Adenosine analogues and related method of treatment

Details Adenosine analogues and related method of treatment Adenosine analogues and related method of treatment

2000-06-27

2002-06-18

Geist, Gary (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C536S027230, C536S027620, C536S027630

Reexamination Certificate

active

06407076

ABSTRACT:

CHEMICAL COMPOUNDS
The present invention relates to novel adenosine derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to their use in medicine. Adenosine derivatives and analogs which possess adenosine agonist activity that are useful as anti-hypertensive, cardioprotective, anti-ischemic and antilipolytic agents have been described in published International Application WO 95/28160.
The present invention provides compounds of formula (I) which are agonists at the adenosine A1 receptor
wherein R
2
represents C
1-3
alkyl, halogen or hydrogen;
R
3
represents a fluorinated straight or branched alkyl group of 1-6 carbon atoms;
R
1
represents a group selected from
(1)—(alk)
n
— (C
3-7
) cycloalkyl, including bridged cycloalkyl, said cycloalkyl group being optionally substituted by one or more substituents selected from OH, halogen, —(C
1-3
) alkoxy, wherein (alk) represents C
1-3
alkylene and n represents 0 or 1.
(2) an aliphatic heterocyclic group of 4 to 6 membered rings containing at least one heteroatom selected from O, N or S and optionally substituted by one or more substituents selected from the group consisting of —(C
1-3
)alkyl, —CO
2
—(C
1-4
) alkyl, —CO(C
1-3
alkyl), —S(═O)
n
—(C
1-3
alkyl), —CONR
a
R
b
(wherein R
a
and R
b
independently represent H or C
1-3
alkyl), or ═O; where there is a sulfur atom in the heterocyclic ring, said sulfur is optionally substituted by (═O)
n
, where n is 1 or 2.
(3) Straight or branched C
1-12
alkyl, optionally including one or more O, S(═O)
n
(where n is 0, 1 or 2), or N groups substituted within the alkyl chain, said alkyl optionally substituted by one or more of the following groups; phenyl, halogen, hydroxy or NR
a
R
b
wherein R
a
and R
b
both represent C
1-3
alkyl or hydrogen.
(4) a fused bicyclic aromatic ring
 wherein B represents a 5 or 6 membered heterocyclic aromatic group containing 1 or more O, N or S atoms wherein the bicyclic ring is attached to the nitrogen atom of formula (I) via a ring atom of ring A and ring B is optionally substituted —CO
2
—(C
1-3
alkyl).
(5) a phenyl group optionally substituted by one or more substituents selected from:
—-halogen, —SO
3
H, —(alk)
n
OH, —(alk)
n
-cyano, —(O)
n
—(C
16
) -alkyl (optionally substituted by one or more halogens), —(alk)
n
—nitro, —(O)
m
—(alk)
n
—CO
2
R
c
, —(alk
n
)—CONR
c
R
d
, —(alk)
n
—COR
c
, —(alk)
n
—SOR
e
, —(alk)
n
—SO
2
R
e
, —(alk)
n
—SO
2
NR
c
R
d
, —(alk)
n
—OR
c
, —(alk)
n
— (CO)
m
—NHSO
2
R
e
, —(alk)
n
—NHCOR
c
, —(alk)
n
—NR
c
R
d
wherein m and n are 0 or 1 and alk represents a C
1-6
alkylene group or C
2-6
alkenyl group.
(6) A phenyl group substituted by a 5 or 6 membered heterocyclic aromatic group, said heterocyclic aromatic group optionally being substituted by C
1-3
alkyl or NR
c
R
d
.
R
c
and R
d
may each independently represent hydrogen, or C
1-3
alkyl or when part of a group NR
c
R
d
, R
c
and R
d
together with the nitrogen atom may form a 5 or 6 membered heterocyclic ring optionally containing other heteroatoms, which heterocyclic ring may optionally be substituted further by one or more C
1-3
alkyl groups.
R
e
represents C
1-3
alkyl.
and salts and solvates thereof, in particular, physiologically acceptable solvates and salts thereof.
Conveniently, the adenosine A1 agonists of the general formula (I) above exhibit greater activity at the adenosine A1 receptor than the other adenosine receptor subtypes, particularly A3.
More particularly the compounds exhibit little or no activity at the A3 receptor.
It will be appreciated that wherein R
1
and/or R
2
in compounds of formula (I) contain one or more asymmetric carbon atoms the invention includes all diastereoisomers of compounds of formula (I) and mixtures thereof. Otherwise the stereochemical configuration of compounds of the invention is as depicted in formula (I) above.
