WO2010041054A1 - Pyridine and pyrimidine based compounds as wnt signaling pathway inhibitors for the treatment of cancer - Google Patents
Pyridine and pyrimidine based compounds as wnt signaling pathway inhibitors for the treatment of cancer Download PDFInfo
- Publication number
- WO2010041054A1 WO2010041054A1 PCT/GB2009/051319 GB2009051319W WO2010041054A1 WO 2010041054 A1 WO2010041054 A1 WO 2010041054A1 GB 2009051319 W GB2009051319 W GB 2009051319W WO 2010041054 A1 WO2010041054 A1 WO 2010041054A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- piperidine
- carboxamide
- dichloropyridin
- mmol
- chloro
- Prior art date
Links
- 0 *CCNC(C(CC1)CCN1c(c(Cl)cnc1)c1Cl)=O Chemical compound *CCNC(C(CC1)CCN1c(c(Cl)cnc1)c1Cl)=O 0.000 description 7
- KKWRVUBDCJQHBZ-UHFFFAOYSA-N Clc(cncc1Cl)c1Cl Chemical compound Clc(cncc1Cl)c1Cl KKWRVUBDCJQHBZ-UHFFFAOYSA-N 0.000 description 3
- WVWKUZCOVSSGRN-UHFFFAOYSA-N NCCNC(C(CC1)CCN1c(c(Cl)cnc1)c1Cl)=O Chemical compound NCCNC(C(CC1)CCN1c(c(Cl)cnc1)c1Cl)=O WVWKUZCOVSSGRN-UHFFFAOYSA-N 0.000 description 2
- HRMRQBJUFWFQLX-UHFFFAOYSA-N CC(C)(C)OC(N(CC1)CC1C(O)=O)=O Chemical compound CC(C)(C)OC(N(CC1)CC1C(O)=O)=O HRMRQBJUFWFQLX-UHFFFAOYSA-N 0.000 description 1
- YUWRFMKBLJHPRL-UHFFFAOYSA-N CNC(C(CC1)CCN1c(c(Cl)cnc1)c1Cl)=O Chemical compound CNC(C(CC1)CCN1c(c(Cl)cnc1)c1Cl)=O YUWRFMKBLJHPRL-UHFFFAOYSA-N 0.000 description 1
- QAJOLLVGOSCKGP-UHFFFAOYSA-N CNC(C1CCNCC1)=O Chemical compound CNC(C1CCNCC1)=O QAJOLLVGOSCKGP-UHFFFAOYSA-N 0.000 description 1
- YTOQAOWDEUXGNG-UHFFFAOYSA-N COc(cc1)ccc1-c(cncc1Cl)c1N(CC1)CC1C(N)=O Chemical compound COc(cc1)ccc1-c(cncc1Cl)c1N(CC1)CC1C(N)=O YTOQAOWDEUXGNG-UHFFFAOYSA-N 0.000 description 1
- NCLHBKCKTURKJS-UHFFFAOYSA-N COc1ccc(CNCCNC(C(CC2)CCN2c(c(Cl)cnc2)c2Cl)=O)cc1 Chemical compound COc1ccc(CNCCNC(C(CC2)CCN2c(c(Cl)cnc2)c2Cl)=O)cc1 NCLHBKCKTURKJS-UHFFFAOYSA-N 0.000 description 1
- GOCVIWPRNVUIOX-UHFFFAOYSA-N Cc1cncc(C)c1N(CC1)CC1C(N)=O Chemical compound Cc1cncc(C)c1N(CC1)CC1C(N)=O GOCVIWPRNVUIOX-UHFFFAOYSA-N 0.000 description 1
- HTYUPPCYXUSCNK-UHFFFAOYSA-N Clc(cncc1Cl)c1N(CC1)CCC1c1ncc[s]1 Chemical compound Clc(cncc1Cl)c1N(CC1)CCC1c1ncc[s]1 HTYUPPCYXUSCNK-UHFFFAOYSA-N 0.000 description 1
- SIKXIUWKPGWBBF-UHFFFAOYSA-N Clc1nc(Cl)ncc1Br Chemical compound Clc1nc(Cl)ncc1Br SIKXIUWKPGWBBF-UHFFFAOYSA-N 0.000 description 1
- NZMRXADDALADJO-UHFFFAOYSA-N N#CC(CC1)CCN1c(c(-c1ccccc1)cnc1)c1Cl Chemical compound N#CC(CC1)CCN1c(c(-c1ccccc1)cnc1)c1Cl NZMRXADDALADJO-UHFFFAOYSA-N 0.000 description 1
- ZVIYJBMVFXMWLA-UHFFFAOYSA-N N#CC(CC1)CCN1c(c(Cl)cnc1)c1Cl Chemical compound N#CC(CC1)CCN1c(c(Cl)cnc1)c1Cl ZVIYJBMVFXMWLA-UHFFFAOYSA-N 0.000 description 1
- FSDNTQSJGHSJBG-UHFFFAOYSA-N N#CC1CCNCC1 Chemical compound N#CC1CCNCC1 FSDNTQSJGHSJBG-UHFFFAOYSA-N 0.000 description 1
- NHJWQBUPPDPSJG-UHFFFAOYSA-N NC(C(CC1)CCN1c(c(Cl)cnc1)c1Cl)=S Chemical compound NC(C(CC1)CCN1c(c(Cl)cnc1)c1Cl)=S NHJWQBUPPDPSJG-UHFFFAOYSA-N 0.000 description 1
- HDDXRDGHAHPMFP-UHFFFAOYSA-N NC(C(CC1)CCN1c1nc(Cl)ncc1Br)=O Chemical compound NC(C(CC1)CCN1c1nc(Cl)ncc1Br)=O HDDXRDGHAHPMFP-UHFFFAOYSA-N 0.000 description 1
- DPBWFNDFMCCGGJ-UHFFFAOYSA-N NC(C1CCNCC1)=O Chemical compound NC(C1CCNCC1)=O DPBWFNDFMCCGGJ-UHFFFAOYSA-N 0.000 description 1
- KJDZVWFZPWNUMB-UHFFFAOYSA-N NCCNC(C(CC1)CCN1c(c(I)cnc1)c1Cl)=O Chemical compound NCCNC(C(CC1)CCN1c(c(I)cnc1)c1Cl)=O KJDZVWFZPWNUMB-UHFFFAOYSA-N 0.000 description 1
- ZCZHRLDATCLESK-UHFFFAOYSA-N OC(C(CC1)CCN1c(c(Cl)cnc1)c1-c1ccccc1)=O Chemical compound OC(C(CC1)CCN1c(c(Cl)cnc1)c1-c1ccccc1)=O ZCZHRLDATCLESK-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/10—Spiro-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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 ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
-
- 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
- C07D401/04—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 directly linked by a ring-member-to-ring-member bond
-
- 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
- C07D401/14—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 three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Definitions
- This invention relates to compounds and their use in therapy, in particular in the treatment, prevention or delay of progression of cancer.
- Oncogenic deregulation of the Wnt signalling pathway is a causal factor in the initiation of cancer in a diverse range of tissues including the colon, breast and liver (see, for example, Barker et al, "Mining the Wnt pathway for cancer therapeutics", Nature Reviews Drug Discovery, Dec 2006 Vol. 5, 997).
- WO 01/27107 discloses heterocyclic sodium/proton exchange inhibitors which are useful in the treatment of cardiovascular disorders. Included are pyrimidine compounds which are substituted by an imidazolylpiperidinyl group.
- W, X and Y are each independently CH, C(R 4 ) or N; Z is C(R 6 ) or N;
- R 1 and R 2 are each independently hydrogen or C 1-6 alkyl; or R 1 and R 2 taken together with the carbon atom to which they are attached may form a 5- or
- R 3 and R 4 are each independently halo or a group selected from Ci -6 alkyl, Ci -6 alkoxy, carbocyclyl and heterocyclyl, any of which is optionally substituted with 1 , 2, 3, 4 or 5 R a ; when Z is N, R 5 is R 7 , -C(O)R 7 , -C(O)OR 7 -, -S(O),R 7 , -C(O)N(R 7 )R 8 , -C(S)N(R 7 )R 8 -, -S(O) ⁇ N(R 7 )R 8 or heterocyclyl optionally substituted with 1 , 2, 3, 4 or 5 R a ; when Z is C(R 6 ), R 5 is H, CN, C(O)OH, -C(O)R 7 , -C(O)OR 7 -,
- R 6 is hydrogen, Ci -6 alkyl, Ci -6 alkoxy, -OH, R 5 , (CH 2 ) m R 5 or -N(R 7 )R 8 ; or R 5 and R 6 taken together with the carbon atom to which they are attached may form a 5- or 6-membered heterocycle which is optionally substituted with 1 , 2, 3, 4 or 5 R a ;
- R 7 and R 8 are each independently hydrogen or a group selected from Ci -6 alkyl optionally containing 1 , 2 or 3 heteroatoms selected from N, O and S, carbocyclyl and heterocyclyl, any of which is optionally substituted with 1 , 2, 3, 4 or 5 R a ; or R 7 and R 8 may be linked so that, together with the atoms to which they are attached, they form a 5- or 6-membered heterocycle which is optionally substituted with 1 , 2, 3, 4 or 5 R a ; each R a is independently selected from halogen, trifluoromethyl, cyano,
- R d is selected from hydrocarbyl (e.g. C 1-6 alkyl), carbocyclyl, carbocyclyl-Ci -6 alkyl, and heterocyclyl, each of which is optionally substituted with 1 , 2, 3, 4 or 5 substituents independently selected from halogen, cyano, amino, hydroxy, Ci -6 alkyl, Ci -6 alkoxy; I is O, 1 or 2; and m and n are each independently 1 , 2 or 3; rmaceutically acceptable salt, N-oxide or prodrug thereof.
- the present invention provides a compound of the formula (I):
- Z is C(R 6 ) or N
- R 1 and R 2 are each independently hydrogen or C 1-6 alkyl; or R 1 and R 2 taken together with the carbon atom to which they are attached may form a 5- or 6-membered carbocycle or heterocycle, either of which is optionally substituted with 1 , 2, 3, 4 or 5 R a ;
- R 3 and R 4 are each independently halo or a group selected from Ci -6 alkyl, Ci -6 alkoxy, carbocyclyl and heterocyclyl, any of which is optionally substituted with 1 , 2, 3, 4 or 5 R a ; when Z is N, R 5 is R 7 , -C(O)R 7 , -S(O),R 7 , -C(O)N(R 7 )R 8 , -S(O),N(R 7 )R 8 or heterocyclyl optionally substituted with 1 , 2, 3, 4 or 5 R a ; when Z is C(R 6 ), R 5 is H, -CN, C(O)OH, -C(O)R 7 , -S(O),R 7 , -N(R 6 )R 7 , - C(O)N(R 7 )R 8 , -S(O) ⁇ N(R 7 )R 8 , -N(R 7 )C(O)R 8 ,
- R 6 is hydrogen, Ci -6 alkyl, Ci -6 alkoxy, -OH, R 5 or -(CH 2 ) m R 5 ; or R 5 and R 6 taken together with the carbon atom to which they are attached may form a 5- or 6-membered heterocycle which is optionally substituted with 1 , 2, 3, 4 or 5 R a ;
- R 7 and R 8 are each independently hydrogen or a group selected from Ci -6 alkyl optionally containing 1 , 2 or 3 heteroatoms selected from N, O and S, carbocyclyl and heterocyclyl, any of which is optionally substituted with 1 , 2, 3, 4 or 5 R a ; each R a is independently selected from halogen, trifluoromethyl, cyano, oxo, nitro, -OR b , -C(O)R b , -C(O)OR b , -OC(O)R b , -S(O),R b , -N(R b )R c , -N(R b )C(O)R c , -C(O)N(R b )R c , -S(O),N(R b )R c and R d ; R b and R c are each independently hydrogen or R d ;
- R d is selected from hydrocarbyl and heterocyclyl, either of which is optionally substituted with 1 , 2, 3, 4 or 5 substituents independently selected from halogen, cyano, amino, hydroxy, Ci -6 alkyl and Ci -6 alkoxy; I is O, 1 or 2; and m and n are each independently 1 , 2 or 3; or a pharmaceutically acceptable salt, N-oxide or prodrug thereof; for use in the treatment, prevention or delay of progression of cancer.
- the invention also provides a pharmaceutical formulation comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
- the invention relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment, prevention or delay of progression of cancer.
- a method of treating, preventing or delaying progression of cancer is also provided, which involves administering a therapeutically effective amount of a compound of the invention to a subject.
- Compounds of the invention can exist in different forms, such as free acids, free bases, esters, N-oxides and other prodrugs, salts and tautomers, for example, and the disclosure includes all variant forms of the compounds.
- Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith.
- hydrocarbyl as used herein includes reference to moieties consisting exclusively of hydrogen and carbon atoms; such a moiety may comprise an aliphatic and/or an aromatic moiety. The moiety may, for example, comprise 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms.
- hydrocarbyl groups include Ci -6 alkyl (e.g. Ci, C 2 , C 3 or C 4 alkyl, for example methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl or tert-butyl); Ci -6 alkyl substituted by aryl (e.g.
- benzyl or by cycloalkyl (e.g cyclopropylmethyl); cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl); alkenyl (e.g. 2-butenyl); alkynyl (e.g. 2-butynyl); aryl (e.g. phenyl, naphthyl or fluorenyl) and the like.
- cycloalkyl e.g cyclopropylmethyl
- cycloalkyl e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl
- alkenyl e.g. 2-butenyl
- alkynyl e.g. 2-butynyl
- aryl e.g. phenyl, naphthyl or fluorenyl
- alkyl and “Ci -6 alkyl” as used herein include reference to a straight or branched chain alkyl moiety having 1 , 2, 3, 4, 5 or 6 carbon atoms. This term includes reference to groups such as methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl or tert-butyl), pentyl, hexyl and the like. In particular, alkyl may have 1 , 2, 3 or 4 carbon atoms.
- alkenyl and C 2-6 alkenyl as used herein include reference to a straight or branched chain alkyl moiety having 2, 3, 4, 5 or 6 carbon atoms and having, in addition, at least one double bond, of either E or Z stereochemistry where applicable. This term includes reference to groups such as ethenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 1-hexenyl, 2-hexenyl and 3-hexenyl and the like.
- alkynyl and C 2-6 alkynyl as used herein include reference to a straight or branched chain alkyl moiety having 2, 3, 4, 5 or 6 carbon atoms and having, in addition, at least one triple bond. This term includes reference to groups such as ethynyl, 1- propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 1-hexynyl, 2-hexynyl and 3-hexynyl and the like.
- alkoxy and "Ci -6 alkoxy” as used herein include reference to -O-alkyl, wherein alkyl is straight or branched chain and comprises 1 , 2, 3, 4, 5 or 6 carbon atoms. In one class of embodiments, alkoxy has 1 , 2, 3 or 4 carbon atoms. This term includes reference to groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentoxy, hexoxy and the like.
- Cycloalkyl as used herein includes reference to an alicyclic moiety having 3, 4,
- the group may be a bridged or polycyclic ring system. More often cycloalkyl groups are monocyclic. This term includes reference to groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, bicyclo[2.2.2]octyl and the like.
- aryl as used herein includes reference to an aromatic ring system comprising
- Aryl is often phenyl but may be a polycyclic ring system, having two or more rings, at least one of which is aromatic. This term includes reference to groups such as phenyl, naphthyl and the like.
- carbocyclyl as used herein includes reference to a saturated (e.g. cycloalkyl) or unsaturated (e.g. aryl) ring moiety having 3, 4, 5, 6, 7, 8, 9 or 10 ring carbon atoms.
- carbocyclyl includes a 3- to 10-membered ring or ring system and, in particular, a 5- or 6-membered ring, which may be saturated or unsaturated.
- a carbocyclic moiety is, for example, selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, bicyclo[2.2.2]octyl, phenyl, naphthyl, and the like.
- heterocyclyl as used herein includes reference to a saturated (e.g. heterocycloalkyl) or unsaturated (e.g. heteroaryl) heterocyclic ring moiety having from 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms, at least one of which is selected from nitrogen, oxygen, phosphorus, silicon and sulphur.
- heterocyclyl includes a 3- to 10- membered ring or ring system and more particularly a 5- or 6-membered ring, which may be saturated or unsaturated.
- a heterocyclic moiety is, for example, selected from oxiranyl, azirinyl, 1 ,2-oxathiolanyl, imidazolyl, thienyl, furyl, tetrahydrofuryl, pyranyl, thiopyranyl, thianthrenyl, isobenzofura- nyl, benzofuranyl, chromenyl, 2A7-pyrrolyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolidinyl, benzimidazolyl, pyrazolyl, pyrazinyl, pyrazolidinyl, thiazolyl, isothiazolyl, dithiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, piperidyl, piperazinyl, pyridazinyl, morpholiny
- heterocycloalkyl as used herein includes reference to a saturated heterocyclic moiety having 3, 4, 5, 6 or 7 ring carbon atoms and 1 , 2, 3, 4 or 5 ring heteroatoms selected from nitrogen, oxygen, phosphorus and sulphur.
- the group may be a polycyclic ring system but more often is monocyclic.
- This term includes reference to groups such as azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, oxiranyl, pyrazolidinyl, imidazolyl, indolizidinyl, piperazinyl, thiazolidinyl, morpholinyl, thiomorpholinyl, quinolizidinyl and the like.
- heteroaryl as used herein includes reference to an aromatic heterocyclic ring system having 5, 6, 7, 8, 9 or 10 ring atoms, at least one of which is selected from nitrogen, oxygen and sulphur.
- the group may be a polycyclic ring system, having two or more rings, at least one of which is aromatic, but is more often monocyclic.
- This term includes reference to groups such as pyrimidinyl, furanyl, benzo[b]thiophenyl, thiophenyl, pyrrolyl, imidazolyl, pyrrolidinyl, pyridinyl, benzo[b]furanyl, pyrazinyl, purinyl, indolyl, benzimidazolyl, quinolinyl, phenothiazinyl, triazinyl, phthalazinyl, 2H-chromenyl, oxazolyl, isoxazolyl, thiazolyl, isoindolyl, indazolyl, purinyl, isoquinolinyl, quinazolinyl, pteridinyl and the like.
- halogen as used herein includes reference to F, Cl, Br or I. In a particular, halogen may be F or Cl, of which F is more common.
- substituted as used herein in reference to a moiety means that one or more, especially up to 5, more especially 1 , 2 or 3, of the hydrogen atoms in said moiety are replaced independently of each other by the corresponding number of the described substituents.
- optionally substituted as used herein means substituted or unsubstituted.
- substituents are only at positions where they are chemically possible, the person skilled in the art being able to decide (either experimen- tally or theoretically) without inappropriate effort whether a particular substitution is possible.
- amino or hydroxy groups with free hydrogen may be unstable if bound to carbon atoms with unsaturated (e.g. olefinic) bonds.
- substituents described herein may themselves be substituted by any substituent, subject to the aforementioned restriction to appropriate substitutions as recognised by the skilled man.
- pharmaceutically acceptable includes reference to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings or animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. This term includes acceptability for both human and veterinary purposes.
- the present invention provides compounds of the formula (I) and pharmaceutically acceptable salts, N-oxides and prodrugs thereof:
- n and n are each independently selected from 1 or 2. In an embodiment, m and n are 1.
- one of m and n is 1 , and the other is 2. In an embodiment, m and n are each 2.
- R 1 and R 2 are each independently hydrogen or methyl; or R 1 and R 2 taken together with the carbon atom to which they are attached form a 5- or 6-membered heterocycle containing a ring heteroatom selected from O and N.
- R 1 and R 2 are each independently hydrogen or methyl. In an embodiment, R 1 and R 2 are each hydrogen.
- X and Y are each independently selected from CH and C(R 4 ), and W is selected from CH, C(R 4 ) and N.
- X and Y are each CH; and W is CH, C(R 4 ) or N.
- W is CH, C(R 4 ), or N. In a particular embodiment, W is C(R 4 ) or N. In a further embodiment, W is C(R 4 ). Of particular mention are compounds in which R 4 is halo, e.g. chloro or bromo.
- the heteroaryl ring shown in Formula (I) contains at least one ring nitrogen atom in the form of an N-oxide. Suitably, in such embodiments, it is the nitrogen atom disposed between atoms X and Y that is in the form of an N-oxide.
- R 3 is halo (e.g. chloro or bromo) or a group selected from Ci -6 alkyl, aryl and heteroaryl, any of which is optionally substituted with 1 , 2, 3, 4 or 5 R a .
- each R a may be independently selected from halogen, cyano, amino, hydroxy, C 1-6 alkyl and C 1-6 alkoxy.
- R 3 is halo (e.g. chloro or bromo) or a group selected from C 1-6 alkyl, C 3-6 cycloalkyl, phenyl, and a 5- or 6-membered heteroaryl, any of which is optionally substituted with 1 , 2, or 3 R a .
- each R a may be independently selected from halogen, cyano, amino, hydroxy, trifluoromethyl, C 1-4 alkyl, NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , -S(O) ⁇ C 1-4 alkyl (where I is 0, 1 or 2) and C 1-4 alkoxy.
- R 3 is halo (e.g.
- each R a may be independently selected from halogen, cyano, amino, hydroxy, Ci -6 alkyl and Ci -6 alkoxy.
- R 3 is halo.
- R 3 is Ci -6 alkoxy.
- R 3 is halo (e.g. chloro or bromo) or a group selected from Ci -6 alkyl (e.g. methyl or ethyl), C 3-6 cycloalkyl (e.g. cyclopropyl), phenyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, pyridinyl, pyridazinyl, pyrimidinyl. and thiophenyl, any of which is optionally substituted with 1 , 2, or 3 R a .
- Ci -6 alkyl e.g. methyl or ethyl
- C 3-6 cycloalkyl e.g. cyclopropyl
- phenyl pyrazolyl, triazolyl, oxazolyl, isoxazolyl, pyridinyl, pyridazinyl, pyrimidinyl. and thiophenyl, any of which
- each R a may be independently selected from halogen, cyano, amino, hydroxy, trifluoromethyl, Ci -4 alkyl, NH(Ci -4 alkyl), N(C 1-4 alkyl) 2 , -S ⁇ C ⁇ alkyl (where I is 0, 1 or 2) and C 1-4 alkoxy.
- R 3 is halo. In an embodiment, R 3 is Ci -6 alkoxy. In an embodiment, R 3 is chloro, bromo or phenyl. In a particular embodiment, R 3 is chloro or bromo. In an embodiment, R 4 is halo (e.g. chloro or bromo) or a group selected from Ci -6 alkyl, C 3-6 cycl oa Iky I, phenyl, and a 5- or 6-membered heteroaryl, any of which is optionally substituted with 1 , 2, or 3 R a . In a furtehr embodiment, R 4 is halo (e.g. chloro or bromo) or a group selected from Ci -6 alkyl (e.g.
- methyl or ethyl C 3-6 cycloalkyl (e.g. cyclopropyl), phenyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, pyridinyl, pyridazinyl, pyrimidinyl. and thiophenyl, any of which is optionally substituted with 1 , 2, or 3 R a .
- each R a may be independently selected from halogen, cyano, amino, hydroxy, trifluoromethyl, Ci -4 alkyl, NH(Ci -4 alkyl), N(d -4 alkyl) 2 , -S(O) ⁇ C 1-4 alkyl (where I is 0, 1 or 2) and Ci -4 alkoxy.
- Z is C(R 6 ).
- R 6 is hydrogen, methyl, methoxy or methoxymethyl.
- R 6 is selected from hydrogen, methyl or -N(R 7 )R 8 .
- R 6 is selected from hydrogen, methyl or -NH-phenyl.
- R 6 is selected from hydrogen or methyl.
- R 6 is hydrogen.
- R 5 is H, CN, -C(O)OH, -C(O)OR 7 -, -C(O)N(R 7 )R 8 or heterocyclyl.
- R 5 is -C(O)OH or -CN.
- R 5 is -CN.
- R 5 is -C(O)N(R 6 )R 7 .
- R 5 and R 6 taken together with the carbon atom to which they are attached form a heterocycle optionally substituted with 1 , 2, 3, 4 or 5 R a .
- R 5 and R 6 taken together with the carbon atom to which they are attached form a heterocycle comprising a ring amide group, e.g. oxazolidone or 2-oxopyrrolidine, wherein the heterocycle is optionally substituted with 1 , 2, 3, 4 or 5 R a .
- each R a may be independently selected from halogen, cyano, amino, hydroxy, Ci-6 alkyl and Ci -6 alkoxy.
- R 5 is not an optionally substituted imidazolyl group.
- R 5 when Z is N, R 5 is R 7 , -C(O)R 7 , -C(O)OR 7 -, -C(O)N(R 7 )R 8 or a 5- or 6-membered heterocyclyl optionally substituted with 1 , 2, 3, 4 or 5 R a .
- R 5 when Z is N, R 5 is C 1-6 alkyl optionally sunstituted with one or more R a , -C(O)R 7 or -C(O)N(R 7 )R 8 .
- R 5 is H, CN, C(O)OH, -C(O)R 7 , -C(O)OR 7 -, -S(O),R 7 , -N(R 7 )R 8 , -C(O)N(R 7 )R 8 , -C(S)N(R 7 )R 8 , -S(O),N(R 7 )R 8 , -N(R 7 )C(O)R 8 , -N(R 7 )S(O),R 8 or an C 1-6 alkyl, phenyl or 5- or 6-membered heterocyclyl group which is optionally substituted with 1 , 2, 3, 4 or 5 R a .
- R 5 is H, CN, C(O)OH, -C(O)R 7 , -C(O)OR 7 -, -N(R 7 )R 8 , -C(O)N(R 7 )R 8 , -C(S)N(R 7 )R 8 , -S(O),N(R 7 )R 8 , -N(R 7 )C(O)R 8 , -N(R 7 )S(O),R 8 or an C 1-6 alkyl or 5- or 6-membered heterocyclyl group which is optionally substituted with 1 , 2, or 3 R a .
- R 5 is CN, C(O)OH, -C(O)R 7 , -C(O)OR 7 -, -N(R 7 )R 8 , -C(O)N(R 7 )R 8 , -C(S)N(R 7 )R 8 -, -N(R 7 )C(O)R 8 , or an C 1-4 alkyl or 5- or 6- membered heterocyclyl group which is optionally substituted with 1 , 2, or 3 R a .
- R 5 and R 6 are linked so that, together with the carbon atom to which they are attached, they form a 5- or 6-membered heterocycle which is optionally substituted with 1 , 2, or 3 R a .
- R 5 and R 6 together form a group -C(O)-N(R 7 )-(CH 2 ) q -, where q is 2 or 3.
- R 7 and R 8 are each independently hydrogen or a group selected from C 1-6 alkyl, carbocyclyl and heterocyclyl, any of which is optionally substituted with 1 , 2, 3, 4 or 5 R a .
- R 7 and R 8 are each independently hydrogen or a group selected from C 1-6 alkyl, phenyl and 5- or 6-membered heterocyclyl, any of which is optionally substituted with 1 , 2 or 3 R a . In a further embodiment, at least one of R 7 and R 8 is hydrogen.
- R 7 and R 8 are connected to a common nitrogen atom and are linked so that, together with the nitrogen atom to which they are attached, they form a 5- or 6- membered heterocycle which is optionally substituted with 1 , 2, 3, 4 or 5 R a .
- R 7 and R 8 are linked so that, together with the nitrogen atom to which they are attached, they form a pyrrolidine, piperidine, piperazine, or morpholine ring which is optionally substituted with 1 , 2 or 3 R a .
- each R a group is independently selected from halogen, trifluoromethyl, cyano, oxo, nitro, -OR b , -C(O)R b , -C(O)OR b , -OC(O)R b , -S(O),R b , -N(R b )R c , -N(R b )C(O)R c , -C(O)N(R b )R c , -S(O),N(R b )R c and R d .
- each R a group is independently selected from halogen, trifluoromethyl, oxo, -OR b , -C(O)R b , -S(O),R b , -N(R b )R c , -N(R b )C(O)R c , -C(O)N(R b )R c and R d .
- R d is selected from C 1-6 alkyl, C 3-6 cycloalkyl, phenyl and a 5- or 6- membered heterocyclyl, each of which is optionally substituted with 1 , 2, 3, 4 or 5 substituents independently selected from halogen, cyano, amino, hydroxy, C 1-6 alkyl and C 1-6 alkoxy.
- R d is selected from C 1-6 alkyl, C 3-6 cycloalkyl, phenyl and a 5- or 6-membered heterocyclyl, each of which is optionally substituted with 1 , 2 or 3 substituents independently selected from halogen, cyano, amino, hydroxy, C 1-4 alkyl and C 1-4 alkoxy.
- the compound is of the following formula:
- T is a bond or -CH 2 -.
- the compound is of the following formula:
- the compound is of the following formula:
- the compound is of the following formula:
- the compound is of the following formula:
- the compound is of the following formula:
- the compound is of the following formula:
- Z is C(R 6 ); R 1 and R 2 are each hydrogen;
- R 3 and R 4 are each independently halo or a group selected from Ci -6 alkyl, Ci -6 alkoxy, carbocyclyl and heterocyclyl, any of which is optionally substituted with 1 , 2, 3, 4 or 5 R a ;
- R 5 is H, CN, -C(O)OH, -C(O)N(R 7 )R 8 , or heterocyclyl;
- R 6 is hydrogen, Ci -6 alkyl, Ci -6 alkoxy, -OH , R 5 ; or (CH 2 ) m R 5 ; or R 5 and R 6 taken together with the carbon atom to which they are attached form a 5- or 6-membered heterocycle which is optionally substituted with 1 , 2, 3, 4 or 5 R a ;
- R 7 and R 8 are each independently hydrogen or a group selected from Ci -6 alkyl optionally containing 1 , 2 or 3 heteroatoms selected from N and O, carbocyclyl and heterocyclyl; each R a is independently selected from halogen, trifluoromethyl, cyano, oxo, nitro, -OR b , -C(O)R b , -C(O)OR b , -OC(O)R b , -S(O),R b , -N(R b )R c , -N(R b )C(O)R c , -C(O)N(R b )R c , -S(O),N(R b )R c and R d ; R b and R c are each independently hydrogen or R d ;
- R d is selected from hydrocarbyl and heterocyclyl, either of which is optionally substituted with 1 , 2, 3, 4 or 5 substituents independently selected from halogen, cyano, amino, hydroxy, Ci -6 alkyl and Ci -6 alkoxy;
- I is 0, 1 or 2; and m and n are each independently 1 or 2; or a pharmaceutically acceptable salt, N-oxide or prodrug thereof.
- the present invention provides any one of the compounds listed in the accompanying examples.
- compositions of the invention may be in the form of pharmaceutically acceptable salts.
- the pharmaceutically acceptable salts of the present disclosure can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts may be found in Remington's Pharmaceutical Sciences, 17 th ed., Mack Publishing Company, Easton, Pa., US, 1985, p.
- the invention thus includes pharmaceutically-acceptable salts of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof, for example the conventional non-toxic salts or the quaternary ammonium salts which are formed, e.g. from inorganic or organic acids or bases.
- acid addition salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3- phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate,
- Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, and so forth.
- the basic nitrogen- containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others.
- lower alkyl halides such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides
- dialkyl sulfates like dimethyl, diethyl, dibutyl
- diamyl sulfates long chain halides
- the invention includes prodrugs for the active pharmaceutical species of the invention, for example in which one or more functional groups are protected or derivatised but can be converted in vivo to the functional group, as in the case of esters of carboxylic acids convertible in vivo to the free acid, or in the case of protected amines, to the free amino group.
- prodrug represents in particular compounds which are rapidly transformed in vivo to the parent compound, for example, by hydrolysis in blood.
- Prodrugs therefore include drugs having a functional group which has been transformed into a reversible derivative thereof.
- such prodrugs are transformed to the active drug by hydrolysis.
- groups include carboxylic groups (reversible derivatives including esters, e.g. acyloxyalkyl esters and amides), alcohol groups
- Prodrugs also include compounds convertible to the active drug by an oxidative or reductive reaction.
- oxidative activation may be mentioned N- and O- dealkylation, oxidative deamination, N-oxidation and epoxidation.
- reductive activation may be mentioned azo reduction, sulfoxide reduction, disulfide reduction, bioreductive alkylation and nitro reduction.
- the compounds of the disclosure may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism. All diastereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation. The various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques. Alternatively the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation, or by derivatisation, for example with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means (e.g. HPLC, chromatography over silica).
- HPLC chromatography over silica
- Geometric isomers may also exist in the compounds of the present disclosure.
- the present disclosure contemplates the various geometric isomers and mixtures thereof resulting from the arrangement of substituents around a carbon-carbon double bond and designates such isomers as of the Z or E configuration, wherein the term "Z” represents substituents on the same side of the carbon-carbon double bond and the term “E” represents substituents on opposite sides of the carbon-carbon double bond.
- the disclosure therefore includes all variant forms of the defined compounds, for example any tautomer or any pharmaceutically acceptable salt, ester, acid or other variant of the defined compounds and their tautomers as well as substances which, upon administration, are capable of providing directly or indirectly a compound as defined above or providing a species which is capable of existing in equilibrium with such a compound.
- a compound of the invention may be prepared according to the processes described herein. It will be understood that these processes are solely for the purpose of illustrating the invention and should not be construed as limiting. A process utilising similar or analogous reagents and/or conditions known to one skilled in the art may also be used to obtain a compound of the invention.
- Any mixtures of final products or intermediates obtained can be separated on the basis of the physico-chemical differences of the constituents, in a known manner, into the pure final products or intermediates, for example by chromatography, distillation, fractional crystallisation, or by the formation of a salt if appropriate or possible under the circumstances.
- the compounds of the invention will normally be administered orally, intravenously, subcutaneously, buccally, rectally, dermally, nasally, tracheally, bronchially, by any other parenteral route, as an oral or nasal spray or via inhalation,
- the compounds may be administered in the form of pharmaceutical preparations comprising prodrug or active compound either as a free compound or, for example, a pharmaceutically acceptable non-toxic organic or inorganic acid or base addition salt, in a pharmaceutically acceptable dosage form.
- the compositions may be administered at varying doses.
- the pharmaceutical compounds of the invention may be administered orally or parenterally ("parenterally” as used herein, refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion) to a host.
- parenterally refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion
- the compounds may be administered alone or as compositions in combination with pharmaceutically acceptable diluents, excipients or carriers.
- Actual dosage levels of active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active compound(s) that is effective to achieve the desired therapeutic response for a particular patient, compositions, and mode of administration.
- the selected dosage level will depend upon the activity of the particular compound, the route of administration, the severity of the condition being treated and the condition and prior medical history of the patient being treated. However, it is within the skill of the art to start doses of the compound at levels lower than required for to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
- an appropriate dosage level will generally be about 0.01 to 500 mg per kg patient body weight per day which can be administered in single or multiple doses.
- the dosage level is about 0.1 to about 250 mg/kg per day; more preferably about 0.5 to about 100 mg/kg per day.
- a suitable dosage level may be about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg per day. Within this range the dosage may be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day.
- the compositions may be provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0,
- the compounds may be administered on a regimen of 1 to 4 times per day, e.g. once or twice per day.
- the dosage regimen may be adjusted to provide the optimal therapeutic response.
- compositions of this invention including a compound of the invention, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
- Pharmaceutical compositions of this invention for parenteral injection suitably comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use.
- aqueous and nonaqueous carriers, diluents, solvents or vehicles examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate.
- polyols such as glycerol, propylene glycol, polyethylene glycol and the like
- vegetable oils such as olive oil
- injectable organic esters such as ethyl oleate.
- Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
- compositions may also contain adjuvants such as preservative, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol or phenol sorbic acid. It may also be desirable to include isotonic agents such as sugars or sodium chloride, for example. Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents (for example aluminum monostearate and gelatin) which delay absorption.
- adjuvants such as preservative, wetting agents, emulsifying agents and dispersing agents.
- Injectable depot forms are suitably made by forming microencapsule matrices of the drug in biodegradable polymers, for example polylactide-polyglycolide.
- the rate of drug release can be controlled.
- biodegradable polymers include poly(orthoesters) and poly(anhydrides).
- Depot injectable formulations may also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
- the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable media just prior to use.
- Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
- the active compound is typically mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or one or more: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) solution retarding agents such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay and i) lubric acid, such as
- the dosage form may also comprise buffering agents.
- Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycol, for example.
- oral formulations contain a dissolution aid.
- the dissolution aid is not limited as to its identity so long as it is pharmaceutically acceptable. Examples include nonionic surface active agents, such as sucrose fatty acid esters, glycerol fatty acid esters, sorbitan fatty acid esters (e.g.
- sorbitan trioleate polyethylene glycol, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene alkyl ethers, methoxypolyoxyethylene alkyl ethers, polyoxyethylene alkylphenyl ethers, polyethylene glycol fatty acid esters, polyoxyethylene alkylamines, polyoxyethylene alkyl thioethers, polyoxyethylene polyoxypropylene copolymers, polyoxyethylene glycerol fatty acid esters, pentaerythritol fatty acid esters, propylene glycol monofatty acid esters, polyoxyethylene propylene glycol monofatty acid esters, polyoxyethylene sorbitol fatty acid esters, fatty acid alkylolamides, and alkylamine oxides; bile acid and salts thereof (e.g.,
- ionic surface active agents such as sodium laurylsulfate, fatty acid soaps, alkylsulfonates, alkylphosphates, ether phosphates, fatty acid salts of basic amino acids; triethanolamine soap, and alkyl quaternary ammonium salts; and amphoteric surface active agents, such as betaines and aminocarboxylic acid salts.
- the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and may also be of a composition such that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, and/or in delayed fashion. Examples of embedding compositions include polymeric substances and waxes.
- the active compounds may also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
- the active compounds may be in finely divided form, for example they may be micronised.
- Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs.
- the liquid dosage forms may contain inert diluents commonly used in the art such as water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan and mixtures thereof.
- inert diluents commonly used in the art such as water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol
- the oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
- Suspensions in addition to the active compounds, may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth and mixtures thereof.
- compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
- suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
- Liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals which are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolisable lipid capable of forming liposomes can be used.
- the present compositions in liposome form can contain, in addition to a compound of the present invention, stabilisers, preservatives, excipients and the like.
- the preferred lipids are the phospholipids and the phosphatidyl cholines (lecithins), both natural and synthetic. Methods to form liposomes are known in the art, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p 33 et seq.
- Dosage forms for topical administration of a compound of this invention include powders, sprays, ointments and inhalants.
- the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers or propellants which may be required.
- Ophthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
- Compounds of the invention may be useful in the therapy of a variety of diseases and conditions.
- the subject of said therapy may be a human or an animal.
- Compounds of the invention may exhibit desirable potency, selectivity and microsomal stability.
- compounds of the invention may be useful in the treatment or prevention of cancer, such as cancer of the colon, breast or liver.
- cancer such as cancer of the colon, breast or liver.
- the following Examples illustrate the invention.
- Example compounds were prepared according to the following reaction schemes.
- Reagents and conditions a) RR'NH, HATU, DIPEA, DMF; b) 4M HCI-dioxane, MeOH 1 :1 ; c) 3,4,5-trichloropyridine, NEt 3 , NMP, 220 0 C, 60 min. Both 4-chloropyridine and 3,4-dichloropyridine were commercially available as their hydrochloride salts.
- the reaction was carried out in water using an excess of isonipecotamide, leading to excellent conversion into the desired products B & C. The products were found to crystallise upon cooling the reaction mixture to 0 0 C.
- Reagents and Conditions a) RCO 2 H, HATU, DIPEA, DMF; b) 4M HCI-dioxane, MeOH 1 :1 ; c)3,4,5-trichloropyridine, NEt 3 , NMP, 220 0 C, 60 min.
- Oxidation of the pyridine ring may be achieved using the conditions developed by Caron et al ⁇ Tetrahedron Lett. 2000, 41, 2299) for the oxidation of electron deficient pyridines.
- the highly reactive oxidising agent pertrifluoroacetic acid is generated in-situ from hydrogen peroxide-urea complex and trifluoroacetic anhydride.
- ⁇ /-Boc-piperazine was coupled to benzoic acid to furnish the amide which was subsequently deprotected and coupled to 3,4,5-trichloropyridine to give H.
- 3,4,5-trichloropyridine has been coupled to commercially available /V-acetyl, ⁇ /-methyl and ⁇ /-ethyl piperazines to furnish compounds I, J, K respectively.
- Carboxybenzyl derivative M was synthesised according to the scheme below, however attempts at deprotection via hydrogenation led to hydrogenation of the chloride groups, to furnish N.
- NHCbz NHCbz
- Compound O was then subjected to reductive amination utilising a diverse set of aldehydes to furnish further analogues P where stoichiometric amounts of aldehyde were employed or Q when an excess of aldehyde was used.
- ethylene diamine based amide analogues Y could be synthesised by coupling of the intermediate pyrrolidine with 3,4,5-trihalo-pyridines.
- 5-Halopyrimidine analogues Z were synthesised by halogenation of 4-pyrimidone followed by coupling with the required cyclic amine.
- 3-halo-5-aryl pyridine analogues CC were prepared from the dichloro- and dibromo-pyridines taking care to avoid double coupling.
- the double Suzuki reaction to furnish only the £>/s-aryl analogues DD could also be performed successfully.
- Chlorine was bubbled through a solution of 4-pyrimidone (1.9 g, 20 mmol) in glacial acetic acid (20 ml.) for 1 h and the reaction mixture was stirred for a further 2 h. Chlorine was bubbled through the solution for a further 15 min and the mixture stirred for a further 90 min. The mixture was filtered and the cake was washed with hexane (3 * 25 mL) to furnish the title compound as a white solid (2.28 g).
- the mixture was extracted with CH 2 CI 2 (2 x 20 ml_), the combined organic extracts were washed with a saturated solution of NaHCOs (20 ml_), brine (20 ml_), dried (MgSO 4 ) and the solvent removed under reduced pressure.
- the crude product was purified by flash column chromatography on silica gel (CH 2 CI 2 /Me0H, 98:2) to furnish the title compound as a white solid (20 mg, 19%), m.p. 130-133 0 C; u max (CHCI 3 )/ cm "1 3026. 2855, 1724, 1452, 1273, 1 107.
- Examples 54 and 55 8-(3,5-dichloropyridin-4-yl)-1-phenyl-1 ,3,8-triazaspiror4.5ldecan -4- one E54 and 1-(3, ⁇ -dichloropvridin ⁇ -vlM-fphenvlaminolpiperidine ⁇ -carboxamide E55
- the crude product was purified by flash column chromatography on silica gel (CH 2 CI 2 , EtOH, 96:4-80:20, biotage 25+S) to yield the a mixture of starting material and product (50 mg, 2:5), along with dehalogenated monochloro starting material (7 mg, 1 1%).
- the product/starting material mixture was further purified by preparative hplc (CH 3 CN, H 2 O, gradient 1 :9 to 9:1 , 15 min) to furnish the title compound (9 mg, 10%) as a clear colourless oil, along with recovered 1-(3,5- dichloropyridin-4-yl)piperidine-4-carboxamide (30 mg, 40%) as a white solid, LC-MS (ESI, 4 min) R, 2.31 min, m/z 322 (100%, [M+H] + ); m/z (ESI) Ci 5 H 16 N 3 OSCI requires 321.0703, found [M+H] + 321.0700.
- Examples 82 and 83 1-(3-bromo-5-otolylpyridin-4-yl)piperidine-4-carboxamide E82 and 1-(3,5-dio-tolylpyridin-4-yl)piperidine-4-carboxamide E83
- luciferase reporter cell based assay A luciferase reporter cell line was developed in HEK293 cells, which contained an estrogen receptor-DSH (ER-DSH) construct and a TCF-luciferase-l RES-GFP construct.
- ER-DSH estrogen receptor-DSH
- a high-throughput assay was performed by inducing TCF-dependent transcription in the ER-DSH HEK293 cell line by the addition of estrogen (2 ⁇ M) resulting in at least a 14-fold increase in reporter activity measured at 24 hours.
