Calcium channel blockers

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

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Details

C514S255030, C514S315000

Reexamination Certificate

active

06294533

ABSTRACT:

TECHNICAL FIELD
The invention relates to compounds useful in treating conditions associated with calcium channel function. More specifically, the invention concerns compounds containing benzhydril and 6-membered heterocyclic moieties that are usefull in treatment of conditions such as stroke and pain.
BACKGROUND ART
Native calcium channels have been classified by their electrophysiological and pharmacological properties as T, L, N, P and Q types (for views see McCleskey, E. W. et al.
Curr Topics Membr
(1991) 39:295-326, and Dunlap, K. et al.
Trends Neurosci
(1995) 18:89-98). T-type (or low voltage-activated) channels describe a broad class of molecules that transiently activate at negative potentials and are highly sensitive to changes in resting potential. The L, N, P and Q-type channels activate at more positive potentials (high voltage activated) and display diverse kinetics and voltage-dependent properties. There is some overlap in biophysical properties of the high voltage-activated channels, consequently pharmacological profiles are usefull to further distinguish them. L-type channels are sensitive to dihydropyridine agonists and antagonists, N-type channels are blocked by the
Conus geographus
peptide toxin, &ohgr;-conotoxin GVIA, and P-type channels are blocked by the peptide aagatoxm IVA from the venom of the funnel web spider,
Agelenopsis aperta
. A fourth type of high voltage-activated calcium channel (Q-type) has been described, although whether the Q- and P-type channels are distinct molecular entities is controversial (Sather, W. A et al.
Neuron
(1995) 11:291-303; Stea, A. et al.
Proc Natl Acad Sci USA
(1994) 91:10576-10580; Bourinet, E. etal.
Nature Neuroscience
(1999) 2:407415). Several types of calcium conductances do not fall neatly into any of the above categories and there is variability of properties even within a category suggesting that additional calcium channels subtypes remain to be classified.
Biochemical analyses show that neuronal high voltage activated calcium channels are hetero oligomeric complexes consisting of three distinct subunits (&agr;
1
, &agr;
2
&dgr; and &bgr;) (reviewed by De Waard, M. et at.
Ion Channels
(1997) vol. 4, Narahashi, T. ed. Plenum Press, NY). The &agr;
1
subunit is the major pore-forming subunit and contains the voltage sensor and binding sites for calcium channel antagonists. The mainly extracellular &agr;
2
is disulfide-linked to the transmembrane &dgr; subunit and both are derived from the same gene and are proteolytically cleaved in vivo. The &bgr; subunit is a nonglycosylated, hydrophilic protein with a high affinity of binding to a cytoplasmic region of the &agr;
1
subunit. A fourth subunit, &ggr;, is unique to L-type calcium channels expressed in skeletal muscle T-tubules. The isolation and characterization of &ggr;-subunit-encoding cDNAs is described in U.S. Pat. No. 5,386,025 which is incorporated herein by reference.
Recently, each of these &agr;
1
subtypes has been cloned and expressed, thus permitting more extensive pharmacological studies. These channels have been designated &agr;
1A
-&agr;
1I
and &agr;
1S
and correlated with the subtypes set forth above. &agr;
1A
channel s are of the P/Q type; &agr;
1B
represents N; &agr;
1C
, &agr;′
1D
, &agr;
1F
and acs represent L; &agr;
1E
represents a novel type of calcium conductance, and &agr;
1G-&agr;
1I
represent members of the T-type family, reviewed in Stea, A. et al. in Handbook of Receptors and Channels (1994), North, R. A. ed. CRC Press; Perez-Reyes, et al.
Nature
(1998) 391:896-900; Cribbs, L. L. et al.
Circulation Research
(1998) 83:103-109; Lee, J. H. et al.
Journal of Neuroscience
(1999) 19:1912-1921.
