EP1601357A1 - Heterocyclic kinase inhibitors: methods of use and synthesis - Google Patents
Heterocyclic kinase inhibitors: methods of use and synthesisInfo
- Publication number
- EP1601357A1 EP1601357A1 EP04719237A EP04719237A EP1601357A1 EP 1601357 A1 EP1601357 A1 EP 1601357A1 EP 04719237 A EP04719237 A EP 04719237A EP 04719237 A EP04719237 A EP 04719237A EP 1601357 A1 EP1601357 A1 EP 1601357A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- alkyl
- independently
- heterocyclyl
- heteroaryl
- halo
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
Definitions
- BACKGROUND Kinases are a class of enzymes that function in the catalysis of phosphoryl transfer. Protein kinases participate in the signaling events, which control the activation, growth and differentiation of cells in response to extracellular mediators and to changes in the environment.
- kinases fall into several groups; those that preferentially phosphorylate serine and/or threonine residues are generally referred to as serine/threonine kinases and those that preferentially phosphorylate tyrosine residues are generally referred to as tyrosine kinases [S.K. Hanks and T. Hunter, FASEB J., 1995, 9, 576-596].
- the tyrosine kinases include membrane- spanning growth factor receptors such as EGFR (S. Iwashita and M. Kobayashi, Cellular
- cytosolic non-receptor kinases such as Lck, ZAP-70 and Syk kinases (C. Chan et. AL, Ann. Rev. Immun., 1994, 12, 555-592).
- T cells plays a key role in transplant rejection, autoimmune diseases and the initiation of inflammatory responses and are thus a primary target for pharmaceutical intervention in these indications.
- the activation of T cells is a complex process that results in cell growth and differentiation.
- the engagement of the T cell receptor on mature peripheral T cells initiates multiple intracellular signals that lead to cellular proliferation and the acquisition of complex functions.
- the biochemical mechanisms that couple receptor binding to these intracellular events have been investigated (J.E.M., Van Leeuwen, and L.E. Samelson, Current Opin. Immun. 1999, 11, 242-248).
- the Syk family of tyrosine kinases comprising Syk and ZAP-70, play a role in the initiation and the amplification of receptor signal transduction (D.H. Chu et.al., Immunol. Rev. 1998, 165, 167-180).
- ZAP-70 is expressed solely in T cells and NK cells.
- Syk is found in B cells, mast cells, neutrophils, macrophages, and platelets and is involved in B cell receptor and Fc receptor signal transduction.
- kinase inhibitors of ZAP-70 and Syk have potential therapeutic benefits for treating diseases resulting from activation and differentiation of T cells, NK cells, B cells, mast cells, neutrophils, macrophages, and platelets.
- the invention relates to novel compounds and compositions including those compounds, as well as methods of using and making the compounds.
- the compounds are heterocyclic compounds that are useful in therapeutic applications, including modulation of disease or disease symptoms in a subject (e.g., mammal, human, dog, cat, horse).
- the compounds (including stereoisomers thereof) are created either singly or in a combinatorial fashion to give structurally, and stereochemically diverse libraries of compounds.
- the compounds are useful as ZAP-70 and Syk inhibitors through their binding to these receptors.
- the invention features a compound of the formula (I)
- A forms a benzene, pyridine, pyrimidine, thiophene, pyrrole, imidazole, pyrrazole, thiazole, or oxazole ring;
- X is O, S, NR 3 , N(R 3 )N(R 3 ), C(O), N(R 5 )C(0), C(0)NR 5 , or alkyl;
- R x is H, cycloalkyl, alkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkynyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, heteroarylalkynyl, R 5 0-alkyl 3 (R 5 ) 3 Si, acyl, wherein R x is optionally substituted with 1-4 R 4 ; each R is independently H, NR 5 2 , alkyl, cycloalkyl, alkenyl, alkynyl, heteroaryl, heterocyclyl, aryl, halo, acetyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, heteroarylalkynyl, hydroxy, alkoxy, aryloxy, or heteroaryloxy, each of which is optionally substituted with
- Q is H, halo, C(0)R 5 , C(0)R 9 , C(S)R 5 , C(S)R 9 , C(0)NR 5 2 , C(0)NR 5 R 9 , S(0)R 5 , S(0)R 9 , S(0)NR 5 2, S(0)NR 5 R 9 , S0 2 R 5 , S0 2 R 9 , S0 2 NR 5 2 , S0 2 NR 5 R 9 , NR 5 2 , NR 5 R 9 ,R 9 S -alkyl, alkyl, or heterocyclyl, wherein each alkyl or heterocyclyl is optionally substituted with 1-4 R 10 ; each R 9 is independently aryl, heterocyclyl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted with 1-4 R 10 ; each R 10 is independently alkyl, CF 3 , C(NH)NR 5 R n , C(NH)R ⁇ , CN, R 5 2 N-
- A forms a benzene ring.
