Methods of treating periodontal disease

Details Methods of treating periodontal disease Methods of treating periodontal disease

2002-03-26

2004-08-03

Rose, Shep K. (Department: 1624)

Drug, bio-affecting and body treating compositions

Dentifrices

Ammonia, amine, or derivative thereof

C424S049000

Reexamination Certificate

active

06770267

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to glycol derivatives of xanthines, processes for their preparation, pharmaceutical formulations comprising them, and their use in medicine, particularly in the treatment and prophylaxis of inflammatory conditions, immune disorders, septic shock, circulatory disorders and gastrointestinal inflammation, infection or damage.
BACKGROUND OF THE INVENTION
Leukocyte adhesion to vascular endothelium plays a critical role in the pathogenesis of various diseases. This adhesion is an early and requisite step in the migration of leukocytes into surrounding tissues, and is essential for the initiation and perpetuation of inflammatory and immune disorders. The adhesion process is dependent on the induction or upregulation of adhesion molecules on the endothelium, thereby representing an important target for diseases in which leukocytes contribute significantly to vascular and tissue damage.
The discovery and development of small molecules which specifically block or inhibit the adhesive interactions of leukocytes and the endothelium is an attractive area of therapeutic intervention, particularly for inflammatory diseases. Current antiiflammatory treatments have limited efficacy, often accompanied by severe side-effects. We here describe the discovery of a series of complex esters and amides of selected phenyl xanthine derivatives which, at low concentrations, inhibits the expression of adhesion molecules on cultured human umbilical vein endothelial cells. These compounds are therefore indicated for the treatment of inflammatory conditions, immune disorders, infectious diseases, circulatory disorders, and a number of other conditions in which the adhesion between leukocytes and endothelium plays a major role.
PCT application publication No. WO 9604280 describes compounds of formula:
Wherein m and n are independently integers from 0 to 10;
X and Y are independently oxygen or sulphur;
(—Q—) is (—CH
2
—)
p
or (—CH═CH—)
p
where p is an integer of from 1 to 4; and
A and B are independently methyl, branched C
3-6
alkyl, C
3-8
cycloalkyl or C
3-8
cycloalkenyl;
and salts, solvates and pharmaceutically acceptable esters and amides thereof; and their use in treatment of inflammatory diseases, immune disorders, septic shock, circulatory disorders and gastrointestinal inflammation, infection or damage.
SUMMARY OF THE INVENTION
Accordingly the present invention provides a compound of formula (I):
wherein
Z represents a 5 or 6 membered cycloalkyl, aryl, substituted cycloalkyl, or substituted aryl, said cycloalkyl, aryl, substituted cycloalkyl, or substituted aryl optionally containing one or more heteroatoms selected from O, N or S;
R
1
represents hydrogen or methyl;
R
2
represents hydrogen, C
1-12
alkyl, aryl, or aralkyl;
k represents 0 or 1
n represents an integer of 1 to 50;
X represents —O—, —N(H), —N(C
1-6
alkyl)—, —N(C
3-8
cycloalkyl)—, —N(C
1-8
alkyl)(C
3-8
cycloalkyl), —N[(CH
2
CH
2
O)
m
(C
1-12
alkyl, aryl, or aralkyl)]—, —CH
2
O—, —CH
2
NH—, —CH
2
N(C
1-6
alkyl)—, —CH
2
N(C
3-8
cycloalkyl), or —C
1-12
alkyl—,
m represents 0-12
Q represents (—CH
2
)
p
, (—CH═CH—)
p
, (—C≡C—)
p
, (—(O)
p1
CH
2
—)
p
or (—CH
2
(O)
p1
)
p
where p and p
1
independently represent an integer of from 0 to 4;
y and y′ independently represent integers from 0 to 10;
R
3
represents H, straight or branched C
1-12
alkyl (optionally substituted by phenyl, —CO-phenyl, CN, —CO(C
1-3
)alkyl, —CO
2
(C
1-3
)alkyl, or containing one or more O atoms in the alkyl chain); C
1-6
straight or branched alkenyl (optionally substituted by phenyl, —CO-phenyl, CN, —CO(C
1-3
)alkyl, —CO
2
(C
1-3
)alkyl, or containing one or more O atoms in the alkyl chain); C
1-6
straight or branched alkynyl or a group —C
1-3
alkyl —NR
8
R
9
wherein R
8
and R
9
are independently H, C
