Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-04-28
2001-01-16
Jones, Dwayne C. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S326000, C514S422000, C514S428000
Reexamination Certificate
active
06174898
ABSTRACT:
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a 35 U.S.C. 371 national application of PCT/DK96/00453 filed Oct. 31, 1996 and claims priority under 35 U.S.C. 119 of Danish application 1230/95 filed Nov. 3, 1995, the contents of which are fully incorporated herein by reference.
FIELD OF THE INVENTION
The present invention relates to the use of N-substituted azaheterocyclic carboxylic acids and esters thereof in which a substituted alkyl chain forms part of the N-substituent and salts thereof in the clinical treatment of filariae in the lymphatic system.
BACKGROUND OF THE INVENTION
Of the six major tropical diseases (filariasis, schistosomiasis, malaria, leishmaniasis, trypanosomiasis and leprosy) recognized by WHO as the main cause of morbidity, mortality and poor socio-economic growth in the tropics, filariasis is one of the most widespread and debilitating diseases of humans.
Filariasis is a helminthic infection caused by a number of slender and thread-like nematodes which invade blood circulation, lymphatics, lymph nodes, connective and subcutaneous tissues, peritoneal cavities and other parts of the human body.
The disease is transmitted to man by a large variety of hematophagous arthropods, often mosquitoes and flies, which introduce a large number of infective larvae in blood circulation while feeding on the human blood. The female worms produce microfilariae which make their way to blood circulation and subcutaneous tissues from where they are taken up by a suitable insect vector. On reaching the insect's body, the microfilariae (first stage larvae, Li larvae) undergo several moultings to form infective larvae (L3 larvae) which reach the blood circulation of the definite host through the bites of the insect. Soon the infective larvae enter into lymphatic system and connective tissues where they slowly mature into adult male and female worms. The male and female adult mate to produce microfilariae which find their way to peripheral blood circulation.
It is estimated that nearly 300 to 400 million people around the world are infected with different forms of filariasis and many more are living at the risk of acquiring such infections.
The clinical manifestations of lymphatic filariasis are characterized by three phases:
(1) Inflammatory, leading to high fever, chills, vomiting, malaise, enlargement of lymph nodes, pain and swelling in the testes and thickening of spermatic cord.
(2) Obstructive, causing blockade of the lymphatic circulation which slowly leads to hydrocele and chyluria.
(3) Elephantiasis, marked by massive enlargement of legs, arms, scrotum and breasts.
The early stage of onchocerciasis (river blindness) is marked by skin rash and persistent pruritis (onchodermatitis) followed by pachydermia over thighs and buttocks. Later the patient may develop pain in the eyes, photophobia, lacrimation and edema of eyelids which slowly leads to chronic conjuctivitis; finally the patient loses vision. River blindness thus poses a serious problem in many parts of the African continent causing loss of vision and blindness due to damage of cornea, iris and pupil by entrance of microfilariae into the eyeball of a large number of patients every year.
In recent years much pharmacological research concerning y-aminobutyric acid (hereinafter designated GABA), an inhibitory neurotransmitter in the mammalian central nervous system, has been carried out. As a result, much interest has been focused on the various potential pharmacological approaches to the enhancement of GABA'ergic function in humans, for example, by the direct agonism on GABA receptors, the inhibition of enzymatic breakdown of GABA, or by the inhibition of the uptake of GABA into neuronal and glial cell bodies. Recently, the discovery of high levels of GABA in microfilariae suggested the existence of GABA receptors in such organisms, thereby creating a new field of interest in filariae therapeutics by GABA'ergic compounds (J. Pharm. Pharmacol. 1989, 41, 191). It has been shown that filariae are sensitive (paralysis or death) to high concentrations of GABA inside the parasite. However, the passage of GABA through the parasite cuticle is poor due to its relatively polar nature excluding this compound as a therapeutic. The obvious modification by preparation of the more lipophilic prodrug esters of GABA has been investigated (J. Pharm. Pharmacol. 1989, 41, 191). A different approach to enhancement of GABA'ergic function inside the parasite is the embodiment of this invention where compounds known as lipophilic GABA uptake inhibitors now has been shown to exhibit paralysis and death of such parasites. Furthermore, the compounds of the invention has been found to be orally active.
DESCRIPTION OF THE INVENTION
The method of this invention comprises administering to a patient suffering from filariae in the lymphatic system an effective amount of a compound of formula I
wherein A is
wherein R
1
and R
2
independently are furanyl, imidazolyl, oxazolyl, phenyl, pyrazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, thiazolyl, thienyl or triazolyl wherein each aromatic ring is optionally substituted with one, two or three substituents selected from —NR
8
R
9
, C
1-8
-alkylthio, C
1-6
-alkoxy, azido, cyano, halogen, hydroxy, C
1-6
-alkyl, nitro, mercapto or trifluoromethyl; and
X is —CH
2
—, —O— or —N(R
3
)— wherein R
3
is hydrogen or C
1-6
-alkyl; and
R
4
is hydrogen or C
1-6
-alkyl; and
m is 1 or 2; and
n is 1 when m is 1 and n is 0 when m is 2; and
R
5
and R
6
each represents hydrogen or may when m is 2 together represent a bond; and
R
7
is hydroxy or C
1-6
-alkoxy; and
R
8
and R
9
independently are hydrogen or C
1-6
-alkyl; and
p is 0, 1, 2 or 3; and
q is 0, 1 or 2; and
r is 0, 1 or 2; or a pharmaceutically acceptable salt thereof.
The compounds according to the invention may optionally exist as pharmaceutically acceptable acid addition salts or—when the carboxylic acid group is not esterified—as pharmaceutically acceptable metal salts or—optionally alkylated—ammonium salts.
Examples of such salts include inorganic and organic acid addition salts such as hydrochloride, hydrobromide, sulphate, phosphate, acetate, fumarate, maleate, citrate, lactate, tartrate, oxalate, or similar pharmaceutically acceptable inorganic or organic acid addition salts, and include the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 66, 2 (1977) which are hereby incorporated by reference.
The compounds of formula I may exist as geometric and optical isomers and all isomers and mixtures thereof are included herein. Isomers may be separated by means of standard methods such as chromatographic techniques or fractional crystallization of suitable salts.
As used herein, the term patient includes any mammal which could benefit from treatment of filariae in the lymphatic system. The term particularly refers to a human patient, but is not intended to be so limited.
The compounds used in the presently claimed invention and methods of preparing them have been disclosed and claimed in EP Appl. no. 89108850.2, EP appl. no. 89123400.7 and EP appl. no. 90917178.7 herein incorporated by reference in their entirety. In these references there is no disclosure of using the compounds to treat filariae.
It has been demonstrated that compounds of formula I possess useful pharmacological properties, in that they cause paralysis and death of filariae. Compounds of formula I may be used to treat, for example, lymphatic filariasis, onchocerciasis and loasis in man.
Pharmacological Methods
Values for the filaricidal activity of the invention compounds were assessed essentially by the method of Deverre et al (J. Pharm. Pharmacol. 1989, 41, 191).
Microfilariae (
Brugia Pahangi
or
Acanthocheilonema vitae
) were obtained from the peritoneal cavity of infected gerbils by lavage with the incubation medium (HEPES-buffered RPMI 1640 supplemented with 50 &mgr;g of gentamycin/ml).
The assays were performed in flat-bottomed 96 well trays. Each well contained approximately 100 microfilariae in 15
Andersen Knud Erik
Weis Jan Ulrik
Jones Dwayne C.
Lambiris Esq. Elias J.
Novo Nordisk A S
Zelson, Esq. Steve T.
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