- the invention features a compound of formula (11) formula (II)
- X is O, S, NR 3 , N(R 3 )N(R 3 ), C(O), N(R 5 )C(0), C(0)NR 5 , or alkyl;
- R is H, cycloalkyl, alkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkynyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, heteroarylalkynyl, R 5 0-alkyl, (R 5 ) 3 Si, acyl, wherein R x is optionally substituted with 1-4 R 4 ; each R 2 is independently H, NR 5 2 , alkyl, cycloalkyl, alkenyl, alkynyl, heteroaryl, heterocyclyl, aryl, halo, acetyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, heteroarylalkynyl, hydroxy, alkoxy, aryloxy, or heteroaryloxy, each of which is optionally substituted with 1-4
- Het is attached through a ⁇ ng-nitrogen atom;
- X is NR , or alkyl; and
- R x is cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, or heterocyclyl wherem R x is optionally substituted with 1-4 R 4 ; and R 2 is H.
- Het is
- the invention features a compound of formula (III), formula (III)
- X is O, S, NR 3 , N(R 3 )N(R 3 ), C(0), N(R 5 )C(0), C(0)NR 5 , or alkyl;
- R x is H, cycloalkyl, alkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkynyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, heteroarylalkynyl, R 5 0-alkyl, (R 5 ) 3 Si, acyl, wherein R x is optionally substituted with 1-4 R 4 ; each R 2 is independently H, NR 5 2 , alkyl, cycloalkyl, alkenyl, alkynyl, heteroaryl, heterocyclyl, aryl, halo, acetyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, heteroarylalkynyl, hydroxy, alkoxy, aryloxy, or heteroaryloxy, each of which is optionally substituted with
- R 2 is H. In some instances R 12 . is
- the invention features a compound of formula (IV)
- X is O, S, NR 3 , N(R 3 )N(R 3 ), C(O), N(R 5 )C(0), C(0)NR 5 , or alkyl;
- R x is H, cycloalkyl, alkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkynyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, heteroarylalkynyl, R 5 0-alkyl, (R 5 ) 3 Si, acyl, wherein R x is optionally substituted with 1-4 R 4 ; each R 2 is independently H, NR 5 2 , alkyl, cycloalkyl, alkenyl, alkynyl, heteroaryl, heterocyclyl, aryl, halo, acetyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroaryl
- each alkyl or heterocyclyl is optionally substituted with 1-4 R 10 ; each R 9 is independently aryl, heterocyclyl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted with 1-4 R 10 ; each R 10 is independently alkyl, CF 3 , C(NH)NR 5 R ⁇ , C(NH)R ⁇ , CN, R 5 2 N-alkyl,
- R n -alkyl R 5 0-alkyl, R 11 , heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is optionally substituted with alkyl or OR 5 ; each R ⁇ is independently arylalkyl, heteroarylalkyl, cycloalkyl, or heterocyclyl; and
- R 14 is halo, NH 2 , alkyl, OH, C(0)Me, aryl, heteroaryl, or C(0)NHR 5 .
- the invention features a compound of formula (V) formula (V)
- A forms a benzene, pyridine, pyrimidine, thiophene, pyrrole, imidazole, pyrrazole, thiazole, or oxazole ring;
- R ⁇ is H, halo, aryl, heteroaryl, cycloalkyl, heterocyclyl, alkynyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, or heteroarylalkynyl, wherein R ⁇ is optionally substituted with 1- 4 R 4 ; each R 2 is independently H, NR 5 2 , alkyl, cycloalkyl, alkenyl, alkynyl, heteroaryl, heterocyclyl, aryl, halo, acetyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, heteroarylalkynyl, hydroxy, alkoxy, aryloxy, or heteroaryloxy, each of which is optionally substituted with 1-4 R 7 ; wherein R 2 is not Me when R ⁇ is halo, indole substituted with halo,
- Q is H, halo, C(0)R 5 , C(0)R 9 , C(S)R 5 , C(S)R 9 , C(0)NR 5 2 , C(0)NR 5 R 9 , S(0)R 5 , S(0)R 9 , S(0)NR 5 2 , S(0)NR 5 R 9 , S0 2 R 5 , S0 2 R 9 , S0 2 NR 5 2 , S0 2 NR 5 R 9 , NR 5 2 , NR 5 R 9 , R 9 S-alkyl, alkyl, or heterocyclyl, wherein each alkyl or heterocyclyl is optionally substituted with 1-4 R 1 ; each R is independently aryl, heterocyclyl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted with 1-4 R 10 ; each R 10 is independently alkyl, CF 3 , C(NH)NR 5 R ⁇ , C(NH)R ⁇ , CN, R 5 2 N-
- A forms a benzene ring.