1-3
alkyl or together form a 5 or 6 membered heterocyclic group, optionally containing other heteroatoms selected from O, N or S;
R
4
and R
5
independently represent
C
3-8
cycloalkyl
straight chain or branched C
1-6
alkyl
hydrogen
straight or branched C
2-6
alkenyl
aryl or substituted aryl;
heterocyclic group or subsituted heterocyclic group, including heteroaryl and substituted heteroaryl groups;
R
6
and R
7
independently represent O or S;
with the proviso that when
y and y′ both represent 1,
k represents 1,
p
1
represents zero,
R
2
represents H or Me,
R
3
represents H,
X represents O or NH, and
Z represents phenyl
R
4
and R
5
do not both represent cyclohexyl;
or a solvate thereof.
The present invention also provides a compound of formula (Ia):
wherein
Z represents a 5 or 6 membered cycloalkyl, aryl, substituted cycloalkyl, or substituted aryl, said cycloalkyl, aryl, substituted cycloalkyl, or substituted aryl optionally containing one or more heteroatoms selected from O, N or S;
R
1
represents hydrogen or methyl;
R
2
represents hydrogen, C
1-12
alkyl, aryl, or aralkyl;
k represents 0 or 1
n represents an integer of 1 to 50;
X represents —O—, —N(H)—, —N(C
1-6
alkyl)—, —N(C
3-8
cycloalkyl)—, —N[(CH
2
CH
2
O)
m
(C
1-12
alkyl aryl, or aralkyl)]—, —CH
2
O—, —CH
2
NH—, —CH
2
N(C
1-6
alkyl)—, —CH
2
N(C
3-8
cycloalkyl)—, or —C
1-12
alkyl—,
m represents 0-12
Q represents (—CH
2
)
p
, (—CH═CH—)
p
, (—C≡C—)
p
, (—(O)
p1
CH2—)
p
or (CH
2
(O)
p1
)
p
where p and p
1
independently represent an integer of from 0 to 4;
y and y′ independently represent integers from 0 to 10;
R
3
represents H, straight or branched C
1-12
alkyl (optionally substituted by phenyl, —CO-phenyl, CN, —CH(C
1-3
)alkyl, CO
2
(C
1-3
)alkyl, or containing one or more O atoms in the alkyl chain); C
1-6
straight or branched alkenyl, C
1-6
straight or branched alkynyl or a group —C
1-3
alkyl —NR
8
R
9
wherein R
8
and R
9
are independently H, C
1-3
alkyl or together form a 5 or 6 membered heterocyclic group, optionally containing other heteroatoms selected from O, N or S;
R
4
and R
5
independently represent
C
3-8
cycloalkyl
straight chain or branched C
1-6
alkyl
hydrogen
straight or branched C
2-6
alkenyl
aryl or substituted aryl;
heterocyclic group or substituted heterocyclic group, including heteroaryl and substituted heteroaryl groups;
R
6
and R
7
independently represent O or S;
with the proviso that when
y and y′ both represent 1,
k represents 1,
p
1
represents zero,
R
3
represents H,
X represents O or NH, and
Z represents phenyl
R
4
and R
5
do not both represent cyclohexyl;
or a solvate thereof.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, the term “aryl” refers to a carbocyclic group having 6-14 carbon atoms with at least one aromatic ring (e.g., phenyl or biphenyl) or multiple condensed rings in which at least one ring is aromatic, (e.g., 1,2,3,4,-tetrahydronaphthyl, naphthyl, anthryl, or phenanthryl).
As used herein, the term “substituted aryl” refers to aryl optionally substituted with one or more functional groups, e.g., halogen, lower alkyl, lower alkoxyl lower alkylthio, trifluoromethyl, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, hetroaryl, substituted heteroaryl, nitro, cyano, alkylthio, thiol, sulfamido and the like.
As used herein, the term “aralkyl” refers to a C
1-12
alkyl that may be a straight or a branched alkyl group that is substituted by an aryl or substituted aryl group.
As used herein, the term “substituted alkyl” or “substituted cycloalkyl” refers to alkyl or cycloalkyl optionally substituted with one or more functional groups, e.g., halogen, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, hetroaryl, substituted heteroaryl, nitro, cyano, alkylthio, thiol, sulfamido and the like.
As used herein, the term “heterocylic group” refers to a saturated, unsaturated, or aromatic carbocyclic group having up to seven members in a single ring (e.g. imidazolidinyl, piperidyl, piperazinyl, pyrrolidinyl, morpholinyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, pyranyl, furyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, t

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