As used herein, the term “alkyl” means a straight or branched alkyl group. Examples of suitable alkyl groups within R
1
and R
2
include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl and 2,2-dimethylpropyl.
As used herein, the term “alkylene” means a straight or branched chain alkylene group containing 1 to 6 carbon atoms e.g. methylene.
As used herein, the term “C
2-6
alkenyl” means a straight or branched chain alkenyl group containing 2 to 6 carbon atoms. Allyl represents an example of a suitable C
2-6
alkenyl group.
The term “halogen” means fluorine, chlorine, bromine or iodine.
By aliphatic heterocyclic group is meant a cyclic group of 4-6 carbon atoms wherein one or more of the carbon atoms is/are replaced by heteroatoms independently selected from nitrogen, oxygen or sulfur. This group may optionally be substituted as defined hereinabove.
The term heterocyclic aromatic group refers to an aromatic mono or bicyclic ring system comprising from 5 to 10 carbon atoms wherein one or more of the carbon atoms is/are replaced by heteroatoms independently selected from nitrogen, oxygen and sulfur, which ring system may optionally be substituted as defined hereinabove.
Pharmaceutically acceptable salts of the compounds of formula (I) include those derived from pharmaceutically acceptable inorganic and organic acids. Examples of suitable acids include hydrochloric, hydrobromic, sulphuric, nitric, perchloric, fumaric, maleic, phosphoric, glycollic, lactic, salicylic, succinic, toluene-p-sulphonic, tartaric, acetic, citric, methanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic and benzenesulfonic acids. A particularly suitable pharmaceutically acceptable salt of the compounds of formula (I) is the hydrochloride salt. Other acids such as oxalic, while not in themselves pharmaceutically acceptable, may be useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts. The solvates may be, for example, hydrates.
R
3
preferably represents a C
1-3
fluoroalkyl group especially a fluoromethyl group. More preferably R
3
represents a trifluromethyl group.
R
2
preferably represents hydrogen, methyl or halogen, more preferably hydrogen, methyl or chlorine.
Conveniently, R
1
may represent (alk)
n
—C
3-6
-cycloalkyl wherein n is 0 or 1 and the said cycloalkyl is either substituted by at least one substituent selected from halogen, particularly fluorine, and OH or is unsubstituted. Preferably, n represents zero. More preferably, the cycloalkyl group is monosubstituted by OH or fluorine. More preferably the cycloalkyl ring has 5 carbon members.
Alternatively R
1
may represent a substituted or unsubstituted aliphatic heterocyclic group, the substitutent being selected from the group consisting of —(CO
2
)—(C
1-4
)alkyl —CO—(C
1-3
)alkyl, —S(═O)
n
—(C
1-3
)alkyl, CONR
a
R
b
wherein R
a
and R
b
are defined herein above, and when there is a heteroatom S in the ring, this heteroatom may optionally be substituted by (═O), where n is 0, 1 or 2. More preferably the heterocyclic ring is unsubstituted or the substituents are —CO
2
(C
1-4
)alkyl, or when the heteroatom is S, the substituent (═O)
n
is attached to the heterocyclic S atom. More preferably, when there is a sulfur heteroatom in the ring this S is unsubstituted.
Conveniently the alphatic heterocyclic group is unsubstituted or when the substituent is —CO
2
(C
1-4
)alkyl the heteroatom is nitrogen and the substituent is attached directly to said ring nitrogen atom.
Preferably the heterocyclic ring is 5 or 6 membered and more preferably contains only one O, N or S heteroatom.
Alternatively, R
1
may represent a straight or branched alkyl of 1-5 carbon atoms optionally with at least one S (═O)
n
where n=0, 1 or 2 and/or N—H substituted in the chain. Where there is an S(═O)
n
in the chain, preferably n is 1 or 2. The alkyl group conveniently may be unsubstituted or substituted by at least one OH group.
Alternatively R
1
may represent a phenyl group which is substituted by one or more substituents selected from OH and halogen. Preferably the phenyl is disubstituted in the

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