WO2002085859A1 - HETEROARYL UREAS CONTAINING NITROGEN HETERO-ATOMS AS p38 KINASE INHIBITORS - Google Patents
HETEROARYL UREAS CONTAINING NITROGEN HETERO-ATOMS AS p38 KINASE INHIBITORS Download PDFInfo
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- WO2002085859A1 WO2002085859A1 PCT/US2002/012064 US0212064W WO02085859A1 WO 2002085859 A1 WO2002085859 A1 WO 2002085859A1 US 0212064 W US0212064 W US 0212064W WO 02085859 A1 WO02085859 A1 WO 02085859A1
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- WIPO (PCT)
- Prior art keywords
- substituted
- halo
- group
- per
- alkyl
- Prior art date
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- 0 *c1ccccc1 Chemical compound *c1ccccc1 0.000 description 1
- VFBATACGUFXQMA-UHFFFAOYSA-N C/[O]=C(\Nc1cccc(Sc2ccncc2)c1)/Nc1ccc(C(F)(F)F)cn1 Chemical compound C/[O]=C(\Nc1cccc(Sc2ccncc2)c1)/Nc1ccc(C(F)(F)F)cn1 VFBATACGUFXQMA-UHFFFAOYSA-N 0.000 description 1
- KOZSKYWQXWPXOD-UHFFFAOYSA-N CCCCOc(cc1)ccc1Sc(cc1)ccc1N Chemical compound CCCCOc(cc1)ccc1Sc(cc1)ccc1N KOZSKYWQXWPXOD-UHFFFAOYSA-N 0.000 description 1
- CQOXJJMNEPQCMZ-UHFFFAOYSA-N CN(c(cc1)ccc1N)c1ccncc1 Chemical compound CN(c(cc1)ccc1N)c1ccncc1 CQOXJJMNEPQCMZ-UHFFFAOYSA-N 0.000 description 1
- ZLPYKIGLDGVFAU-UHFFFAOYSA-N CNC(c1cc(Oc(cc2)ccc2I)ccn1)=O Chemical compound CNC(c1cc(Oc(cc2)ccc2I)ccn1)=O ZLPYKIGLDGVFAU-UHFFFAOYSA-N 0.000 description 1
- KEWJTIYHRJBAHE-UHFFFAOYSA-N COc(cc1)ncc1OC1C=CC([N+]([O-])=O)=CC1 Chemical compound COc(cc1)ncc1OC1C=CC([N+]([O-])=O)=CC1 KEWJTIYHRJBAHE-UHFFFAOYSA-N 0.000 description 1
- AALQUOHYAMXZRQ-UHFFFAOYSA-N Cc(cc1)ccc1Oc(cc1)ccc1OC Chemical compound Cc(cc1)ccc1Oc(cc1)ccc1OC AALQUOHYAMXZRQ-UHFFFAOYSA-N 0.000 description 1
- DUOKGZWRUWUHQT-UHFFFAOYSA-N Cc1ccc(CC2CNCCC2)cc1 Chemical compound Cc1ccc(CC2CNCCC2)cc1 DUOKGZWRUWUHQT-UHFFFAOYSA-N 0.000 description 1
- DGHAOTHIDTUSJY-UHFFFAOYSA-N Nc1ccc(C[n]2cncc2)cc1 Chemical compound Nc1ccc(C[n]2cncc2)cc1 DGHAOTHIDTUSJY-UHFFFAOYSA-N 0.000 description 1
- CSKNSYBAZOQPLR-UHFFFAOYSA-N O=S(c1ccccc1)(Cl)=O Chemical compound O=S(c1ccccc1)(Cl)=O CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 1
- RMVRSNDYEFQCLF-UHFFFAOYSA-N Sc1ccccc1 Chemical compound Sc1ccccc1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 1
Classifications
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- 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
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
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- A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
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- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
- A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
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Definitions
- This invention relates to the use of a group of heteroaryl ureas containing nitrogen hetero atoms in treating cytokine mediated diseases and proteolytic enzyme ' mediated diseases, and pharmaceutical compositions for use in such therapy.
- effector molecules which are critical for the progression of rheumatoid arthritis are pro-inflammatory cytokines and tissue degrading proteases. Recently, a family of kinases was described which is mstrumental in controlling the transcription and translation of the structural genes coding for these effector molecules.
- the mitogen-activated protein (MAP) kinase family is made up of a series of structurally related proline-directed serine/threonine kinases which are activated either by growth factors (such as EGF) and phorbol esters (ERK), or by IL-1, TNF ⁇ or stress (p38, INK).
- the MAP kinases are responsible for the activation of a wide variety of transcription factors and proteins involved in transcriptional control of cytokine production.
- a pair of novel protein kinases involved in the regulation of cytokine synthesis was recently described by a group from SmithKline Beecham (Lee et al. Nature 1994, 372, 739).
- CSACDSs cytokine suppressive anti-inflammatory drugs
- Inhibition of p38 has been shown to inhibit both cytokine production (eg., TNF ⁇ , IL-1, JX-6, E -8) and proteolytic enzyme production (eg., MMP-1, MMP-3) in vitro and/or in vivo.
- cytokine production eg., TNF ⁇ , IL-1, JX-6, E -8
- proteolytic enzyme production eg., MMP-1, MMP-3
- TNF ⁇ production and/or signaling have linked TNF ⁇ production and/or signaling to a number of diseases including rheumatoid arthritis (Maini. J. Royal Coll. Physicians London 1996, 30, 344).
- excessive levels of TNF ⁇ have been implicated in a wide variety of inflammatory and/or immunomodulatory diseases, including acute rheumatic fever (Yegin et al. Lancet 1997, 349, 170), bone resorption (Pacifici et al. J. Clin. Endocrinol. Metabol. 1997, 82, 29), postmenopausal osteoperosis (Pacifici et al. J. Bone Mineral Res. 1996, 11, 1043), sepsis (Blackwell et al. Br. J. Anaesth.
- TNF ⁇ levels have also been related to host-versus-graft reactions (Piguet et al. Immunol. Ser. 1992, 56, 409) including ischemia reperfusion injury (Colletti et al. J. Clin. Invest. 1989, 85, 1333) and allograft rejections including those of the kidney (Maury et al. J. Exp. Med.
- liver Imagawa et al. Transplantation 1990, 50, 219
- heart Boiling et al. Transplantation 1992, 53, 283
- skin Step et al. Transplant. Proc. 1990, 22, 1924
- lung allograft rejection Grossman et al. Immunol. Allergy Clin. N. Am.
- TNF ⁇ has also been linked to infectious diseases (review: Beutier et al. Crit. Care Med. 1993, 21, 5423; Degre. Biotherapy 1996, 8, 219) including tuberculosis (Rook et al. Med. Malad. Infect. 1996, 26, 904), Helicobacter pylori infection during peptic ulcer disease (Beales et al.
- p38 inhibitors will be useful in treatment of the above listed diseases.
- a number of diseases are thought to be mediated by excess or undesired matrix- destroying metalloprotease (MMP) activity or by an imbalance in the ratio of the MMPs to the tissue inhibitors of metalloproteinases (TIMPs). These include osteoarthritis (Woessner et al.
- Inhibitors of p38 are active in animal models of TNF ⁇ production, including a muirne lipopolysaccharide (LPS) model of TNF ⁇ production. Inhibitors of p38 are active in a number of standard animal models of inflammatory diseases, including carrageenan-induced edema in the rat paw, arachadonic acid-induced edema in the rat paw, arachadonic acid-induced peritonitis in the mouse, fetal rat long bone resorption, murine type II collagen-induced arthritis, and Fruend's adjuvant-induced arthritis in the rat. Thus, inhibitors of p38 will be useful in treating diseases mediated by one or more of the above-mentioned cytokines and/or proteolytic enzymes.
- This invention provides compounds, generally described as heteroaryl ureas containing nitrogen hetero atoms, including pyridine, quinoline and isoquinoline. ureas, which inhibit p38 mediated events and thus inhibit the production of cytokines (such as TNF ⁇ , IL-1 and IL-8) and proteolytic enzymes (such as MMP-1 and MMP-3).
- the invention also provides compositions which contain heteroaryl ureas and a method of treating a cytokine mediated disease state in humans or mammals with heteroaryl ureas, wherein the cytokine is one whose production is affected by p38. Examples of such cytokines include, but are not limited to TNF ⁇ , EL-1 and IL-8.
- the invention also provides a method of treating a protease mediated disease state; in Jiumans or mammals, wherein the protease is one whose production is affected by p38, e.g. disease states mediated by one or more cytokines or proteolytic enzymes produced and/or activated by a p38 mediated process.
- proteases include, but are not limited to collagenase (MMP-1) and stromelysin (MMP-3).
- these compounds are useful therapeutic agents for such acute and chronic inflammatory and/or immunomodulatory diseases as rheumatoid arthritis, osteoarthritis, septic arthritis, rheumatic fever, bone resorption, postmenopausal osteoperosis, sepsis, gram negative sepsis, septic shock, endotoxic shock, toxic shock syndrome, systemic inflammatory response syndrome, inflammatory bowel diseases including Crohn's disease and ulcerative colitis, Jarisch-Herxheimer reactions, asthma, adult respiratory distress syndrome, acute pulmonary fibrotic diseases, pulmonary sarcoidosis, allergic respiratory diseases, silicosis, coal worker's pneumoconiosis, alveolar injury, hepatic failure, liver disease during acute inflammation, severe alcoholic hepatitis, malaria including Plasmodium falciparum malaria and cerebral malaria, non- ' insulin-dependent diabetes mellitus (NLODM), congestive heart failure, damage following heart disease, atherosclerosis, Alzheimer's disease, acute
- lung allograft rejection including chronic lung allograft rejection (obliterative bronchitis) as well as complications due to total hip replacement, and infectious diseases including tuberculosis, Helicobacter pylori infection during peptic ulcer disease, Chaga's disease resulting from Trypanosoma cruzi infection, effects of Shiga-like toxin resulting from E.
- the present invention therefore, provides hetaryl urea compounds containing nitrogen hetero-atoms, and compositions which comprise hetaryl urea compounds containing nitrogen heteroatoms and a method for treating of p38-mediated disease states in humans or mammals, e.g., disease states mediated by one or more cytokines or proteolytic enzymes produced and/or activated by a p38 mediated process.
- a compound of formula I, or a pharmaceutically acceptable salt thereof is administered, A - D - B (I) .
- D is -NH-C(O)-NH-
- A is a substituted or unsubstituted pyridyl, quinolinyl or isoquinoliyl group
- B is a substituted or unsubstituted, up to tricyclic aryl or heteroaryl moiety of up to 50 carbon atoms with a cyclic stmcture bound directly to D containing at least 5 members with 0-4 members of the group consisting of nitrogen, oxygen and sulfur.
- the moiety B is preferably either a substituted or unsubstituted bridged cyclic stmcture of up to 30 carbon atoms of the formula -L- ML 1 ) ⁇ a substituted or unsubstituted 6 member cyclic aryl moiety or hetaryl moiety or a substituted or unsubstituted 2-3 fused ring stmcture (aryl, hetaryl or both).
- B can be phenyl, substituted phenyl, napthyl substituted napthyl, pyridinyl, substituted pyridinyl, pyrimidinyl, substituted pyrimidinyl, quinolinyl, substituted quinolinyl, isoquinolinyl, substituted isoquinolinyl or of the formula -L( L l ) q .
- L in the formula -L ⁇ ML ⁇ q is a 5 or 6 membered cyclic stmcture bond directly to D, L 1 is a cyclic moiety of at least 5 members,
- M is a bridging group having at least one atom and q is an integer of 1-3.
- Each cyclic stmcture of L and L 1 contains from 0-4 members of the group consisting of N, O and S.
- the substituents for the groups of A are preferably selected from the group consisting of halogen, up to per-halo, and Wn, where n is 0-3 and each W is independently selected from the group consisting of C ⁇ o alkyl, C ⁇ o alkoxy, C . ⁇ o cycloalkyl having at least five cyclic members and 0-3 heteroatoms, C 2 . 10 alkenyl, C O alkenoyl, substituted C MO alkyl, substituted C O alkoxy, a substituted C 3 .
- W is a substituted group, it is substituted by halogen, up to per halo, or by one or more substituents independently selected from the group consiting of -CN, -CO 2 R 7 , -C(O)NR 7 R 7' , -C(O)-R 7 , -NO 2 , -OR 7 , -SR 7 , -NR 7 R 7' , -NR 7 C(O)OR 7' , - NR 7 C(O)R 7' with each R 7 and R 7 independently as defined above.
- each substituents are selected from the group consisting of halogen, up to per-halo, and J n , where n is O-3 " and " each" J is independently selected from the group consisting of -CN, -CO 2 R 7 , -C(O)NR 7 R 7' , -C(O)-R 7 , -NO 2 , -OR 7 , -SR 7 , - NR 7 R 7' , -NR 7 C(O)OR 7' , -NR 7 C(O)R 7' , with each R 7 and R 7' independently as defined above , C MO alkyl, C M O alkoxy, C 3 .
- J is a substituted group, it is substituted by halogen, up to per halo, or by one or more substituents independently selected from the group consisting of -CN, - CO 2 R 7 , -C(O)-R 7 , -C(O)NR 7 R 7' , -OR 7 , -SR 7 , -NR 7 R 7' , -NO 2 , -NR 7 C(O)R 7' , and - NR 7 C(O)OR 7' ; with each R 7 and R 7' independently as defined above for W.
- Q is preferably a single bond, -O-, -S-, -N(R 7 )-, -(CH 2 )m-, -
- Ar is a 5- or 6-member aromatic stmcture.
- This aromatic stmcture of Ar a) contains 0-2 members selected from the group consisting of nitrogen, oxygen and sulfur, b) is optionally substituted by halogen, up to per-halo, and c) is optionally substituted by Z nl , wherein nl is 0 to 3 and each Z is independently selected from the group consisting of -CN, -NO 2 , -OR 7 , - SR 7 , -NR 7 R 7' , -NR 7 C(O)OR 7' , -NR 7 C(O)R 7' , with each R 7 and R 7' independently as defined above for W, C O -alkyl-,-.
- A is a substituted pyridyl, substituted quinolinyl or isoquinolinyl group
- A is preferably substituted 1 .to 3 times by 1 or more substituents selected from the group consisting of-CN, halogen, CrC 10 alkyl, Ci-Cio alkoxy, -OH, up to per halo substituted
- L 1 can be substituted by the substituents -C(O)R a , - C(NR a )R b , -C(O)NR a R b , -SO 2 NR a R b , -and -SO 2 R a wherein each R a and R are independently hydrogen or a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O, and optionally substituted by halogen.
- R a and R b preferably are each, independently, CM O alkyl, C O alkoxy, C 3 . 10 cycloalkyl having at least 5 cyclic members and 0-3 heteroatoms selected from N, S and O, C 2 - 10 alkenyl, C MO alkenoyl, C 6 -u aryl, C 3 . 12 hetaryl having 1-3 heteroatoms selected from N, S and O, C 7 .
- R a and/or R are a substituted group, they are substituted by halogen up to per halo hydroxy, C MO alkyl, C 3 . 12 cycloalkyl having 0-3 heteroatoms selected from O, S and N, C 3 . 12 hetaryl having 1-3 heteroatoms selected from N, S and O, C MO alkoxy, C 6 .
- R a and R b can also be
- R f is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen; or
- one of R a or R b can be -C(O)-, a C ! -C 5 divalent alkylene group or a substituted C 1 -C 5 divalent alkylene group bound to the moiety L to form a cyclic stmcture with at least 5 members, wherein the substituents of the substituted C ⁇ -C 5 divalent alkylene group are selected from the group consisting of halogen, hydroxy, and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen.
