Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-09-28
2001-06-05
Lambkin, Deborah C. (Department: 1613)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C558S145000, C558S169000
Reexamination Certificate
active
06242615
ABSTRACT:
This invention relates to a chemical process and to chemical intermediates useful in such a process.
The chemical process of this invention is useful for preparing compounds which are inhibitors of the production of TNF (Tumour Necrosis Factor) which is believed to be formed by the cleavage of a pro-form, or larger precursor, by the enzyme pro-TNF Convertase. The chemical process of this invention is also useful for preparing compounds which are intermediates in the production of compounds which are inhibitors of the production of TNF.
Compounds which are inhibitors of the production of TNF will be useful in the treatment of disease or medical conditions in which excessive TNF production is known to give rise via a cascade of processes to a variety of physiological sequelae including the production of physiologically-active eicosanoids such as the prostaglandins and leukotrienes, the stimulation of the release of proteolytic enzymes such as collagenase, the activation of osteoclast activity leading to the resorption of calcium, the stimulation of the release of proteoglycans from, for example, cartilage, the stimulation of cell proliferations and to angiogenesis. It is also known that, in certain cellular systems, TNF production precedes and mediates the production of other cytokines such as interleukin-1 (IL-1) and interleukin-2 (IL-2) which are also believed to contribute to the pathology of disease states such as inflammatory and allergic diseases and cytokine-induced toxicity. Excessive TNF production has also been implicated in mediating or exacerbating the development of various inflammatory and allergic diseases such as inflammation of the joints (especially rheumatoid arthritis, osteoarthritis and gout), inflammation of the gastrointestinal tract (especially inflammatory bowel disease, ulcerative colitis and gastritis), skin disease (especially psoriasis, eczema and dermatitis) and respiratory disease (especially asthma, bronchitis and allergic rhinitis), and in the production and development of various cardiovascular disorders such as myocardial infarction, angina and peripheral vascular disease. Excessive TNF production has also been implicated in mediating complications of bacterial, fungal and/or viral infections such as endotoxic shock, septic shock and toxic shock syndrome. Excessive TNF production has also been implicated in mediating or exacerbating the development of adult respiratory distress syndrome, diseases involving cartilage or muscle resorption, Paget's disease and osteoporosis, pulmonary fibrosis, cirrhosis, renal fibrosis, the cachexia found in certain chronic diseases such as malignant disease and acquired immune deficiency syndrome (AIDS), tumour invasiveness and tumour metastasis and multiple sclerosis.
The compounds able to be prepared by the process of this invention may also be inhibitors of one or more matrix metalloproteinases such as collagenases, stromelysins and gelatinases. Thus they may also be of use in the therapeutic treatment of disease conditions mediated by such enzymes for example arthritis (rheumatoid and osteoarthritis), osteoporosis and tumour metastasis.
The present invention relates, more specifically, to a process for preparing compounds of the formula (I):
P
1
OOC—CH(OH)—CHR
1
—CONH—Z (I)
wherein P
1
is hydrogen, a salt forming cation or a protecting group, Z is a group —CHR
2
COOP
2
or —CHR
2
CONR
3
R
4
wherein P
2
is hydrogen or a protecting group and R
1
-R
4
are values known in this structural type of TNF inhibitor.
The compounds of the formula (1), when Z is —CHR
2
CONR
3
R
4
and P
1
is hydrogen or a salt-formling cation are active TNF inhibitors.
The compounds of the formula (I) wherein P
1
is hydrogen or a salt-forming cation may also be converted to the corresponding hydroxamic acid of the formula (II):
HONHCO—CH(OH)—CHR
1
—CONH—Z (II)
wherein R
1
and Z are as hereinbefore defined.
Compounds of the formulae (II) wherein Z is —CHR
2
CONR
3
R
4
are known TNF inhibitors. Compounds of the formula (II) wherein Z is —CHR
2
COOP
2
may be converted to compounds of the formula (II) wherein Z is —CHR
2
CONR
3
R
4
by standard methods.