- the invention features a compound of formula (VI), wherein
- R ⁇ is H, halo, aryl, heteroaryl, cycloalkyl, heterocyclyl, alkynyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, or heteroarylalkynyl, wherein R is optionally substituted with 1-
- each R 2 is independently H, NR 5 2 , alkyl, cycloalkyl, alkenyl, alkynyl, heteroaryl, heterocyclyl, aryl, halo, acetyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, heteroarylalkynyl, hydroxy, alkoxy, aryloxy, or heteroaryloxy, each of which is optionally substituted with 1-4 R 7 ; wherein R 2 is not Me when R ⁇ is halo, indole substituted with halo, phenyl, or phenyl substituted with halo; wherein R 2 is not isopropyl when R ⁇ is phenyl substituted with halo; each R 2 is independently H, halo, NH 2 , alkyl, OH, C(0)Me, aryl, heteroaryl; each R 3 is independently H,
- Het is heterocyclyl optionally substituted with 1-4 R 10 ; each R 10 is independently alkyl, CF 3 , C(NH)NR 5 R ⁇ , C(NH)R n , CN, R 5 2 N-alkyl, NR 5 R n -alkyl, R 5 0-alkyl, R 11 , heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is optionally substituted with alkyl or OR 5 ; and each R 11 is independently arylalkyl, heteroarylalkyl, cycloalkyl, or heterocyclyl.
- Het is attached through a ring-nitrogen atom; R 2 is not H; and
- R 1 is H.
- Het is
- the invention features a compound of formula (VII)
- R ⁇ is H, halo, aryl, heteroaryl, cycloalkyl, heterocyclyl, alkynyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, or heteroarylalkynyl, wherein R ⁇ is optionally substituted with 1- 4 R 4 ; each R is independently H, NR 2 , alkyl, cycloalkyl, alkenyl, alkynyl, heteroaryl, heterocyclyl, aryl, halo, acetyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, heteroarylalkynyl, hydroxy, alkoxy, aryloxy, or heteroaryloxy, each of which is optionally substituted with 1-4 R ; wherein R is not phenyl when R is H; each R is independently H, halo, NH 2 , al
- R 2 is not H; and R 2 is H.
- R is
- the invention features a compound of formula (VIII),
- R > Y is H, halo, aryl, heteroaryl, cycloalkyl, heterocyclyl, alkynyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, or heteroarylalkynyl, wherein R ⁇ is optionally substituted with 1- 4 R 4 ; each R 2 is independently H, NR 5 2 , alkyl, cycloalkyl, alkenyl, alkynyl, heteroaryl, heterocyclyl, aryl, halo, acetyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, heteroarylalkynyl, hydroxy, alkoxy, aryloxy, or heteroaryloxy, each of which is optionally substituted with 1-4 R 7 ; wherein R 2 is not Me when R ⁇ is halo, indole substituted with halo
- Q is H, halo, C(0)R 5 , C(0)R 9 , C(S)R 5 , C(S)R 9 , C(0)NR 5 2 , C(0)NR 5 R 9 , S(0)R 5 , S(0)R 9 , S(0)NR 5 2 , S(0)NR 5 R 9 , S0 2 R 5 , S0 2 R 9 , S0 2 NR 5 2 , S0 2 NR 5 R 9 , NR 5 2 , NR 5 R 9 , R 9 S-alkyl, alkyl, or heterocyclyl, wherein each alkyl or heterocyclyl is optionally substituted with 1-4 R 10 ; each R 9 is independently aryl, heterocyclyl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted with 1-4 R 10 ; each R 10 is independently alkyl, CF 3 , C(NH)NR 5 R ⁇ , C(NH)R ⁇ , CN, R 5 2 N
- R 14 is halo, NH 2 , alkyl, OH, C(0)Me, aryl, heteroaryl, or C(0)NHR 5 . hi some instances, n is 1 and R 2 is not H.
- the invention features the compound of formula (XIV),
- R x is H, cycloalkyl, alkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkynyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, heteroarylalkynyl, R 5 0-alkyl, (R 5 ) 3 Si, acyl, wherein R x is optionally substituted with 1-4 R 4 ; each R is independently H, NR 5 2 , alkyl, cycloalkyl, alkenyl, alkynyl, heteroaryl, heterocyclyl, aryl, halo, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, heteroarylalkynyl, aryloxy, or heteroaryloxy, each of which is optionally substituted with 1-4 R 7 ; n is 0-3; each
- Q is H, halo, C(0)R 5 , C(0)R 9 , C(S)R 5 , C(S)R 9 , C(0)NR 5 2 , C(0)NR 5 R 9 , S(0)R 5 , S(0)R 9 , S(0)NR 5 2, S(0)NR 5 R 9 , S0 2 R 5 , S0 2 R 9 , S0 2 NR 5 2 , S0 2 NR 5 R 9 , NR 5 2 , NR 5 R 9 , R 9 S -alkyl, alkyl, or heterocyclyl, wherein each alkyl or heterocyclyl is optionally substituted with 1-4 R 10 ; each R 9 is independently aryl, heterocyclyl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted with 1-4 R 10 ; each R 10 is independently alkyl, CF 3 , C(NH)NR 5 R n , C(NH)R ⁇ , CN, R 5 2 N-
- the invention features a method of making a compound of formula (II) formula (II) wherein X, R »x , R , R , and Het are as defined below.
- the the method includes; treating the compound of formula (IX) with malonic acid, to provide a ring expansion compound of formula (X);
- formula (XII) formula (XIIT) coupling the compound of formula (XIII) with one or more coupling agents formula (XIII) formula (11) to provide a compound of formula (II), wherein for formulae II and IX to XIII, X is O, S, NR 3 , N(R 3 )N(R 3 ), C(O), N(R 5 )C(0)R 5 , C(0)NR 5 , or alkyl;
- R is H, cycloalkyl, alkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkynyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, heteroarylalkynyl, R 5 0-alkyl, (R 5 ) 3 Si, acyl, wherein R x is optionally substituted with 1-4 R 4 ; each R 2 is independently NR 5 2 , alkyl, cycloalkyl, alkenyl, alkynyl, heteroaryl, heterocyclyl, aryl, halo, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, heteroarylalkynyl, aryloxy, or heteroaryloxy, each of which is optionally substituted with 1-4 R 7 ;
- Het is heterocyclyl optionally substituted with 1-4 R 10 ; each R 10 is independently alkyl, CF 3 , C(NH)NR 5 R ⁇ , C(NH)R U , CN, R 5 2 N-alkyl, NR 5 R ⁇ -alkyl, R 5 0-alkyl, R 11 , heteroaryl, heterocyclyl, or heterocyclylalkyl, each of which is optionally substituted with alkyl or OR 5 ; and each R 11 is independently arylalkyl, heteroarylalkyl, cycloalkyl, or heterocyclyl.
- the H of Het-H is attached to a nitrogen.
- the coupling agent is H 2 N x . In some instances, the coupling agents are MgCl-R x , and Pd.
- the coupling agent is HSR x .
- the invention features a method of treating an autoimmune disorder in a subject including administering to the subject any of the compounds or compositions described herein.
- the method includes administering an additional therapeutic agent.
- the autoimmune disorder is lupus.
- the invention features a method of treating organ transplant rejection in a subject comprising administering to the subject any of the any of the compounds or compositions described herein.
- the invention features a method of treating an inflammatory disorder in a subject comprising administering to the subject any of the compounds or compositions described herein.
- the method includes administering an additional therapeutic agent.
- the additional therapeutic agent can be an analgesic, or a steroid.
- the inflammatory disorder is arthritis.
- the arthritis can be, for example, rheumatoid arthritis, rheumatoid spondylitis, gouty artliritis, traumatic arthritis, rubella arthritis, psoriatic arthritis, or osteoarthritis.
- the inflammatory disorder is inflammatory bowel disease or Crohn's disease.
- the invention features a composition including any of the compounds described herein.
- composition can include a pharmaceutically acceptable carrier.
- composition can include an additional therapeutic agent.
- the invention features a library of the compounds of any of formulae
- the invention features a method of inhibiting IL-2 production in a subject including administering to the subject any of the compounds or compositions described herein.
- the invention features a method of modulating ZAP-70 or Syk in a subject including administering to the subject any of the compounds or compositions described herein.
- the compounds, compositions, and methods delineated herein are those of any of the compounds of Table 1 herein.
- halo refers to any radical of fluorine, chlorine, bromine or iodine.
- alkyl refers to a hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms. For example, C ⁇ -C 10 indicates that the group may have from 1 to 10 (inclusive) carbon atoms in it.
- lower alkyl refers to a C Cg alkyl chain. In the absence of any numerical designation, “alkyl” is a chain (straight or branched) having 1 to 10 (inclusive) carbon atoms in it.
- alkoxy refers to an -O-alkyl radical.
- alkylene refers to a divalent alkyl (i.e., -R-).
- alkylenedioxo refers to a divalent species of the structure -0-R-O-, in which R represents an alkylene.
- aminoalkyl refers to an alkyl substituted with an amino.
- mercapto refers to an -SH radical.
- thioalkoxy refers to an -S-alkyl radical.
- alkenyl refers to a hydrocarbon chain that may be a straight chain or branched chain having one or more carbon-carbon double bonds. The alkenyl moiety contains the indicated number of carbon atoms.
- C2-C10 indicates that the group may have from 2 to 10 (inclusive) carbon atoms in it.
- lower alkenyl refers to a C 2 -C 8 alkenyl chain. In the absence of any numerical designation, “alkenyl” is a chain (straight or branched) having 2 to 10 (inclusive) carbon atoms in it.
- alkynyl refers to a hydrocarbon chain that may be a straight chain or branched chain having one or more carbon-carbon triple bonds.
- the alkynyl moiety contains the indicated number of carbon atoms.
- C2-C10 indicates that the group may have from 2 to 10 (inclusive) carbon atoms in it.
- lower alkynyl refers to a C 2 -C 8 alkynyl chain. In the absence of any numerical designation, “alkynyl” is a chain (straight or branched) having 2 to 10 (inclusive) carbon atoms in it.
- aryl refers to a 6-carbon monocyclic or 10-carbon bicyclic aromatic ring system wherein 0, 1, 2, 3, or 4 atoms of each ring may be substituted by a substituent. Examples of aryl groups include phenyl, naphthyl and the like.
- arylalkyl or the term “aralkyl” refers to alkyl substituted with an aryl.
- alkyl substituted with an aryl refers to alkyl substituted with an aryl.
- alkyl refers to an alkenyl substituted with an aryl.
- arylalkynyl refers to an alkynyl substituted with an aryl.
- arylalkoxy refers to an alkoxy substituted with aryl.
- cycloalkyl as employed herein includes saturated and partially unsaturated cyclic hydrocarbon groups having 3 to 12 carbons, preferably 3 to 8 carbons, and more preferably 3 to 6 carbons, wherein the cycloalkyl group may be optionally substituted.
- Preferred cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.
- heteroaryl refers to an aromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, or S if monocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2, 3, or 4 atoms of each ring may be substituted by a substituent.
- heteroaryl groups include pyridyl, furyl or furanyl, imidazolyl, benzimidazolyl, pyrimidinyl, thiophenyl or thienyl, quinolinyl, indolyl, thiazolyl, and the like.
- heteroarylalkyl or the term “heteroaralkyl” refers to an alkyl substituted with a heteroaryl.
- heteroarylalkenyl refers to an alkenyl substituted with a heteroaryl.
- heteroarylalkynyl refers to an alkynyl substituted with a heteroaryl.
- heteroarylalkoxy refers to an alkoxy substituted with heteroaryl.
- heterocyclyl refers to a nonaromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, or S if monocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent.
- heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tefrahydroftiranyl, and the like.
- heterocyclylalkyl refers to an alkyl substituted with a heterocyclyl.
- oxo refers to an oxygen atom, which forms a carbonyl when attached to carbon, an N-oxide when attached to nitrogen, and a sulfoxide or sulfone when attached to sulfur.
- acyl refers to an alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heterocyclylcarbonyl, or heteroarylcarbonyl substituent, any of which may be further substituted by substituents.
- sulfonyl refers to a sulfur attached to two oxygen atoms through double bonds.
- alkylsulfonyl refers to an alkyl substituted with a sulfonyl.
- substituted refers to a group “substituted” on an alkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl group at any atom of that group.
- Suitable substituents include, without limitation, halo, hydroxy, mercapto, oxo, nitro, haloalkyl, alkyl, aryl, aralkyl, alkoxy, thioalkoxy, aryloxy, amino, alkoxycarbonyl, amido, carboxy, alkanesulfonyl, alkylcarbonyl, and cyano groups.
- Me means methyl
- dppf 1,1 bis(diphenylphosphino) ferrocene.
- Mops means 3-(N-Morpholino) propanesulfonic acid.
- BSA bovine serum albumin.
- LAT means a palmitoylated p36/38 kDa plasma membrane-associated protein expressed in all T lymphocytes and it is the physiologic substrate of activated ZAP-70.
- TMB means 3, 3', 5, 5' - Tetrametliylbenzidine.
- kinase mediated disorder means a disorder wherein a protein kinase is involved in signaling, mediation, modulation, or regulation of the disease process or symptoms.
- Kinase mediated disorders are exemplified by the following classes of diseases and disorders: cancer, autoimmunological, metabolic, inflammatory, infection (bacterial, viral, yeast, fungal, etc.), diseases of the central nervous system, degenerative neural disease, allergy/asthma, dermatology, angiogenesis, neovascularization, vasculogenesis, cardiovascular, and the like.
- Table 1 Representative compounds of the invention**
- ZAP-70 and Syk mediated diseases are exemplified by the following: lupus, organ transplant rejection, and inflammatory disorders.
- inflammatory disorders include arthritis (e.g., rheumatoid arthritis, rheumatoid spondylitis, gouty arthritis, traumatic arthritis, rubella artliritis, psoriatic arthritis, or osteoarthritis), inflammatory bowel disease, and Crohn's disease.
