Chemical compounds

Details Chemical compounds Chemical compounds

2000-06-15

2003-04-08

Richter, Johann (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C536S027620, C536S027630

Reexamination Certificate

active

06544960

ABSTRACT:

The present invention relates to novel adenosine derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to their use in medicine.
Thus the 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 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, 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, and 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 by —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
1-6
-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;
With the proviso that, when R
3
represents C
1-6
alkyl, R
2
represents C
1-3
alkyl, R
1
cannot represent phenyl optionally substituted by one or more substituents selected from halogen, C
1-3
alkyl, trifluoromethyl, nitro, cyano, —CO
2
R
c
, —CONR
c
R
d
, —COR
c
, —SOR
e
, —SO
2
R
e
, —SO
3
H, —SO
2
NR
c
R
d
, —OR
c
, —NHSO
2
R
e
, —NHCOR
c
and —NR
c
R
d
;
and salts and solvates thereof, in particular, physiologically acceptable solvates and salts thereof.
Conveniently, the adenosine A1 agonists of general formula (I) above exhibit greater activity at the adenosine receptor than the other adenosine receptor subtypes, particularly A3. More preferably the compounds exhibit little or no activity at the adenosine 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 chain 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 “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.
As used herein the term “alkylene” means a straight or branched chain alkylene group containing 1 to 6 carbon atoms e.g. methylene.
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, methanesulphonic, formic, benzoic, malonic, naphthalene-2-sulphonic and benzenesulphonic 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
alkyl group especially a methyl or ethyl group more preferably methyl.
R
2
preferably represents hydrogen, methyl or halogen, more preferably hydrogen or methyl.
Conveniently, R
1
may represent (alk)
n
- C
5-7
cycloalkyl, including bridged cycloalkyl wherein n is 0 or 1 and the said cycloalkyl is either substituted by at least one substituent selected from halogen, particularly fluorine, —(C
1-3
) alkoxy, particularly methoxy and OH or is unsubstituted. Preferably, when substituted the substituent is fluorine and, the cycloalkyl is mono-substituted. Preferably, n represents zero.
Alternatively R
1
may represent a substituted or unsubstituted aliphatic heterocyclic group, which when substituted, the substitutent being selected from the group consisting Of C
1-3
alkyl, —(CO
2
) —(C
1-4
)alkyl, ═O, —CO—(C
1-3
)alkyl, —S(═O)
n
—(C
1-3
)alkyl (where n is 1 or 2), 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 S is optionally substituted by (═O)
n
where n is 1 or 2. More preferably the substituents are —CO
2
C
(1-4)
alkyl or methyl.
Conveniently the aliphatic heterocyclic group is unsubstituted or when the substituent is —CO
2
(C
1-4)
alkyl the heteroatom is N and the substituent is directly attached to said ring nitrogen atom.
Preferably the heterocyclic ring is 6 membered and more preferably contains only one N, O or S heteroatom.
Alternatively, R
1
may represent a straight or branched alkyl of 1-6 carbon atoms optionally including at least one S (═O)
2
, O or N substituted in the chain. The alkyl group conveniently may be further substituted by at least one group selected from OH, phenyl and fluorine or is unsubstututed.
Alternatively R
1
may represent a phenyl group which is substituted by one or more substituents selected from OH, halogen, (O)
m
(alk)
n
CO
2
R
c
, and -(alk)
n
OH. Preferably the phenyl is disubstituted in the 2,4 positions. Preferably both substituents are halogen more particularly, fluorine and chlorine. For example

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