- Particular compounds of the invention possess and IC50 in the above-mentioned luciferase assay of less than 10 ⁇ M.
- Preferred compounds have an IC50 of less than 1 ⁇ M and most preferred compounds have an IC50 of less than 0.5 ⁇ M.
- DN-LRP a component of the Wnt receptor
- Ax-2 a dominant negative form of axin
- DN- ⁇ -catenin a stabilised form of ⁇ -catenin
- VP16- TCF a TCF transcription factor active in the absence of ⁇ -catenin
- the growth inhibitory activity of compounds was also determined against a small panel of human colorectal cell lines (HCT116, HT29, and SW480).
- Certain compounds were found to have a Gl 50 against the HT29 cell line of less than 100 ⁇ M and an IC 50 against the Luciferase reporter vector of less than 100 ⁇ M.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pyridine Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Description
Claims
Priority Applications (13)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN200980139464.8A CN102171202B (en) | 2008-10-06 | 2009-10-06 | Pyridine and pyrimidine based compounds as WNT signaling pathway inhibitors for the treatment of cancer |
JP2011529640A JP5711129B2 (en) | 2008-10-06 | 2009-10-06 | Pyridine and pyrimidine compounds as inhibitors of the Wnt signaling pathway for the treatment of cancer |
EA201170531A EA021828B1 (en) | 2008-10-06 | 2009-10-06 | Pyridine and pyrimidine based compounds as wnt signaling pathway inhibitors for the treatment of cancer |
MX2011003697A MX2011003697A (en) | 2008-10-06 | 2009-10-06 | Pyridine and pyrimidine based compounds as wnt signaling pathway inhibitors for the treatment of cancer. |
CA2739527A CA2739527C (en) | 2008-10-06 | 2009-10-06 | Compounds and their use |
US13/122,555 US8778925B2 (en) | 2008-10-06 | 2009-10-06 | Pyridine and pyrimidine based compounds as Wnt signaling pathway inhibitors for the treatment of cancer |
KR1020117010186A KR101666517B1 (en) | 2008-10-06 | 2009-10-06 | Pyridine and pyrimidine based compounds as wnt signaling pathway inhibitors for the treatment of cancer |
EP09740521A EP2331523A1 (en) | 2008-10-06 | 2009-10-06 | Pyridine and pyrimidine based compounds as wnt signaling pathway inhibitors for the treatment of cancer |
AU2009300869A AU2009300869B2 (en) | 2008-10-06 | 2009-10-06 | Pyridine and pyrimidine based compounds as Wnt signaling pathway inhibitors for the treatment of cancer |
BRPI0920847A BRPI0920847A2 (en) | 2008-10-06 | 2009-10-06 | compound, pharmaceutical formulation, and method for treating, preventing or retarding cancer progression in a patient |
IL211825A IL211825A (en) | 2008-10-06 | 2011-03-20 | Pyridine and pyrimidine based compounds for use as wnt signaling pathway inhibitors, pharmaceutical formulations comprising such compounds and use thereof as medicaments for the treatment and/or prophylaxis of cancer |
ZA2011/02520A ZA201102520B (en) | 2008-10-06 | 2011-04-05 | Pyridine and pyrimidine based compounds as wnt signaling pathway inhibitors for the treatment of cancer |
US14/303,448 US20140350015A1 (en) | 2008-10-06 | 2014-06-12 | Pyridine and pyrimidine based compounds as wnt signaling pathway inhibitors for the treatment of cancer |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB0818241.2 | 2008-10-06 | ||
GBGB0818241.2A GB0818241D0 (en) | 2008-10-06 | 2008-10-06 | Compounds and their use |
Related Child Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US13/122,555 A-371-Of-International US8778925B2 (en) | 2008-10-06 | 2009-10-06 | Pyridine and pyrimidine based compounds as Wnt signaling pathway inhibitors for the treatment of cancer |
US14/303,448 Continuation US20140350015A1 (en) | 2008-10-06 | 2014-06-12 | Pyridine and pyrimidine based compounds as wnt signaling pathway inhibitors for the treatment of cancer |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2010041054A1 true WO2010041054A1 (en) | 2010-04-15 |
Family
ID=40042322
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/GB2009/051319 WO2010041054A1 (en) | 2008-10-06 | 2009-10-06 | Pyridine and pyrimidine based compounds as wnt signaling pathway inhibitors for the treatment of cancer |
Country Status (14)
Country | Link |
---|---|
US (2) | US8778925B2 (en) |
EP (1) | EP2331523A1 (en) |
JP (1) | JP5711129B2 (en) |
KR (1) | KR101666517B1 (en) |
CN (1) | CN102171202B (en) |
AU (1) | AU2009300869B2 (en) |
BR (1) | BRPI0920847A2 (en) |
CA (1) | CA2739527C (en) |
EA (1) | EA021828B1 (en) |
GB (1) | GB0818241D0 (en) |
IL (1) | IL211825A (en) |
MX (1) | MX2011003697A (en) |
WO (1) | WO2010041054A1 (en) |
ZA (1) | ZA201102520B (en) |
Cited By (19)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102558173A (en) * | 2010-12-31 | 2012-07-11 | 广州源生医药科技有限公司 | Compound inhibiting conduction of WNT signal, and composition and application thereof |
WO2013110433A1 (en) * | 2012-01-28 | 2013-08-01 | Merck Patent Gmbh | Azaheterocyclic compounds |
WO2014007228A1 (en) * | 2012-07-03 | 2014-01-09 | 小野薬品工業株式会社 | Compound having agonistic activity on somatostatin receptor, and use thereof for medical purposes |
WO2014063778A1 (en) | 2012-10-08 | 2014-05-01 | Merck Patent Gmbh | 2-aminopyridine compounds |
WO2014086453A1 (en) * | 2012-12-07 | 2014-06-12 | Merck Patent Gmbh | Azaheterobicyclic compounds |
WO2015046482A1 (en) | 2013-09-30 | 2015-04-02 | 小野薬品工業株式会社 | Compound having agonistic activity to somatostatin receptor and medicinal use thereof |
CN104530042A (en) * | 2010-12-31 | 2015-04-22 | 广州源生医药科技有限公司 | Compound inhibiting WNT signal conduction, composition, and application of two |
WO2015144290A1 (en) * | 2014-03-27 | 2015-10-01 | Merck Patent Gmbh | Pyridyl piperidines |
WO2018013676A1 (en) * | 2016-07-14 | 2018-01-18 | Crinetics Pharmaceuticals, Inc. | Somatostatin modulators and uses thereof |
EP3359154A4 (en) * | 2015-10-08 | 2019-05-15 | Suzhou Yunxuan Yiyao Keji Youxian Gongsi | Wnt signaling pathway inhibitors and therapeutic applications thereof |
US10464918B2 (en) | 2018-01-17 | 2019-11-05 | Crinetics Pharmaceuticals, Inc. | Process of making somatostatin modulators |
CN112707888A (en) * | 2021-02-03 | 2021-04-27 | 上海雅本化学有限公司 | Synthesis method of N-2-pyridyl 5-pyrimidyl methylamine |
US11028068B2 (en) | 2017-07-25 | 2021-06-08 | Crinetics Pharmaceuticals, Inc. | Somatostatin modulators and uses thereof |
US11072598B2 (en) | 2017-03-16 | 2021-07-27 | Crinetics Pharmaceuticals, Inc. | Somatostatin modulators and uses thereof |
US11186590B2 (en) | 2018-09-18 | 2021-11-30 | Crinetics Pharmaceuticals, Inc. | Somatostatin modulators and uses thereof |
US11266641B1 (en) | 2020-09-09 | 2022-03-08 | Crinetics Pharmaceuticals, Inc. | Formulations of a somatostatin modulator |
US11479540B2 (en) | 2019-08-14 | 2022-10-25 | Crinetics Pharmaceuticals, Inc. | Nonpeptide somatostatin type 5 receptor agonists and uses thereof |
US11608335B2 (en) | 2018-02-12 | 2023-03-21 | Crinetics Pharmaceuticals, Inc. | Somatostatin modulators and uses thereof |
US11773076B2 (en) | 2021-02-17 | 2023-10-03 | Crinetics Pharmaceuticals, Inc. | Crystalline forms of a somatostatin modulator |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR101376338B1 (en) * | 2011-09-06 | 2014-03-19 | 재단법인 제이씨비 공동생물과학연구소 | Pharmaceutical composition comprising statin-based drug and Wnt signal transduction regulator for preventing or treating arteriosclerosis and stroke |
CN103435555B (en) * | 2013-08-27 | 2015-06-24 | 贵州威顿晶磷电子材料股份有限公司 | Preparation method of 4-chloro-5-methylpyrimidine |
CN107759584B (en) * | 2016-08-16 | 2021-06-01 | 苏州云轩医药科技有限公司 | Amino five-membered heterocyclic compound with Wnt signal channel inhibition activity and application thereof |
