Pyrimidine, cyanoguanidines as K-channel blockers

{
  "publication_number": "US5633374A",
  "country": "US",
  "kind": "A",
  "title": "Pyrimidine, cyanoguanidines as K-channel blockers",
  "abstract": "PCT No. PCT/US93/11332 Sec. 371 Date Nov. 20, 1995 Sec. 102(e) Date Nov. 20, 1995 PCT Filed Jul. 21, 1993 PCT Pub. No. WO94/29280 PCT Pub. Date Dec. 22, 1994Pyrimidine-cyanoguanidine compounds of Formula I and its pharmaceutically acceptable acid addition salts wherein R1 is hydrogen or methyl; R2 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C5 cycloalkyl, C3-C5, hydroxy methyl, cycloalkyl methoxy-C1-C5 alkyl, or R1 and R2 are combined to form a C3-C6 carbocyclic ring; R3 and R4 are each independently selected to be hydrogen, C1-C4 alkyl, F, Cl, Br, I or CF3; R5 is hydrogen, F or Cl; R6 is hydrogen, -NH2, -NHCH3, -NHC2H5, -NHCH(CH3) 2, -N(CH3)2, -N(C2H5)2, NH(CH2)m-OC1-C3 alkyl (where m is 2 or 3), -NHC(O)C1-C3 alkyl, Cl or Br; and n is 0 or 1. The compounds of Formula I are potassium channel blockers useful in the treatment of cardiovascular disorders such as congestive heart failure and hypertension and as a diuretic.",
  "claims": [
    "1. A compound of Formula I and its pharmaceutically acceptable acid addition salts ##STR5## wherein R 1 is hydrogen or methyl; R 2 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 5 cycloalkyl, C 3 -C 5 cycloalkenyl, hydroxy methyl, methoxy-C 1 -C 5 alkyl, or R 1 and R 2 are combined to form a C 3 -C 6 carbocyclic ring; R 3 and R 4 are each independently selected to be hydrogen, C 1 -C 4 alkyl, F, Cl, Br, I or CF 3; R 5 is hydrogen, F or Cl; R 6 is hydrogen, --NH 2, --NHCH 3, --NHC 2 H 5, --NHCH(CH 3) 2, --N(CH 3) 2, --N(C 2 H 5) 2, NH(CH 2) m --OC 1 --C 3 alkyl, (where m is 2 or 3), --NHC(O)C 1 -C 3 alkyil, Cl or Br, and n is 0 or 1.",
    "2. The compound of claim 1 where R 1 and R 2 are joined to form cyclobutyl.",
    "3. The compound of claim 1 where R 1 is hydrogen and R 2 is ethyl.",
    "4. The compound of claim 1 where R 6 is NH 2, NHCH 3 or NHC 2 H 5.",
    "5. The compound of claim 1 which is a) (R)-N\"-Cyano-N-(5-pyrimidyl)-N'-(1-phenyl)ethylguanidine; b) N-(2-Amino-5-pyrimidyl)-N\"-cyano-N'-(1-phenyl)cyclobutylguanidine."
  ],
  "description_excerpt": "This application is a 371 of pct/81593/11332 filed Jul. 21, 1993.\n\nThe 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.\n\nIt is known that K + channels are important for regulating potassium excretion by the kidney and it has been proposed that inhibition of ATP-sensitive K + 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 + -2Cl - -K + co-transporter. It has also been proposed that inhibition of the ATP-sensitive K + channels of apical membranes in principal cells of the initial and cortical collecting tubule would reduce K + secretion, the primary source of urinary potassium. K + channel antagonist activities necessary to produce the observed eukalemic natriuresis have been documented in the rat kidney.\n\nThe 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.",
  "cpc": [
    "C07D 239/42",
    "C07D 239/48"
  ],
  "ipc": [
    "C07D 239/42",
    "C07D 239/48"
  ],
  "assignees": [
    "Upjohn Co"
  ],
  "inventors": [
    "Stephen J. Humphrey",
    "Kaushik D. Meisheri",
    "James H. Ludens",
    "Jackson B. Hester, Jr."
  ],
  "filing_date": "1993-07-21",
  "publication_date": "1997-05-27",
  "grant_date": "1997-05-27",
  "priority_date": "1993-11-26",
  "application_number": "US-55330895-A",
  "family_id": "24208927",
  "cited_by_count": 1018,
  "citations": [
    "US4057636A",
    "EP0503627A1"
  ]
}