- the compounds, compositions and methods of the present invention are useful in treating, for example, lupus, organ transplant rejection (e.g., kidney, liver, heart, lunch, pancreas (islet cells), bone marrow, cornea, small bowel, skin allografts or xenografts), and inflammatory disorders.
- organ transplant rejection e.g., kidney, liver, heart, lunch, pancreas (islet cells), bone marrow, cornea, small bowel, skin allografts or xenografts
- inflammatory disorders include, but are not limited to, arthritis (e.g., rheumatoid arthritis, rheumatoid spondylitis, gouty arthritis, traumatic arthritis, rubella arthritis, psoriatic arthritis, or osteoarthritis), asthma, allergy, eczema, inflammatory bowel disease, and Crohn's disease.
- compositions having a compound of any of the formulae described herein and a pharmaceutically acceptable carrier; or a compound of any of the formulae described herein, an additional therapeutic agent (e.g., anti-inflammatory; non- steroidal anti-inflammatory drugs (NSAID); steroid, and the like), and a pharmaceutically acceptable carrier; or a compound of any of the formulae described herein, an additional therapeutic agent, and a pharmaceutically acceptable carrier, wherein the additional therapeutic agent is an kinase binding agent (e.g., a polypeptide, an antibody or organic molecule).
- an additional therapeutic agent e.g., anti-inflammatory; non- steroidal anti-inflammatory drugs (NSAID); steroid, and the like
- NSAID non- steroidal anti-inflammatory drugs
- Yet another aspect of this invention relates to a method of treating a subject (e.g., mammal) having a kinase mediated disorder or disorder symptom (including, but not limited to pain and inflammation).
- the method includes administering to the subject (including a subject identified as in need of such treatment) an effective amount of a compound described herein, or a composition described herein to produce such effect. Identifying a subject in need of such treatment can be in the judgment of a subject or a health care professional and can be subjective (e.g. opinion) or objective (e.g. measurable by a test or diagnostic method).
- the invention further relates to a product (i.e., a compound of any of the formulae herein) made by the methods described above.
- a product i.e., a compound of any of the formulae herein
- Combinations of substituents and variables envisioned by this invention are only those that result in the formation of stable compounds.
- stable refers to compounds which possess stability sufficient to allow manufacture and which maintains the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject).
- the compound of formula (XII) is treated with a chlorinating agent, such as POCl 3 , and the carboxylic acid is coupled with a heterocyclic (e.g., heteroaryl or heterocyclyl) compound ("Het") to provide a compound of formula (XIII).
- a chlorinating agent such as POCl 3
- Het heterocyclic compound
- the resulting compound is then coupled with one or more coupling agents to provide a compound of formula (IT).
- Coupled agent means a chemical agent that is used in a reaction that forms a bond between one chemical moiety and another moiety from the coupling agent.
- Some examples of coupling agents include transition metals such as Pd, Cu, and Mg and and transition metal catalysts, as well as boron containing compounds such as boranes.
- Coupling agents can also include nucleophiles such as amines, alkoxides, sulfides or corresponding protonated forms. As can be appreciated by the skilled artisan, further methods of synthesizing the compounds of the formulae herein will be evident to those of ordinary skill in the art.
- the compounds of this invention may contain one or more asymmetric centers and thus occur as racemates and racemic mixtures, single enantiomers, individual diastereomers and diastereomeric mixtures. All such isomeric forms of these compounds are expressly included in the present invention.
- the compounds of this invention may also be represented in multiple tautomeric forms, in such instances, the invention expressly includes all tautomeric forms of the compounds described herein (e.g., alkylation of a ring system may result in alkylation at multiple sites, the invention expressly includes all such reaction products). All such isomeric forms of such compounds are expressly included in the present invention. All crystal forms of the compounds described herein are expressly included in the present invention.
- the compounds of this invention including the compounds of formulae described herein, are defined to include pharmaceutically acceptable derivatives or prodrugs thereof.
- a "pharmaceutically acceptable derivative or prodrug” means any pharmaceutically acceptable salt, ester, salt of an ester, or other derivative of a compound of this invention which, upon administration to a recipient, is capable of providing (directly or indirectly) a compound of this invention.
- Particularly favored derivatives and prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a mammal (e.g., by allowing an orally administered compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) relative to the parent species.
- Preferred prodrugs include derivatives where a group which enhances aqueous solubility or active transport through the gut membrane is appended to the structure of formulae described herein.
- the compounds of this invention may be modified by appending appropriate functionalities to enhance selective biological properties. Such modifications are known in the art and include those which increase biological penetration into a given biological compartment (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.
- Pharmaceutically acceptable salts of the compounds of this invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases.
