Organic compounds -- part of the class 532-570 series – Organic compounds – Chalcogen bonded directly to ring carbon of the purine ring...
Reexamination Certificate
2001-06-01
2002-08-20
Berch, Mark L. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Chalcogen bonded directly to ring carbon of the purine ring...
Reexamination Certificate
active
06437124
ABSTRACT:
The present invention relates to complex esters and amides of phenyl xanthine derivatives, processes for their preparation, pharmaceutical formulations comprising them, and their use in medicine, particularly in the prophylaxis and treatment of septic shock, inflammatory conditions, as well as immune disorders.
Septic shock is induced by means of a complex series of events involving many different pathways and mediators of disease response (see for instance, The Lancet, Vol. 338 (1991), p732-739, and Annals Of Internal Medicine Vol. 115 (1991), p457-469), including, inter alia, products of arachidonic acid metabolism and platelet aggregation.
The adhesion of circulating leukocytes to the vascular endothelium is a crucial event in the pathogenesis of inflammatory responses. Inflammatory and immune mediators can stimulate the adhesion process by increasing the adhesiveness of the leukocyte or the endothelial cell through the activation, upregulation, or induction of various adhesion molecules on the cell surface.
Anti-inflammatory drugs currently available have limited efficacy, often with side effects. Monoclonal antibodies used experimentally for anti-adhesion therapies have theoretical disadvantages for treatment of chronic diseases. Therefore, 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.
PCT Application No. GB 9501808 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 septic shock, allergic, and inflammatory conditions. The compounds had been found to inhibit one or more of the enzymes 5-lipoxygenase, cyclooxygenase, and lyso-PAF: acetyl-CoA acetyltransferase.
We have now surprisingly discovered a series of complex esters and amides of selected phenyl xanthine derivatives which inhibit the expression of adhesion molecules on human umbilical vein endothelial cell (HUVEC) monolayers at very low concentrations and which are therefore indicated for treatment of inflammatory conditions and immune disorders.
DETAILED DESCRIPTION OF THE INVENTION
Accordingly the present invention provides a compound of formula (I):
or a solvate thereof wherein:
X is —O— or —NH—;
Q is (—CH
2
—)
p
, (—CH═CH—)
p
, (—C≡C—)
p
where p is an integer of from 0 to 4;
R
1
is hydrogen or methyl;
R
2
and R
3
independently represent O or S.
n is an integer of 1 to 50; and
R is hydrogen or methyl.
According to a further aspect, the present invention provides a compound of formula (I) as defined above wherein X is —O— or —NH— and R
1
is H; of these, compounds wherein n is an integer of 8 to 20 are preferred, and those wherein n is an integer of 8 to 15 are more preferred.
Conveniently R
3
represents O and R
2
represents O or S but more preferably R
3
and R
2
both represent O.
According to a further aspect of the invention, P preferably represents 0 or 1.
According to a further aspect, the present invention provides a compound of formula (I) as defined above wherein Q is (—CH═CH—)
p
.
Preferably the
substituent is attached to the phenyl ring in the para position.
The invention also includes mixtures of compounds of formula (I) in any ratio, for example wherein n varies within the same sample.
A particular subgroup of compounds is of formula 1a
or a solvate thereof wherein:
X is —O— or —NH—;
Q is (—CH
2
—)
p
or (—CH═CH—)
p
where
P is an interger from 1 to 4;
R
1
is hydrogen or methyl
n is an integer of 1 to 50; and
R is hydrogen or methyl.
Particularly preferred compounds of the invention include
(E)-4-(1,3-Bis(cyclohexylmethyl)-1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl)cinnamic Acid Decaethylene Glycol Methyl Ether Ester;
(E)-4-(1,3-Bis(cyclohexylmethyl)-1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl)cinnamic Acid Nonaethylene Glycol Methyl Ether Ester;
(E)-3-[1,3-Bis(cyclohexylmethyl)-1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl]cinnamic Acid Nonaethylene Glycol Methyl Ether Ester;
(E)-4-[1,3-Bis(cyclohexylmethyl)-1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl)cinnamic acid Nonaethylene Glycol Methyl Ether Amide and
(E)-4-[1,3-Bis(cyclohexylmethyl)-1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl]benzoic acid Nonaethylene Glycol Methyl Ether Ester
or a solvate thereof.
The compounds of the present invention are capable of existing as geometric and optical isomers. All such isomers, individually and as mixtures, are included within the scope of the present invention. Where Q contains a double bond, compounds in the form of the E-geometric isomers are preferred.
As mentioned hereinbefore, compounds of formula (I) and solvates thereof, have use in the prophylaxis and treatment of inflammatory conditions and immune disorders, as demonstrated hereinafter in the biological assays in which representative compounds of the present invention have been shown to be active.
Examples of inflammatory conditions or immune disorders are those of the lungs, joints, eyes, bowel, skin, and heart; particularly those associated with the infiltration of leucocytes into inflamed tissue. Conditions of the lung include asthma, adult respiratory distress syndrome, bronchitis and cystic fibrosis (which may additionally or alternatively involve the bowel or other tissue(s)). Conditions of the joint include rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions. Inflammatory eye conditions include uveitis (including iritis) and conjunctivitis. Inflammatory bowel conditions include Crohn's disease, ulcerative colitis and distal proctitis. Skin diseases include those associated with cell proliferation, such as psoriasis, eczema and dermatitis (whether or not of allergic origin). Conditions of the heart include coronary infarct damage. Other inflammatory conditions and immune disorders include tissue necrosis in chronic inflammation, endotoxin shock, smooth muscle proliferation disorders (for example, restenosis following angioplasty), and tissue rejection following transplant surgery.
Accordingly, the present invention provides a method for the prophylaxis or treatment of an inflammatory condition or immune disorder in a mammal, such as a human, which comprises administration of a therapeutically effective amount of a compound of formula (I), or a pharmaceutically-acceptable solvate thereof. The present invention further provides a method for the prophylaxis or treatment of septic shock in a mammal, such as a human, which comprises administration of a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable solvate thereof
In the alternative, there is also provided a compound of formula (I), or a pharmaceutically acceptable solvate thereof for use in medical therapy; particularly, for use in the prophylaxis or treatment of an inflammatory condition or immune disorder in a mammal, such as a human. The present invention further provides a compound of formula (I), or a pharmaceutically acceptable solvate thereof for use in the prophylaxis or treatment of septic shock.
The amount of a compound of formula (I) or pharmaceutically acceptable solvate thereof, which is required to achieve the desired biological effect will depend on a number of factors such as the use for which it is intended, the means of administration, and the recipient. A typical daily dose for the treatment of septic shock, for instance, may be expected to lie in the range of 0.005 mg/kg-100 mg/kg, preferably 0.5-100 mg/kg, and most preferably 0.5-20 mg/kg. This dose may be administered as a single unit dose or as several separate unit doses or as a continuous infusion. An intravenous dose may be expected to lie in the ra
Daluge Susan Mary
Livingston Douglas Alan
Wolberg Gerald
Berch Mark L.
Morgan Lorie Ann
SmithKline Beecham Corporation
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