Substituted phenyl derivatives, their preparation and use

Details Substituted phenyl derivatives, their preparation and use Substituted phenyl derivatives, their preparation and use

1999-09-30

2001-10-02

Dentz, Bernard (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C361S310000, C361S310000, C361S310000, C544S314000, C546S268400, C548S136000, C548S144000, C548S187000, C548S213000, C548S253000, C548S264200, C548S269400, C548S319500, C548S370100, C549S418000

Reexamination Certificate

active

06297261

ABSTRACT:

The present invention relates to novel substituted phenyl derivatives which are potent chloride channel blockers and as such useful in the treatment of sickle cell anemia, brain oedema following ischaemia or tumours, diarrhoea, hypertension (diuretic), osteoporosis, 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 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 anemia form a new therapeutic approach.
Sickle cell anemia 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, (283-15 288 (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.
The compounds of the present invention are potent blockers of chloride channels as measured by concomitant measurements of conductive netfluxes of chloride and membrane potentials in suspensions of erythrocytes, and the compounds are therefore predicted to be useful in the treatment of sickle-cell disease.
Several chloride channel blockers and the use thereof have already been described:
Pflügers Arch (1986), 407 (suppl. 2), pages 128-141 describes several compounds with chloride channel blocking activity. A very potent compound described herein is 5-nitro-2-(3-phenylpropylamino)benzoic acid. The use of chloride channel blockers for the treatment of sickle cell anaemia is not disclosed herein.
U.S. Pat. No. 4.889.612 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 reduction of the intraocular pressure and specifically the use of chloride channel blockers for the treatment of glaucoma.
The present invention relates to a series of substituted phenyl derivatives which are potent chloride channel blockers, and their use in the treatment of sickle-cell anaemia, for example.
OBJECTS OF THE INVENTION
It is an object of the present invention to provide novel substituted phenyl derivatives 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, diarrhoea, hypertension (diuretic), osteoporosis, glaucoma and in particular sickle-cell anaemia.
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
, R2 and R
3
is a cyclic or heterocyclic acidic functional group having a pKa value below 8 or a group which is convertible in vivo to such a group;
R
4
, R
5
and the two other substituents R
1
, R
2
and R
3
are each independently selected from hydrogen; alkyl; alkoxy; hydroxy; halogen; trifluoromethyl; cyano; nitro; amino; alkylamino; —COOR
7
; —NHSO
2
-alkyl; —SO
2
N(R
7
)
2
; —SO
2
OR
7
; —CO—R
7
; aryl, biphenyl phenylamino, phenoxy or heteroaryl, wherein the aryl, biphenyl, phenylamino, phenoxy or heteroaryl group may be substituted one or more times with substituents selected from alkyl, hydroxy, alkoxy, halogen, trifluoromethyl, cyano, nitro, amino and alkylamino; aryl and heteroaryl, or R
3
and R
4
or R
4
and R
5
together form a cyclic structure and the other substituents R
1
, R
2
, R
3
, R
4
and R
5
is as defined above;
and R
7
is hydrogen, alkyl, amino or phenyl;
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—, —N═CH—, or —CH═N—
R
6
is hydrogen, or alkyl;
R
11
, R
12
, R
13
, R
14
and R
15
are each independently selected from hydrogen; alkyl; alkoxy; hydroxy; halogen; trifluoromethyl; cyano; nitro; amino; alkylamino; —COOR
7
; —NHSO
2
—alkyl; —SO
2
N(R
7
)
2
; —SO
2
OR
7
; —CO—R
7
; aryl, biphenyl, phenylamino, phenoxy or heteroaryl, wherein the aryl, biphenyl, phenylamino, phenoxy or heteroaryl group may be substituted one or more times with substituents selected from alkyl, hydroxy, alkoxy, halogen, trifluoromethyl, cyano, nitro, amino and alkylamino; aryl and heteroaryl, or one of R
11
and R
12
, R
12
and R
13
, R
13
and R
14
and R
14
and R
15
together form a cyclic structure and the other substituents R
11
, R
12
, R
13
, R
14
and R
15
is as defined above and R
7
is as defined above;
a compound as above wherein one of R
1
, R
2
and R
3
is 3-hydroxy-4-oxo-pyranyl, 2-hydroxy-4-oxo-pyrimidyl, 4-hydroxy-1,2,4-triazolyl, 3,5-dioxo-1,2,4-oxadiazolidinyl, 2,4-dioxo-imidazolidinyl, 2,5-dioxo-3-hydroxy-pyrrolyl, 2,5-dioxo-pyrrolidinyl, 2, 4-dioxo-1,3-thiazolidinyl, 3-hydroxy-isoxazolyl, 5-hydroxy-isoxazolyl, 3-hydroxy-isothiazolyl, 3-hydroxy-1,2,5-thiadiazolyl, tetrazolyl, 3-hydroxy-triazolyl, 3-hydroxy-pyrazolyl, 2-hydroxy-1,3,4-oxadiazolyl or 2-hydroxy-3,4-dioxo-cyclobutenyl, 3-oxo-1, 2-dihydro-1,2,4-trizaolyl, 2-oxo-3H-1,3,4-oxadizolyl, 3-oxo-1,2-dihydro-1,2,4-triazolyl; Z is NR
6
and Y is CO;
a compound as above, said compound being:
3-Trifluoromethylphenyl-4-nitro-2-(5-tetrazolyl)phenyl urea;
3-Trifluoromethylphenyl-4-(2-naphthyl)-2-(5-tetrazolyl

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