Calcium channel blockers

Details Calcium channel blockers Calcium channel blockers

1997-12-02

2003-04-01

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...

C514S310000

Reexamination Certificate

active

06541479

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to a class of aromatic compounds which are blockers of calcium channels. The invention also relates to pharmaceutical compositions, methods of blocking calcium channels, kits and methods of treatment using the class of compounds described herein, as well as intermediate compounds useful in the preparation of the compounds.
BACKGROUND OF THE INVENTION
Calcium channel blockers are a chemically diverse class of compounds having important therapeutic value in the control of a variety of diseases including several cardiovascular disorders, such as hypertension, angina, and cardiac arrhythmias (Fleckenstein,
Cir. Res
. v. 52, (suppl. 1), p.13-16 (1983); Fleckenstein,
Experimental Facts and Therapeutic Prospects
, John Wiley, New York (1983); McCall, D.,
Curr Pract Cardiol
, v. 10, p. 1-11 (1985)).
Calcium channel blockers are a heterogenous group of drugs that prevent or slow the entry of calcium into cells by regulating cellular calcium channels. (Remington,
The Science and Practice of Pharmacy
, Nineteenth Edition, Mack Publishing Company, Eaton, Pa., p.963 (1995)). The regulation of calcium entry into the cells of the cardiovascular system is of paramount importance to the proper functioning of this system. Cardiac and vascular smooth muscle cells have calcium channels within the cell membrane. Calcium influx through these channels initiates a process of electromechanical coupling which ultimately leads to muscle contraction. The ability to regulate the entry of calcium into cardiac and vascular smooth muscle cells is a powerful therapeutic approach in the treatment of angina and hypertension respectively. Likewise, blocking calcium influx into cardiac tissues and conduction systems provides a useful approach to control certain types of arrhythmia.
Calcium channel blockers are also believed to be useful in the treatment of other disorders in which the regulation of calcium plays a role in normal hemostasis. Such disorders include, for example, pulmonary hypertension, peripheral vascular disease, mild congestive heart failure, hypertrophic subaortic stenosis, protection against ischemic injury, stroke, migraine, tumor resistance to anti-neoplastic drugs, achalasia, esophageal spasms, bronchial asthma, premature labor, dysmenorrhea, and enhancement of success in renal transplantation. (Remington,
The Science and Practice of Pharmacy
, Nineteenth Edition, Mack Publishing Company, Eaton, Pa., p.963 (1995)).
Most of the currently available calcium channel blockers belong to one of three major chemical groups of drugs, the dihydropyridines, such as nifedipine, the phenyl alkyl amines, such as verapamil, and the benzothiazepines such as diltiazem. While the structure activity relationships (SAR) of the dihydropyridines and the phenyl alkyl amines are well defined and extensively studied, very limited information is available on the SAR of benzothiazepines such as diltiazem. Diltiazem is a chiral molecule, with a seven membered fused-ring system, having a thiazepine, which is fused with a benzene ring. The structure is further characterized by three key functional groups, a 4-methoxybenzyl substituent at position “2”; an actoxy ester at position “3”; and positions “4” and “5” forming an amide function with N,N-dimethylaminoethyl substitution at the amide nitrogen. Scientists at central research laboratory at Osaka, Japan, synthesized a series of potent calcium channel blockers in which the seven membered ring of diltiazem was replaced with 6- and 5-membered fused-ring systems. These two new classes of calcium channel blockers, the benzothiazine and benzothiazole respectively (Yamamoto, K.,
J. Med. Chem
., v. 31, p. 919-930(1988); Fujita, M.,
J. Med. Chem
