Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-12-15
2002-06-11
Jones, Dwayne C. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S252120, C514S255040
Reexamination Certificate
active
06403589
ABSTRACT:
The present invention is concerned with the use of nucleoside transport inhibitors, in particular compounds of formula (I) for the manufacture of a medicament for the treatment of warm-blooded animals, including humans, suffering from chronic pain conditions, such as neuropathic pain.
Nucleoside Transport Inhibition
Nucleoside transport inhibition is a pharmacological activity mainly associated with treatment of problems arising during myocardial ischemia and reperfusion. Indeed adenosine exhibits a multitude of pharmacological properties which makes it particularly suitable for tackling the above mentioned problems. The nucleoside transporter plays a key role in the catabolism and fate of endogenous adenosine, produced in the interstitial space during ischemia. Being located almost exclusively in endothelial cells lining the vasculature, this transporter facilitates diffusion according to the existing gradient. Hence, because of extensive catabolism within these cells, the transporter accelerates adenosine breakdown. In addition, if perfusion prevails or during reperfusion, when the vascular compartment constitutes a major sink, the transporter will carry the adenosine, surviving intra-endothelial metabolism, into the lumen and enhance the washout. Paracellular passage (via clefts in between the endothelial layer) seems to be a very slow process, so that the main escape of adenosine (and inosine) through the endothelial barrier depends on a functioning transporter. While not provoking adenosine formation, inhibition of the transporter will considerably prolong the presence of adenosine at its site of formation by preventing uptake and catabolism in the endothelial cells.
An overview of how nucleoside transport inhibition can be experimentally determined is given in “Comparative pharmacology of nucleoside transport inhibitors” in
Nucleosides and Nucleotides
10:975-982, 1991 (Van Belle H, Janssen P A J).
Known potent nucleoside transport inhibitors are dipyridamole, dilazep, and members of lidoflazine family (e.g. lidoflazine, mioflazine, soluflazine, R 75231 and draflazine, which is the (−)-enantiomer of R 75231).
The only nucleoside transport inhibitor thus far approved for human therapy is dipyridamole. The mean therapeutic uses for dipyridamole are the prophylaxis of angina pectoris and as an antithrombotic.
Other nucleoside transport inhibitors are the compounds of formula (I) as shown hereinafter.
Some compounds of formula (I) are disclosed in the prior art as inhibitors of nucleoside transport through membranes, in particular 3-(aminocarbonyl)-4-[4,4-bis(4-fluoro-phenyl)-butyl]-N-(2,6-dichlorophenyl)-1-piperazineacetamide dihydrochloride monohydrate, generically known as mioflazine, is described in
Molecular Physiology
8:615-630 (1985). In EP-A-0,068,544, published on Jan. 5, 1983, and WO-91/07967, published on Jun. 13, 1991, N-aryl-piperazinealkanamides, in particular S-(−)-2-(aminocarbonyl)-N-(4-amino-2,6-dichlorophenyl)-4-[5,5-bis(4-fluorophenyl)-pentyl]-1-piperazineacetamide, generically known as draflazine, are disclosed as agents useful for protecting the heart from myocardial injury caused by ischaemia or hypoxia. EP-A-0,285,219, published on Oct. 5, 1988, discloses N-aryl-piperazine-alkanamides for improving sleep or counteracting sleep disorders.
In the
European Journal of Pharmacology,
vol 11, no 1, Jul. 1, (1970) Türker et al. disclose lidoflazine significantly increased reaction time of mice to thermal stimulation and increased pain treshold to electrical stimulation of incisor teeth in rabbits, but not of canine teeth in dogs. The pain stimuli used in these models are typically acute pain stimuli. These types of pain are not related to chronic pain conditions, more particularly neuropatic pain.
In the
Eur. J. Pharmacol., Mol. Pharmacol. Sect.,
1989, 273-81, Ijzerman et al introduce a new series of compounds related to the nucleoside transport inhibitors, lidoflazine and mioflazine. The article does not mention any relationship between these compounds and pain, more specifically chronic pain conditions, more particularly neuropathic pain.
In the European Journal of Clinical Pharmacology, 51(1) (1996) 7-13 Andersen et al discuss a randomized, double-blind, placebo-controlled study, wherein the tolerability and safety of draflazine in the treatment of patients with unstable angina was evaluated. The article discloses that the mean duration of chest pain during the 24 hour observation period was 91.4 min in the placebo group (i.e. the group not treated with draflazine) compared to 75.5 min in draflazine treated patients. The chest pain experienced by these patients is not a chronic pain condition, more particularly neuropathic pain.
Surprisingly it has now been found that the compounds of formula (I) are useful for the treatment of warm-blooded animals suffering from chronic pain conditions such as neuropatic pain, inflammatory pain and cancer pain.
The present invention concerns the use of nucleoside transport inhibitors, and especially the compounds of formula
the N-oxide forms, the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof, wherein
R
1
is C
1-4
alkyl, aminocarbonyl or mono- or di(C
1-4
alkyl)aminocarbonyl;
L is a radical of formula
wherein
Ar
1
is phenyl, phenyl substituted with halo or C
1-4
alkyloxy;
Ar
2 y
is phenyl; phenyl substituted with halo, C
1-4
alkyloxy; or pyridinyl;
Alk is C
1-4
alkanediyl;
Ar is a radical of formula
wherein
R
2
and R
3
each independently are halo or C
1-4
alkyl;
R
4
is hydrogen, halo, nitro, amino, mono- or di(C
1-4
alkyl)amino, C
1-4
alkylcarbonylamino, aminocarbonylamino, C
1-4
alkyl, C
1-4
alkyloxy, C
1-4
alkyloxycarbonyl, C
1-4
alkylcarbonyl, aminocarbonyl, mono- or di(C
1-4
alkyl)aminocarbonyl, cyano or aminomethyl;
R
5
is C
1-4
alkylcarbonyl;
R
6
is hydrogen, amino, mono- or di(C
1-4
alkyl)amino, C
1-4
alkylcarbonylamino, aminocarbonylamino, aminocarbonyl or cyano;
R
7
is C
1-4
alkyl;
R
8
is halo or C
1-4
alkylcarbonyl;
R
9
is hydrogen or C
1-4
alkyl;
R
10
is halo or C
1-4
alkyl;
R
11
is hydrogen, hydroxy or C
1-4
alkyl;
R
12
is halo or C
1-4
alkyl;
R
13
is hydrogen or;
R
12
and R
13
taken together may also form a C
3-5
alkanediyl radical;
each R
14
is C
1-4
alkyl; and
R
15
is C
1-4
alkyl or amino;
for the manufacture of a medicine for the treatment of warm-blooded animals suffering from pain.
As used in the foregoing definitions and hereinafter, halo is generic to fluoro, chloro, bromo and iodo; C
1-4
alkyl defines straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, 1-methylethyl, 2-methylpropyl, 2,2-dimethylethyl and the like; C
1-4
alkanediyl defines bivalent straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example, methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl and the like; C
3-5
alkanediyl defines bivalent straight and branched chain saturated hydrocarbon radicals having from 3 to 5 carbon atoms such as, for example, 1,3-propanediyl, 1,4-butanediyl, 1,5-pentanediyl and the like.
The pharmaceutically acceptable acid addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid addition salt forms which the compounds of formula (I) are able to form. The compounds of formula (I) which appear in their free form as a base can be converted in their acid addition salt by treating said free base form with an appropriate acid. Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid; sulfuric; nitric; phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.
Conversely
Meert Theo Frans
Van Belle Herman
Ciambrone Coletti Ellen
Janssen Pharmaceutica N.V.
Jones Dwayne C.
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