Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-03-08
2002-07-02
Higel, Floyd D. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S381000, C514S384000, C548S265800, C548S253000, C548S144000
Reexamination Certificate
active
06413996
ABSTRACT:
The present invention relates to novel phenyl derivatives which are potent chloride channel blockers and as such useful in the treatment of sickle cell anaemia, brain oedema following ischaemia or tumours, diarrhoea, hypertension (diuretic), osteoporosis, bone metastasizing cancers and for the reduction of the intraocular pressure for the treatment of disorders such as glaucoma.
BACKGROUND
Chloride channels serve a wide variety of specific cellular functions. Thus, chloride channels contribute to the normal function of skeletal and smooth muscle cells. Blockers of chloride channels are known to be useful in the treatment of brain oedema following ischaemia or tumours, diarrhoea, hypertension (diuretic), osteoporosis, bone metastasizing cancers, and for the reduction of the intraocular pressure in disorders such as glaucoma. The compounds of the invention may also be useful in the treatment of allergic and inflammatory conditions and for the promotion of wound healing.
The use of blockers of chloride channels for the treatment sickle-cell anaemia form a new therapeutic approach.
Sickle cell anaemia and the existence of sickle haemoglobin was the first genetic disease to be understood at the molecular level. The genetic defect underlying sickle cell anaemia causes the substitution of a single amino acid resulting in a mutant haemoglobin, sickle haemoglobin.
The physical manifestations of sickle cell disease is anaemia and painful ischaemic crises due to occlusion of the microcirculation by deformed erythrocytes (sickle cells). The primary cause of sickle erythrocyte deformation and distortion (or sickling) is a reversible polymerisation and gelation of sickle haemoglobin induced at the low oxygen tensions prevalent in metabolically active tissues. Sickle cells are also characterised by an enhanced cation permeability, resulting in cation depletion and cellular dehydration. Since the delay time for the polymerisation has been described as an extremely steep function of the sickle haemoglobin concentration itself, any decrease in cell volume will greatly increase the probability of sickling and thereby of vessel occlusion. Compounds which blocks the deoxygenation induced salt and volume (water) loss may delay the sickling process enough to avoid occlusion upon the passage of the sickle erythrocyte through metabolically active tissue. It has been estimated that a delay time of only 10 sec may suffice.
Several membrane ion channels and transporters present in normal erythrocytes has been suggested to participate in the altered membrane permeabilities of sickle cells. The favoured hypothesis has been stimulation of the Ca
2+
-activated K
+
-channel and several blockers of this channel has been suggested as therapeutic agents for the treatment of sickle-cell anaemia ( Effects of Cetiedil on Monovalent Cation Permeability in the Erythrocyte: An explanation for the Efficacy of Cetiedil in the treatment of Sickle Cell Anaemia, Berkowitz, L. R., Orringer, E. P., Blood cells, (283-288 (1982) and U.S. Pat. No. 5.273.992).
Since, K
+
efflux through a K-channel must be followed by an equal efflux of Cl
−
to maintain electroneutrality, blockade of erythrocyte chloride channels should be as effective as blocking the K-channels itself. An advantage to the use of chloride channel blockers is that salt loss which may occur due to activation of unknown K-channel types will indirectly be blocked too.
Osteoporosis and other osteoclast associated disorders.
The bone tissue is constantly renewed by the controlled activity of two cell types, osteoblasts, which lay down the new bone mass, and osteoclasts, which degrade and reabsorb the bone tissue by secretion of proteolytic enzymes such as cathepsin as well as acid, in particular HCl onto the bone surface. In osteoporosis the balance between the degradation and the synthesis is severely disturbed, which results in a progressive loss of bone material and gradual weakening of the skeleton. Clinically, hormone replacement studies has shown that the decline in estrogen levels at the onset of menopause is an important hormonal factor for the triggering of the disease.
In vitro studies has shown that the osteoclasts are important targets cells for estrogen (i.e. Mano et al., 1996) and that the hormone inhibits the bone reabsorbing activity of osteoclasts via induction of osteoclast apoptosis (Kameda et al., 1997) and/or via altered resorbtion capacity of the individual cells. Thus, the major estrogene effect on bone metabolism seems to be an inhibition of bone degradation by a direct effect on the osteoclasts.
Osteoclast physiology
As an alternative to hormone replacement down regulation of osteoclast acid producing activity by modulators of membrane transporters is an attractive, but hitherto clinical untested possibility. The physiological process whereby the osteoclast secrete HCl—a key event in bone reabsorbtion—is relatively well understood and is conceptually similar to epithelial transport. Like epithelia cells osteoclasts are morphologically highly polarised cells with membrane transporters asymmetrically distributed between the bone-facing ruffled membrane and the smooth outer membrane. At the border between the ruffled and smooth membrane segments the osteoclast is tightly attached to the bone surface, thus creating a sealed cavity between the cell and the bone surface. Pits are formed beneath the cavity the as a result of HCl-induced demineralisation and enzymatic break-down of the bone matrix. The ultimate event in the osteoclast HCl secretion across the ruffled membrane is an active transport of H
+
by a vacuolar-type proton pump and a passive transport of Cl
−
mediated via an outwardly rectifying Cl-channel. Due to HCl secretion the intracellular pH tend to increase and Cl
−
i
tend to decrease, which—if allowed to occur—would quickly lead to cessation of acid secretion. Osteoclasts posses two important back-up systems aimed at maintaining a constant supply of intracellular H
+
and Cl
−
for the ruffled membrane transporters. First, the cell contains very high concentrations of the cytosolic enzyme carbonic anhydrase II, which catalyses the slow normally quite slow hydration of CO
2
to H
2
CO
3
, a molecule which spontaneously dissociate to form H
+
and HCO
−
3
. Second, the osteoclast outer membrane is packed with transporters (AE2), which mediate obligatory Cl
−
/HCO
−
3
exchange. Hence, HCO
−
3
produced by the carbonic anhydrase exzyme is exchanged with extracellular Cl
−
. Apart from erythrocytes, osteoclasts are the mammalian cell type with the highest expression level of this protein.
In conclusion, the proton pump and the Cl-channel are fed by H
+
and Cl
−
, respectively, via the concerted activity of the carbonic anhydrase and the anion exchanger.
Possible pharmacological intervention
In principle, any of the four proteins described above which are directly involved in the transcellular secretion of HCl are valid targets for interference with the resorptive properties of osteoclasts.
Direct block of the proton pump is achievable with the antibiotic bafilomycin A1, which is an extremely potent, reversible inhibitor, whereas omeprazol—an irreversible inhibitor of the proton pump responsible for acid production in the stomac—is ineffective. In vitro bafilomycin A1 completely eliminates bone resorbtion in the bone slice assay pit formation test (Ohba et al, 1996). In vivo the compound depresses bone degration in growing young rats (Keeling et al, 1997). The general applicability of the compound is limited due to its toxicity, which may be due to undesired inhibition of proton pumps in other areas of the body. Subtypes of the vacuolar proton pump exists, however it is not known if it will be possible to obtain pharmacological selectivity between these isoforms.
Inhibition of the carbonic anhydrase enzyme with acetacolamide is effective in vitro in the pit formation assay (Ohba et al, 1996). Various inhibitors of the kidney carbonic anhydr
Christophersen Palle
Dahl Bjarne H.
Birch & Stewart Kolasch & Birch, LLP
Higel Floyd D.
Neurosearch A/S
Small Andrea D.
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