U.S. Pat. No. 5,998,387.
8. U.S. Pat. No. 5,998,388
9. U.S. Pat. No. 5,498,605.
10. U.S. Pat. No. 4,791,103.
2. Background of the Invention
Adenosine is an extracellular messenger generated by all cells in the body. It is known to regulate different physiological processes within cells through binding to specific cell surface receptors—A
1
and A
2
receptors
(1,2,3)
. It was recently demonstrated that adenosine inhibits proliferation of tumor cells and induces proliferation of bone marrow cells
(4)
. Further more it was also shown that adenosine can protect white blood cells, particularly neutrophils, from destruction which is otherwise caused by chemotherapeutic drugs
(4)
.
SUMMARY OF THE INVENTION
The present invention is based on the surprising findings that (i) the effect of adenosine in inducing proliferation of bone marrow cells can be inhibited by A
1
receptor antagonists (antagonist that inhibits binding of adenosine to adenosine A
1
receptor), and (ii) the effect of adenosine can be mimicked by an adenosine A
1
receptor agonist (“A
1
RAg”). These findings led to the conclusion that the bone marrow proliferation-induction effect of adenosine is mediated, at least to some extent through the A
1
receptor, and that accordingly A
1
RAg may be used to induce proliferation of bone marrow cells, in a wide variety of clinical situations where such proliferation is therapeutically beneficial.
The present invention provides, by a first of its aspects, a pharmaceutical composition for use in inducing proliferation of bone marrow cells, comprising a pharmaceutically acceptable carrier, excipient or diluent and, as an active ingredient, an effective amount of an A
1
RAg.
The present invention provides, by a second of its aspects, use of an A
1
RAg for the production of a pharmaceutical composition for use in inducing proliferation of bone marrow cells.
The present invention further provides a method of inducing proliferation of bone marrow cells in a subject, comprising administering to the subject an effective amount of an A
1
RAg.
The term “effective amount” used above and below should be understood as meaning an amount of an A
1
RAg which is capable of achieving a desired therapeutic effect, particularly, in inducing proliferation of bone marrow cells. The desired therapeutic effect depends on the type and mode of treatment. When, for example, said A
1
RAg is administered to counter drug-induced leukopenia, an effective amount thereof may be an amount which protects the treated subject against the drug-induced reduction in the count of leukocytes, particularly neutrophils; an amount of the active ingredient which can give rise to an increase in an already decreased level of such cells, e.g. restore the level to a normal level or sometimes even above; etc. The man of the art will have no difficulties, on the basis of a limited number of routine experiments, to determine an effective amount in each case.
As will be appreciated, the effective amount may also depend on the treated subject's gender, on the individual's weight, on the therapeutic regime, namely whether the A
1
RAg is administered once daily, several times daily, once in several days, etc. Furthermore, the effective amount may depend on the exact nature or etiology of the disease or condition which is being treated or intended to be prevented.
According to one embodiment of the invention, the A
1
RAg are adenosine derivatives carrying at least an N
6
-substituent. Other positions may also be substituted. In fact, it has been found that the biological activity of an adenosine derivative may be enhanced by modifying other parts of the nucleotide, for example, at the 2- and/or 5′-positions (e.g. with chloro atoms). Such substituents were found to increase the molecule's A
1
selectivity.
The adenosine derivatives which can be used according to the present invention are generally defined by the following formula (I):
wherein
R
1
represents a lower alkyl, cycloalkyl, preferably C
3
-C
8
cycloalkyl (including the well known cyclohexyl and cyclopentyl containing derivatives, recognized as CPA and CHA, respectively), the cycloalkyl group may be substituted with, for example, a hydroxyl or lower alkyl; R
1
also represents a hydroxyl or hydroxyalkyl; a phenyl anilide, or lower alkyl phenyl, all optionally substituted by one or more substituents, for example, halogen, lower alkyl, haloalkyl such as trifluoromethyl, nitro, cyano, —(CH
2
)
m
CO
2
R
a
, —(CH
2
)
m
CONR
2
R
4
R
b
, —(CH
2
)
m
COR
a
, m representing an integer from 0 to 6; —SOR
c
, —SO
2
R
c
, —SO
3
H, —SO
2
NR
a
R
b
, —OR
a
, —SR
a
, —NHSO
2
R
c
, —NHCOR
a
, —NR
a
R
b
or —NHR
a
CO
2
R
b
; wherein
R
a
and R
b
represent independently a hydrogen, lower alkyl, alkanoyl, phenyl or naphthyl (the latter may be partially saturated) the alkyl group optionally being substituted with a substituted or unsubstituted phenyl or phenoxy group; or when R
1
represents —NR
a
R
b
, said R
a
and R
b
form together with the nitrogen atom a 5- or 6- membered heterocyclic ring optionally containing a second heteroatom selected from oxygen or nitrogen, which second nitrogen heteroatom may optionally be further substituted by hydrogen or lower alkyl; or —NR
a
R
b
is a group of general formulae (II) or (III):
 wherein
n is an integer from 1 to 4;
Z is hydrogen, lower alkyl or hydroxyl;
Y is hydrogen, lower alkyl, or OR′ where R′ is hydrogen, lower alkyl or lower alkanoyl;
A is a bond or a lower alkylene, preferably, C
1
-C
4
alkenyl; and
X and X′ are each independently hydrogen, lower alkyl, lower alkoxy, hydroxy, lower alkanoyl, nitro, haloalkyl such as trifluoromethyl, halogen, amino, mono- or di-lower alkyl amino, or when X and X′ are taken together a methylenedioxy group;
R
c
represents a lower alkyl;
R
2
represents a hydrogen; halogen; substituted or unsubstituted lower alkyl or alkenyl group; lower haloalkyl or haloalkenyl; cyano; acetoamido; lower alkoxy; lower alkylamino; NR
d
R
e
where R
d
and R
e
are independently hydrogen, lower alkyl, phenyl or phenyl substituted by lower alkyl, lower alkoxy halogen or haloalkyl such as trifluoromethyl or alkoxy; or —SR
f
where R
f
is hydrogen, lower alkyl, lower alkanoyl, benzoyl or phenyl;
W represents the group —OCH
2
—, —NHCH
2
—, —SCH
2
— or —NH(C═O)—;
R
3
, R
4
and R
5
represent independently a hydrogen, lower alkyl or lower alkenyl, branched or unbranched C
1
-C
12
alkanoyl, benzoyl or benzoyl substituted by lower alkyl, lower alkoxy, halogen, or R
4
and R
5
form together a five membered ring optionally substituted by a lower alkyl or alkenyl; R
3
further represents independently a phosphate, hydrogen or dihydrogen phosphate, or an alkali metal or ammonium or dialkali or diammonium said thereof;
R
6
represents a hydrogen, halogen atom; or
one of the R groups (i.e. R
1
to R
6
) is a sulfohydrocarbon radical of the formula R
g
—SO
3
—R
h
—, wherein R
g
represents a group selected from C
1
-C
10
aliphatic, phenyl and lower alkyl s

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