WO1996025157A1 - Il-8 receptor antagonists - Google Patents

Il-8 receptor antagonists Download PDF

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Publication number
WO1996025157A1
WO1996025157A1 PCT/US1996/002260 US9602260W WO9625157A1 WO 1996025157 A1 WO1996025157 A1 WO 1996025157A1 US 9602260 W US9602260 W US 9602260W WO 9625157 A1 WO9625157 A1 WO 9625157A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
urea
hydroxy
phenyl
alkenyl
Prior art date
Application number
PCT/US1996/002260
Other languages
French (fr)
Inventor
Katherine Louisa Widdowson
Daniel Frank Veber
Anthony Joseph Jurewicz
Melvin Clarence Rutledge, Jr.
Robert Philip Hertzberg
Original Assignee
Smithkline Beecham Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Smithkline Beecham Corporation filed Critical Smithkline Beecham Corporation
Priority to US08/894,291 priority Critical patent/US6005008A/en
Priority to EP96906547A priority patent/EP0809492A4/en
Priority to JP8525199A priority patent/JPH11503110A/en
Priority to AU69007/96A priority patent/AU725456B2/en
Priority to APAP/P/1998/001315A priority patent/AP9801315A0/en
Priority to EA200000788A priority patent/EA200000788A1/en
Priority to CZ982569A priority patent/CZ256998A3/en
Priority to IL14112196A priority patent/IL141121A/en
Priority to BR9612779-1A priority patent/BR9612779A/en
Priority to SK1101-98A priority patent/SK110198A3/en
Priority to CN96180245A priority patent/CN1215990A/en
Priority to NZ316710A priority patent/NZ316710A/en
Priority to PCT/US1996/013632 priority patent/WO1997029743A1/en
Priority to CA002245927A priority patent/CA2245927A1/en
Priority to EA199800733A priority patent/EA001436B1/en
Priority to JP9529318A priority patent/JP2000504722A/en
Priority to KR1019980706361A priority patent/KR19990082622A/en
Priority to HU0000467A priority patent/HUP0000467A3/en
Priority to IL12571796A priority patent/IL125717A0/en
Priority to CA002432662A priority patent/CA2432662A1/en
Priority to PL96328562A priority patent/PL328562A1/en
Priority to EP96929723A priority patent/EP0896531A4/en
Priority to CNA2004100324238A priority patent/CN1539816A/en
Priority to TR1998/01592T priority patent/TR199801592T2/en
Publication of WO1996025157A1 publication Critical patent/WO1996025157A1/en
Priority to BG102690A priority patent/BG102690A/en
Priority to NO983737A priority patent/NO983737L/en
Priority to OA9800145A priority patent/OA10840A/en
Priority to US09/240,354 priority patent/US6180675B1/en

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    • 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
    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
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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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    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
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    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
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    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
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Definitions

  • Thi.s invention relates to a novel group of phenyl urea compounds, processes for the preparation thereof, the use thereof in treating IL-8, GRO ⁇ , GRO ⁇ , GRO ⁇ and NAP-2 mediated diseases and pharmaceutical compositions lor use in such therapy
  • Interleukin-8 such as neutrophil attractant/activauon protein- 1 (NAP-1), monocyte derived neutrophil chemotactic factor (MDNCF), neutrophil activating factor (NAF), and T-cell lymphocyte chemotactic factor
  • lnierleukin-8 is a chemoattractant for neutrophils, ba.sophil.s, and a sub.sct of T-cells. It is produced by a majority of nucleated cells including macrophages, fibroblasts, endothehal and epithelial cells exposed to TNF, IL- 1 ⁇ , IL-1 ⁇ or LPS. and by neutrophils themselves when exposed to LPS or chemotactic factors such as FMLP.
  • GRO ⁇ and NAP-2 also belong to the chemokinc ⁇ family. Like IL-8 these chemokincs have also been referred to by different names For instance GRO ⁇ , ⁇ , ⁇ havc been referred to as MGSA ⁇ , ⁇ and ⁇ respectively (Melanoma Growth Stimulating Activity). see Richmond et al. J. Cell Phy.siologv 129, 375 ( 1986) and Chang et al. J. Immunol 148. 45 1 ( 1992). All ot the chemokines of the ⁇ -lamily which possess the ELR motif directly preceding the CXC motif bind to the 1L-8 B receptor
  • IL-8 Gro ⁇ . GRO ⁇ . GRO ⁇ and NAP-2 stimulate a number offuncti ons in vitro They have all been shown to have chemoattraciani properties lor neutrophils. while IL-8 and GRO ⁇ have demonstrated T-lymphocytes, and basophiles chemotactic activity In addition IL-8 can induce histamine release irom basophils Iron, both normal and atopic individuals GRO- ⁇ and IL-8 can in addition, induce lyso/omal enzyme release and respiratory burst from neutrophils IL-8 has also been shown to increase the surface expression of Mac- 1 (CD I l b/CD 18 ) on neutrophils without de novo protein synthesis This may contribute to increased adhesion oi the neutrophils to vascular endothelial cells Many known diseases are characterized by massive neutrophil infiltration As IL-8.
  • GRO ⁇ and NAP- 2 promote the accumulation and activation of neutrophils.
  • these chemokines have been implicated in a wide range of acute and chronic inflammatory disorders including psoriasis and rheumatoid arthritis. Baggiolini et al, FEBS Lett 307, 97 ( 1992). Miller et al. Crit. Rev, Immunol 12, 17 ( 1992); Oppcnheim et al, Annu Rev, Immunol. 9, 617 (1991 ). Seitz et al., J Clin, Invest 87, 463 ( 1991 ). Miller et al., Am. Rev.
  • IL-8, Gro ⁇ , GRO ⁇ , GRO ⁇ and NAP-2 induce neutrophil shape change, chemotaxis, granule release, and respiratory burst, by binding to and activating receptors of the seven-transmembrane.
  • G-protein-linked family in particular by binding to IL-8 receptors, most notably the B-receptor Thomas et al , J. Biol, Chem, 266 14839 ( 1991). and Holmes et al., Science 253, 1278 ( 1991 )
  • the development of non-peptide small molecule antagonists for members of this receptor family has precedent. For a review see R. Freidinger in;
  • the IL-8 receptor represents a promising target for the development of novel anti-inflammatory agents.
  • IL- 8R ⁇ Two high affinity human IL-8 receptors (77% homology) have been characterized IL- 8R ⁇ , which binds only IL-8 with high affinity, and IL-8R ⁇ , which has high affinity for IL-8 as well as for GRO- ⁇ , GRO ⁇ , GRO ⁇ and NAP-2.
  • IL- 8R ⁇ Two high affinity human IL-8 receptors (77% homology) have been characterized IL- 8R ⁇ , which binds only IL-8 with high affinity
  • IL-8R ⁇ which has high affinity for IL-8 as well as for GRO- ⁇ , GRO ⁇ , GRO ⁇ and NAP-2.
  • This invention provides for a method of treating a chemokine mediated disease wherein the chemokine is one which binds to an IL-8 ⁇ or ⁇ receptor and which method comprises administering an effective amount of a compound of Formula (I) or a
  • chemokine is IL-8
  • This invention also relates to a method of inhibiting the binding of IL-8 to its receptors in a mammal in need thereof which comprises administering to said mammal an effective amount of a compound of Formula (I).
  • R is any functional moiety having an ionizable hydrogen and a pKa of 10 or less;
  • R 1 is independently selected from hydrogen: halogen; nitro: cyano; halosubstituted C 1-10 alkyl: C 1-10 alkyl: C 2-10 alkenyl; C 1-10 alkoxy; halosubstituted C 1-10 alkoxy: azide: S(O) t R 4 : hydroxy: hydroxy C 1-4 alkyl; aryl; aryl C 1-4 alkyl: aryloxy: aryl C 1-4 alkyloxy: heteroaryl: heteroarylalkyl; heterocyclic, heterocyclic C 1-4 alkyl: heteroaryl C 1-4 alkyloxy; aryl C 2-10 alkenyl; heteroaryl C 2-10 alkenyl; heterocyclic C 2-10 alkenyl; NR 4 R 5 : C 2-10 alkenyl C(O)NR 4 R 5 ; C(O)NR 4 R 5 ; C(O)NR 4 R 10 ; S(O) 3 H; S(O) 3 R 8
  • C(O)R 11 ; C 2-10 alkenyl C(O)R 11 ; C 2-10 alkenyl C(O)OR 11 : C(O)R 11 : C(O)OR 12 : OC(O) R 11 ; NR 4 C(O)R 11 : or two R 1 moieties together may form O-(CH 2 ) s O- or a 5 to 6 membered unsaturated ring;
  • t is 0, or an integer having a value of 1 or 2;
  • s is an integer having a value of 1 to 3;
  • R 4 and R 5 are independently hydrogen, optionally substituted C 1-4 alkyl, optionally
  • Y is independently selected Irom hydrogen; halogen: nitro: cyano: halosubstituted C 1-10 alkyl.
  • C 1-10 alkyl C 2-10 alkenyl: C 1-10 alkoxy: halosubstituted C 1-10 alkoxy: azide: S(O) 1 R 4 : hydroxy: hydroxyC 1-4 alkyl: aryl: aryl C 1-4 alkyl: aryloxy: arylC 1-4 alkyloxy: heteroaryl: heteroarylalkyl: heteroaryl C 1-4 alkyloxy; heterocyclic, heterocyclic C 1-4 alkyl: aryl C 2-10 alkenyl: heteroaryl C 2-10 alkenyl: heterocyclic C 2-10 alkenyl: NR 4 R 5 : C 2-10 alkenyl C(O)NR 4 R 5 ; C(O)NR 4 R 5 ; C(O)NR 4 R 10 : S(O) 3 H: S(O) 3 R 8 : C 1-10 alkyl C(O) R 11 .
  • C 2-10 alkenyl C(O)R 11 ; C 2-10 alkenyl C(O)OR 11 ; C(O)R 11 ; C(O)OR 12 ; OC(O) R 11 ; NR 4 C(O) R 11 ; or two Y moieties together may lorm O-(CH2)sO- or a 5 to 6 membered unsaturated ring:
  • n is an integer having a value of 1 to 3:
  • n is an integer having a value of 1 to 3:
  • R 8 is hydrogen or C 1-4 alkyl:
  • R 10 is C 1-10 alkyl C(O) 2 R 8 :
  • R 1 1 is hydrogen, C 1 -4 alkyl, optionally substituted aryl, optionally substituted aryl C 1 -4 alkyl. optionally substituted heteroaryl. optionally substituted heteroaryl C 1 -4 alkyl. optionally substituted heterocyclic, or optionally substituted heterocyclic C 1 -4 alkyl;
  • R 12 is hydrogen, C 1- 10 alkyl, optionally substituted aryl or optionally subsututed arylalkyl. or a pharmaceutically acceptably salt thereof.
  • Another aspect of the present invention is to a method of treating a chemokine mediated disease, wherein the chemokine is one which binds to an IL-8 ⁇ or ⁇ receptor and which method comprises administering an effective amount of a compound of Formula (II) or a pharmaceutically acceptable salt thereof, as defined herein
  • This invention also relates to a method of inhibiting the binding of IL-8 to us receptors in a mammal in need thereof which comprises administering to said mammal an effective amount of a compound of Formula (II), as defined herein.
  • This invention also relates to the novel compounds of Formula (II), or a
  • Another aspect of the present invention is to a method of treating a chemokine mediated disease, wherein the chemokine is one which binds to an IL-8 ⁇ or ⁇ receptor and which method comprises administering an effective amount of a compound of Formula (III) or a pharmaceutically acceptable salt thereof, as defined herein
  • This invention also relates to a method of inhibiting the binding of IL-8 to its receptors in a mammal in need thereof which comprises administering to said mammal an cflccuvc amount of a compound of Formula (III), as defined herein
  • This invention also relates to the novel compounds of Formula (III ), or a
  • the compounds of Formula (I) may also be used in association with the veterinary treatment of mammals, other than humans, in need of inhibition of IL-8 or other chemokines which bind to the IL-8 ⁇ and ⁇ receptors Chemokine mediated diseases for treatment.
  • R is suitably any functional moiety which provides an ionizable hydrogen having a pKa of 10 or less, preferably from about 3 to 9, more preferably from about 3 to 7
  • Such functional groups include, but are not limited to. hydroxy, carboxylic acid, thiol, -SR 2 -OR 2 , -NH-C(O)R a , -C(O)NR 6 R 7 , a substituted sulfonamides of the formula -NHS(O) 2 R b , -S(O) 2 NHR c , NHC(X 2 )NHR b .
  • X 2 is oxygen or sulfur, preferably oxygen
  • the functional group is other than a sulfonic acid. either directly or as a substituent group on the aryl. heteroaryl, or heterocyclic moiety ring, such as in SR 2 or OR 2 . More preferably R is OH, SH, or NHS(O) 2 R b .
  • R 2 is a substituted aryl, heteroaryl, or heterocyclic moiety which ring has the founnaclti moiety providing the ionizable hydrogen having a pKa of 10 or less.
  • R 6 and R 7 are independently hydrogen or a C 1 -4 alkyl group, or R 6 and R 7 together with the nitrogen to which they are attached form a 5 to 7 member ring which ring may optionally contain an additional heteroatom which heteroatom is selected from oxygen, nitrogen or sulfur. This heteroring may be optionally substituted as defined herein.
  • R a is an alkyl, aryl, arylC 1 -4 alkyl, heteroaryl, heteroarylC 1 -4 alkyl.
  • R b is a NR 6 R 7 , alkyl, aryl, arylC 1 -4 alkyl, arylC 2-4 alkenyl, heteroaryl. heteroarylC 1-4 alkyl, heteroarylC 2-4 alkenyl, heterocyclic. or heterocyclic C 1 -4 alkyl, or a heterocyclic C 2-4 alkenyl moiety, camphor, all of which may be optionally substituted one to three times independently by halogen; nitro: halosubstituted C 1-4 alkyl.
  • R b is preferably an optionally subsututed phenyl. benzyl, or styryl When Rb is a heteroaryl preferably it is an opuonally subsututed thiazole. optionally substituted thienyl, or optionally substituted quinolinyl ring
  • R 9 is hydrogen or a C 1-4 alkyl. preferably hydrogen, and suitably when the substituent group is NR 9 C(O)R a , then R a is preferably an alkyl group, such as methyl
  • R c is hydrogen, alkyl. aryl. arylC 1-4 alkyl. arylC 1 -4 alkenyl, heteroaryl.
  • heteroarylC 1 -4 alkyl heteroarylC 1 -4 alkenyl. heterocyclic. or heterocyclic C 1 -4 alkyl. or a heterocyclic C 1 -4 alkenyl moiety, all of which may be optionally substituted one to three times independently by halogen, nitro. halosubstituted C 1-4 alkyl. C 1-4 alkyl, C 1-4 alkoxy.
  • R 9 is hydrogen or a C 1 -4 alkyl.
  • Rc is an optionally substituted phenyl
  • R is an OR 2 or SR 2 moiety 11 is lecognized by one of skill in the art that the aryl ring must, theretore. contain the required ionizable hydrogen
  • the aryl ring may also be additionally substituted, independently, by one to three groups, which groups may al.so contain an additional lonizable group, and which include but are not limited to. halogen, nitro.
  • C 1 -4 alkyl halosubstituted C 1 -4 alkyl.
  • C 1 -4 alkyl C 1 -4 alkoxy, hydroxy, SH, -C(O)NR 6 R 7 .
  • R 1 is independently selected from hydrogen; halogen: nitro; cyano: halosubstituted C 1- 10 alkyl. such asCF 3 ; C 1- 10 alkyl. such as methyl, ethyl, isopropyl. or n-propyl; C 2-10 alkenyl; C 1- 10 alkoxy, such as methoxy.
  • orethoxy halosubstituted C 1- 10 alkoxy, such as trifluoromethoxy; azide: S(O) t R 4 .
  • t is 0, 1 or 2; hydroxy; hydroxy C 1-4 alkyl. such as methanol or ethanol; aryl, such as phenyl or naphthyl: aryl C 1-4 alkyl, such as benzyl; aryloxy, such as phenoxy; aryl C 1-4 alkyloxy, such as benzyloxy; heteroaryl: heteroarylalkyl: heteroaryl C 1-4 alkyloxy: aryl C 2-10 alkenyl ;
  • R 1 is other than azido or S(O) 3 R 8 .
  • R 1 When R 1 forms a dioxybridge, s is preferably 1. When R 1 forms an additional unsaturated ring, it is preferably 6 membered resulting in a naphthylene ring system. This naphthylene ring may be substituted independently, 1 to 3 times by the other R 1 moieties as defined above.
  • R 4 and R 5 are independently hydrogen, optionally substituted C 1-4 alkyl. optionally substituted aryl optionally substituted aryl C 1-4 alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C 1-4 alkyl heterocyclic, heterocyclic C 1-4 alkyl, or R 4 and R 5 together with the nitrogen to which they are attached form a 5 to 7 member ring which may optionally comprise an additional heteroatom selected from O/N/S.
  • R 10 is suitably C 1-10 alkyl C(O) 2 R 8 , such as CH 2 C(O) 2 H or CH 2 C(O) 2 CH 3 .
  • R 11 is suitably hydrogen, C 1-4 alkyl, aryl, aryl C 1-4 alkyl, heteroaryl, heteroaryl C 1-4 alkyl, heterocyclic, or heterocyclic C 1-4 alkyl
  • R 12 is suitably hydrogen. C 1-10 alkyl. optionally substituted aryl or optionally substituted arylalkyl
  • R 1 is halogen, cyano. nitro. CF 3 , C(O)NR 4 R 5 . alkenyl C(O)NR 4 R 5 . C(O) R 4 R 10 , alkenyl C(O)OR 12 , heteroaryl, heteroarylalkyl, heteroaryl alkenyl, or S(O)NR 4 R 5 . and prelerably R 4 and R 5 are both hydrogen or one is phenyl.
  • a preferred ring substitution lor R 1 is in the 4-position of the phenyl ring.
  • R is OH, SH or NSO 2 R b than R 1 is preferably substituted in the 3-position, the 4-position or di substituted in the 3,4-position.
  • the substituent group is suitably an electron withdrawing moiety.
  • R 1 is nitro. halogen, cyano. trifluoromethyl group. C(O)NR 4 R 5 .
  • R 1 is carboxylic acid, than R 1 is preferably hydrogen, or R 1 is preferably substituted in the 4-position. more preferably substituted by trifluoromethyl or chloro.
  • Y is independently selected from hydrogen: halogen; nitro: cyano: halosubstituted C 1-10 alkyl: C ⁇ io alkyl: C 2-10 alkenyl; C 1 -io alkoxy: halosubstituted C 1-10 alkoxy: azide: S(O) t R 4 : hydroxy: hydroxy C 1-4 alkyl: aryl: aryl C 1-4 alkyl: aryloxy: arylC 1-4 alkyloxy: aryl C 2-10 alkenyl; heteroaryl: heteroarylalkyl; heteroaryl C 1-4 alkyloxy: heteroaryl C 2-10 alkenyl: heterocyclic, heterocyclic C 1-4 alkyl: heterocyclicC 2 - 10 alkenyl: NR 4 R 5 : C 2-10 alkenyl C(O)NR 4 R 5 : C(O)NR 4 R 10 ; S
  • C(O)R 11 ; C(O)OR 12 ; OC(O) R 11 ; NR 4 C(O)R 11 ; azido; or two Y moieties together may form O-(CH 2 ) s O- or a 5 to 6 membered unsaturated ring.
  • s is preferably 1
  • Y forms an additional unsaturated ring it is preferably 6 membered resulting in a naphthylene ring system
  • Tms naphthylene ring may be substituted 1 to 3 times by other Y moieties as defined above
  • the aryl, heteroaryl and heterocyclic moieties noted above may all be optionally substituted as defined herein.
  • R 1 is other than azido or S(O) 3 R 8
  • Y is prclerably a halogen. C 1-4 alkoxy. optionally substituted aryl. opuonally substituted aryloxy or arylalkoxy. methylene dioxy. NR 4 R 5 , thio C 1-4 alkyl, thioaryl, halosubstituted alkoxy, optionally substituted C 1-4 alkyl, or hydroxy alkyI.
  • Y is more preferably mono-subsututed halogen, disubstituted halogen, mono-substituted alkoxy.
  • Y may be substituted in any of the 5 ring positions, prclerably when R is OH SH. or NSO 2 R b .
  • Y is prelerably mono-substituted in the 2-position or 3-position, with the 4-preferably being unsubstituted It the ring is disubstituted. when R is OH, SH, or
  • NSO 2 R b substuuents are preferably in the 2' or 3' position of a monocyclic ring. While both R 1 and Y can both be hydrogen, it is prclered that at least one of the rings be substituted, prelerably both rings are substituted.
  • X is suitably oxygen or sulfur, preferably oxygen.
  • Prefered compounds of Formula (I ) include:
  • halogen such as fluorine, chlorine, bromine or iodine
  • hydroxy hydroxy substituted C 1 - 10 alkyl
  • C 1 - 1 0 alkoxy such as methoxy or ethoxy
  • halosubstituted C 1 - 10 alkyl such CF 3 ; an opuonally substituted aryl, such as phenyl, or an optionally subsututed arylalkyl. such as benzyl or phenethyl. optionally substituted heterocylic, optionally substituted heterocylicalkyl. optionally subsututed heteroaryl. optionally substituted heteroaryl alkyl.
  • aryl , hetroaryl, or heterocyclic moieties may be substituted one to two times by halogen; hydroxy; hydroxy substituted alkyl; C 1 - 10 alkoxy: S(O) m , C 1 - 10 alkyl; amino, mono & di-substituted amino, such as in the NR 4 R 5 group; C 1-10 alkyl, or halosubstituted C 1-10 alkyl, such as CF 3 .
  • R 13 is suitably C 1-4 alkyl, aryl, aryl C 1-4 alkyl, heteroaryl, heteroarylC 1-4 alkyl. heterocyclic, or heterocyclicC 1-4 alkyl.
  • This invention also relates to the pharmaceutical compositions comprising a compound of Formula (II) and a
  • Compounds of Formula (II) are also useful tor treating a chemokine mediated disease, wherein the chemokine is one which binds to an IL-8 ⁇ or ⁇ receptor and which method comprises administering an effective amount of a compound of Formula (II) or a pharmaceutically acceptable salt thereof.
  • Compounds of Formula (II) are also useful tor treating a chemokine mediated disease, wherein the chemokine is one which binds to an IL-8 ⁇ or ⁇ receptor and which method comprises administering an effective amount of a compound of Formula (II) or a pharmaceutically acceptable salt thereof.
  • X is oxygen or sulfur
  • R is any functional moiety having an lonizable hydrogen and a pKa of 10 or less:
  • R 1 is independently selected from hydrogen; halogen; nitro; cyano; halosubstituted C 1-10 alkyl: C 1-10 alkyl: C 2-10 alkenyl: C 1-10 alkoxy; halosubstiiuied C 1-10 alkoxy: azide;
  • OC(O) R 11 ; NR 4 C(O)R 11; or two R 1 moieties together may form O-(CH 2 ) s O- or a 5 to 6 membered unsaturated ring:
  • t is 0, or an integer having a value of 1 or 2;
  • s is an integer having a value of 1 to 3;
  • R 4 and R 5 are independently hydrogen, opuonally substituted C 1-4 alkyl. optionally
  • Y is independently selected from hydrogen: halogen: nitro; cyano: halosubsuiuicd C 1-10 alkyl: C 1-10 alkyl: C 2-10 alkenyl; C 1-10 alkoxy: halosubstituted C 1-10 alkoxy: azide: S(O)(R4: hydroxy: hydroxy C 1-4 alkyl; aryl; aryl C 1-4 alkyl: aryloxy; aryl C 1-4 alkyloxy: heteroaryl heteroarylalkyl: heteroarylC 1-4 alkyloxy; heterocyclic,
  • n is an integer having a value of 1 to 3;
  • n is an integer having a value of 1 to 3;
  • R 8 is hydrogen or C 1-4 alkyl
  • R 10 is C 1-10 alkyl C(O) 2 R 8 ;
  • R 11 is hydrogen. C 1-4 alkyl, optionally substituted aryl. optionally subsututed aryl C 1-4 alkyl optionally subsututed heteroaryl, optionally subsututed heteroarylC 1-4 alkyl, opuonally subsututed heterocyclic, or optionally substituted heterocyclicC 1-4 alkyl;
  • R 12 is hydrogen, C 1-10 alkyl, optionally substituted aryl or optionally substituted arylalkyl;
  • E is opuonally selected from
  • the variables for Formula (II), such as X, R, R 1 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , Y, R a , R b , R c , n, m, and s terms, etc. are as defined in Formula (I) above
  • the E ring denoted by its point of attachment through the asterix (*) may opuonally be present If ll it is not present the ring is a phenyl moiety which is substituted by the R and R 1 terms as shown At least one E ring is necessary.
  • the E ring may be substituted by the R 1 moiety in any ring, saturated or unsaturated. and is shown for purposes herein substituted only in the unsaturated ring(s)
  • Another aspect of the present invention are the novel compounds of Formula (III), or a pharmaceutically acceptable salt thereof. as described below, which are al.so useful in inhibiting the binding of IL-8 to its receptors in a mammal in need thereof
  • This invention al.so relates to the pharmaccuueal compositions comprising a compound of Formula (III) and a
  • Compounds of Formula (III) are also useful for treating a chemokine mediated disease, wherein the chemokine is one which binds to an IL-8 ⁇ or ⁇ receptor and which method comprises administering an effective amount of a compound of Formula (III) or a pharmaceuucally acceptable salt thereof
  • Compounds of Formula (III ) are represented by the formula:
  • X is oxygen or sulfur
  • R is any functional moiety having an ionizable hydrogen and a pKa of 10 or less.
  • R 1 is independently selected from hydrogen: halogen: nitro; cyano: halosubstituted C 1-10 alkyl: C 1-10 alkyl; C 2-10 alkenyl: C 1-10 alkoxy: halosubstituted C 1-10 alkoxy; azide; S(O) t R 4 ; hydroxy; hydroxyC 1-4 alkyl; aryl; aryl C 1-4 alkyl; aryloxy;arylC 1-4 alkyloxy; heteroaryl; heteroarylalkyl; heterocyclic, heterocyclicC 1-4 alkyl.
  • NR 4 R 5 ; C 2-10 alkenyl C(O)NR 4 R 5 ; C(O)NR 4 R 5 ; C(O)NR 4 R 10 ; S(O) 3 H; S(O) 3 R 8 ; C 1-10 alkyl C(O)R 11 ; C 2-10 alkenyl C(O)R 11 ; C 2-10 alkenyl C(O)OR 11 ; C(O)R 11 ; C(O)O R12; OC(O)R 11 ; NR 4 C(O)R 11 ; or two R 1 moieties together may form O-(CH 2 ) s O- or a 5 to 6 membered unsaturated ring:
  • t is 0. or an integer having a value of 1 or 2;
  • s is an integer having a value of 1 to 3.
  • R 4 and R 5 are independently hydrogen, optionally substituted C 1-4 alkyl, optionally
  • subsututed aryl optionally substituted aryl C 1-4 alkyl. optionally substituted heicroaryl. optionally substituted heteroaryl C 1-4 alkyl.
  • heterocyclic, heterocyclicC 1-4 alky 1 or R 4 and R 5 together with the nitrogen to which they are attached form a 5 to 7 member ring ulnd. may optionally comprise an additional heteroaiom selected Irom O/N/S.
  • Y is independently selected Irom hydrogen: halogen; nitro: cyano; halosubstituted C 1-10 alkyl;
  • heteroarylalkyl heteroarylC 1-4 alkyloxy; heterocyclic, heterocyclicC 1-4 alkyl; aryl C 2-10 alkenyl; heteroaryl C 2-10 alkenyl: heterocyclicC 2-10 alkenyl: NR 4 R 5 ; C C 1-10 alkenyl C(O)NR 4 R 5 ; C(O)NR 4 R 5 : C(O)NR 4 R 1 »: SfOt ⁇ H: S(O) 3 R 8 - C 1-10 alkyl C(O)R 11 ; C 2-10 alkenyl C(O)R 11 ; C 2-10 alkenyl C(O)OR 11 ; C(O)R 11 ; C(O)OR 12 ; OC(O) R 11 :
  • NR 4 C(O)R 11 may form O-(CH 2 ) s O- or a 5 to 6 membered unsaturated ring;
  • n is an integer having a value of 1 to 3;
  • n is an integer having a value of 1 to 3;
  • R 8 is hydrogen or C 1 -4 alkyl
  • R 10 is C 1-10 alkyl C(O) 2 R 8 ;
  • R 11 is hydrogen, C 1-4 alkyl, optionally substituted aryl, opuonally subsututed aryl C 1-4 alkyl, optionally substituted heteroaryl, optionally subsututed heteroarylC 1-4 alkyl, optionally subsututed heterocyclic, or opuonally substituted heterocyclicC 1-4 alkyl;
  • R 12 is hydrogen, C 1-10 alkyl, optionally substituted aryl or optionally substituted arylalkyl; or a pharmaceutically acceptably salt thereof.
  • variables, etc. for Formula (II) are the same as ihosc defined for Formula (I) above, such as for example the R variable
  • Exemplified compounds of Formula (III) are N-(2-Hydroxy-4-nitrophenyl)-N'-(3- methoxy-2-thienyl)urea; and N-(2-hydroxy-5-nitrophenyl)-N'-(3-methoxy-2-thienyl)urea.
  • Another aspect ot the present invention is the novel compounds of Formula (Ia), a subset of compounds of Formula (I) useful lor treating a chemokine mediated disease as defined herein
  • This invenuon also relates to the phamiaccuucal compositions comprising a compound of Formula (la) and a pharmaceuucally acceptable diluent or carrier
  • the compounds of Formula (la) are represented by the strucuture:
  • X is oxygen or sulfur
  • R a is an alkyl, aryl, arylC 1-4 alkyl, heteroaryl, heteroaryl C 1-4 alkyl, heterocyclic, or a
  • R b is a NR 6 R 7 , alkyl, aryl, arylC 1-4 alkyl, arylC 2-4 alkenyl, heteroaryl, heteroarylC 1-4 alkyl, heteroarylC 2-4 alkenyl, heterocyclic, or heterocyclic C 1-4 alkyl, or a heterocyclic
  • R 6 and R 7 are independently hydrogen or a C 1-4 alkyl group, or R 6 and R 7 together with the nitrogen to which they are attached torm a 5 to 7 member ring which ring may opuonally contain an additional heteroatom which heteroatom is selected from oxygen, nitrogen or sullur, which ring may be optionally substitued;
  • R 9 is hydrogen or a C 1-4 alkyl, preferably hydrogen
  • R 1 is independently selected from hydrogen; halogen; nitro; cyano; halosubstituted C 1-10 alkyl; C 1-10 alkyl; C 2-10 alkenyl; C 1 - 10 alkoxy; halosubstituted C 1-10 alkoxy; azide; S(O) t R 4 ; hydroxy; hydroxy C 1-4 alkyl; aryl; aryl C 1-4 alkyl; aryloxy; aryl C 1-4 alkyloxy; heteroaryl; heteroarylalkyl; heterocyclic, heterocyclic C 1-4 alkyl; heteroaryl C 1-4 alkvloxy, aryl C 2-10 alkenyl; heteroaryl C 2-10 alkenyl; heterocyclicC 2-10 alkenyl; NR 4 R 5 ; C 2-10 alkenyl C(O)NR 4 R 5 ; C(O)NR 4 R 5 ; C(O)NR 4 R 10 ; S(O) 3 H; S(O) 3
  • t is 0, or an integer having a value of 1 or 2.
  • s is an integer having a value of 1 to 3;
  • R 4 and R 5 are independently hydrogen, opuonally subsututed C 1-4 alkyl, optionally
  • substituted aryl optionally substituted aryl C 1-4 alkyl, opuonally substituted heteroaryl, opuonally substituted heteroaryl C 1-4 alkyl, heterocyclic, heterocyclicC 1 -4 alkyl, or R 4 and R 5 together with the nitrogen to which they are attached lorm a 5 to 7 member ring which may optionally comprise an additional heicroatom selected from O/N/S.
  • Y is independently selected Irom hydrogen; halogen; nitro; cyano; halosubstituted C 1-10 alkyl.
  • C 1-10 alkyl C 2-10 alkenyl; C 1-10 alkoxy; halosubstituted C 1-10 alkoxy; azide; S(O) t R 4 ; hydroxy; hydroxyC 1-4 alkyl; aryl; aryl C 1-4 alkyl; aryloxy; arylC 1-4 alkyloxy; heteroaryl. heteroarylalky 1; heteroarylC 1-4 alkyloxy. heterocyclic, heterocyclicC 1-4 alkyl; aryl C 2-10 alkenyl; heteroaryl C 2-10 alkenyl; heterocyclicC 2-10 alkenyl; NR 4 R 5 .
  • C 1-10 alkyl C(O)R 11 ; C 2-10 alkenyl C(O)R 11 ; C 2-10 alkenyIC(O)OR 11 ; C(O)R 11 ; C(O)OR 12 ; OC(O)R 11 ; NR 4 C(O)R 11 ; or two Y moieties logethei may lorm O-(CH 2 ) s O-or a 5 to 6 membered unsaturated ring.
  • n is an integer having a value of 1 to 3;
  • n is an integer having a value of 1 to 3;
  • R 8 is hydrogen or C 1-4 alkyl.
  • R 10 is C 1 - 10 alkyl C(O) 2 R 8 ;
  • R 1 1 is hydrogen, C 1-4 alkyl, optionally substituted aryl, optionally substituted aryl C 1 -4 alkyl. optionally substituted heteroaryl, optionally substituted heteroarylC 1 -4 alkyl, optionally substituted heterocyclic, or opuonally substituted heterocyclicC 1 -4 alkyl;
  • R 12 is hydrogen, C 1 - 10 alkyl, optionally substituted aryl or optionally substituted arylalkyl; or a pharmaceutically acceptably salt thereof.
  • R 1 variable is monosubstituted in the 3-position, or the 4- position, or di-substituted in the 3,4- position.
  • the substituent group is suitably an electron withdrawing moiety,
  • R 1 is nitro, halogen, cyano, trifluoromethyl group, or
  • Y may be substituted in any of the 5 ring positions, preferably the ring with the Y moiety is mono-substituted in the 2-position or 3- position, with the 4- preferably being unsubstituted. If the ring is di-substituted. substituents are preferably in the 2'-, 3 - positions of a monocyclic ring. While both R 1 and Y can both be hydrogen, it is prefered that at least one of the rings be substituted, preferably both rings are at least mono-substituted, i.e. n amd m are each equal to 1 or more.
  • Y is more preferably a mono-substituted halogen, disubstituted halogen, mono-substituted alkoxy, disubstituted alkoxy, methylenedioxy, aryl, or alkyl. preferably these groups are substituted in the 2'- position or 2'-,3'-position.
  • Another aspect of the present invention is the novel compounds of Formula (Ib), a subset of compounds of Formula (I) useful for treating a chemokine mediated disease.
  • This invention also relates to the pharmaceutical compositions comprising a compound of Formula (Ib) and a pharmaceutically acceptable diluent or carrier.
  • the compounds of Formula (Ib) are represenied by the sirucuture:
  • X is oxygen or sulfur
  • X 1 is oxygen or sulfur
  • R 1 is independently selected from hydrogen; halogen; nuro; cyano; halosubstituted C 1-10 alkyl; C 1-10 alkyl; C 2-10 alkenyl; C 1-10 alkoxy; halosubstituted C 1-10 alkoxy; azide; S(O) t R 4 ; hydroxy; hydroxyC 1-4 alkyl; aryl; aryl C 1-4 alkyl; aryloxy; arylC 1-4 alkyloxy; heteroaryl; heteroarylalkyl; heterocyclic, heterocyclic C 1-4 alkyl; heteroaryl C 1-4 alkyloxy; aryl C 2-10 alkenyl; heteroaryl C 2-10 alkenyl; heterocyclicC 2-10 alkenyl: NR 4 R 5 , C 2-10 alkenyl C(O)NR 4 R 5 ;C(O)NR 4 R 5 ;C(O)NR 4 R 10 ;S(O) 3 H;S(O) 3 R 8
  • t is 0, or an integer having a value of 1 or 2;
  • s is an integer having a value of 1 to 3;
  • R 2 is a substituted aryl, heteroaryl, or heterocyclic ring which ring has a functional moiety providing the ionizable hydrogen having a pKa of 10 or less;
  • R 4 and R 5 are independently hydrogen, optionally substituted C 1-4 alkyl, optionally substituted aryl, optionally substituted aryl C 1-4 alkyl, optionally substituted heteroaryl. optionally substituted heteroaryl C 1-4 alkyl, heterocyclic. heterocyclicC 1-4 alkyl, or R 4 and R 5 together with the nitrogen to which they are attached form a 5 to 7 member ring which may opuonally comprise an additional heteroatom selected from O/N/S;
  • Y is independently selected from hydrogen: halogen: nitro; cyano: halosubstituted C 1-10 alkyl;
  • C(O)NR 4 R 5 ; C(O)NR 4 R 5 ; C(O)NR 4 R 10 ; S(O)3H; S(O) 3 R 8 ; C 1-10 alkyl C(O)R 11 ; C 2-10 alkenyl C(O)R 11 : C 2-10 alkenyl C(O)OR 11 ; C(O)R 11 ; C(O)OR 12; OC(O) R 11 ; NR 4 C(O)R 11 ; or two Y moieties together may form O-(CH2)sO- or a 5 to 6 membered unsaturated ring;
  • n is an integer having a value of 1 to 3;
  • n is an integer having a value of 1 to 3;
  • R 8 is hydrogen or C 1 - 4 alkyl
  • R 10 is C 1-10 alkyl C(O) 2 R 8 ;
  • R 11 is hydrogen, C 1-4 alkyl. optionally substituted aryl, optionally substituted aryl C 1-4 alkyl, opuonally substituted heteroaryl, optionally substituted heteroarylC 1-4 alkyl, optionally substituted heterocyclic, or opuonally substituted heterocyclicC 1-4 alkyl;
  • R 12 is hydrogen. C 1-10 alkyl, optionally substituted aryl or optionally substituted arylalkyl; or a pharmaceutically acceptable salt thereof.
  • the variable, etc. for Formula (lb) are the same as those defined for Formula
  • functional groups include, but are not limited to. hydroxy, carboxylic acid, thiol, -NH-C(O)R a , -C(O)NR 6 R 7 . substituted sulfonamides of the formula -NHS(O) 2 Rb,- -S(O)2NHR c . NHC(X 2 )NHR n . or tetrazoyl (as defined for Formula (I).
  • R 1 is in the 3-position. the 4- position or is preferably di substituted in the 3.4- position.
  • the substituent group is suitably an electron withdrawing moiety .
  • R 1 is nitro, halogen, cyano. trifluoromethyl group, or C(O)NR 4 R 5 .
  • Y moiety is mono-substituted in the 2-position or 3- position, with the 4- preferably being unsubstituted. If the ring is disubstituted. substituents are prelerably in the 2' or 3' position of a monocyclic ring. While both R 1 and Y can both be hydrogen, it is prefered that at least one of the rings be substituted, preferably both rings are at least mono-substituted, i.e. n amd m are each equal to 1 or more.
  • Y is more preferably disubstituted halogen, mono-substituted halogen, disubstituted alkoxy, mono-substituted alkoxy, methylencdioxy, aryl, or alkyl, preferably in the 2'position or 2'.3'-position.
  • Another aspect of the present invention is the novel compounds of Formula (Ic), a subset of compounds of Formula (I) useful for treating a chemokine mediated disease.
  • This invention also relates to the pharmaceutical compositions comprising a compound of Formula (Ic) and a pharmaceuucally acceptable diluent or carrier.
  • the compounds of Formula (Ic ) are represented by the strucuture:
  • X is oxygen or sulfur
  • X 1 is oxygen or sulfur
  • R 1 is independently selected from hydrogen; halogen; nitro; cyano; halosubstituted C 1 - 10 alkyl; C 1 - 10 alkyl; C 2-10 alkenyl; C 1 - 10 alkoxy; halosubstituted C 1 - 10 alkoxy; azide; S(O) t R 4 ; hydroxy; hydroxyC 1-4 alkyl; aryl; aryl C 1-4 alkyl; aryloxy; aryl C 1-4 alkyloxy; heteroaryl; heteroarylalkyl; heterocyclic.
  • heterocyclicC 1-4 alkyl; heteroarylC 1-4 alkyloxy; aryl C 2-10 alkenyl; heteroaryl C 2-10 alkenyl; heterocyclic C 2-10 alkenyl; NR 4 R 5 ; C 2-10 alkenyl C(O)NR 4 R 5 ; C(O)NR 4 R 5 ; C(O)NR 4 R 10 ; S(O) 3 H; S(O) 3 R 8 ; C 1 - 10 alkyl C(O)R 11 ; C 2-10 alkenyl C(O)R 11 ; C 2-10 alkenyl C(O)OR 11 ; C(O)R 11 ; C(O)OR 12 OC(O) R 11 ; NR 4 C(O)R 11 ; or two R 1 moieties together may form O-(CH 2 ) s O- or a 5 to6 membered unsaturated ring:
  • t is 0. or an integer having a value of 1 or 2;
  • s is an integer having a value of 1 to 3;
  • R 4 and R 5 are independently hydrogen, optionally substituted C 1-4 alkyl. optionally
  • substituted aryl optionally substituted aryl C 1-4 alkyl. optionally substituted heteroaryl. opuonally substituted heteroaryl C 1-4 alkyl, heterocyclic. heterocyclic C 1-4 alkyl, or R 4 and R 5 together with the nitrogen to which they are attached form a 5 to 7 member ring which may optionally comprise an additional heteioatom selected from O/N/S;
  • Y is independently selected from halogen; nitro; cyano; halosubstituted C 1 - 10 alkyl; C 1 - 10 alkyl; C 2-10 alkenyl; C 1 - 10 alkoxy; halosubstituted C 1 - 10 alkoxy; azide; S(O) t R 4;
  • n is an integer having a value of 1 to 3;
  • n is an integer having a value of 1 to 3;
  • R 8 is hydrogen or C 1-4 alkyl
  • R 10 is C 1-10 alkyl C(O) 2 R 8 ;
  • R 11 is hydrogen. C 1-4 alkyl, optionally substituted aryl, optionally substituted aryl C 1-4 alkyl, optionally substituted heteroaryl, optionally substituted heteroarylC 1-4 alkyl, opuonally substituted heterocyclic, or optionally substituted heterocyclicC 1-4 alkyl;
  • R 12 is hydrogen. C 1-10 alkyl, optionally substituted aryl or optionally substituted arylalkyl; provided that
  • R 1 is in the 3-position, the 4- position or di substituted in the 3.4- position.
  • R 1 is other than hydrogen.
  • the substituent group is suitably an electron withdrawing moiety.
  • R 1 is nitro, halogen, cyano. trifluoromethyl group, or C(O)NR 4 R 5 .
  • Y may be substituted in any of the 5 ring positions, preferably the ring with the Y moiety is mono-substituted in the 2-position or 3- position, with the 4- preferably being unsubstituted. If the ring is disubstituted, substituents are preferably in the 2' or 3' position of a monocyclic ring. While both R 1 and Y can both be hydrogen, it is prefered that at least one of the rings be substituted, preferably both rings are at least mono-substituted, i.e. n amd m are each equal to 1 or more.
  • Y is more preferably a mono-substituted halogen, disubstituted halogen, mono-substituted alkoxy, di substituted alkoxy,
  • 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, methane sulphonic acid, ethane sulphonic acid, acetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinie acid, lumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid and mandelic acid,
  • pharmaceuucally acceptable salts of compounds of Formula (I) may also be formed with a pharmaceutically acceptable cation, for instance, if a substituent group comprises a carboxy moiety.
  • Suitable pharmaceutically acceptable cations are well known to those skilled in the art and include alkaline, alkaline earth, ammonium and quaternary ammonium cations.
  • halo all halogens, that is chloro, fluoro. bromo and iodo.
  • C 1 - 10 alkyl or “alkyl” - both straight and branched chain radicals of 1 to 10 carbon atoms, unless the chain length is otherwise limited, including, but not limited to. methyl, ethyl, n-propyl, i.s o-propyl, n-butyl, sec -butyl, iso-butyl. tert-butyl. n-pentyl and the like
  • cycloalkyl is used herein to mean cyclic radicals, preferably of 3 to 8 carbons, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl, and the like
  • alkenyl is used herein at all occurrences to mean straight or branched chain radical of 2- 10 carbon atoms, unless the chain length is limited thereto, including, but not limited to ethenyl, 1 -propenyl. 2-propenyl, 2-methyl- 1 -propenyl, 1 -butenyl, 2-butenyl and the like.
  • heteroaryl on its own or in any combination, such as “heteroaryloxy”, or
  • heteroaryl alkyl a 5- 10 membered aromatic ring system in which one or more rings contain one or more heteroatoms selected from the group consisting of N. O or S. such as, but not limited, to pyrrole, pyrazole, furan, thiophene, quinoline. lsoquinolinc, quinazolinyl, pyridine, pyrimidine, oxazole, thiazole, thiadiazole, triazole, imidazole, or benzimidazole.
  • heterocyclic (on its own or in any combination, such as “heterocyclicalkyl”) - a saturated or partially unsaturated 4- 10 membered ring system in which one or more rings contain one or more heteroatoms selected from the group consisting of N. O, or S; suc0 000 but not limited to, pyrrohdine, piperidine, piperazme, morpholine, tetrahydropyran, or
  • arylalkyl or “heteroarylalkyl” or “heterocyclicalkyl” is used herein to mean C 1 - 10 alkyl. as defined above, attached to an aryl, heteroaryl or heterocyclic moiety, as also defined herein, unless otherwise indicated .
  • R 1 moieties or two Y moieties may together form a 5 or 6 membered unsaturated ring
  • a napthylene ring system or a phenyl moiety having attached a 6 membered partially unsaturated ring such as a C 6 cycloalkenyl. i.e hexene. or a C 5 cyloalkenyl moiety, cyclopentene.
  • the compounds of Formula (I), (la), (lb), ( Ic), ( II) and (III) may be obtained by applying synthetic procedures, some of which are illustrated in the Schemes below .
  • the synthesis provided for in these Schemes is applicable f or the producing compounds of Formula (I), ( Ia), (II ) and (III) having a variety of dif ferent R, R 1 , and Ar groups which are reacted, employing optional subsutuents which are suitably protected, to achieve compatibility with the reactions outlined herein. Subsequent deprotection, in those cases, then affords compounds of the nature generally disclosed.
  • further compounds of these formulas may be prepared by applying standard techniques for functional group interconversion. well known in the art. While the schemes are shown with compounds only of Formula (I) this is merely for illustration purposes only.
  • Ortho substituted phenyl ureas shown in 2-scheme 1 may be prepared by standard conditions involving the condensation of commercially available ortho substituted
  • the corresponding nitro compound can be prepared from 3-scheme 2. under standard nitration conditions (using HNO 3 or BF 4 NO 3 ) at 23 °C. The nitro compound is then reduced to the corresponding aniline using SnCl 2 in EtOH(or alternately H 2 /Pd or LiAlH 4 ). £
  • the desired 2-amino benzenethiol 8-scheme 3 is not commercially available it can be synthesized by reaction of the phenyl aniline with the thiocyanate anion in the presence ot an oxidant(like bromine) to produce the 2-am ino benzthiazole 7-scheme 3. This thiazole can then be hydrolyzed to the desired 2-amino benzenethiol 8 -scheme 3 with a strong base like NaOH in a protic solvent (i.e . EtOH).
  • a protic solvent i.e . EtOH
  • the thiourea or urea 1 1 -scheme 4 may be prepared from the commercially available ortho substituted aniline.
  • This compound is first protected with a protecting group (tert-butyl dimethyl silyl or benzyl ) by conditions well known in the art (see Greene. T Protecting Groups in Organic Synthesis, Wiley&Sons, New York, 1981 ).
  • This protected aniline is then reacted, in the presence ot a base(like methyl amine or sodium bicarbonate), with either thiophosgene or a solution of phosgene in an aprotic solvent (ie.
  • the urea can be formed using a Curtius rearrangement from the
  • compositions of Formula (I) may be obtained in known manner, for example by treatment thereof with an appropriate amount of acid or base in the presence of a suitable solvent.
  • Another aspect of the present invention is the novel synthesis of cyano nitrophenol intermediates.
  • Numerous conversions of aryl halides to aryl cyano derivatives with copper (I) cyanide have been published. However, no examples of an aryl ring with a hydroxy group present were mentioned.
  • Several attempts to obtain a cyano phenol moiety with published results failed. Using known conditions of elevated temperatures, greater than 170oC. such as from 180 to 210 did not yield displacment of the halogen to a cyano moiety. Standard bases such as DMF and pyridine further provided no desired product.
  • one aspect of the invention is to a process for producing a cyano phenol derivative of the formula:
  • R 1 is as defined for Formula (I) above, which method comprises reacting a compound of the formula:
  • X is halogen with copper (I) cyanide, dimethylformamide, triethylamine and a catalytic amount of dimethylamino pyridine.
  • the process is run at reduced temperatures of about 60 to about 80°C.
  • X is bromine.
  • N-[2-Hydroxy-4-(methoxycarbonyl)phenyl]-N'-phenyl urea was prepared from methyl-4-amino-3-hydroxybenzoate (200 mg, 1.19 mmol) and phenyl isocyanate ( 1.19 mmol ) according to the procedure noted above in General Method A. The product was pur ified by precipitation from toluene, and filtering, to afford the titled compound (309 mg, 90%). mp:
  • N-[5-nitro-2-hydroxyphenyl]-N'-phenyl urea was prepared f rom the 5- nitro 2. hydroxy aniline and phenyl isocyanaie according to the procedure in General Method A. The product was purified by precipitation from toluene and filtering to af ford the titled compound
  • N-(2-Hydroxy-4-fiuorophenyl )-N'-phenyl urea was prepared f rom 2-amino-5-fluoro phenol (200 mg, 1.57 mmol ) and phenyl isocyanaie according to the procedure in General
  • N-(2-Carboxy-4-hydroxyphenyl)-N'-phenyl urea was prepared from 2-amino-5-hydroxy benzoic acid ( 1 g, 6.53 mmol) according to the procedure in General Method B.
  • the reaction mixture was partitioned between ethyl acetate and water.
  • the organic phase was washed with brine, dried over MgSO 4 and filtered. Removal of solvent under reduced pressure and chromatography of the resulting solid on silica gel (hexane : ethyl acetaie, 1 : 1 to 100% ethyl acetate) gave the titled compound ( 1.5 g. 84% ).
  • N - [2 - Hydroxy - 4- (trilluoromethyl) phenyl ] - N" - phenyl urea was prepared from 2-amino-5-trifluoromethylphenol ( 150 mg, 1.09 mmol ) and phenyl isocyanate( 1.09 mmol) according to the procedure in General method A.
  • letrabuty lammonium fluoride 1 M, 0.09 mL, 0.089 mmol
  • the reaction mixture w as surred at 2 3°C. After 1 hour , the starling material had disappeared.
  • the combined otganic phase was dried over MgSO 4 and filtered.
  • N-(2-tert-Butyldimethysilyloxy-4-nitrophenyl)-N'-phenyl-thiourea was prepared by treating a biphasic solution of 2-tert-butyldimethysilyloxy-4-nitroaniline(80 mg, 0.308 mmol) and NaHCO 3 in CHCl 3 :H 2 O(2.5: 1 , 7mL) with thiophosgene at 0°C. The solution was allowed to warm to 23°C and the reaction was continued overnight. The CHCl 3 layer was separated and dried over sodium sulfate.
  • N-(2-Hydroxy-4-nitrophenyl)-N'-phenyl-2-thiourea was prepared by treating a solution of N-(2-tert-butyldimethysilyloxy-4-nitrophenyl)-N'-phenyl-thiourea (100 mg, 0.248 mmol) in CH 3 CN (1 mL) with Et 3 N ⁇ HF (100uL, 0.62 mmol) in acetonitrile for 10 minutes at
  • the lesulting solid was recrystallized (EtOH) to af ford desired (0.275 g. 9% ).
  • N-(4- nitro 2-(phenylsulfonylamino)phenyl)-N'-phenyl urea was prepared from 4-nitro 2-(phenylsulfonylamino) aniline(82 mg) and phenyl isocyanaie(33 mg) by method A. The reaction was cooled and then partitioned between saturated ammonium chloride and 9: 1 methylene chloride and methanol. The organic phase was dried over magnesium sulfate.
  • N-(2-Hydroxy-4-nitrophenyl)-N'-(3-methoxyphenyl)urea was prepared from 2-hydroxy 4-nitro aniline (154 mg, 1.0 mmol) and 3-methoxy phenyl isocyanate( 1.0 mmol) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound ( 140 mg, 46%). EI-MS m/z 302(M-H) -
  • N-(2-Hydroxy-4-nitrophenyl)-N'-(2-methoxyphenyl)urea was prepared from 2-hydroxy 4-nitro aniline (154 mg, 1.0 mmol) and 2-methoxy phenyl isocyanate( l mmol.) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound (82 mg. 27% ). EI-MS m/z 302(M-H)-
  • N-(2-Hydroxy-4-nitrophenyl)-N'-(3-methoxyphenyl)urea was prepared f rom 2-hydroxy 4-nitro aniline (154 mg. 1.0 mmol) and 3-trifluoromethyl phenyl isocyanaie ( 1 mmol according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound ( 180 mg. 52% ). EI-MS m/z 342(M+H) +
  • N-(2-Hydroxy-4-nitrophenyl)-N'-(2-trifluoromethylphenyl)urea was prepared from 2-hydroxy 4-nitro aniline ( 154 mg. 1.0 mmol) and 2-trifluoromethyl phenyl isocyanate ( 1.0 mmol) according 10 the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound ( 180 mg. 52% ). EI-MS m/z 342(M+H) +
  • N-(2-hydroxy-4-nurophenyl)-N"-(4-trifluoromethylphenyl )urea N-(2-Hydroxy-4-nitrophenyl)-N'-(4-trifluoromethylphenyl)urea was prepared f rom 2-hydroxy 4-nitro aniline ( 154 mg, 1.0 mmol) and 4-trifluoromethyl phenyl isocyanate ( 1.0 mmol) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound ( 1 1 1 mg, 32%). EI-MS m/z 340(M-H)-
  • N-(2-Hydroxy-4-nitrophenyl)-N'-(2-bromophenyl)urea was prepared f rom 2-hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 2-bromophenyl isocyanate (3.24 mmol ) according to the procedure in General Method B.
  • the product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound(530 mg. 47% ) EI-MS m/z 350(M-H) -
  • N-(2-Hydroxy-4-nitrophenyl)-N'-(3-bromo phenyl )urea was prepared from 2-hydroxy 4-nitro aniline (500 mg. 3.24 mmol) and 3-bromo phenyl isocyanate (3.24 mmol)according to the procedure in General Method B.
  • the product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound(0.96g. 87% ) EI-MS m/z 350(M-H) -
  • N-(2-Hydroxy-4-nitrophenyl)-N'-(4-bromo phenyl)urea was prepared f rom 2-hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 4-bromo phenyl isocyanate (3.24 mmol ) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound (0.41 g. 37% ) EI-MS m/z 352(M+H) + Example 21
  • N-(2-Hydroxy-4-nitrophenyl)-N'-(2-phenylphenyl )urea was prepared f rom 2-hydioxy 4-nitio aniline (5(X) mg. 3.24 mmol) and 2-phenyl phenyl isocyanate (3 24 mmol ) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound(0.22 g. 19% ). EI-MS m/z 350(M+H) +
  • N-(2-Hydroxy-4-nitrophenyl)-N'-( 1 -naphthyl)urea was prepared f rom 2-hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 1 -naphthyl isocyanate (3.24 mmol) according to the procedure in General Method B.
  • the product precipitated from methylene chloride and filtered.
  • the resulting solid was titruated with 1 :3 triethyl amine:methylene chloride.
  • the filteraie was concentrated in vacuo.
  • the resulting residue was dissolved in methylene chloride and treated with 1N C1 in water.
  • Example 23 Example 23
  • N-(2-Hydroxy-4-nitrophenyl)-N'-(2-nitro phenyl)urea was prepared from 2-hydroxy
  • N-(2-Hydroxy-4-nitrophenyl)-N'-(2,6-difluorophenyl)urea was prepared f rom 2- hydroxy 4-nitro aniline (500 mg. 3.24 mmol) and 2.6-difluoro phenyl isoey anate(3.24 mmol , according to the procedure in General Method B.
  • the product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound( 0.9 1 g. 91 %).
  • N-(2-Hydroxy-4-nitrophenyl)-N'-(2-ethoxyphenyl)urea w as prepared from 2-hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 2-cihoxy phenyl isocyanate (3.24 mmol ) according to the procedure in General Method B.
  • the product was purified by dilution wiih methylene chloride and precipitation with hexanes. Filtering afforded the title compound(0.84 g. 8 1 % ) .
  • N-(2-Hydroxy-4-nitrophenyl)-N'-(2-ethylphenyl)urea was prepared from 2-hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 2-ethyl phenyl isocyanate (3.24 mmol) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation wilh hexanes. Filtering afforded the title compound(044 g, 43%). EI-MS m/z 302(M+H) +
  • N-(2-Hydroxy-4-nitrophenyl)-N'-(2-trifluoromeihyloxyphenyl)urea was prepared from 2-hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 2-trifluoromeihoxy phenyl isocyanate (3.24 mmol) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes Filtering afforded the title compound(0.69 g. 60%). EI-MS m/z 358(M+H) +
  • the urea was prepared from 2-hydroxy 4-nitro aniline (500 mg . 3.24 mmol) and 2-methylthio phenyl isocyanate(3.24 mmol) by general Method B.
  • the product was purified by dilution with methylene chloride and precipitation wilh hexanes Filtering afforded the title compound(0.63 g. 61 % ).
  • the urea was prepared from 2-hydroxy 4-n itro aniline (500 mg. 3.24 mmol ) and 2-chloro 6-methyl phenyl isocyanate by general Method B. It was purified by dilution with methylene chloride and precipiiauon wilh hexane. Filtering af forded the desired
  • the urea was synthesized by treatment of N-( 2-hydroxy 4-nitro phenyl) N'-(2-methy l thio phenyl) urea(example 28. 100 mg ) with sodium periodate( 100 mg ) in t-butanol/water f or 12 hours at 23 oC. The product precipitated f rom the reaction mixtur e(30 mg, 29% ). EI-MS m/z 336(M+H) +
  • the urea was prepared from 2-hydroxy 4-trifluoromethyl anilineiexamplc 7a. 0. 171 g, 1 mmol) and 2-bromo phenyl isocyanated mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the desired compound(0.25 g, 54% ). EI-MS m/z 375(M+H) +
  • the urea was prepared from 2-hydroxy 4-carbomeihoxy aniline(0.167 g. 1 mmol) and 2-bromo phenyl isocyanate ( 1 mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the desired
  • the urea was prepared from 2-hydroxy 4-trifluoromethyl aniline(example 7a, 0.171 g, 1 mmol)) and 2-phenyl phenyl isocyanate by general Method B. it was purified by dilution with methylene chloride and precipitation with hexane. Filiering afforded the desired compound(0.24 g, 64%). EI-MS m/z 373(M+H) +
  • the urea was prepared from 2-hydroxy 4-carbomethoxy aniline (0. 167 g, 1 mmol ) and 2-phenyl phenyl isocyanated mmol) by general Method B. It was purif ied by dilution with methylene chloride and precipitation with hexane. Filtering af forded the desired
  • the urea was prepared from 4-nitro 2-hydroxy aniline(308 mg, 2 mmol) and 2-chloro phenyl isocyanate(2 mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the title compound(0.29 g. 47% ). EI-MS m/z 308(M+H) +
  • the urea was prepared from 4-nitro 2-hydroxy aniline(308 mg. 2 mmol) and 2,4-dibromo phenyl isocyanate(2 mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the title compound(0.34 g. 39%). EI-MS m/z 430(M+H) + Example 40
  • the urea was prepared from 1 -amino 2-hydroxy napthalene( 195 mg. 1 mmol) and 2-bromo phenyl isocyanate( 1 mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane Filiering afforded the title compound(0.030 g. 8% ) EI-MS m/z 357(M+H) +
  • the urea was prepared from 2-hydroxy 4-nitro aniline(308 mg, 2 mmol) and 2-chloro 3-methoxy phenyl isocyanate(2 mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the title compound(0.48 g, 63% ). EI-MS m/z 338(M+H) +
  • the urea was prepared from 2-hydroxy 4-nitro aniline(308 mg. 2 mmol) and 2-meihyl phenyl isocyanatc(2 mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filiering afforded the title compound(0.38 g. 53% ). EI-MS m/z 288(M+H) +
  • the urea was prepared from 2-hydroxy 4-nitro aniline(616 mg. 4 mmol) and dianidisdine diisocyanate(2 mmol ) by general Method B(except 2 equiv. of 4-nitro 2-hydroxy aniline was used instead of 1 equiv.).
  • the product was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the title compound ( 0.08 g. 6% ).
  • the urea was prepared from 3-hydroxy 4-amino benzoic acid (3.69 g, 24 mmol) and 2-bromo phenyl isocyanate(24 mmol) by general Method B. It was purified by dilution of the DMF solution with methylene chloride and precipitation with hexane(4.0 g, 48% ). EI-MS m/z 351 (M+H) +
  • the urea was prepared from 2-hydroxy 4-fluoro aniline(254 mg. 2 mmol) and 2-bromo phenyl isocyanate by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane( 173 mg. 26% ). EI-MS m/z 325 (M+H) + Example 49
  • the urea was prepared from 2-hydroxy 3.4-difluoro aniline(0.290 g. 2 mmol) and 2-bromo phenyl isocyanate(0.4 g) by general Method B. It was purified by dilu tion with methylene chloride and precipitation with hexane(0.254 g, 37%). EI-MS m/z 343(M+H) +
  • the urea was prepared from 3-amino 2-hydroxy napthalene(0.320 g. 2 mmol) and 2-bromo phenyl isocyanate(.40 g) by general Method B. It was purified by dilution of the with methylene chloride and precipitation with hexane(0.339. 47% ). EI-MS m/z 357(M+H) +
  • the urea was prepared from 2-hydroxy 4-phenyl aniline(0.185 g. 1 mmol) and 2-bromo phenyl isocyanate(0.198 g) by general Method B. It was purified by dilution of the DMF solution with methylene chloride and precipitation with hexane(215 mg, 56% ). EI-MS m/z 383(M+H) +
  • the urea was prepared from 2-hydroxy 4-methyl aniline(.274g. 2 mmol) and 2-bromo phenyl isocyanate(0.40 g, 2 mmol) by general Method B. It was purified by dilution of the DMF solution with methylene chloride and precipitation with hexane(249 mg, 39% ). EI-MS m/z 319(M-H) -
  • the urea was synthesized by the treatment of 2-tertbutyldimethylsilyloxy 4-nitro pheny I isocyanate(example 9a, 0.419g, 1.5 equiv.) with 2-anilino aniline(0.184 g. 1 equiv. ) in THF overnight at 40 °C.
  • the urea was prepared from 2-hydroxy 3-amino benzoic acid(300 mg. 2 mmol) and 2-bromo phenyl isocyanate by general Method B. It was purified by dilution of the DMF solution with methylene chloride and precipitation with hexane(.287 g. 41 % ). EI-MS mlz 35 1 (M+H) + Example 55
  • the urea was synthesized by the treatment of 2-iodo benzoic acid(5 g. 20 mmol) with diphenyl phosphoryl azidc( 1 equiv.) and triethyl amine ( 1 equiv. ) in DMF at 80 °C alter gas evolution ceased the 5-nitro 2-amino phenol (3 g. 1 equiv. ) was added The reaction was heated overnight at 80°C. The reaction mixture was purified by filtering through a plug of silica with methylene chloride. The desired product was then precipitated out w ith hexanc. Filtering aftorded the desired compound( 1.08 g. 13% ) EI-MS m/z 398(M-H) -
  • the thiourea was synthesized by treatment ot the 2-tert-butyldimethylsilyloxy 4-nitro phenyl thioisocyanate(see example 9a , 3.73 mmol) with 2-bromo aniline in toluene at 88°C over 36 h.
  • the solution was concentrated and the residue was purified by flash chromatography(EtOAc/Hexanes)
  • This traction was concentrated and then treated with triethyl amine hydrofluoride in acetonitrile for 15 minutes at 23 °C
  • the reaction mixture was then concentrated in vacua and the residue was purified by flash chromatography(ethyl)
  • the urea was synthesized from 2-(phenylsulf amido) 4-amino benzonitrile(77 mg. 0 2S mmol) and 2-bromo phenyl isocyanate by general Method C. It was purif ied by column chromatography(ethyl acetate/hexane) to af ford the title compound (30 mg. 22% ) EI-MS m/z 469(M-H) -
  • the sulfonamide was synthesized from phenyl sulfonyl chloridc(0.01 mmol) and o-phenylene diamine( 1.08 g, 0.01 mmol) by general Method C It was purified by
  • the urea was synthesized 2-(phenyl sulfamido) aniline( 1 mmol )
  • the sulfonamide was synthesized from styryl sulfonyl chloride(001 mol) and o-phenylene diamine(0.01 mol) by general Method C. It was purified by recrystallizaiion from EtOH(1.2 g, 60%)EI-MS m/z 199(M+H) + .
  • the urea was synthesized from 2-(styryl sulfamido) aniline( 1 mmol) and 2-bromo phenyl isocyanate(1 mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane Filtering afforded the desired compound(0.309 g. 65% ). EI-MS m/z 472(M+H) +
  • the sulfonamide was synthesized from 3,4-dimethoxy phenyl sulfony l chloride(0.01 mol) and o-phenylenc diamine by general Method C. It was purified by recrystallization f rom
  • the sulfonamide was synthesized from 2-thiophene sulfonyl chloride(0.01 mol) and o-phenylene diamine(0.01 mol) by general Method C. It was purified by recrystallization from EtOH(0.77 g, 30% ). EI-MS m/z 255 (M+H) +
  • the urea was synthesized from 2-( 2-thiophene sulfonyl amino) anilined mmol) and 2-bromo phenyl isocyanated mmol) by general Method B. It was purified by dilution with methylene chloride and precipiiation with hexane. Filtering afforded the desired
  • the sultonamide was synthesized from 3-tolyl sulfonyl chloride(0.01 mol ) and o-phenylene diamine(0.01 mol) by general Method C. It was purified by recrystallization from
  • the urea was synthesized from 2-(3-tolyl sulfonyl amino) aniline( 1 mmol ) and 2-bromo phenyl isocyanate( 1 mmol ) by general Method B. It was purilied by dilution with methylene chloride and precipitation with hexanes It was recrysallized two times with
  • the urea was synthesized from 2-((8-quinolinyl) sulfonyl amino) anilined mmol) and
  • the sultonamide was synthesized from benzyl sulfonyl chloride(0.01 mol) and o-phenylene diamine(0.01 mol) by general Method C. It was purified by recrystallization from EtOH(0.87g, 33%) EI-MS m/z 263(M+H)+.
  • the urea was synthesized from 2-( benzyl sulfonyl amino) anilined mmol)
  • the N-(2-hydioxy -4-aminophenyl)-N'-(2-methoxyphenyl)urea (300 mg. 1.17 mmol ) was added to HCl/H 2 O ( 1.17 mL/2.34 mL). cooled to 0°C Sodium nitrite (80.7 mg. 1.17 mmol ) w as added to the reaction mixture. The reaction mixture was stirred at 0°C tor 30 minutes. The sodium azide (76 mg. 1.17 mmol ) was added to reaction mixture and it was warmed to room lemperaiure. The reaction mixture was stirred at room temperature for 18 hours. Then it was extracted with three times by ethyl acetaie.
  • N-[2-hydroxy-5-cyanophenyl]-N'-[2-bromophenyl] urea was prepared from 2-amino- 4-cyanophenol(268mg, 2.00 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane( 1/20) and filtering (540mg.81% ).
  • N-[2-Hydroxy-3-fluorophenyl]-N'-[ 2-bromo phenyl] urea was prepared from 2-amin ⁇ -3-fluorophenol (254mg, 2.00 mmol ) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane( 1/20) and f iltering ( 500 mg. 77% ) 1 H NMR (CD 3 OD): 8 8.05 (d, 1 H), 7.50 (d, 1 H), 7.26 (t, 1 H), 7.18 (d. 1 H). 6 92 (t, 1 H), 6 86-6 68 (m, 2H).
  • N-2-[ 1-hydroxyfluorene]-N'-[2-bromo phenyl] urea was prepared from 2- amino- 1 -hydroxyfluorene ( 170mg, 0.86 mmol) according to the procedure in General Method B. The product was purified by chromatography of the resulting solid on silica gel (30%EtOAc/ Hexane) to give the desired product (300mg, 84.5%).
  • urea was prepared from 2-hydroxy-3-aminoanthraquinone(480mg, 2.00 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane( 1/20) and filtering. (610mg, 70%).
  • N-[2-hydroxy-3-chlorophenyl]-N'-(2-bromophenyl] urea was prepared from 2-amino-3-chlorophenol ( 143mg, 1.00 mmol) according to the procedure in General Method B. The product was purified by chromatography of the resulung solid on siliea gel (30%EtOAc/ Hexane) to give the desired product( 195mg. 57%).
  • N-[2-hydroxy-3-trifluoromethylphenyl]-N'-[2-bromophenyl) urea was prepared from 2-amino-6-trifluoromethylphenol (280mg. 1.60 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane( 1/20) and filtering. (390mg, 65%).
  • 2-bromophenyl] urea was prepared from 2-amino-5,6 diphenylphenol (50mg, 0.19 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane(1/20) and filtering (61mg. 69%).
  • N-[2-hydroxy-3-glycinemethylestercarbonylphenyl ]-N'-[2-bromophenyl] urea was prepared from 6-glycinemethylestercarbonyl-2-aminophenol (50mg. 0.22 mmol). purchased from the University of New Hampshire, according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexanc( 1/20) and filtering
  • 2-bromophenyl] urea was prepared from N-[2-hydroxy-3-glyeinemethylestercarbonylphenyl ]-N '-[ 2-bromophenyl ] urea (50mg. 0.12 mmol) by stirring in a 3/1 ratio of methanol/water ( 10 mL) Addition of 1 equiv of lithium hydroxide was added and stirring continued until the starting material had disappeared (45mg. 92% ). The product was purified by chromatography of the resulting solid on silica gel (9/1/0.
  • N-[2-Hydroxy-3,5-dichlorophenyl]-N'-[2-bromophenyI] urea was prepared from 2-amino-4,6-dichlorophenol ( 143mg, 1.00 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane( 1/20) and filtering (660mg, 88% ).
  • N-[2-hydroxy-4-naphthalenesulfonic acid]-N'-[2-bromophenyl ] urea was prepared from 1 -amino-2-hydroxy-4-naphthalensulfonie acid (0.48g. 2.0 mmol) according to the procedure in General Method B and the addition of l mL of triethylamine The product was purif ied by precipitation from methylene chloride/ hexane( 1/20) and filtering.
  • N-[2-hydroxy -5-naphthalenesulfonic acid]-N'-12-bromophenyl] urea N-3-[2-hydroxy-5-naphthalensulfonic acid]-N'-[2-bromophenyl] urea was prepared from 2-amino-3-hydroxy-6-naphthalensulfonic acid (0.48g, 2.0 mmol ) according to the procedure in General Method B and the addition of 1 mL of triethylamine The product was purified by precipitation from methylene chloride/ hexane(1/20) and filtering. (715 mg, 82% ).
  • N-[2-Hydroxy-3,4-dichlorophenyl]-N'-[2-bromophenyl] urea was prepared from 2-amino-5,6-dichlorophenol (350mg, 2.00 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane( 1/20) and filtering (670mg, 89% ).
  • N-[2-Hydroxy-3-cyanophenyl]-N'-[2-bromophenyl] urea was prepared from 2-amino-6-cyanophenol ( 134mg, 1.00 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane( 1/20) and filtering. (260mg. 78% ).
  • N-[2-Hydroxy-4-cyanophenyl]-N'-[2-bromophenyl] urea was prepared from 2-amino-5-cyanophenol ( 170mg, 1.27 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane( 1/20) and filtering (310mg, 74%).
  • N-[2-Hydroxy-4-cyanophenyl]-N'-[4-methoxyphenyl] urea was prepared from 2-amino-5-cyanophenol (60mg, 0.45 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane(1/20) and filtering. ( 1 10mg,86%).
  • N-[2-hydroxy-4-cyanophenyl]-N'-[2-phenylphenyl] urea was prepared from 2-amino-5-cyanophenol ( 170 mg. 1.27 mmol) according to the procedure in General Mediod B. The product was purified by precipitation from methylene chloride/ hexane( 1/20) and filtering. ( 150mg, 85% ), 1 H NMR (CD 3 OD): 6 8.20 (d, 1 H), 7.73 (d, 1 H), 7.51 -7.20 (m, 8H), 7. 13 (d, 1 H), 7.01 (s, ( 1 H) .
  • N-[2-Hydroxy-4-cyanophenyl]-N'-[2-methylphenyl] urea was prepared from 2-amino-5-cyanophenol (60mg, 0.45 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexanc( 1/20) and filtering (90mg, 75% ).
  • N-[2-hydroxy-4-cyanophenyl]-N'-[2-trifluoromethylphenyl] urea was prepared from 2-amino-5-cyanophenol (60mg, 0.45 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane(1/20) and filtering. ( 1 10mg, 76% ).
  • N-[2-hydroxy-4-cyanophenyl]-N'-[3-trifluoromethylphenyl] urea was prepared from 2-amino-5-cyanophenol (60mg, 0.45 mmol) according to the procedure in General Method B The product was purified by precipitation from methylene chloride/ hexane(1/20) and filtering ( 1 14mg, 79%).
  • N-[2-Hydroxy-3-n-propyl phenyl ]-N'-[2-bromo phenyl] urea was prepared from 2-amino-6-n-propyl phenol (302mg, 2.00 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane( 1/20) and filtering. (640mg,92%).
  • N-[2-Hydroxy-4-ethylphenyl]-N'-(2-bromo phenyl] urea was prepared from 2- amino-5-ethylphenol (274mg, 2.00 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane( 1/20) and filtering. (520 mg. 77%).

Abstract

This invention relates to the novel use of phenyl ureas in the treatment of disease states mediated by the chemokine, Interleukin-8 (IL-8).

Description

IL-8 RECEPTOR ANTAGONISTS
FIELD OF THE INVENTION
Thi.s invention relates to a novel group of phenyl urea compounds, processes for the preparation thereof, the use thereof in treating IL-8, GROα, GROβ, GROγand NAP-2 mediated diseases and pharmaceutical compositions lor use in such therapy
BACKGROUND OF THE INVENTION
Many different names have been applied to Interleukin-8 (IL-8), such as neutrophil attractant/activauon protein- 1 (NAP-1), monocyte derived neutrophil chemotactic factor (MDNCF), neutrophil activating factor (NAF), and T-cell lymphocyte chemotactic factor, lnierleukin-8 is a chemoattractant for neutrophils, ba.sophil.s, and a sub.sct of T-cells. It is produced by a majority of nucleated cells including macrophages, fibroblasts, endothehal and epithelial cells exposed to TNF, IL- 1 α, IL-1β or LPS. and by neutrophils themselves when exposed to LPS or chemotactic factors such as FMLP. M. Baggiolini et al. J. Clin. Invest. 84, 1045 ( 1989); J. Schroder et al, J. Immunol. 139, 3474 (1987) and J. Immunol. 144. 2223 ( 1990) : Strieter. et al. Science 243. 1467 ( 1989) and J. Biol. Chem. 264. 10621 ( 1989); Cassatella et al, J. Immunol. 148. 3216 ( 1992).
Groα, GROβ. GROγ and NAP-2 also belong to the chemokinc α family. Like IL-8 these chemokincs have also been referred to by different names For instance GROα, β, γ havc been referred to as MGSAα, β and γ respectively (Melanoma Growth Stimulating Activity). see Richmond et al. J. Cell Phy.siologv 129, 375 ( 1986) and Chang et al. J. Immunol 148. 45 1 ( 1992). All ot the chemokines of the α-lamily which possess the ELR motif directly preceding the CXC motif bind to the 1L-8 B receptor
IL-8. Groα. GROβ. GROγ and NAP-2 stimulate a number offuncti ons in vitro They have all been shown to have chemoattraciani properties lor neutrophils. while IL-8 and GROα have demonstrated T-lymphocytes, and basophiles chemotactic activity In addition IL-8 can induce histamine release irom basophils Iron, both normal and atopic individuals GRO-α and IL-8 can in addition, induce lyso/omal enzyme release and respiratory burst from neutrophils IL-8 has also been shown to increase the surface expression of Mac- 1 (CD I l b/CD 18 ) on neutrophils without de novo protein synthesis This may contribute to increased adhesion oi the neutrophils to vascular endothelial cells Many known diseases are characterized by massive neutrophil infiltration As IL-8. Groα, GROβ. GROγ and NAP- 2 promote the accumulation and activation of neutrophils. these chemokines have been implicated in a wide range of acute and chronic inflammatory disorders including psoriasis and rheumatoid arthritis. Baggiolini et al, FEBS Lett 307, 97 ( 1992). Miller et al. Crit. Rev, Immunol 12, 17 ( 1992); Oppcnheim et al, Annu Rev, Immunol. 9, 617 (1991 ). Seitz et al., J Clin, Invest 87, 463 ( 1991 ). Miller et al., Am. Rev. Respir, Dis 146, 427 ( 1992) ; Donnely et al., Lancet 341 , 643 ( 1993) In addition the ELR chemokines (those containing the amino acids ELR motif just prior to the CXC motif) have also been implicated in angiostasis Stricter et al, Science 258, 1798 ( 1992)
In vitro. IL-8, Groα, GROβ, GROγ and NAP-2 induce neutrophil shape change, chemotaxis, granule release, and respiratory burst, by binding to and activating receptors of the seven-transmembrane. G-protein-linked family, in particular by binding to IL-8 receptors, most notably the B-receptor Thomas et al , J. Biol, Chem, 266 14839 ( 1991). and Holmes et al., Science 253, 1278 ( 1991 ) The development of non-peptide small molecule antagonists for members of this receptor family has precedent. For a review see R. Freidinger in;
Progress in Drug Research, Vol 40, pp 33-98, Birkhauser Verlag, Basel 1993. Hence, the IL-8 receptor represents a promising target for the development of novel anti-inflammatory agents.
Two high affinity human IL-8 receptors (77% homology) have been characterized IL- 8Rα, which binds only IL-8 with high affinity, and IL-8Rβ, which has high affinity for IL-8 as well as for GRO-α, GROβ, GROγ and NAP-2. See Holmes et al., supra; Murphy et al., Science 253, 1280 ( 1991 ): Lee et al., J Biol, Chem, 267, 16283 ( 1992) LaRosa et al ., J. Biol Chem 267, 25402 ( 1992); and Gayle et al. , J. Biol Chem 268, 7283 ( 1993).
There remains a need for treatment, in this field, for compounds which are capable of binding to the IL-8 α or β receptor Therefore, conditions associated with an increase in IL-8 production (which is responsible for chemotaxis ot neutrophil and T-cells subsets into the inflammatory site) would benefit by compounds which are inhibitors of IL-8 receptor binding SUMMARY OF THE INVENTION
This invention provides for a method of treating a chemokine mediated disease wherein the chemokine is one which binds to an IL-8 α or β receptor and which method comprises administering an effective amount of a compound of Formula (I) or a
pharmaceutically acceptable salt thereof. In particular the chemokine is IL-8
This invention also relates to a method of inhibiting the binding of IL-8 to its receptors in a mammal in need thereof which comprises administering to said mammal an effective amount of a compound of Formula (I).
Compounds of Formula (1 ) useful in the present invention are represented by the structure
Figure imgf000005_0001
wherein
X i.s oxygen or sulfur;
R is any functional moiety having an ionizable hydrogen and a pKa of 10 or less;
R1 is independently selected from hydrogen: halogen; nitro: cyano; halosubstituted C1-10 alkyl: C1-10 alkyl: C2-10 alkenyl; C1-10 alkoxy; halosubstituted C1-10 alkoxy: azide: S(O)tR4: hydroxy: hydroxy C1-4alkyl; aryl; aryl C1-4 alkyl: aryloxy: aryl C1-4 alkyloxy: heteroaryl: heteroarylalkyl; heterocyclic, heterocyclic C1-4alkyl: heteroaryl C1-4 alkyloxy; aryl C2-10 alkenyl; heteroaryl C2-10 alkenyl; heterocyclic C2-10 alkenyl; NR4R5: C2-10 alkenyl C(O)NR4R5; C(O)NR4R5; C(O)NR4R10; S(O)3H; S(O)3R8: C1-10 alkyl
C(O)R11; C2-10 alkenyl C(O)R11; C2-10 alkenyl C(O)OR11 : C(O)R11 : C(O)OR12: OC(O) R11; NR4C(O)R11 : or two R1 moieties together may form O-(CH2)sO- or a 5 to 6 membered unsaturated ring;
t is 0, or an integer having a value of 1 or 2;
s is an integer having a value of 1 to 3;
R4 and R5 are independently hydrogen, optionally substituted C1-4 alkyl, optionally
substituted aryl, optionally substituted aryl C1-4alkyl, optionally substituted heteroaryl. optionally substituted heteroaryl C1-4alkyl, heterocyclic. heterocyclic C1-4 alkyl. or R4 and R5 together with the nitrogen to which they are attached form a 5 to 7 member ring which may optionally comprise an additional heteroatom selected lrom O/N/S:
Y is independently selected Irom hydrogen; halogen: nitro: cyano: halosubstituted C1-10 alkyl.
C1-10 alkyl: C2-10 alkenyl: C1-10 alkoxy: halosubstituted C1-10 alkoxy: azide: S(O)1R4: hydroxy: hydroxyC1-4alkyl: aryl: aryl C1-4 alkyl: aryloxy: arylC1-4 alkyloxy: heteroaryl: heteroarylalkyl: heteroaryl C1-4 alkyloxy; heterocyclic, heterocyclic C1-4alkyl: aryl C2-10 alkenyl: heteroaryl C2-10 alkenyl: heterocyclic C2-10 alkenyl: NR4R5: C2-10 alkenyl C(O)NR4R5; C(O)NR4R5; C(O)NR4R10: S(O)3H: S(O)3R8: C1-10 alkyl C(O) R11. C2-10 alkenyl C(O)R 11; C2-10 alkenyl C(O)OR 11 ; C(O)R11 ; C(O)OR12; OC(O) R11; NR4C(O) R11 ; or two Y moieties together may lorm O-(CH2)sO- or a 5 to 6 membered unsaturated ring:
n is an integer having a value of 1 to 3:
m is an integer having a value of 1 to 3:
R8 is hydrogen or C1-4 alkyl:
R10 is C1-10 alkyl C(O)2R8: R 1 1 is hydrogen, C 1 -4 alkyl, optionally substituted aryl, optionally substituted aryl C 1 -4alkyl. optionally substituted heteroaryl. optionally substituted heteroaryl C 1 -4alkyl. optionally substituted heterocyclic, or optionally substituted heterocyclic C 1 -4alkyl;
R 12 is hydrogen, C 1- 10 alkyl, optionally substituted aryl or optionally subsututed arylalkyl. or a pharmaceutically acceptably salt thereof.
Another aspect of the present invention is to a method of treating a chemokine mediated disease, wherein the chemokine is one which binds to an IL-8 α or β receptor and which method comprises administering an effective amount of a compound of Formula (II) or a pharmaceutically acceptable salt thereof, as defined herein
This invention also relates to a method of inhibiting the binding of IL-8 to us receptors in a mammal in need thereof which comprises administering to said mammal an effective amount of a compound of Formula (II), as defined herein.
This invention also relates to the novel compounds of Formula (II), or a
pharmaceutically acceptable salt thereof, as defined herein.
Another aspect of the present invention is to a method of treating a chemokine mediated disease, wherein the chemokine is one which binds to an IL-8 α or β receptor and which method comprises administering an effective amount of a compound of Formula (III) or a pharmaceutically acceptable salt thereof, as defined herein
This invention also relates to a method of inhibiting the binding of IL-8 to its receptors in a mammal in need thereof which comprises administering to said mammal an cflccuvc amount of a compound of Formula (III), as defined herein
This invention also relates to the novel compounds of Formula (III ), or a
pharmaceutically acceptable salt thereof. as defined herein
DETAILED DESCRIPTION OF THE INVENTION
The compounds of Formula (I) may also be used in association with the veterinary treatment of mammals, other than humans, in need of inhibition of IL-8 or other chemokines which bind to the IL-8 α and β receptors Chemokine mediated diseases for treatment.
therapeutically or prophylactically, in animals include disease states such as those noted herein in the Methods of Treatment section
In compounds of Formula (I). R is suitably any functional moiety which provides an ionizable hydrogen having a pKa of 10 or less, preferably from about 3 to 9, more preferably from about 3 to 7 Such functional groups include, but are not limited to. hydroxy, carboxylic acid, thiol, -SR2 -OR2, -NH-C(O)Ra, -C(O)NR6R7, a substituted sulfonamides of the formula -NHS(O)2Rb, -S(O)2NHRc, NHC(X2)NHRb. or a tetrazolyl; wherein X2 is oxygen or sulfur, preferably oxygen Preferably, the functional group is other than a sulfonic acid. either directly or as a substituent group on the aryl. heteroaryl, or heterocyclic moiety ring, such as in SR2 or OR2. More preferably R is OH, SH, or NHS(O)2Rb. Suitably, R2 is a substituted aryl, heteroaryl, or heterocyclic moiety which ring has the founnaclti moiety providing the ionizable hydrogen having a pKa of 10 or less.
Suitably, R6 and R7 are independently hydrogen or a C 1 -4 alkyl group, or R6 and R7 together with the nitrogen to which they are attached form a 5 to 7 member ring which ring may optionally contain an additional heteroatom which heteroatom is selected from oxygen, nitrogen or sulfur. This heteroring may be optionally substituted as defined herein.
Suitably Ra is an alkyl, aryl, arylC 1 -4alkyl, heteroaryl, heteroarylC 1 -4alkyl.
heterocyclic, or a heterocyclic C 1 -4alkyl moiety, all of which may be optionally substituted, as defined herein below. Suitably, Rb is a NR6R7, alkyl, aryl, arylC 1 -4alkyl, arylC2-4alkenyl, heteroaryl. heteroarylC 1-4alkyl, heteroarylC2-4 alkenyl, heterocyclic. or heterocyclic C1 -4alkyl, or a heterocyclic C2-4alkenyl moiety, camphor, all of which may be optionally substituted one to three times independently by halogen; nitro: halosubstituted C 1-4alkyl. such as CF3: C 1-4 alkyl, such as methyl; C 1-4 alkoxy. such as methoxy: NR9C(O)Ra: C(O)NR6R7, S(O)3H. or C(O)OC1 -4 alkyl. Rb is preferably an optionally subsututed phenyl. benzyl, or styryl When Rb is a heteroaryl preferably it is an opuonally subsututed thiazole. optionally substituted thienyl, or optionally substituted quinolinyl ring Wherein R9 is hydrogen or a C 1-4 alkyl. preferably hydrogen, and suitably when the substituent group is NR9C(O)Ra, then Ra is preferably an alkyl group, such as methyl
Suitably Rc is hydrogen, alkyl. aryl. arylC 1-4alkyl. arylC 1 -4alkenyl, heteroaryl.
heteroarylC1 -4alkyl. heteroarylC 1 -4alkenyl. heterocyclic. or heterocyclic C 1 -4alkyl. or a heterocyclic C 1 -4alkenyl moiety, all of which may be optionally substituted one to three times independently by halogen, nitro. halosubstituted C 1-4 alkyl. C 1-4 alkyl, C 1-4alkoxy.
NR9C(O)Ra, C(O)NR6R7- S(O)3H, or C(O)OC 1 -4 alkyl. wherein R9 is hydrogen or a C 1 -4 alkyl. Preferably, Rc is an optionally substituted phenyl
When R is an OR2 or SR2 moiety 11 is lecognized by one of skill in the art that the aryl ring must, theretore. contain the required ionizable hydrogen The aryl ring may also be additionally substituted, independently, by one to three groups, which groups may al.so contain an additional lonizable group, and which include but are not limited to. halogen, nitro.
halosubstituted C1 -4 alkyl. C1 -4 alkyl. C 1 -4 alkoxy, hydroxy, SH, -C(O)NR6R7.
-NH-C(O)Ra, -NHS(O)2Rb, S(O)2NR6R7, C(O)OR8, or a tetrazolyl ring In compounds of Formula (I), suitably R1 is independently selected from hydrogen; halogen: nitro; cyano: halosubstituted C1- 10 alkyl. such asCF3; C1- 10 alkyl. such as methyl, ethyl, isopropyl. or n-propyl; C2-10 alkenyl; C1- 10 alkoxy, such as methoxy. orethoxy: halosubstituted C1- 10 alkoxy, such as trifluoromethoxy; azide: S(O)tR4. wherein t is 0, 1 or 2; hydroxy; hydroxy C1-4alkyl. such as methanol or ethanol; aryl, such as phenyl or naphthyl: aryl C1-4alkyl, such as benzyl; aryloxy, such as phenoxy; aryl C1-4 alkyloxy, such as benzyloxy; heteroaryl: heteroarylalkyl: heteroaryl C1-4 alkyloxy: aryl C2-10 alkenyl ;
heteroaryl C2-10 alkenyl: NR4R5 ; C2-10 alkenyl-C(O)NR4R5; C(O)NR4R5: C(O)NR4R10; S(O)3H; S(O)3R8: C 1.10 alkyl C(O)R11 : C2-10 alkenyl C(O)R11 , C2-10 alkenyl C(O)OR11 ; C(O)R11 : C(O)OR 12- such as carboxy, methylcarboxylate or phenylbenzoate: OC(O) R11 ; NR4C(O)R11; azido: or two R1 moieties together may form O-(CH2)sO- or a 5 to 6 membered unsaturated ring; and s is an integer having a value of 1 to 3 The aryl, arylalkyl. arylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heterocyclic, heterocyclicalkyl, and heterocyclicalkenyl moieties may all be optionally substituted as defined herein below.
Preferably R1 is other than azido or S(O)3R8.
When R1 forms a dioxybridge, s is preferably 1. When R 1 forms an additional unsaturated ring, it is preferably 6 membered resulting in a naphthylene ring system. This naphthylene ring may be substituted independently, 1 to 3 times by the other R1 moieties as defined above.
Suitably, R4 and R5 are independently hydrogen, optionally substituted C1-4 alkyl. optionally substituted aryl optionally substituted aryl C1-4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C1-4alkyl heterocyclic, heterocyclic C1-4 alkyl, or R4 and R5 together with the nitrogen to which they are attached form a 5 to 7 member ring which may optionally comprise an additional heteroatom selected from O/N/S.
R10 is suitably C1-10 alkyl C(O)2R8, such as CH2C(O)2H or CH2C(O)2CH3.
R11 is suitably hydrogen, C1-4alkyl, aryl, aryl C1-4 alkyl, heteroaryl, heteroaryl C1-4alkyl, heterocyclic, or heterocyclic C1-4alkyl
R12 is suitably hydrogen. C1-10 alkyl. optionally substituted aryl or optionally substituted arylalkyl
Preferably R1 is halogen, cyano. nitro. CF3, C(O)NR4R5. alkenyl C(O)NR4R5. C(O) R4R10, alkenyl C(O)OR12, heteroaryl, heteroarylalkyl, heteroaryl alkenyl, or S(O)NR4R5. and prelerably R4 and R5 are both hydrogen or one is phenyl. A preferred ring substitution lor R1 is in the 4-position of the phenyl ring.
When R is OH, SH or NSO2Rb than R1 is preferably substituted in the 3-position, the 4-position or di substituted in the 3,4-position. The substituent group is suitably an electron withdrawing moiety. Preferably when R is OH, SH or NSO2Rb, than R1 is nitro. halogen, cyano. trifluoromethyl group. C(O)NR4R5.
When R is carboxylic acid, than R1 is preferably hydrogen, or R1 is preferably substituted in the 4-position. more preferably substituted by trifluoromethyl or chloro.
In compounds of Formula (I), suitably Y is independently selected from hydrogen: halogen; nitro: cyano: halosubstituted C1-10 alkyl: Cμio alkyl: C2-10 alkenyl; C1-io alkoxy: halosubstituted C1-10 alkoxy: azide: S(O)tR4: hydroxy: hydroxy C1-4alkyl: aryl: aryl C1-4 alkyl: aryloxy: arylC1-4 alkyloxy: aryl C2-10 alkenyl; heteroaryl: heteroarylalkyl; heteroaryl C1-4 alkyloxy: heteroaryl C2-10 alkenyl: heterocyclic, heterocyclic C1-4alkyl: heterocyclicC2-10 alkenyl: NR4R5: C2-10 alkenyl C(O)NR4R5: C(O)NR4R5: C(O)NR4R10; S(O)3H:
S(O)3R8: C1-10 alkyl C(O)R11; C2-10 alkenyl C(O)R11; C2-10 alkenyl C(O)OR11;
C(O)R11 ; C(O)OR12; OC(O) R11 ; NR4C(O)R11 ; azido; or two Y moieties together may form O-(CH2)sO- or a 5 to 6 membered unsaturated ring. When Y forms a dioxybridge, s is preferably 1 When Y forms an additional unsaturated ring, it is preferably 6 membered resulting in a naphthylene ring system Tms naphthylene ring may be substituted 1 to 3 times by other Y moieties as defined above The aryl, heteroaryl and heterocyclic moieties noted above may all be optionally substituted as defined herein. Preferably R 1 is other than azido or S(O)3R8
Y is prclerably a halogen. C1-4 alkoxy. optionally substituted aryl. opuonally substituted aryloxy or arylalkoxy. methylene dioxy. NR4R5, thio C1-4alkyl, thioaryl, halosubstituted alkoxy, optionally substituted C1-4 alkyl, or hydroxy alkyI. Y is more preferably mono-subsututed halogen, disubstituted halogen, mono-substituted alkoxy.
disubstituted alkoxy, methylenedioxy, aryl, or alkyl, more preferably these groups are mono or di-subsiuuted in the 2'-position or 2'-,3-position
While Y may be substituted in any of the 5 ring positions, prclerably when R is OH SH. or NSO2Rb. Y is prelerably mono-substituted in the 2-position or 3-position, with the 4-preferably being unsubstituted It the ring is disubstituted. when R is OH, SH, or
NSO2Rb, substuuents are preferably in the 2' or 3' position of a monocyclic ring. While both R 1 and Y can both be hydrogen, it is prclered that at least one of the rings be substituted, prelerably both rings are substituted.
In compounds of Formula (I), X is suitably oxygen or sulfur, preferably oxygen.
While not explicitly covered by Formula (I), (Ia-c), (II), or (III), another aspect of this invention are the symmetrical bis compounds which are included for each structure
Compounds exemplified by this bis like structure include:
N-(Bis (2-hydroxy-4-nitro phenyl) N'-(dianisdine) diurea
4-Methylene bis(N-(2-chloro phenyl) N'-(2-hydroxy 4-nitro phenyl) urea) Exemplified compounds of Formula (I) include:
N-[2-Hy droxy-4-(methoxycarbonyl)phenyl]-N'-phenylurea;
N-[5-Nitro-2-hydroxyphenyl]-N'-phenyl urea
3-Hydroxy-4-{[(phenylamino)carbonyl]amino} benzamide
N-(2-Hydroxy-4-fluorophenyl)-N'-phenyl urea
2-{ [(Phenylamino)carbonyl]amino }thiphenol
N-(2-carboxy-4-hydroxyphenyl)-N'-phenyl urea
N-[2-Hydroxy-4-(trifluoromethyl)phenyI]-N'-phenyl urea
N-(2-H ydroxy-4-nitrophenyl)-N'-(2-hydroxy-4-nitrophenyl) urea
N-(2-Hydroxy-4-nitrophenyl)-N'-phenyl-thiourea
N-(4-Nuro-2-(phenylsulfonylamino)phenyl)-N'-phenyl urea
N-(2-Hydroxy-5-nitrophenyl)-N'-(3-methoxy-2-thienyl)urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(3-methoxy-2-thienyl)urea
N-(2-Hydroxy -4-nitrophenyl)-N'-(3-methoxyphenyl )urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(2-methoxyphenyl)urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(3-trifluoromethyiphenyl )urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(2-trifluoromethylphenyl )urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(4-trifluoromethylphenyl )urea
N-(2-H ydroxy-4-nitrophenyl)-N'-(2-bromophenyl )urea
N-(2-Hydroxy-4-mtrophenyl)-N'-(3-bromophenyl )urea
N-(2-Hydroxy -4-nitrophenyl)-N'-(4-bro mophenyl)urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(2-phenylphenyl )urea
N-(2-Hydroxy-4-nitrophenyl)-N'-( 1 -naphthyl)urea:
N-(2-Hydroxy-4-nitrophenyl)-N'-(2-nitrophenyl )urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(2-fluorophenyl)urea
N-(2-Hydroxv-4-nitrophenyl )-N'-(2,6-difluorophenyl )urea N-(2-Hydroxy-4-nitrophenyl)-N'-(2-ethoxyphenyl)urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(2-ethylphenyl)urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(2-trifluoromethoxyphenyl)urea
N-(2-Hydroxy-4-nitrophenyl) N'-(2-methylthiophenyl) urea
N-(2-Hydroxy-4-nilrophenyl) N'-(2-chloro 6-methyl phenyl) urea
N-(2-Hydroxy-4-nitrophenyl) N'-(2-sulfoxymethyl phenyl) urea
N-(4-Trifluoromethyl-2-hydroxy phenyl) N'-(2-bromo phenyl) urea
N-(4-Carbomethoxy 2-hydroxy phenyl) N'-(2-bromophenyl) urea
N-(4-Trifluoromethyl-2-hydroxy phenyl) N'-(2-phenyl phenyl) urea
N-(4-Carbomethoxy 2-hydroxy phenyl) N'-(2-phenyl phenyl) urea
N-(2-Hydroxy-4-nitrophenyl) N'-(2,3-dichloro phenyl) urea
N-(2-Hydroxy-4-nitrophenyl) N'-(2.4-dichloro phenyl) urea
N-(2-Hydroxy-4-nitrophenyl) N'-(2-chloro phenyl) urea
N-(2-Hydroxy-4-nitrophenyl) N'-(2.4-dibromo phenyl) urea
N-(2-Hydroxy- 1-napthyl)-N'-(2-bromo phenyl) urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(2,3-methylenedioxyphenyl)urea
N-(2-Hydroxy-4-nitrophenyl) N'-(3-chloro 2-methoxy phenyl) urea
N-(2-Hydroxy-4-nitrophenyl) N'-(2-methyl phenyl) urea
N-[4-(Benzylamino)carbonyl-2-hydroxyphenyl]-N'-(2-bromophenyl)urea N-(2-Hydroxy-4-nitrophenyl)-N'-(2-phenoxy phenyl) urea
N-(2-Hydroxy-4-fluoro phenyl)-N'-(2-bromo phenyl) urea
N-(2-Hydroxy 3-napthyl) N'-(2-bromo phenyl) urea;
N-(3.4-Difluoro 2-hydroxy phenyl) N'-(2-bromo phenyl) urea
N-(2-Hydroxy 4-phenyl phenyl) N'-(2-bromo phenyl) urea
N-(2-Hydroxy 4-methyl phenyl) N'-(2-bromo phenyl) urea
N-(2-Hvdroxy-4-nitro phenyl) N'-(2-phenylamino phenyl) urea
N-(2-Hydroxy 3-carboxyphenyl) N'-(2-bromo phenyl) urea
N-(2-Sulfhydryl 4-bromo phenyl) N'-(2-bromo phenyl) urea
N-(2-Hydroxy 4-nitro phenyl) N'-(2-iodo phenyl) urea
N-(2-Hydroxy 4-nitro phenyl) N'-(2-bromo phenyl) thiourea
N-|(2-Phenylsullamido) 4-cyanophenyl]- N'-(2-bromo phenyl) urea
N-(2-(Amino sulfonamido phenyl) phenyl) N'-(2-bromo phenyl) urea
N-(2-(Amino sulfonyl styryl) phenyl) N'-(2-bromo phenyl) urea
2-[ (3.4 Di-methoxyplicnylsulfonyl )amino] phenyl) N'-(2-bromo phenyl ) urea N-(2-|(4-Acciamidopheny.sulfonyl)amino] phenyl) N'-(2-bromo phenyl ) urea
N-(2-(Amino sulfonyl (2-thiophenc) phenyl) N'-(2-bromo phenyl) urea
N-(2-(Amino sulfonyl (3-tolyl) phenyl ) N'-(2-bromo phenyl) urea
N-(2-(Amino sulfonyl (8-quinolinyl)) phenyl) N'-(2-bromo phenyl) urea N-(2-(Amino sulfonyl benzyl) phenyl) N'-(2-bromo phenyl) urea
N-(2-Hydroxy-4-azidophenyl)-N'-(2-methoxyphenyl )urea
N-[2-Hydroxy-5-cyanophenyl]-N'-[2-bromophenyl] urea
N-[2-Hydroxy-3-fluorophenyl]-N'-[2-bromophenyl ] urea
N-[2-Hydroxy-3-fluoro-5-bromophenyl]-N'-[2-bromophenyl] urea
N-[2-Hydroxy-3-chlorophenyl]-N'-[2-bromophenyl ) urea
N-[2-Hydroxy-3-trifluoromethylphenyl]-N'-[2-bromophenyl] urea
N-[2-Hydroxy-3.4-diphenyl-phenyl]-N'-[2-bromophenyl] urea
N-[2-Hydroxy-3-glycinemethylestercarbonylphenyl]-N'-[2-bromophenyl| urea
N-|2-hHydroxy-3-glycincarbonylphenyl]-N'-f2-bromophenyl) urea
N-[2-Hydroxy-3,5-dichlorophenyl ]-N'-[2-bromophenyl] urea
N-[2-Hydroxy-3-nitrophenyl]-N'-[2-bromophenyl] urea
N-[2-Hydroxy-3,4-dichlorophenyl]-N'-[2-bromophenyl] urea
N-[2-Hydroxy-3-cyanophenyl]-N'-[2-bromophenyl] urea
N-[2-Hydroxy-4-cyanophenyl]-N'-[2-bromophenyl] urea
N-[2-Hydroxy-4-cyanophenyl]-N'-[4-methoxyphenyl] urea
N-[2-Hydroxy-4-cyanophenyl]-N'-[2-phenylphenyl] urea
N-|2-Hydroxy-4-cyanophenyl]-N'-[2-methylphenyl) urea
N-[2-Hydroxy-4-cyanophenyl]-N'-[2-trifluoromethylphenyl] urea
N-[2-Hydroxy-4-cyanophenyl]-N'-[3-trifluoromethylphenyl] urea
N-[2-Hydroxy-4-cyanophenyl]-N'-[4-trifluoromethylphenyI] urea
N-[2-Hydroxy-3-n-propylphenyl]-N'-[2-bromophenyl) urea
N-[2-Hydroxy-4-ethylphenyl]-N'-[2-bromophenyl ] urea
N-[2-Hydroxy-3-phenylaminocarbonyl phenyl]-N'-[2-bromophenyI ] urea
N-[2-Hydroxy-3-cyano-4-methylphenyl)-N'-[2-bromophenyl ] urea
N-[2-Hydroxy-4-carbophenyl phenyl]-N'-(2-bromophenyl] urea
N-[2-Hydroxy-3-carbophenyl phenyl]-N'-[2-bromophenyl] urea
N-[3-Benzyloxy-2-hydroxyphenyl]-N'-[2-bromophenyl ] urea
(E)-N-|4-[2-(Methoxycarbonyl) ethenyl]-2-hydroxyphenyl]-N'-[2-brυmophenyl ] urea (E)-N-[3-[2-(Methoxycarbonyl ) ethenyl]-2-hydroxyphenyl]-N'-[2-hromophenyl ] urea- N'-[2- bromophenyl] urea
(E)-N-[3-[2-(Aminocarbonyl) ethenyl]-2-hydroxyphenyl]-N'-[2-bromophenyl ]urea-N'-[ 2- bromophenyl] urea
(E)-N-[4-[2-(Aminocarbonyl) ethenyl]-2-hydroxyphenyl|-N'-[ 2-bromophenyl ]urea-N'-[ 2- bromophenyl] urea
N-[2-Hydroxy-4-benzamide phenyl]-N'-[2-bromophenyl] urea
N-[4-Aminocarbonyl-2-hydroxyphenyl]-N'-[2-bromophenyl] urea
N-(2-Hydroxy-3,5,6-triflu orophenyl)-N'-(2-bromophenyl )urea N-(2-Hydroxy-3-fluoro-4-trifluoromethylphenyl )-N'-(2-bromophenyl )urea N-(2-Hydroxy-3-iodophenyl )-N'-(2-bromophenyl )urea
N-[2-[[[2-(Trifluoromethyl)phenyl]sulfonyl]amino|phenyl)-N'-(2-bromophenyl)urea N-(2-Bromophenyl)-N'-[2-dimethylaminosulfonylamino]phenyl ]urea
N-[2-(Phenethylsulfonylamino)phenyl)-N'-(2-bromophenyl)urea
N-[2-[(2-Acetamido-4-methylthiazol-5-yl)sulfonylamino)phenyl ]-N'-(2-bromophenyl)urea N-[2-Hydroxy-4-cyanυphenyl]-N'-[4-phenyl phenyl ] urea
N-[2-Hydroxy-4-cyanophenyl]-N'-[2,3-dichlorophenyl] urea
N-[2-Hydroxy-4-cyanophenyl]-N'-[2-methoxyphenyl] urea
N-[2-Hydroxy-4-cyanophenyl]-N'-[3-methoxyphenyl) urea
N-[2-Hydroxy-5-fluorophenyl]-N'-[2-bromophenyl] urea
N-[2-Hydroxy-5-trifluoromethylphenyl]-N'-[2-bromophenyl] urea
N-[2-Hydroxyphenyl]-N'-[2-bromophenyl] urea
N-[Trans-3-styrl-2-hydroxyphenyl]-N'-[2-bromophenyl ] urea
N-[2-Hydroxy-3,4-dichlorophenyl]-N'-[2-methoxyphenyl] urea
N-[2-Hydroxy-3,4-dichlorophenyl]-N'-[4-methoxyphenyl] urea
N-[2-Hydroxy-3,4-dichlorophenyl]-N'-[3-trifluoromethylphenyl) urea
N-[2-Hydroxy-3,4-dichlorophenyI]-N'-[2-phenyl phenyl ] urea
N-[2-Hydroxy-3,4-dichlorophenyl)-N'-[4-phenylphenyl] urea
N-[2-Hydroxy-3,4-dichlorophenyl]-N'-[2,3-dichlorophenyl] urea
N-[2-Hydroxy-4-isopropylphenyl]-N'-[3-trifluoromethylphenyl] urea
N-[2-Hydroxy-3-naphthy]]-N'-[2,3-dichlorophenyl ] urea
N-[2-[(2,3-Dichlorothien-5-yl)lsulfonylamino]phenyl ]-N'-(2-bromophenyl )urea
N-[2-[(3,5-Bistrifluoromethylphenyl)sulfonylamino]phenyl |-N'-(2-bromophenyl )urea N-[2-[(2-Benzyl)sulfonylamino]-(5-trifluoromethyl)phenyl)-N'-(2-bromophenyl)urea N-[2-|2-(3-Nitrophenyl)sulfonylamino]phenyl ]-N'-(2-bromophenyl )urea N-[2-[2-(4-Phenoxyphenyl)sulfonylamino]phenyl ]-N'-(2-bromophenyl ) urea
N-[[2-( 1S)- 10-Camphorsulfonylamino]phenyl ]-N'-(2-bromophenyl )urea
N-[[2-( 1R)- 10-Camphorsulfonylamino]phenyl]-N'-(2-bromophenyl )urea
N-[2-[2-(2-Nitro-(4-trifluoromethyl)phenyl)sulfonylamino]phenyl-N'-(2-bromophenyl)urea N-[2-Hydroxy-4-azidophenyl)-N'-(2-iodophenyl )urea
N-[2-Hydroxy-3-azidophenyl)-N'-(2-bromophenyl )urea
N-[2-Hydroxy-3-cyanophenyl ]-N'-[2-methoxyphenyl ] urea
N-[2-Hydroxy-3-cyanophenyl]-N'-[3-trifluoromethylphenyl ] urea
N-[2-Hydroxy-3-cyanophenyl)-N'-[2-phenylphenyl ] urea
N-[2-Hydroxy-3-cyanophenyl]-N'-[2,3-dichlorophenyl ) urea
N-[2-Hydroxy-4-isopropylphenyl]-N'-[2,3-dichlorophenyl] urea N-[2-Hydroxy-4-isopropylphenyl]-N'-[2-chloro-5-trifluoromethylphenyl ] urea
N-[2-Hydroxy-3-phenylphenyl]-N'-[2,3-dichlorophenyl] urea
N-[2-Hydroxy-5-nitrophenyl]-N'-[2-methoxyphenyl] urea
N-[2-Hydroxy-5-nitrophenyl ]-N'-[3-trifluoromethylphenyl] urea
N-[2-Hydroxy-5-nitrophenyl]-N'-[2-phenylphenyl ] urea
N-[2-Hydroxy-5-nitrophenyl|-N'-[2,3-dichlorophenyl] urea
N-[2-Hydroxy-5-ethylsulfonylphenyl|-N'-[2,3-dichlorophenyl) urea
N-[2-(2- Amino-(4-trifluoromethyl) phenyl) sulfonylamino] phenyl]- N'-(2- bromophenyl)urea
N-[2-(Aminosulfonyl phenyl) 3-amino phenyl] N'-(2-bromo phenyl) urea
N-(2-Hydroxy-3,4-dichlorophenyl]-N'-[2,4 dimethoxyphenyl] urea
N-[2-Hydroxy-3,4-dichlorophenyl]-N'-[2-chloro-5-trifluoromethylphenyl] urea
N-[2-Hydroxy-3-naphthyI]-N'-[3-trifluoromethylphenyl] urea
N-[2-Hydroxy-5-naphthalenesulfonic acid]-N'-[2-bromophenyl] urea;
N-[2-Hydroxy-4-naphthalenesulfonic acid]-N'-[2-bromophenyl] urea;
1 , 1 '-(4-Methyl-2-phenylene)bis[2-thio-3-3-tolylurea]
N-(2-Carboxyphenyl)-N'-phenylurea
N-(2-Hydroxy-4-nitrophenyl)-N'-phenylurea;
1-(2-Carboxyphenyl)-3-(4-chlorophenyl)urea ;
2-(3,4-Dichlorophenylcarbonyldiimino)-5-trilluoromethylbenzoic acid:
2-(4-Chlorophenylcarbonyldiimino)-5-trifluoromethylbenzoic acid:
1 -(p-Anisyl)-3-(2-carboxyphenyl)urea;
1 -(2-Carboxyphenyl)-3-(3-fluorophenyl)urea;
1 -(2-Carboxyphenyl)-3-(3-chlorophenyl)urea;
1 -(m-Anisyl)-3-(2-carboxyphneyl)urea;
1 -(o-Anisyl)-3-(2-carboxyphenyl)urea ;
1 -(2-Carboxyphenyl)-3-(3,4-dichlorophenyl )urea;
1 -(2-Carboxyphenyl)-3-(2,4-dichlorophenyl )urea;
N-(5-Chloro-2-hydroxy-4-nitrophenyl)-N, -phenyl urea;
N-(2-Hydroxy-4-nitrophenyl)-N'-(4-nitrophenyl)urea;
Prefered compounds of Formula (I ) include:
N-(2-Hydroxy-4-nitrophenyl)-N'-(2-methoxyphenyl )urea
N-(2-Hydroxy -4-nitrophen\ l )-N'-( 2-bromophenyl )urea
N-(2-Hydroxy -4-nitrophenyl)-N'-(2-phenylphenyl )urea
N-(2-Hydroxy -4-nitrophenyl)-N'-(2-methylthiophenyl)urea
N-(2-Hydroxy -4-nitrophenyl )-N'-(2,3-dichlorophenyl)urea
N-(2-hydroxy 4-nitro phenyl ) N'-( 2-chloro phenyl) urea N'-(2-Hydroxy-4-nitrophenyl)-N'-(2,3-meihylcnedioxyphenyl )urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(2-methoxy-3-chlorophenyl)urea
N-(2-hydroxy 4-nitro phenyl) N'-(2-phenyloxy phenyl) urea
N-(3-Chloro-2-hydroxyphenyl)-N'-(bromophenyl)urea
N-(2-Hydroxy-3-glycinemethylestercarbonylphenyl)-N'-(2-bromophenyl)urea
N-(3-Nitro-2-hydroxyphenyl)-N'-(2-bromophenyl)urea
N-(2-Hydroxy-4-cyanophenyl)-N'-(2-bromophenyl)urea
N-(2-Hydroxy-3,4-dichlorophenyl)-N'-(2-bromophenyl)urea
N-(3-Cyano-2-hydroxyphenyl)-N'-(2-bromophenyl)urea
N-(2-Hydroxy-4-cyanophenyl)-N'-(2-methoxyphenyl)urea
N-(2-Hydroxy-4-cyanophenyl)-N'-(2-phenylphenyl)urea
N-(2-Hydorxy-4-cyanophenyl-N'-(2.3-dichlorophenyl)urea
N-(2-Hydrυxy-4-cyanophenyl)-N'-(2-methylphenyl)urea
N-(2-Hydroxy-3-cyano-4-methylphenyl)-N'-(2-bromophenyl)urea
N-(4-Cyano-2-hydroxyphenyl)-N'-(2-trifluoromethylphenyl)urea
N-(3-Trinuoromethyl-2-hydroxyphenyl)-N'-(2-bromophenyl)urea
N-(3-Phenylaminocarbonyl-2-hydroxyphenyl)-N'-(2-bromophenyl)urea
N-(2-hydroxy 4-nitro phenyl) N'-(2-iodo phenyl) urea
N-(2-hydroxy 4-nitro phenyl) N'(2-bromo phenyl) thiourea
N-(2-phenylsulfonamido)-4-cyanophenyl-N'(2-bromo phenyl)urea
(E)-N-[3-[(2-Aminocarbonyl)ethenyl]-2-hydroxyphenyl]-N'-(2-bromophenyl)urea
N-(2-Hydroxy,3,4-dichlorophenyl)-N'-(2-methoxyphenyl)urea
N-(2-Hydroxy,3,4-dichlorophenyl)-N'-(2-phenylphenyl)urea
N-(2-Hydroxy-3,4-dichlorophenyl)-N'-(2,3-dichlorophenyl )urea
N-(2-Hydroxy-5-nitrophenyl)-N'-(2.3-dichlorophenyl)urea
N-(2-Hydrox y- 3-cyanophenyl)-N'-(2,3 dichlorophenyburea
As used herein, "optionally substituted" unless specifically defined shall mean such groups as halogen, such as fluorine, chlorine, bromine or iodine ; hydroxy; hydroxy substituted C 1 - 10alkyl; C 1 - 1 0 alkoxy, such as methoxy or ethoxy; S(O)m ' C 1 - 1 0 alkyl, wherein m' is 0. 1 or 2, such as methyl thio, methyl sulfinyl or methyl sulfonyl; amino, mono & di-substituted amino, such as in the NR4R5 group: NHC(O)R4: C(O)NR4R5: C(O)OH: S(O)2NR4R5. NHS(O)2R 1 3, C 1 - 1 0 alkyl, such as methyl, ethyl, propyl. isopropyl. or t-butyl:
halosubstituted C 1 - 10 alkyl, such CF3; an opuonally substituted aryl, such as phenyl, or an optionally subsututed arylalkyl. such as benzyl or phenethyl. optionally substituted heterocylic, optionally substituted heterocylicalkyl. optionally subsututed heteroaryl. optionally substituted heteroaryl alkyl. wherein these aryl , hetroaryl, or heterocyclic moieties may be substituted one to two times by halogen; hydroxy; hydroxy substituted alkyl; C 1 - 10 alkoxy: S(O)m, C 1 - 10 alkyl; amino, mono & di-substituted amino, such as in the NR4R5 group; C1-10 alkyl, or halosubstituted C1-10 alkyl, such as CF3.
R13 is suitably C1-4 alkyl, aryl, aryl C1-4alkyl, heteroaryl, heteroarylC1-4alkyl. heterocyclic, or heterocyclicC1-4alkyl.
Another aspect of the present invention are the novel compounds of Formula (II), or a pharmaceutically acceptable salt thereof, as described below, which are also useful in inhibiting the binding of IL-8 to its receptors in a mammal in need thereof. This invention also relates to the pharmaceutical compositions comprising a compound of Formula (II) and a
pharmaceutically acceptable diluent or carrier. Compounds of Formula (II) are also useful tor treating a chemokine mediated disease, wherein the chemokine is one which binds to an IL-8α or β receptor and which method comprises administering an effective amount of a compound of Formula (II) or a pharmaceutically acceptable salt thereof. Compounds of Formula
(II) are represented by the structure:
Figure imgf000016_0001
wherein
X is oxygen or sulfur:
R is any functional moiety having an lonizable hydrogen and a pKa of 10 or less:
R1 is independently selected from hydrogen; halogen; nitro; cyano; halosubstituted C1-10 alkyl: C1-10 alkyl: C2-10 alkenyl: C1-10 alkoxy; halosubstiiuied C1-10 alkoxy: azide;
S(O)tR4; hydroxy; hydroxyC1-4alkyl; aryl; aryl C1-4 alkyl; aryloxy: arylC1 -4 alkyloxy; heteroaryl; heteroarylalkyl; heterocyclic, heterocyclicC1-4alkyl; heteroarylC1-4 alkyloxy; aryl C2-10 alkenyl: heteroaryl C2-10 alkenyl; heterocyclicC2- 10 alkenyl; NR4R5; C2-10 alkenyl C(O)NR4R5; C(O)NR4R5; C(O)NR4R10; S(O)3H; S(O)3R8; C1-10 alkyl C(O)R11; C2-10 alkenyl C(O)R 11 : C2-10 alkenyl C(O)OR11; C(O)R11; C(O)OR12;
OC(O) R11; NR4C(O)R 11; or two R1 moieties together may form O-(CH2)sO- or a 5 to 6 membered unsaturated ring:
t is 0, or an integer having a value of 1 or 2;
s is an integer having a value of 1 to 3;
R4 and R5 are independently hydrogen, opuonally substituted C1-4 alkyl. optionally
substituted aryl, optionally substituted aryl C1-4alkyl, optionally subsututed heteroaryl, optionally substituted heteroaryl C1-4alkyl, heterocyclic. heterocyclicC1-4 alkyl, or R4 and R5 together with the nitrogen to which they are attached torm a 5 to 7 member ring which may optionally comprise an additional heteroatom selected Irom O/N/S; Y is independently selected from hydrogen: halogen: nitro; cyano: halosubsuiuicd C1-10 alkyl: C1-10 alkyl: C2-10 alkenyl; C1-10 alkoxy: halosubstituted C1-10 alkoxy: azide: S(O)(R4: hydroxy: hydroxy C1-4alkyl; aryl; aryl C1-4 alkyl: aryloxy; aryl C1-4 alkyloxy: heteroaryl heteroarylalkyl: heteroarylC1-4 alkyloxy; heterocyclic, heterocyclic C1-4alkyl: aryl C2- 10 alkenyl: heteroaryl C2-10 alkenyl: heterocyclic C2-10 alkenyl: NR4R5: C2-10 alkenyl C(O)NR4R5; C(O)NR4R5; C(O)NR4R10 S(O)3H: S(O)3R8; C1-10 alkyl C(O)R11; C2-10 alkenyl C(O)R11; C2-10 alkenyl C(O)OR11; C(O)R11; C(O)OR 12: OC(O) R11; NR4C(O)R11; or two Y moieties together may form O-(CH2)sO- or a 5 to 6 membered unsaturated ring;
n is an integer having a value of 1 to 3;
m is an integer having a value of 1 to 3;
R8 is hydrogen or C1-4 alkyl;
R10 is C1-10 alkyl C(O)2R8;
R11 is hydrogen. C1-4 alkyl, optionally substituted aryl. optionally subsututed aryl C1-4alkyl optionally subsututed heteroaryl, optionally subsututed heteroarylC1-4alkyl, opuonally subsututed heterocyclic, or optionally substituted heterocyclicC1-4alkyl;
R12 is hydrogen, C1-10 alkyl, optionally substituted aryl or optionally substituted arylalkyl;
E is opuonally selected from
Figure imgf000017_0001
asterix * denoting point of attachment of the ring, with at least one E being present;
or a pharmaceutically acceptably salt thereof.
Suitably, the variables for Formula (II), such as X, R, R1, R4 , R5, R6, R7, R8, R9, Y, Ra, Rb, Rc, n, m, and s terms, etc. are as defined in Formula (I) above The E ring denoted by its point of attachment through the asterix (*) may opuonally be present If ll it is not present the ring is a phenyl moiety which is substituted by the R and R1 terms as shown At least one E ring is necessary. The E ring may be substituted by the R1 moiety in any ring, saturated or unsaturated. and is shown for purposes herein substituted only in the unsaturated ring(s)
Exemplified compounds of Formula (III) are
N-[2-hydroxy-5-indanonc]-N'-[2-bromophenyl] urea.
N-[1-hydroxyfluorcne]-N'-[2-bromophenyl] urea; N-[3-hydroxy-9,10-anthraquinon-2-yl]-N'-[2-bromophenyl]urea
Another aspect of the present invention are the novel compounds of Formula (III), or a pharmaceutically acceptable salt thereof. as described below, which are al.so useful in inhibiting the binding of IL-8 to its receptors in a mammal in need thereof This invention al.so relates to the pharmaccuueal compositions comprising a compound of Formula (III) and a
pharmaceutically acceptable diluent or carrier Compounds of Formula (III) are also useful for treating a chemokine mediated disease, wherein the chemokine is one which binds to an IL-8 α or β receptor and which method comprises administering an effective amount of a compound of Formula (III) or a pharmaceuucally acceptable salt thereof Compounds of Formula (III ) are represented by the formula:
Figure imgf000018_0001
wherein
X is oxygen or sulfur;
R is any functional moiety having an ionizable hydrogen and a pKa of 10 or less.
R1 is independently selected from hydrogen: halogen: nitro; cyano: halosubstituted C1-10 alkyl: C1-10 alkyl; C2-10 alkenyl: C1-10 alkoxy: halosubstituted C1-10 alkoxy; azide; S(O)tR4; hydroxy; hydroxyC1-4alkyl; aryl; aryl C1-4 alkyl; aryloxy;arylC1-4 alkyloxy; heteroaryl; heteroarylalkyl; heterocyclic, heterocyclicC1-4alkyl. heteroaryIC1-4 alkyloxy; aryl C2-10 alkenyl; heteroaryl C2-10 alkenyl; heterocyclicC2-10 alkenyl. NR4R5; C2-10 alkenyl C(O)NR4R5; C(O)NR4R5; C(O)NR4R10; S(O)3H; S(O)3R8; C1-10alkyl C(O)R11; C2-10 alkenyl C(O)R11; C2-10 alkenyl C(O)OR11; C(O)R11; C(O)OR12; OC(O)R11; NR4C(O)R11; or two R1 moieties together may form O-(CH2)sO- or a 5 to 6 membered unsaturated ring:
t is 0. or an integer having a value of 1 or 2;
s is an integer having a value of 1 to 3.
R4 and R5 are independently hydrogen, optionally substituted C1-4 alkyl, optionally
subsututed aryl, optionally substituted aryl C1-4alkyl. optionally substituted heicroaryl. optionally substituted heteroaryl C1-4alkyl. heterocyclic, heterocyclicC1-4 alky 1 or R4 and R5 together with the nitrogen to which they are attached form a 5 to 7 member ring ulnd. may optionally comprise an additional heteroaiom selected Irom O/N/S.
Y is independently selected Irom hydrogen: halogen; nitro: cyano; halosubstituted C1-10 alkyl;
C1-10 alkyl; C2-10 alkenyl: C1-io alkoxy. halosubstiiuted C1-10 alkoxy; azide; S(O)tR4; hydroxy; hydroxyC1-4alkyl; aryl; aryl C1-4alkyl; aryloxy: arylC1-4 alkyloxy; heteroaryl. heteroarylalkyl: heteroarylC1-4alkyloxy; heterocyclic, heterocyclicC1-4alkyl; aryl C2-10 alkenyl; heteroaryl C2-10 alkenyl: heterocyclicC2-10 alkenyl: NR4R5; C C1-10 alkenyl C(O)NR4R5; C(O)NR4R5: C(O)NR4R1»: SfOtøH: S(O)3R8- C1-10 alkyl C(O)R11; C2-10 alkenyl C(O)R11; C2-10 alkenyl C(O)OR11; C(O)R11; C(O)OR12; OC(O) R 11 :
NR4C(O)R11; or two Y moieties together may form O-(CH2)sO- or a 5 to 6 membered unsaturated ring;
n is an integer having a value of 1 to 3;
m is an integer having a value of 1 to 3;
R8 is hydrogen or C 1 -4 alkyl;
R10 is C1-10 alkyl C(O)2R8;
R11 is hydrogen, C1-4 alkyl, optionally substituted aryl, opuonally subsututed aryl C1-4alkyl, optionally substituted heteroaryl, optionally subsututed heteroarylC1-4alkyl, optionally subsututed heterocyclic, or opuonally substituted heterocyclicC1-4alkyl;
R12 is hydrogen, C1-10 alkyl, optionally substituted aryl or optionally substituted arylalkyl; or a pharmaceutically acceptably salt thereof.
Suitably, the variables, etc. for Formula (II) are the same as ihosc defined for Formula (I) above, such as for example the R variable
Exemplified compounds of Formula (III) are N-(2-Hydroxy-4-nitrophenyl)-N'-(3- methoxy-2-thienyl)urea; and N-(2-hydroxy-5-nitrophenyl)-N'-(3-methoxy-2-thienyl)urea.
Another aspect ot the present invention is the novel compounds of Formula (Ia), a subset of compounds of Formula (I) useful lor treating a chemokine mediated disease as defined herein This invenuon also relates to the phamiaccuucal compositions comprising a compound of Formula (la) and a pharmaceuucally acceptable diluent or carrier The compounds of Formula (la) are represented by the strucuture:
Figure imgf000019_0001
wherein
X is oxygen or sulfur;
Ra is an alkyl, aryl, arylC1-4alkyl, heteroaryl, heteroaryl C1-4alkyl, heterocyclic, or a
heterocyclic C1-4alkyl moiety, all of which may be optionally subsututed. Rb is a NR6R7, alkyl, aryl, arylC1-4alkyl, arylC2-4alkenyl, heteroaryl, heteroarylC1-4alkyl, heteroarylC2-4 alkenyl, heterocyclic, or heterocyclic C1-4alkyl, or a heterocyclic
C2-4alkenyl moiety, camphor, all of which may be optionally substituted one to three times independendy by halogen; nitro; halosubsututed C1-4 alkyl; C1-4 alkyl; C1-4 alkoxy; NR9C(O)Ra; C(O)NR6R7, S(O)3H, or C(O)OC1-4 alkyl;
R6 and R7 are independently hydrogen or a C1-4 alkyl group, or R6 and R7 together with the nitrogen to which they are attached torm a 5 to 7 member ring which ring may opuonally contain an additional heteroatom which heteroatom is selected from oxygen, nitrogen or sullur, which ring may be optionally substitued;
R9 is hydrogen or a C1-4 alkyl, preferably hydrogen;
R1 is independently selected from hydrogen; halogen; nitro; cyano; halosubstituted C1-10 alkyl; C1-10 alkyl; C2-10 alkenyl; C1- 10 alkoxy; halosubstituted C1-10 alkoxy; azide; S(O)tR4; hydroxy; hydroxy C1-4alkyl; aryl; aryl C1-4alkyl; aryloxy; aryl C1-4 alkyloxy; heteroaryl; heteroarylalkyl; heterocyclic, heterocyclic C1-4alkyl; heteroaryl C1-4alkvloxy, aryl C2-10 alkenyl; heteroaryl C2-10 alkenyl; heterocyclicC2-10 alkenyl; NR4R5; C2-10 alkenyl C(O)NR4R5; C(O)NR4R5; C(O)NR4R10; S(O)3H; S(O)3R8- C1-10 alky) C(O)R11; C2-10 alkenyl C(O)R11; C2-10 alkenyl C(O)OR11; C(O)R11; C(O)OR12; OC(O) R11; NR4C(O)R11; or two R1 moieties together may form O-(CH2)sO- or a 5 to 6 membered unsaturated ring;
t is 0, or an integer having a value of 1 or 2.
s is an integer having a value of 1 to 3;
R4 and R5 are independently hydrogen, opuonally subsututed C1-4 alkyl, optionally
substituted aryl, optionally substituted aryl C1-4alkyl, opuonally substituted heteroaryl, opuonally substituted heteroaryl C1-4alkyl, heterocyclic, heterocyclicC 1 -4 alkyl, or R4 and R5 together with the nitrogen to which they are attached lorm a 5 to 7 member ring which may optionally comprise an additional heicroatom selected from O/N/S.
Y is independently selected Irom hydrogen; halogen; nitro; cyano; halosubstituted C1-10 alkyl.
C1-10 alkyl. C2-10 alkenyl; C1-10 alkoxy; halosubstituted C1-10 alkoxy; azide; S(O)tR4; hydroxy; hydroxyC1-4alkyl; aryl; aryl C1-4 alkyl; aryloxy; arylC1-4 alkyloxy; heteroaryl. heteroarylalky 1; heteroarylC1-4 alkyloxy. heterocyclic, heterocyclicC1-4alkyl; aryl C2-10 alkenyl; heteroaryl C2-10 alkenyl; heterocyclicC2-10 alkenyl; NR4R5. C2-10 alkenyl C(O)NR4R5- C(O)NR4R5; C(O)NR4R10; S(O)3H; S(O)3R8. C1-10 alkyl C(O)R11; C2-10 alkenyl C(O)R11; C2-10 alkenyIC(O)OR11; C(O)R11; C(O)OR12; OC(O)R11; NR4C(O)R11; or two Y moieties logethei may lorm O-(CH2)sO-or a 5 to 6 membered unsaturated ring.
n is an integer having a value of 1 to 3;
m is an integer having a value of 1 to 3;
R8 is hydrogen or C1-4 alkyl. R 10 is C 1 - 10 alkyl C(O)2R8;
R 1 1 is hydrogen, C 1-4 alkyl, optionally substituted aryl, optionally substituted aryl C 1 -4alkyl. optionally substituted heteroaryl, optionally substituted heteroarylC 1 -4alkyl, optionally substituted heterocyclic, or opuonally substituted heterocyclicC 1 -4alkyl;
R 12 is hydrogen, C 1 - 10 alkyl, optionally substituted aryl or optionally substituted arylalkyl; or a pharmaceutically acceptably salt thereof.
A preferred ring substitution for R 1 variable is monosubstituted in the 3-position, or the 4- position, or di-substituted in the 3,4- position. The substituent group is suitably an electron withdrawing moiety, Preferably R 1 is nitro, halogen, cyano, trifluoromethyl group, or
C(O)NR4R5.
While Y may be substituted in any of the 5 ring positions, preferably the ring with the Y moiety is mono-substituted in the 2-position or 3- position, with the 4- preferably being unsubstituted. If the ring is di-substituted. substituents are preferably in the 2'-, 3 - positions of a monocyclic ring. While both R 1 and Y can both be hydrogen, it is prefered that at least one of the rings be substituted, preferably both rings are at least mono-substituted, i.e. n amd m are each equal to 1 or more.
Y is more preferably a mono-substituted halogen, disubstituted halogen, mono-substituted alkoxy, disubstituted alkoxy, methylenedioxy, aryl, or alkyl. preferably these groups are substituted in the 2'- position or 2'-,3'-position.
Exemplified compounds of Formula (Ia) are
N-(4-Nitro 2-(phenylsulfonylamino)phenyl)-N'-phenyl urea
N-[(2-Phenylsulfamido) 4-cyanophenyl]- N'-(2-bromo phenyl) urea
N-(2-(Amino sulfonamido phenyl) phenyl) N'-(2-bromo phenyl) urea
N-(2-(Amino sulfonyl styryl) phenyl) N'-(2-bromo phenyl) urea
2-[(3,4 Di-meihoxyphenylsulfonyI)amino] phenyl) N'-(2-bromo phenyl) urea
N-(2-[(4-Acetamidophenylsulfonyl)amino] phenyl) N'-(2-bromo phenyl) urea
N-(2-(Amino sulfonyl (2-thiophene) phenyl) N'-(2-bromo phenyl) urea
N-(2-(Am ino sulfonyl (3-tolyl) phenyl) N'-(2-bromo phenyl ) urea
N-(2-(Am ino sulfonyl (8-quinolinyl)) phenyl) N'-(2-bromo phenyl) urea
N-(2-(Amino sulfonyl benzyl) phenyl) N'-(2-bromo phenyl) urea
N-[ 2-[[ [2-(Trifluoromethyl)phenyl]sulfonyl]amino]phenyl]-N'-(2-bromophenyl)urea
N-(2- Bromophenyl )-N'-[2-dimethylaminosuIfonylamino]phenyl]urea
N-[2-(Phenethylsulfonylamino)phenyl]-N'-(2-bromophenyl)urea
N-[2-[(2-Acetamido-4-methylthiazol-5-yl)sulfonylamino]phenyl]-N'-(2-bromophenyl)urea
N-[2-[(2,3-Dichlorothien-5-yl)]sulfonylamino]phenyl]-N'-(2-bromophenyl)urea
N-[2-[(3,5-Bistrifluoromethylphenyl)sulfonylamino]phenyl]-N'-(2-bromophenyl)urea N-[2-[(2-Benzyl)sulfonylamino]-(5-trifluoromethyl)phenyl]-N'-(2-bromophenyl)urea N-[2-[2-(3-Nitrophenyl)sulfonylamino)phenyl]-N'-(2-bromophenyl)urea
N-[2-[2-(4-Phenoxyphenyl)sulfonylamino]phenyl]-N'-(2-bromophenyl)urea
N-[[2-(1S)-10-Camphorsulfonylamino]phenyl]-N'-(2-bromophenyl)urea
N-[[2-(1R)-10-Camphorsulfonylamino]phenyl]-N'-(2-bromophenyl)urea
N-[2-[2-(2-Nitro-(4-trifluoromethyl)phenyl)sulfonylamino]phenyl-N'-(2-bromophenyl)urea N-[2-(2-Amino-(4-trifluoromethyl)phenyl)sulfonylamino]phenyl]-N'-(2- bromophenyl)urea
N-[2-(aminosulfonylphenyl)3-aminophenyl]N'-(2-bromophenyl)urea
Another aspect of the present invention is the novel compounds of Formula (Ib), a subset of compounds of Formula (I) useful for treating a chemokine mediated disease. This invention also relates to the pharmaceutical compositions comprising a compound of Formula (Ib) and a pharmaceutically acceptable diluent or carrier. The compounds of Formula (Ib) are represenied by the sirucuture:
Figure imgf000022_0001
wherein
X is oxygen or sulfur;
X1 is oxygen or sulfur;
R1 is independently selected from hydrogen; halogen; nuro; cyano; halosubstituted C1-10 alkyl; C1-10 alkyl; C2-10 alkenyl; C1-10 alkoxy; halosubstituted C1-10 alkoxy; azide; S(O)tR4; hydroxy; hydroxyC1-4alkyl; aryl; aryl C1-4 alkyl; aryloxy; arylC1-4 alkyloxy; heteroaryl; heteroarylalkyl; heterocyclic, heterocyclic C1-4alkyl; heteroaryl C1-4alkyloxy; aryl C2-10 alkenyl; heteroaryl C2-10 alkenyl; heterocyclicC2-10 alkenyl: NR4R5, C2-10 alkenyl C(O)NR4R5;C(O)NR4R5;C(O)NR4R10;S(O)3H;S(O)3R8;C1-10 alkyl C(O)R11; C2-10 alkenyl C(O)R11; C2-10 alkenyl C(O)OR11; C(O)R11; C(O)OR 12: OC(O)R11; NR4C(O)R11; or two R1 moieties together may form O-(CH2)sO- or a 5 to 6 membered unsaturated ring;
t is 0, or an integer having a value of 1 or 2;
s is an integer having a value of 1 to 3;
R2 is a substituted aryl, heteroaryl, or heterocyclic ring which ring has a functional moiety providing the ionizable hydrogen having a pKa of 10 or less; R4 and R5 are independently hydrogen, optionally substituted C1-4 alkyl, optionally substituted aryl, optionally substituted aryl C1-4alkyl, optionally substituted heteroaryl. optionally substituted heteroaryl C1-4alkyl, heterocyclic. heterocyclicC1-4 alkyl, or R4 and R5 together with the nitrogen to which they are attached form a 5 to 7 member ring which may opuonally comprise an additional heteroatom selected from O/N/S;
Y is independently selected from hydrogen: halogen: nitro; cyano: halosubstituted C1-10 alkyl;
C1-10 alkyl; C2- 10 alkenyl; C1-10 alkoxy: halosubstituted C1-10 alkoxy; azide; S(O)tR4; hydroxy; hydroxyC1-4alkyl; aryl; aryl C1-4 alkyl; aryloxy; arylC1-4 alkyloxy; heteroaryl; heteroarylalkyl; heteroarylC1-4 alkyloxy; heterocyclic. heterocyclicC1-4alkyl; aryl C2-10 alkenyl; heteroaryl C2-10 alkenyl; heterocyclicC2-10 alkenyl; NR4R5; C2-10 alkenyl
C(O)NR4R5; C(O)NR4R5 ; C(O)NR4R10; S(O)3H; S(O)3R8; C1-10 alkyl C(O)R11; C2-10 alkenyl C(O)R 11 : C2-10 alkenyl C(O)OR 11 ; C(O)R 11 ; C(O)OR 12; OC(O) R 11 ; NR4C(O)R 11 ; or two Y moieties together may form O-(CH2)sO- or a 5 to 6 membered unsaturated ring;
n is an integer having a value of 1 to 3;
m is an integer having a value of 1 to 3;
R8 is hydrogen or C 1 - 4 alkyl;
R10 is C 1-10 alkyl C(O)2R8;
R11 is hydrogen, C1-4 alkyl. optionally substituted aryl, optionally substituted aryl C1-4alkyl, opuonally substituted heteroaryl, optionally substituted heteroarylC1-4alkyl, optionally substituted heterocyclic, or opuonally substituted heterocyclicC1-4alkyl;
R12 is hydrogen. C1-10 alkyl, optionally substituted aryl or optionally substituted arylalkyl; or a pharmaceutically acceptable salt thereof. Suitably, the variable, etc. for Formula (lb) are the same as those defined for Formula
(I) above, such as for example the functional moieties on the R2 group having an ionizable hydrogen with a pKa of 10 or less. Suitably such functional groups include, but are not limited to. hydroxy, carboxylic acid, thiol, -NH-C(O)Ra, -C(O)NR6R7. substituted sulfonamides of the formula -NHS(O)2Rb,- -S(O)2NHRc. NHC(X2)NHRn. or tetrazoyl (as defined for Formula (I).
Suitably for compounds of Formula (lb), a preferred ring substitution for R1 is in the 3-position. the 4- position or is preferably di substituted in the 3.4- position. The substituent group is suitably an electron withdrawing moiety . Preferably R1 is nitro, halogen, cyano. trifluoromethyl group, or C(O)NR4R5.
While Y may be substituted in any of the 5 ring positions. preferably the ring with the
Y moiety is mono-substituted in the 2-position or 3- position, with the 4- preferably being unsubstituted. If the ring is disubstituted. substituents are prelerably in the 2' or 3' position of a monocyclic ring. While both R1 and Y can both be hydrogen, it is prefered that at least one of the rings be substituted, preferably both rings are at least mono-substituted, i.e. n amd m are each equal to 1 or more.
Suitably for compounds of Formula (lb), Y is more preferably disubstituted halogen, mono-substituted halogen, disubstituted alkoxy, mono-substituted alkoxy, methylencdioxy, aryl, or alkyl, preferably in the 2'position or 2'.3'-position.
Another aspect of the present invention is the novel compounds of Formula (Ic), a subset of compounds of Formula (I) useful for treating a chemokine mediated disease. This invention also relates to the pharmaceutical compositions comprising a compound of Formula (Ic) and a pharmaceuucally acceptable diluent or carrier. The compounds of Formula (Ic ) are represented by the strucuture:
Figure imgf000024_0001
wherein
X is oxygen or sulfur;
X1 is oxygen or sulfur;
R1 is independently selected from hydrogen; halogen; nitro; cyano; halosubstituted C1 - 10 alkyl; C1 - 10 alkyl; C2-10 alkenyl; C1 - 10 alkoxy; halosubstituted C1 - 10 alkoxy; azide; S(O)tR4; hydroxy; hydroxyC1-4alkyl; aryl; aryl C1-4 alkyl; aryloxy; aryl C1-4 alkyloxy; heteroaryl; heteroarylalkyl; heterocyclic. heterocyclicC1-4alkyl; heteroarylC1-4 alkyloxy; aryl C2-10 alkenyl; heteroaryl C2-10 alkenyl; heterocyclic C2-10 alkenyl; NR4R5; C2-10 alkenyl C(O)NR4R5; C(O)NR4R5; C(O)NR4R10; S(O)3H; S(O)3R8; C1 - 10 alkyl C(O)R11; C2-10 alkenyl C(O)R11 ; C2-10 alkenyl C(O)OR11 ; C(O)R11; C(O)OR12 OC(O) R11; NR4C(O)R11; or two R1 moieties together may form O-(CH2)sO- or a 5 to6 membered unsaturated ring:
t is 0. or an integer having a value of 1 or 2;
s is an integer having a value of 1 to 3;
R4 and R5 are independently hydrogen, optionally substituted C1-4 alkyl. optionally
substituted aryl, optionally substituted aryl C1-4alkyl. optionally substituted heteroaryl. opuonally substituted heteroaryl C1-4 alkyl, heterocyclic. heterocyclic C1-4 alkyl, or R4 and R5 together with the nitrogen to which they are attached form a 5 to 7 member ring which may optionally comprise an additional heteioatom selected from O/N/S;
Y is independently selected from halogen; nitro; cyano; halosubstituted C1 - 10 alkyl; C1 - 10 alkyl; C2-10 alkenyl; C1 - 10 alkoxy; halosubstituted C1 - 10 alkoxy; azide; S(O)tR4;
hydroxy; hydroxy C1-4alkyl; aryl; aryl C1-4 alkyl; aryloxy; arylC1-4 alkyloxy; heteroaryl; heteroarylalkyl; heteroarylC1-4 alkyloxy; heterocyclic, heterocyclic C 1-4alkyl; aryl C2-10 alkenyl; heteroaryl C2-10 alkenyl; heterocyclic C2-10 alkenyl; NR4R5; C2-10 alkenyl C(O)NR4R5; C(O)NR4R5; C(O)NR4R10; S(O)3H; S(O)3R8: C1-10 alkyl C(O)R11; C2-10 alkenyl C(O)R 11; C2-10 alkenyl C(O)OR 11 : C(O)R 11 : C(O)OR 12: OC(O) R 11 : NR4C(O)R 11 ; or two Y moieties together may form O-(CH2)sO- or a 5 to 6 membered unsaturated ring;
n is an integer having a value of 1 to 3;
m is an integer having a value of 1 to 3;
R8 is hydrogen or C 1-4 alkyl;
R10 is C1-10 alkyl C(O)2R8;
R11 is hydrogen. C 1-4 alkyl, optionally substituted aryl, optionally substituted aryl C 1-4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylC 1-4alkyl, opuonally substituted heterocyclic, or optionally substituted heterocyclicC 1-4alkyl;
R12 is hydrogen. C1-10 alkyl, optionally substituted aryl or optionally substituted arylalkyl; provided that
when n =1 than Y is substituted in the 2- or 3- position;
when n =2 than Y is di-substituted in the 2'- 3'- position, the 2'-5'- position, the 2'-6' position, the 3'-5' or the 3'-6' position;
when b = 3 than Y is trisubstituted in the 2'-3'-5' or the 2'-3'-6- positions;
further provided that
when X1 is O, m=2, R1 is 2-t-buty1.4-methyl, and n=3 than Y is not 2-OH.3'-t- butyl.5-methyl;
when X1 is O, m=1, R1 is 4-methyl, and n=2 than Y is not 2'-OH.5 '-methyl;
when X1 is O, m=1, R1 is hydrogen, and n=2 than Y is not 2'-6'-diethyl;
when X1 is O, m=1, R1 is 6-OH, and n=2 than Y is not 2'-5'-methyl;
when X1 is S, m=1, R1 is 4-ethyl, and n=1 than Y is not 2-methoxy;
or a pharmaceutically acceptably salt thereof.
Suitably, the variables, etc. for Formula (Ic) are the same as those defined for Formula (I) above unless indicated.
Suitably for compounds of Formula (Ic), a preferred ring substitution for R1 is in the 3-position, the 4- position or di substituted in the 3.4- position. Preferably R1 is other than hydrogen. The substituent group is suitably an electron withdrawing moiety. Preferably R1 is nitro, halogen, cyano. trifluoromethyl group, or C(O)NR4R5.
While Y may be substituted in any of the 5 ring positions, preferably the ring with the Y moiety is mono-substituted in the 2-position or 3- position, with the 4- preferably being unsubstituted. If the ring is disubstituted, substituents are preferably in the 2' or 3' position of a monocyclic ring. While both R 1 and Y can both be hydrogen, it is prefered that at least one of the rings be substituted, preferably both rings are at least mono-substituted, i.e. n amd m are each equal to 1 or more.
Suitably for compounds of Formula (Ic), Y is more preferably a mono-substituted halogen, disubstituted halogen, mono-substituted alkoxy, di substituted alkoxy,
methylenedioxy, aryl, or alkyl, preferably with these groups in the 2'position or 2,3-position Exemplified compounds of Formula (Ic) are;
N-[2-Hydroxy-4-(methoxycarbonyl)phenyI ]-N'-phenyl urea;
N-[2-Hydroxy-5-nitro-phenyl]-N'-phenyl urea
N-[2-Hydroxy-4-tluorophenyl)-N'-phenyl urea
N-[2-Hydroxy-4-(trifluoromethyl)phenyl]-N'-phenyl urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(2-hydroxy-4-nitrophenyl) urea
N-(2-Hydroxy-4-nitrophenyI)-N'-phenyl-thiourea
N-(2-Hydroxy-5-nitrophenyl)-N'-(3-methoxy-2-thienyl)urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(3-methoxy-2-thienyl)urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(3-methoxyphenyl)urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(2-methoxyphenyl)urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(3-trifluoromethylphenyl)urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(2-trifluoromethylphenyl)urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(4-trifluoromethylphenyl)urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(2-bromophenyl) urea
N-(2-Hydroxy-4-n itrophenyl)-N'-(3-bromophenyl)urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(4-bromophenyl)urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(2-phenylphenyl)urea
N-(2-Hydroxy-4-n itrophenyl)-N'-(2-nitrophenyl)urea
N-(2-Hydroxy -4-nitrophenyl)-N'-(2-fluorophenyl)urea
N-(2-Hydroxv-4-nitrophenyT)-N'-(2.6-difluorophenyl )urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(2-cihoxyphenyl )urea
N-(2-Hydroxy -4-nitrophenyl)-N'-(2-ethylphenyl )urea
N-(2-Hydroxy -4-nitrophenyl)-N'-(2-trifluoromethoxyphenyl)urea
N-(2-Hydroxy -4-nitrophenyl) N'-(2-methylihiophenyl ) urea
N-(2-Hydroxy-4-n itro-phenyl) N'-(2-chloro 6-methyl phenyl) urea
N-(2-Hydroxy -4-nitro-phenyl) N'-(2-sulloxymethyl phenyl) urea
N-(2-Hydroxy -4-trifluoromethyl phenyl)-N'-(2-bromo phenyl) urea
N-(2-Hydroxy-4-trifluoromethyl phenyl)-N'-(2-phenyl phenyl) urea
N-(2-Hydroxy-4-carbomethoxy phenyl)-N'-( 2-phenyl phenyl) urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(2.3-diehloro phenyl) urea N-(2-Hydroxy-4-nitrophenyl)-N'-(2,4-dichloro phenyl) urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(2-chloro phenyl) urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(2,4-dibromo phenyl) urea
N-(2-Hydroxy- 1-napthyl)-N'-(2-bromo phenyl) urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(2,3-methylenedioxyphenyl)urea
N-(2-Hydroxy-4-nitrophenyl) N'-(3-chloro 2-methoxy phenyl) urea
N-[2-Hydroxy-4-(Benzylamino)carbonyl phenyl]-N'-(2-bromophenyl)urea
N-(2-Hydroxy-4-nitro phenyl)-N'-(2-phenoxy phenyl) urea
N-(2-Hydroxy-4-fluoro phenyl)-N'-(2-bromo phenyl) urea
N-(2-Hydroxy-3,4-difluoro phenyl)-N'-(2-bromo phenyl) urea
N-(2-Hydroxy 4-phenyl phenyl) N'-(2-bromo phenyl) urea
N-(2-Hydroxy 4-methyl phenyl)-N'-(2-bromo phenyl) urea
N-(2-Hydroxy-4-nitro phenyl)-N'-(2-phenylamino phenyl) urea
N-(2-Hydroxy 3-carboxyphenyl)-N'-(2-bromo phenyl) urea
N-(2-Sulfhydry1-4-bromo phenyl)-N'-(2-bromo phenyl) urea
N-(2-Hydroxy 4-nitro phenyl)-N'-(2-iodo phenyl) urea
N-(2-Hydroxy 4-nitro phenyl)-N'-(2-bromo phenyl) thiourea
N-(2-Hydroxy-4-azidophenyl)-N'-(2-methoxyphenyl)urea
N-[2-Hydroxy-5-cyanophenyl]-N'-[ 2-bromophenyl] urea
N-[2-Hydroxy-3-fluorophenyl]-N'-[2-bromophenyI] urea
N-[2-Hydroxy-3-fluoro-5-bromophenyl]-N'-[2-bromophenyl] urea
N-[2-Hydroxy-3-chlorophenyl]-N'-[2-bromophenyl] urea
N-[2-Hydroxy-3-trifluoromethylphenyl]-N'-[2-bromophenyl] urea
N-[2-hydroxy-3,4-diphenyl phenyl]-N'-[2-bromophenyl] urea
N-[2-Hydroxy-3-glycinemethylestercarbonylphenyl]-N'-[2-bromophenyl] urea
N-[2-Hydroxy-3-glycincarbonylphenyl]-N'-[2-bromophenyl] urea
N-[2-Hydroxy-3,5-dichlorophenyl]-N'-|2-bromophenyl] urea
N-[2-Hydroxy-3-nitrophenyl]-N'-(2-bromophenyl] urea
N-[2-Hydroxy-3,4-dichlorophenyl]-N'-[2-bromophenyl] urea
N-[2-Hydroxy-3-cyanophenyl]-N'-(2-bromophenyl] urea
N-[2-Hydroxy-4-cyanophenyl]-N'-f2-bromophenyl] urea
N-[2-Hydroxy-4-cyanophenyl]-N'-(4-methoxyphenyl] urea
N-[2-Hydroxy-4-cyanophenyl]-N'-[2-phenylphenyl] urea
N-[2-Hydroxy-4-cyanophenyl]-N'-[2-methylphenyl] urea
N-[2-Hydroxy-4-cyanophenyl]-N'-[2-trifluoromethylphenyl] urea
N-[2-Hydroxy-4-cyanophenyl]-N'-[3-trifluoromethylphenyl] urea
N-[2-Hydroxy-4-cyanophenyl]-N'-(4-trifluoromethylphenyl] urea
N-[2-Hydroxy-3-n-propylphenyl]-N'-[2-bromophenyl] urea N-[2-Hydroxy-4-ethylphenyl]-N'-[2-bromophenyl] urea
N-[2-Hydroxy-3-phenylaminocarbonyl phenyl]-N'-|2-bromophenyl] urea
N-[2-Hydroxy-3-cyano-4-methylphenyl]-N'-[2-bromophenyl ] urea
N-[2-Hydroxy-4-carbophenyl phenyl]-N'-(2-bromophenyl] urea
N-[2-Hydroxy-3-carbophenyl phenyl]-N'-[2-bromophenyl] urea
N-[2-Hydroxy-3-benzyloxy phenyl]-N'-[2-bromophenyl] urea
(E)-N-[4-[2-(Methoxycarbonyl) ethenyl]-2-hydroxyphenyl|-N'-[2-bromophenyl ] urea (E)-N-[3-[2-(Methoxycarbonyl)ethenyI]-2-hydroxyphenyl]-N'-[2-bromophenyl ]urea-N -bromophenyl] urea
(E)-N-[3-[2-(Aminocarbonyl)ethenyl]-2-hydroxyphenyl]-N'-[2-brυmophenyl ]urea-N -[ 2- bromophenyl] urea
(E)-N-[4-[2-(Aminocarbonyl)ethenyl]-2-hydroxyphenyl]-N'-[2-bromophenyl]urea-N -[2- bromophenyl] urea
N-[2-Hydroxy-4-benzamide phenyl]-N'-[2-bromophenyl] urea
N-[2-Hydroxy-4-aminocarbonyl phenyl]-N'-[2-bromophenyl] urea
N-(2-Hydroxy-3,5,6-trifluorophenyl)-N'-(2-bromophenyl)urea
N-(2-Hydroxy-3-fluoro-4-trifluoromethylphenyl)-N'-(2-bromophenyl)urea
N-(2-Hydroxy-3-iodophenyl)-N'-(2-bromophenyl)urea
N-[2-Hydroxy-4-cyanophenyl]-N'-[4-phenylphenyl] urea
N-[2-Hydroxy-4-cyanophenyl]-N'-[2,3-dichlorophenyl] urea
N-[2-Hydroxy-4-cyanophenyl]-N'-[2-methoxyphenyl] urea
N-[2-Hydroxy-4-cyanophenyl]-N'-[3-methoxyphenyl] urea
N-[2-Hydroxy-5-fluorophenyl]-N'-[2-bromophenyl] urea
N-[2-Hydroxy-5-trifluoromethylphenyl]-N'-[2-bromophenyl] urea
N-[2-Hydroxyphenyl]-N'-[2-bromophenyl] urea
N-[Trans-3-styrl-2-hydroxyphenyl]-N'-[2-bromophenyl] urea
N-[2-Hydroxy-3.4-dichlorophenyl]-N'-(2-methoxyphenyl ] urea
N-[2-Hydroxy-3.4-dichlorophenyl]-N'-|4-methoxyphenyl ] urea
N-[2-Hydroxy-3.4-dichlorophenyl]-N'-[3-trifluoromethylphenyl] urea
N-[2-Hydroxy-3.4-dichlorophenyl]-N'-|2-phenylphenyl] urea
N-[2-Hydroxy-3.4-dichlorophenyl]-N'-[4-phenylphenyl] urea
N-[2-Hydroxy-3.4-dichlorophenyl]-N'-[2.3-dichlorophenyl ] urea
N-[2-Hydroxy-4-isopropylphenyl]-N'-[3-irifluoromethylphenyl] urea
N-[2-Hydroxy-3-naphthyl]-N'-[2.3-dichlυrophenyl] urea
N-(2-Hydroxy-4-azidophenyl)-N'-(2-iodophenyl)urea
N-(2-Hydroxy-3-azidophenyl)-N'-(2-bromophenyl)urea
N-[2-Hydroxy-3-cyanophenyl]-N'-[2-methoxyphenyl] urea
N-[2-Hvdroxy-3-cyanophenyl]-N'-[3-trifluoromethylphenyl] urea N-[2-Hydroxy-3-cyanophenyl]-N'-[2-phenylphenyl] urea
N-[2-Hydroxy-3-cyanophenyl]-N'-[2.3-dichlorophenyl] urea
N-[2-Hydroxy-4-isopropylphenyl]-N'-[2,3-dichlorophenyl] urea
N-[2-Hydroxy-4-isopropylphenyl]-N'-(2-chloro-5-trifluoromethylphenyl ] urea
N-[2-Hydroxy-3-phenylphenyl ]-N'-[2,3-dichlorophenyl ] urea
N-[2-Hydroxy-5-nitrophenyl]-N'-[2-methoxyphenyl] urea
N-[2-Hydroxy-5-nitrophenyl]-N'-(3-trifluoromethylphenyl] urea
N-[2-Hydroxy-5-nitrophenyl]-N'-[2-phenylphenyl] urea
N-[2-Hydroxy-5-nitrophenyl]-N'-[2,3-dichlorophenyl] urea
N-[2-Hydroxy-5-ethylsulfonylphenyl]-N'-[2,3-dichlorophenyl] urea
N-[2-Hydroxy-3,4-dichlorophenyl ]-N'-[2,4 dimethoxyphenyl] urea
N-[2-Hydroxy-3,4-dichlorophenyl]-N'-[2-chloro-5-trifluoromeihylphenyl ] urea
N-[2-Hydroxy-3,4-dichlorophenyI]-N'-[benzyl] urea
N-[2-Hydroxy-4-isopropylphenyl]-N'-[3-trifluoromethylphenyl] urea
N-[2-Hydroxy-3-naphthyl]-N'-[3-trifluoromethylphenyl ] urea
N-[2-Hydroxy-3-naphthyl]-N'-[2,3-dichlorophenyl] urea
N-[2-Hydroxy-3-naphthyl]-N'-[benzyl] urea
N-[2-hydroxy-3-(phenylaminocarbonyl) phenyl]-N'-[benzoyI] urea
N-[2-Hydroxy-3-trifluoromethylphenyl]-N'-[benzoyl] urea
N-[2-Hydroxy-4-cyanophenyl]-N'-[benzoyl] urea
N-[ 2-Hydroxy-5-naphthalenesulfonic acid]-N'-[2-bromophenyl] urea;
N-[2-Hydroxy-4-naphthalcnesullonic acid]-N'-[2-bromophenyl ] urea;
N-(2-Hydroxy 3-napihyl) N'-(2-bromo phenyl) urea;
N-(2-Hydroxy- 1 -napthyl)-N'-(2-bromo phenyl) urea;
N-(2-Hydroxy-4-nitrophenyl)-N'-( 1 -naphthyl)urea;
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, methane sulphonic acid, ethane sulphonic acid, acetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinie acid, lumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid and mandelic acid, In addition, pharmaceuucally acceptable salts of compounds of Formula (I) may also be formed with a pharmaceutically acceptable cation, for instance, if a substituent group comprises a carboxy moiety. Suitable pharmaceutically acceptable cations are well known to those skilled in the art and include alkaline, alkaline earth, ammonium and quaternary ammonium cations.
The following terms, as used herein, refer to.
• "halo" - all halogens, that is chloro, fluoro. bromo and iodo. • "C 1 - 10alkyl" or "alkyl" - both straight and branched chain radicals of 1 to 10 carbon atoms, unless the chain length is otherwise limited, including, but not limited to. methyl, ethyl, n-propyl, i.s o-propyl, n-butyl, sec -butyl, iso-butyl. tert-butyl. n-pentyl and the like
• The term "cycloalkyl" is used herein to mean cyclic radicals, preferably of 3 to 8 carbons, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl, and the like
• The term "alkenyl" is used herein at all occurrences to mean straight or branched chain radical of 2- 10 carbon atoms, unless the chain length is limited thereto, including, but not limited to ethenyl, 1 -propenyl. 2-propenyl, 2-methyl- 1 -propenyl, 1 -butenyl, 2-butenyl and the like.
• "aryl" - phenyl and naphthyl;
• "heteroaryl" (on its own or in any combination, such as "heteroaryloxy", or
"heteroaryl alkyl") - a 5- 10 membered aromatic ring system in which one or more rings contain one or more heteroatoms selected from the group consisting of N. O or S. such as, but not limited, to pyrrole, pyrazole, furan, thiophene, quinoline. lsoquinolinc, quinazolinyl, pyridine, pyrimidine, oxazole, thiazole, thiadiazole, triazole, imidazole, or benzimidazole.
• "heterocyclic" (on its own or in any combination, such as "heterocyclicalkyl") - a saturated or partially unsaturated 4- 10 membered ring system in which one or more rings contain one or more heteroatoms selected from the group consisting of N. O, or S; suc0 000 but not limited to, pyrrohdine, piperidine, piperazme, morpholine, tetrahydropyran, or
lmidazolidine.
• The term "arylalkyl" or "heteroarylalkyl" or "heterocyclicalkyl" is used herein to mean C 1 - 10 alkyl. as defined above, attached to an aryl, heteroaryl or heterocyclic moiety, as also defined herein, unless otherwise indicated .
• "sulfinyl" - the oxide S (O) of the corresponding sulfide, the term "thio' refers to the sulf ide. and the term "sulfonyl" refers to the fully oxidized S(O)2 moiety .
• The term "wherein two R 1 moieties (or two Y moieties) may together form a 5 or 6 membered unsaturated ring" is used herein to mean the formation of a napthylene ring system or a phenyl moiety having attached a 6 membered partially unsaturated ring such as a C6 cycloalkenyl. i.e hexene. or a C5 cyloalkenyl moiety, cyclopentene.
The compounds of Formula (I), (la), (lb), ( Ic), ( II) and (III) may be obtained by applying synthetic procedures, some of which are illustrated in the Schemes below . The synthesis provided for in these Schemes is applicable f or the producing compounds of Formula (I), ( Ia), (II ) and (III) having a variety of dif ferent R, R 1, and Ar groups which are reacted, employing optional subsutuents which are suitably protected, to achieve compatibility with the reactions outlined herein. Subsequent deprotection, in those cases, then affords compounds of the nature generally disclosed. Once the urea nucleus has been established, further compounds of these formulas may be prepared by applying standard techniques for functional group interconversion. well known in the art. While the schemes are shown with compounds only of Formula (I) this is merely for illustration purposes only.
Figure imgf000031_0001
Ortho substituted phenyl ureas shown in 2-scheme 1 may be prepared by standard conditions involving the condensation of commercially available ortho substituted
aniline(Aldrich Chemical Co., Milwaukee, Wi) with the commercially available optionally substituted aryl isocyanate (Aldrich Chemical Co., Milwaukee, Wi) in an aprotic solvent (DMF, toluene). When the 1-(RSO2NH)2-(NH2)Ph is not commercially available it can be made by treating the commercially available RSO2CI with the cooresponding 2-phenylene diamine in the presence of an base like methyl amine or NaH in an aprotic solvent (like methylene chloride or DMF).
Figure imgf000031_0002
If the desired 2-substit uted aniline 5-scheme 2. is not commercially available the corresponding nitro compound can be prepared from 3-scheme 2. under standard nitration conditions (using HNO3 or BF4NO3) at 23 °C. The nitro compound is then reduced to the corresponding aniline using SnCl2 in EtOH(or alternately H2/Pd or LiAlH4). £
Figure imgf000032_0001
If the desired 2-amino benzenethiol 8-scheme 3 is not commercially available it can be synthesized by reaction of the phenyl aniline with the thiocyanate anion in the presence ot an oxidant(like bromine) to produce the 2-am ino benzthiazole 7-scheme 3. This thiazole can then be hydrolyzed to the desired 2-amino benzenethiol 8 -scheme 3 with a strong base like NaOH in a protic solvent (i.e . EtOH).
UC X
Figure imgf000032_0002
In the case where the thioisoeyanate or phenyl isocyanate is not commercially available. the thiourea or urea 1 1 -scheme 4 may be prepared from the commercially available ortho substituted aniline. This compound is first protected with a protecting group (tert-butyl dimethyl silyl or benzyl ) by conditions well known in the art (see Greene. T Protecting Groups in Organic Synthesis, Wiley&Sons, New York, 1981 ). This protected aniline is then reacted, in the presence ot a base(like methyl amine or sodium bicarbonate), with either thiophosgene or a solution of phosgene in an aprotic solvent (ie. DMF, toluene), followed by aniline to produce the protected thiourea or urea respectively. The corresponding urea or thiourea is then deprotected. using conditions standard in the art. to form the desired thiourea or urea 1 1 -scheme 4.
Figure imgf000033_0001
2
Alternately the urea can be formed using a Curtius rearrangement from the
corresponding aromatic or thiophene carboxylic acid 12-scheme 5. The carboxylic acid is submitted to standard Curtius conditions ((PhO)2PON3, Et3N or CICOCOCI followed by NaN3) and the intermediate isocyanate is trapped by an appropriately substituted aniline.
Pharmaceutically acceptable salts of compounds of Formula (I) may be obtained in known manner, for example by treatment thereof with an appropriate amount of acid or base in the presence of a suitable solvent.
Another aspect of the present invention is the novel synthesis of cyano nitrophenol intermediates. Numerous conversions of aryl halides to aryl cyano derivatives with copper (I) cyanide have been published. However, no examples of an aryl ring with a hydroxy group present were mentioned. Several attempts to obtain a cyano phenol moiety with published results failed. Using known conditions of elevated temperatures, greater than 170ºC. such as from 180 to 210 did not yield displacment of the halogen to a cyano moiety. Standard bases such as DMF and pyridine further provided no desired product. Intermediates such as 2- amino-5- fuorophenol, 2-nitro-5-fluorophenol, 2-nitro-5-methyl-6-bromophenol were tried with a change of halogens, from fluorine to chlorine to bromine, and with use of copper ( I ) cyanide. The use of a bromine derivative, such as 2-nitro-5-methyl-6-bromophenol . with dimethyllormamide and using triethylamine with a catalytic amount of dimethylamino pyridine and copper (I) cyanide at reduced temperatures, i.e. <100°C, preferably 60 to about 80º C for reduced times from strandarized procedures, i.e., < 18 hours, preferably about 4 to 6 hour s yielded the desired products.
Therefore one aspect of the invention is to a process for producing a cyano phenol derivative of the formula:
Figure imgf000034_0002
wherein R 1 is as defined for Formula (I) above, which method comprises reacting a compound of the formula:
Figure imgf000034_0001
' wherein X is halogen with copper (I) cyanide, dimethylformamide, triethylamine and a catalytic amount of dimethylamino pyridine. Preferably, the process is run at reduced temperatures of about 60 to about 80°C. Preferably X is bromine.
In the Examples, all temperatures are in degrees Centigrade (°C). Mass spectra were performed upon a VG Zab mass spectrometer using fast atom bombardment, unless otherwise indicated. 1 H-NMR (hereinafter "NMR") spectra were recorded at 250 MHz or 400MHz using a Bruker AM 250 or Am 400 spectrometer, respectively. Multiplicities indicated are; s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet and br indicates a broad signal. Sat, indicates a saturated solution, equiv. indicates the proportion of a molar equivalent of reagent relative to the principal reactant.
Flash chromatography is run over Merck Silica gel 60 (230 - 400 mesh).
SYNTHETIC EXAMPLES
The invention will now be described by reference to the following examples which are merely illustrative and are not to be construed as a limitation of the scope of the present invention. All temperatures are given in degrees centigrade, all solvents used herein are of the highest available purity and all reactions are run under anhydrous conditions in an argon atmosphere unless otherwise indicated.
General Method A: Synthesis of N, N'- phenyl urea To a solution of substituted phenyl isocyanate (1.0 equiv.) in toluene (5 miliLiters (hereinafter "mL")) the corresponding aniline ( 1.0 equiv.) was added. The reaction mixture was stirred at about 80°C until complete (24-48 hours (hereinafter "hrs" or "h")). then cooled to room temperature. The purifications, yields and spectral characteristics for each individual compound are listed below .
General Method B: Synthesis of N, N'- phenyl urea To a solution ot phenyl isocyanate ( 1.0 equiv.) in dimethyl formamide ( 1mL) the corresponding aniline ( 1 .0 equiv. ) was added. The reaction mixture was stirred at about 80°C until complete (24-48 hours), then the solvent was removed under vacuum. The purifications, yields and spectral characteristics for each individual compound are listed below.
General Method C:Synthesis of sulfonamide The ortho substituted aniline ( 1 equiv. ), triethyl amine ( 1 equiv.) and the desired sulfonyl chloride ( 1 equiv. ) were combined in methylene chloride and allowed to stir at about 23 °C until complete ( 12-36 h). The reaction mixture was partitioned between water and methylene chloride. The organic layer was separated and dried over magnesium sulfate, filtered and concentrated in vacuo. The purifications of each compound are listed below.
Example 1
Preparation of N-[2-Hydroxy-4-(methoxycarbonyl)phenyl]-N'-phenyl urea
N-[2-Hydroxy-4-(methoxycarbonyl)phenyl]-N'-phenyl urea was prepared from methyl-4-amino-3-hydroxybenzoate (200 mg, 1.19 mmol) and phenyl isocyanate ( 1.19 mmol ) according to the procedure noted above in General Method A. The product was pur ified by precipitation from toluene, and filtering, to afford the titled compound (309 mg, 90%). mp:
188.4- 188.8°C: 1 H NMR (CD3OD/CDCI3): 8 8.15 (d, 1H. J = 8.25 Hz), 7.70 (s, 1H), 7.51
(d, 1H, J = 8.25 Hz), 7.43 (d, 2H, J = 8.25 Hz), 7.30 (t, 2H, J = 8.25 Hz), 7.01 (t, 1 H, J =
8.25 Hz), 3.87 (s, 3H); EI-MS m/z 286 (M+H)+; Anal. (C15H 14N2O4) C, H, N.
Example 2
Preparation of N-[5-nitro-2-hydroxyphenyl]-N'-phenyl urea
The N-[5-nitro-2-hydroxyphenyl]-N'-phenyl urea was prepared f rom the 5- nitro 2. hydroxy aniline and phenyl isocyanaie according to the procedure in General Method A. The product was purified by precipitation from toluene and filtering to af ford the titled compound
( 100 mg, 30% ). 1 H NMR (CD3OD); 8 9.48 (s, 1 H, NH), 9.07 (d, J = 1.56 Hz, NH ), 8.55
(s, 1 H), 7.80 (dd, 1 H, J = 6.25 Hz and J = 1 .56 Hz), 7.50 (d, 2H, J = 6.25 Hz), 7.30 (t, 2H.
J = 6.25 Hz), 7.01 (m. 2H) EI-MS m/z 273 (M+H)+. Example 3
Preparation of 3-hydroxy-4-{[(phenylamino)carbonyl]amino}benzamide
a)Preparation of 0.67 Molar (hereinafter "M") Stock Solutions of Aluminum Amide Reagents
To a suspension ot the appropriate hydrochloride (0.02 mole ( hereinafter "mol" )) in dr y toluene (20 mL) at about 0°C, was slowly added a solution of (2M, 10 mL) ot trimethyl aluminum in toluene. After the addition was complete, me reaction mixture was allowed to warm to room temperature and was stirred for about 1 -2 hours until gas ev olution has ceased b)Preparation of 3-hydroxy-4-{[(phenylamino)carbonyl]amino }benzam ide To a solution of the N-[2-hydroxy-4-(methoxycarbonyl)phenyl ]-N'-phenyl urea (60 miligram (hereinafter "mg"), 0.2 mmol) in toluene (2 mL) was added aluminum amide reagent (0.9 mL, 0.67M). The reaction mixture was stirred at reflux for about 12 hours. The reaction mixture was cooled to room temperature and was carefully quenched with 5% HCl. The organic layer was separated and the aqueous layer was extracted three times with ethyl acetate. The organic extracts were combined, dried over MgSO4, filtered and concentrated under reduced pressure. Chromatography of the resulting solid on silica gel (ethyl acetate) gave the desired amide (28 mg, 49%). mp: 106.8- 107.1 °C; 1H NMR (CD3OD/CDCI3): δ 7.98 (d, 1 H, J = 8.25 Hz), 7.35 (d, 2H, J = 8.25 Hz), 7.30 (d, 2H, J = 8.25 Hz), 7.17 (1, 2H, J = 8.25 Hz), 6.91 (t, 1 H, J = 8.25 Hz); EI-MS m/z 271 (M+H)+; Anal. (C 1 4H 1 3N3O3) C, H, N.
Example 4
Preparation of N-(2-hydroxy-4-fluorophenyl)-N'-phenyl urea
a)Preparation of 2-amino-5-fluoro phenol
A mixture of 5-fluoro-2-nitrophenol (500 mg, 3. 18 mmol) and tin (II) chloride ( 1.76 g, 9.2 mmol) in ethanol ( 10 mL) was heated at 80°C under argon. After 30 min. the starting material had disappeared and the solution was allowed to cool down and then poured into ice.
The pH was made slightly basic (pH 7-8), by addition of 5% aqueous sodium bicarbonate, before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and filtered. Evaporation of the solvent gave the title compound(335 mg, 83%). Η
NMR (CD3OD/CDC l3): 8 6.6 (m, 1 H), 6.38 (dd. I H, J = 8.3 Hz and J = 2.8 Hz). 6.29 (m.
1 H).
b)Preparation of N-(2-hydroxy-4-fluorophenyl)-N'-phenyl urea
N-(2-Hydroxy-4-fiuorophenyl )-N'-phenyl urea was prepared f rom 2-amino-5-fluoro phenol (200 mg, 1.57 mmol ) and phenyl isocyanaie according to the procedure in General
Method A. The product was purified by precipiiation f rom toluene and filtering to allord the titled compound (352 mg. 91 % ) mp: 195.5- 195.7°C; 1 H NMR (CD3OD/CDCl3); δ 7 70 ( m,
1 H), 7.3 (d. 2H. J = 8.25 Hz). 7. 15 ( t, 2H, J = 8.25 Hz). 6.89 (t, 1 H, J = 8.25 Hz). 6 50 -
6.38 (m. 2H): EI-MS m/z 246 (M+H)+. Anal (C 13H1 1 N2O2 F) C. H. N
Example 5
Preparation of 2- { 1(phenylamino )carbonyl ]amino }thiophenol
2-{ [(Phenylamino)carbony l]amino }thiophenol was prepared f rom 2-aminoihiophenol
(200 mg. 1 .6 mmol ) and phenyl isocyanaie according to the piocedure in General Method A . The product was purified by precipitation from toluene and filtering lo allord the titled compound (330 mg. 85 %). mp; 194.5°C; 1H NMR (CD3OD/CDCl3): δ 7 48 - 7.26 (m. 4H).
7.25 - 7 10 (m. 3H), 7.04 - 6.79 (m, 2H); EI-MS m/z 244 (M+H )+; Anal . (C 1 3H 1 2N2OS) C.
H. N . Example 6
Preparation of N-(2-Carboxy-4-hydroxyphenyl)-N"-phenyl urea
N-(2-Carboxy-4-hydroxyphenyl)-N'-phenyl urea was prepared from 2-amino-5-hydroxy benzoic acid ( 1 g, 6.53 mmol) according to the procedure in General Method B. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over MgSO4 and filtered. Removal of solvent under reduced pressure and chromatography of the resulting solid on silica gel (hexane : ethyl acetaie, 1 : 1 to 100% ethyl acetate) gave the titled compound ( 1.5 g. 84% ). 1H NMR (CD3OD/CDCI3): δ 8.36 (d, 1 H, J = 8.25 Hz), 7.63 (m. 4H), 7.48 (t, 2H, J = 8.25 Hz), 7.20 (m, 1 H); EI-MS m/z 272 (M+H)+; Anal. (C14H12N2O4) C, H, N.
Example 7
Preparation of N - [2 - hydroxy - 4- (trifluoromethyl) phenyl] - N' - phenyl urea
a)Preparation of 2-nitro-5-trifluoromethylphenol
2-Nitro-5-trifluoromethylphenol was prepared by adding concentrated HNO3 (6 mL) drop-wise to α,α,α-trifluoro-m-cresol (5g, 30.8 mmol) at room temperature. After the addition was complete the reaction was quenched with saturated ammonium acetate and extracted with EtOAc. The organic was separated, dried over sodium sulfate and filtered. Concentration of the solution in vacuo afforded an oil which was purified by column chromatography (gradient 100% hexane to 50% EtOAc/hexanes) to allord the tilled compound as an oil( 1.7 g, 27 % ), 1 H NMR (CDCl3): 10.6 (s. 1 H, OH), 8.26(d, 1 H. J = 7.8 Hz). 7.45(s, 1 H, arom ), 7.26(d. 1 H, J= 7.8 Hz)
b)Prcparation of 2-amino-5-trifluoromeihylphenol
2-4Amino-5-trifluoromeihylphenol was prepared by treating 2-nitro-5-trifluoromethylphenol (500 mg. 2.41 mmol ) with a solution of SnCl 2(3.5g. mmol ) in EtOH at 23 °C for 12h. The mixture was concentrated to 50 mL and adjusted 10 pH 7 using saturated sodium bicarbonate. The reaction mixture was partitioned between H2O and EtOAc. The aqueous layer was separated and extracted with EtOAc The combined organie extracts were dried over sodium sulfate. filtered and concentrated in vacuo. The resulting colorless oil(370 mg. 87% ) was used without f urther purification. 1 H NMR (CDCl3): 7.6 ( s, 1 H), 7.39(d, 1 H, J = 8.5 Hz), 7.08(d, 1 H, J= 8.5 Hz)
c)Preparation of N - [2 - hydroxy - 4- (trif luoromethyl ) phenyl] - N" - phenyl urea
N - [2 - Hydroxy - 4- (trilluoromethyl) phenyl ] - N" - phenyl urea was prepared from 2-amino-5-trifluoromethylphenol ( 150 mg, 1.09 mmol ) and phenyl isocyanate( 1.09 mmol) according to the procedure in General method A. The product was purified by precipitation from methylene chloride and filtering to allord the titled compound ( 230 mg. 87% ) mp: °C: 1 H NMR (DMSO-d6): δ 9.45 (s, 1 H, NH). 8.50 (s, 1 H, NH), 8.31 (d, 1 H, J = 10.0 Hz). 7.45 (d, 2H, J = 10.0 Hz), 7.29 (t, 2H, J = 6.67 Hz), 7 .10 (m, 2H), 6.99 (t, 1 H, J = 6.67 Hz) EI-MS m/z 296 (M+), Anal. (C14H1 1N2O2F3 )C, H, N.
Example 8
Preparation of N-(2-hydroxy-4-nitrophenyl)-N'-(2-hydroxy-4-nitrophenyl) urea a)Preparation of 2-(tert-butyldimethylsilyloxy)-4-ni troaniline
To a solution of 2-amino-5-mtrophenol ( 1 g, 6.49 mmol) and imidazole (0.88 g, 12.3 mmol) in DMF ( 15 mL), tert -butyldimethylsilyl chloride ( 1 1.2 mL, 64.9 mmol) was added. The resulting mixture was allowed to stir at 23°C for 48 hours. The reaction mixture was partiuoned between 0.1 % HCl and ethyl acetate. The combined organic phase was washed with brine, dried over MgSO4 and filtered Removal of solvent at reduced pressure and chromatography of the resulting oil on silica gel (hexane : ethyl acetate: 5: 1 ) gave the titled compound ( 1.7 g, 98 % ), 1H NMR (CDCl3): δ 7.78 (dd, 1H, J = 6.7 Hz and J = 2.7 Hz), 7 61 (d, 1 H, J = 2.7 Hz), 6.7 (d, 1 H, J = 8.8 Hz), 1.0 (s, 9H), 0.28 (s. 6H)
b)Preparation of N-[(2-tert-butyldimethylsilyloxy)-4-nitrophenyl]-N'-|(2-tert-butyldimethylsiloxy)-4- nitrophenyl] urea
To a solution of 2-(tert-butyldimethylsilyloxy)-4-nitroan iline(200 mg, 0.75 mmol) in toluene ( 10 mL) triethylamine (0.13 mL, 1.64 mmol) and triphosgene (88.4 mg, 0.3 mmol) were added. The reaction mixture was surred at 70°C for 2 hours, then cooled to room temperature. Then more 2-(tert -buiyldimethylsilyloxy)-4-nitroanilinc (2(X) mg, 0.75 mmol) was added. The resulting mixture was allowed to stir at 70°C for 48 hours then cooled to room lemperaiure. The reaction mixture was partitioned between water and ethyl acetate. The combined organic phase was washed with brine, dried over MgSO4 and filtered Removal of solvent at reduced pressure and chromatography of the resulting oil on silica gel (hexane : ethy l acetate. 10.1 ) gav e the tilled compounds 30 mg, 31 % ) 1 H NMR (CDCl3) δ 8.36 (d. 2H. J =
8.3 Hz), 7.90 (dd, 2H. J = 8.3 Hz and J = 2 8 Hz), 7.71 (d. 2H. J = 2 S Hz), 7.22 (s. 2H ) 1 .02 (s, 18H), 0.35 (s, 12H)
αPreparation of N-(2-Hydroxy-4-nitrophenyl)-N'-(2-hydroxy-4-nitrophenyl) urea
To a solution of N-[(2-tert-butyldimethylsilyloxy)-4-nitrophenyl]-N'-](2-tert- butyldimethylsily loxy)-4- nitrophenyl ] urea(50 mg. 0.089 mmol ) in THF (2 mL),
letrabuty lammonium fluoride ( 1 M, 0.09 mL, 0.089 mmol ) was added at 0°C. The reaction mixture w as surred at 2 3°C. After 1 hour , the starling material had disappeared. The reaction mixture w as partitioned between water and ethyl acetate. The combined otganic phase was dried over MgSO4 and filtered. Removal of solvent at reduced pressure and chromatography of the resulting oil on silica gel (hexane ethyl acetate; 1 : 1 to 100%- ethyl acetate) gave the titled compound(24 mg, 8 1 % ), 1H NMR (CD3OD/CDCl3): δ 8.32 (d, 2H, J = 8.25 Hz), 7.80 (dd, 2H, J = 8.25 Hz and J = 2.06 Hz), 7.7 (d, 2H, J = 2.06 Hz). EI-MS m/z 334 (M+H )+. Anal. (C 13H 1 0N4O7) C, H, N.
Example 9
Preparation of N-(2-hydroxy-4-nitrophenyl)-N'-phenyl-thiourea
a)Preparation of N-(2-tert-butyldimethysilyloxy-4-nitrophenyl)-N'-phenyl-thiourea
N-(2-tert-Butyldimethysilyloxy-4-nitrophenyl)-N'-phenyl-thiourea was prepared by treating a biphasic solution of 2-tert-butyldimethysilyloxy-4-nitroaniline(80 mg, 0.308 mmol) and NaHCO3 in CHCl3:H2O(2.5: 1 , 7mL) with thiophosgene at 0°C. The solution was allowed to warm to 23°C and the reaction was continued overnight. The CHCl3 layer was separated and dried over sodium sulfate. The solution was concentrated in vacuo and the residue was dissolved in toluene and treated with aniline (100 uL) at 23 °C for 12 h. The reaction mixture was concentrated and the residue was purified by flash chromatography ( 10% EtOAc/hexanes) to afford the titled compound as a yellow solid (120.8 mg, 98%) mp: 144-145ºC; 1H NMR (CD3OD/CDCI3): δ 8.65 (d, 1H, J = 10.0 Hz), 7.58 (d, 1H, J = 10.0 Hz), 7.47 (d, 1H, J =
1.25 Hz), 7.26 (m, 4H), 7. 10 (m, 1H).
b)Preparation of N-(2-hydroxy-4-nitrophenyl)-N'-phenyl-thiourea
N-(2-Hydroxy-4-nitrophenyl)-N'-phenyl-2-thiourea was prepared by treating a solution of N-(2-tert-butyldimethysilyloxy-4-nitrophenyl)-N'-phenyl-thiourea (100 mg, 0.248 mmol) in CH3CN (1 mL) with Et3N●HF (100uL, 0.62 mmol) in acetonitrile for 10 minutes at
23°C. The solution was concentrated and flushed through a silica plug with EtOAc to afford the desired compound as an orange solid (55 mg, 77%).
mp: 144- 145°C; 1H NMR (CD3OD/CDCI3): δ 8.65 (d, 1H, J = 10.0 Hz), 7.58 (d, 1 H, J =
10 0 Hz), 7.47 (d, 1 H, J = 1.25 Hz), 7.26 (m, 4H), 7. 10 (m, 1 H).
Example 10
Preparation of N-(4- nitro 2-(phenylsulfonylamino)phenyl)-N'-phenyl urea
a ) Preparation of 4-n itro 2-(phenylsulfonylamino) aniline
A solution of 4-nitro 1,2-phenylene diamine( 1.53 g. 10.0 mmol) in DMF was treated with phenyl sulfonyl chloride( 1.76 g. 10.0 mmol) and tr iethyl amine( 1.01 g ) in DMF f or 12 h at 23 ºC. The reaction mixture was partitioned between saturated NH4Cl and methylene chloride. The organic layer was dried over sodium sullate. filtered and concentrated in vacuo .
The lesulting solid was recrystallized (EtOH) to af ford desired (0.275 g. 9% ). Η
NMR(DMSO) 9.5(s, 1 H, br ), 7.83 (dd, 1H, J= 10 Hz, 2 Hz), 7.74(d. 2H, J=8 Hz), 7.76(t. 1 H, J=8 Hz), 7.56(t, 2H, 1=8 Hz), 7.55(d, 1 H, J=2Hz), 6.79 (d. 1 H. J=8Hz), 6.5(s. 2H. br)
b)Preparation of N-(4- nitro 2-(phenylsulfonylamino)phenyl)-N'-phenyl urea N-(4-Nitro 2-(phenylsulfonylamino)phenyl)-N'-phenyl urea was prepared from 4-nitro 2-(phenylsulfonylamino) aniline(82 mg) and phenyl isocyanaie(33 mg) by method A. The reaction was cooled and then partitioned between saturated ammonium chloride and 9: 1 methylene chloride and methanol. The organic phase was dried over magnesium sulfate.
iltered and concentrated in vacuo. The residue was purified by column chromaiography (ethyl acetaie/hexanes) to af ford desired(30.8 mg, 26% ). EI-MS m/z 413(M+H)+
Example 1 1
Preparation of N-(2-hydroxy-5-nitrophenyl)-N'-(3-methoxy-2-thienyl)urea
a)Preparauon of 3-methoxy-2-thienylcarboxlic acid
To a solution of 3-methoxyth iophene (4.81 g, 42. 1 mmol) in ether (20 mL) at -78ºC. butyllithium ( 17 mL, 47.6 mmol) was added. The reaction mixture was stirred at -78°C for 1 hour, then it was warmed to 0 °C for 3 hours. After to recooling -78°C the reaction mixture was poured into a beaker filled with crushed dry ice ( 14.5 g) and allowed to stand until the excess dry ice had completely sublimed. Then the reaction mixture was poured into a mixture of ice ( 10 g) to which conc. HCl (24 mL) had been added. The product was purified by precipitation from ether and filtering (6.42 g, 96 %) EI-MS m/z 159 (M+H)+.
b)Preparation of N-(2-hydroxy-5-nitrophenyl)-N'-(3-methoxy-2-thienyl)urea
To a solution of 3-methoxy-2-thiophene carboxylic acid (200 mg, 1.27 mmol) in benzene, (PhO)2PON3 (0.33 mL), 2-amino-4-nitrophenol (195.7 mg, 1.27 mmol) and triethylamine ( 1 .1 equiv ., 0.25 mL) were added. The reaction mixture was stirred at reflux overnight. The reaction mixture was partitioned between 5% curie acid and ethyl acetate. The organic layer was separated and the aqueous layer was extracted three times with ethyl acctate The organic extracts were combined, dried over MgSO4. filtered and concentrated under reduced pressure Chromatography of the resulting solid on silica gel (hexane:ethyl acetate: 1 : 1 ) gave a solid product ( 160 mg, 41 % ). mp 172.6- 173.0ºC; 1 H NMR
(CD3OD/CDCl3): δ 8.96 (d. I H, J = 2.5 Hz). 7.74 (dd. 1H. J =5.0 Hz and J = 1 .25 Hz). 6.82 (d. 1 H. J =7 5 Hz). 6 76 (s. 2H), 3 80 (s. 3H); EI-MS m/z 309 ( M+H )+; Anal
(C 12H 11N3 O5S) C, H, N .
Example 12
Preparation of N-(2-hydroxy-4-nitrophenyl)-N'-(3-methoxy -2-thieny l )urea
To a solution ol 3-methoxy-2-thiophene carboxylic acid (example 1 1 a, 200 mg 1.27 mmol) in toluene. (PhO)2PON3 (0.33 mL) and triethylamine ( 1 .1 equiy . 0.25 mL ) were added. The reaction mixture was stirred at 70°C for 2 hours and cooled down to room temperature then 2-amino-5-nitrophenol was added . The reaction mixture was suned at 70°C overnight. The reaction mixture was parti tioned between 5%- citric acid and ethyl acetate. The organic layer was separated and the aqueous layer was extracted three times with ethyl acetate . The organic extracts were combined, dried over MgSO4, filtered and concentrated under reduced pressure. Chromatography of the resulting solid on silica gel (hexane.ethyl acetate; 1 : 1 ) gave the product ( 190 mg, 48%). 1H NMR (CD3OD/CDCI3): δ 8.38 (d. 1 H, J = 5.0 Hz), 7.85 (dd, 1 H, J = 5.0 Hz and J = 1.25 Hz), 7.76 (d. I H, J = 2.5 Hz), 6.9 (s, 2H). 3.95 (s, 3H): EI-MS m/z 309 (M+H)+: Anal. (C12H1 1N3O5S) C, H, N.
Example 13
Preparation of N-(2-hydroxy-4-nitrophenyl)-N'-(3-methoxyphenyl)urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(3-methoxyphenyl)urea was prepared from 2-hydroxy 4-nitro aniline (154 mg, 1.0 mmol) and 3-methoxy phenyl isocyanate( 1.0 mmol) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound ( 140 mg, 46%). EI-MS m/z 302(M-H) -
Example 14
Preparation of N-(2-hydroxy-4-nitrophenyl)-N'-(2-methoxyphenyl)urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(2-methoxyphenyl)urea was prepared from 2-hydroxy 4-nitro aniline (154 mg, 1.0 mmol) and 2-methoxy phenyl isocyanate( l mmol.) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound (82 mg. 27% ). EI-MS m/z 302(M-H)-
Examnle 15
Preparation of N-(2-hydroxy-4-nitrophenyl)-N'-(3-trifluoromethylphenyl )urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(3-methoxyphenyl)urea was prepared f rom 2-hydroxy 4-nitro aniline (154 mg. 1.0 mmol) and 3-trifluoromethyl phenyl isocyanaie ( 1 mmol according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound ( 180 mg. 52% ). EI-MS m/z 342(M+H) +
Example 16
Preparation of N-(2-hydroxy-4-n itrophenyl)-N'-(2-trifluoromethylphenyl)urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(2-trifluoromethylphenyl)urea was prepared from 2-hydroxy 4-nitro aniline ( 154 mg. 1.0 mmol) and 2-trifluoromethyl phenyl isocyanate ( 1.0 mmol) according 10 the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound ( 180 mg. 52% ). EI-MS m/z 342(M+H) +
Example 17
Preparation of N-(2-hydroxy-4-nurophenyl)-N"-(4-trifluoromethylphenyl )urea N-(2-Hydroxy-4-nitrophenyl)-N'-(4-trifluoromethylphenyl)urea was prepared f rom 2-hydroxy 4-nitro aniline ( 154 mg, 1.0 mmol) and 4-trifluoromethyl phenyl isocyanate ( 1.0 mmol) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound ( 1 1 1 mg, 32%). EI-MS m/z 340(M-H)-
Example 18
Preparation of N-(2-hydroxy-4-nitrophenyl)-N'-(2-bromophenyl)urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(2-bromophenyl)urea was prepared f rom 2-hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 2-bromophenyl isocyanate (3.24 mmol ) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound(530 mg. 47% ) EI-MS m/z 350(M-H) -
Example 19
Preparation of N-(2-hydroxy-4-nitrophenyl)-N'-(3-bromophenyl)urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(3-bromo phenyl )urea was prepared from 2-hydroxy 4-nitro aniline (500 mg. 3.24 mmol) and 3-bromo phenyl isocyanate (3.24 mmol)according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound(0.96g. 87% ) EI-MS m/z 350(M-H) -
Example 20
Preparation of N-(2-hydroxy-4-nitrophenyl)-N'-(4-hromophenyl)urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(4-bromo phenyl)urea was prepared f rom 2-hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 4-bromo phenyl isocyanate (3.24 mmol ) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound (0.41 g. 37% ) EI-MS m/z 352(M+H) + Example 21
Preparation of N-(2-hydroxy-4-nitrophenyl)-N'-(2-phenylphenyl)urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(2-phenylphenyl )urea was prepared f rom 2-hydioxy 4-nitio aniline (5(X) mg. 3.24 mmol) and 2-phenyl phenyl isocyanate (3 24 mmol ) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound(0.22 g. 19% ). EI-MS m/z 350(M+H) +
Example 22 Preparation of N-(2-hydroxy-4-nitrophenyl)-N'-( 1 -naphthyl)urea
N-(2-Hydroxy-4-nitrophenyl)-N'-( 1 -naphthyl)urea was prepared f rom 2-hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 1 -naphthyl isocyanate (3.24 mmol) according to the procedure in General Method B. The product precipitated from methylene chloride and filtered. The resulting solid was titruated with 1 :3 triethyl amine:methylene chloride. The filteraie was concentrated in vacuo. The resulting residue was dissolved in methylene chloride and treated with 1N C1 in water. The desired product precipitated from solution and was collected by filtration(0.1 l g, 10%). EI-MS m/z 324(M+H) + Example 23
Preparation of N-(2-hydroxy-4-nitrophenyl .-N'-(2-nitrophenyl)urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(2-nitro phenyl)urea was prepared from 2-hydroxy
4-nitro aniline (500 mg, 3.24 mmol) and 2-nitro phenyl isocyanate (3.24 mmol) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound(0.44 g. 44% ).
EI-MS m/z 319(M+H) +
E-sample 24
Preparation of N-(2-hydroxv-4-nitrophenyl .-N'-(2-fluorophenyl)urea
N-(2-Hydroxy-4-nitrophenyI)-N'-(2-fluorophenyl)urea was prepared from 2-hydroxy
4-nitro aniline (500 mg, 3.24 mmol) and 2-fluoro phenyl isocyanate (3.24 mmol) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound(0.59 g. 31 % )
EI-MS m/z 292(M+H) +
Example 25
Preparation of N-(2-hydroxy-4-nitrophenyl)-N'-(2.6-difluorophenyl )urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(2,6-difluorophenyl)urea was prepared f rom 2- hydroxy 4-nitro aniline (500 mg. 3.24 mmol) and 2.6-difluoro phenyl isoey anate(3.24 mmol , according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound( 0.9 1 g. 91 %). EI-MS m/z 308(M-H) -
Example 26
Preparation of N-(2-hydroxy-4-nitrophenyl )-N'-(2-ethoxyphenyl)urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(2-ethoxyphenyl)urea w as prepared from 2-hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 2-cihoxy phenyl isocyanate (3.24 mmol ) according to the procedure in General Method B. The product was purified by dilution wiih methylene chloride and precipitation with hexanes. Filtering afforded the title compound(0.84 g. 8 1 % ) .
