Cellular accumulation of phosphonate analogs of HIV protease inhibitor compounds

• US 7,649,015 B2
• Filed: 04/25/2003
• Issued: 01/19/2010
• Est. Priority Date: 04/26/2002
• Status: Active Grant

• Current Assignee: Gilead Sciences Inc.
• Original Assignee: Gilead Sciences Inc.
• Inventors: Xu, Lianhong, Zhang, Lijun, Yang, Zheng-Yu, Pyun, Hyung-Jung, He, Gong-Xin, Sparacino, Mark, Arimili, Murty N., Zhang, Jiancun, Fardis, Maria, Mitchell, Michael L., Kim, Choung U., Lin, Kuei-Ying, Wang, Jianying, Chen, Xiaowu, Swaminathan, Sundaramoorthi, Liu, Hongtao, Yu, Richard H., Jin, Haolun, Lee, William A., Mackman, Richard L., Williams, Matthew A.
• Primary Examiner(s): Solola; Taofiq A
• Application Number:
  US10/423,496
• Publication Number:
  US 20050209197A1
• Time in Patent Office: 2,461 Days
• Field of Search: 549/218, 549/464, 549/465, 549/220, 514/470
• US Class Current: 514/470
• CPC Class Codes: A61K 31/66 Phosphorus compounds
• CPC Class Codes: A61K 31/675 having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 213/75 Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
• CPC Class Codes: C07D 213/85 in position 3
• CPC Class Codes: C07D 231/12 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 231/20 One oxygen atom attached in position 3 or 5
• CPC Class Codes: C07D 233/42 Sulfur atoms
• CPC Class Codes: C07D 239/49 with an aralkyl radical, or substituted aralkyl radical, attached in position 5, e.g. trimethoprim
• CPC Class Codes: C07D 239/80 Oxygen atoms
• CPC Class Codes: C07D 243/04 having the nitrogen atoms in positions 1 and 3
• CPC Class Codes: C07D 265/18 with hetero atoms directly attached in position 2
• CPC Class Codes: C07D 307/68 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 403/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 471/14 Ortho-condensed systems
• CPC Class Codes: C07D 491/04 Ortho-condensed systems
• CPC Class Codes: C07F 9/4006 Esters of acyclic acids which can have further substituents on alkyl
• CPC Class Codes: C07F 9/58 Pyridine rings
• CPC Class Codes: C07F 9/645 : having two nitrogen atoms as the only ring hetero atoms
• CPC Class Codes: C07F 9/6506 : having the nitrogen atoms in positions 1 and 3
• CPC Class Codes: C07F 9/650905 : having the nitrogen atoms in the positions 1 and 2
• CPC Class Codes: C07F 9/650947 : condensed with carbocyclic rings or carbocyclic ring systems
• CPC Class Codes: C07F 9/6512 : having the nitrogen atoms in positions 1 and 3
• CPC Class Codes: C07F 9/65128 : condensed with carbocyclic rings or carbocyclic ring systems
• CPC Class Codes: C07F 9/65335 : condensed with carbocyclic rings or carbocyclic ring systems
• CPC Class Codes: C07F 9/65515 : the oxygen atom being part of a five-membered ring
• CPC Class Codes: C07F 9/65583 : each of the hetero rings containing nitrogen as ring hetero atom
• CPC Class Codes: C07F 9/6561 : containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
• CPC Class Codes: C12N 9/16 : acting on ester bonds (3.1)
• CPC Class Codes: C12Q 1/18 : Testing for antimicrobial activity of a material
• CPC Class Codes: C12Q 1/37 : involving peptidase or proteinase
• CPC Class Codes: C12Q 1/44 : involving esterase
• CPC Class Codes: C40B 40/04 : Libraries containing only organic compounds
• CPC Class Codes: G01N 2333/16 : HIV-1, HIV-2
• CPC Class Codes: G01N 2500/04 : Screening involving studying the effect of compounds C directly on molecule A (e.g. C are potential ligands for a receptor A, or potential substrates for an enzyme A)
• CPC Class Codes: G01N 33/5038 : involving detection of metabolites per se

Abstract

Phosphonate substituted compounds with HIV protease inhibitory properties having use as therapeutics and for other industrial purposes are disclosed. The compositions inhibit HIV protease activity and/or are useful therapeutically for the treatment of AIDS and other antiviral infections, as well as in assays for the detection of HIV protease.

Claims

1. A compound having the following structural formula:

2. The compound of claim 1, Z is —

O—

CH2-.

3. The compound of claim 1, R is hydroxy or methoxy.

9. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

4. A compound having the following structural formula:

5. The compound of claim 4, wherein R₁ and R₂ are ethoxy.

10. A pharmaceutical composition comprising a compound of claim 4 and a pharmaceutically acceptable carrier.

11. A pharmaceutical composition comprising a compound of claim 5 and a pharmaceutically acceptable carrier.

6. A compound having the following structural formula:

7. A compound having the following structural formula:

8. A compound having the following structure: