Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Reexamination Certificate
1999-01-22
2002-07-09
Killos, Paul J. (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
C560S034000, C514S535000
Reexamination Certificate
active
06417393
ABSTRACT:
The present invention relates to phenyl derivatives which are valuable blockers of chloride channels and as such useful for the treatment of sickle cell anaemia, brain oedema following ischaemia or tumours, diahreea, hypertension (diuretic) and for the reduction of the intraocular pressure for the treatment of disorders such as glaucoma. The compounds of the invention may also be useful in the treatment of allergic or inflammatory conditions and for the promotion of wound healing.
BACKGROUND
Chloride channels serve a wide variety of specific cellular functions and 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, diahreea, hypertension (diuretic) and for the reduction of the intraocular pressure in disorders such as glaucoma.
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 are predicted to 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.
The compounds of the present invention are valuable blockers of chloride channels as determined by concomitant measurements of conductive netfluxes of chloride and membrane potentials in suspensions of erythrocytes, and the compounds are therefore predicted to be useful for the treatment of ailments responsive to the blockade of chloride channels, including sickle cell anaemia.
The use of blockers of chloride channels for the treatment of sickle-cell anaemia form a new therapeutic approach.
Several chloride channel blockers and the use thereof have already been described in the technical literature:
Pflügers Arch (1986), 407 (suppl. 2), pages
128-141 describe several compounds with chloride channel blocking activity. A very potent compound described herein is
5-nitro-2-(3-phenylpropylamino)benzoic acid. The reference do not disclose the use of chloride channel blockers for the treatment of sickle cell anaemia.
U.S. Pat. No. 5,489,612 describes Calixarene derivatives and their use as chloride channel blockers.
U.S. Pat. No. 4.994.493 describes certain 5-nitrobenzoic acid derivatives and their use in the treatment of cerebral oedema.
WO 96/16647 describes the use of chloride channel blockers for the reduction of the intraocular pressure and specifically the use of chloride channel blockers for the treatment of glaucoma.
OBJECTS OF THE INVENTION
It is an object of the present invention to provide a series of phenyl derivatives carrying an acidic group and pharmaceutically acceptable salts thereof which are useful in the treatment of disorders or diseases responsive to the blockade of chloride channels.
Still another object of the present invention is to provide a method of treating disorders or diseases responsive to the blockade of chloride channels, such as for example brain oedema following ischaemia or tumours, diahreea, hypertension (diuretic), glaucoma and in particular sickle-cell anaemia. A further object of the present invention is to provide a method for the treatment of allergic or inflammatory conditions and for the promotion of wound healing.
SUMMARY OF THE INVENTION
The invention then comprises, inter alia, alone or in combination:
A compound having the formula
or a pharmaceutically acceptable salt thereof wherein
one of R
1
, R
2
and R
3
is a non-cyclic acidic group having a pKa value below 8 or a group which is in vivo convertible to such a group; R
4
, R
5
and the other two of the substituents R
1
, R
2
and R
3
are each independently selected from hydrogen; alkyl; cycloalkyl; cycloalkylalkyl; alkenyl; alkynyl; alkoxy; hydroxy; halogen; trifluoromethyl; trifluoromethoxy; cyano; nitro; amino; and aryl, aralkyl, arylamino, aryloxy, aryl-CO—, or heteroaryl, wherein the aryl and heteroaryl groups may be substituted one or more times with substituents selected from alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, hydroxy, alkoxy, halogen, trifluoromethyl, trifluoromethoxy, cyano, nitro and amino; or R
3
and R
4
or R
4
and R
5
together form a fused 4 to 7 membered carbocyclic ring which may be unsaturated, or partially or fully saturated, while the other substituents R
1
, R
2
, R
3
, R
4
and R
5
is as defined above;.
Y is —CO—, —CS—, —SO
2
—, or —C(═N—R
8
)—, wherein R
8
is hydrogen, alkyl, or cyano;
X is —NH—, —CH
2
—NH—, or —SO
2
—NH—;
Z is NR
6
, O, —CH═CH—, —C≡C—, —N═CH—, or —CH═N—; wherein R
6
is hydrogen, or alkyl;
R
11
R
12
, R
13
, R
14
and R
15
are each independently selected from hydrogen; alkyl; cycloalkyl; cycloalkylalkyl; alkenyl; alkynyl; alkoxy; hydroxy; halogen; trifluoromethyl; trifluoromethoxy; cyano; nitro; amino; —NHSO
2
—R
7
, —COOR
7
, —SO
2
N(R
7
)
2
, —SO
2
OR
7
and —CO—R
7
, wherein R
7
is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, aryl or aralkyl; and aryl, aralkyl, arylamino, aryloxy, aryl-CO—, or heteroaryl, wherein the aryl and heteroaryl groups may be substituted one or more times with substituents selected from alkyl, cycloalkyl; cycloalkylalkyl; alkenyl; alkynyl; hydroxy, alkoxy, halogen, trifluoromethyl, trifluoromethoxy, cyano, nitro and amino; or one of R
11
and R
12
, R
12
and R
13
, R
13
and R
14
or R
14
and R
15
together form a fused 4 to 7 membered carbocyclic ring which may be unsaturated, or partially or fully saturated, while the other substituents R
11
, R
12
, R
13
, R
14
and R
15
is as defined above;.
a compound as above wherein one of R
1
, R
2
and R
3
is NH
2
, —COOR
9
, —CH
2
COOR
9
, —CONH
2
, —NHSO
2
—R
9
, —SO
2
N(R
9
)
2
, —SO
2
OR
9
, —PO
3
H
2
, —PO
3
RH, —PO
2
NH
2
, —CONHOH, —CONHCN, —CONH
2
SO
2
R
9
and —CONHNH
2
, wherein R
9
is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, aryl or aralkyl, and the other of R
1
, R
2
and R
3
is as defined above;
a pharmaceutical composition comprising a therapeutically effective amount
Christophersen Palle
Pedersen Ove
Birch & Stewart Kolasch & Birch, LLP
Killos Paul J.
Neurosearch A/S
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