Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-06-25
1997-09-16
Reamer, James H.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546306, 514869, A61K 3144, C07D21375
Patent
active
056681577
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The present invention is directed toward cyanoguanidine compounds which are potassium channel blockers useful in the treatment of cardiovascular disorders such as congestive heart failure and hypertension. The cyanoguanidine compounds of this invention, unlike other cyanoguanidines, block potassium channel conduction in vascular smooth muscle and in ATP-sensitive potassium channels in apical membranes of the kidney.
It is known that K.sup.+ channels are important for regulating potassium excretion by the kidney and it has been proposed that inhibition of ATP-sensitive K.sup.+ channel conduction in apical cell membranes of the thick ascending limb of Henle's loop would reduce potassium recycling across the membrane and thus reduce sodium resorption via the Na.sup.+ -2Cl.sup.- -K.sup.+ co-transporter. It has also been proposed that inhibition of the ATP-sensitive K.sup.+ channels of apical membranes in principal cells of the initial and cortical collecting tubule would reduce K.sup.+ secretion, the primary source of urinary potassium. K.sup.+ channel antagonist activities necessary to produce the observed eukalemic natriuresis have been documented in the rat kidney.
The subject compounds are effective blockers for the ATP-sensitive potassium channels of the thick ascending limb of Henle's loop and the principal cells of the initial and cortical collecting tubules of the kidney. This activity results in an enhanced urinary excretion of sodium and water without enhanced potassium excretion. This provides a useful diuresis which is not complicated by an undesirable reduction in plasma potassium levels or hypokalemia.
Thus, the subject series of cyanoguanidines, although very closely related to the K.sup.+ channel agonist pinacidil and related compounds, are potent K.sup.+ channel antagonists.
INFORMATION DISCLOSURE STATEMENT
U.S. Pat. No. 4,057,636 discloses pyridylguanidine compounds structurally similar to the subject compounds except that the subject compounds have a multiply substituted pyridine ring and branched methylene linking group to a phenyl which can be optionally substituted. Surprisingly, the subject compounds are potassium channel blockers whereas the compounds of 4,057,636 are potassium channel openers.
Pinacidil, its pyridine N-oxide and its related pyridylcyanoguanidines are a class of compounds structurally related to the subject invention. Articles disclosing these compounds are as follows: Smallwood, J. K., J. Card. Pharm., 12:102-9 (1988); and Peterson, H. J., J. Med. Chem., 21(8):773-81 (1978).
Other publications include, JP 166119, published Jan. 2, 1991, discloses cyanoguanidine derivatives have a branched alkyl group at the C-1 position but no phenyl group attached thereto. GB 055209, Dec. 20, 1974, Leo Pharmaceutical, discloses N-cyano-N'-pyridyl guanidine as hypotensives.
European Patent Application 92104287.5 discloses compounds having a pyridine N-oxide and amine substitutions although not linked to a phenyl.
The state of the art on potassium channel mechanisms and pinacidil is discussed in Annual Reports in Medicinal Chemistry, Robertson D. W., et al. 24, Ch 10, 91-100 (1989).
SUMMARY OF THE INVENTION
In one aspect the present invention is a compound of Formula I and its pharmaceutically acceptable acid addition salts ##STR2## wherein R.sub.1 is hydrogen or methyl; -C.sub.6 alkynyl, C.sub.3 -C.sub.5 cycloalkyl, C.sub.3 -C.sub.5 cycloalkenyl, hydroxymethyl, methoxy C.sub.1 -C.sub.5 alkyl, or R.sub.1 and R.sub.2 are combined to form a C.sub.3 -C.sub.6 carbocyclic ring; -C.sub.4 alkyl, F, Cl, Br, I or CF.sub.3 ; NHCH(CH.sub.3).sub.2, N(CH.sub.3).sub.2, N(C.sub.2 H.sub.5).sub.2, NH(CH.sub.2).sub.m OC.sub.1 -C.sub.3 alkyl, NHC(O)C.sub.1 -C.sub.3 alkyl, F, Cl, Br, C.sub.1 -C.sub.3 alkyl, NH(CH.sub.2).sub.m F, 1-imidazolyl, NHOC.sub.1 -C.sub.3 alkyl, NHOH, NHSO.sub.2 C.sub.1 -C.sub.3 alkyl, SH, SC.sub.1 -C.sub.3 alkyl, NHC(O)OC.sub.1 -C.sub.3 alkyl, NHC(O)NHC.sub.1 -C.sub.3 alkyl, NHSO.sub.2 NHC.sub.1 -C.sub.3 alkyl, NHSO.sub.2 N(C.sub.1 -C.sub.3 alkyl)
REFERENCES:
patent: 4057636 (1977-11-01), Petersen
patent: 5006523 (1991-04-01), Atwal
patent: 5401758 (1995-03-01), Atwal et al.
patent: 5567722 (1996-10-01), Humphrey et al.
G. Giebisch, Eur J Clin Pharmacol (1993) 44 [Suppl 1]:S3-S5, Diuretic action of potassium channel blockers.
Hans Jorgen Peterson, et al, Journal of Medicinal Chemistry, 1978, vol. 21, No. 8, pp. 773-781, Synthesis and Hypotensive Activity of N-Alkyl-n"-cyano-N'-pyridylguanidines.
J.K. Smallwood, et al., Pharm., 12:102-9 (1988).
D.W. Robertson, et al., Annual Reports in Medicinal Chemistry, 24, Ch 10, 91-100 (1989).
Hester, Jr. Jackson B.
Humphrey Stephen J.
Ludens James H.
Meisheri Kaushik D.
Corneglio Donald L.
Pharmacia & Upjohn Company
Reamer James H.
LandOfFree
Cyanoguanidines as K-channel blockers does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Cyanoguanidines as K-channel blockers, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Cyanoguanidines as K-channel blockers will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-218646