- Suitable acid salts include acetate, adipate, benzoate, benzenesulfonate, butyrate, citrate, digluconate, dodecylsulfate, formate, fumarate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride,.hydrobromide, hydroiodide, lactate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, palmoate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate, tosylate and undecanoate.
- Salts derived from appropriate bases include alkali metal (e.g., sodium), alkaline earth metal (e.g., magnesium), ammonium and N-(alkyl) salts.
- alkali metal e.g., sodium
- alkaline earth metal e.g., magnesium
- ammonium e.g., ammonium
- N-(alkyl) salts e.g., ammonium
- This invention also envisions the quaternization of any basic nitrogen- containing groups of the compounds disclosed herein. Water or oil-soluble or dispersible products may be obtained by such quaternization.
- the compounds of the formulae described herein can, for example, be administered by injection, intravenously, intraarterially, subdermally, intraperitoneally, intramuscularly, or subcutaneously; or orally, buccally, nasally, transmucosally, topically, in an ophthalmic preparation, or by inhalation, with a dosage ranging from about 0.001 to about 100 mg/kg of body weight, preferably dosages between 10 mg and 1000 mg/dose, every 4 to 120 hours, or according to the requirements of the particular drug.
- the methods herein contemplate administration of an effective amount of compound or compound composition to achieve the desired or stated effect.
- the pharmaceutical compositions of this invention will be administered from about 1 to about 6 times per day or alternatively, as a continuous infusion.
- Such administration can be used as a chronic or acute therapy.
- the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
- a typical preparation will contain from about 5% to about 95% active compound (w/w).
- such preparations contain from about 20% to about 80% active compound.
- a maintenance dose of a compound, composition or combination of this invention may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.
- compositions of this invention comprise a compound of the fo ⁇ nulae described herein or a pharmaceutically acceptable salt thereof; an additional agent including for example, a steroid or an analgesic; and any pharmaceutically acceptable carrier, adjuvant or vehicle.
- Alternate compositions of this invention comprise a compound of the formulae described herein or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier, adjuvant or vehicle.
- the compositions delineated herein include the compounds of the formulae delineated herein, as well as additional therapeutic agents if present, in amounts effective for achieving a modulation of disease or disease symptoms, including kinase mediated disorders or symptoms thereof.
- the compositions are made by methods including the steps of combining one or more compounds delineated herein with one or more carriers and, optionally, one or more additional therapeutic agents delineated herein.
- pharmaceutically acceptable carrier or adjuvant refers to a carrier or adjuvant that may be administered to a patient, together with a compound of this invention, and which does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the compound.
- compositions maybe in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension.
- This suspension maybe formulated according to techniques known in the art using suitable dispersing or wetting agents
- the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
- a non-toxic parenterally acceptable diluent or solvent for example, as a solution in 1,3-butanediol.
- acceptable vehicles and solvents that maybe employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution.
- sterile, fixed oils are conventionally employed as a solvent or suspending medium.
- any bland fixed oil may be employed including synthetic mono- or diglycerides.
- Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
- These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms such as emulsions and or suspensions.
- Other commonly used surfactants such as Tweens or Spans and/or other similar emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
- compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions.
- carriers which are commonly used include lactose and corn starch.
- Lubricating agents such as magnesium stearate, are also typically added.
- useful diluents include lactose and dried corn starch.
- compositions of this invention may also be administered in the form of suppositories for rectal administration.
- These compositions can be prepared by mixing a compound of this invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components.
- suitable non-irritating excipient include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.
- Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d- ⁇ -tocopherol polyethyleneglycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene
- the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery form.
- parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrastemal, intrathecal, intralesional and intracranial injection or infusion techniques.
- Topical administration of the pharmaceutical compositions of this invention is useful when the desired treatment involves areas or organs readily accessible by topical application.
- the pharmaceutical composition should be formulated with a suitable ointment containing the active components suspended or dissolved in a carrier.
- Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water.
- the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier with suitable emulsifying agents.
- Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
- the pharmaceutical compositions of this invention may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation. Topically-transdermal patches are also included in this invention.
- compositions of this invention maybe administered by nasal aerosol or inhalation.
- Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.
- compositions of this invention comprise a combination of a compound of the formulae described herein and one or more additional therapeutic or prophylactic agents
- both the compound and the additional agent should be present at dosage levels of between about 1 to 100%, and more preferably between about 5 to 95% of the dosage normally administered in a monotherapy regimen.
- the additional agents maybe administered separately, as part of a multiple dose regimen, from the compounds of this invention. Alternatively, those agents may be part of a single dosage form, mixed together with the compounds of this invention in a single composition.