Compounds of the formnulae (I) and/or (II), wherein Z is —CHR
2
CONR
3
R
4
are disclosed as TNF inhibitors for example in: WO 9633165, WO 961693 1, WO 9606074, WO 9532944, WO 9519961, WO 9519957, WO 9519956, WO 9424140, WO 9402447, WO 9402446, WO 9533709, EPA 497192, EPA 236872, WO 9633176, WO 9633968, WO 9506031 and WO 9522966.
Accordingly the present invention provides a process for preparing a compound of the formula (I) or a salt thereof:
P
1
OOC—CH(OH)—CHR
1
—CONH—Z (I)
wherein P
1
is hydrogen or a protecting group;
Z is a group —CHR
2
COOP
2
or —CHR
2
CONR
3
R
4
wherein P
2
is hydrogen or a protecting group and R
1
-R
4
are values known in the afore-mentioned disclosures, which process comprises reacting a compound of the formula (III):
P
1
OOC—CHL—CHR
1
—COOH (III)
wherein L is a leaving group, with a compound of the formula (IV):
NH
2
Z (IV)
and thereafter if necessary:
i) removing any protecting groups,
ii) forming a salt.
L is a leaving group. Suitably L is a leaving group such as halo, for example chloro, bromo or iodo, or a sulphonyloxy group, such as C
1-6
alkanesulphonyloxy for example methanesulphonyloxy, benzenesulphonyloxy or 4-methylbenzenesulphonyloxy.
The reaction between the compounds of the formulae (III) and (IV) is conveniently performed at a non-extreme temperature for example −25° C. to +50° C. and more conveniently 0° C. to +30° C. and most conveniently at ambient temperature.
The reaction is typically performed in a substantially inert organic solvent for example an aprotic solvent such as acetonitrile or diethyl ether.
The reaction of the compounds of the formulae (III) and (IV) is believed to proceed via the formation of the lactone of the formula (V).
wherein P
1
and R
1
are as hereinbefore defined.
The compound of the formula (IV) acts as a base which is believed to convert the carboxylic acid function of the compound of the formula (III) to a carboxylate anion and which then displaces the leaving group L to form the lactone. The lactone is believed to be ring-opened by nucleophilic attack of the compound of the formula (IV) to form the compound of the formula (I).
Therefore another aspect of the present invention provides a process for preparing a compound of the formula (I) or salt thereof as hereinbefore defined which comprises reacting a lactone of the formula (V) with a compound of the formula (IV) and thereafter, if necessary, removing any protecting groups and/or forming a salt.
The reaction between the compounds of the formulae (IV) and (V) takes place under conditions analogous to those for the reaction of compounds of the formnulae (III) and (IV).
In another aspect the present invention provides a process for preparing a compound of the formula (V) as hereinbefore defined which comprises reacting a compound of the formula (III) with a non-nucleophilic base. In this way the base converts the carboxylic acid function of the compound of the formula (III) to a carboxylate anion which displaces L to form the lactone. However the non-nucleophilic base does not substantially react further with the lactone which may be isolated.
Suitable non-nucleophilic bases include both organic and inorganic bases.
Preferably the base is an inorganic base such as an alkali metal or alkaline earth metal carbonate or bicarbonate for example sodium bicarbonate, potassium carbonate, sodium carbonate or potassium bicarbonate. Suitably the reaction is performed under biphasic conditions with the compound of the formula (III) dissolved in an aprotic organic solvent such as acetonitrile, diethyl ether or dichloromethane which is stirred, typically vigorously, with an aqueous solution of the base at a non-extreme temperature for example at ambient temperature. The reaction may be monitored by thin layer chromatography or any other convenient methodology and, after a suitable period o
Bird Thomas Geoffrey Colerick
Pasquet Marie-Jeanne
Pelleter Jacques
Lambkin Deborah C.
Pillsbury & Winthrop LLP
Zeneca Limited
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