Adamantylglycine-based inhibitors of dipeptidyl peptidase IV and methods

• US 6,995,183 B2
• Filed: 07/27/2004
• Issued: 02/07/2006
• Est. Priority Date: 08/01/2003
• Status: Active Grant

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol Myers Squibb Co.
• Inventors: Hamann, Lawrence G., Sutton, James C., Simpkins, Ligaya M., Magnin, David R., Kirby, Mark S., Robl, Jeffrey, Khanna, Ashish
• Primary Examiner(s): McKane, Joseph
• Assistant Examiner(s): FREISTEIN, ANDREW B
• Application Number:
  US10/899,641
• Publication Number:
  US 20050038020A1
• Time in Patent Office: 560 Days
• Field of Search: 544/59, 544/106, 546/112, 546/195, 548/200, 548/215, 548/452, 548/528, 548/953, 514/210.01, 514/227.5, 514/231.2, 514/299, 514/319, 514/367, 514/374, 514/412
• US Class Current: 514/412
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07C 255/46 to carbon atoms of non-condensed rings
• CPC Class Codes: C07C 255/47 to carbon atoms of rings being part of condensed ring systems
• CPC Class Codes: C07C 2601/08 the ring being saturated
• CPC Class Codes: C07C 2602/18 the ring system containing six carbon atoms
• CPC Class Codes: C07C 2603/74 Adamantanes
• CPC Class Codes: C07D 207/16 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 209/52 condensed with a ring other than six-membered
• CPC Class Codes: C07D 277/04 having no double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 295/185 from aliphatic carboxylic acids

Abstract

Compounds are provided having the formula (I)

• • wherein:
  • n is 0, 1 or 2;
  • m is 0, 1 or 2;
  • the sum of n+m less then or equal to 2;
  • the dashed bonds forming a cyclopropyl ring can only be present when Y is CH;
  • X is H or CN;
  • Y is CH, CH₂, CHF, CF₂, O, S, SO, or SO₂; and
  • A is adamantyl.

Further provided are methods of using such compounds for the treatment of diabetes and related diseases, and to pharmaceutical compositions containing such compounds.

Claims

1. A compound of formula (I)

wherein:

n is 0, 1 or 2;

m is 0, 1 or 2;

the sum of n plus m is less then or equal to 2;

the dashed bonds forming a cyclopropyl ring when Y is CH;

X is hydrogen or CN;

Y is CH, CH₂, CHF, CF₂, O, S, SO, or SO₂

A is adamantyl which can be optionally substituted with from zero to six substituents each independently selected from OR¹, NR¹R², alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, bicycloalkyl, bicycloalkylalkyl, alkylthioalkyl, arylalkylthioalkyl, cycloalkenyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl and cycloheteroalkylalkyl, all optionally substituted through available carbon atoms with 1, 2, 3, 4 or 5 groups selected from hydrogen, halo, alkyl, polyhaloalkyl, alkoxy, haloalkoxy, polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, heteroarylamino, arylamino, cycloheteroalkyl, cycloheteroalkylalkyl, hydroxy, hydroxyalkyl, nitro, cyano, amino, substituted amino, alkylamino, dialkylamino, thiol, alkylthio, alkylcarbonyl, acyl, alkoxycarbonyl, aminocarbonyl, alkynylaminocarbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, alkylsulfonylamino, alkylaminocarbonylamino, alkoxycarbonylamino, alkylsulfonyl, aminosulfonyl, alkylsulfinyl, sulfonamido and sulfonyl;

R¹ and R² are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl and heteroaryl;

including pharmaceutically acceptable salts thereof, and prodrug esters thereof, and all stereoisomers thereof,

with the proviso that the compound of formula (I) is not selected from

2. The compound as defined in claim 1 selected from

3. The compound as defined in claim 1 selected from

6. A pharmaceutical composition comprising a compound as defined in claim 1 and a pharmaceutically acceptable carrier therefor.

7. A pharmaceutical composition that inhibits DPP-IV containing a compound as defined in claim 1.

4. A compound of the formula

5. A compound of the formula