Quinazoline compounds and compositions thereof for the treatment of disease

• US 5,792,771 A
• Filed: 06/05/1995
• Issued: 08/11/1998
• Est. Priority Date: 11/13/1992
• Status: Expired due to Term

• Current Assignee: Yissum Research Development Company of the Hebrew University of Jerusalem Ltd. (Hebrew University of Jerusalem), Sugen Incorporated (Pharmacia Corp.)
• Original Assignee: Yissum Research Development Company of the Hebrew University of Jerusalem Ltd. (Hebrew University of Jerusalem), Sugen Incorporated (Pharmacia Corp.)
• Inventors: Levitzki, Alexander, Gazit, Aviv, Tang, Peng Cho, App, Harald, McMahon, Gerald M.
• Primary Examiner(s): Grumbling, Matthew V.
• Application Number:
  US08/462,391
• Time in Patent Office: 1,163 Days
• Field of Search: 514/259, 544/291-293, 544/287
• US Class Current: 514/266.3
• CPC Class Codes: A61K 31/235 having an aromatic ring attached to a carboxyl group
• CPC Class Codes: A61K 31/275 Nitriles; Isonitriles
• CPC Class Codes: A61K 31/277 having a ring, e.g. verapamil
• CPC Class Codes: A61K 31/38 having sulfur as a ring hetero atom
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 31/415 1,2-Diazoles
• CPC Class Codes: A61K 31/42 Oxazoles
• CPC Class Codes: A61K 31/495 having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazinesA61K31/48 takes precedence ; with three nitrogen atoms A61K31/53
• CPC Class Codes: A61K 31/502 ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
• CPC Class Codes: A61K 31/505 Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
• CPC Class Codes: A61K 31/517 ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• CPC Class Codes: A61K 31/535 having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: C07C 229/60 with amino and carboxyl groups bound in meta- or para- positions
• CPC Class Codes: C07C 255/36 the carbon skeleton being further substituted by hydroxy groups
• CPC Class Codes: C07C 255/40 the carbon skeleton being further substituted by doubly-bound oxygen atoms
• CPC Class Codes: C07C 255/41 the carbon skeleton being further substituted by carboxyl groups, other than cyano groups
• CPC Class Codes: C07C 255/66 having cyano groups and nitrogen atoms being part of hydrazine or hydrazone groups bound to the same carbon skeleton
• CPC Class Codes: C07C 317/46 the carbon skeleton being further substituted by singly-bound oxygen atoms
• CPC Class Codes: C07C 327/44 to carbon atoms of an unsaturated carbon skeleton
• CPC Class Codes: C07D 209/18 : Radicals substituted by 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 231/38 : Nitrogen atoms nitro radicals C07D231/16
• CPC Class Codes: C07D 239/93 : Sulfur atoms
• CPC Class Codes: C07D 239/94 : Nitrogen atoms
• CPC Class Codes: C07D 241/42 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 241/44 : with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems
• CPC Class Codes: C07K 14/71 : for growth factors; for growth regulators
• CPC Class Codes: C07K 16/2863 : against receptors for growth factors, growth regulators
• CPC Class Codes: C07K 2319/00 : Fusion polypeptide
• CPC Class Codes: C07K 2319/32 : fusions with soluble part of a cell surface receptor, "decoy receptors"
• CPC Class Codes: G01N 2333/71 : for growth factors; for growth regulators
• 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 33/5008 : for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
• CPC Class Codes: G01N 33/5011 : for testing antineoplastic activity
• CPC Class Codes: G01N 33/502 : for testing non-proliferative effects
• CPC Class Codes: G01N 33/5041 : involving analysis of members of signalling pathways
• CPC Class Codes: G01N 33/5064 : Endothelial cells
• CPC Class Codes: G01N 33/5091 : for testing the pathological state of an organism
• CPC Class Codes: G01N 33/6893 : related to diseases not provided for elsewhere

Abstract

The present invention relates to organic molecules capable of modulating tyrosine kinase signal transduction and particularly KDR/FLK-1 receptor signal transduction in order to regulate and/or modulate vasculogenesis and angiogenesis. The invention is based, in part, on the demonstration that KDR/FLK-1 tyrosine kinase receptor expression is associated with endothelial cells and the identification of vascular endothelial growth factor (VEGF) as the high affinity ligand of FLK-1. These results indicate a major role for KDR/FLK-1 in the signaling system during vasculogenesis and angiogenesis. Engineering of host cells that express FLK-1 and the uses of expressed FLK-1 to evaluate and screen for drugs and analogs of VEGF involved in FLK-1 modulation by either agonist or antagonist activities is also described.

The invention also relates to the use of the disclosed compounds in the treatment of disorders, including cancer, diabetes, hemangioma and Kaposi'"'"'s sarcoma, which are related to vasculogenesis and angiogenesis.

Claims

1. A compound having the formula:

##STR21## or a pharmaceutically acceptable salt thereof, wherein;

R₁ is OCH₃, CH₃ or H,

R₂ is OCH₃ or H,

R₃ is H or chloro, and

R₄ is (4-methylphenyl)mercapto.

2. The compound of claim 1, wherein R₁ is CH₃ or H, and R₂ is H.

3. The compound of claim 2, wherein R₃ is chloro.

7. A pharmaceutical composition comprising a compound of claim 1, 2, 3, 4, 5, or 6 and a pharmaceutical carrier or excipient.

8. The pharmaceutical composition of claim 7, wherein said carrier is VPD:

D5W.

9. A method for modulating vasculogenesis or angiogenesis which comprises administering to a human an effective amount of a compound of claim 1, 2, 3, 4, 5, or 6.

4. A compound having the formula:

##STR22## or a pharmaceutically acceptable salt thereof, wherein;

R₁ is OCH₃, CH₃ or H,

R₂ is OCH₃ or H,

R₃ is chloro, and

R₄ is (4-methylphenyl)mercapto or (3-hydroxyphenyl)amino.

5. The compound of claim 4, wherein R₁ is CH₃ or H, and R₂ is H.

6. The compound of claim 5, wherein R₄ is (3-hydroxyphenyl)amino.

10. A method for modulating vasculogenesis or angiogenesis in a human having a non-cancer disorder, which comprises administering to said human an effective amount of a compound having the formula:

##STR23## or a pharmaceutically acceptable salt thereof, wherein;

R₁ is OCH₃, CH₃ or H,

R₂ is OCH₃ or H,

R₃ is H or chloro, and

R₄ is (3-chlorophenyl)amino, (4-methylphenyl)mercapto, (4-iodophenyl)amino or (3-hydroxyphenyl)amino.

11. The method of claim 10, wherein:

R₁ is CH₃ or H;

R₂ is OCH₃ or H; and

R₄ is (4-methylphenyl)mercapto or (3-hydroxyphenyl)amino.

12. The method of claim 10, wherein said non-cancer disorder is selected from the group consisting of diabetes, diabetic retinopathy, rheumatoid arthritis and hemangioma.