- 6-Benzo[l,3]dioxol-5-yl-2-oxo-l,2-dihydro-quinoline-4-carboxylic acid 3 (1.0 g, 3.2 mol) in 10 mL of oxyphosphourus chloride was refluxed for 4h and cooled to room temperature. The solution was concentrated to dryness to yield a brownish yellow solid. The solid was then dissolved in 20 mL of methylene dichloride. Diisopropylethylamine (1.50 g, 11.5 mmol) and 2- (S)-pyrroldinylmethyl pyrrolidine (0.59 g, 3.84 mmol) were slowly added into the solution at 0°C. The mixture was allowed to stir at room temperature for 12 h.
- Pre-incubation reactions contained 62.5 mM Mops pH 7.0, 12.5 mM MgCl 2 , 12.5% glycerol, 3.1 nM ZAP-70, 62.5 nM biotinylated poly(glu,Tyr), 0.1 mg/ml BSA, 6.25% DMSO and 0-100 mM compound in a total volume of 40 ml. After a 10 minute room temperature incubation, 10 ml of 5 mM ATP was added to start the reaction. Reactions were incubated at room temperature for
- biotinylated poly(glu,tyr) was measured using the Dissociation Enhanced Lantha ide Fluorescence nmuno-assay (DELFIA) from Perkin Elmer according to manufacturers protocol. Briefly, biotinylated poly (glytyr) was captured on streptavidin coated plates, washed twice, then incubated with Europium labeled-anti-phosphotyrosine antibody.
- DELFIA Dissociation Enhanced Lantha ide Fluorescence nmuno-assay
- A means the compound has an IC5 0 of >10 ⁇ M in vitro
- B means the compound has an IC 50 between 1 and 10 ⁇ M in vitro
- C means the compound has an IC 50 of ⁇ 1 ⁇ M in vitro.
- Example 6 Cell-based Assay of ZAP-70-mediated LAT Phosphorylation ZAP-70 tyrosine kinase activity present in activated Jurkat T cells was measured by assessing the phosphorylation status of LAT.
- LAT is a palmitoylated p36/38 kDa plasma membrane-associated protein expressed in all T lymphocytes and it is the physiologic substrate of activated ZAP-70.
- ZAP-70 becomes activated and phosphorylates two tyrosine residues on LAT, Tyr-191 & Tyr-226.
- the immunoprecipitated phosphotyrosine proteins are liberated from the agarose beads by boiling and denaturing and are resolved by SDS-PAGE and transferred to nitrocellulose membranes.
- LAT phosphorylated on Tyr-191 and Tyr-226 is then detected by standard western blotting technology using commercially available phospho-specific antibodies that react specifically with either phospho-Tyr- 191 or phospho-Tyr-226 on LAT (Upstate Biotechnology Inc.), an enzyme-conjugated secondary antibody (horseradish peroxidase-conjugated goat anti- rabbit IgG antiserum), and a Storm Imaging system (Amersham-Pharmacia). Inhibition was observed with representative compounds described herein.
- Example 7 IL-2 Inhibition Cell-based Assay
- IL-2 production was measured in Jurkat cells following co-stimulation with Anti-CD3 and Anti-CD28 antibodies.
- Cells were seeded at 1 x 10 5 /well (200 ⁇ l/well of culture) in 96 well plates precoated with anti-CD3 antibody (BD Biocoat T-cell activation plates, Anti-human CD3 plate - Cat. No. 354725 from BD BioSciences).
- Anti-CD28 antibody eBioScience, Cat# 16-0289-85; Functional Grade, co-stimulatory, clone 28.2 is added to the plate at the final concentration of 20 ng/well. Cells are incubated for 48 hrs after which a 50 ⁇ l aliquot of cell supernatant is removed for IL-2 titration.
- IL-2 titration was performed using the Endogen enzyme-linked immunosorbent assay (ELISA) Kit (Endogen of Pierce, Cat# EH2-IL2-5) as described by the manufacturer.
- ELISA Endogen enzyme-linked immunosorbent assay
- this assay consists of using a 96 well microtiter plate that has been precoated with anti-IL-2 antibodies for the capture of human IL-2.
- a biotinylated second anti-IL-2 antibody is added to all wells. This results in a sandwiching of any IL-2 (capture IL-2 Ab C IL-2 C detection IL-2 -biotin Ab).
- HRP horseradish peroxidase
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- 2004-03-10 EP EP04719237A patent/EP1601357A4/en not_active Withdrawn
- 2004-03-10 MX MXPA05009722A patent/MXPA05009722A/en not_active Application Discontinuation
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Also Published As
Publication number | Publication date |
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EP1601357A4 (en) | 2007-10-03 |
MXPA05009722A (en) | 2006-03-09 |
JP2006519846A (en) | 2006-08-31 |
CA2518398A1 (en) | 2004-09-23 |
WO2004080463A1 (en) | 2004-09-23 |
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