., v.33, p. 1898-1905 (1990)) demonstrated potent calcium channel blocking activity. Some of these compounds even demonstrated more tissue selectivity toward calcium channels in blood vessels.
SUMMARY OF THE INVENTION
A new family of calcium channel blockers, which are defined by the structures set forth below, have been identified according to the invention. The members of the new family of compounds constitute a new class of calcium channel blockers which is not encompassed by any of the three known classes of calcium channel blockers, the dihydropyridines, the phenyl alkyl amines, or the benzothiazepines. Of the three known classes the compounds of the invention are most structurally similar to the benzothiazepine class of calcium channel blockers, which have the following structural formula.
Prior to the instant invention it was believed that the fused ring structure of the benzothiazepines was essential for the calcium channel blocking activity of these compounds. Applicants, however, have surprisingly discovered that compounds having the basic central atomic structure of the benzothiazepines but lacking the fused ring structure have calcium channel blocking activity and actually demonstrate comparable anti-hypertensive activity to traditional benzothiazepines such as diltiazem.
In one aspect the invention is a composition of a compound having the following structural formula:
Ar
1
—X—Ar
2
wherein Ar
2
is an aryl group or a heteroaryl group, wherein the heteroaryl is a ring having 5, 6, or 7 atoms, and wherein at least one atom of the heteroaryl is selected from the group consisting of a sulfur, a nitrogen, and an oxygen atom, and which is substituted with R
1
, R
2
, R
3
, R
4
, and R
5
;
wherein Ar
1
is an aryl group or a heteroaryl group,wherein the heteroaryl is a ring having 5, 6, or 7 atoms, and wherein at least one atom of the heteroaryl is selected from the group consisting of a sulfur, a nitrogen, and an oxygen atom, and which is substituted with R
6
, R
7
, R
8
, R
9
, and R
10
;
wherein R
1
, R
2
, R
3
, R
4
, R
5
, R
7
, R
8
, R
9
, and R
10
independent of one another, are selected from the group consisting of —H, halogen, piperonyl, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkenyl, (C
1
-C
6
)alkynyl, (C
1
-C
6
)alkoxy —CN, —OR′, —SR′, —NO
2
, —NR′R′, amino acid, —C(O)R′, —C(S)R′, —C(O)OR′, —C(S)OR′, —C(O)SR, —C(S)SR′, —C(O)N(R′)
2
, —C(O)C(O)R′, —C(S)C(O)R′, —C(O)C(S)R′, —C(S)C(S)R′, —C(O)C(O)OR′, —C(S)C(O)OR′, —C(O)C(S)OR′, —C(O)C(O)SR′, —C(S)C(S)OR′, —C(S)C(O)SR′, —C(O)C(S)SR′, —C(S)C(S)SR′, —C(O)C(O)N(R′)
2
, —C(S)C(O)N(R′)
2
, —C(O)C(S)N(R′)
2
, or —C(S)C(S)N(R′)
2
;
wherein R
6
is in the ortho position and is selected from the group consisting of —CO—NH—(CH
2
)
2-5
NH
2
, —CO—NH—(CH
2
)
2-5
NH—(CH
2
)
z
—H, —CO—NH(CH
2
)
2-5
NR
15
(CH
2
)
z
—H, —CO—R′, —CO—OR′, —CO—SR′, —CO—N(R′)
2
, —CO—CO—R′, —CO—CS—R′, —CO—CO—OR′, —CO—CS—OR′, —CO—CO—SR′, —CO—CS—SR′, —CO—CO—N(R′)
2
, —CO—CS—N(R′)
2
, —NH—CO—NH—(CH
2
)
2-5
NH
2
, —NH—CO—NH—(CH
2
)
2-5
NH—(CH
2
)
z
—H, —NH—CO—NH(CH
2
)
2-5
NR
15
(CH
2
)
z
—H, —NH—CO—R′, —NH—CO—OR′, —NH—CO—SR′, —NH—CO—NO
2
, —NH—CO—N(R′)
2
, —NH—CO—CO—R′, —NH—CO—CS—R′, —NH—CO—CO—OR′, —NH—CO—CS—OR′, —NH—CO—CO—SR′, —NH—CO—CS—SR′, —NH—CO—CO—N(R′)
2
, and —NH—CO—CS—N(R′)
2
,
wherein each R′ is (CH
2
)
z
—NR″R″ and wherein R″ is independently selected from the group consisting of (C
1
-C
6
)alkyl, (C
1
-C
6
)alkenyl, (C
1
-C
6
)alkoxy, (C
1
-C
6
)alkynyl, (C
6
-C
20
)aryl, (C
6
-C
20
)substituted aryl, (C
6
-C
26
)alkaryl, substituted (C
6
-C
26
)alkaryl, and (C
5
-C
7
)heteroaryl wherein at least one atom of the heteroaryl is selected from the group consisting of a sulfur, a nitrogen, or an oxygen atom, wherein the aryl and alkaryl substituents are each independently selected from the group consisting of hydrogen, halogen, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkenyl, (C
1
-C
6
)alkynyl and trihalomethyl;
wherein z is 1-6;
wherein R
15
is selected from the group consisting of halogen, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkenyl, (C
1
-C
6
)alkynyl, and

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