EI-MS m/z 318(M+H) + Example 27
Preparation of N-(2-hydroxy-4-nitrophenyl)-N'-(2-ethylphenyl)urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(2-ethylphenyl)urea was prepared from 2-hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 2-ethyl phenyl isocyanate (3.24 mmol) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation wilh hexanes. Filtering afforded the title compound(044 g, 43%). EI-MS m/z 302(M+H) +
Example 28
Preparation of N-(2-hydroxy-4-nitro phenyl)-N'-(2-trifluoromethoxyphenyl)urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(2-trifluoromeihyloxyphenyl)urea was prepared from 2-hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 2-trifluoromeihoxy phenyl isocyanate (3.24 mmol) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes Filtering afforded the title compound(0.69 g. 60%). EI-MS m/z 358(M+H) +
Example 29
Synthesis of N-(2-hydroxy-4-nitro phenyl) N'-(2-methylthio phenyl) urea
The urea was prepared from 2-hydroxy 4-nitro aniline (500 mg . 3.24 mmol) and 2-methylthio phenyl isocyanate(3.24 mmol) by general Method B. The product was purified by dilution with methylene chloride and precipitation wilh hexanes Filtering afforded the title compound(0.63 g. 61 % ). EI-MS m/z 320(M+H) +
Example 30
Synthesis of N-(2-hydroxy-4-nitro phenyl) N'-(2-chloro 6-methyl pheny l ) urea
The urea was prepared from 2-hydroxy 4-n itro aniline (500 mg. 3.24 mmol ) and 2-chloro 6-methyl phenyl isocyanate by general Method B. It was purified by dilution with methylene chloride and precipiiauon wilh hexane. Filtering af forded the desired
compound(0.31 g. 29% ). EI-MS m/z 322(M+H) +
Example 31
Synthesis of N-(2-hydroxy -4-nitro phenyl) N'-(2- methyl sulf oxypheny l ) urea
The urea was synthesized by treatment of N-( 2-hydroxy 4-nitro phenyl) N'-(2-methy l thio phenyl) urea(example 28. 100 mg ) with sodium periodate( 100 mg ) in t-butanol/water f or 12 hours at 23 ºC. The product precipitated f rom the reaction mixtur e(30 mg, 29% ). EI-MS m/z 336(M+H) +
Example 32 Synthesis of N-(2-hydroxy 4-trifluoromethyl phenyl) N'-(2-bromo phenyl) urea
The urea was prepared from 2-hydroxy 4-trifluoromethyl anilineiexamplc 7a. 0. 171 g, 1 mmol) and 2-bromo phenyl isocyanated mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the desired compound(0.25 g, 54% ). EI-MS m/z 375(M+H) +
Example 33
Synthesis of N-(2-hydroxy 4-carbomethoxy phenyl) N'-(2-bromo phenyl) urea
The urea was prepared from 2-hydroxy 4-carbomeihoxy aniline(0.167 g. 1 mmol) and 2-bromo phenyl isocyanate ( 1 mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the desired
compound(0.12 g. 33%). EI-MS m/z 363(M-H) -
Example 34
Synthesis of N-(2-hydroxy 4-trifluoromethyl phenyl) N'-(2-phenyl phenyl) urea
The urea was prepared from 2-hydroxy 4-trifluoromethyl aniline(example 7a, 0.171 g, 1 mmol)) and 2-phenyl phenyl isocyanate by general Method B. it was purified by dilution with methylene chloride and precipitation with hexane. Filiering afforded the desired compound(0.24 g, 64%). EI-MS m/z 373(M+H)+
Example 35
Synthesis of N-(2-hydroxy 4-carbomethoxy phenyl) N'-(2-phenyl phenyl) urea
The urea was prepared from 2-hydroxy 4-carbomethoxy aniline (0. 167 g, 1 mmol ) and 2-phenyl phenyl isocyanated mmol) by general Method B. It was purif ied by dilution with methylene chloride and precipitation with hexane. Filtering af forded the desired
compound(0.185 g. 50% ). EI-MS m/z 363(M-H) -
Example 36
Synthesis of N-(2-hydroxy 4-nitro phenyl) N'-(2.3-diehloro phenyl ) urea The urea was prepared from 2-hydroxy 4-nitro aniline(308 mg. 2 mmol ) and 2.3-dichloro phenyl isocyanate(2 mmol) by general Method B. It was purified by dilution with methylene ehloride and precipitation with hexane. Filtering af f orded the title compound(0.5 g. 73% ) EI-MS mlz 342(M+H ) + Example 37
Synthesis of N-(2-hydroxy 4-nitro phenyl) N'-(2,4-dichloro phenyl ) urea The urea was prepared from 2-hydroxy 4-nitro aniline(308 mg. 2 mmol) and 2,4-dichloro phenyl isocyanate(2 mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane . Filtering afforded the title compound(0.26 g. 38% ). EI-MS m/z 342 (M+H) +
Example 38
Synthesis of N-(2-hydroxy-4-nitro phenyl) N'-(2-chloro phenyl) urea
The urea was prepared from 4-nitro 2-hydroxy aniline(308 mg, 2 mmol) and 2-chloro phenyl isocyanate(2 mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the title compound(0.29 g. 47% ). EI-MS m/z 308(M+H) +
Example 39
Synthesis of N-(2-hydroxy-4-nitrophenyl) N'-(2.4-dibromo phenyl) urea
The urea was prepared from 4-nitro 2-hydroxy aniline(308 mg. 2 mmol) and 2,4-dibromo phenyl isocyanate(2 mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the title compound(0.34 g. 39%). EI-MS m/z 430(M+H) + Example 40
Synthesis of N-(2-hydroxynapthyl) N'-(2-hromo phenyl) urea
The urea was prepared from 1 -amino 2-hydroxy napthalene( 195 mg. 1 mmol) and 2-bromo phenyl isocyanate( 1 mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane Filiering afforded the title compound(0.030 g. 8% ) EI-MS m/z 357(M+H) +
Example 41
Synthesis of N-(2-hydroxy-4-nitrophenyl )-N'-(2.3-meihylenedioxyphenyl)urea a Preparation of 2.3-methylenedioxyphenylearboxylic acid
A solution of 1 .3-benzodioxole (3.09 g. 32 mmol ) in dry ether (50 mL) w as treated dropwise at - 1 0ºC with 2.5 M n-butyllithium ( 15 mL. 35 mmol) in hexane. When the addition w as complete, the mixture was stirred under reflux f or one hour. After cooling to room temperature, it w as added to crushed solid carbon dioxide, and after 24 hours, the residue was treated with 10 % aq. NaHCO3 and ether. The alkali layer was separated, washed with ether, then acidified with cold concentrated C1 , and extracted with chloroform. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure ( 1.1 g. 20 % ). EI-MS m/z 167 (M+H)- b)Preparation of N-(2-hydroxy-4-nitrophenyl)-N'-(2,3-methylencdioxyphenyl)urea
To a solution of the 2,3-methylenedioxyphenylcarboxylic acid in toluene, triethylamine (0.27 mL, 1.95 mmol) and diphenylphosphoryl azide (DPPA) (0.32 mL, 1.5 mmol) were added. The reaction mixture was stirred at 60°C for 2 hours, then 2-amino-5-nitrophenol (250 mg, 1.5 mmol) was added. The reaction mixture was stirred at 100°C for 18 hours. After the reaction mixture was cooled to room temperature, it was partitioned between 5 % citric acid and ethyl acetate. The organic layer was separated and the aqueous layer was extracted three limes with ethyl acetate. The organic extracts were combined, dried over MgSO4, filtered and concentrated under reduced pressure. Chromatography of the resulting solid on silica gel (hexane : ethyl acetate; 5: 1 ) gave product (200 mg, 42 %). EI-MS m/z 318 (M+H)+
Example 42
Synthesis of N-(2-hydroxv 4-nitro phenyl) N'-(2-methoxy 3-chloro phenyl) urea
The urea was prepared from 2-hydroxy 4-nitro aniline(308 mg, 2 mmol) and 2-chloro 3-methoxy phenyl isocyanate(2 mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the title compound(0.48 g, 63% ). EI-MS m/z 338(M+H) +
Example 43
Synthesis of N-(2-hydroxy 4-nitro phenyl) N'-(2-methyl phenyl) urea
The urea was prepared from 2-hydroxy 4-nitro aniline(308 mg. 2 mmol) and 2-meihyl phenyl isocyanatc(2 mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filiering afforded the title compound(0.38 g. 53% ). EI-MS m/z 288(M+H) +
Example 44
Synthesis of N(bis (2-hydroxy 4-nitro phenyl) N'-(dianisdine) diurea
The urea was prepared from 2-hydroxy 4-nitro aniline(616 mg. 4 mmol) and dianidisdine diisocyanate(2 mmol ) by general Method B(except 2 equiv. of 4-nitro 2-hydroxy aniline was used instead of 1 equiv.). The product was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the title compound ( 0.08 g. 6% ). EI-MS m/z 605(M+H) +
Example 45
Synthesis of 4-methylene bis(N-(2-chloro phenyl) N'-(2-hydroxy 4-nitro phenyl) urea) The urea was prepared from 2-hydroxy 4-nitro aniline(616 mg. 4 mmol) and 4-methylene bis(N-(2-chloro phenyl) diisocyanate(2 mmol) by general Method B(excepi 2 equiv of 4-nitro 2-hydroxy aniline was used instead of lequiv.). The product was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the title compound(0. 10 g, 8%).
EI-MS m/z 627(M+H) +
Example 46
Synthesis of N-I2-hydroxy 4-(benzylamino)carbonyl phenyl]-N'-(2-hromophenyl)urea a)Synthesis of N-(2-hydroxy 4-carboxylate phenyl) N'-(2-bromo phenyl) urea
The urea was prepared from 3-hydroxy 4-amino benzoic acid (3.69 g, 24 mmol) and 2-bromo phenyl isocyanate(24 mmol) by general Method B. It was purified by dilution of the DMF solution with methylene chloride and precipitation with hexane(4.0 g, 48% ). EI-MS m/z 351 (M+H) +
b)Preparation of N-[4-(benzylamino)carbonyl-2-hydroxyphenyl]-N'-(2-bromophenyl)urea To a solution of the N-(2-hydroxy 4-carboxylate phenyl) N'-(2-bromo phenyl) urea (200 mg, 0.58 mmol) in DMF ( 15 mL), EDC ( 121.9 mg, 0.58 mmol), HOBT ( 156.6 mg, 1 1.6 mmol) were added . The reaction mixture was stirred at room temperature for 16 hours. Then the benzyl amine (123 mg, 1 1.6 mmol) was added. The reaction mixture was stined at same temperature for 24 hours. Then the reaction mixture was partitioned between water and ethyl aectate. The organic layer was separated and the aqueous layer was extracted three times with ethyl acetate. The organic extracts were combined, dried over MgSO4, filtered and concentrated under reduced pressure. Chromatography of the resulting solid on silica gel (hexane : ethyl acetaic; 1 : 1 ) gave benzylamino product (500 mg. 65 %). EI-MS m/z 441 (M+H)+
Example 47
Synthesis of N-(2-hydroxy 4-nitro phenyl) N'-(2-phenoxy phenyl) urea The urea was synthesized by the treatment of 2-phenoxyphenyl carboxylic acid(2 mmol.) with diphenyl phosphoryl azide(0.475 mL) and triethyl amine(. 14 mL) in DMF at 80 °C after 24 hours the 2-amino 5-nitro phenol ( 1 equiv.) was added. The reaction was heated for 24 hours at 80°C. The reaction product was oiled out with hexane. The residue was dissolved in methanol and the solid was precipitated out with water.( l 80 mg. 24% ) EI-MS m/z 364(M-H) - Example 48
Synthesis of N-(2-hydroxy-4-fluoro phenyl) N'-(2-bromo phenyl) urea
a)Synthesis of 2-hydroxy 4-fluoro aniline 3-fluoro 6-nitro phenol (2 g, 1 1 mmol) was treated with 10%Pd/C( I g) at 23 °C. The reaction mixture was flushed with hydrogen gas and the reaction was allowed to stir 12 h before it was filtered through celite. The filtrate was concentrated in vacuo to af ford the title compound ( 1.4 g, 77% ). EI-MS m/z 169(M+H) +
b)Synthesis of N-(2-hydroxy-4-fluoro phenyl) N'-(2-bromo phenyl) urea
The urea was prepared from 2-hydroxy 4-fluoro aniline(254 mg. 2 mmol) and 2-bromo phenyl isocyanate by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane( 173 mg. 26% ). EI-MS m/z 325 (M+H)+ Example 49
Synthesis of N-( 2-hydroxy 3,4-difluoro phenyl) N'-(2-bromo phenyl) urea
a)Synthesis of 2-hydroxy 3,4-difluoro aniline
2,3 difluoro 6-nitro phenol (2 g, 1 1 mmol) was treated with 10% Pd/C( l g) at 23 ºC.
The reaction mixture was flushed with hydrogen gas and the reaction was allowed to stir 12 h before it was filtered through celite. The filtrate was concentrated in vacuo to afforded the title compound ( 1.6 g. 97%). EI-MS m/z 146(M+H)+
b)Synthesis of N-(2-hydroxy 3,4-difluoro phenyl) N'-(2-bromo phenyl) urea
The urea was prepared from 2-hydroxy 3.4-difluoro aniline(0.290 g. 2 mmol) and 2-bromo phenyl isocyanate(0.4 g) by general Method B. It was purified by dilu tion with methylene chloride and precipitation with hexane(0.254 g, 37%). EI-MS m/z 343(M+H)+
Example 50
Synthesis of N-(2-hydroxy 3-napthyl) N'-(2-bromo phenyl) urea
The urea was prepared from 3-amino 2-hydroxy napthalene(0.320 g. 2 mmol) and 2-bromo phenyl isocyanate(.40 g) by general Method B. It was purified by dilution of the with methylene chloride and precipitation with hexane(0.339. 47% ). EI-MS m/z 357(M+H)+
Example 51
Synthesis ot N-(2-hydroxy 4-phenyl phenyl) N'-(2-bromo phenyl) urea
a)Synthesis ol 2-nitro 5-phenyl phenol
A solution of 3-phenyl phenol(2 g. 1 1 mmol ) in acetic acid was treated with concentrated nitric acid drop-wise until all starling material was consumed . The solution was partitioned between water and methylene chloride. The organic phase w as separated and the aqueous phase was extracted once more with methylene chloride. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica get chromatography(ethyl acetate/hexanes) to afford desired ( 1.2 g. 50% ) .1 H NMR (CDCl 3); δ 10.65(s, 1 H), 8.18 (d, 1 H, J = 10.0 Hz), 7.65 (d. 2H, .1 = 6.0 Hz), 7 49 (m, 3H), 7.34 (s. 1H), 7.10 (d, I H, J=10.0Hz)
b)Synthesis of 2-amino 5-phenyl phenol
A solution of 2-nitro 5-phenyI phenol( 1.2 g, 5.5 mmol) in methanol was treated with 10% Pd/C( 1.2g). The reaction mixture was flushed with hydrogen and allowed to stir overnight. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to afford desired ( 1.01 g, 98%).EI-MS m/z 186(M+H)+
c)Synthesis of N-(2-hydroxy 4-phenyl phenyl) N'-(2-bromo phenyl) urea
The urea was prepared from 2-hydroxy 4-phenyl aniline(0.185 g. 1 mmol) and 2-bromo phenyl isocyanate(0.198 g) by general Method B. It was purified by dilution of the DMF solution with methylene chloride and precipitation with hexane(215 mg, 56% ). EI-MS m/z 383(M+H) +
Example 52
Synthesis of N-(2-hydroxy 4-methyl phenyl) N'-(2-bromo phenyl) urea
The urea was prepared from 2-hydroxy 4-methyl aniline(.274g. 2 mmol) and 2-bromo phenyl isocyanate(0.40 g, 2 mmol) by general Method B. It was purified by dilution of the DMF solution with methylene chloride and precipitation with hexane(249 mg, 39% ). EI-MS m/z 319(M-H) -
Example 53
Synthesis of N(2-hydroxy 4-nitro phenyl) N'-(2-phenylamino phenyl) urea
The urea was synthesized by the treatment of 2-tertbutyldimethylsilyloxy 4-nitro pheny I isocyanate(example 9a, 0.419g, 1.5 equiv.) with 2-anilino aniline(0.184 g. 1 equiv. ) in THF overnight at 40 °C. The desired product precipitated out of the reaction m ixture(30 mg. 8% ) EI-MS m/z 365(M+H) +
Example 54
Synthesis of N-(2-hydroxy 3-carhoxylate phenyl) N'-(2-bromo phenyl ) urea
The urea was prepared from 2-hydroxy 3-amino benzoic acid(300 mg. 2 mmol) and 2-bromo phenyl isocyanate by general Method B. It was purified by dilution of the DMF solution with methylene chloride and precipitation with hexane(.287 g. 41 % ). EI-MS mlz 35 1 (M+H) + Example 55
Synthesis of N(2-sulfhydryl 4-bromo phenyl) N"-(2-bromo phenyl ) urea
a)Synthesis of 2-amino 6-bromo thiazole 4-Bromo aniline(4.3 g, 25 mmol, 1 equiv.) and ammonium thiocyanatc(5 7 g. 3equiv ) was dissolved in aceuc acid and treated with bromine(4 g, 1 equiv. ) at room temperature After complete disappearance of starting material the reaction mixture was poured into water and the solid was collected. The solid was used in the next step without any purification(3.6 g. 46% ) EI-MS m/z 229(M+H) +
b)Synthesis of bis (3-bromo 6-amino phenyl) disulfide
The 2-amino 6-bromo thiazole hydrobromide (500 mg, 1 6 mmol) in water(5mL) was treated with KOH (2.5 g) was heated at reflux for 8 h at reflux. The reaction mixture was then acidified to ph 4 with acetic acid and extracted with methylene chloride. The methylene chloride mixture was concentrated in vacuo. The residue was dissolved in DMSO and treated with 12. After stirring overnight at room temperature me reaction mixture was partitioned between methylene chloride and saturated sodium bicarbonate. The methylene chloride layer was dried with magnesium sulfate and concentrated in vacua. The resulung solid was purified by flash chromatography(ethyl acetate/hexane) to afford the utle compound (230 mg. 34%). EI-MS m/z 405(M+H) +
c)Synthesis of N(2-sulfhydryl 4-bromo phenyl) N'-(2-bromo phenyl) urea
A solution of (3-bromo 6-amino phenyl) disulfide(201 mg, .5 mmol) in DMF was treated with 2-bromo phenyl isocyanate( 1 mmol) at 80 °C overnight The reaction mixture was diluted with methylene chloride and a solid was precipitated out with hexanes The solution was dissolved in MeOH and treated with NaBH4. After gas evolution ceased the reaction mixture was carefully acidified with 1 N HCl and the resulting solid was f iltered(52 mg. 13%) EI-MS m/z 399 (M-H) -
Example 56
Synthesis of N-(2-hydroxy 4-nitro phenyl) N'-(2-iodo phenyl) urea
The urea was synthesized by the treatment of 2-iodo benzoic acid(5 g. 20 mmol) with diphenyl phosphoryl azidc( 1 equiv.) and triethyl amine ( 1 equiv. ) in DMF at 80 °C alter gas evolution ceased the 5-nitro 2-amino phenol (3 g. 1 equiv. ) was added The reaction was heated overnight at 80°C. The reaction mixture was purified by filtering through a plug of silica with methylene chloride. The desired product was then precipitated out w ith hexanc. Filtering aftorded the desired compound( 1.08 g. 13% ) EI-MS m/z 398(M-H) -
Example 57
Synthesis of N-(2-hydroxy 4-nitro phenyl) N'-(2-bromo phenyl) thiourea
The thiourea was synthesized by treatment ot the 2-tert-butyldimethylsilyloxy 4-nitro phenyl thioisocyanate(see example 9a , 3.73 mmol) with 2-bromo aniline in toluene at 88°C over 36 h. The solution was concentrated and the residue was purified by flash chromatography(EtOAc/Hexanes) The traction slightly lower rf than starting material contained the desired compound This traction was concentrated and then treated with triethyl amine hydrofluoride in acetonitrile for 15 minutes at 23 °C The reaction mixture was then concentrated in vacua and the residue was purified by flash chromatography(ethyl
actate/hexanes) to give N-(2-hydroxy 4-nitro phenyl) N'-(2-bromo phenyl) thiourea(52 mg. 4%) EI-MS m/z 369(M+H) +
Example 58
Synthesis of N-(2-phenylsulfamido) 4-cyanonhenyl N'-(2-bromo phenyl) urea
a)Synthesis of 3-(phenylsulfamido) benzonitrile
The of 3-(phenylsulfamido) benzonitrile was synthesized from the 3-cyano aniline (23.9 g, .2 mol) by Method C It was purified by recrystalization from EtOH( 15 8 g.
31 %).1H NMR (CDCI3): 6 7.95(s, 1H), 7 84 (d, 2H, J = 8.0 Hz), 7.59 (1. 1 H, J = 8 0 Hz). 7.45 (m, 2H), 7.35 (m, 4H).
b)Synthesis of 3-(phenylsulfamido) 4-nitro benzonitrile
The 3-(phenylsulfamido) benzonitrile(10 g, 39 mmol) was dissolved in acetic anhydride and treated with concentrated nitric acid dropwise at room temperature until all the starting material had been consumed. The reaction mixture was then quenched by carefully pouring it into sodium bicarbonate and left to sit until all gas evolution had subsided It was then partitioned between methylene chloride and water The organic layer was dried over sodium sulfate and filtered The reaction mixture was concentrated in vacua, absorbed onto silica gel and purified by column chromatography ( methylene chloride/hexane) to allord the title compound ( 1 7g, 15%) EI-MS m/z 302(M+H) +
c)Synthesis of 3-(phenylsulfamido) 4-amino benzonitrile
The 3-(phenylsultamido) 4-nitro benzonitrile( l 5 g. 4 9 mmol ) w as treated with tin chloride dihydrate in EtOH at 80 °C for 12h It was then concentrated and flushed through a plug of silica gel with 5% methanol/methylene chloride The filterate was absorbed onto silica gel and purified by Hash chromatography(ethyl acetate/hexane) to afford the title compound (0.9 g, 60% ), EI-MS m/z 274 (M+H) +
d)Synthesis of N-(2-phenylsultamido) 4-cyanophenyl N'-(2-bromo phenyl ) urea
The urea was synthesized from 2-(phenylsulf amido) 4-amino benzonitrile(77 mg. 0 2S mmol) and 2-bromo phenyl isocyanate by general Method C. It was purif ied by column chromatography(ethyl acetate/hexane) to af ford the title compound (30 mg. 22% ) EI-MS m/z 469(M-H) -
Example 59
Synthesis of N-(2-(phenyl sulfamido) phenyl) N'-(2-bromo phenyl) urea a)Synthesis of 2-( phenyl sulfamido) aniline
The sulfonamide was synthesized from phenyl sulfonyl chloridc(0.01 mmol) and o-phenylene diamine( 1.08 g, 0.01 mmol) by general Method C It was purified by
recrystallization from EtOH( 1.0 g, 40%).EI-MS m/z 249(M+H) +
b)Synthesis of N-(2-(phenyl sulfamido) phenyl) N'-(2-bromo phenyl ) urea
The urea was synthesized 2-(phenyl sulfamido) aniline( 1 mmol )
and 2-bromo phenyl isocyanate by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering allorded the desired
compound(0.234 g, 52%).EI-MS m/z 446(M+H) +
Example 60
Synthesis of N-(2-( styryl sulfamido) phenyl) N'-(2-bromo phenyl) urea
a)Synthesis of 2-( styryl sulfamido) aniline
The sulfonamide was synthesized from styryl sulfonyl chloride(001 mol) and o-phenylene diamine(0.01 mol) by general Method C. It was purified by recrystallizaiion from EtOH(1.2 g, 60%)EI-MS m/z 199(M+H) +.
b)Synthesis of N-(2-(styryl sulfamido) phenyl) N'-(2-bromo phenyl) urea
The urea was synthesized from 2-(styryl sulfamido) aniline( 1 mmol) and 2-bromo phenyl isocyanate(1 mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane Filtering afforded the desired compound(0.309 g. 65% ). EI-MS m/z 472(M+H) +
Example 61
Synthesis of 2-[(3,4 dimethoxyphenyl )sulfonyl amino] phenyl) N'-(2-bromo phenyl ) urea a)Synthesis of 2-[(3,4-dimethoxyphenyl)sulfonyl amino]phenyl aniline
The sulfonamide was synthesized from 3,4-dimethoxy phenyl sulfony l chloride(0.01 mol) and o-phenylenc diamine by general Method C. It was purified by recrystallization f rom
EtOH(0.65 g. 21 % ) EI-MS m/z 309(M+H ) +
b)Synthesis of 2-[(3,4-dimethoxyphenyl)sulfonylamino] phenyl ) N '-( 2-bromo phenyl) urea The urea was synthesized from 2-[(3,4-dimethoxypheny l )sulfony I aminolpheny I aniline(1 mmol) and 2-bromo phenyl isocyanate by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the desired compound(0.062 g. 12% ) EI-MS m/z 504(M-H ) - Example 62
Synthesis of N-(2-[(4-acetamidophenyl)sulfonylamino] phenyl ) N '-(2-bromo phenyl ) urea a)Synthesis of 2-[(4-acetamidophenyl)sulfonylamino]phenyl aniline The sulfonamide was synthesized f rom 4-acctamidophenyl sulfonyl chloride.0.01 mol ) and o-phenylene diamine(0.01 mol) by general Method C. It was purified by recrystallization from EtOH( 1.27 g.40%)EI-MS m/z 304(M-H)
b)Synthesis of N-(2-[(4-acetamidophenylsulfonyl)amino] phenyl) N'-(2-bromo phenyl) urea The urea was synthesized from 2-[(4-acetamidophenyl)sulfonylamino]phenyl aniline( 1 mmol) and 2-bromo phenyl isocyanate( 1 mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the desired compounds. 12 g. 24%). EI-MS m/z 501(M-H) - Example 63
Synthesis of N-(2-(2-thiophene sulfamido phenyl) N'-(2-bromo phenyl) urea a)Synthesis of 2-(2-thiophene sulfamido) aniline
The sulfonamide was synthesized from 2-thiophene sulfonyl chloride(0.01 mol) and o-phenylene diamine(0.01 mol) by general Method C. It was purified by recrystallization from EtOH(0.77 g, 30% ). EI-MS m/z 255 (M+H)+
b)Synthesis of N-(2-(2-thiophenc sulfonyl amino phenyl) N'-(2-bromo phenyl) urea
The urea was synthesized from 2-( 2-thiophene sulfonyl amino) anilined mmol) and 2-bromo phenyl isocyanated mmol) by general Method B. It was purified by dilution with methylene chloride and precipiiation with hexane. Filtering afforded the desired
compound(0.29 g. 64% ). EI-MS m/z 450(M-H ) -
Example 64
Synthesis of N-(2-( 3-tolyl sulfonyl amino phenyl) N'-(2-bromo phenyl ) urea
a)Syndiesis of 2-( 3-lolyl sulfonyl amino) aniline
The sultonamide was synthesized from 3-tolyl sulfonyl chloride(0.01 mol ) and o-phenylene diamine(0.01 mol) by general Method C. It was purified by recrystallization from
EtOH(0.73g. 28% ). EI-MS m/z 263 (M+H )+
b)Synthesis ol N-(2-(( 3-tolyl sul fonyl amino) phenyl ) N'-(2-bromo phenyl) urea
The urea was synthesized from 2-(3-tolyl sulfonyl amino) aniline( 1 mmol ) and 2-bromo phenyl isocyanate( 1 mmol ) by general Method B. It was purilied by dilution with methylene chloride and precipitation with hexanes It was recrysallized two times with
EtOH(25 mg. 5% ) EI-MS mlz 458(M-H) - Example 65
Synthesis of N-(2-(8-quinolinyl sulfonyl amino) phenyl) N'-(2-bromo phenyl) urea
a)Synthesis of 2-(8-quinolinyl sulfonyl amino) aniline The sulfonamidc was synthesized from 8-quinolinyl sul fonyl chloride(0.01 mol) and o-phenylene diamine(0.01 mol) by general Method C. It was purified by recrystallization from EtOH(0.82 g. 27% ).EI-MS m/z 300 (M+H) +
b)Synthesis of N-(2-( (8-quinolinyI) sulfonyl amino) phenyl) N'-(2-bromo phenyl) urea
The urea was synthesized from 2-((8-quinolinyl) sulfonyl amino) anilined mmol) and
2-bromo phenyl isocyanate(1 mmol) by general Method B. It was purified by dilution with methylene chlonde and precipitation with hexane Filtering afforded the desired
compound(0.23 g. 46% ). EI-MS m/z 495(M-H)- Example 66
Synthesis of N-(2-( benzyl sulfonyl amino) phenyl) N'-(2-bromo phenyl) urea
a)Synthesis of 2-(benzyl sulfonyl amino) aniline
The sultonamide was synthesized from benzyl sulfonyl chloride(0.01 mol) and o-phenylene diamine(0.01 mol) by general Method C. It was purified by recrystallization from EtOH(0.87g, 33%) EI-MS m/z 263(M+H)+.
b)Synthesis of N-(2-( benzyl sulfonyl amino) phenyl) N'-(2-bromo phenyl) urea
The urea was synthesized from 2-( benzyl sulfonyl amino) anilined mmol)
and 2-bromo phenyl isocyanate( 1 mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the desired compound(0 .1 1 g. 23% ) EI-MS m/z 460 (M+H )+
Example 67
Synthesis of N-(2-hydroxy-4-azidophenyl)-N'-(2-methoxyphenyl)urea
a)Synthesis of N-(2-hydroxy -4-aminophenyl)-N'-(2-methoxyphenyl)urea
To a solution of N-(2-hydroxy-4-nitro phenyl )-N'-(2-methoxyphenyl )urea( 1.0 g. example 15) in methanol. palladium (on activated carbon. 10% ) ( 100 mg ) was added Then the reaction mixture was hydrogenated under a hydrogen balloon for 18 hours. The solid was filtered of f by celite and washed three times by methanol. The filtrate was concentrated under reduced pressure to giv e amine compound (0 8 g. 89% ) EI-MS m/z 274 ( M+H)+
b)Synthesis of N-(2-hydroxy-4-azidophenyl)-N'-(2-meihoxyphenyI)urea
The N-(2-hydioxy -4-aminophenyl)-N'-(2-methoxyphenyl)urea (300 mg. 1.17 mmol ) was added to HCl/H2O ( 1.17 mL/2.34 mL). cooled to 0°C Sodium nitrite (80.7 mg. 1.17 mmol ) w as added to the reaction mixture. The reaction mixture was stirred at 0°C tor 30 minutes. The sodium azide (76 mg. 1.17 mmol ) was added to reaction mixture and it was warmed to room lemperaiure. The reaction mixture was stirred at room temperature for 18 hours. Then it was extracted with three times by ethyl acetaie. The organic extracts were combined, dried over MgSO4. filtered and concentrated under reduced pressure and chromatography of the resulting solid on silica gel (hexane : ethyl acetate: 5: 1 ) gave product ( 125 mg. 38% ) EI-MS m/z 300 (M+H)+
Example 68
Preparation of N-[ 2-hydroxy-5-cyanophenyl]-N'-12-hromophenyl] urea
a)Preparation of 2-amino-4-cyanophenol
To a solution of 2-nitro-4-cyanophenol( 10g, 61 mmol) in methanol(250mL) was added 10% Pd/C ( 1 g). The mixture was flushed with argon, then hydrogen was bubbled through the solution for 10 min. and a hydrogen atmosphere was maintained at balloon pressure overnight. The mixture was filtered through celite and the celite was washed with methanol. The solvent was evaporated and chromatography of the resulting solid on silica gel (5% MeOH/ CH2Cl2) gave the desired product(8.0 g, 97% ). 1H NMR (CD3OD): 8 6.96 (d. 1 H), 6.90 (dd. 1 H).
6.77 (d, 1 H)
b)Preparation of N-[2-hydroxy-5-cyanophenyl]-N'-[2-bromophenyl] urea
N-[2-hydroxy-5-cyanophenyl]-N'-[2-bromophenyl] urea was prepared from 2-amino- 4-cyanophenol(268mg, 2.00 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane( 1/20) and filtering (540mg.81% ). 1H NMR (CD3OD): 8 8.10 (d, 1 H), 7.87 (d, 1H). 7 43 (d. 1H), 7.20 (t. 1H).
7.09 (d. 1 H). 6.86 (t. 1 H). 6.77 (d, 1H).
Example 69
Preparation of N-12-hydroxy-3-fluorophenyl]-N'-12-bromophenyl ] urea
a )Preparation of 2-amino-3-fluorophenol
To a solution of 2-nitro-3-fluorophenol( lg. 6.4mmol) in methanol(250mL) was added 10% Pd/C (1g). The mixture was flushed with argon, then hydrogen w as bubbled through the solution for 10 min. and a hydrogen atmosphere was maintained at balloon pressure overnight The mixture was filtered through celite and the celite was washed with medianol. The soivent was evaporated and chromatography of the resulting solid on silica gel (5%MeOH/ CH2Cl 2) gave the desired product(650 mg, 80.2 % ) 11H NMR (CD3OD): 8 6.41 -6.17 (m. 3H).
b)Preparation of N-[ 2-hydroxy-3-fluorophenyl ]-N'-[2-bromophenyl ] urea
N-[2-Hydroxy-3-fluorophenyl]-N'-[ 2-bromo phenyl] urea was prepared from 2-aminυ-3-fluorophenol (254mg, 2.00 mmol ) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane( 1/20) and f iltering ( 500 mg. 77% ) 1H NMR (CD3OD): 8 8.05 (d, 1 H), 7.50 (d, 1 H), 7.26 (t, 1 H), 7.18 (d. 1 H). 6 92 (t, 1 H), 6 86-6 68 (m, 2H).
Example 70
Preparation of N-2-[ 1 -hydroxyfluorene[-N -(2-bromophenyl ] urea a)Preparation of 2-amino- 1 -hydroxyfluorenc
To a solution of 1 -hydroxy-2-nitrofluorene(250 mg, 1.23mmol) in methanol(250mL) was added 10% Pd/C ( 1 g). The mixture was flushed with argon, then hydrogen was bubbled through the solution for 10 mm. and a hydrogen atmosphere was maintained at balloon pressure overnight. The mixture was filtered through celite and the celite was washed with methanol. The solvent was evaporated and chromatography of the resulting solid on silica gel (5%MeOH/ CH2Cl2) gave the desired product( 171 mg, 81.2 %). 1H NMR (CD3OD): 8 7.60 (d, 1 H), 7.47 (d. 1 H), 7.28 (t. 1H), 7. 18 (m, 2H), 6.82 (d. 1H), 3.76 (s. 2H).
b)Preparation of N-2-[ 1-hydroxyfluorene]-N'-(2-bromophenyl] urea
N-2-[ 1-hydroxyfluorene]-N'-[2-bromo phenyl] urea was prepared from 2- amino- 1 -hydroxyfluorene ( 170mg, 0.86 mmol) according to the procedure in General Method B. The product was purified by chromatography of the resulting solid on silica gel (30%EtOAc/ Hexane) to give the desired product (300mg, 84.5%). 1H NMR (CD3Cl): δ 8.04 (d, 1H),
7.66 (d, 1H), 7.49 (t. 2H), 7.35-7.20 (m, 4H). 7.09 (d. 1H). 6.90 (t. 1 H).
Example 71
Preparation of N-3-[2-hydroxy-9, 10-anthraquinonyl]-N'-[2-bromonhenyl] urea
N-3-[2-Hydroxy-9,10-anthraquinonyl]-N'-[2-bromophenyl| urea was prepared from 2-hydroxy-3-aminoanthraquinone(480mg, 2.00 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane( 1/20) and filtering. (610mg, 70%). 1H NMR (CD3OD): 8 8.93 (s.1H). 8.12 (m. 2H). 8.02 (d. 1 H). 7.77 (m, 2H), 7.61 (d, 1 H), 7.52 (s. 1 H), 7.38 (t. 1 H). 7.05 (t. 1 H)
Example 72
Preparation of N-[2-hydroxy-3-[luoro-5-bromophenyl ]-N"-12-bromophenyl ] urea
a)Preparation of 2-amino-6-fluoro-4-bromophenol
A mixture of 4-bromo-2-fluoro 6-nitrophenol( 1 g, 4.2mmol) and tin (II) chloride (4.78 g, 21.2mmol) in ethanol(50mL) was heated at 80°C under argon. After 2 hours, the starting material had disappeared and the solution was allowed to cool down and then poured into ice The pH was made slightly basic (pH7-8), by addition of solid NaOH, bef ore being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/ CH2Cl2) gave the desired product(710 mg. 82 % ) 1H NMR (CD3OD): 8 6.51 -6.40 (m. 2H ) b)Preparation of N-[2-hydroxy-3-fluoro-5-bromophenyl]-N'-[2-bromophenyl] urea
N-[2-hydroxy-3-fluoro-5-bromophenyl]-N'-[2-bromophenyl ] urea was prepared from
2-amino-6-fluoro-4-bromophenol (254mg, 2.00 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane( 1/20) and tillering. (500 mg, 77%;). 1H NMR (CD3OD): 6 7.98 (s, 1 H). 7.91 (d, 1 H), 7.60 (d. 1 H). 7.33 (t, 1 H), 7.00 (t, 1 H), 6.94 (d. 1 H )
Example 73
Preparation of N-[2-hydroxy-3-chlorophenyl]-N'-[2-bromophenyl] urea
a)Preparation of 2-amino-3-chlorophenol
A mixture of 3-chloro-2-nitrophenol(250 mg, 1.4mmol) and tin (II) chloride ( 1.2 g. 5.3mmol) in ethanol(50mL) was heated at 80°C under argon Alter 2 hours, the starting material has disappeared and the solution was allowed to cool down and then poured into ice. The pH was made slightly basic (pH7-8). by addition of solid NaOH. before being extracted with ethyl acetate. The organic phase was washed with brine. dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulung solid on silica gel (4%-MeOH/CH2Cl2) gave the desired product( 143 mg. 69 %) 1H NMR (CD3OD): 6 6.75 (t.1 H), 6.70 (d. 1 H), 6.65 (d, 1H)
b)Preparation of N-[2-hydroxy-3-chlorophenyl]-N'-[2-bromophenyl ] urea
N-[2-hydroxy-3-chlorophenyl]-N'-(2-bromophenyl] urea was prepared from 2-amino-3-chlorophenol ( 143mg, 1.00 mmol) according to the procedure in General Method B. The product was purified by chromatography of the resulung solid on siliea gel (30%EtOAc/ Hexane) to give the desired product( 195mg. 57%). 1H NMR (CD3OD): 6 7.81 (d, 1 H). 7.68 (d, 1H), 7.47 (d, 1 H). 7.20 (t, 1 H). 6.90 (m, 2H), 6.70 (t. 1 H)
Example 74
Preparation of N-[2-hydroxy-3-trifluoromethylphenyl ]-N'-[ 2-hron ophenyl ] urea
a)Preparation of 2-nitro-6-trifluoromethylphenol
2-trifluoromethylphenol (3.00g. 18 5mmol) was dissolved in methylene
chloride(40mL) followed by the addition of sodium nitrate ( 1 .73g. 20.4mmol). The addition of sulfuric acid (23 mL/ 3M) was then made, lollowed by addition ol a catalytic amount ol sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methylene chloride and extracted with water The organie layer was dried over MgSO4 and filtered. The solvent was ev aporated and chromatography of the resulting solid on silica gel (4% MeOH/ CH2Cl2) gave the desired productd(1.84 g.47 % ) 1H NMR
(CD3COCD 3): 8 8.35 (d.1 H). 7.95 ( d. 1 H). 7.1 3 (t.. 1 H).
b)Preparation of 2-amino-6- trifluoromethylphenol
A mixture of 6-trifluoromethy l-2-nitrophenol( 1.84 g. 8.67mmol ) and tin (II ) chloride (6.0 g. 26.2 mmol) in ethanol( 150mL) was heated at 80°C under argon. After 2 hours, the starting material has disappeared and the solution was allowed to cool down and then poured into ice. The pH was made slightly basic (pH7-8), by addition of solid NaOH. betore being extracted with ethyl acetate. The organic phase was washed with brinc. dricd over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulung solid on siliea gel (4%MeOH/ CH2Cl 2) gave the desired product( 1.35 g. 88 % ). 1H NMR (CD3OD): 8 6.93 (d. 1 H), 6.82 (t, 1 H), 6.78 (d, 1 H).
c)Preparation of N-[2-hydroxy-3- trifluoromethylphenyl]-N'-]2-bromophenyl] urea
N-[2-hydroxy-3-trifluoromethylphenyl]-N'-[2-bromophenyl) urea was prepared from 2-amino-6-trifluoromethylphenol (280mg. 1.60 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane( 1/20) and filtering. (390mg, 65%). 1H NMR (CD3OD): 8 7.99 (d, 1 H), 7.60 (d, 1 H), 7.58 (d, 1 H), 7.34 (t, 1 H), 7.30 (d, 1 H), 7.00 (t, 1 H), 6.96 (d, 1 H).
Example 75
Preparation of N-[3,4 diphenyl-2-hydroxyphenyl]-N'-[2-bromophenyl] urea
N-[3,4 diphenyl-2-hydroxyphenyl]-N'-|2-bromophenyl] urea was prepared from 2-amino-5,6 diphenylphenol (50mg, 0.19 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane(1/20) and filtering (61mg. 69%). 1H NMR (CD3OD): 8 7.97 (d. 1 H). 7.66 (d, 1 H), 7.58 (d. 1H). 7.31 (t, 1 H), 7.25-7.00 (m, 1 1 H), 6.91 (d, 1 H). Example 76
Preparation of N-[2-hydroxy-3-glycinemethylestercarbonylphenyl ]-N'-[2-bromophenyl] urea N-[2-hydroxy-3-glycinemethylestercarbonylphenyl]-N'-[2-bromophenyl] urea was prepared from 6-glycinemethylestercarbonyl-2-aminophenol (50mg. 0.22 mmol). purchased from the University of New Hampshire, according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexanc( 1/20) and filtering
(65mg, 69% ) 1H NMR (CD3OD): 6 8.14 (d, 1 H), 7.96 (d, 1 H ), 7.49 (d, 1 H ), 7.24 ( t, 2H),
6.89 (dd, 1 H), 6.81 (t, 1 H), 4.10 (s.2H). 3.74 (s.3H )
Example 77
Preparation of N-[2-hydroxy-3-glycinecarbonylphenyl ]-N"-[ 2-bromopheny l ] urea
N-(2-Hydroxy-3-glyeinecarbonylphenyl ]-N'-|2-bromophenyl] urea was prepared from N-[2-hydroxy-3-glyeinemethylestercarbonylphenyl ]-N '-[ 2-bromophenyl ] urea (50mg. 0.12 mmol) by stirring in a 3/1 ratio of methanol/water ( 10 mL) Addition of 1 equiv of lithium hydroxide was added and stirring continued until the starting material had disappeared (45mg. 92% ). The product was purified by chromatography of the resulting solid on silica gel (9/1/0. 1 CH2Cl2/ MeOH/ AcOH) to give the desired produe ( 195mg. 57% ) 1H NMR (CD3OD): 8 8.14 (d, 1 H), 7.92 (d, 1 H), 7.60 (d, 1 H), 7 46 (d, 1 H), 7 34 (t, 1 H), 7.04 (t, 1 H), 6 82 (t, 1 H). 3.96 (2H). Example 78
Preparation of N-[2-hydroxy-3,5-dichlorophenyl]-N'-12-bromophenyl] urea
a)Prcparation of 2-amino-4,6-dichlorophenol
A mixture of 4,6-dichloro-2-nitrophenol( 1 g, 4.8mmol) and tin (II) chloride (3.2 g,
14.4mmol) in ethanol(50mL) was heated at 80°C under argon. After 2 hours, the starting material had disappeared and the solution was allowed to cool down and then poured into ice. The pH was made slightly basic (pH7-8), by addition of solid NaOH. before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/CH2Cl2) gave the desired product(685 mg, 80 % ) 1H NMR (CD3OD): 8 6.75 (s.1 H), 6.61 (s, 1 H)
b)Preparation of N-[2-hydroxy-3,5-dichlorophenyl]-N'-[2-bromophenyl] urea
N-[2-Hydroxy-3,5-dichlorophenyl]-N'-[2-bromophenyI] urea was prepared from 2-amino-4,6-dichlorophenol ( 143mg, 1.00 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane( 1/20) and filtering (660mg, 88% ). 1H NMR (CD3OD): 6 7.96 (s. 1H), 7.89 (d, 1H). 7.60 (d, 1H), 7.35 (t. 1 H). 7.00 (t, 1 H). 6.95 (dd, 1 H). Example 79
Preparation of N-[2-hydroxy-3-nitrophenyl]-N'-[2-bromophenyl] urea
N-[2-Hydroxy-3-nitrophenyl ]-N'-[2-bromophenyl] urea was prepared trom 2-hydroxy-3-nitroaniline ( 1.25g. 8.1 mmol) according to the procedure in General Method B . The product was purified by precipitation from methylene chloride/ hexane( 1/20) and filtering. (2.4g. 84% ) 1H NMR (CD3OD): 8 8.45 (d, 1 H), 7.94 (d, 1 H), 7.78 (d, 1 H), 7.60 (d, 1 H), 7.35 ( t. 1 H), 7.01 (m, 2H)
Example 80
Preparation of N-[2-hydroxy -4-naphthalenesulfonic acid]-N'-[2-bromophenyl] urea
N-[2-hydroxy-4-naphthalenesulfonic acid]-N'-[2-bromophenyl ] urea was prepared from 1 -amino-2-hydroxy-4-naphthalensulfonie acid (0.48g. 2.0 mmol) according to the procedure in General Method B and the addition of l mL of triethylamine The product was purif ied by precipitation from methylene chloride/ hexane( 1/20) and filtering. (690 mg, 79% ), 1H NMR (CD3OD ): δ 8.14 ( s, 1 H ), 8.04 (d, 1 H), 7.98 ( m, 2H), 7.61 -7.55 (m, 3H), 7.43 (t, 1 H), 6.98 (t, 1 H).
Example 81
Preparation of N-[2-hydroxy -5-naphthalenesulfonic acid]-N'-12-bromophenyl] urea N-3-[2-hydroxy-5-naphthalensulfonic acid]-N'-[2-bromophenyl] urea was prepared from 2-amino-3-hydroxy-6-naphthalensulfonic acid (0.48g, 2.0 mmol ) according to the procedure in General Method B and the addition of 1 mL of triethylamine The product was purified by precipitation from methylene chloride/ hexane(1/20) and filtering. (715 mg, 82% ). 1H NMR (CD3OD): δ 8.09 (s, 1 H), 7.96 (d, 1 H), 7.65-7.48 (m, 3H), 7.36 (t, 1 H), 7.25 (s, 1 H), 7.04 (m, 2H).
Example 82
Preparation of N-[2-hydroxy-3,4-dichlorophenyl]-N'-[2-bromophenyl] urea
a)Preparation of 2-nitro-5,6 dichlorophenol
2,3-dichlorophenol (3.26g, 20mmol) was dissolved in methylene chloride(40mL) followed by the addition of sodium nitrate ( 1.88g, 22mmol). The addition of sulfuric acid (20mL/ 3M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/CH2Cl2) gave the desired product( 1.8 g, 44 %). 1H NMR (CD3COCD3):
δ 8.04 (d, 1 H), 7. 15 (d, 1H).
b)Preparation of 2-amino-5,6 dichlorophenol
A mixture of 5.6-dichloro-2-nitrophenol( 1.8 g. 8.7mmoI) and tin (II) chloride (5.8 g.
26. 1 mmol) in ethanol(50mL) was heated at 80°C under argon. After 2 hours, the starting material had disappeared and the solution was allowed to cool down and then poured into ice The pH was made slightly basic (pH7-8), by addition of solid NaOH. before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and filtered The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/ CH2Cl2) gave the desired product( 1 .4 mg, 90 % ). 1H NMR (CD3OD): δ 6.71 (d, 1 H), 6.45 (d, 1 H).
c)Preparation of N-[2-hydroxy-3.4-dichlorophenyl]-N'-[2-bromophenyl] urea
N-[2-Hydroxy-3,4-dichlorophenyl]-N'-[2-bromophenyl] urea was prepared from 2-amino-5,6-dichlorophenol (350mg, 2.00 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane( 1/20) and filtering (670mg, 89% ). 1H NMR (CD3OD): δ 7.90 (d, 1 H), 7.85 (d, 1 H), 7.59 (d, 1 H ), 7.3 1 (t, 1 H), 6.99 ( t, 1 H), 6.96 (d, ( 1 H). Example 83
Preparation of N-[ 2-hydroxy-3-cyanophenyl]-N'-[2-bromophenyl] urea
a)Preparation of 2-nitro-6-cyanophenol 2-cyanophenol (2.38g. 20mmol) was dissolved in methylene chloride(40mL) followed by the addition of sodium nitrate ( 1.88g, 22mmol). The addition ol sulfuric acid (20mL/ 3M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/ CH2Cl2) gave the desired product( 1.4 g, 42 % ). 1H NMR (CD3COCD3): δ 8.47 (d.1 H). 8. 15 (d. 1 H), 7.30 (t, 1 H).
b)Preparation of 2-amino-6-cyanophenol
A mixture of 6-cyano-2-nitrophenol(600 mg, 1.0mmol) and tin (II) chloride (3.2 g.
