Synthesis of carboxylic acid derivatives

Details Synthesis of carboxylic acid derivatives Synthesis of carboxylic acid derivatives

1998-05-14

1999-11-16

Kumar, Shailendra

Organic compounds -- part of the class 532-570 series

Organic compounds

Carboxylic acids and salts thereof

546309, 560 39, 560 41, 562565, 562621, 558414, C07C22926

Patent

active

059861320

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to a process for the preparation of biologically active carboxylic acid derivatives, especially matrix metalloproteinase inhibitors, and intermediates for such compounds.


BACKGROUND TO THE INVENTION

Compounds which have the property of inhibiting the action of metalloproteinases involved in connective tissue breakdown such as the collagenases, stromelysins and gelatinases (known as "matrix metalloproteinases", and herein referred to as MMPs) are thought to be potentially useful for the treatment or prophylaxis of conditions involving such tissue breakdown, for example rheumatoid arthritis, osteoarthritis, osteopenias such as osteoporosis, periodontitis, gingivitis, corneal epidermal or gastric ulceration, and tumour metastasis, invasion and growth. It has been found that hydroxamic acid MMP inhibitors can also inhibit the production of the cytokine tumour necrosis factor ("TNF"). Compounds which inhibit the production or action of TNF are thought to be potentially useful for the treatment or prophylaxis of many inflammatory, infectious, immunological or malignant diseases. These include, but are not restricted to, septic shock, haemodynamic shock and sepsis syndrome, post ischaemic reperfusion injury, malaria, Crohn's disease, mycobacterial infection, meningitis, psoriasis, congestive heart failure, fibrotic disease, cachexia, graft rejection, cancer, autoimmune disease, rheumatoid arthritis, multiple sclerosis, radiation damage, toxicity following administration of immunosuppressive monoclonal antibodies such as OKT3 or CAMPATH-1 and hyperoxic alveolar injury.
Metalloproteinases are characterised by the presence in the structure of a zinc(II) ionic site. It is now known that there exists a range of metalloproteinase enzymes that includes fibroblast collagenase (Type 1), PMN-collagenase, 72 kDa-gelatinase, 92 kDa-gelatinase, stromelysin, stromelysin-2 and PUMP-1. Many known MMP inhibitors are peptide derivatives, based on naturally occuring amino acids, and are analogues of the cleavage site in the collagen molecule. Other known MMP inhibitors are less peptidic in structure, and may more properly be viewed as pseudopeptides or peptide mimetics. Such compounds usually have a functional group capable of binding to the zinc (II) site in the MMP, and known classes include those in which the zinc binding group is a hydroxamic acid, carboxylic acid, sulphydryl, and oxygenated phosphorus (eg phosphinic acid and phosphonamidate including aminophosphonic acid) groups.
Two known classes of pseudopeptide or peptide mimetic MMP inhibitors have a hydroxamic acid group and a carboxylic group respectively as their zinc binding groups. With a few exceptions, such known MMPs may be represented by the structural formula (A) ##STR2## in which Z is the zinc binding hydroxamic acid (--CONHOH) or carboxylic acid (--COOH) group and the groups R.sub.1 to R.sub.5 are variable in accordance with the specific prior art disclosures of such compounds. Examples of patent publications disclosing such structures are given below.
The following patent publications disclose hydroxamic acid- and/or carboxylic acid-based MMP inhibitors:


BRIEF DESCRIPTION OF THE INVENTION

One interesting subclass of pseudopeptide hydroxamic- and carboxylic acid-based MMP inhibitors has a hydroxy group as the R.sub.1 substituent of formula (A). These hydroxy-substituted compounds are accessible via the multistage syntheses described in the literature relating to the compounds in question (see, eg, WO 94/02446, WO 94/02447, WO 95/19956 and WO 95/19961). However, the known methods of synthesis are not optimum, and there is a continuing need for new synthetic routes which provide more efficient and/or stereoselective access to these compounds. The present invention provides such a route, based on the reaction between a lactone and an alpha amino acid derivative to prepare an intermediate which may then be further manipulated chemically to provide desired compounds of, for example, type (A) above wherein R.sub.1 is hydroxy, and R

REFERENCES:
Griesbeck et al, Helv. Chim. Acta, pp. 1326-1332, vol. 70, 1987.
Rosenmund et al, Archiv Der Pharmazie, vol. 287, No. 8, pp. 441-446, 1954.

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