U.S. Pat. No. 5,646,149 describes calcium antagonists of the formula A—Y—B wherein B contains a pipelazine or piperidine ring directly linked to Y. An essential component of these molecules is represented by A, which must be an antioxidant; the pipeazine or piperidine itself is said to be important. The exemplified compounds contain a benzhydril substituent, based on known calcium channel blockers (see below). U.S. Pat. No. 5,703,071 discloses compounds said to be useful in treating ischemic diseases. A mandatory portion of the molecule is a tropolone residue; among the substituents permitted are piperazine derivatives, including their benzhydril derivatives. U.S. Pat. No. 5,428,038 discloses compounds which are said to exert a neural protective and antiallergic effect. These compounds are coumarin dervatives which may include derivatives of piperazine and other six-membered heterocycles. A permitted substituent on the heterocycle is diphenylhydroxymethyl. Thus, approaches in the art for various indications which may involve calcium channel blocking activity have employed compounds which incidentally contain piperidine or piperazine moieties substituted with benzhydril but mandate additional substituents to mantain functionality.
Certain compounds containing both benzhydril moieties and piperidine or piperazine are known to be calcium channel antagonists and neuroleptic drugs. For example, Gould, R. J. et al.
Proc Natl Acad Sci USA
(1983) 80:5122-5125 describes antischizophrenic neuroleptic drugs such as lidoflaine, fluspirilene, pimozide, clopimozide, and penfluridol. It has also been that fluspirilene binds to sites on L-type calcium channels (King, V. K. et al.
J Biol Chem
(1989) 264:5633-5641) as well as blockdng N-type calcium cuerent (Grantm C. J. etal.
Brit J Pharmacol
(1944) 111:483-488). In addition, lomerizine, as marketed by Kenebo K K, is a known calcium channel blocker. A review of publications concerning lomeriine is found in Dooley, D., Current
Opinion in CPNS Investigational Drugs
(1999) 1:116-125.
The present invention is based on the recognition that the combination of a six-membered heterocyclic ring contaiing at least one nitrogen coupled optionally through a linker to a benzhydril moiety not only results in calcium channel blocking activity, but also enhanced specificity for N-type channels, thus making these compounds particularly useful for treating stroke and pain. By focusing on these moieties, compounds useful in treating indications associated with excessive calcium channel activity and combinatorial libraries that contain these compounds can be prepared.
DISCLOSURE OF THE INVENTION
The invention relates to compounds usefull in treating conditions such as stroke, chronic and acute pain, epilepsy, hypertension, cardiac arrhytmias, and other indications associated with calcium metabolism. The compounds of the invention are benzhydril derivatives of piperidine, piperazine, or morpholine with substituents which enhance the calcium channel blocking activity of the compounds but do not contain substituents that are antioxidants, tropholones or coumarins. Thus, in one aspect, the invention is directed to therapeutic methods that employ compounds of the formula
wherein m is 0, 1 or 2;
wherein when m is 0, Z is O, when m is 1, Z is N, and when m is 2, Z is C;
Y is H, OH, NH
2
, or an organic moiety of 1-20C, optionally additionally containing 1-8 heteroatoms selected from the group consisting of N, P, O, S and halo;
each 1
1
and 1
2
is independently
0-5;
1
3
is 0 or 1;
each of R
1
, R
2
and R
3
is independently alkyl (1-6C), aryl (6-10C) or arylalkyl (7-16C) optionally containing 14 heteroatoms selected from the group consisting of halo, N, P, O, and S or each of R
1
and R
2
may independently be halo, COOR, CONR
2
, CF
3
, CN or NO
2
, wherein R is H or lower alkyl (1-4C) or alkyl (1-6C);
n is 0 or 1;
X is a linker,
with the proviso that Y is not a tropolone, a coumarin, or an antioxidant containing an aromatic group and with the fuirther proviso that if 1
3
is 0, neither R
1
nor R
2
represents F in the para position.
The invention is direct to methods to antagonize calcium channel activity using the compounds of formula (1) and thus to treat associated conditions. It will be noted that the conditions may be associated with abnormal calcium channel activity, or the subject may have no

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