WO2020123670A1 (en) * | 2018-12-11 | 2020-06-18 | Arizona Board Of Regents On Behalf Of The University Of Arizona | Small molecule inhibitors of the androgen receptor activity and/or expression and uses thereof |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001027107A2 (en) * | 1999-10-12 | 2001-04-19 | Bristol-Myers Squibb Company | Heterocyclic sodium/proton exchange inhibitors and method |
CA2431171A1 (en) * | 2000-12-08 | 2002-06-13 | Takeda Chemical Industries, Ltd. | Substituted thiazole derivatives bearing 3-pyridyl groups, process for preparing the same and use thereof |
WO2005068468A2 (en) * | 2003-12-02 | 2005-07-28 | Vertex Pharmaceuticals, Inc. | Heterocyclic protein kinase inhibitors and uses thereof |
WO2007092435A2 (en) * | 2006-02-07 | 2007-08-16 | Wyeth | 11-beta hsd1 inhibitors |
WO2007135427A1 (en) * | 2006-05-23 | 2007-11-29 | Astrazeneca Ab | 1,4-disubstituted piperazine and 1,4-disubstituted azepane as 11 -beta-hydroxysteroid dehydrogenase 1 inhibitors |
Family Cites Families (19)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB8603120D0 (en) * | 1986-02-07 | 1986-03-12 | Pfizer Ltd | Anti-dysrhythmia agents |
GB8609630D0 (en) * | 1986-04-19 | 1986-05-21 | Pfizer Ltd | Anti-arrhythmia agents |
GB9516709D0 (en) | 1995-08-15 | 1995-10-18 | Zeneca Ltd | Medicament |
CZ45699A3 (en) | 1996-08-14 | 1999-05-12 | Zeneca Limited | Substituted pyrimidine derivatives, process of their preparation and pharmaceutical composition containing thereof |
US6440972B1 (en) | 1997-02-13 | 2002-08-27 | Zeneca Limited | Heterocyclic compounds useful as oxido-squalene cyclase inhibitors |
KR20010052694A (en) | 1998-06-08 | 2001-06-25 | 에가시라 구니오 | Benzamidine derivative |
DE19920936A1 (en) * | 1999-05-07 | 2000-11-09 | Basf Ag | Heterocyclically substituted benzimidazoles, their preparation and use |
EP1608373A4 (en) | 2003-03-19 | 2010-09-29 | Exelixis Inc | Tie-2 modulators and methods of use |
EP1680114A4 (en) | 2003-10-28 | 2008-09-24 | Amgen Inc | Triazole compounds and uses related thereto |
US7354938B2 (en) | 2004-03-23 | 2008-04-08 | Amgen Inc. | Pyrazole compounds and uses related thereto |
JP4906715B2 (en) * | 2004-05-08 | 2012-03-28 | ニューロジェン・コーポレーション | 4,5-disubstituted-2-arylpyrimidines |
CA2585797C (en) * | 2004-11-10 | 2015-01-06 | Incyte Corporation | Lactam compounds and their use as pharmaceuticals |
US20080200431A1 (en) * | 2005-07-08 | 2008-08-21 | Astrazeneca Ab | Heterocyclic Sulfonamide Derivatives as Inhibitors of Factor Xa |
AU2006322060A1 (en) * | 2005-12-05 | 2007-06-14 | Incyte Corporation | Lactam compounds and methods of using the same |
GB0525083D0 (en) * | 2005-12-09 | 2006-01-18 | Astrazeneca Ab | Pyrimidine derivatives |
WO2007076055A2 (en) * | 2005-12-22 | 2007-07-05 | Entremed, Inc. | Compositions and methods comprising proteinase activated receptor antagonists |
WO2007083182A2 (en) * | 2006-01-19 | 2007-07-26 | Orchid Research Laboratories Limited | Novel heterocycles |
MX2008013400A (en) | 2006-04-19 | 2008-11-10 | Astellas Pharma Inc | Azolecarboxamide derivative. |
TW200835487A (en) * | 2006-12-28 | 2008-09-01 | Basf Ag | 2-substituted pyridines I in therapy |
-
2008
- 2008-10-06 GB GBGB0818241.2A patent/GB0818241D0/en not_active Ceased
-
2009
- 2009-10-06 AU AU2009300869A patent/AU2009300869B2/en not_active Ceased
- 2009-10-06 KR KR1020117010186A patent/KR101666517B1/en active IP Right Grant
- 2009-10-06 US US13/122,555 patent/US8778925B2/en not_active Expired - Fee Related
- 2009-10-06 EA EA201170531A patent/EA021828B1/en not_active IP Right Cessation
- 2009-10-06 MX MX2011003697A patent/MX2011003697A/en active IP Right Grant
- 2009-10-06 CN CN200980139464.8A patent/CN102171202B/en not_active Expired - Fee Related
- 2009-10-06 WO PCT/GB2009/051319 patent/WO2010041054A1/en active Application Filing
- 2009-10-06 JP JP2011529640A patent/JP5711129B2/en not_active Expired - Fee Related
- 2009-10-06 BR BRPI0920847A patent/BRPI0920847A2/en not_active IP Right Cessation
- 2009-10-06 EP EP09740521A patent/EP2331523A1/en not_active Withdrawn
- 2009-10-06 CA CA2739527A patent/CA2739527C/en not_active Expired - Fee Related
-
2011
- 2011-03-20 IL IL211825A patent/IL211825A/en not_active IP Right Cessation
- 2011-04-05 ZA ZA2011/02520A patent/ZA201102520B/en unknown
-
2014
- 2014-06-12 US US14/303,448 patent/US20140350015A1/en not_active Abandoned
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001027107A2 (en) * | 1999-10-12 | 2001-04-19 | Bristol-Myers Squibb Company | Heterocyclic sodium/proton exchange inhibitors and method |
CA2431171A1 (en) * | 2000-12-08 | 2002-06-13 | Takeda Chemical Industries, Ltd. | Substituted thiazole derivatives bearing 3-pyridyl groups, process for preparing the same and use thereof |
WO2005068468A2 (en) * | 2003-12-02 | 2005-07-28 | Vertex Pharmaceuticals, Inc. | Heterocyclic protein kinase inhibitors and uses thereof |
WO2007092435A2 (en) * | 2006-02-07 | 2007-08-16 | Wyeth | 11-beta hsd1 inhibitors |
WO2007135427A1 (en) * | 2006-05-23 | 2007-11-29 | Astrazeneca Ab | 1,4-disubstituted piperazine and 1,4-disubstituted azepane as 11 -beta-hydroxysteroid dehydrogenase 1 inhibitors |
Non-Patent Citations (3)
Title |
---|
DATABASE REGISTRY CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 21 February 2006 (2006-02-21), "1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxylic acid", XP002560163 * |
PARK C H ET AL: "Quercetin, a potent inhibitor against beta-catenin/Tcf signaling in SW480 colon cancer cells", BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, ACADEMIC PRESS INC. ORLANDO, FL, US, vol. 328, no. 1, 4 March 2005 (2005-03-04), pages 227 - 234, XP004723763, ISSN: 0006-291X * |
See also references of EP2331523A1 * |
Cited By (42)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104530042A (en) * | 2010-12-31 | 2015-04-22 | 广州源生医药科技有限公司 | Compound inhibiting WNT signal conduction, composition, and application of two |
CN102558173A (en) * | 2010-12-31 | 2012-07-11 | 广州源生医药科技有限公司 | Compound inhibiting conduction of WNT signal, and composition and application thereof |
JP2015505542A (en) * | 2012-01-28 | 2015-02-23 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツングMerck Patent Gesellschaft mit beschraenkter Haftung | Aza heterocyclic compounds |
CN104080773A (en) * | 2012-01-28 | 2014-10-01 | 默克专利股份公司 | Azaheterocyclic compounds |
WO2013110433A1 (en) * | 2012-01-28 | 2013-08-01 | Merck Patent Gmbh | Azaheterocyclic compounds |
US9493444B2 (en) | 2012-01-28 | 2016-11-15 | Merck Patent Gmbh | Azaheterocyclic compounds |
AU2013212175B2 (en) * | 2012-01-28 | 2017-03-02 | Cancer Research Technology Limited | Azaheterocyclic compounds |
US10214540B2 (en) | 2012-07-03 | 2019-02-26 | Ono Pharmaceutical Co., Ltd. | Compound having agonistic activity on somatostatin receptor, and use thereof for medical purposes |
WO2014007228A1 (en) * | 2012-07-03 | 2014-01-09 | 小野薬品工業株式会社 | Compound having agonistic activity on somatostatin receptor, and use thereof for medical purposes |
US9975904B2 (en) | 2012-07-03 | 2018-05-22 | Ono Pharmaceutical Co., Ltd. | Compound having agonistic activity on somatostatin receptor, and use thereof for medical purposes |
US9630976B2 (en) | 2012-07-03 | 2017-04-25 | Ono Pharmaceutical Co., Ltd. | Compound having agonistic activity on somatostatin receptor, and use thereof for medical purposes |
WO2014063778A1 (en) | 2012-10-08 | 2014-05-01 | Merck Patent Gmbh | 2-aminopyridine compounds |