14.4mmol) in acetic acid(50mL) was heated at 80°C under argon. After 2 hours, the starting material has disappeared and the solution was allowed to cool down and then poured into ice. The pH was made slightly basic (pH7-8), by addition of solid NaOH. before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and filtered The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/CH2Cl2) gave the desired product(365 mg. 75 %). 1H NMR (CD3OD): 8 6.92 (d, 1 H). 6.85-6.69 (m,2H).
c)Preparation of N-[2-hydroxy-3-cyanophenyl]-N'-[2-bromophenyl] urea
N-[2-Hydroxy-3-cyanophenyl]-N'-[2-bromophenyl] urea was prepared from 2-amino-6-cyanophenol ( 134mg, 1.00 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane( 1/20) and filtering. (260mg. 78% ). 1H NMR (CD3OD): 8 7.98 (d. 1H). 7.74 (d. 1 H). 7.57 (d. 1 H). 7.30 (t. 1 H). 7.22 (d. 1 H). 6.98 (t. 1H), 6.94 (t, ( 1 H). Example 84
Preparation of N-[2-hydroxy-4-cyanophenyl]-N'-[2-bromophenyl] urea
a)Preparation of 2-nitro-5-cyanophenol
3-cyanophenol (2.38g. 20mmol) was dissolved in methylene chloride(40mL) followed by the addi tion of sodium nitrate ( 1.88g. 22mmol). The addition ol sulfurie acid (20mL/ 3M) was then made, followed by addition ol a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methylene chloride and exiracted with water. The organic layer was dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%-MeOH/ CH2Cl2) gave the desired product(910 mg. 28 % ) 1H NMR (CD3COCD3): δ 8.30 (d, 1 H), 7.67 (s, 1 H), 7.49 (d, 1 H).
b)Preparation of 2-amino-5-cyanophenol
A mixture of 5-cyano-2-nitrophenol(250 mg, 1.5mmol) and tin (II) chloride (3.2 g. 14.4mmol) in ethanol(50mL) was heated at 80°C under argon. After 2 hours, the starting material has disappeared and the solution was allowed to cool down and then poured into ice. The pH was made slightly basic (pH7-8), by addition of solid NaOH. before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%. MeOH/CH2Cl2) gave the desired product( 175 mg, 86 % ). 1H NMR (CD3OD): 8 7.00 (d, 1 H). 6.88 (s, 1 H), 6.69 (d, 1H).
c)Preparation of N-[2-hydroxy-4-cyanophenyl]-N'-[2-bromophenyl] urea
N-[2-Hydroxy-4-cyanophenyl]-N'-[2-bromophenyl] urea was prepared from 2-amino-5-cyanophenol ( 170mg, 1.27 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane( 1/20) and filtering (310mg, 74%). 1H NMR (CD3OD): δ 8.25 (d, 1H), 7.91 (d, 1 H), 7.59 (d, 1 H), 7.33 (t, 1 H), 7.17 (d, 1H), 7.07 (s, 1H), 7.01 (t, ( 1 H).
Example 85
Preparation of N-[2-hydroxy-4-cyanophenyl]-N'-[4-methoxyphenyl] urea
N-[2-Hydroxy-4-cyanophenyl]-N'-[4-methoxyphenyl] urea was prepared from 2-amino-5-cyanophenol (60mg, 0.45 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane(1/20) and filtering. ( 1 10mg,86%). 1H NMR (CD3OD): δ 8.23 (d, 1 H), 7.61 -7.51 (m. 2H), 7.32 (d, 1 H), 7.20 (d, 1H), 7.15 (d, 1H), 7.03 (s, 1H).
Example 86
Preparation of N-[2-hydroxy-4-cyanophenyl]-N'-[2-phenylphenyl] urea N-[2-Hydroxy -4-cyanophenyl ]-N'-[2-phenylphenyl] urea was prepared from 2-amino-5-cyanophenol ( 170 mg. 1.27 mmol) according to the procedure in General Mediod B. The product was purified by precipitation from methylene chloride/ hexane( 1/20) and filtering. ( 150mg, 85% ), 1H NMR (CD3OD): 6 8.20 (d, 1 H), 7.73 (d, 1 H), 7.51 -7.20 (m, 8H), 7. 13 (d, 1 H), 7.01 (s, ( 1 H) .
Example 87
Preparation of N-[2-hydroxy-4-cyanophenyl -N'-[2-methylphenyl] urea
N-[2-Hydroxy-4-cyanophenyl]-N'-[2-methylphenyl] urea was prepared from 2-amino-5-cyanophenol (60mg, 0.45 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexanc( 1/20) and filtering (90mg, 75% ). 1H NMR (CD3OD): δ 8.25 (d, 1 H), 7.59 (d, 1 H), 7.26-7.00 (m, 5H), 2.30 (s, 3H).
Example 88
Preparation of N-[2-hydroxy-4-cyanophenyl]-N'-[2-trifluoromethylphenyl] urea N-[2-Hydroxy-4-cyanophenyl]-N'-[2-trifluoromethylphenyl] urea was prepared from 2-amino-5-cyanophenol (60mg, 0.45 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane(1/20) and filtering. ( 1 10mg, 76% ). 1H NMR (CD3OD): δ 8.25 (d, 1 H), 7.81 (d, 1 H). 7.68 (d, 1 H), 7.61 (t. 1H). 7.32 (t. 1H), 7.15 (dd, 1 H), 7.09 (s, ( 1H).
Example 89
Preparation of N-[2-hydroxy-4-cyanophenyl]-N'-[3-trifluoromethylphenyl] urea
N-[2-hydroxy-4-cyanophenyl]-N'-[3-trifluoromethylphenyl] urea was prepared from 2-amino-5-cyanophenol (60mg, 0.45 mmol) according to the procedure in General Method B The product was purified by precipitation from methylene chloride/ hexane(1/20) and filtering ( 1 14mg, 79%). 1H NMR (CD3OD): 8 8.30 (d, 1H), 7.92 (s, 1 H), 7.60 (d, 1H), 7.47 (t, 1 H), 7.29 (d, 1H), 7. 18 (dd, 1H), 7.06 (s, 1H). Example 90
Preparation of N-[2-hydroxy-4-cyanophenyl]-N'-[4-tri fluoromethylphenyl] urea
N-[2-Hydroxy-4-cyanophenyl]-N'-[4-trifluoromethylphenyl] urea was prepared from
2-amino-5-cyanophenol (60mg, 0.45 mmol) according to the procedure in General Method B.
The product was purified by precipitation from methylene chloride/ hexane(l/20) and filtering. ( 108mg, 75% ). 1H NMR (CD3OD): δ 8.31 (d, 1H), 7.68 (d, 2H), 7.59 (d, 2H), 7.20 (dd, 1 H), 7.07 (s, 1 H).
Example 91
Preparation of N-[2-hydroxy-3-n-propylphenyl]-N'-[2-hromophenyl] urea
a)Preparation of 2-nitro-6-n-propylphenol
2-n-propylphenol (5.00g, 36.8mmol) was dissolved in methylene chloride(40mL) followed by the addition of sodium nitrate (3.43g, 40.5mmol). The addi tion of sulf uric acid (45mL/ 3M) was then made, followed by addition of a catalytic amount of sodium nitrite The mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO4 and filtered The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/CH2Cl2) gave the desired product(3.2 mg, 48 % ). 1H NMR (CD3COCD3): δ 7.99 (d, 1 H ), 7.46 dd, 1 H), 6.90 (t, 1H), 2.70 (t, 2H), 1.70 ( m, 2H), 1.00 (t, 3H).
b)Preparation of 2-amino-6-n-propylphenol
To a solution of 2-nitro-6-n-propylphenol (2g, 1 1.0mmol ) in methanol ( 100mL) was added 10% Pd/C (200 mg). The mixture was Hushed with argon, then hydrogen was bubbled through the solution for 10 min. and a hydrogen atmosphere was maintained at balloon pressure overnight. The mixture was filtered through celite and the celite was washed with methanol. The solvent was evaporated and chromatography of the resulting solid on silica gel (5% MeOH/ CH2Cl2) gave the desired product(1.50 g. 80.2 % ). 1H NMR (CD3OD): 8 6.65 (m. 2H), 6.55 (t, 1 H), 2.58 (t. 2H), 1.61 (m, 2H), 0.96 (t, 3H).
c)Preparation of N-[2-hydroxy-3-n-propylphenyl]-N'-[2-bromophenyl ] urea
N-[2-Hydroxy-3-n-propyl phenyl ]-N'-[2-bromo phenyl] urea was prepared from 2-amino-6-n-propyl phenol (302mg, 2.00 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane( 1/20) and filtering. (640mg,92%). 1H NMR (CD3OD): 6 8.00 (d, 1 H), 7.58 (d. 1 H). 7.32 (t. 1 H). 7.26 (t, 1 H), 6.96 (dd, 1 H), 6.89 (t, 1 H), 6.78 (d. 1 H).
Example 92
Preparation of N-[2-hydroxy-4-ethylphenyl]-N'-[2-hromophenyl] urea
a)Preparation of 2-nitro-5-ethylphenol
3-ethylphenoI (5.00g, 41 mmol) was dissolved in methylene chloride(40 mL) followed by the addition of sodium nitrate (3.83g, 45 mmol). The addition of sulfuric acid (50mL/ 3M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/ CH2Cl2) gave the desired product( 1.7 g, 25 %). 1 H NMR (CD3COCD3): 6 8.02 (d.1 H). 6.99 (s.1 H). 6.85 (d, 1 H), 2.69 (q. 2H), 1.30 (t, 3H).
b)Preparation of 2-amino-5-ethyllphenol
To a solution of 2-nitro-5-ethylphenol( 1g. 6.4mmol) in methanol(250mL) was added 10% Pd/C (100 mg). The mixture was flushed with argon, then hydrogen was bubbled through the solution for 10 min. and a hydrogen atmosphere was maintained at balloon pressure overnight. The mixture was filtered through celite and the celite was washed with methanol. The solvent was evaporated and chromatography of the resulting solid on silica gel (5% MeOH/ CH2Cl2) gave the desired product(750 mg, 91 % ). 1 H NMR (CD3OD): δ 6.41 -6. 17 (m, 3H).
c)Preparation of N-[2-hydroxy-4-ethylphenyl]-N'-[2-bromophenyl] urea
N-[2-Hydroxy-4-ethylphenyl]-N'-(2-bromo phenyl] urea was prepared from 2- amino-5-ethylphenol (274mg, 2.00 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane( 1/20) and filtering. (520 mg. 77%). 1H NMR (CD3OD): 8 7.96 (d. 1 H). 7.62 (s. 1 H). 7.56 (d. 1 H). 7.30 ( t. 1 H). 6.96 (t, 1 H). 6.82 (d. 1 H). 6.76 (d, 1 H).
Example 93
Preparation of N-(2-hydroxy 3-phenylaminocarbonyl phenyl]-N'-[2-bromophenyl ] urea a)Preparation of 2-nitro-6-phenylaminocarbonylphenol
2-Phenylaminocarbonylphenol (5.00g. 23 mmol) was dissolved in methylene chloride(40mL) followed by the addition of sodium nitrate (2.20g. 25.5 mmol). The addition of sulfuric acid (30mL/ 3M) was then made, followed by addition of a catalytic amount ol sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH2Cl2) gave the desired product(2.50 g. 42 % ). 1H NMR
(CD3COCD3): δ 8. 15 (d, 1 H), 8.09 (d, 1 H), 7.51 (d, 1 H), 7.30 (d, 1 H), 7 10 (t, 1H), 7.01 (t, 1 H).
b) Preparation of 2-amino-6-phenylaminocarbonylphenol
To a solution of 2-nitro-6-phenylaminocarbonylphenol ( 1g. 4.0 mmol) in
methanol(250mL) was added 10%.Pd/C ( 100 mg). The mixture was Hushed with argon, then hydrogen was bubbled through the solution for 10 m in. and a hydrogen atmosphere was maintained at balloon pressure overnight. The mixture was filtered through celite and the celite was washed with methanol. The solvent was evaporated and chromatography of the resulting solid on silica gel (5%MeOH/ CH2Cl2) gave the desired producl(800 mg, 91 %). 1H NMR (CD3OD): 8 7.73-7.57 (m, 2H), 7.43-7.27 (m, 3H), 7.25-7.10 (m. 1 H). 6.94 (t. 1H). 6.74 (t, 1H).
c) Preparation of N-[2-hydroxy 3-phenylaminocarbonyl phenyl]-N'-]2-bromophenyl] urea N-[2-hydroxy 3-Phenylaminocarbonyl phenyl]-N'-[2-bromo phenyl] urea was prepared from 2-amino-6-phenylaminocarbonylphenoI (456mg. 200 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane( 1/20) and filtering. (800mg.94% ) 1H NMR (CD3OD ) 1H NMR (CD3OD): δ 25 (d, 1H), 7.94 (d. 1 H). 7.75-7.57 (m. 4H). 7 48-7.30 (m. 3H). 7.21 (t. 1 H). 7.02 (dd. 1 H), 6.92 (t, 1 H).
Example 94
Preparation of N-[2-hydroxy-3-cyano-4-methylphenyl]-N'-[2-hromophen yl ] urea
a) Preparation ot the 2-nitro 5-methyl 6-bromo phenol
A solution of t-butyl amine(6.88 mL. 4 79 g. 2 equiv .) in methylene chloride was treated with bromine ( 1.67 mL. 5.2 g. 1 equiv ) at -20 ºC The flask w as then cooled to -78 °C and the the 2-nitro 5-methyl 6-bromo phenol (5 g. 1 equiv., in methylenc chloride) was added drop-wise with vigrous stirring. The reaction mixture was slowly warmed to -30 ºC for 1 h. then to - 10 ºC for 2 hours. The reaction mixture was then partitioned between methylene chloride and 5% aqueous acetic acid. The organic layer was dried over magnesium sulfate. filtered and concentrated in vacuo. The reaction mixture was purified by flash chromatography(Ethyl acetate/ hexanes) to remove dibrominated species. The 2-nitro 4-bromo 5-methyl phenol was then selectively crystallized out of methylene chloride. A final silica gel column(5% ethyl acetate/ hexanes) yielded desired isomer in 90% purity.( 1.05 g. 14% ) 1H NMR (CDCl3): δ 7.95 (d, 1 H, J = 10.0 Hz), 6.91 (d, 1 H, J = 10.0 Hz). 2.52 (s, 3H).
b) Preparation of 2-nitro-5-methyl-6-cyanophenol
2-Nitro-5-methyl-6-bromophenol ( 100 mg, 0.433 mmol) was dissolved in dimethyl formamide (2mL) followed by the addition of triethylamine (0.175g, 1.73 mmol). The addition of a catalytic amount dimethylamino pyridine was then made, followed by addition of copper (I) cyanide (155mg, 1.73mmoI). The mixture was allowed to stir at 80°C for 4 hours. The solvent was evaporated and chromatography of the resulting solid on silica gel (2%MeOH/CH2Cl2) gave the desired product (70 mg. 91 %). 11H NMR (CD3COCD3): δ 8.30 (d, 1 H), 7. 15 (d, 1 H), 2.61 (s, 3H).
c) Preparation of 2-amino-5-methyl 6-cyanophenol
A mixture of 5-cyano-2-nitrophenol(70 mg, 0.39mmol) and tin (II) chloride (265 mg. 1.18mmol) in ethanol(20mL) was heated at 80°C under argon. After 2 hours, the starting material has disappeared and the solution was allowed to cool down and then poured into ice.
The pH was made slightly basic (pH7-8), by addition of solid NaOH, before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and filtered.
The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/CH2Cl2) gave the desired producK 175 mg, 86 %). 1H NMR (CD3OD): 8 6.87 (d, 1H), 6.75
(d.1 H). 6.32 (s. 3H).
d) Preparation of N-[2-hydroxy 3-cyano 4-methy] phenyl]-N'-[2-bromophenyl] urea
N-[2-hydroxy 3-cyano 4-methyl phenyl]-N'-[2-bromophenyl] urea was prepared from 2-amino-5-methy]-6-cyano phenol (50mg, 0.34 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane( 1/20) and filtering (70mg. 60% ) 1H NMR (CD3OD): 6 7.92 (d. 1 H). 7.68 (d. 1 H). 7.59 (d. 1 H). 7.31 (t. 1 H). 7.00 (t. 1 H). 6.62 (t. 1 H). 2.49 (s. (3H)
Example 95
Preparation of N-[2-hydroxy 4-Carboxyphenyl phenyl ]-N"-[2-hromophenyl ] urea
a)Preparation of 4-nitro-3-hydroxybenzophenonc
3-Hydroxybenzophenone (3.00g, 15. 1 mmol) was dissolved in methylene
chloride(40mL) followed by the addition of sodium nitrate ( 1.42g. 16.7mmol) The addition of sulfuric acid (25mL/ 3M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. Af ter 24 hours, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/ CH2Cl2) gave the desired product( 1.10 g. 30 % ). 11H NMR (CD3COCD6): δ 8.25 (d, 1 H), 7.86 (d,1 H), 7.71 (m, 1 H), 7.59 (d, 1 H), 7.48 (s, 1 H), 7.39
(dd, 1 H).
b)Preparation of 4-amino-3-hydroxybenzophenone
A mixture of 4-nitro-3-hydroxybenzophenone (900 mg, 3.7mmol) and tin (II) chloride (2.5 g. 1 1.1 mmol) in ethanol(50mL) was heated at 80°C under argon . After 2 hours, the starting material has disappeared and the solution was allowed to cool down and then poured into ice. The pH was made slightly basic (pH7-8), by addition of solid NaOH, before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/ CH2Cl2) gave the desired product(685 mg, 87 % ). 1 H NMR (CD3OD): 8 7.65 (d,
2H), 7.55 (d,1H), 7.49 (t, 2H). 7.26 (s, 1 H), 7.16 (dd, 1H), 6.68 (d, 1H).
c)Preparation of N-[4-Carboxyphenyl-2-hydroxyphenyl]-N'-[2-bromophenyl] urea
N-[4-Carboxyphenyl-2-hydroxyphenyl]-N'-[2-bromophenyl] urea
was prepared from 4-amino-3-hydroxybenzophenone (330mg, 1.5 mmol) according to the procedure in General Mediod B. The product was purified by precipitation from methylene chloride/ hexaned/20) and filtering. (490mg, 79%). 1H NMR (CD3OD): 6 8.40 (d, 1H),
8.09 (d, 1 H), 7.83 (d. 2H), 7.65-7.60 (m, 4H), 7.48 (s, 1H), 7.43 (d, 1H), 7.35 (d, (1 H),
7. 10 (1.1H). Example 96
Preparation of N-[2-hydroxy 3-carboxyphenyl phenyl]-N'-[2-hromophenyl] urea
a)Prcparation of 3-nitro-2-hydroxybenzophenone
2-Hydroxybenzophenone (3.00g, 15. 1 mmol) was dissolved in methylene
chloride(40mL) followed by the addition of sodium nitrate ( 1.42g. 16 7mmol) The addition of sulfuric acid (25mL/ 3M) was then made, followed by addition of a catalytic amount of sodium nitrit e. The mixture was allowed to stir Af ter 24 hours, the reaction mixture was diluted wi th methylene chloride and extracted with water. The organic layer was dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/ CH2Cl 2) gave the desired produet( 1 .60 g. 44 % ) 1H NMR
(CD3COCD3): δ 8.30 (d, 1 H ), 7.86 (m,3H), 7.7 1 ( m, 1 H), 7.78 (d, 1 H). 7 56 (dd 2H ), 7.24
(t, 1 H) .
b)Preparation of 3-amino-2-hydroxybenzophenone
A mixture of 3-nitro-2-hydroxybenzophenone (600 mg. 2.5mmol ) and tin (II) chloride ( 1 7 g, 7.5mmol) in ethanol(50mL) was heated at 80°C under argon. Alter 2 hours, the starting material had disappeared and the solution was allowed to cool down and then poured into ice. The pH was made slightly basic (pH7-8). by addition of solid NaOH. before being extracted with ethyl acetate. The organic phase was washed with brine. dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH2C l2) gave the desired product(490 mg, 92 % ). 1H NMR (CD3OD): δ 7.65-7.40 (m, 5H), 6.98 (d, 1H), 6.86 (d, 1 H), 6.67 (t, 1H).
c)Preparation of N-[2-hydroxy 3-carboxyphenyl phenyI]-N'-[2-bromophenyl] urea
N-[2-hydroxy 3-carboxyphenyl phenyl]-N'-[2-bromophenyl] urea was prepared from 3-amino-2-hydroxybenzophenone (250mg, 1.20 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane( 1/20) and filtering. (200mg, 78% ). 1H NMR (CD3OD): δ 8.35 (d, 1 H), 7.96 (d, 1 H). 7.72 (d. 2H), 7.65-7.50 (m, 4H), 7.35 (d. 1 H). 7.30 (d, 1H). 7.01 (dd. ( 1 H). 6.92 (t. 1 H)
Example 97
Preparation of N-[2-hydroxy 3-benzyloxy phenyI]-N'-[2-hromophenyl] urea
a)Preparation of 2-nitro-6-benzyloxy phenol
2-Benzyloxyphenol (5.00g. 25.0mmol) was dissolved in methylene chloride(40mL) followed by the addition of sodium nitrate (2.30g, 27.5mmol). The addition of sulfuric acid (31mL / 3M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methylene chloride and extracted wilh water. The organic layer was dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH2Cl2) gave the desired product(2.6 g, 43 %). 1H NMR (CD3COCD3): 8 7.70 (d, 1 H). 7.50-7.28 (m, 5H), 7. 14 (d. 1 H), 6.92 (t, 1H), 5.21 (s, 2H).
b)Preparation of 2-amino-6-benzyloxy phenol
A mixture of 2-nitro-6-benzyloxy phenol (1.00 g, 4.10mmol) and tin (II) chloride (2.75 g. 12.2 mmol) in ethanol( 150mL) was heated at 80°C under argon. After 2 hours, the starting material had disappeared and the solution was allowed to cool down and then poured into ice. The pH was made slightly basic (pH7-8). by addition of solid NaOH. betore being extracted with ethyl acetate. The organic phase was washed wilh brine. dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%-MeOH/ CH2Cl2) gave the desired product( 1.35 g. 88 % ). 1H NMR (CD3OD): 87.46 (d, 2H), 7.40-7.35 (m, 5H), 6.55 (d, 1 H), 6.40 (d. 1 H). 5. 10 (s. 2H)
b)Preparation of N-[2-hydroxy3-benzyloxy phenyl]-N'-]2-bromophenyl] urea
N-[3-benzyloxy-2-hydroxyphenyl]-N'-[2-bromophenyl] urea was prepared from 2-nitro-6-benzylox y phenol (430mg. 2.00 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane( 1/20) and fillering (630mg. 76% ). 1H NMR (CD3OD): δ 7.93 (d, 1 H), 7.58 (d, 1 H), 7.54-7.42 (m, 3H), 7.40-7.25 (m, 4H), 7.00 (t, 1 H ), 6 69 (d, 2H), 5. 16 (s, 2H).
Example 98 Preparation of N-3-[2-hydroxy-5-indanone]-N'-[2-hromophenyl] urea
a)Preparation of 2-hydroxy-3-nitro-5-indanone
2-Hydroxy-5-indanone(3.00g, 20.0mmol) was dissolved in methylene chloride(40mL) followed by the addition of sodium nitrate ( 1.95g, 21.0mmol). The addition of sulfuric acid (25mL/ 3M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO4 and filtered The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/ CH2Cl2) gave the desired product(1.5 g, 39 %). 1H NMR (CD3COCD3): 8 7.70 (d.1 H), 7.04 (d. 1 H), 3.04 (d, 2H). 2.74 (d, 2H).
b)Preparation of 3-amino-2-hydroxy-5-indanone
A mixture of 2-hydroxy-3-nitro-5-indanone ( 1.50 g, 7.80mmol) and tin (II) chloride (5.25 g, 23.3 mmol) in ethanol( 150mL) was heated at 80°C under argon. After 2 hours, the starting material had disappeared and the solution was allowed to cool down and then poured into ice. The pH was made slightly basic (pH7-8), by addition of solid NaOH, before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH2Cl2) gave the desired product(1.00 g, 79 %). 1H NMR (CD3OD): 8 6.85 (d, 1 H), 6.45 (d, 1H), 2.95 (d, 2H), 2.60 (d, 2H).
c)Preparation N-3-[2-hydroxy-5-indanone]-N'-[2-bromophenyl] urea
N-[2-Hydroxy-5-indanone]-N'-[2-bromophenyl] urea was prepared from 3-amino-2- hydroxy-5-indanone (326mg, 2.00 mmol) according to the procedure in General Method B . The product was purified by precipitation from methylene chloride/ hexane( 1/20) and filtering (610mg. 85% ) 1H NMR (CD 3OD): 6 7.92 (d, 1 H), 7.65 (m, 2H), 7 45 (t, 1 H), 7 09 ( t, 1 H), 7 00 (d, 1H), 2.90 (d, 2H), 2.66 (d. 2H)
Example 99
Preparation of (E)-N-[4-[ 2-(Methoxycarbonyl) ethenyl]-2-hydroxyphenyl]-N'-[2-bromophenyl] urea a)Preparation of 4-nitro-3-hydroxycinnamic acid
3-Hydroxycinnamic acid (3.00g, 18.3 mmol) was dissolved in methylene
chloride(40mL) followed by the addition of sodium nitrate ( 1.70 g. 26.1 mmol). The addition of sulf uric acid (25 mL/ 3M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over
MgSO4 and filtered. The solvent was evaporated and chromatography ot the resulting solid on si lica gel (4%MeOH/ CH2Cl2) gave the desired product( 1.0 g, 26 % ). 1H NMR (CD3COCD3): 6 8.07 (d, 1H), 7.69 (d, 1H), 7.51 (s, 1H) , 7.46 (d, 2H), 6.75 (d.1H)
b) Preparation of 4-nitro-3-hydroxymethylcinnamate
4-Nitro-3-hydroxycinnamic acid was stirred in excess methanol with a catalytic amount of sulfuric acid. The solvent was evaporated and chromatography of the resulung solid on silica gel (4% MeOH/ CH2Cl2) gave the desired product( 1.0 g, 94 %) 1H NMR (CD3COCD3): 8 8.17 (d, 1H), 7.69 (d, 1H), 7.52 (s, 1H), 7.45 (d, 2H), 6.75 (d.1H). 3 80 (s, 3H) c)Preparation of 4-amino-3-hydroxymethylcinnamate
A mixture of 4-nitro-3-hydroxymethylcinnamate ( 1.0 g, 4.50mmol) and tin (II) chloride (3.0 g. 13.4 mmol) in ethanol(50mL) was heated at 80°C under argon. After 2 hours. the starting material had disappeared and the solution was allowed to cool down and then poured into ice. The pH was made slightly basic (pH7-8), by addition of solid NaOH. before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH2Cl2) gave the desired product (650 mg, 75 % ) 1H NMR (CD3OD): 87.50 (d,1H), 6.94 (s, 1H), 6.89 (d, 1H), 6.68 (d, 1H), 6.18 (d, 1H). 3.74 (s, 3H).
d)Preparation (E)-N-[4-[2-(Methoxycarbonyl) ethenyl]-2-hydroxyphenyl]-N'-[2-bromophenyl] urea
(E)-N-[4-[2-(Methoxycarbonyl) ethenyI]-2-hydroxyphenyl]-N'-[2-bromophenyl ] urea was prepared from 4-amino-3-hydroxymethylcinnamate (250mg, 1.3 mmol) according to the procedure in General Mediod B. The product was purified by precipitation from methylene chloride/ hexane(1/20) and filtering (300mg. 59% ) 1H) NMR (CD3OD): 8 8.24 (d.1H). 8.05 (d. 1H), 7 69 (d, 1 H), 7.65 (d, 1H), 7.42 (t, 1 H), 7.21 (s, 1 H), 7.19 (d, 1 H), 7. 10 ( t, 1 H ) 6.45 (d, 1H) 3.81 (s, 3H).
Example 100
Preparation of (E)-N-[3-[2-(Methoxycarbonyl) ethenyl]-2-hydroxyphenyl]-N'-[2-bromophenyl] urea N'-[2-hromophenyl ] urea
a)Preparation of 3-nitro-2-hydroxycinnamic acid
2-Hydroxycinnamic acid (3.00g, 18.3 mmol) was dissolved in methylene
chloride(40mL) followed by the addition of sodium nitrate (2.21 g. 26.1 mmol). The addition of sulfuric acid (30 mL/ 3M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to sur After 24 hours, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH2Cl2) gave the desired product(2.0 g. 52 % ) 1H) NMR (CD3COCD 3 ) δ 8.21 (d, 1 H ), 8. 16 (d, 1 H ), 8.05 (d, 1 H ), 7 19 (t, 1 H ), 6.72 (d, 1 H ) b) Preparation of 3-nitro-2-hydroxymethylcinnamate
3-nitro-2-hydroxycinnamic acid was stirred in excess methanol with a catalytic amount of sulf uric acid The solvent was evaporated and chromatography ot the resulting solid on silica gel (4%MeOH/ CH2Cl2) gave the desired product( 1.0 g, 94 % ) 1H NMR (CD3COCD3): δ 8.25 (d, 1 H), 7.8.15 (d, 1 H), 8.06 (s, 1 H), 7.20 (t, 2H), 6.76 (d, 1 H), 3.80 (s, 3H).
c)Preparation of 3-amino-2-hydroxymethylcinnamate
A mixture of 3-nitro-2-hydroxymethylcinnamate ( 1.0 g, 4 5 mmol) and tin (II) chloride (3.0 g. 13.4 mmol) in ethanol(50mL) was heated at 80°C under argon. After 2 hours, the starting material had disappeared and the solution was allowed to cool down and then poured into ice . The pH was made slightly basic (pH7-8). by addition ol solid NaOH. bef ore being extracted with ethyl acetate. The organic phase was washed with brine. dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH2Cl2) gave the desired product (700 mg, 81 % ). 1H NMR (CD3OD): 8 8.04 (d. 1H), 6.93 (d, 1H),6.79 (d, 1H), 6.71 (t, 1H), 6 43 (d, 1 H), 3 72 (s. 3H)
d) Preparation(E)-N-[3-[2-(Methoxycarbonyl) ethenyl]-2-hydroxyphenyl]-N'-[2-bromophenyl ]urea
(E)-N-[3-[2-(Methoxycarbonyl) ethenyl]-2-hydroxyphenyl]-N'-[ 2-bromophenyl ] urea was prepared from 3-amino-2-hydroxymethylcinnamate (100 mg, 0.52 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane(1/20) and filtering ( 150mg, 74% ) 1H NMR (CD3OD): 6 8.10 (d.1 H). 8.00 (d. 1 H). 7 69 (d, 1H), 7.65 (d, 1 H), 7 42 (t, 1H), 7 38 (l. 1 H). 7 32 (d. 1 H) 7 0S (t. 1 H) 6 55 (d.1 H) 3 81 (s, 3H)
Example 101
Preparation of (E)-N-[3-[2-(Aminocarbonyl) ethenyl]-2-hydroxyphenyl]-N'-[ 2-bromopheny l ]urea N'-[2-bromophenyl] urea
a)Preparation of 2-hydroxycinnamide
2-Hydroxycinnamic acid (2.00g, 12.3 mmol) was dissolved in dimethyl
formamide( 10mL) followed by the addition of benzotriazol- 1 -yloxy¬tris(dimethylamino)phosphonium hexafluorophosphate (5.4g. 12.3 mmol) and triethy lamme ( 1.7mL. 12.3mmol) Ammonia gas was bubbled into the reaction mixture for 30 minutes The mixture was allowed to stir for 24 hours, the reaction mixture was diluted wilh methylene chloride and extracted with water The organic layer was dricd over MgSO4 and filteied. The solvent was evaporated and chromaiographv of the resulting solid on silica gel (4% MeOH/ CH2Cl2) gave the desired produet(1.5 g, 75 % ).
b)Preparation of 3-nitro-2-hydroxycinnamide
2-Hydroxycinnamide (750 mg. 4 6 mmol) was dissolved in methylene chloride(40mL) followed by the addition of sodium nitrate (430 mg, 5.1mmol). The addition ol sulfuric acid (7 mL/ 3M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/CH2Cl2) gave the desired product (350 mg, 36 % ). 1H NMR (CD3COCD3): 8 8.19 (d, 1 H). 8.02 (d, 1 H), 7.88 (d, 1 H), 7. 15 (t, 1 H), 6.84 (d, 1 H)
c)Preparation of 3-amino-2-hydroxycinnamide
A mixture of 3-nitro-2-hydroxymethylcinnamate (350 mg. 1.7 mmol) and tin (II) chloride (3.0 g. 13.4 mmol) in edianol(50mL) was heated at 80°C under argon. After 2 hours. the starting material had disappeared and the solution was allowed to cool down and then poured into ice. The pH was made slightly basic (pH7-8). by addition of solid NaOH. before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/ CH2Cl2) gave the desired product(244 mg.80% ).
d)Preparation of (E)-N-[3-[2-(Aminocarbonyl) ethenyl]-2-hydroxyphenyl]-N'-[2- bromophenyl] urea
(E)-N-[3-[2-(Aminocarbonyl) ethenyl]-2-hydroxyphenyl]-N'-[2-bromophenyl] urea was prepared from 3-amino-2-hydroxycinnamide (100 mg, 0.56 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane( 1/20) and filtering. ( 1 10 mg, 52%).1H NMR (CD3OD): 8 8.00 (d, 1 H), 7.90 (d, 1 H), 7.63 (d, 1 H), 7.55 (d, 1 H), 7 35 (m, 2H), 7.05 (t, 1 H), 6.95 (t, 1 H), 6.70 (d, 1 H ) .
Example 102
Preparation of (E)-N-[4-[2-(Aminocarbonyl ) ethenyl]-2-hydroxyphenyl ]-N'-[2-bromophenyI ] urea N'-[2-bromophenyl ] urea
a)Preparation of 3-hydroxycinnamide
3-Hydroxvcinnamic acid (2.00 g. 12.3 mmol ) was dissolved in dimethyl formanude( 10 mL) followed by the addition ol benzotriazol- l -yloxy-tris(dimethylamino)phosphonium hexatluorophosphate (5.4g. 12.3 mmol ) and triethylamine ( 1.7 mL. 12.3mmol) Ammonia gas was bubbled into the reaction mixture f or 30 minutes The mixture was allowed to stir f or 24 hours, the reaction mixture was diluted with methylene chloride and extracted with water The organic layer was dried over MgSO4 and filtered. The solvent was evaporated and chromatography ol the resulting solid on silica get (4% MeOH/ CH2Cl2) gave the desired product( 1.3 g. 65 % )
b)Preparation of 4-nitro-3-hydroxycinnamide
3-Hydroxycinnamide (750 mg. 4 6 mmol) was dissolved in methylene chloride(40 mL ) followed by the addition of sodium nitrate (430 mg, 5.1 mmol ). The addition ot sulfuric acid (7 mL/ 3M) was then made, followed by addition of a catalytic amount ot sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dricd over MgSO4 and filtered The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/CH2Cl2) gave the desired product(240 mg, 25 %.). 1H NMR (CD3COCD3): 8 8.09 (d. 1 H). 7.49 (d, 1 H). 7.26 (s, 1H). 7. 16 (d, 1 H), 6.71 (d, 1 H)
c)Preparation of 4-amino-2-hydroxycinnamide
A mixture of 4-nitro-3-hydroxymethylcinnamate (300 mg. 1.40 mmol) and tin (II) chloride (980 mg, 4.30 mmol) in ethanol(50 mL) was heated at 80°C under argon. After 2 hours, the starting material had disappeared and the solution was allowed to cool down and then poured into ice. The pH was made slightly basic (pH 7-8). by addition ol solid NaOH. before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH2Cl2) gave the desired product (200 mg. 74 % ).
d) Preparation(E)-N-[3-[2-(Aminocarbonyl) ethenyl]-2-hydroxyphenyl]-N'-]2-bromophenyl] urea
(E)-N-[3-[2-(Aminocarbonyl) ethenyl]-2-hydroxyphenyl]-N'-(2-bromophenyl ] urea was prepared from 4-amino-2-hydroxycinnamide (100mg. 0.56 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane( 1/20) and filtering. ( 125mg, 54% ).1H NMR (CD3OD): 8 8.05 (d.1H). 7.92 (d, 1 H). 7.60 (d, 1 H), 7.4 5 (d. 1 H), 7.35 (t, 1 H), 7.05 (m. 2H). 6.50 (d.1 H)
Example 103
Preparation of N-[2-hydroxy 4-(phenyl amino carhoxy) phenyl ]-N'-[ 2-hromophenyl] urea N-[2-hydroxy 4-(phenyl amino carboxy) phenyl ]-N'-[2-bromophenyl ] urea was prepared from 5-(phenyl amino carboxy) 2-amino phenol (0.50 mmol ) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane( 1/20) and filtering ( 150 mg, 70% ). 1H NMR (CD3OD): δ 8.25 (d, 1 H) 8 00 (d, 1 H), 7.75 (d, 2H), 7.64 (d, 1 H), 7.50 (d, 2H), 7.41 (m, 3H), 7. 16 ( t, 1 H), 7.05 ( t, 1 H ) .
Example 104
Preparation of N-[4-aminocarbonyl-2-hydroxyphenyl ]-N"-[2-bromophenyl ] urea
N-[4-Aminocarbonyl -2-hydroxyphenyl]-N'-[2-bromophenyl ] urea was prepared from 5-aminocarbonyl-2-amino phenol (304 mg. 0.50 mmol ) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane( 1/20) and filtering (440 mg, 62% ). 1H NMR (CD3OD): δ 8.09 (d, 1H), 7.91 (d, 1 H), 7.60 (d, 1 H), 7.45 (m, 3H), 7.00 (d, 1 H). Example 105
Preparation of N-(2-Hydroxy-3.5.6-trifluorophenyl)-N'-(2-bromophenyl)urea
N-(2-Hydroxy-3.5,6-trifluorophenyl)-N'-(2-bromophenyl)urea was prepared from 3.5.6-trifluoro-2-hydroxyaniline (83 mg, 0.51 mmol) and 2-(bromophenyl)isocyanate ( 100 mg, 0.53 mmol) according to the procedure in General Method B. The product was purified by preparation thin layer chromatography. EI-MS m/z 359 (M-H) .
Example 106
Preparation of N-(2-Hydroxy-3-fluoro-4-trifluoromethylphenyl)-N'-(2-bromophenyl )urea
N-(2-Hydroxy-3-fluoro-4-trifluoromethylphenyl)-N'-(2-bromophenyl)urea was prepared from 4-trifluoromethyl-3-fluoro-2-hydroxyaniline (239 mg. 1.2 mmol) and 2-(bromophenyl)isocyanate (243 mg, 1.2 mmol) according to the procedure in General Method B. Removal of solvent under reduced pressure and chromatography of the resulting solid on silica gel (hexane:ethyl acetate) gave the title compound (20 mg, 4%). EI-MS m/z 391 (M-H)
Example 107
Preparation of N-(2-Hydroxy-3-iodophenyl)-N'-('2-bromophenyl)urea
N-(2-Hydroxy-3-iodophenyl)-N'-(2-bromophenyl)urea was prepared from 3-iodo-2-hydroxyaniline (200 mg. 0.85 mmol) and 2-(bromophenyl)isocyanaie ( 169 mg, 0.85 mmol) according to the procedure in General Mediod B. Removal of solvent under reduced pressure and chromatography of the resulting solid on silica gel (hexane:ether) gave the tide compound (40 mg. 1 1 % ). 1H NMR (DMSO): 6 9.45 (s, 1 H). 9. 15 (s. 1 H). 8.8 (s. 1 H). 7.95 (d. 1 H). 7.8 (d. 1 H).7.65 (d. 1H). 7 4 (d. 1 H), 7.3 (t. 1 H). 7.0 (t, 1 H). 6.65(1. 1 H) Example 108
Preparation of N-[2-[ [[2-(trinuoromethyl)phenyl]sul fonyl]aminolphenyl]-N'-(2- bromophenyl)urea
a)Preparation of [2-[2-(trifluoromethyl)phenyl](sulfonamido)aniline]
The title compound was prepared according to General Method C using 2-(trifluoromethyl)benzenesul fbnyl chloride ( 1 equiv.). The product was purified by
chromatography on silica gel (methylene chloride:methanol) ( 1.04 g. 33% ) EI-MS m/z 3 17
(M+H)+
b)Preparation of N-[2-[[[ 2-(trifluoromethyl )phenyl )sultonyl ]amino]pheny l ]-N'-(2- bromophenyl)urea
The title compound was prepared using[2-[2(tritluoromethyl)phenyl]
(sulfonamido)aniline ( 1 .04 g. 3.2 mmol) and 2-(bromophenyl)isocyanate (652 mg. 3.2 mmol ) according to General Method B. The solvent was evaporated to give the desired urea ( 1.03 g,
61 % ). EI-MS m/z 5 14 (M+H)+ Example 109
Preparation of N-(2-Bromophenyl)-N'-[2-dimethylaminosulfonylamino]phenyl]urea a)Preparation of [2-[ 1 , 1-(dimethylamino)]sulfonamidoaniline]
The title compound was prepared according to General Method C using
dimethylsulfamoyl chloride ( 1 equiv.). The product was purified by chromatography on silica gel (methylene chloride:methanol). ES-MS m/z 216 (M+H)+.
b)Preparation of N-(2-Bromophenyl)-N'-[2-(dimethylaminosulfonylamino]phenyl]urea
The title compound was prepared from [2-[ 1 ,1-(dimethlyamino)sulfonamido-aniline ( 137 mg. 0.6 mmol) and 2-(bromophenyl)isocyanate ( 126 mg, 0.6 mmol) according to General Method B. The solvent was evaporated and chromatography on silica gel (ethyl acetate :hexane) gave the desired urea. EI-MS m/z 413 (M+H)+ Example 1 10
Preparation of N-[2-(Phenethylsulfonylamino) phenyl]-N'-(2-bromophenyl)urea
[2-(Phenethylsulfonamido) aniline] (example 60, 300mg, 1.09 mmol) was placed in a
Parr shaker bottle containing palladium ( 180 mg) under an argon stream. Methanol ( 150 mL) was added and the container placed on a Parr shaker (55 psi) for several hours. The reaction mixture was filtered through Celite and the filtrate was evaporated to give the desired aniline
(269 mg. 90% ). EI-MS m/z 277 (M+H)+.
b)Preparation of N-[2-(Phenethylsulfonylamino)phenyl]-N'-(2-bromophenyl)urea
The title compound was prepared from [2-(phenethylsulfonamido) aniline] (269 mg.
0.97 mmol) and 2-(bromophenyl)isocyanaic ( 193 mg. 0 97 mmol) according to General Method B. The desired urea was precipitated out of toluenc/hexane (384 mg. 78% ). EI-MS m/z 472 (M-H)
Example 1 1 1
Preparation of N-[2-[(2-acetamido-4-methylthiazol-5-yl)sulfonylaminolphenyl].N'-(2-bromophenyl)urea
a)Preparation of [ 2-[(2-acetamido-4-methyl-5-thiazole)sulfonamido]aniline]
The title compound was prepared using 2-acciamido-4-methy l- 5-thiazolesulfonyl chloride ( 1 equiv. ) according to General Method C A solid precipataied f rom the reaction mixture and was filtered to give the desired aniline ( 1 .68 g. 52% ) ES-MS mlz 327 (M+H )+ b)Preparation of N-[2-[(2-acetamido-4-methylthiazol-5-yl)sulfonylamino]phenyl ]-N'-(2- bromophenyl)urea
The title compound was prepared from [ 2-[(2-acetamido-4-methyl-5- thiazole)sulfonamido]aniline] ( 1.68 g.5. 14 mmol ) and 2-(bromophenyl)isocyanate ( 1.02 g, 5. 14 mmol) according to General Method B . The product was precipitated from ethyl acetate/hexanc (220 mg, 8% ). EI-MS m/z 524 (M+H)+.
Example 1 12
Preparation of N-[2-hydroxy-4-cyanophenyl]-N -[4-phenylphenyl] urea N-(2-Hydroxy-4-cyanophenyl]-N'-[4-phenylphenyl] urea was prepared from 2-amino-5-cyanophenol (60mg. 0.45 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexanc(1/20) and filtering. ( 135 mg. 75% ) 1H NMR (CD3OD): δ 8.33 (d, 1 H), 7.71-7.29 (m. 9H), 7.25 (d, 1 H), 7. 12 (s, 1 H).
Example 1 13
Preparation of N-[2-hydroxy-4-cyanophenyl]-N'-[2,3-dichlorophenyl] urea
N-[2-Hydroxy-4-cyanophenyl]-N'-[2,3 dichlorophenyl) urea was prepared from 2-amino-5-cyanophenol (60mg, 0.45 mmol) according to the procedure in General Method B . The product was purified by precipitation from methylene chloride/ hexane(1/20) and filtering (125mg, 86%). 1H NMR (CD3OD): δ 8.27 (d, 1H), 8. 15 (m, 1 H). 7.39-7.20 (m. 2H), 7. 16 (d, 1H), 7.06 (s, 1 H).
Example 1 14
Preparation of N-[2-hydroxy-4-cyanophenyl]-N'-[2-methoxyphenyl] urea
N-[2-Hydroxy-4-cyanophenyl]-N'-[2-methoxyphenyl) urea was prepared from 2-amino-5-cyanophenoI (60mg, 0.45 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane( 1/20) and filtering ( 105mg, 83% ) 1H NMR (CD3OD): δ 8.26 (d, 1H ), 8.02 (d, 1 H ), 7.14 (d, 1H ), 7.05 ( s, 1 H), 7.00-6.83 (m, 1H), 3.84 (s, 3H ).
Example 1 15
Preparation of N-[ 2-hydroxy-4-cyanophenyl]-N'-[3-methoxyphenyl] urea
N-[2-Hydroxy-4-cyanophenyl]-N'-[3-methoxyphenyl ] urea was prepared from 2-amino-5-cyanophenol (60mg, 0.45 mmol ) according to the procedure in General Method B The product was purified by precipitation from methylene chloride/ hexane( 1/20) and filtering ( 102mg, 80% ). 1H NMR (CD3OD): 6 8.25 (d, 1 H), 7.25-7.08 ( m, 3H ), 7 04 ( s, 1 H ), 6.90 (t, 1 H), 6.58 ( d, 1 H ). Example 1 16
Preparation of N-[2-hydroxy-5-fluorophenyl ]-N'-[2-hromophenyl ] urea
a)Preparation of 2-amino-4-fluorophenol A mixture of 4-fluoro-2-mirophenol( lg. 4 64mmol ) and tin (II) chloride (5 4 g, 24.2mmol) in ethanol(50mL) was healed at 80°C under argon. Af ter 2 hours, the starting material had disappeared and the solution was allowed to cool down and then poured into ice. The pH is made slightly basic (pH7-8), by addition of solid NaOH, before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/CH2Cl2) gave the desired product (622 mg. 85 % ) 1H NMR (CD3OD): 8 6.51 (dd, 1 H), 6.32 (dd, 1 H), 6.17 (ddd, 1H).
b)Preparation of N-[2-hydroxy-5-fluorophenyl]-N'-[2-bromophenyl] urea
N-[2-Hydroxy-5-fluorophenyl ]-N'-[2-bromophenyl ] urea was prepared from 2-amino- 6-fluoro phenol (254mg, 2 00 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane( 1/20) and filtering. (520mg,80%). 1H NMR (CD3OD): 6 7.88 (d, 1H), 7 79 (dd, 1H), 7.57 (d, 1H), 7.31 (t, 1 H), 7.00 (t, 1 H), 6.76 (dd, 1 H), 6.57 (ddd, 1 H).