- the carbon based moieties of R f and the substituents on R a and R b include C MO alkyl, C MO alkyl, CM O alkoxy, C 3 -C 10 cycloalkyl having 0-3 heteroatoms selected from O, S and N, C_-n aryl, C 3 -C12 hetaryl having 1-3 heteroatoms selected from O, S and N, C - 24 aralkyl, substituted C M O alkyl, substituted C1-C10 alkoxy, substituted C 3 -C12 cycloalkyl having 0-3 heteroatoms selected from O, S and N, substituted C 3 -C 12 heteraryl having 1-3 heteroatoms selected from O, S, and N, substituted C 6 -i 2 aryl, and substituted C .
- R f is a substituted group it is substituted halogen up to per halo, hydroxy, CM O alkyl, C 3 - 12 cycloalkyl having 0-3 heteroatoms selected from O, S and N, C 3 .
- R g is C MO alkyl; -CN, -CO 2 Rd, -ORd, -SR_, -NO 2 , -C(O) R-, -NRjRe, -NRj C(O)OR e and -NRj C(O)Re, and Rd and R» are independently selected from the group consisting of hydrogen, C MO , alkyl, C MO alkoxy, C 3 - 1 0 cycloalkyl having 0-3 heteroatoms selected from O, N and S, C 6 -i 2 aryl, C 3 -C 12 hetaryl with 1-3 heteroatoms selected from O, N and S and C 7 -C 24 aralkyl, C -C2 alkaryl, up to per halo substituted Ci-do alkyl, up to per halo substituted C 3 -C10 cycloalkyl having 0-3 heteroatoms selected from O, N and S, up to per halo substituted C 6 -C ⁇
- the bridging group M in the formula -L-CML 1 ⁇ , for B is preferably selected from the group consisting of -O-, -S-, -N(R 7 )-, -(CH 2 ) m -, -C(O)-, -CH(OH)-, -(CH 2 ) m O-, -( CH 2 ) m S-, -( CH 2 ) m N(R 7 )-, -O(CH 2 ) m - CHX ⁇ -CX a 2 -, -S-(CH 2 ) m -, -N(R 7 )(CH 2 ) m - and
- M is -O-, -CH 2 - 3 -S-, -NH-, -C(O)-, -O-CH 2 - and -CH 2 -O-.
- the moieties L and L 1 in the formula -L ⁇ ML 1 ⁇ for B are typically each, independently, a substituted aryl moiety having at least 6 cyclic members, a substituted heterocyclic moiety having at least 5 cyclic members, an unsubstituted aryl moiety having at least 6 cyclic members or an unsubstituted heterocyclic moiety having at least 5 cyclic members.
- the heterocyclic and hetaryl moietes for L and L' typically have 1 to 4 members selected from the group of hetero atoms consisting of nitrogen, oxygen and sulfur with the balance of the hetaryl or heterocyclic moiety being carbon.
- More typical moieties for L 1 and L are selected from the group consisting of thiophene, substituted thiophene, phenyl, substituted phenyl, pyridinyl, substituted pyridinyl, pyrimidinyl and substituted pyrimidinyl.
- the substituents are selected from the group consisting of halogen, up to per-halo, and Jn where n is 0-3, and J is as defined above.
- Preferred compounds of Formula I include those wherein the cyclic structures of B and L bound directly to D are not substituted in the ortho position by-OH.
- the invention provides hetaryl compounds containing nitrogen hetero-atoms of formula ⁇
- D is as defined above for formula I and A' is either a substituted t- butylpyridyl, unsubstituted t-butylpyridyl, substituted (trifluoromethyl)pyridyl, unsubstituted (trifluoromethyl)pyridyl, substituted isopropylpyridyl, unsubstituted sopropylpyridyl, substituted ⁇ (2-methylr2-butyl)pyridyl, unsubstituted (2-methyl-2- butyl)pyridyl, substituted (3-ethyl-3-pentyl)pyridyl, unsubstituted (3-ethyl-3- pentyl)pyridyl, substituted isoquinolinyl, unsubstituted isoquinolinyl or unsubstituted quinolinyl.
- B' can be a substituted or unsubstituted 6 member cyclic aryl ring, at least a 5 member heterocylic ring or from 2-3 fused rings of up to 30 carbon atoms (aryl hetaryl or both).
- A' is substituted or unsubstituted t-butylyridyl, (trifluoromethyl)pyridyl, isopropylpyridyl, (2-methyl-2-butyl)pyridyl or (3-ethyl-3- pentyl)pyridyl.
- A' is a substituted isoquinolinyl, unsubsituted isoquinolinyl or unsubstituted quinolinyl group.
- the substituents for the substituted groups of A' are as defined for A.
- Preferred substituents are selected from the group consisting of up to per halo substituted CM O alkoxy, up to per halo substituted C MO alkyl and C ⁇ o heteroyclic moieties comprising 1 to 2 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.
- B' is a 6 member cyclic aryl ring, at least a 5 member heterocyclic ring o ' r 2-3 fused rings of up to 30 carbon atoms
- R 7 and R 7' are, independently, as defined above.
- the substituents are selected from the group consisting of - C ⁇ , halogen, OH, - ⁇ O 2 , -OR 7 , -SR 7 , -NR 7 R 7' , -NR 7 C(O)OR 7' , C M0 alkyl, C MO alkoxy, C2- 10 alkenyl, C MO alkenoyl, substituted C MO alkoxy, substituted C2-10 alkenyl and substituted alkenoyl C MO , with R 7 and R 7' as defined above.
- R a and R b preferably are each, independently, C MO alkyl, C O alkoxy, C3-10 cycloalkyl having at least 5 cyclic members and 0-3 heteroatoms, C 2 - 10 alkenyl, CMO alkenoyl, C 6 . 12 aryl, C 3 . 12 hetaryl having at least 5 cyclic members and 1-3 heteroatoms selected from N, S and O, C 24 aralkyl, C 7 .
- B' is a substituted pyridyl, substituted quinolinyl or isoquinolinyl group
- B' is preferably substituted 1 to 3 times by 1 or more substituents selected from the group consisting of-CN, halogen, C 1 -C10 alkyl, C 1 -C 10 alkoxy, -OH, up to per halo substituted d-do alkyl, up to per halo substituted d-do alkoxy or phenyl substituted by halogen up to per halo.
- suitable hetaryl groups include, but are not limited to, 4-12 carbon-atom aromatic rings or ring systems containing 1-3 rings, at least one of which is aromatic, in which one or more, e.g., 1-4 carbon atoms in one or more of the rings can be replaced by oxygen, nitrogen or sulfur atoms.
- Each ring typically has 5-7 member atoms.
- B can be 2- or 3 -furyl, 2- or 3-thienyl, 2- or 4-triazinyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5- isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6- pyrimidinyl, 1,2,3-triazol-l-, -4- or -5-yl, 1,2,4-triazol-l-, -3- or -5-yl, 1- or 5-tetrazolyl, l,2,3-oxadiazol-4- or -5-yl, l,2,4-oxadiazol-3- or -5-yl, l,3,4-thiadiazol-2- or -5-yl, l,2,4-oxadiazol
- B can be 4-methyl-phenyl, 5-methyl-2 -thienyl, 4-methyl-2 -thienyl, l-methyl-3- pyrryl, l-methyl-3-pyrazolyl, 5-methyl-2-thiazolyl or 5-methyl-l,2,4-thiadiazol-2-yl.
- Suitable alkyl groups and alkyl portions of groups, e.g., alkoxy, etc. throughout include methyl, ethyl, propyl, butyl, etc., including all straight-chain and branched isomers such -as, isopropyl, isobutyl, .sec-butyl, tert-butyl, etc.
- Suitable aryl groups which do not contain heteroatoms include, for example, phenyl and 1- and 2-naphthyl.
- cycloalkyl refers to cyclic structures with or without alkyl substituents such that, for example, "C cycloalkyl” includes methyl substituted cyclopropyl groups as well as cyclobutyl groups.
- cycloalkyl as used herein also includes saturated heterocyclic groups. Suitable halogen groups include F, Cl, Br, and/or I, from one to per-substitution (i.e. all H atoms on a group replaced by a halogen atom) being possible where an alkyl group is substituted by halogen, mixed substitution of halogen atom types also being possible on a given moiety.
- Suitable pharmaceutically acceptable salts are well known to those skilled in the art and include basic salts of inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, trifluoromethanesulfonic acid, benzenesulphonic acid, j?-toluenesulfonic acid, 1- naphthalenesulfonic acid, 2-naphthalenesulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid.
- basic salts of inorganic and organic acids such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, trifluoromethanesulfonic acid,
- pharmaceutically acceptable salts include acid salts of inorganic bases, such as salts containing alkaline cations (e.g., Li + Na + or K + ), alkaline earth cations (e.g., Mg +2 , Ca +2 or Ba +2 ), the ammonium cation, as well as acid salts of organic bases, including aliphatic and aromatic substituted ammonium, and quaternary ammonium cations, such as those arising from protonation or peralkylation of triethylamine, N,N-diethylamine, N,N-dicyclohexylamine, lysine, pyridine, N,N-dimethylaminopyridine (DMAP), 1,4- diazabiclo[2.2.2]octane (DABCO), l,5-diazabicyclo[4.3.0]non-5-ene (DB ⁇ ) and 1,8- diazabicyclo[5.4.0]undec-7-ene (
- a number of the compounds of Formulae I and 11 possess asymmetric carbons and can therefore exist in racemic and optically active forms. Methods of separation of enantiomeric and diastereomeric mixtures are well known to one skilled in the art.
- the present invention encompasses any racemic or optically active form of compounds described in Formula II which possess progesterone receptor binding activity.
- the compounds of Formulae I and J3 may be prepared by the use of known chemical reactions and procedures, some from starting materials which are commercially available. Nevertheless, general preparative methods are provided below to aid one skilled in the art in synthesizing these compounds, with more detailed examples being provided in the Experimental section which follows.
- Substituted and unsubstituted aminoquinolines, aminoisoquinolines and aminopyridines maybe prepared using standard methods (see, for example: A.R. Katritzky et al. (Eds.). Comprehensive Heterocyclic Chemistry II, Vol. 5. M.H. Palmer. Heterocyclic
- aryl amines are commonly synthesized by reduction of nitroaryls using a metal catalyst, ' such as Ni, Pd, or Pt, and H or a hydride transfer agent, such as formate, cyclohexadiene, or a borohydride (Rylander. Hydrogenation Methods; Academic Press: London, UK (1985)). Nitroaryls may also be directly reduced using a strong hydride source, such as LiAlH (Seyden-Penne.
- Nitroaryls are commonly formed by electrophilic aromatic nitration using HNO , or an alternative NO 2 + source. Nitroaryls may be further elaborated prior to reduction. Thus, nitroaryls substituted with
- potential leaving groups may undergo substitution reactions on treatment with nucleophiles, such as thiolate (exemplified in Scheme II) or phenoxide. Nitroaryls may also undergo Ullman-type coupling reactions (Scheme IT).
- Nitroaryls may also undergo transition metal mediated cross coupling reactions.
- nitroaryl electrophiles such as nitroaryl bromides, iodides or triflates
- palladium mediated cross coupling reactions with aryl nucleophiles, such as arylboronic acids (Suzuki reactions, exemplified below), aryltins (StiUe reactions) or arylzincs (Negishi reaction) to afford the biaryl (5).
- aryl nucleophiles such as arylboronic acids (Suzuki reactions, exemplified below), aryltins (StiUe reactions) or arylzincs (Negishi reaction)
- Either nitroaryls or anilines may be converted into the corresponding arenesulfonyl chloride (7) on treatment with chlorosulfonic acid.
- Reaction of the sulfonyl chloride with a fluoride source, such as KF then affords sulfonyl fluoride (8).
- Reaction of sulfonyl fluoride 8 with trimethylsilyl trifluoromethane in the presence of a fluoride source, such as tris(dimethylamino)sulfonium difluorotrimethylsiliconate (TASF) leads to the corresponding trifluoromethylsulfone (9).
- TASF tris(dimethylamino)sulfonium difluorotrimethylsiliconate
- sulfonyl chloride 7 may be reduced to the arenethiol (10), for example with zinc amalgum.
- Reaction of thiol 10 with CHC1F 2 in the presence of base gives the difluoromethyl mercaptan (11), which may be oxidized to the sulfone (12) with any of a variety of oxidants, including CrO 3 -acetic • anhydride (Sedova et al. Zh. Org. Khim. 1970, 6, (568).
- non-symmetrical urea formation may involve reaction of an aryl isocyanate (14) with an aryl amine (13).
- the heteroaryl isocyanate may be synthesized from a heteroaryl amine by treatment with phosgene or a phosgene equivalent, such as trichloromethyl chloroformate (diphosgene), bis(trichloromethyl) carbonate (triphosgene), or N,N'-carbonyldiimidazole (GDI).
- the isocyanate may also be derived from a heterocyclic carboxylic acid derivative, such as an ester, an acid halide or an anhydride by a Curtius-type rearrangement.
- a heterocyclic carboxylic acid derivative such as an ester, an acid halide or an anhydride by a Curtius-type rearrangement.
- reaction of acid derivative 16 with an azide source, followed by rearrangement affords the isocyanate.
- the corresponding carboxylic acid (17) may also be subjected to Curtius-type rearrangements using diphenylphosphoryl azide (DPP A) or a similar reagent.
- DPP A diphenylphosphoryl azide
- ureas may be further manipulated using methods familiar to those skilled in the art.
- the invention also includes pharmaceutical compositions including a compound of Formula I, and a physiologically acceptable carrier.
- the compounds may be administered orally, dermally, parenterally, by injection, by inhalation or spray, or sublingually, rectally or vaginally in dosage unit formulations.
- administration includes intravenous, intraarticular, intramuscular, subcutaneous and parenteral injections, as well as use of infusion techniques.
- Dermal administration may include topical application or transdermal administration.
- One or more compounds may be present in association with one or more non-toxic pharmaceutically acceptable carriers and if desired other active ingredients.
- compositions intended for oral use may be prepared according to any suitable method known to the art for the manufacture of pharmaceutical compositions.
- Such compositions may contain one or more agents selected from the group consisting of diluents, sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide palatable preparations.
- Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
- excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; and binding agents, for example magnesium stearate, stearic acid or talc.
- the tablets may be uncoated or they may be coated by known techniques to delay disintegration and adso ⁇ tion in the gastrointestinal tract and thereby provide a sustained action over a longer period.
- a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
- These compounds may also be prepared in solid, rapidly released form.
- Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
- an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
- water or an oil medium for example peanut oil, liquid paraffin or olive oil.
- Aqueous suspensions containing the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions may also be used.
- excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropyl-methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbit
- the aqueous suspensions may also contain one or more preservatives, for example ethyl, or «-propyl, -hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
- Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those aheady mentioned above. Additional excipients, for example, sweetening, flavoring and coloring agents, may also be present.
- the compounds may also be in the form of non-aqueous liquid formulations, e.g., oily suspensions which may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or peanut oil, or in a mineral oil such as liquid paraffin.
- the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. hese compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
- compositions of the invention may also be in the form of oil-in-water emulsions.
- the oil phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
- Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally- occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
- the emulsions may also contain sweetening and flavoring agents.
- Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The compounds may also be adir ⁇ iistered in the form of suppositories for rectal or vaginal administration of the dmg.
- sweetening agents for example glycerol, propylene glycol, sorbitol or sucrose.
- Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
- the compounds may also be adir ⁇ iistered in the form of suppositories for rectal or vaginal administration of the dmg.
- These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal or vaginal temperature and will therefore melt in the rectum or vagina to release
- Compounds of the invention may also be administered transdermally using methods known to those skilled in the art (see, for example: Chien; “Transdermal Controlled Systemic Medications”; Marcel Dekker, Inc.; 1987. Lipp et al. WO94/04157 3Mar94).
- a solution or suspension of a compound of Formula I in a suitable, volatile solvent optionally containing penetration enhancing agents can be combined with additional additives known to those skilled in the art, such as matrix materials and bacteriocides. After sterilization, the resulting mixture can be formulated following known procedures into dosage forms.
- a solution or suspension of a compound of Formula I may be formulated into a lotion or salve.
- Suitable solvents for processing transdermal delivery systems are known to those skilled in the art, and include lower alcohols such as ethanol or isopropyl alcohol, lower ketones such as acetone, lower carboxylic acid esters such as ethyl acetate, polar ethers such as tetrahydrofuran, lower hydrocarbons such as hexane, cyclohexane or benzene, or halogenated hydrocarbons such as dichlorome bane, chloroform, trichlorotrifluoroethane, or trichlorofluoroethane.
- Suitable solvents may also include mixtures one or more materials selected from lower alcohols, lower ketones , lower carboxylic acid esters, polar ethers, lower hydrocarbons, halogenated hydrocarbons.
- Suitable penetration enhancing materials for transdermal delivery systems include, for example, monohydroxy or polyhydroxy alcohols such as ethanol, propylene glycol or benzyl alcohol, saturated or unsaturated C 8 -C 18 fatty alcohols such as lauryl alcohol or cetyl alcohol, saturated or unsaturated C 8 -C ⁇ 8 fatty acids such as stearic acid, saturated or unsaturated fatty esters with up to 24 carbons such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl isobutyl tert-butyl or monoglycerin esters of acetic acid, capronic acid, lauric acid, myristinic acid, stearic acid, or palmitic acid, or diesters of saturated or unsaturated dicarboxylic acids with a total of up to 24 carbons such as diisopropyl adipate, diisobutyl adipate, diiso
- Additional penetration enhancing materials include phosphatidyl derivatives such as lecithin or cephalin, terpenes, amides, ketones, ureas and their derivatives, and ethers such as dimethyl isosorbid and diethyleneglycol monoethyl ether.
- Suitable penetration enhancing formulations may also include mixtures one or more materials selected from monohydroxy or polyhydroxy alcohols, saturated or unsaturated C 8 -C 18 fatty alcohols, saturated or unsaturated C 8 -C 18 fatty acids, saturated or unsaturated fatty esters with up to 24 carbons, diesters of saturated or unsaturated dicarboxylic acids with a total of up to 24 carbons, phosphatidyl derivatives, terpenes, amides, ketones, ureas and their derivatives, and ethers.
- Suitable binding materials for transdermal delivery systems include polyacrylates, silicones, polyurethanes, block polymers, styrene- butadiene coploymers, and natural and synthetic rubbers.
- Cellulose ethers, derivatized polyethylenes, and silicates may also be used as matrix components. Additional additives, such as viscous resins or oils may be added to increase the viscosity of the matrix.
- the daily oral dosage regimen will preferably be from 0.01 to 200 mg/Kg of total body weight.
- the daily dosage for administration by injection including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques will preferably be from 0.01 to 200 mg/Kg of total body weight.
- the daily rectal dosage regimen will preferably be from 0.01 to 200 mg/Kg of total body weight.
- the daily vaginal dosage regimen will preferably be from 0.01 to 200 mg/Kg of total body weight.
- These daily dosages can be administered incrementally during the day, on a weekly basis on a biweekly basis or longer periods. Long term dosages typically range from 100-600 mg/kg of total body weight and preferably range from 100-400 mg/kg of total body weight.
- Dosages for oral, vaginal and rectal administration and administration by injection can range from 0.01 mg - 600 mg/kg of total body weight.
- the daily topical dosage regimen will preferably be from 0.1 to 200 mg administered between one to four times daily.
- the transdermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg Kg.
- the daily inhalation dosage regimen will preferably be from 0.01 to 10 mg/Kg of total body weight.
- the particular method of administration will depend on a variety of factors, all of which are considered routinely when administering therapeutics. It will also be understood, however, that the specific dose level for any given patient will depend upon a variety of factors, including, but not limited to the activity of the specific compound employed, the age of the patient, the body weight of the patient, the general health of the patient, the gender of the patient, the diet of the patient, time of administration, route of administration, rate of excretion, drug combinations, and the severity of the condition undergoing therapy.
- the optimal course of treatment ie., the mode of treatment and the daily or weekly number of doses of a compound of Formulae I or JJ or a pharmaceutically acceptable sal ⁇ hereof given for a defined number of days, can be ascertained by those skilled in the art using conventional treatment tests.
- N- cyclohexyl-N'-(methylpolystyrene)carbodiimide was purchased from Calbiochem- ⁇ ovabiochem Corp.
- Visualization of plates was effected by one or more of the following techniques: (a) ultraviolet illumination, (b) exposure to iodine vapor, (c) immersion of the plate in a 10% solution of phosphomolybdic acid in ethanol followed by heating, (d) immersion of the plate in a cerium sulfate solution followed by heating, and/or (e) immersion of the plate in an acidic ethanol solution of 2,4- dinitrophenylhydrazine followed by heating. Column chromatography (flash chromatography) was performed using 230-400 mesh EM Science ® silica gel.
- Carbon ( 13 C) NMR spectra were measured with a General Electric GN-Omega 300 (75 MHz) spectrometer with solvent (CDC1 3 ⁇ 77.0; MeOD-d 3 ; ⁇ 49.0; DMSO-d 6 ⁇ 39.5) as standard.
- Low resolution mass spectra (MS) and high resolution mass spectra (HRMS) were either obtained as electron impact (El) mass spectra or as fast atom bombardment (FAB) mass spectra.
- Electron impact mass spectra (EI-MS) were obtained, with a Hewlett Packard 5989A mass spectrometer equipped with a Vacumetrics Desorption Chemical loniza ion-Probe for sample introduction. The ion source was maintained at 250 °C.
- Electron impact ionization was performed with electron energy of 70 eV and a trap current of 300 ⁇ A.
- Liquid-Cesium secondary ion mass spectra FAB-MS
- FAB-MS Liquid-Cesium secondary ion mass spectra
- CI-MS Chemical ionization mass spectra
- HPLC - electrospray mass spectra were obtained using a Hewlett-Packard 1100 HPLC equipped with a quaternary pump, a variable wavelength detector, a C-18 column, and a Finnigan LCQ ion trap mass spectrometer with electrospray ionization.
- Spectra were scanned from 120-800 amu using a variable ion time according to the number of ions in the source.
- Gas chromatography - ion selective mass spectra (GC-MS) were obtained with a Hewlett Packard 5890 gas chromatograph equipped with an HP-1 methyl silicone column (0.33 mM coating; 25 m x 0.2 mm) and a Hewlett Packard 5971 Mass Selective Detector (ionization energy 70 eV). Elemental analyses were conducted by Robertson Microlit Labs, Madison NJ.
- Step 1 l-Methoxy-4-(4-nitrophenoxy)benzene: To a suspension of NaH.(95%, 1.50 g, 10 59 mmol) in DMF (100 mL) at room temp, was added dropwise a solution of 4- methoxyphenol (7.39 g, 59 mmol) in DMF (50 mL). The reaction was stirred 1 h, then a solution of l-fluoro-4-nitrobenzene (7.0 g, 49 mmol) in DMF (50 mL) was added dropwise to form a dark green solution. The reaction was heated at 95 °C overnight, then cooled to room temp., quenched with H 2 O, and concentrated in vacuo.
- Step 2 4-(4-Methoxyphenoxy)aniline: To a solution of l-methoxy-4-(4- nitrophenoxy)benzene (12.0 g, 49 mmol) in EtOAc (250 mL) was added 5% Pt/C (1.5 g) 25 and the resulting slurry was shaken under a H 2 atmosphere (50 psi) for 18 h.
- Step 1 3-(Trifluoromethyl)-4-(4-pyridinylthio)nitrobenzene: A solution of 4- mercaptopyridine (2.8 g, 24 mmoles), 2-fluoro-5-nitrobenzotrifluoride (5 g, 23.5 mmoles), and potassium carbonate (6.1 g, 44.3 mmoles) in anhydrous DMF (80 mL) was stirred at room temperature and under argon overnight. TLC showed complete reaction. The mixture was diluted with Et 2 O (100 mL) and water (100 mL) and the aqueous layer was back-extracted with Et 2 O (2 x 100 mL).
- Step 2 3-(Trifluoromethyl)-4-(4-pyridinylthio)aniline: A slurry of 3-trifluoromethyl- 4-(4-pyridinylthio)nitrobenzene (3.8 g, 12.7 mmol), iron powder (4.0 g, 71.6 mmol), acetic acid (100 mL), and water (1 mL) were stirred at room temp, for 4 h. -Tho mixture was diluted with Et 2 O (100 mL) and water (100 mL). The aqueous phase was adjusted to pH 4 with a 4 N NaOH solution. The combined organic layers were washed with a saturated NaCl solution (100 mL), dried (MgSO ), and concentrated under reduced pressure.
- Step 1 4-(2-(4-Phenyl)thiazolyl)thio-l -nitrobenzene: A solution of 2-mercapto-4- phenylthiazole (4.0 g, 20.7 mmoles) in DMF (40 mL) was treated with l-fluoro-4- nitrobenzene (2.3 mL, 21.7 mmoles) followed by K 2 CO 3 (3.18 g, 23 mmol), and the mixture was heated at approximately 65 °C overnight. The reaction mixture was then diluted with EtOAc (100 mL), sequentially washed with water (100 mL) and a saturated NaCl solution (100 mL), dried (MgSO 4 ) and concentrated under reduced pressure.
- EtOAc 100 mL
- Step 2 4-(2-(4-Phenyl)thiazolyl)thioamline: 4-(2-(4-Phenyl)thiazolyl)thio-l-nitro- benzene was reduced in a manner analagous to that used in the preparation of 3-
- Step 1 4-(6-Methyl-3-pyridinyloxy)-l-nitrobenzene: To a solution of 5-hydroxy-2- methylpyridine (5.0 g, 45.8 mmol) and l-fluoro-4-nitrobenzene (6.5 g, 45.8 mmol) in anh DMF (50 mL) was added K 2 CO3 (13.0 g, 91.6 mmol) in one portion. The mixture was heated at the reflux temp, with stirring for 18 h and then allowed to cool to room temp. The resulting mixture was poured into water (200 mL) and extracted with EtOAc (3 x 150 mL).
- Step 2 4-(6-Methyl-3-pyridinyloxy)aniline: A solution of 4-(6-methyl-3- pyridinyloxy)- 1 -nitrobenzene (4.0 g, 17.3 mmol) in EtOAc (150 mL) was added to 10%> Pd C (0.500 g, 0.47 mmol) and the resulting mixture was placed under a H 2 atmosphere (balloon) and was allowed to stir for 18 h at room temp. The mixture was then filtered through a pad of Celite ® and concentrated in vacuo to afford the desired product as a tan solid (3.2 g, 92%): EI-MS m/z 200 (M + ).
- Step 1 4-(3,4-Dimethoxyphenoxy)-l-nitrobenzene: To a solution of 3,4- dimethoxyphenol (1.0 g, 6.4 mmol) and l-fluoro-4-nitrobenzene (700 ⁇ L, 6.4 mmol) in anh DMF (20 mL) was added K 2 CO 3 (1.8 g, 12.9 mmol) in one portion. The mixture was heated at the reflux temp with stirring for 18 h and then allowed to cool to room temp. The mixture was then poured into water (100 mL) and extracted with EtOAc (3 x 100 mL).
- Step 2 4-(3,4-Dimethoxyphenoxy)aniline: A solution of 4-(3,4-dimethoxy-phenoxy)-l- nitrobenzene (0.8 g, 3.2 mmol) in EtOAc (50 mL) was added to 10% Pd/C (0.100 g) and the resulting mixture was placed under a H 2 atmosphere (balloon) and was allowed to stir for 18 h at room temp. The mixture was then filtered through a pad of Celite ® and concentrated in vacuo to afford the desired product as a white solid (0.6 g, 75%): EI-MS m/z 245 (W ).
- Step 1 3-(3-Pyridinyloxy)-l-nitrobenzene: To a solution of 3-hydroxypyridine (2.8 g, 29.0 mmol), l-bromo-3-nitrobenzene (5.9 g, 29.0 mmol) and copper(I) bromide (5.0 g, 34.8 mmol) in anh DMF (50 mL) was added K 2 CO 3 (8.0 g, 58.1 mmol) in one portion. The resulting mixture was heated at the reflux temp, with stirring for 18 h and then allowed to cool to room temp. The mixture was then poured into water (200 mL) and extracted with EtOAc (3 x 150 mL).
- Step 1 3-(5-Methyl-3-pyridinyloxy)-l-nitrobenzene: To a solution of 3-hydroxy-5- methylpyridine (5.0 g, 45.8 mmol), l-bromo-3 -nitrobenzene (12.0 g, 59.6 mmol) and co ⁇ per(I) iodide (10.0 g, 73.3 mmol) in anh DMF (50 mL) was added K 2 CO 3 (13.0 g, 91.6 mmol) in one portion. The mixture was heated at the reflux temp, with stirring for 18 h and then allowed to cool to room temp. The mixture was then poured into water (200 mL) and extracted with EtOAc (3 x 150 mL).
- Step 2 3-(5-Methyl-3-pyridinyloxy)-l-nitrobenzene: A solution of 3-(5-methyl-3- pyridinyloxy)-l -nitrobenzene (1.2 g, 5.2 mmol) in EtOAc (50 mL) was added to 10% Pd/C (0.100 g) and the resulting mixture was placed under a H 2 atmosphere (balloon) and was allowed to stir for 18 h at room temp. The mixture was then filtered through a pad of Celite ® and concentrated in vacuo to afford the desired product as a red oil (0.9 g, 86%): CI-MS m/z 201 ((M+H) + ).
- Step 1 5-Nitro-2-(4-methylphenoxy)pyridine: To a solution of 2-chloro-5- nitropyridine (6.34 g, 40 mmol) in DMF (200 mL) were added of 4-methylphenol (5.4 g, 50 mmol, 1.25 equiv) and K 2 CO 3 (8.28 g, 60 mmol, 1.5 equiv). The mixture was stirred overnight at room temp. The resulting mixture was treated with water (600 mL) to generate a precipitate.
- Step 1 4-(3-Thienylthio)-l-nitrobenzene: To a solution of 4-nitrothiophenol (80%pure;
- Step 2 4-(3-Thienylthio)aniline: 4-(3-Thienylthio)-l -nitrobenzene was reduced to the aniline in a manner analogous to that described in Method Al .
- 4-(5-Pyrimininyloxy)aniline 4-Aminophenol (1.0 g, 9.2 mmol) was dissolved in DMF (20 mL) then 5-bromopyrimidine (1.46 g, 9.2 mmol) and K2CO3 (1.9 g, 13.7 mmol) were added. The mixture was heated to 100 °C for 18 h and at 130 °C for 48 h at which GC- MS analysis indicated some remaining starting material. The reaction mixture was cooled to room temp, and diluted with water (50 mL). The resulting solution was extracted with EtOAc (100 mL).
- the bright orange reaction mixture was warmed to 0 °C and was treated with a mixture of a 3 N NaOH solution (25 mL, 71.77 mmol) and a hydrogen peroxide solution (30%; approx. 50 mL).
- the resulting yellow and slightly turbid reaction mixture was warmed to room temp, for 30 min and then heated to the reflux temp, for 1 h.
- the reaction mixture was then allowed to cool to room temp.
- the aqueous layer was neutralized with a IN HCI solution then extracted with Et 2 O (2 x 100 mL).
- the combined organic layers were dried (Na 2 SO 4 ) and concentrated under reduced pressure to give a viscous yellow oil (3.5g, 60%).
- Step 3 4-(5-(2-Methoxy)pyridyl)oxy-l-nitrobenzene: To a stirred slurry of NaH (97%, 1.0 g, 42 mmol) in anh DMF (100 mL) was added a solution of 5-hydroxy-2- methoxypyridine (3.5g, 28 mmol) in DMF (100 mL). The resulting mixture was allowed to stir at room temp, for 1 h, 4-fluoronitrobenzene (3 mL, 28 mmol) was added via syringe. The reaction mixture was heated to 95 °C overnight, then treated with water (25 mL) and extracted with EtOAc (2 x 75 mL).
- Step 1 MethyI(4-nitrophenyl)-4-pyridylamine: To a suspension of N-methyl-4- nitroaniline (2.0 g, 13.2 mmol) and K 2 CO 3 (7.2 g, 52.2 mmol) in DMPU (30mL) was added 4-chloropyridine hydrochloride (2.36 g, 15.77 mmol). The reaction mixture was heated at 90 °C for 20 h, then cooled to room temperature. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL). The organic layer was washed with water (100 mL), dried ( ⁇ a 2 SO ) and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, gradient from 80%> EtOAc /20% hexanes to 100% EtOAc) to afford methyl(4-nitrophenyl)-4-pyridylamine (0.42 g)
- Step 2 Methyl(4-aminophenyl)-4-pyridylamine: Methyl(4-nitrophenyl)-4- pyridylamine was reduced in a manner analogous to that described in Method Al.
- Step 1 4-(4-Butoxyphenyl)thio-l-nitrobenzene: To a solution of 4-(4-nitro ⁇ henyl- thio)phenol (1.50 g, 6.07 mmol) in anh DMF (75 ml) at 0 °C was added NaH (60% in mineral oil, 0.267 g, 6.67 mmol). The brown suspension was stirred at 0 °C until gas evolution stopped (15 min), then a solution of iodobutane (1.12 g, .690 ml, 6.07 mmol) in anh DMF (20 mL) was added dropwise over 15 min at 0 °C.
- reaction was stirred at room temp, for 18 h at which time TLC indicated the presence of unreacted phenol, and additional iodobutane (56 mg, 0.035 mL, 0.303 mmol, 0.05 equiv) and NaH (13 mg, 0.334 mmol) were added.
- additional iodobutane 56 mg, 0.035 mL, 0.303 mmol, 0.05 equiv
- NaH 13 mg, 0.334 mmol
- Step 2 4-(4-Butoxyphenyl)thioaniline: 4-(4-Butoxyphenyl)thio-l -nitrobenzene was reduced to the aniline in a manner analagous to that used in the preparation of 3- (trifluoromethyl)-4-(4-pyridmylthio)aniline (Method A3b, Step 2): TLC (33% EtOAc/77% hexane) R-0.38.
- the resulting mixture was diluted with Et 2 O (200 mL), sequentially washed with a saturated NaHCO 3 solution (100 ml), water (100 mL) and a saturated NaCl solution (50 mL), dried (MgSO4), and concentrated under reduced pressure.
- the resulting white solid was purified by silica gel chromatography (gradient from 33% EtOAc/67% hexane to 50% EtOAc/50% hexane) to afford the desired.
- Step 1 3-(4-Nitrobenzyl)pyridine: A solution of 3-benzylpyridine (4.0 g, 23.6 mmol) and 70% nitric acid (30 mL) was heated overnight at 50 °C. The resulting mixture was allowed to cool to room temp, then poured into ice water (350 mL). The aqueous mixture then made basic with a IN NaOH solution, then extracted with Et 2 O (4 x 100 mL). The combined extracts were sequentially washed with water (3 x 100 mL) and a saturated NaCl solution (2 x 100 mL), dried (Na 2 SO ), and concentrated in vacuo.
- Step 2 3-(4-Pyridinyl)methylaniline: 3-(4-Nitrobenzyl)pyridine was reduced to the aniline in a manner analogous to that described in Method Al .
- Step 1 4-(l-Imidazolylmethyl)-l -nitrobenzene: To a solution of imidazole (0.5 g, 7.3 mmol) and 4-nitrobenzyl bromide (1.6 g, 7.3 mmol) in anh acetonitrile (30 mL) was added K 2 CO 3 (1.0 g, 7.3 mmol). The resulting mixture was stirred at room temp, for 18 h and then poured into water (200 mL) and the resulting aqueous solution was extracted with EtOAc (3 x 50 mL).
- Step 2 4-(l-Imidazolylmethyl)aniline: 4-(l-lmidazolylmethyl)-l -nitrobenzene was reduced to the aniline in a manner analogous to that described in Method A2.
- Step 1 4-(l-Hydroxy-l-(4-pyridyl)methyl-l -nitrobenzene: To a stirred solution of 3- (4-nitrobenzyl)pyridine (6.0 g, 28 mmol) in CH 2 C1 2 (90 mL) was added m-CPBA (5.80 g, 33.6 mmol) at 10 °C, and the mixture was stirred at room temp, overnight. The reaction mixture was successively washed with a 10%> NaHSO 3 solution (50 mL), a saturated K 2 CO 3 solution (50 mL) and a saturated NaCl solution (50 mL), dried (MgSO ) and concentrated under reduced pressure.
- 3- (4-nitrobenzyl)pyridine 6.0 g, 28 mmol
- m-CPBA 5.80 g, 33.6 mmol
- Step 2 4-(l-Hydroxy-l-(4-pyridyl)methyIaniIine: 4-(l -Hydroxy- 1 -(4-pyridyl)-methyl- 1 -nitrobenzene was reduced to the aniline in a manner analogous to that described in Method A3d, Step2.
- Step 1 2-(N-methylcarbamoyl)-4-chloropyridine. (Caution: this is a highly hazardous, potentially explosive reaction.) To a solution of 4-chloropyridine (10.0 g) inN- methylformamide (250 mL) under argon at ambient temp was added cone. H 2 SO 4 (3.55 mL) (exotherm). To this was added H2O 2 (17 mL, 30%> wt in H 2 O) followed by FeSO 4 ' 7H 2 O (0.55 g) to produce an exotherm. The reaction was stirred in the dark at ambient temp for lh then was heated slowly over 4 h at 45 °C. When bubbling subsided, the reaction was heated at 60 °C for 16 h.
- Step lb Synthesis of 4-chloropyridine-2-carbonyl chloride HCI salt via picolinic acid
- Anhydrous DMF (6.0 mL) was slowly added to SOCl 2 (180 mL) between 40° and 50 °C. The solution was stirred in that temperature range for 10 min. then picolinic acid (60.0 g, 487 mmol) was added in portions over 30 min. The resulting solution was heated at 72 °C (vigorous SO 2 evolution) for 16 h to generate a yellow solid precipitate. The resulting mixture was cooled to room temp., diluted with toluene (500 mL) and concentrated to 200 mL. The toluene addition/concentration process was repeated twice.
- Step 3a Synthesis of 4-chloro-iV-methyl-2-pyridmecarboxamide from methyl
- Step 3b Synthesis of 4-chIoro-N-methyl-2-pyridinecarboxamide from 4- chloropyridine-2-carbonyl chloride
- Step 2 Synthesis of 5-(4 ⁇ nitrophenoxy)isoindoline-l,3-dione To a stirring slurry of NaH (1.1 g, 44.9 mmol) in DMF (40 mL) at 0 °C was added a solution of 5-hydroxyisoindoline-l,3-dione (3.2 g, 19.6 mmol) in DMF (40 mL) dropwise. The bright yellow-green mixture was allowed to return to room temp, and was stirred for 1 h, then l-fluoro-4-nitrobenzene (2.67 g, 18.7 mmol) was added via syringe in 3-4 portions.
- Step 1 4-(4-Methylsulfonylphenoxy)-l-nitrobenzene: To a solution of 4-(4- methylthiophenoxy)-l-ntirobenzene (2 g, 7.66 mmol) in CH 2 C1 2 (75 mL) at 0 °C was slowly added wCPBA (57-86%, 4 g), and the reaction mixture was stirred at room temperature for 5 h. The reaction mixture was treated with a 1 N NaOH solution (25 mL).
- Step 2 4-(4-Methylsulfonylphenoxy)-l-aniline: 4-(4-Methylsulfonylphenoxy).-l- nitrobenzene was reduced to the aniline in a manner anaologous to that described in Method A3d, step 2.
- Step 1 4-(3-Methoxycarbonyl-4-methoxyphenoxy)-l-nitrobenzene: To a solution of -(3-carboxy-4-hydroxyphenoxy)-l-nitrobenzene (prepared in a manner analogous to that described in Method A3 a, step 1, 12 mmol) in acetone (50 mL) was added K 2 CO 3 (5 g) and dimethyl sulfate (3.5 mL). The resulting mixture was heated at the reflux temperature overnight, then cooled to room temperature and filtered through a pad of Celite ® .
- Step 2 4-(3-Carboxy-4-rnethoxyphenoxy)-l-nitrobenzene: A mixture of 4-(3- methoxycarbonyl-4-methoxyphenoxy)-l -nitrobenzene (1.2 g), KOH (0.33 g),and water (5 mL) in MeOH (45 mL) was stirred at room temperature overnight and then heated at the reflux temperature for 4 h. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in water (50 mL), and the aqueous mixture was made acidic with a IN HCI solution. The resulting mixture was extracted with EtOAc (50 mL). The orgarucjavetwas dried (MgSO 4 ) and concentrated under reduced pressure to give 4-(3-carboxy-4-methoxyphenoxy)-l -nitrobenzene (1.04 g).
- N-(4-tert-butylpyridyl)-N , -(2,3-dichlorophenyl) urea A solution of 2-amino-4-tert- butylpyridine (192 mg) and 2,3-dichlorophenyl isocyanate (240 mg) in anh. toluene (15 mL) was heated at 70 °C under argon for 24 h. The resulting mixture was diluted with EtOAc (200 mL) then washed with water (125 mL). The organic layer was dried (MgSO 4 ) and concentrated under reduced pressure to give a gum.
- N-(4-tert-Butylpyridyl)-N'-(4-(4-chlorophenoxy)phenyl) urea A solution of 4-tert- butyl-2-aminopyridine (0.177 g, 1.18 mmol, 1 equiv.) in 1.2 mL of anh. CH 2 ⁇ 2 (1.2 mL) was added to CDI (0.200 g, 1.24 mmol, 1.05 equiv) and the mixture was allowed to stir under argon at room temperature 1 d. To the resulting solution was added 4-(4- chlorophenoxy)aniline (0.259 g, 1.18 mmol, 1 equiv.) in one portion.
- the resulting mixture was stirred at room temperature for 1 d, then was treated with a 10% citric acid solution (2 mL) and allowed to stir for 1 h.
- the resulting organic layer was extracted with EtOAc (3 x 5 mL).
- the combined organic layers were dried (MgSO ) and concentrated in vacuo.
- the resultant residue was treated with CH 2 C1 2 (10 mL) and a 1 N aqueous NaOH solution. This mixttire was allowed to stir overnight.
- the resulting organic layer was extracted with CH 2 C1 2 (3 x 5 mL).
- the combined organic layers were (MgSO 4 ) and concentrated in vacuo.
- the resultant solids were suspended in diethyl ether (10 mL) and sonicated for 15 minutes.
- N-(2-(5-trifluoromethyl)pyridyloxy)-iV-(3-(4-pyridylthio)phenyl) urea A solution of 3-(4-pyridylthib)a ' n ⁇ e 300 mg, 1.48 mmoles) in CH 2 C1 2 (12 mL) was treated with CDI (253 mg, 1.56 mmoles). The solution was stirred at room temperature and under argon for 2 h. The resulting mixture was treated with 2-amino-5-(trifluoromethyl)pyridine (238 mg, 1.47 mmoles) and heated at 40 °C overnight.
- Entry 9 4-tert-Butyl-2-aminopyridine was reacted with 4-(4-methoxyphenoxy)aniline according to Method B2c to afford the urea.
- Entry 10 4-(4-Ammophenoxy)pyridine was prepared starting from 4-hydroxypyridine and l-bromo-3-nitrobenzene according to Method A3F. 4-tert-Butyl-2-aminopyridine was reacted with 4-(4-aminophenoxy)pyridine according to Method B2a to afford the urea.
- Entry 18 3-Aminoisoquinoline was reacted with 1 -naphthyl isocyanate according to Method B 1 to afford the urea.
- Entry 19 3-Aminoisoquinoline was reacted with 4-(4-pyridylmethyl)aniline according to Method B2a to afford the urea.
- Entryl lO 4-Chloro-N-methyl-2 -pyridinecarboxamide, which was synthesized according to Method AlO, Step 3a, was reacted with 3-aminophenol according to Method AlO, Step 4 using DMAC in place of DMF to give 3-(-2-(N-methylcarbamoyl)-4- pyridyloxy)aniline. 3-Amino-2-methoxyquinoline was reacted with 3-(-2-(N- methylcarbamoyl)-4-pyridyloxy)aniline according to Method B6 to afford the urea.
- the in vivo inhibitory properties of selected compounds were determined using a murine LPS induced TNF ⁇ production in vivo model.
- BALB/c mice Charles River Breeding Laboratories; Springfield, NY
- endotoxin E. coli lipopolysaccharide (LPS) 100 ⁇ g
- LPS lipopolysaccharide
- animals were euthanized by carbon dioxide asphyxiation and plasma was obtained from individual animals by cardiac puncture into heparinized tubes.
- the samples were clarified by centrifugation at 12,500 x g for 5 min at 4 °C.
- the supematants were decanted to new tubes, which were stored as needed at -20 °C.
- TNF ⁇ levels in sera were measured using • a commercial murine TNF ELISA kit (Genzyme).
Abstract
Description
Claims
Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2002583386A JP4359817B2 (en) | 2001-04-20 | 2002-04-17 | Nitrogen heteroatom-containing heteroaryl ureas as p38 inhibitors |
MXPA03009649A MXPA03009649A (en) | 2001-04-20 | 2002-04-17 | HETEROARYL UREAS CONTAINING NITROGEN HETERO-ATOMS AS p38 KINASE INHIBITORS. |
EP02725709A EP1379507B1 (en) | 2001-04-20 | 2002-04-17 | HETEROARYL UREAS CONTAINING NITROGEN HETERO-ATOMS AS p38 KINASE INHIBITORS |
CA2443952A CA2443952C (en) | 2001-04-20 | 2002-04-17 | Heteroaryl ureas containing nitrogen hetero-atoms as p38 kinase inhibitors |
AT02725709T ATE520663T1 (en) | 2001-04-20 | 2002-04-17 | HETEROARYL-UREASES CONTAINING NITROGEN ATOMS AS INHIBITORS OF P38 KINASE |
HK04105147.7A HK1062440A1 (en) | 2001-04-20 | 2004-07-14 | Heteroaryl ureas containing nitrogen hetero-atoms as p38 kinase inhibitors |
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US09/838,286 | 2001-04-20 | ||
US09/838,286 US20020065296A1 (en) | 1999-01-13 | 2001-04-20 | Heteroaryl ureas containing nitrogen hetero-atoms as p38 kinase inhibitors |
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PCT/US2002/012064 WO2002085859A1 (en) | 2001-04-20 | 2002-04-17 | HETEROARYL UREAS CONTAINING NITROGEN HETERO-ATOMS AS p38 KINASE INHIBITORS |
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US (1) | US20020065296A1 (en) |
EP (2) | EP1379507B1 (en) |
JP (1) | JP4359817B2 (en) |
AT (1) | ATE520663T1 (en) |
CA (1) | CA2443952C (en) |
ES (1) | ES2372020T3 (en) |
HK (1) | HK1062440A1 (en) |
MX (1) | MXPA03009649A (en) |
WO (1) | WO2002085859A1 (en) |
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MXPA03009649A (en) | 2005-10-05 |
JP4359817B2 (en) | 2009-11-11 |
HK1062440A1 (en) | 2004-11-05 |
CA2443952A1 (en) | 2002-10-31 |
CA2443952C (en) | 2011-05-24 |
JP2004537511A (en) | 2004-12-16 |
US20020065296A1 (en) | 2002-05-30 |
EP2386545A1 (en) | 2011-11-16 |
EP1379507B1 (en) | 2011-08-17 |
ES2372020T3 (en) | 2012-01-13 |
ATE520663T1 (en) | 2011-09-15 |
EP1379507A1 (en) | 2004-01-14 |
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