Organic compounds -- part of the class 532-570 series – Organic compounds – Nitrogen attached directly or indirectly to the purine ring...
Patent
1995-11-20
1997-05-27
Gupta, Yogendra N.
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitrogen attached directly or indirectly to the purine ring...
544298, 544319, 544325, 544330, C07D23942, C07D23948
Patent
active
056333749
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
This application is a 371 of pct/81593/11332 filed Jul. 21, 1993.
The present invention is directed toward pyrimidine-cyanoguanidine compounds which are potassium channel blockers useful in the treatment of cardiovascular disorders such as congestive heart failure and hypertension. The pyrimidine-cyanoguanidine compounds of this invention, unlike other cyanoguanidines, block potassium channel conduction in vascular smooth muscle and ATP-sensitive potassium channels in apical membranes of 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 branched methylene linking group to a phenyl which can be optionally substituted. Surprisingly, the subject compounds are potassium channel blockers whereas the compounds of U.S. Pat. No. 4,057,636 are potassium channel openers.
Pinacidil, its pyridine N-oxide and 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 at., 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 (where m is 2 or 3), --NHC(O)C.sub.1 -C.sub.3 alkyl, Cl or Br,, and n is 0 or 1.
In another aspect, the subject invention is useful as a potassium channel blocker and can be used in the treatment of cardiovascular disorders such as congestive heart failure, hypertension
REFERENCES:
patent: 4057636 (1977-11-01), Petersen et al.
HJ Petersen, J. Med. Chem., 21(8):773-781, 1978.
JK Smallwood, et al., J. Card. Pharm., 12:102-109, 1988.
DW Robertson, et al., Ann. Reports Med. Chem., 10:91-99, 1989.
Hester, Jr. Jackson B.
Humphrey Stephen J.
Ludens James H.
Meisheri Kaushik D.
Corneglio Donald L.
Gupta Yogendra N.
The Upjohn Company
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