Example 1 17
Preparation of N-[2-hydroxy-5-trifluoromethy]phenyl]-N'-[2-bromophenyl] urea
a)Prcparation of 2-amino-4- trifluoromethylphenol
A mixture of 4-trifluoromethyl-2-nitrophenol ( 1 .0 g, 4.8mmol) and tin (II) chloride (5.4 g, 24.2 mmol) in ethanol( 150mL) was healed at 80°C under argon. After 2 hours, the starting material had disappeared and the solution was allowed to cool down and then poured into ice . The pH was made slightly basic (pH7-8), by addition of solid NaOH. belore being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and filtered The solvent was evaporated and chromatography of the resul ting solid on silica gel (4% MeOH/ CH2Cl2) gave the desired product(708 mg, 83 % ) . 1H NMR (CD3OD): δ 6.87 (s, 1 H) 6.80 (d, 1 H), 6.69 (d, 1 H).
b)Preparation of N-[2-hydroxy-5trifluoromethylphenyl ]-N'-[2-bromophenyl ] urea
N-| 2-hydroxy-5-trifluoromethylphenyl ]-N'-[ 2-bromophenyl] urea was prepared from 2-amino-4-trifluoromethylphenol ( 354mg. 2 00 mmol ) according to the procedure in General Method B . The product was purified by precipitation from methylene chloride/
hexane(lequiv /20equiv ) and filtering (490mg. 65% ) 1H NMR (CD3OD) 8 8.40 ( s, 1 H) 7.94 (d 1 H) 7.60 (d. 1 H ) 7.3S ( t, 1 H ) 7. 18 (d. 1 H) 7.03 ( t. 1 H) 6.95 (d, 1 H ).
Example 1 I 8
Preparation of N-[2-hydroxy pheny l ]-N'-[ 2-bromophenyl ] urea
N-[2-hydroxypheny l]-N'-[2-bromo phenyl] urea was prepared from 2- amino-phenol ( 141 mg. 1.30 mmol) according to the procedure in General Method B . The product was purified by precipitation from methylene chloride/ hexane( 1/20) and filtering (300mg.75% ) 1H NMR (CD 3OD): 8 8.05 (d. 1 H ). 7 49 (d. 1 H), 7.25 (t. 2H), 6 96 (t. 1 H). 6.90 ( t, 2H ).
6.68 (t 1 H)
Example 1 19
Preparation of N-[trans-3-styrl 2-hydroxy phenyl]-N'-[2-bromophenyl] urea
a)Prcparation of trans-6-styrl-2-nitrophenol
Trans-2-styrlphenol (500 mg, 2.55 mmol) was dissolved in methylene chloride(40mL) followed by the addition ol sodium nitrate (240 mg, 2 81 mmol). The addition of sulturic acid (3 mL ol 3M) was then made, followed by addition of a catalytic amount of sodium nitrite The mixture was allowed to stir . After 24 hours, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO4 and tiltered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%-MeOH/ CH2Cl2) gave the desired product (200 mg, 36 %) 1H NMR (CD3COCD3): δ 8.05 (d. 1 H). 7.90 (d, 2H),7.65-7.20 (m,7H),7.00 (t, 1H)
b)Prcparation of trans-6-styrl-2-aminophenol
A mixture ol trans-6-styrI-2-nitrophenol (200 mg, 0.83 mmol) and tin (II) chloride (560 mg. 2.60 mmol) in ethanoI(50mL) was heated at 80°C under argon After 2 hours, the starting material has disappeared and the solution was allowed to cool down and then poured into ice. The pH is made slightly basic (pH7-8), by addition of solid NaOH, before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and filtered . The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/ CH2Cl2) gave the desired product (50 mg. 29 % ) 1H NMR (CD3OD): 8 7.51 (m 3H ). 7 29 ( m. 3H).7 1 I (t. 1 H). 7 00 (m, 2H). 6 69 (m. 2H)
c (Preparation of N-[trans-3-styrl-2-hydroxyphenyl]-N'-[2-bromophenyI| urea
N-[ trans-3-sty rl-2-hydroxyphenyl]-N'-[2-bromophenyl] urea was prepared from trans- 6-styrl-2-aminophenol (35mg. 0.17 mmol) according to the procedure in General Method B The product was purified by precipitation from methylene chloride/ hexanc( 1/20) and filtering ( 36mg, 53% ) 1H NMR (CD3OD) 87.97 (d, 1 H), 7.62-7.48 (m, 4H), 7.45-7.26 ( m, 5H),
7.25 ( t, 1 H), 7.15 (d, 1 H), 7.01 (t, 1H), 6.88 (t 2H).
Example 120
Prcparation ot N-[2-hydroxy -3,4-diehlorophenyl ]-N"[{2-methoxyphenyl ] urea
N-[2-hy droxy -3 4-dichlorophenyl|-N'-[2-methoxy phenyl] urea was prepared from 2-amino 5.6-dichlorophenol (80mg 0.50 mmol. example 82b) according to the procedure in General Method B The product was purilied by precipiiation from methylene chloride/hexane( 1/20) and filtering ( 125mg,77% ) 1H NMR (CD3OD) δ 8.02 (d, 1 H) 7.79 (d, 1 H) 7.05-6.86 (m, 4H ) 3.92 (s, 3H). Example 121
Preparation of N-[2-hydroxy-3.4-dichlorophenyl]-N'-14-methoxyphenyl] urea
N-[2-hydroxy-3,4-dichlorophenyl]-N'-[4-methoxyphenyl ] urea was prepared from 2-amino-5,6-dichlorophenol (80mg, 0.50 mmol, example 82b) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane( 1 equiv./20equiv.) and filtering. ( 120mg, 74%). 1H NMR (CD3OD): δ 7.89 (d, 1 H), 7.35 (d, 2H), 6.99 (d, 1 H), 6.90 (dd, 2H), 3.80 (s, 3H). Example 122
Preparation of N-[2-hydroxy-3,4-dichlorophenyl]-N'-[3-trifluoromethylphenyl] urea
N-[2-hydroxy-3,4-dichlorophenyl]-N'-[3-trifluoromethylphenyl] urea was prepared from 2-amino-5,6-dichlorophenol (80mg, 0.50 mmol, example 82b) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane(lequiv./20equiv.) and filtering. (130mg, 71%). 1H NMR (CD3OD): 6 7.96
(d, 2H). 7.60 (d, 1H), 7.48 (t, 1 H), 7.30 (d, 1 H), 7.00 (d, 1 H). Example 123
Preparation of N-[2-hydroxy-3,4-dichlorophenyl]-N'-[2-phenylphenyI ] urea
N-[2-hydroxy-3,4-dichlorophenyl]-N'-[2-phenylphenyl] urea was prepared from 2-amino-5,6-dichlorophenoI (80mg. 0.50 mmol. example 82b) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/hexane( 1equiv./20equiv ) and filtering. ( 1 10mg, 59% ) 1H NMR (CD3OD): δ 7.77 (d. 1 H). 7.73 (d, 1 H), 7.53-7.14 (m, 8H), 6.95 (d, 1 H)
Example 124
Preparation of N-[2-hydroxy-3,4-dichlorophenyl]-N'-[2,3-dichlorophenyl ] urea
N-[2-Hydroxy-3,4-dichlorophenyl]-N'-[2,3-dichlorophenyl] urea was prepared from 2-amino-5,6-dichlorophenol (80mg. 0.50 mmol, example 82b) according to the procedure in General Method B The product was purified by precipitation from methylene chloride/hexane (1equiv /20eqinv ) and filtering ( 1 30mg, 71 % ) 1H NMR (CD3OD ): δ 8.06 (dd. 1 H) 7.9 1 (d, 1 H), 7.25 ( m, 2H ), 7.00 (d, 1 H).
Example 125
Preparation ol N-[2-hydroxy-4-isopropylphenyl ]-N'-[3-trifluoromethylphenyl ] urea
a)Preparation of 2-nitro-5-isopropylphenol
3-isopropylphenol (3.00g. 22 mmol ) was dissolved in methylene chloride(40ml ) followed by the addition of sodium nitrate (2.06g, 24mmol) The addition of sulfuric acid (25mL/ 3M) is then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 h, the reaction mixture is diluted with methylene chloride and extracted with water. The organic layer is dried over MgSO4 and filtered The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/ CH2Cl2) gave the desired product(1.09g, 27 %). 1H NMR (CD3COCD3): δ 7.95 (d. 1 H), 7.62 (d.1 H). 7.1 1 (d, 1 H), 2.95 (m, 1 H), 1.24 (d, 6H).
b) Preparation of 2-amino-5-isopropylphenol
To a solution of 2-nitro-5-isopropylphenol( 1g. 6.4 mmol) in methanol(50 mL) was added 10% Pd/C ( 100 mg). The mixture was Hushed with argon, then hydrogen was bubbled through the solution for 10 min. and a hydrogen atmosphere was maintained at balloon pressure overnight. The mixture was filtered through celite and the celite was washed with methanol. The solvent was evaporated and chromatography of the resulting solid on silica gel (5%MeOH/ CH2Cl2) gave the desired product(775 mg, 93 % ). 1H NMR (CD3OD): δ 6.71 - 6.44 (m, 3H). 2.73 (m, 1H), 1.20 (d, 6H).
c) Preparation of N-[2-hydroxy-4-isopropylphenyl]-N'-[3-trifluoromeihylphenyl] urea
N-[2-hydroxy-4-isopropylphenyl]-N'-[3-trifluoromethylphenyl] urea was prepared from 2-amino-5-isopropylphenol (75mg, 0.50 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/
hexane(lequiv./20equiv.) and filtering. ( 140mg. 83% ). 1H NMR (CD3OD): δ 7.91 (d. 2H). 7.62 (d, 1H). 7 47 (t, 1 H), 7.39 (d, 1 H), 6.75 (s. 1 H), 6.72 (d, 1 H). 2 80 (m, 1 H). 1 21 (d. 6H).
Example 126
Preparation of N-[2-hydroxy-3-naphthyl]-N'-[2,3-dichlorophenyl ] urea
N-[2-hydroxy-3-naphthyl]-N'-[2,3-dichlorophenyl] urea was prepared from 3-amino- 2-naphthol ( 160mg. 1.00 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexaned equiv./20cquiv.) and filtering. (285mg. 82% ). 1H NMR (CD3OD): δ 8.48 (s. 1 H). 8.10 (d. 1 H). 7.68 td. 1 H)
7.57 (d. 1 H). 7.40-7.23 ( m. 4H), 7.18 (d. 1 H).
Example 127
Preparation of N-[ 2-[(2,3-Dichloroihien-5-yl )]sulfonylamino]phenyl ]-N"-(2-bromopheny ] urea a)Preparation of [2-[(2,3-Dichlorothien-5-yl)]sultonylaminoaniline]
The title compound was prepared according to General Method C using 2,3-dichloroihiophenc-5-sulfonyl chloride (( 1 eq). The product was purified by flash
chromatography on silica gel (ethyl acetate/hexane 20/80-methylenc chloride:methanol 90/10) ( 1.25 g. 39 % ). EI-MS m/z 321 (M-H) b) Preparation of N-[2-[(2,3-Dichloroihien-5-yl)]sulfonylamino]phenyl ]-N'-(2-bromophenyl)urea.
The title compound was prepared from [2-[(2,3-dichlorothien-5-yl)]sulfonylaminoaniline ( 1.25 g,3.9 mmol) and 2-(bromophenyI)isocyanate (768 mg, 3.9 mmol) according to General Method B. The product was purified by flash chromatography on silica gel (ethyl acetale: hexane 30/70) (272 mg. 13 % ) EI-MS m/z 520 (M-H).
Example 128
Preparation of N-[2-[(3,5-Bistrifluoromethylphenyl)sulfonylamino]phenyl ]-N'-(2-bromophenyl)urea
a) Preparation of [2-(3,5-Bistrifluoromethylphenyl)sulfonylaminoanilinc]
The title compound was prepared according to General Method C using 3,5-(bistrifluoromethyl)phenylsulfonyl chloride ( 1.28 g, 4.1 mmol) and o-phenylenediamme (441 mg, 4.1 mmol). The product was purified by flash chromatography on silica gel (methylene chloride:methanol 95/5) (61 1 mg, 39 %). EI-MS m/z 383 (M-H).
b) Preparation of N-[2-[(3,5-Bistrifluoromethylphenyl)sulfonylamino]phenyl]-N'-(2-bromophenyl)urea.
The title compound was prepared from [2-(3,5-bisirifluoromethylphenyl)
sulfonylaminoaniline (591 mg, 1.5 mmol) and 2-bromophenylisocyanatc (305 mg. 1.5 mmol) according to General Method B. The product was purified by Hash chromatography on silica gel (ethyl acetate:hexane 30/70) ( 10 mg. 1 % ). EI-MS m/z 580 (M-H).
Example 129
Preparation of N-[2-[(2-Benzyl)sulfonylamino ]-(5-trifluoromethyl )phenyl ]-N'-(2-bromophenyl)urea
a)Preparation of [(4-Benzylsulfonylanuno)-(3 -nitro)-benzotrifluoride ]
4-Amino-3-nitro-benzotrifluoride ( 1.0 g. 4 85 mmol ) was mixed in DMF and the reaction mixture was cooled to 0ºC Sodium hydride ( 175 mg. 7.28 mmol ) was added to the cold mixture and allowed to mix f or ten minutes ( a deep red color was noted).
Toluenesulfonyl chloride (925 mg. 4.85 mmol ) was added ( reaction color changed to yellow ) and the reaction was mixed f or sixteen hours at room temperature. The reaction w as quenched in NH4Cl and extracted with ethyl acetatc:hexane ( 1 :1 ). The product w as purified by flash chromatography on silica gel ( ethyl aceiatc:hexane 30/70) (878 mg. 52 % ) EI-MS ml/ 359 (M-
H)
b)Preparation of [(4-Benzylsulfonylamino)-(3-amino)-benzotrifluoride ]
[(4-Benzylsulfonylamino)-(3-nitro)-benzotrifluoride (230 mg. 0.64 mmol) was mixed in methanol and poured into a Parr bottle. Palladium on carbon ( 15 mg ) was added under an argon stream. The reaction mixture was placed on a Parr shaker ( 55 psi, H2) for several hours. The reaction mixture was filtered through Celite to give the title compound. (210 mg.
99% ) EI-MS m/z 329 (M-H) .
c)Preparation of N-[2-[(2-BenzyI)sulfonylamino]-(5-trifluoromethyl)phenyl]-N'-(2-bromophenyl)urea
The title compound was prepared from [(4-benzylsulfonylamino)-(3-amino)-benzotritluoride (210 mg, 0.64 mmol) and 2-bromophenylisocyanate ( 126 mg. 0.64 mmol) according to the procedure in General Method B. The product was purified by Hash chromatography on silica gel (ethyl acetate: hexane 30/70) (70 mg, 21% ) EI-MS m/z 526 (M-H)
Example 130
Preparation of N-[2-[2-(3-Nitrophenyl)sulfonylamino]phenyl]-N'-(2-bromophenyl)urea a) Preparation of [2-((3-Nitrophenyl)sulfonylamino)aniline]
The title compound was prepared according to General Method C using 3-nitrobenzenesulfonyl chloride ( 1 eq). The product was purified by flash chromatogrphy on silica gel (methylene chloride:methanol 96/4).( 1.07 g, 37 %) EI-MS m/z 294 (M+H)+ b) Preparation of N-[2-[(3-Nitrophenyl)sulfonylamino]phenyl]-N'-(2-bromophenyl)urea
The title compound was prepared from [2-(3-nitrophenyl)sulfonylaminoanilinc] (590 mg, 2.0 mmol) and 2-(bromophenyl)isocyanate (398 mg. 2.0 mmol) according to the procedure in General Method B. The product was purified by Hash chromatography on silica gel (ethyl acetate:hexanc 30/70) (400 mg. 40% ). EI-MS m/z 489 (M-H)-
Example 131
Preparation of N-[2-[2-(4-Phenoxyphenyl)sulfonylaminolphenyl ]-N'-(2-hromophenyl ) urea a) Preparation of [2-((4-Phenoxyphenyl)sulfonylamino)aniline]
The title compound was prepared according to General Method C using 4-phenoxyphenylsulfonyl chloride (969 mg, 3.6 mmol) and o-phenylenediamine (300 mg. 2.77 mmol). The reaction mixture was partitioned between water (200 ml) and ioluenc:methyIcne chloride ( 1 :3). The organic phase collected and the methylene chloride evaporated leaving the toluene. Hexane added and the product precipatated from solution. (317 mg. 34 % ) EI-MS m/z 341 (M+H )- b) Preparation ol N-[2-[(4-Phenoxyphenyl )sulfonylamino]phenyl]-N'-(2-bromophenyl )urea The title compound was prepared from [2-(4-phenoxyphenyl)sulfonyl
aminoaniline (276 mg. 0.8 mmol) and 2-(bromophenyl)isocyanate ( 161 mg. 0.8 mmol) according to the procedured in General Method B. The product was purified by flash chromatography on silica gel (ethyl acetate:hexane 30/70) (240 mg. 55 %) EI-MS m/z 536 (M- H)- Example 132
Preparation of N-[[2-(1S)- 10-Camphorsulfonylamino]phenyl]-N'-(2-bromophenyl)urea a) Preparation of 2-(( 1 S)- 10-Camphorsulfonylamino)aniline
The title compound was prepared according to General Method C using (1 S)(+)- 10- Camphorsulfonyl chloride ( 1.16 g, 4.6 mmol) and o-phenylenediamine (500 mg. 4.6 mmol) The reaction mixture was partitioned between water (200 ml) and toluene:methylene chloride ( 1 :3) The organic phase was separated and the methylene chloride evaporated leaving the toluene Hexane was added and solid precipitated from solution. ( 130 mg. 9% ) EI-MS m/z 323 (M+H)- b) Preparation of N-[[2-( 1 S)- 10-Camphorsulfonylamino]phenyl]-N'-(2-bromophenyl )urea
The title compound was prepared from [2-(1S)- 10-camphorsulfonylamino]aniline ( 130 mg. 0.4 mmol) and 2-(bromophenyl)isocyanate (80 mg, 0.4 mmol) according to the procedure in General Method B. The solvent was evaporated and product was precipitated from methylene chloride:hexane. (200 mg. 95 %). EI-MS m/z 518 (M-H)-
Example 133
Preparation of N-[[2-(1R)- 10-Camphorsulfonylaminolphenyl]-N'-(2-bromophenyl)urea a) Preparation of 2-(( 1R)- 10-Camphorsulfonylamino)aniline
The title compound was prepared according to General Method C using ( 1 R)(-)- 10-camphorsullonyl chloride ( 1. 16 g. 4.6 mmol) and o-phenylenediamine (5(X) mg. 4 6 mmol) The reaction mixture was partitioned between water (2(X) mL) and toluene:methylene chloride( 1 .3). The organic phase was separated and the methylene chloride evaporated leaving the toluene. Hexane was added and the product precipitated from solution. (563 mg. 38% ). EI-MS m/z 323 (M+H)+
b) Preparation of N-[ [ 2-( 1R)- 10-Camphorsulfonylamino]phenyl]-N'-(2-bromophenyl)urea
The title compound was prepared from [ 1-( 1R)- 10-camphorsulfonylaminoaniline] (563 mg. 1.75 mmol) and 2-(bromophenyl )isocyanaie (346 mg. 1 75 mmol ) according to the procedure in General Method B. The product was purified by flash chromatography on silica gel (ethy l acetate:hexane 30/70) (263 mg, 29 % ) EI-MS m/z 518 (M-H)
Example 134
Preparation of N-[2-[ 2-(2-Nitro-(4-trifluoromethy l)phenyl)sulf onylaminolphenyl-N'-(2- biomophenyl)urea
a Preparation of [2-[(2-Nitro)-(4-trifluoromethyl(phenyl]sulfonylamino]aniline
The title compound was prepared according to General Method C using 2-nitro-4- (trifluoromethyl)benzenesulfonyl chloride ( 1 eq). The product was purified by flash chromatography on silica gel ( methylene chloride:methanol 96/4) (875 mg. 25 % ) EI-MS m/z 362 (M+H)+
b) Preparation of N-[2-[2-(2-Nitro-(4-trifluoromethyl)phenyl)sulfonylamino]phenyl-N'-(2-bromophenyl)urea
The title compound was prepared from [2-[(2-nitro)-(4-tritluoromethyl)
phenyl]sulfonylamino]aniline (740 mg. 2. 1 mmol) and 2-(bromophenyl)isocyanate (406 mg. 2. 1 mmol) according to General Method B. The product was purified by flash
chromatography on silica gel (ethyl acetate:hexane 30/70). The product was further purified by recrystallization in ethyl acetate:hexane. (320 mg, 28 % ) EI-MS m/z 557 (M-H)-
Example 135
Preparation of N-(2-hydroxy-4-azidophenyl)-N'-(2-iodophenyl)urea
a)Preparation of N-(2-hydroxy-4-aminophenyl)-N'-(2-iodophenyl)urea
To a solution of N-(2-hydroxy-4-nitrophenyl)-N'-(2-iodophenyl)urea (220 mg. 0.55 mmol) in eihanol (15 mL), Tin chloride (522 mg, 2.75 mmol) was added. The reacuon mixture was stirred at reflux for 16 hours then cooled to room temperature. The reacuon mixture was basified to pH 8 with aq. NaHCO3 then extracted with ethyl acetate (3x). The organic extracts were combined, dried over MgSO4, filtered and concentrated under reduced pressure to give product (180 mg, 89%). EI-MS m/z 370 (M+H)+
b)Preparation of N-(2-hydroxy-4-azidophenyl)-N'-(2-iodophenyI)urea
The N-(2-hydroxy-4-aminophenyl)-N'-(2-iodophenyl)urea (77 mg. 0.21 mmol) was added to HCl/H2O (0.21 mL/0.42 mL), and cooled to 0°C. Sodium nitrate ( 14.5 mg. 0.21 mmol) was added to the reaction mixture. The reaction mixture was stirred at 0°C for 30 minutes. Sodium azide ( 14 mg, 0.21 mmol) was added to reaction mixture and it was warmed to room temperature. The reaction mixture was stined ai room temperature lor 18 hours. Then it was extracted with three limes by ethyl acetate. The organic extracts were combined, dried over MgSO4. filtered and concentrated under reduced pressure and chromatography of the resulting solid on silica gel (hexane : ethyl acctate: 5: 1 ) gave product (20 mg. 24% ) EI-MS mlz 396 ( M+H)+
Example 136
Preparation of N-(2-hydroxy-3-azidophenyl)-N'-(2-bromophenyl)urea
a) Preparation of N-(2-hydroxy-3-aminophenyl )-N"-(2-bromophenyl)urea
To a solution of N-(2-hydroxy-3-nitropheny!)-N'-(2-bromophenyl )urea (300 mg. 0.85 mmol ) in ethanol (20 mL). Tin chloride (958 mg. 4.25 mmol ) was added. The reaction mixture w as stirred at reflux for 16 hours then cooled to room temperature. The reaction mixture was basified to pH 8 with aq. NaHCO3 then extracted with ethyl acetate (3x) The organic extracts were combined, dried over MgSO4. filtered and concentrated under reduced pressure to give product (274 mg. 99% ). EI-MS m/z 323 (M+H)+. b) Preparation of N(2-hydroxy-3-azidophenyl)-N'-(2-bromophenyl)urea
The N-(2-hydroxy-3-aminophenyl)-N'-(2-bromophenyl)urea(274 mg. 0 85 mmol ) was added to HCl/H2O (0.85 mL/1.7 mL), cooled to 0°C. Sodium nitrate (58 6 mg. 0 85 mmol ) was added to the reaction mixture. The reaction mixture was stirred at 0ºC for 30 minutes Sodium azide (55 mg, 0.85 mmol) was added to reaction mixture and it was warmed to room temperature The reaction mixture was stirred at room temperature for 18 hours then n was extracted with three times with ethyl acetate. The organic extracts were combined . dried over MgSO4, filtered and concentrated under reduced pressure and chromaiography of the resulting solid on silica gel (hexane : ethyl acetate: 5: 1 ) gave product (210 mg. 71 %) EI-MS m/z 349 (M+H)+.
Example 137
Preparauon of N-[2-hydroxy-3-cyanophenyl ]-N'-[2-methoxyphenyl] urea
N-[2-hydroxy-3-cyanophenyl]-N'-[2-meihoxyphenyl] urea was prepared from 2-amino-6-cyanophenol (134mg, 1.00 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane( lequiv /20equiv ) and filtering (230 mg, 81%). 1H NMR (CD3OD); δ 8.06 (d, 1 H), 7.79 (d, 1 H), 7.49-7.35 (m, 2H), 7.05-6.87 (m, 3H), 3.95 (s, 3H). Example 138
Preparation of N-[2-hydroxy-3-cyanophenyl]-N'-[3-trifluoromethylphenyl] urea
N-[2-hydroxy-3-cyanophenyl]-N'-[3-trifluoromethylphenyl] urea was prepared from
2-amino-6-cyanophenol ( 134mg, 1.00 mmol. example 83a) according to the procedure in
General Method B The product was purified by precipitation from methylene chloride/hexane(lequiv./20equiv.) and filtering (280mg. 87% ) 1H NMR (CD 3OD); δ 8.10 (d, 1 H ),
7.96 (s. 1 H). 7.54 (d, 1 H), 7.55-7.25 (m, 3H ), 7.01 (t, 1 H).
Example 139
Preparation of N-[2-hydroxy-3-cyanophenyl]-N'-[2-phenylphenyl] urea
N-[2-hydroxy-3-cyanophenyl]-N'-[2-phenylphenyl] urea was prepared from 2-amino- 6-cyanophenol ( 134mg, 1.00 mmol, example 83a) according to the procedu re in General Method B. The product was purified by precipitation from methylene chloride/
hexaned equiv./20equiv.) and filtering (270mg, 82% ). 1H NMR (CD3OD); δ 7.81 (d, 1 H ), 7.75 (d, 1 H), 7.56-7.15 (m, 9H), 6.91 ( t, 1 H).
Example 140
Preparation of N-[2-hydroxy-3-cyanophenyl ]-N'-[2,3-diehlorophenyl ] urea N-(2-hydroxy-3-cyanophenyl]-N'-[2,3 dichlorophenyl] urea was prepared from 2-amino-6-cyanophenol ( 134mg, 1.00) mmol. example 83a) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane( 1equiv./20equiv.) and filtering. (300mg. 93% ). 1H NMR (CD3OD): δ 8.11 (d, 1H), 8.01 (d, 1H), 7.33-7.25 (m, 3H), 7.00 (t, 1H).
Example 141
Preparation of N-[2-hydroxy-4-isopropylphenyl]-N'-[2,3-dichlorophenyl] urea N-[2-hydroxy-4-isopropylphenyl]-N'-[2,3-dichloropnenyl] urea was prepared from 2-amino-5-isopropylphenol ( 150 mg, 1.00 mmol, example 128a) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/
hexane(1equiv./20equiv.) and filtering (285mg, 84%). 1H NMR (CD3OD): δ 8.05 (d, 2H). 7.77 (s, 1H), 7.26 (m, 2H), 6.88 (m, 2H), 2.82 (m, 1H), 1.25 (d, 6H) . Example 142
Preparation of N-[2-hydroxy-4-isopropylphenyl]-N'-[2-chloro-5-trifluoromethylphenyl] urea N-[2-hydroxy-4-isopropylphenyl]-N'-[2-chloro-5-trifluoromethylphenyl] urea was prepared from 2-amino-5-isopropylphenol ( 150mg, 1.00 mmol, example 128a) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane( 1equiv./20equiv.) and filtering. (275mg. 82% ). 1H NMR (CD3OD): δ 8.50
(s, 1H), 7.70 (s, 1H), 7.51 (d, 1H), 7.22 (d, 1H), 6.70 (m, 2H). 6 62 (dd, 1H), 2 76 (m,
( 1H), 1.16 (d, 6H).
Example 143
Preparation of N-12-hydroxy-3-phenylphenyl]-N'-[2,3-dichlorophenyl ] urea
a)Preparation of 2-nitro-6-phenylphenoI
2-phenylphenol (3.00g. 17.6mmoI) was dissolved in methylene chloride(40ml ) followed by the addition of sodium nitrate ( 1.65g, 19.4mmol) The addition of sulfuric acid (25ml/ 3M ) was then made, followed by addition of a catalytic amount of sodium nitrite The mixture was allowed to stir. After 24 hrs. the reaction mixture w as diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/ CH2Cl2) gave the desired product(900 mg. 24 % ). 1H NMR (CD3COCD3): δ 8.19 (d, 1H),
7.79 (d, 1H), 7.64 (d, 2H), 7.50 (t, 2H), 7.45 (t, 1H), 7.22 (t, 1H).
b)Preparation of 2-amino-6-phenylphenol
To a solution of 2-nitro-6-phenylphenol(900 mg. 4.2mmol) in methanol(50ml) was added 10%r Pd/C ( 100 mg). The mixture was flushed with argon, then hydrogen was bubbled through the solution for 10 mm and a hydrogen atmosphere was maintained at balloon pressure overnight. The mixture was filtered through celite and the celite was washed with methanol. The solvent was evaporated and chromatography of the resulting solid on silica gel (5%MeOH/ CH2Cl2) gave the desired product(700 mg. 90 % ). 1H NMR (CD3OD): δ 7.55-7.27 (m, 5H), 6.77-6.61 (m, 3H)
c)Preparation of N-[2-hydroxy-3-phenylphenyl]-N'-[2,3-dichlorophenyl] urea
N-[2-hydroxy-3-phenylphenyl]-N'-[2.3-dichlorophenyl] urea was prepared from 2-amino-6-phenylphenol (92.5mg, 0.50 mmol) according to the procedure in General Method B The product was purified by precipitation from methylene chloride/ hexane( 1equiv./20equiv.) and filtering. ( 150mg,81 % ). 1H NMR (CD3OD): δ 8.06 (d, 1H),7.65 (d, 1H), 7.54 (d, 2H), 7.40 (t, 2H), 7.32 (d, 1H) 7.22 (m, 2H), 7.04-6.88
Preparation of N-[2-hydroxy-3-phenylphenyl]-N'-[2,3-dichlorophenyl] urea
b)N-[2-hydroxy-3-phenylphenyl]-N'-(2,3-dichlorophenyl] urea was prepared from 2- amino-6-phenylphenol (92.5mg, 0.50 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane( 1equiv./20equiv.) and filtering. (150 mg, 81%). 1H NMR (CD3OD): δ 8.06 (d, 1H),7.65 (d, 1H), 7.54 (d, 2H), 7.40 (t, 2H), 7.32 (d, 1H) 7.22 (m, 2H), 7.04-6.88 (m, 2H).
Example 144
Preparation of N-[2-hydroxy-5-nitrophenyl]-N'-[2-methoxyphenyl] urea
N-[2-hydroxy-5-nitrophenyl]-N'-[2-methoxyphenyl] urea was prepared from 2-amino- 4-nitrophenol ( 154 mg, 1.00 mmol) according to the procedure in General Method B The product was purified by precipitation from methylene chloride/ hexane( 1equiv./20equiv.) and filtering. (270 mg. 89% ). 1H NMR (CD3OD): δ 9. 10 (s, 1H), 8.10 (d, 1H), 7.85 (d, 1H), 7.08-6 88 (m, 4H), 3.96 (s, 3H).
Example 145
Preparation of N-[2-hydroxy-5-nitrophenyl]-N'-[ 3-trifluoromethylphenyl] urea
N-[2-hydroxy-5-nitrophenyl]-N'-[3-influoromethylphenyl] urea was prepared from 2- amino-4-nitrophenol ( 154 mg. 1 .00 mmol ) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane( 1equiv. /20equiv.) and filtering. (290 mg. 85% ) 1H NMR (CD3OD): δ 9.12 (s, 1H), 7.89 (d, 1H), 7.68 (d, 1H), 7.55 (m, 2H), 7 45 (d, 1H), 7 00 (d. 1H).
Example 146
Preparation of N-[2-hydroxy-5-nittophenyl]-N'-[2-phenylphenyl] urea
N-|2-hydroxy-5-mirophenyl]-N'-[2-phenylphenyl] urea was prepared from 2-amino-4-nitrophenol ( 154 mg. 1.00 mmol ) according 10 the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane( 1equiv. /20equiv.) and filiering. (285 mg. 81 % ). 1H NMR (CD3OD): δ 8.09 (s, 1H ), 7.86 (d, 1H), 7.58-7.20 (m, 9H), 6.95 (d, 1H) .
Example 147
Preparation of N-[2-hydroxy-5-nitrophenyl]-N'-[2,3-dichlorophenyl] urea
N-[2-hydroxy-5-nitrophenyI]-N'-[2,3-dichlorophenyl] urea was prepared from 2-amino-4-nitrophenol ( 154 mg, 1.00 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/ hexane(1equiv./20equiv.) and filtering. (290 mg, 85% ). 1H NMR (CD3OD): δ 9.1 1 (s, 1H), 8.17 (d, 1H), 7.89 (d, 1H), 7.34 (m, 2H). 6.95 (d, 1H).
Example 148
Preparation of N-[2-hydroxy-5-ethylsulfonylphenyl]-N'-[2,3-dichlorophenyl] urea
N-[2-hydroxy-5-ethylsulfonylphenyl]-N'-[2,3-dichlorophenyl] urea was prepared from 2-amino-4-(ethylsulfonyl)phenol (185 mg. 1.00 mmol) according to the procedure in General Method B. The product was purified by precipitation from methylene chloride/
hexane( 1equiv./20cquiv.) and filtering. (310 mg, 84%). 1H NMR (CD3OD): δ 8.65 (s, 1H), 8. 18 (d, 1H), 7.45 (d, 1H), 7.26 (m, 2H), 7.00 (d, 1H), 3.33 (q, 2H), 1.24 (t, 3H). The following compounds of Formula (I) may be prepared in accordance with the examples and schemes as described above:
Example 149 : N-[2-(2-Amino-(4-trilluoromethyl) phenyl) sulfonylamino] phenyl]- N'-(2- bromophenypurea EI-MS m/z 527 (M-H) .
Example 150 : N-(2-(aminosulfonyl phenyl) 3-amino phenyl] N'-(2-bromo phenyl) ureaEI-MS m/z 426 (M+H)+.
The following compounds of Formula (I) may be prepared in accordance with the examples and schemes as described above, or may also be purchased commercially from well recognized sources. For instance. from Aldrich Chemical Company:
N-(2-Hydroxy-4-nitrophenyl)-N'-phenylurea
For instance, from the Alfred Bader Collection of Aldrich Chemical:
1-(2-Carboxyphenyl)-3-(3-fluorophenyl)urea
1-(2-Carboxypheny!)-3-(3-chlorophenyl)urea
Available from Gallard Schlesinger Company and/or the Sigma Aldrich Library of Rare Compounds: 1-(2-Carboxyphenyl)-3-(4-chlorophenyl)urea
1-(p-Anisyl)-3-(2-carboxyphenyl)urea
Available from Gallard Schlisinger Company :
2-(3,4-Dichlorophenylcarbonyldiimino)-5-trifluoromethylbenzoic acid
2-(4-Chlorophenylcarbonyldiimino)-5-trifluoromethylbenzoic acid
N-Phenyl-N'-(2-carboxyphenyl)urea
From Maybridge Chemical Company, Cambridge England:
1,1'-(4-Methyl-2-phenylene)bis(3-tolyl)]thiourea
N-(5-Chloro-2-hydroxy-4-nitrophenyl)-N'-phenylurea
The following compounds of Formula (I) may be prepared in accordance with the examples and schemes as described above, or as indicated by their respective citations in Chemical Abstracts:
1-(m-Anisyl)-3-(2-carboxyphneyl)urea;
1-(o-Anisyl)-3-(2-carboxyphenyl)urea ;
1-(2-Carboxyphenyl)-3-(3,4-dichlorophenyl)urea;
1-(2-Carboxyphenyl)-3-(2,4-dichlorophenyl)urea; METHOD OF TREATMENT
The compounds of Formula (I), (la), (II) and (III), or a pharmaceutically acceptable salt thereof can be used in the manufacture of a medicament for the prophylactic or therapeutic treatment of any disease stale in a human, or other mammal, which is exacerbated or caused by excessive or unregulated IL-8 cytokine production by such mammal's cell, such as but not limited to monocytes and/or macrophages, or other chemokines which bind to the IL-8 α or β receptor, also referred to as the type I or type II receptor.
For purposes herein, the compounds of Formula (I), (Ia), (Ib), (Ic), (II) and (III) all have the same dosages, and dosage formulations as that of Formula (I ) are used
interchangeably.
Accordingly, the present invention provides a method of treating a chemokine mediated disease, wherein the chemokine is one which binds to an IL-8 α or β receptor and which method comprises administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In particular, the chemokines ars IL-8, GROα, GROβ, GROγ or NAP-2.
The compounds of Formula (I) are administered in an amount sufficient to inhibit cytokine function, in particular IL-8,GROα, GROβ, GROγ or NAP-2 , such that they are biologically regulated down to normal levels of physiological function, or in some case to subnormal levels, so as to ameliorate the disease state. Abnormal levels of IL-8. GROα. GROβ, GROγ or NAP-2 for instance in the context of the present invention, consuiute: (i) levels of free IL-8 greater than or equal to 1 picogram per mL: (ii) any cell associated IL-8. GROα, GROβ, GROγ or NAP-2 above normal physiological levels: or (iii)the presence of IL- 8, GROα, GROβ. GROγ or NAP-2 above basal levels in cells or tissues in which IL-8, GROα, GROβ. GROγ or NAP-2respectively, is produced.
There are many disease states in which excessive or unregulated IL-8 production is implicated in exacerbating and/or causing the disease. Chemokine mediated diseases include psoriasis, atopic dermatitis, arthritis, asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, inflammatory bowel disease, Crohn's disease, ulcerative colitis. stroke, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, cardiac and renal reperfusion injury, glomerulonephritis. thrombosis, graft vs. host reaction, alzheimers disease, allograft rejections, malaria. restinosis, angiogenesis or undesired hematopoietic stem cells release.
These diseases are primarily characterized by massive neutrophil infiltration, T-cell infiltration, or neovascular growth, and are associated with increased IL-8, GROα, GROβ, GROγ or NAP-2 production which is responsible for the chemotaxis of neutrophils into the inflammatory site or the directional growth of endothelial cells. In contrast to other
inflammatory cytokines (IL- 1, TNF. and IL-6), IL-8. GROα, GROβ. GROγ or NAP-2 has the unique property of promoting neutrophil chemotaxis, enzyme release including but not limited to elastase release as well as superoxide production and activation The α-chemokines but particularly. GROα. GROβ. GROγ or NAP-2. working through the IL-8 type 1 or II receptor can promote the neovascularizaiion of tumors by promoting the directional growth of endothelial cells. Thcreforc. the inhibition of IL-8 induced chemotaxis or activation would lead to a direct reduction in the neutrophil infiltration.
The compounds of Formula (I) are administered in an amount sufficient to inhibit IL-N binding to the IL-8 alpha or beta receptors, from binding to these receptors, such as evidenced by a reduction in neutrophil chemotaxis and activation. The discovery that the compounds of Formula (I) are inhibitors of IL-8 binding is based upon the effects of the compounds of Formulas (I) in the in vitro receptor binding assays which are described herein. The compounds of Formula (I) have been shown to be dual inhibitors of both recombinant type I and type II IL-8 receptors. Preferably the compounds are inhibitors of only one receptor, preferably Type II As used herein, the term "IL-8 mediated disease or disease state" refers to any and all disease states in which IL-8. GROα. GROβ, GROγ or NAP-2 plays a role, cither by production of IL-8, GROα, GROβ, GROγ or NAP-2 themselves, or by IL-8. GROα, GROβ, GROγ or NAP-2 causing another monokine to be released, such as but not limited to IL- 1. IL-6 or TNF. A disease state in which, for instance, IL- 1 is a major component, and whose production or action, is exacerbated or secreted in response to IL-8, would therefore be considered a disease stated mediated by IL-8
As used herein, the term "chemokine mediated disease or disease stale" refers to any and all disease states in which a chemokine which binds to an IL-8 α or β receptor plays a role such as but not limited to IL-8, GRO-α, GRO-β, GRO-γ, or NAP-2 This would include a disease state in which, IL-8 plays a role, either by production of IL-8 itself , or by IL-8 causing another monokine to be released, such as but not limited to IL- 1. IL-6 or TNF A disease stale in which, for instance, IL- 1 is a major component, and whose production or action, is exacerbated or secreted in response to IL-8, would therefore be considered a disease staled mediated by IL-8.
As used herein, the term "cytokine" refers to any secreted polypeptide that affects the functions of cells and is a molecule which modulates interactions between cells in the immune. inflammatory or hematopoietic response. A cytokine includes, but is not limited to, monokines and lymphokines, regardless of which cells produce them For instance, a monokine is generally referred to as being produced and secreted by a mononuclcar cell, such as a macrophage and/or monocyte. Many other cells however also produce monokines. such as natural killer cells, fibroblasts. basophils, neutrophils, endothelial cells, brain astrocytes. bone marrow siromal cells, epideral keratinocytes and B-lymphocytcs Lymphokines are general!y referred to as being produced by lymphocyte cells Examples of cytokines include, but are not limited to. Interleukin- 1 (IL- 1 ). Interleukin-6 (IL-6), Interlcukin-8 (1L-8). Tumor Necrosis Factor-alpha (TNF-α) and Tumor Necrosis Factor beta (TNF-ß) As used herein, the term "chemokine" refers to any secreted polypeptide that affects the functions of cells and is a molecule which modulates interactions beiween cells in the immune inflammatory or hematopoieuc response, similar to the term cyiokine" above A chemokine is primarily secreted through cell transmembranes and causes chemotaxis and activation of specific while blood cells and leukocytes, neutrophils. monocytes. macrophages. T-cells. B- cells, endothelial cells and smooth muscle cells Examples of chemokines include, but are not limited to. IL-8. GRO-α, GRO-β. GRO-γ. NAP-2. IP- 10. MlP- l α. MlP-β. PF4 and MCP 1 , 2, and 3 In order to use a compound of Formula (I) or a pharmaceutically acceptable sail thereof in therapy, ii will normally be formulated into a pharmaceutical composition in accordance with standard pharmaceutical practice This invention, therefore. also relates to a pharmaceutical composition comprising an effective. non-toxic amount of a compound of Formula (I) and a pharmaceutically acceptable carrier or diluent
Compounds of Formula (I), pharmaceutically acceptable salts thereof and
pharmaceutical compositions incorporating such may conveniently be administered by any of the routes conventionally used for drug administration, for instance, orally, topically, parenterally or by inhalation The compounds of Formula (I ) may be administered in conventional dosage forms prepared by combining a compound of Formula (I) with standard pharmaceutical carriers according to conventional procedures The compounds of Formula (I) may also be administered in conventional dosages in combination with a known, second therapeutically active compound These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation It will be appreciated that the form and character of the pharmaceutically acceptable character or diluent is dictated by the amount of active ingredient with which it is to be combined, the route of administration and other well-known variables The carrier(s) must be "acceptable" In the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof
The pharmaceutical carrier employed may be for example, either a solid or liquid Exemplary of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar. pectin, acacia. magnesium stearate, stearic acid and the like Exemplar, of liquid carriers are syrup peanut oil. olive oil, water and the like Similarly, the carrier or diluent may include time delay material well known to the art. such as glyceryl mono-stearate or glyceryl distearate alone or with a wax .
A wide variety of pharmaceutical forms can be employed Thus, if a solid carrier is used, the preparation can be tableted. placed in a hard gelatin capsule in powder or pellet form or in the form of a troche or lozenge. The amount of solid carrier will vary widely but preferably will be from about 25mg to about 1 g When a liquid carrier is used, the preparation will be in the form of a syrup, emulsion, soft gelatin capsule ster ile injectable liquid such as an ampule or nonaqueous liquid suspension
Compounds of Formula (I) may be administered topically, that is by non-systemic administration This includes the application of a compound of Formula (I ) externally to the epidermis or the buccal cavity and the insullation of such a compound into the ear, eye and nose, such that the compound does not significantly enter the blood stream. In contrast, systemic administration refers 10 oral, intravenous, intraperitoneal and intramuscular administration. Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation such as liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye. car or nose. The active ingredient may comprise, for topical administration, from 0.001 % to 10% w/w, for instance from 1 % to 2% by weight of the Formulation. It may however comprise as much as 10% w/w but preferably will comprise less than 5% w/w, more preferably from 0. 1 % to 1 % w/w of the Formulation.
Lotions according to the present invention include those suitable for application to the skin or eye. An eye lotion may comprise a sterile aqueous solution optionally containing a bactericide and may be prepared by methods similar to those for the preparation of drops.
Lotions or liniments for application to the skin may also include an agent to hasten drying and to cool the skin, such as an alcohol or acetone, and/or a moisturizer such as glycerol or an oil such as castor oil or arachis oil Creams, ointments or pastes according to the present invention are semi-solid formulations of the active ingredient for external application They may be made by mixing the active ingredient in finely-divided or powdered form. alone or in solution or suspension in an aqueous or non-aqueous fluid, with the aid of suitable machinery, with a greasy or non-greasy base The base may comprise hydrocarbons such as hard, soft or liquid paraffin. glycerol. beeswax, a metallic soap, a mucilage: an oil of natural origin such as almond, corn, arachis. castor or olive oil: wool fat or us derivatives or a laity acid such as steric or oleic acid together with an alcohol such as propylene glycol or a macrogel The formulation may incorporate any suitable surface active agent such as an anionic. canonic or non-ionic surfactant such as a sorbitan ester or a polyoxyethylene derivative thereof Suspending agents such as natural gums, cellulose derivatives or inorganic materials such as silicaceous silicas, and other ingredients such as lanolin, may also be included
Drops according to the present invention may comprise sterile aqueous or oily solutions or suspensions and may be prepared by dissolving the active ingredient in a suitable aqueous solution of a bactericidal and/or fungicidal agent and/or any other suitable preservative, and preferably including a surface active agent. The resulting solution may then be clarified by filtration, transferred to a suitable container which is then sealed and sterilized by autoclaving or maintaining at 98- 100°C f or hall an hour . Alternatively. the solution may be sterilized by filiration and transferred to the container by an aseptic technique. Examples of bactericidal and fungicidal agents suitable for inclusion in the drops are phenylmercuric nitrate or acetale (0.(X)2%r), benzalkonium chloride (0.01 %) and chlorhexidine acetate (0.01 %). Suitable solvents for the preparation of an oily solution include glycerol, diluted alcohol and propylenc glycol
Compounds of formula (I) may be administered parenterally, that is by intravenous, intramuscular, subcutaneous intranasal, intrarectal, intravaginal or inirapcritoneal
administration. The subcutaneous and intramuscular forms of parenteral administration are generally preferred. Appropriate dosage forms for such administration may be prepared by conventional techniques. Compounds of Formula (I) may also be administered by inhalation, that is by intranasal and oral inhalation administration. Appropriate dosage forms for such administration, such as an aerosol formulation or a metered dose inhaler, may be prepared by-conventional techniques.