US9834541B2 (en) | 2012-10-08 | 2017-12-05 | Cancer Research Technology Limited | 2-aminopyridine compounds |
WO2014086453A1 (en) * | 2012-12-07 | 2014-06-12 | Merck Patent Gmbh | Azaheterobicyclic compounds |
RU2666352C2 (en) * | 2013-09-30 | 2018-09-07 | Оно Фармасьютикал Ко., Лтд. | Compound having agonistic activity to somatostatin receptor and medicinal use thereof |
KR20160062023A (en) | 2013-09-30 | 2016-06-01 | 오노 야꾸힝 고교 가부시키가이샤 | Compound having agonistic activity to somatostatin receptor and medicinal use thereof |
WO2015046482A1 (en) | 2013-09-30 | 2015-04-02 | 小野薬品工業株式会社 | Compound having agonistic activity to somatostatin receptor and medicinal use thereof |
AU2014325078B2 (en) * | 2013-09-30 | 2018-10-25 | Ono Pharmaceutical Co., Ltd. | Compound having agonistic activity to somatostatin receptor and medicinal use thereof |
US9643951B2 (en) | 2013-09-30 | 2017-05-09 | Ono Pharmaceutical Co., Ltd. | Compound having somatostatin receptor agonistic activity and pharmaceutical use thereof |
US9926319B2 (en) | 2014-03-27 | 2018-03-27 | Merck Patent Gmbh | Pyridyl piperidines |
WO2015144290A1 (en) * | 2014-03-27 | 2015-10-01 | Merck Patent Gmbh | Pyridyl piperidines |
AU2015236855B2 (en) * | 2014-03-27 | 2018-11-01 | Cancer Research Technology Limited | Pyridyl piperidines |
EP3359154A4 (en) * | 2015-10-08 | 2019-05-15 | Suzhou Yunxuan Yiyao Keji Youxian Gongsi | Wnt signaling pathway inhibitors and therapeutic applications thereof |
US10450300B2 (en) | 2015-10-08 | 2019-10-22 | Suzhou Yunxuan Yiyao Keji Youxian Gongsi | Wnt signaling pathway inhibitors and therapeutic applications thereof |
US9896432B2 (en) | 2016-07-14 | 2018-02-20 | Crinetics Pharmaceuticals, Inc. | Somatostatin modulators and uses thereof |
WO2018013676A1 (en) * | 2016-07-14 | 2018-01-18 | Crinetics Pharmaceuticals, Inc. | Somatostatin modulators and uses thereof |
US10351547B2 (en) | 2016-07-14 | 2019-07-16 | Crinetics Pharmaceuticals, Inc. | Somatostatin modulators and uses thereof |
US11414397B2 (en) | 2016-07-14 | 2022-08-16 | Crinetics Pharmaceuticals, Inc. | Somatostatin modulators and uses thereof |
US10597377B2 (en) | 2016-07-14 | 2020-03-24 | Crinetics Pharmaceuticals, Inc. | Somatostatin modulators and uses thereof |
US10875839B2 (en) | 2016-07-14 | 2020-12-29 | Crinetics Pharmaceuticals, Inc. | Somatostatin modulators and uses thereof |
US11072598B2 (en) | 2017-03-16 | 2021-07-27 | Crinetics Pharmaceuticals, Inc. | Somatostatin modulators and uses thereof |
US11028068B2 (en) | 2017-07-25 | 2021-06-08 | Crinetics Pharmaceuticals, Inc. | Somatostatin modulators and uses thereof |
US10889561B2 (en) | 2018-01-17 | 2021-01-12 | Crinetics Pharmaceuticals, Inc. | Process of making somatostatin modulators |
US10464918B2 (en) | 2018-01-17 | 2019-11-05 | Crinetics Pharmaceuticals, Inc. | Process of making somatostatin modulators |
US11608335B2 (en) | 2018-02-12 | 2023-03-21 | Crinetics Pharmaceuticals, Inc. | Somatostatin modulators and uses thereof |
US11186590B2 (en) | 2018-09-18 | 2021-11-30 | Crinetics Pharmaceuticals, Inc. | Somatostatin modulators and uses thereof |
US11834462B2 (en) | 2018-09-18 | 2023-12-05 | Crinetics Pharmaceuticals, Inc. | Somatostatin modulators and uses thereof |
US11479540B2 (en) | 2019-08-14 | 2022-10-25 | Crinetics Pharmaceuticals, Inc. | Nonpeptide somatostatin type 5 receptor agonists and uses thereof |
US11266641B1 (en) | 2020-09-09 | 2022-03-08 | Crinetics Pharmaceuticals, Inc. | Formulations of a somatostatin modulator |
US11957674B2 (en) | 2020-09-09 | 2024-04-16 | Crinetics Pharmaceuticals, Inc. | Formulations of a somatostatin modulator |
CN112707888A (en) * | 2021-02-03 | 2021-04-27 | 上海雅本化学有限公司 | Synthesis method of N-2-pyridyl 5-pyrimidyl methylamine |
US11773076B2 (en) | 2021-02-17 | 2023-10-03 | Crinetics Pharmaceuticals, Inc. | Crystalline forms of a somatostatin modulator |
Also Published As
Publication number | Publication date |
---|---|
JP2012504592A (en) | 2012-02-23 |
KR20110118611A (en) | 2011-10-31 |
EA201170531A1 (en) | 2011-10-31 |
CA2739527A1 (en) | 2010-04-15 |
BRPI0920847A2 (en) | 2015-12-22 |
US8778925B2 (en) | 2014-07-15 |
GB0818241D0 (en) | 2008-11-12 |
CA2739527C (en) | 2016-08-30 |
AU2009300869B2 (en) | 2014-11-20 |
ZA201102520B (en) | 2013-09-25 |
CN102171202B (en) | 2015-01-07 |
EA021828B1 (en) | 2015-09-30 |
IL211825A0 (en) | 2011-06-30 |
CN102171202A (en) | 2011-08-31 |
JP5711129B2 (en) | 2015-04-30 |
EP2331523A1 (en) | 2011-06-15 |
US20140350015A1 (en) | 2014-11-27 |
KR101666517B1 (en) | 2016-10-14 |
AU2009300869A1 (en) | 2010-04-15 |
MX2011003697A (en) | 2011-11-18 |
IL211825A (en) | 2016-08-31 |
US20110190297A1 (en) | 2011-08-04 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU2009300869B2 (en) | Pyridine and pyrimidine based compounds as Wnt signaling pathway inhibitors for the treatment of cancer | |
AU2008241610B2 (en) | Novel n- (8-heteroaryltetrahydronaphtalene-2yl) or n- (5- heteroarylchromane-3-yl) carboxamide derivatives for the treatment of pain | |
CN115721648A (en) | Novel heterocyclic derivatives useful as SHP2 inhibitors | |
EP1819332B1 (en) | Pyrrolopyridine-2-carboxylic acid amides | |
AU2015275730A1 (en) | Substituted indazole compounds as IRAK4 inhibitors | |
IL172159A (en) | 2-oxo-pyridine derivatives and pharmaceutical compositions containing the same and uses thereof | |
WO2015110999A1 (en) | Ezh2 inhibitors and uses thereof | |
CN111410659B (en) | PDE9 inhibitors and uses thereof | |
JP2007506803A5 (en) | ||
AU2001245856A1 (en) | Thrombin inhibitors | |
KR20100052507A (en) | Novel heterocyclic compounds as mglu5 antagonists | |
AU2017327304B2 (en) | Use of morphinan derivative for therapeutic treatment of opioid δ receptor agonist-related disease | |
CA2709314A1 (en) | 5-alkyl/alkenyl-3-cyanopyridines as kinase inhibitors | |
CN115515589A (en) | ULK1/2 inhibitors and methods of use thereof | |
WO2022010882A1 (en) | Dihydroquinoxaline and dihydropyridopyrazine derivatives as rsv inhibitors | |
US20030199544A1 (en) | Farnesyltransferase inhibitors | |
CN114787143A (en) | ZESTE enhancer homolog 2 inhibitors and uses thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WWE | Wipo information: entry into national phase |
Ref document number: 200980139464.8 Country of ref document: CN |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 09740521 Country of ref document: EP Kind code of ref document: A1 |
|
REEP | Request for entry into the european phase |
Ref document number: 2009740521 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2009740521 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2739527 Country of ref document: CA Ref document number: 2011529640 Country of ref document: JP Ref document number: 13122555 Country of ref document: US |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: MX/A/2011/003697 Country of ref document: MX |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2684/DELNP/2011 Country of ref document: IN |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2009300869 Country of ref document: AU |
|
ENP | Entry into the national phase |
Ref document number: 20117010186 Country of ref document: KR Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 201170531 Country of ref document: EA |
|
ENP | Entry into the national phase |
Ref document number: 2009300869 Country of ref document: AU Date of ref document: 20091006 Kind code of ref document: A |
|
ENP | Entry into the national phase |
Ref document number: PI0920847 Country of ref document: BR Kind code of ref document: A2 Effective date: 20110405 |