For all methods of use disclosed herein for the compounds of Formula (I), the daily oral dosage regimen will preferably be from about 0.01 to about 80 mg/kg of total body weight. The daily parenteral dosage regimen about 0.001 to about 80 mg/kg of total body weight. The daily topical dosage regimen will preferably be from 0.1 mg to 150 mg, administered one to lour, preferably two or three times daily. The daily inhalation dosage regimen will preferably be from about 0.01 mg/kg to about 1 mg/kg per day. It will also be recognized by one of skill in the art that the optimal quantity and spacing of individual dosages of a compound of Formula (I) or a pharmaceutically acceptable sail thereof will be determined by the nature and extent of the condition being treated, the form. route and site of
administration, and the particular patient being treated, and that such optimums can be determined by conventional techniques. It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e.. the number of doses of a compound of Formula (I ) or a pharmaceutically acceptable salt thereof given per day for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment determination tests
The invention will now be described by reference to the following biological examples which are merely illustrative and are not to be construed as a limitation of the scope of the present invention
BIOLOGICAL EXAMPLES
The IL-8. and Gro-α chemokine inhibitiory effects of compounds of the present invention were determined by the following m vitro assay: Receptor Binding Assays:
[ 125I] IL-8 (human recombinant) was obtained from Amersham Corp , Arlington Heights. IL, with specific activity 2000 Ci/mmol Gro-α was obtained from NEN- New England Nuclear. All other chemicals were of analytical grade. High levels of recombinant human IL-8 type α and β receptors were individually expressed in Chinese hamster ovary cells as described previously (Holmes, et al.. Science, 1991, 253, 1278) The Chinese hamster ovary membranes were homogenized according to a previously described protocol (Haour. et al., J Biol Chem., 249 pp 2195-2205 ( 1974)). Except that the homogenization buffer was changed to 10mM Tris-HCL, 1mM MgSO4, 0.5mM EDTA (ethylene-diaminetetra-acetic acid). 1 mMPMSF (α-toluenesulphonyl fluoride), 0.5 mg/L Leupepun, pH 7.5. Membrane protein concentration was determined using Pierce Co. micro-assay kit using bovine serum albumin as a standard. All assays were performed in a 96-well micro plate format Each reaction mixture contained 125I IL-8 (0.25 nM) or 125I Gro-α and 0.5 μg/mL of IL-8Rα or 1.0 μg/mL of IL-8Rβ membranes in 20 mM Bis-Trispropane and 0.4 mM Tris C1 buflers, pH 8.0. containing 1.2 mM MgSO4, 0.1 mM EDTA, 25 mM NaCl and 0.03% CHAPS In addition, drug or compound of interest was added which had been pre-dissolved in DMSO so as to reach a final concentration of between 0.01 nM and 100 uM. The assay was initiated by addition of 125I-IL-8 After 1 hour at room temperature the plate was harvested using a Tomtec 96-well harvester onto a glass fiber filtermat blocked with 1% polyethylenimine/0.5% BSA and washed 3 times with 25 mM NaCl. 10 mM TrisHCl, 1 mM MgSO4, 0.5 mM EDTA. 0.03 % CHAPS. pH 7 4 The filter was then dried and counted on the Betaplate liquid scintillation counter The recombinant IL-8 Rα, or Type I, receptor is also referred to herein as the non-permissive receptor and the recombinant IL-8 Rβ, or Type II, receptor is referred to as the permissive receptor
All of the exemplified compounds of Formulas (I) to (III) noted herein in the S ynthetic Chemistry Section, of Examples 1 to 150 plus the additional purchased compounds demonstrated an IC50 from about 45 to about < 1 μg/mL in the permissive models for IL-8 receptor inhibition All of these compounds were also found to be inhibitors of Gro-a binding at about the same level The compound 1 -(2-Carboxyphenyl)-3-(4-chloro-2-methylphenyl)urea was found to be active at about 75 μg/mL
The following compounds, generally tested at levels of up to 45 μg/mL were found to not demonstrate levels of IL-8 receptor antagonism within the criteria set forth above at the dosage levels tested These compounds are
1 -(4-Chloro-alpha.alpha,alpha-trifluoro-3-tolyl)-3-[2-(4-chlorophenyl)thio]-5- chlorophenyl urea 1-(6-Chloro-alpha,alpha,alpha-trifluoro-3-tolyI)-3-[2-(4-chlorophenoxy)-5- chlorophenyl]urea
1-(2-Mercaptophenyl)-3-phenyl-2-thiourea
1-(2-Hydroxyphenyl)-3-phenyl-2-thiourea
3,3'-(Carbonothioyldiimino)bis[4-hydroxybenzoic acid]
m,m'-(1 ,3-thioureylene)di(4-hydroxybenzoic acid)
1-(2-Tolyl)-3-(3-chloro-6-hydroxyphenyl)-2-thiourea
1-[(2-Hydroxy-4-aminophenyI)]-(3-phenyl)-urea
N-(2-Carboxy-4-trifluromethylphenyl)-N'-(3-chlorophenyl)urea
N-(2-Carboxyphenyl)-N'-(2,5-dichlorophenyl)urea
1-(2-Carboxyphenyl)-3-(2-Chloro-5-trifluoromethylphenyl)urea
2-[2-[3-(4-Bromophenyl)ureido]-4-trifluoromethylphenoxy]benzoic acid;
2-[2-[3-(4-Chlorophenyl)ureido]phenoxy]benozic acid
2-[2-[3-(4-Chloro3-(trifluromethyl)phenyl)ureido]phenoxy]benozic acid N- (2-Hydroxyphenyl) -N'-phenyl urea
N-[2-Hydroxy-5-(methoxycarbonyl)phenyl]-N'-phenylurea
N-[4-Carboxy-2-hydroxyphenyl]-n'-phenylurea
N-(2-Hydroxy-4-nitrophenyl)-N'-(4-nitrophenyI)urea;
1-(2-Carboxyphenyl)-3-(2,6-xylyl)urea
1-(6-Carboxy-2,4-dichlorophenyl)-3-(2,4,6-trichlorophenyl)urea
1-(2-Carboxyphenyl)-3-(2,5-dimethoxyphenyl)urea
1-(2-Carboxyphenyl)-3-(2-methylphenyI)urea
1-[(2-Hydroxyphenyl)-3-(2-methyl)-5-nitrophenyl]urea
1-(2,5-Dichlorophenyl)-3-(2-hydroxy-4-nitrophenyI)urea
1-(2-Carboxyphenyl)-3-(4-chloro-2-methylphenyl)urea
N-(2-phenylsulfonylaminophenyl-N'-phenylurea
N-(2-Hydroxy-4-nitrophenyl)-N'-(4-ethoxycarbonylphenyl)urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(2-ethoxycarbonylphenyl)urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(3-ethoxycarbonylphenyl)urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(4-phenylphenyl)urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(4-phenoxyphenyl)urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(4-propylphenyl)urea
N-(4-Tritluromethyl-2-(4-nitrobenzenesulfonyl)amino]-N'-phenylurea
N-(3-Carboxyphenyl)-N'-2-hydroxy-4-nitrophenyl)urea
N-(4-Trilluromethyl-2-(methylsulfonyl)amino]-N'-phenylurea
N-(2-Hydroxy-4-nitrophenyl)-N'-f2-(isopropyl)phenyl)urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(2,6-dimethylphenyl)urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(2-fluoro-5-nitrophenyl)urea N-(2-Hydroxy-4-nitrophenyl)-N'-(2-chloro-5-trifluromethylphenyl)urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(2-methoxy-4-nitrophenyl)urea
N-(2-Hydroxy- 1-napthyl)-N'-(2-phenylphenyl)urea
N-(2-Hydroxy-5-ethylsulfonylphenyl)-N'-(2-bromophenyl)urea
N-(2-hydroxy 3,4 dichlorophenyl )-N'-(4-phenylphenyl)urea
N-(2-hydroxy-3-naphthyl)-N'-(2-methoxyphenyl)urea
N-(2-hydroxy-3-naphthyl)-N'-(2-phenylphenyl)urea
N-(2-Hydroxy-3-naphthyl)-N'-(4-methoxyphenyl)urea
N-(2-Hydroxy-3-naphthyl)-N'-(3-trifluoromethylphenyl)urea
N-(2-Hydroxy-3-naphthyl)-N'-(4-phenylphenyl)urea
N-[2-(2-Carboxyphenylsulfonylamino)phenyl]-N'-(2-bromophenyl )urea
N-(2-Hydroxy-3-phenylphenyl)-N'-(2-methoxyphenyl)urea
N-(2-Hydroxy-3-phenylphenyl)-N'-(4-meϋιoxyphenyl)urea
N-(2-Hydroxy-3-phenylphenyl)-N'-(3-triflouromethylphenyl)urea
N-(2-Hydroxy-3-phenylphenyl)-N'-(2-phenylphenyl)urea
N-(2-Hydroxy-3-phenylphenyl)-N'-(4-phenylphenyl)urea
N-f2-[(2,5-Dichlorothien3-yl)sulfonylamino]phenyl]-N'-(2-bromophenyl)urea
N-(2-Hydroxy,3,4-dichlorophenyl)-N'-(2,4 dimethoxyphenyl)urea
N-(2-Hydroxy,3,4-dichlorophenyl)-N'-(2-chloro-5-trifloromethylphenyl)urea N-(2-Hydroxy-3-naphthyl)-N'-(2,4 dimethoxyphenyl)urea
N-(2-Hydroχy-3-naphthyl)-N'-(2-chloro-5-trifluoromethylphenyl)urea
N-(2-Hydroxy-3 phenylphenyl)-N'-(2.4-dimethoxyphenyl)urea
N-(2-Hydroxy-4-isopropylphenyl)-N'-(2,4-dimeihoxyphenyl )urea
N-(2-Hydroxy-3-phenylphenyl)-N'-(2-chloro-5-trifluoromethylphenyl)urea N-(2-Hydroxy-5-nitrophenyl)-N'-(2.4-dimeihoxyphenyl)urea
N-(2-Hydroxy-5-nilrophenyl)-N'-(2-chloro-5-trifluoromeihylphenyl)urea
N-(2-Hydroxy -3-cyanophenyl)-N'-(4-methoxyphenyl)urea
N-(2-Hydroxy-3-cyanophenyl)-N'-(4-phenylphenyl)urea
N-(2-Hydroxy -3-cyanophenyl)-N'-(2,4 dimethoxyphenyl )urea
N-(2-Hydroxy-3-cyanophenyl)-N'-(2-chloro-5-trifluoromeihylphenyl)urea
N-(2-Hydroxy - 5-phenylphenyl)-N'-(2-meιhoxyphenyl)urea
N-(2-Hydroxy - 5-phenylphenyl)-N'-(4-methoxyphenyl)urea
N-(2-Hydroxy - 5-phenylphenyl)-N'-( 3-iriHuoromethylphenyl)urea
N-(2-Hydroxy - 5-phenylphenyl)-N -(2-phenylphenyl )urea
N-(2-Hydroxy -5-phenylphenyl)-N'-(4-phenylphenyl)urea
N-(2-Hydroxy-5-phenylphenyl)-N'-(2.3-dichlorophenyl)urea
N-(2-Hydroxy -5-phenylphenyl)-N'-(2,4-dimeihoxyphenyl)urea
N-(2-Hvdroxy -5-phenylphenyl )-N'-(2-chloro-5-trifluoromethylphenyl )urea N-(2-Hydroxy-5-ethylsullonylphenyp-N'-(4-methoxyphenyl)urea
N-(2-Hydroxy-5-ethylsulfonylphenyl)-N'-(3-trifluoromethylphenyl)urea
N-(2-Hydroxy-5-ethylsulfonylphenyl)-N'-(2-phenylphenyl)urea
N-(2-Hydroxy-5-eihylsulfonylphenyl)-N'-(4-phenylphenyl)urea
N-(2-Hydroxy-5-ethylsullfonylphenyl)-N'-(2,4-dimethoxyphenypurea
N-(2-Hydroxy-5-ethylsulfonylphenyl)-N'-(2-chloro-5-trifluoromethylphenyl)urea
N-[2-Hydroxy-3,4-dichlorophenyI]-N'-[2,4 dimethoxyphenyl] urea
N-(2-Hydroxy-3,4-dichlorophenyl]-N'-[2-chloro-5-trifluoromethylphenyl] urea
N-[2-Hydroxy-3-naphihyl ]-N'-|3-trifluoromeihylphenyl] urea
Chemotaxis Assay :
The in vitro inhibitory properties of these compounds were determined in the neutrophil chemotaxis assay as described in Current Protocols in Immunology, vol I. Suppl 1. Unit 6.12.3.. whose disclosure is incorporated herein by reference in us entirety.
Neutrophils where isolated from human blood as described in Current Protocols in
Immunology Vol I. Suppl 1 Unit 7.23. 1 , whose disclosure is incorporated herein by reference in its entirety. The chemoattractants IL-8, GRO-α. GRO-β. GRO-γ and NAP-2 where placed in the bottom chamber of a 48 multiwell chamber (Neuro Probe. Cabin John, MD) at a concentration between 0.1 and 100 nM. The two chambers where separated by a 5um polycarbonate filler. When compounds of this invention were tested, they where mixed with the cells (0.001 - 1000 nM) just prior to the addition of the cells to the upper chamber Incubation was allowed to proceed for between about 45 and 90 min at about 37°C in a humidified incubator with 5% CO2 At the end of the incubation period, the polycarbonate membrane was removed and the top side washed, the membrane was then stained using the Diff Quick sunning protocol (Baxter Products. McGaw Park. IL. USA) Cell which had chemotaxed 10 the chemokine were visually counted using a microscope Generally, four fields where counted for each sample, these number where averaged to give the average number of cells which had migrated. Each sample was tested in triplicate and each compound repeated at least four times To certain cells (positive control cells) no compound was added. these cells represent the maximum chemotactic response of the cells. In the case where a negative control (unstimulated) was desired, no chemokine was added to the bottom chamber. The difference between the positive control and the negative control represents the chemotactic activity of the cells Elastase Release Assay :
The compounds of this invention where tested for their ability to prevent Elastase release from human neutrophils. Neutrophils where isolated from human blood as described in Current Protocols in Immunology Vol I. Suppl 1 Unit 7.23. 1. PMNs 0.88 × 1 06 cells suspended in Ringer's Solution (NaCl 1 18. KCl 4.56, NaHCO3 25, KH2PO4 1 03. Glucose 1 1 1 . HEPES 5 mM. pH 7 4) where placed in each well of a 96 well plate in a volume of 50 ul. To this plate was added the test compound (0.001 - 1000 nM) in a volume of 50 ul, Cytochalasin B in a volume of 50 ul (20ug/ml) and Ringers buffer in a volume of 50 ul These cells where allowed to warm (37 °C, 5% CO2, 95% RH) for 5 mm before IL-8,
GROα. GROβ. GROγ or NAP-2 at a final concentration of 0.01 - 1000 nM was added The reaction was allowed to proceed for 45 min before the 96 well plate was ccntriluged (800 ×g 5 mm) and 1(X) ul of the supernatant removed. This suppernatant was added to a second 96 well plate lollowed by an artificial elastase substrate (MeOSuc-Ala-Ala-Pro-Val-AMC. Nova Biochem. La Jolla. CA) to a final concentration of 6 ug/ml dissolved in pho.sphate buffered saline Immediately, the plate was placed in a fluorescent 96 well plate reader (Cyiofluor 2350. Millipore. Bedford. MA) and data collected at 3 min intervals according to the method of Nakaμma et al J. Biol Chem 254 4027 ( 1979). The amount of Elastase released from the PMNs was calculated by measuring the rate of MeOSuc-Ala-Ala-Pro-Val-AMC degradation
The above description fully discloses the invention including preferred embodiments thereof. Modifications and improvements of the embodiments specifically disclosed herein are within the scope of the following claims. Without further elaboration, it is believed that one skilled in the are can, using the preceding description, utilize the present invention to its fullest extent Therefore the Examples herein are to be construed as merely illustrative and not a limitation of the scope of the present invention in any way The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows

Claims

1. A method of treating a chemokine mediated disease stale wherein the chemokine binds to an IL-8 α or β receptor in a mammal, which comprises administering to said mammal an effective amount of a compound of the formula:
Figure imgf000101_0001
wherein
X is oxygen or sulfur;
R is any functional moiety having an ionizable hydrogen and a pKa of 10 or less;
R1 is independendy selected from hydrogen; halogen; nitro: cyano: halosubstituted C1-10 alkyl; C1-10 alkyl; C2-10 alkenyl; C1-10 alkoxy; halosubstituted C1-10 alkoxy; azide: S(O)tR4: hydroxy; hydroxy C1-4alkyl; aryl; aryl C1-4alkyl: aryloxy; aryl C1-4alkyloxy ; heteroaryl; heteroarylalkyl; heterocyclic. heterocyclic C1-4alkyl: heteroaryl C1-4 alkyloxy; aryl C2-10 alkenyl; heteroaryl C2-10 alkenyl; heterocyclicC2-10 alkenyl: NR4R5; C2-10 alkenyl C(O)NR4R5;C(O)NR4R5;C(O)NR4R10; S(O)3H; S(O)3R8: C1-10alkyl
C(O)R11:C2-10 alkenyl C(O)R11; C2-10 alkenyl C(O)OR11: C(O)R11: C(O)OR12: OC(O)R11 : NR4C(O)R11 : or two R1 moieties together may form O-(CH2)sO- or a 5 to 6 membered unsaturated ring;
1 is 0. or an integer having a value of 1 or 2:
s is an integer having a value of 1 to 3:
R4 and R5 are independently hydrogen, optionally substituted C1-4alkyl. optionally
substituted aryl, optionally substituted aryl C1-4alkyl. optionally substituted heteroaryl. optionally substituted heteroarylC1-4alkyl. heterocyclic. heterocyclic C1-4 alkyl. or R4 and R5 together with the ntrogen to which they are attached form a 5 to 7 member ring which may optionally comprise an additional heteroatom selected from O/N/S:
Y is independently selected from hydrogen: halogen: nitro: cyano: halosubstituied C1-10alkyl:
C1-10alkyl: C2-10alkenyl: C1-10alkoxy;halosubstituied C1-10 alkoxy: azide: S(O)tR4: hydroxy; hydroxyC1-4alkyl: aryl: arylC1-4alkyl: aryloxy; arylC1-4 alkyloxy; heteioaryl. heteroarylalkyl: heteroarylC1-4 alkyloxy;heterocyclic. heterocyclicC1-4alkyl: aryl C2-10 alkenyl: heicroaryl C2-10 alkenyl: heterocyclicC2-10 alkenyl: NR4R5; C2-10 alkenyl
C(O)NR4R5; C(O)NR4R5; C(O)NR4R10: S(O)3H: S(O)3R8: C1-10alkyl C(O)R11: C2-10alkenylC(O)R11:C2-10alkenylC(O)OR11:C(O)R11:C(O)OR12:OC(O)R11: NR4C(O)R11 : or two Y moieties together may form O-(CH2)sO- or a 5 to 6 membered unsaturated ring:
n is an integer having a value of 1 to 3: m is an integer having a value of 1 to 3.
R8 is hydrogen or C1-4alkyl:
R10 is C1-10 alkyl C(O)2R8:
R11 is hydrogen, C1-4 alkyl, optionally substituted aryl, optionally substituted aryl C1-4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylC1-4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC1-4alkyl:
R12 is hydrogen, C1-10 alkyl, optionally substituted aryl or optionally subsututed arylalkyl: or a pharmaceutically acceptably sail thereof 2. The method according to Claim 1 wherein the lonizable hydrogen has a pKa ot 3 to 10
3. The method according to Claim 2 wherein R is hydroxy, carboxylic acid,thiol. -SR2
-OR2, -NH-C(O)Ra, -C(O)NR6R7, -NHS(O)2Rb, -S(O)2NHRc, NHC(X)NHRb. or tetrazolyl;
wherein R2 is a substituted aryl, heteroaryl. or heterocyclic moiety which ring has the functional moiety providing the ionizable hydrogen having a pKa of 10 or less:
R6 and R7 are independently hydrogen or a C1-4 alkyl group, or R6 and R7 together with the nitrogen to which they are attached form a 5 to 7 member ring which ring may optionally contain an additional heteroatom which heteroatom is selected from oxygen, nitrogen or sulfur;
Ra is an alkyl, aryl, aryl C1-4alkyl, heteroaryl. heteroaryl C1-4alkyl, heterocyclic, or a heterocyclic C1-4alkyl moiety, all of which may be optionally substituted;
Rb is a NR6R7, alkyl. aryl. arylC1-4alkyl. arylC2-4alkenyl. heteroaryl.
heteroarylC1-4alkyl, heteroarylC2-4 alkenyl. heterocyclic. heterocyclic C1-4alkyl. heterocyclicC2-4alkenyl moiety, camphor, all of which may be optionally substituted one to three times independently by halogen, nitro. halosubsliluted C1-4 alkyl: C1-4 alkyl: C1-4 alkoxy.
NR9C(O)Ra. C(O)NR6R7, S(O)3H, or C(O)OC1-4alkyl.
R9 is hydrogen or a C1-4alkyl:
Rc is alkyl, aryl. arylC1-4alkyl. arylC2-4alkenyl. heteroaryl. heteroarylC1-4alkyl. heteroarylC2-4alkenyl. heterocyclic, heterocyclic C1-4alkyl, or a heterocyclic C2-4alkenyl moiety, all of which may be optionally substituted one 10 three times independently by halogen nitro, halosubstituted C1-4 alkyl. C1-4 alkyl. C1-4alkoxy, NR9C(O)Ra, C(O)NR6R7 S(O)3H, or C(O)OC1-4alkyl 4 The method according 10 Claim 3 wherein the R2 is optionally substituted one to three times by halogen, nitro, halosubstituted C1-10 alkyl, C1-10 alkyl C1-10alkoxy, hydroxy, SH, -C(O)NR6R7, -NH-C(O)Ra, -NHS(O)Rb, S(O)NR6R7. C(O)OR8. or a tetrazolyl ring
5. The method according to Claim 3 wherein R is OH. -NHS(O)2Rb or C(O)OH.
6. The method according to Claim I wherein R 1 is halogen, cyano. nitro, CF3,
C(O)NR4R5, alkenyl C(O)NR4R5, C(O) R4R 10. alkenyl C(O)OR 1 2, heteroaryl, heicroarylalkyl , heteroaryl alkenyl, or S(O)NR4R5.
7. The method according to Claim I wherein Y is halogen, C1 -4 alkoxy, optionally substituted aryl, optionally substituted arylalkoxy. methylene dioxy. NR4R5. thioC1 -4alkyl, thioaryl, halosubstituted alkoxy, optionally substituted C1 -4aIkyl, hydroxy alkyl.
8. The method according to Claim 1 wherein R is OH, SH, or NHS(O)sRb and R1 is substituted in the 3-position, the 4- position or di substituted in the 3,4- position by an electron withdrawing moiety. 9. The compound according to Claims 1 or 8 wherein Y is mono-substituted in the 2'-position or 3'- position, or is disubstituted in the 2'- or 3'- position of a monocyclic ring.
10. The compound according to Claims 1 , 8 or 9 wherein n amd m are each equal to I or more.
1 1. The method according to Claim 1 wherein R is a carboxylic acid, and R1 is hydrogen, or R 1 is substituted in the 4-position.
12. The method according to Claim 1 wherein the mammal is afflicted with a chemokine mediated disease selected from psoriasis, or atopic dermatitis, asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, arthritis, inflammatory bowel disease Crohn's disease ulcerative colitis, septic shock, endotoxic shock, gram negative sepsis, toxic-shock syndrome, stroke cardiac and renal reperfusion injury, glomerulo-nephritis. or thrombosis, alzheimers discase. graft vs. host reaction, or allograft rejections.
13. The method according to Claim 1 wherein the compound, or a pharmaceutically acccpatable salt is:
N-(2-Hydroxy-4-nitrophenyl)-N'-(2-methoxyphenyl)urea
N-(2-Hydroxy -4-nitrophenyl)-N'-(2-bromophenyl)urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(2-phenylphenyl)urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(2-methylmiophenyl)urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(2,3-dichlorophenyl)urea
N-(2-Hydroxy 4-nitro phenyl) N'-(2-chloro phenyl) urea N- (2-Hydroxy-4-nitrophenyl)-N'-(2,3-methylcncdioxyphenyl)urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(2-methoxy-3-chlorophenyl)urea
N-(2-hydroxy 4-nitro phenyl) N'-(2-phenyloxy phenyl) urea
N-(3-Chloro-2-hydroxyphenyl)-N'-(bromophenyl)urea
N-(2-Hydroxy-3-glycincmethylestercarbonylphenyl)-N'-(2-bromophenyl)urea N-(3-Nitro-2-hydroxyphenyl)-N'-(2-bromophenyl)urea
N-(2-Hydroxy-4-cyanophenyl)-N'-(2-bromophenyl)urea
N-(2-Hydroxy-3,4-dichlorophenyl)-N'-(2-bromophenyl)urea
N-(3-Cyano-2-hydroxyphenyl)-N'-(2-bromophenyl)urea
N-(2-Hydroxy-4-cyanophenyl)-N'-(2-methoxyphenyl)urea
N- (2-Hydroxy-4-cyanophenyl)-N'-(2-phenylphenyl)urea
N-(2-Hydorxy-4-cyanophenyl-N'-(2,3-dichlorophenyl)urea
N- (2-Hydroxy-4-cyanophenyl)-N'-(2-methylphenyl)urea
N-(2-Hydroxy-3-cyano-4-methylphenyl)-N'-(2-bromophenyl)urea
N-(4-Cyano-2-hydroxyphenyl)-N'-(2-trifluoromethylphenyl)urea
N-(3-Trifluoromethyl-2-hydroxyphenyl)-N'-(2-bromophenyl)urea
N- (3-Phenylaminocarbonyl-2-hydroxyphenyl)-N'-(2-bromophenyl)urea
N-(2-hydroxy 4-nitro phenyl) N'-(2-iodo phenyl) urea
N-(2-hydroxy 4-nitro phenyl) N'(2-bromo phenyl) thiourea
N-(2-phenylsulfonamido)-4-cyanophenyl-N'(2-bromo phenyl)urea
(E)-N-[3-[(2-Aminocarbonyl)ethenyl]-2-hydroxyphenyl]-N'-(2-bromophenyl)urea N-(2-Hydroxy-3,4-dichlorophenyl)-N'-(2-methoxyphenyl)urea
N-(2-Hydroxy-3,4-dichlorophenyl)-N'-(2-phenylphenyl)urea
N-(2-Hydroxy-3,4-dichlorophenyl)-N'-(2,3-dichlorophenyl)urea
N-(2-Hydroxy -5-nitrophenyl)-N'-(2,3-dichlorophenyl)urea; or
N-(2-Hydroxy -3-cyanophenyl)-N'-(2,3 dichlorophenyl)urea.
14. A compound of the formula:
Figure imgf000104_0001
E is optionally selected from
Figure imgf000105_0002
: the asterix * denoting point of attachment of the ring; wherein at least one E ring is present:
or a pharmaceutically acceptably salt thereof. 15. A pharmaceutical composition comprising a compound according to Claim 14 and a pharmaceutically acceptable carrier or diluent.
16 A method of treating a chemokine mediated disease state, wherein the chemokine binds to an IL-8 α or β receptor in a mammal, which comprises administering to said mammal an effective amount of a compound of the formula according to Claim 14.
17. A compound of the formula:
Figure imgf000105_0001
wherein
X is oxygen or sulfur:
R is any functional moiety having an ionizable hydrogen and a pKa of 10 or less:
R1 is independently selected from hydrogen: halogen: nitro: cyano: halosubstituted C1-10 alkyl: C1-10 alkyl: C2-10 alkenyl: C1-10alkoxy; halosubstiiuted C1-10alkoxy: azide. S(O)tR4: hydroxy; hydroxyC1-4alkyl: aryl: aryl C1-4alkyl: aryloxy; arylC1-4alkyloxy . heteroaryl: heteroarylalkyl: heterocyclic. heterocyclicC1-4alkyl: heteroarylC1-4alkyloxy . aryl C2-10 alkenyl: heteroaryl C2-10 alkenyl: heterocyclicC2-10 alkenyl: NR4R5; C2-10 alkenyl C(O)NR4R5; C(O)NR4Rs: C(O)NR4R 10: S(O)3H: S(O)3R8:C1-10alkyl C(O)R11: C2-10 alkenyl C(O)R11 : C2-10 alkenyl C(O)OR11: C(O)R11. C(O)OR12. OC(O)R11:NR4C(O)R11: or two R1 moieties together may form O-(CH2)sO- or a 5 to 6 membered unsaturated ring:
1 is 0, or an intrger having a value of 1 or 2.
s is an integer having a value of 1 to 3:
R4 and R5 are independently hydrogen, optionally substituted C1-4alkyl. optionally
substituted aryl. optionally substituted aryl C1-4alkyl, optionally substituted heteroaryl. optionally substituted heteroaryl C1-4alkyl, heterocyclic. heterocyclicC1-4 alkyl. or R4 and R5 together with the nitrogen to which they are attached form a 5 to 7 member ring which may optionally comprise an additional heteroatom selected from O/N/S;
Y is independently selected from hydrogen; halogen; nitro; cyano: halosubstiiuted C1-10alkyl:
C1-10 alkyl; C2-10 alkenyl; C1-10alkoxy; halosubstituted C1-10 alkoxy; azide S(O)tR4. hydroxy; hydroxyC1-4alkyl; aryl; aryl C1-4alkyl: aryloxy. arylC1-4alkyloxy. heteroaryl heteroarylalkyl; heteroarylC1-4alkyloxy; heterocyclic, heterocyclic C1-4alkyl: aryl C2-10 alkenyl; heteroaryl C2-10 alkenyl. heterocyclicC2-10 alkenyl. NR4R5; C2-10 alkenyl C(O)NR4R5; C(O)NR4R5; C(O)NR4R10. S(O)3H: S(O)3R8: C1-10 alkyl C(O)R11 C2-10 alkenyl C(O)R11 ; C2-10 alkenyl C(O)OR11:C(O)R11: C(O)OR12; OC(O)R11
NR4C(O)R11; or two Y moieties together may form O-(CH2)sO- or a 5 to 6 membered unsaturated ring;
n is an integer having a value of 1 to 3;
m is an integer having a value of 1 to 3:
R8 is hydrogen or C1-4alkyl;
R10 is C1-10alkyl C(O)2R8;
R11 is hydrogen, C1-4 alkyl, optionally substituted aryl, optionally substituted aryl C1-4alkyl. optionally substituted heteroaryl, optionally substituted heteroaryl C1-4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC1-4alkyl:
R12 is hydrogen, C1-10 alkyl, optionally substituted aryl or optionally substiiuied arylalkyl: or a pharmaceutically acceptable salt thereof.
18 A pharmaceutical composition comprising a compound according 10 Claim 17 and a pharmaceutically acceptable carrier or diluent.
19 A method of treating a chemokine mediated disease state. wherein the chemokine binds to an IL-8 α or β receptor in a mammal, which comprises administering to said mammal an effective amount of a compound of the formula according to Claim 17. 20 A compound of the formula.
Figure imgf000106_0001
wherein
X is oxygen or sullur. Ra is an alkyl, aryl, aryl C1-4alkyl, heteroaryl. heteroarylC1-4alkyl. heterocyclic. or a heterocyclic C1-4alkyl moiety, all of which may be optionally substituted:
Rb is a NR6R7. alkyl, aryl. arylC1-4alkyl, arylC2-4alkenyl, heteroaryl. heteroarylC1-4alkyl. heteroarylC2-4 alkenyl, heterocyclic, or heterocyclic C1-4alkyl. or a heterocyclic
C2-4alkenyl moiety, camphor, all of which may be optionally substituted one to three times independendy by halogen: nitro: halosubstituted C1-4alkyl: C1-4 alkyl: C1-4alkoxy; NR9C(O)Ra; C(O)NR6R7, S(O)3H. or C(O)OC1-4alkyl;
R6 and R7 are independently hydrogen or a C1-4 alkyl group, or R6 and R7 together with the nitrogen to which they are attached form a 5 to 7 member ring which ring may optionally contain an additional heteroatom which heteroatom is selected from oxygen, nitrogen or sulfur, which ring may be optionally substitued;
R9 is hydrogen or a C1-4alkyl;
R1 is independendy selected from hydrogen: halogen: nitro: cyano: halosubstituted C1-10
alkyl: C1-10alkyl: C2-10alkenyl: C1-10alkoxy; halosubstituted C1-10 alkoxy; azide: S(O)tR4; hydroxy; hydroxyC1-4alkyl; aryl; aryl C1-4 alkyl: aryloxy; arylC1-4 alkyloxy; heteroaryl: heteroarylalkyl: heterocyclic, heterocyclicC1-4alkyl; heteroarylC 1-4 alkyloxy; aryl C2-10 alkenyl; heteroaryl C2-10 alkenyl; heterocyclicC2-10 alkenyl: NR4R5; C2-10 alkenyl C(O)NR4R5; C(O)NR4R5; C(O)NR4R10: S(O)3H: S(O)3R8: C1-10 alkyl C(O)R11; C2-10 alkenyl C(O)R11 : C2- 10 alkenyl C(O)OR11 : C(O)R11 : C(O)OR12: OC(O) R11 : NR4C(O)R11 : or two R1 moieties together may form O-(CH2)sO- or a 5 to 6 membered unsaturated ring;
t is 0, or an integer having a value of 1 or 2;
s is an integer having a value of 1 to 3:
R4 and R5 are independently hydrogen, optionally substituted C 1-4 alkyI. optionally
substituted aryl. optionally substituted aryl C1-4alkyl. optionally substituted heteroaryl. optionally substituted heteroaryl C1-4alkyl, heterocyclic. heterocyclicC1-4 alkyl. or R4 and R5 together with the nitrogen to which they are attached form a 5 to 7 member ring which may optionally comprise an additional heteroatom selected from O/N/S:
Y is independently selected from hydrogen; halogen: nitro: cyano: halosubstituted C1-10 alkyl C1-10alkyl; C2-10 alkenyl; C1-10 alkoxy; halosubstitiued C1-10alkoxy; azide. S(O)tR4. hydroxy: hydroxyC1-4alkyl; aryl; aryl C1-4 alkyl: aryloxy; arylC1-4 alkyloxy: heteroaryl: heteroarylalkyl: heteroarylC1-4 alkyloxy; heterocyclic. heterocyclicC1-4alkyl: aryl C2-10 alkenyl: heteroaryl C2-10 alkenyl: heterocyclic C2-10 alkenyl: NR4R5; C2-10 alkenyl C(O)NR4R5; C(O)NR4R5; C(O)NR4R10: S(O)3H; S(O)3R8. C1-10alkyl C(O)R11; C2-10 alkenyl C(O)R11; C2-10 alkenyl C(O)OR11; C(O)R11; C(O)OR12; OC(O)R11;
NR4C(O)R11; or two Y moieties together may form O-(CH2)sO- or a 5 to 6 membered unsaturated ring:
n is an integer having a value of 1 to 3; m is an integer having a value of 1 to 3;
R8 is hydrogen orC1-4alkyl;
R10 is C1-10 alkyl C(O)2R8:
R11 is hydrogen,C1-4 alkyl, optionally substituted aryl, optionally substituted aryl C1-4alkyl. optionally substituted heteroaryl, optionally substituted heteroaryl C1-4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclic C1-4alkyl:
R12 is hydrogen, C1-10 alkyl, optionally substituted aryl or optionally substituted arylalkyl: or a pharmaceutically acceptably salt thereof. 21. The compound according to Claim 20 wherein R1 is substituted in the 3-position, the 4- position or di substituted in the 3,4- position by an electron withdrawing moiety.
22. The compound according to Claim 20 or 21 wherein Y is mono-substituted in the 2'- position or 3'- position, or is disubstituted in the 2- or 3- position of a monocyclic ring.
23. The compound according to Claim 20 or 21 wherein n amd m are each equal to 1 or more.
24. The compound according to Claim 20 which is
N-(4-Nitro 2-(phenylsulfonylamino)phenyl)-N'-phenyl urea
N-[(2-Phenylsulfamido) 4-cyanophenyl]-N'-(2-bromo phenyl)urea
N-(2-(Amino sulfonamido phenyl)phenyl) N'-(2-bromo phenyl) urea
N-(2-(Amino sullonyl styryl) phenyl) N'-(2-bromo phenyl)urea
2-[(3,4Di-methoxyphenylsullonyl)amino]phenyl) N'-(2-bromo phenyl)urea
N-(2-[(4-Aceiamidophenylsullonyl)amino]phenyl) N'-(2-bromo phenyl)urea
N-(2-(Amino sullonyl(2-thiophenc)phenyl) N'-(2-bromo phenyl) urea
N-(2-(Amino sulfonyl(3-lolyl)phenyl) N'-(2-bromo phenyl) urea
N'-(2-(Amino sulfonyl(8-quinolinyl))phenyl) N'-(2-bromo phenyl)urea
N-(2-(Amino sultonyl benzyl) phenyl) N'-(2-bromophenyl)urea
N-[2-[[[2-(Tritluoromethypphenyl]sulfonyl]amino]phenyl]-N'-(2-bromophenyl)urea
N-(2-Bromophenyl)-N'-[2-dimethylaminosulfonylamino]phenyl]urea
N-[2-(Phenethylsullonylamino)phenyl]-N'-(2-broniophenyl)urea
N-[2-[(2-Acciamido-4-methylthiazol-5-yl)sullonylamino]phenyl]-N'-(2-biomophenyl)urea N-[2-((2,3-Dichlorothien-5-yl)|sullonylamino]phenyl]-N'-(2-bromophenyl)urea
N-[2-|(3.5-Bisirilluoromethylphenypsullonylamino]phenyl]-N'-(2-bromophenypurea
N-[2-l(2-Benzyl)sullonylamino]-(5-trilluoromethyl)phenyl]-N'-(2-bromophenyl)urea
N-[2-[2-(3-Nitrophenyl)sulfonylamino]phenyl]-N,-(2-bromophenyl)urea
N-[2-[2-(4-Phenoxyphenyl)sultonylamino]phenyl]-N'-(2-bromophenyl)urea N-[[2-(1S)-10-Camphorsulfonylamino]phenyl]-N'-(2-bromophenyl)urea
N-|[2-(1R)-10-Camphorsulfonylamino]phenyl]-N'-(2-bromophenyl)urea
N-[2-[2-(2-Nitro-(4-trifluoromethyl)phenyl)sulfonylamino]phenyl-N'-(2-bromophenyl)urea N-[2-(2-Amino-(4-trifluoromethyl)phenyl)sulfonylamino]phenyl]-N'-(2- bromophenypurea: or
N-[2-(aminosulfonyl phenyl)3-amino phenyl]N'-(2-bromo phenyl)urea.
27. A pharmaceutieal composition comprising a compound according to any of Claims 22 to 27 and a pharmaceutically acceptable carrier or diluent.
28. A compound of the formula:
Figure imgf000109_0001
wherein
X is oxygen or sulfur;
X i is oxygen or sulfur;
R1 is independently selected from hydrogen; halogen: nitro; cyano; halosubstituted C1-10 alkyl: C1-10 alkyl: C2-10 alkenyl: C1-10 alkoxy; halosubstituted C1-10alkoxy; azide: S(O)tR4; hydroxy; hydroxyC1-4alkyl: aryl; aryl C1-4 alkyl: aryloxy; aryl C1-4 alkyloxy; heteroaryl: heteroarylalkyl: heterocyclic. heterocyclic C1-4alkyl: heteroaryl C1-4 alkyloxy; aryl C2-10 alkenyl: heteroaryl C2-10 alkenyl: heterocyclic C2-10 alkenyl: NR4R5; C2-10 alkenyl C(O)NR4R5;C(O)NR4R5;C(O)NR4R10: S(O)3H:S(O)3R8; C1-10alkyl C(O)R11: C2-10 alkenyl C(O)R11 : C2-10 alkenyl C(O)OR11 : C(O)R11: C(O)OR12: OC(O)R11: NR4C(O)R11; or two R1 moieties together may form O-(CH2)sO- or a 5 to 6 membered unsaturated ring;
1 is 0. or an integer having a value of 1 or 2:
s is an integer having a value of 1 to 3:
R4 and R5 are independently hydrogen, optionally substituted C1-4 alkyl. optionally
substituted aryl, optionally substituted aryl C1-4alkyl. optionally substituted heteroaryl. optionally substituted heteroaryl C1-4 alkyl. heterocyclic. heterocyclic C1-4 alkyl. or R4 and R5 together with the nitrogen to which they are attached form a 5 to 7 member ring which may optionally comprise an additional heteroaiom selected from O/N/S:
Y is independently selected trom halogen: nitro; cyano; halosubstituted C1-10 alkyl: C1-10 alkyl: C2-10 alkenyl: C1-10 alkoxy; halosubstituted C1-10 alkoxy; azide: S(O)tR4:
hydroxy; hydroxy C1-4alkyl: aryl: aryl C1-4 alkyl: aryloxy; arylC1-4 alkyloxy; heteroaryl. heteroarylalkyl: heteroarylC1-4alkyloxy; heterocyclic, heterocyclicC1-4alkyl: aryl C2-10 alkenyl: heteroaryl C2-10 alkenyl: heterocyclic C2-10 alkenyl: NR4R5; C2-10 alkenyl C(O)NR4R5; C(O)NR4R5; C(O)NR4R10: S(O)3H; S(O)3R8: C1-10 alkyl C(O)R11: C2-10 alkenyl C(O)R 11; C2-10 alkenyl C(O)OR 11; C(O)R 11 : C(O)OR12: OC(O)R11: NR4C(O)R11: or two Y moieties together may form O-(CH2)sO- or a 5 to 6 membered unsaturated ring;
n is an integer having a value of 1102:
m is an integer having a value of 1 to 3;
R8 is hydrogen or C1-4 alkyl;
R10 is C1-10 alkyl C(O)2R8;
R11 is hydrogen, C1-4alkyl, optionally substituted aryl, optionally substituted aryl C1-4alkyl. optionally substituted heteroaryl, optionally substituted heteroaryl C1-4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclic C1-4alkyl;
R12 is hydrogen,C1-10 alkyl, optionally substituted aryl or optionally substituted arylalkyl: provided that:
when n =1 than Y is substituted in the 2'- or 3'- position;
when n =2 than Y is di-substituted in the 2'- 3'- position;
further provided that
when X1 is S, m=1, R1 is 4-ethyl, and n=1 than Y is not 2-methoxy;
or a pharmaceutically acceptably salt thereof.
27 The compound according to Claim 26 wherein R1 is substituted in the 3-position, the 4- position or di-substituted in the 3,4- position by an electron withdrawing moiety 28 The compound according to Claim 26 or 27 wherein Y is mono-substiiuted in the 2'- position or 3'- position, or is disubstuulcd in the 2' or 3' position of a monocyclic ring
29 The compound according to Claim 26 or 27 wherein n amd m are each equal to 1 or more.
30 A pharmaceutical composition comprising a compound according to any of Claims 26 to 29 and a pharmaceutically acceptable carrier or diluent
31 A process for producing a cyano phenol derivative of the formula:
Figure imgf000111_0001
wherein R 1 is as defined for Formula (I) above, which method comprises
a) reacting a compound of the formula:
Figure imgf000111_0002
wherein X is halogen
with copper (I) cyanide, dimethylformamide, triethylamine and a catalytic amount of dimethylamino pyridine.
32. The process according to Claim 31 wherein the temperature is about 60 to about 80ºC. and X is bromine.
AMENDED CLAIMS
[recei ved by the International Bureau on 16 July 1996 ( 16.07.96 ) ;
or iginal claims 1 -32 replaced by amended claims 1 -32 (3 pages ) ]
N-(2-Bromophenyl)-N'-[2-dimethylaminosulfonylamino]phenyl]urea
N-[2-(Phenethylsulfonylamino)phenyl]-N'-(2-bromophenyl)urea
N-[2-[(2-Acetamido-4-methyIthiazol-5-yl)sulfonylamino]phenyl]-N'-(2-bromophenyl)urea N-[2-[(2,3-Dichlorothien-5-yl)]sulfonylamino]phenyl]-N'-(2-bromophenyl)urea
N-[2-[(3,5-Bistrifluoromethylphenyl)sulfonylamino]phenyl]-N'-(2-bromophenyl)urea N-[2-[(2-Benzyl)sulfonylamino]-(5-trifluoromethyl)phenyl]-N'-(2-bromophenyl)urea N-[2-[2-(3-Nitrophenyl)sulfonylamino]phenyl]-N'-(2-bromophenyl)urea
N-[2-[2-(4-Phenoxyphenyl)sulfonylamino]phenyl]-N'-(2-bromophenyl) urea
N-[[2-(1S)-10-Camphorsulfonylamino]phenyI]-N'-(2-bromophenyl)urea
N-[[2-(1R)-10-Camphorsulfonylamino]phenyl]-N'-(2-bromophenyl)urea
N-[2-[2-(2-Nitro-(4-trifluoromethyl)phenyl)sulfonylamino]phenyl-N'-(2-bromophenyl)urea N-[2-(2-Amino-(4-trifluoromethyl) phenyl) sulfonylamino] phenyl]- N'-(2- bromophenyl)urea ; or
N-[2-(aminosulfonyl phenyl) 3-amino phenyl] N'-(2-bromo phenyl) urea.
25. A pharmaceutical composition comprising a compound according to any of Claims 20 to 24 and a pharmaceutically acceptable carrier or diluent.
26. A compound of the formula:
Figure imgf000112_0001
wherein
X is oxygen or sulfur;
X 1 is oxygen or sulfur;
R1 is independently selected from hydrogen; halogen; nitro; cyano; halosubstituted C 1-10 alkyl; C 1-10 alkyl; C2- 10 alkenyl; C1-10 alkoxy; halosubstituted C 1-10 alkoxy; azid S(O)tR4; hydroxy; hydroxyC1-4alkyl; aryl; aryl C1-4 alkyl; aryloxy; aryl C 1 -4 alkyloxy; heteroaryl; heteroarylalkyl; heterocyclic, heterocyclicC 1 -4alkyl;
heteroarylC1-4 alkyloxy; aryl C2-10 alkenyl; heteroaryl C2- 10 alkenyl; heterocyclic C2- 10 alkenyl; NR4R5; C2- 10 alkenyl C(O)NR4R5. C(O)NR4R5; C(O)NR4R10;
S(O)3H; S(O)3R8 C1- 10 alkyl C(O)R1 1; C2- 10 alkenyl C(O)R1 1; C2- 10 alkenyl C(O)OR1 1 ; C(O)R1 1 ; C(O)OR12; OC(O) R1 1 ; NR4C(O)R1 1 ; or two R 1 moieties together may form O-(CH2)sO- or a 5 to 6 membered unsaturated ring;
t is 0, or an integer having a value of 1 or 2;
s is an integer having a value of 1 to 3; R4 and R5 are independently hydrogen, optionally substituted C1-4 alkyl, optionally substituted aryl, optionally substituted aryl C1-4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C1-4 alkyl, heterocyclic, heterocyclic Cj .4 alkyl, or R4 and R5 together with the nitrogen to which they are attached form a 5 to 7 member ring which may optionally comprise an additional heteroatom selected from O/N/S;
Y is independently selected from halogen; nitro; cyano; halosubstituted C1-10 alkyl; C1-10 alkyl; C2-10alkenyl; C1-10 alkoxy; halosubstituted C1-10 alkoxy; azide; S(O)tR4; hydroxy; hydroxy C1-4alkyl; aryl; aryl C1-4 alkyl; aryloxy; arylC1-4 alkyloxy;
heteroaryl; heteroarylalkyl; heteroarylC1-4alkyloxy; heterocyclic, heterocyclic C1- 4alkyl; aryl C2-10 alkenyl; heteroaryl C2-10 alkenyl; heterocyclic C2-10 alkenyl;
NR4R5; C2-10 alkenyl C(O)NR4R5; C(O)NR4R5; C(O)NR4R10; S(O)3H; S(O)3R8; C1-10 alkyl C(O)R11; C2-10 alkenyl C(O)R11; C2-10 alkenyl C(O)OR11; C(O)R11; C(O)OR12; OC(O) R11; NR4C(O)R 11; or two Y moieties together may form
O-(CH2)sO- or a 5 to 6 membered unsaturated ring;
n is an integer having a value of 1 to 2;
m is an integer having a value of 1 to 3;
R8 is hydrogen or C1-4 alkyl;
R10 is C 1-10 alkyl C(O)2R8;
R11 is hydrogen, C1-4 alkyl, optionally substituted aryl, optionally substituted aryl
C1-4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C1- 4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclic C 1 - 4alkyl;
R12 is hydrogen, C1-10 alkyl, optionally substituted aryl or optionally substituted arylalkyl; provided that:
when n =1 than Y is substituted in the 2'- or 3'-position;
when n =2 than Y is di-substituted in the 2'- 3'-position;
further provided that
when X 1 is S, m=1, R1 is 4-ethyl, and n=1 than Y is not 2-methoxy;
or a pharmaceutically acceptably salt thereof.
27. The compound according to Claim 26 wherein R1 is substituted in the 3-position, the 4-position or di-substituted in the 3,4-position by an electron withdrawing moiety.
28. The compound according to Claim 26 or 27 wherein Y is mono-substituted in the 2'-position or 3'-position, or is disubstituted in the 2' or 3' position of a monocyclic ring.
29. The compound according to Claim 26 or 27 wherein n amd m are each equal to 1 or more.
30. A pharmaceutical composition comprising a compound according to any of Claims 26 to 29 and a pharmaceutically acceptable carrier or diluent.
31. A process for producing a cyano phenol derivative of the formula:
Figure imgf000114_0001
wherein R1 is as defined for Formula (I) above, which mediod comprises
a) reacting a compound of the formula:
Figure imgf000114_0002
wherein X is halogen
with copper (I) cyanide, dimethylformamide, triethylamine and a catalytic amount of dimethylamino pyridine.
32. The process according to Claim 31 wherein the temperature is about 60 to about 80ºC, and X is bromine.
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CA002245927A CA2245927A1 (en) 1995-02-17 1996-08-21 Il-8 receptor antagonists
KR1019980706361A KR19990082622A (en) 1995-02-17 1996-08-21 IL-8 receptor antagonist
EA200000788A EA200000788A1 (en) 1996-02-16 1996-08-21 METHOD OF OBTAINING CYANOPHENOL DERIVATIVES
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IL14112196A IL141121A (en) 1995-02-17 1996-08-21 Process for preparing cyano-phenol derivatives
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EA199800733A1 (en) 1999-04-29
AU725456B2 (en) 2000-10-12
EP0896531A4 (en) 2002-10-30
CN1215990A (en) 1999-05-05
US6180675B1 (en) 2001-01-30
JP2000504722A (en) 2000-04-18
CN1539816A (en) 2004-10-27
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US5886044A (en) 1999-03-23
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OA10840A (en) 2003-02-05
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CA2245927A1 (en) 1997-08-21
AU6900796A (en) 1997-09-02
IL125717A0 (en) 1999-04-11
EP0896531A1 (en) 1999-02-17
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HUP0000467A2 (en) 2000-05-28
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