CZ20014471A3 - IL-8 receptor antagonists - Google Patents

Abstract

This invention provides for a method of treating a chemokine mediated disease, wherein the chemokine is one which binds to an IL-8 alpha or beta 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.

Description

Technical field

The present invention relates to a novel class of phenyl urea compounds, to a process for their preparation, to the use of these compounds in the treatment of diseases mediated by IL-8, GROα, GRO 3, GROγ and NAP-2 and to pharmaceutical compositions for use in such therapy.

BACKGROUND OF THE INVENTION

Interieukinin-8 (abbreviated to IL-8) is referred to by many different names such as neutrophil attractant / activating protein-1 (abbreviated NAP-1), monocyte-derived neutrophil chemotactic factor (MDNCF), neutrophil activating factor (NAF), and chemotactic T cell lymphocyte factor.

Interleukinin-8 is a chemoattractant for neutrophils, basophils and a subset of T cells. Interleukinin-8 is produced by most nucleus-forming cells, including macrophages, fibroblasts, endothelial and epithelial cells exposed to TNF, IL-6α, IL-β or LPS, and neutrophils themselves when exposed to LPS or chemotherapeutic factors such as FMLP . A more detailed discussion can be found in J. Clin. Invest. 1989, 84, 1045 (M. Baggiolini et al.), J. Immunol. 1987, 139, 3474 (J. Schroder et al.), <J. Immunol. 1990,

144, 2223 (J. Schroder et al.), Science 1989, 243, 1467 (Strieter et al.), J. Bicí. Chem. 1989, 264, 10621 (Strieter et al.) And in J. Immunol. 1992, 148, 3216 (Cassatella et al.).

• · ♦ · o · o · · · · ·

It belongs to the chemokinin group and also includes GROα, GROP, GROγ and NAP-2. Like IL-8, these chemokinins are referred to by different names. For example, GROα, β, γ are referred to as MGSAα, β, γ (J. Melanoma Growth Stimulating Activity), see J. Cell Physiology 1986, 129, 375 (Richmond et al.) And J Immunol. 1992, 148, 451 (Chang et al.). All chemokinins of the a-group that contain the ELR structural element that directly precedes the CXC structural element bind to the IL-δβ receptor.

IL-8, GROα, GROP, GROγ and NAP-2 stimulate a number of functions in vitro. All of these agents have been shown to exhibit chemoattractant properties for neutrophils, while IL-8 and GROα exhibit chemotactic activity against T-lymphocytes and basophils. In addition, IL-8 may induce histamine release from basophils, both in normal and atopic individuals, and GROa and IL-8 may additionally induce lysosomal enzyme release and neutrophil-induced respiratory attack. IL-8 has also been shown to increase the surface expression of Mac-1 (CD11b / CD18) on neutrophils without re-synthesis of the protein. This phenomenon may contribute to increased adhesion of said neutrophils to vascular endothelial cells. Massive neutrophil infiltration is a hallmark of many known diseases. Because IL-8, GROα, GROγ, GROγ and NAP-2 promote neutrophil accumulation and activation, these chemokinins are associated with a wide range of acute and chronic inflammatory diseases, including psoriasis and rheumatoid arthritis. See FEBS Lett. 1992, 307, 91 (Baggiolini et al.), Crit. Roar. Immunol. 1992, 12, 17 (Miller et al.), Ann publication. Roar. Immunol.

A A ·

1991, 9, 617 (Oppenheim et al.), J. Clin. Invest. 1991, 87, 463 (Seitz et al.), Am. Roar. Respir. Dis. 1992, 146, 427 (Miller et al.), Lancet 1993, 341, 643 (Donnely et al.). In addition, ELR chemokinins (i.e., chemokinins that contain an ELR amino acid structural element immediately preceding the CXC structural element) have an association with angiostasis. Science 1992, 258,

1798 (Strieter and collaborators).

IL-8, GROα, GROP, GROγ and NAP-2 induce in vitro neutrophil shape change, chemotaxis, granule release and respiratory seizure by binding to, and activation of, G-protein-coupled seven-transmembrane receptors, in particular by binding to IL-8 receptors, especially the β-receptor. This topic is discussed in more detail in J. Biol. Chem. 1991, 266, 14839 (Thomas et al.) And Science 1991, 253, 1278 (Holmes et al.). The development of non-peptide low molecular weight antagonists of members of this family of receptors has been the subject of previous studies. A comprehensive article on this topic was published in R. Freidinger: Progress in Drug Research, Vol. 40, pp. 33-98, Birkhauser Verlag, Basel, 1993.

Two human IL-8 receptors (with 77 percent homology) with high affinity have been reported: IL-8Rα, which binds only IL-8 with high affinity, and IL-8RP, which has high affinity for IL-8 as well as for GROα, GROP, GROy and NAP-2 (see Science 1991, 253, 1278 (Holmes et al.), Science 1991, 253, 1280 (Murphy et al.), J. Biol. Chem. 1992, 267, 16283

(Lee et al.), J. Biol. Chem. 1992, 26Ί, 25402 (LaRosa et al.) And J. Biol. Chem. 1993, 268, 7283 (Gayle et al.).

In this field of treatment, there is still a demand for compounds that are capable of binding to the IL-80 or β receptor. Therefore, conditions associated with an increase in IL-8 production (which is responsible for chemotaxis of neutrophil and T-cell subgroups to the site of inflammation) would be favorably affected by compounds that function as inhibitors of IL-8 receptor binding.

SUMMARY OF THE INVENTION

The present invention provides a method of treating a chemokinin-mediated disease that is a chemokinin that binds to the IL-8α or β receptor, the method comprising administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In particular, said chemokinin is IL-8.

The present invention also relates to a method of inhibiting binding of IL-8 to its receptors in a mammal in need thereof, said method comprising administering to said mammal an effective amount of a compound of formula (I).

The compounds of formula (I) may suitably be used according to the present invention:

O-A

Η H

= <R 1) m (D where

X is an oxygen or sulfur atom;

R is any ionizable group having an ionizable hydrogen _{and a} pKa of which is 10 or less;

R 1 is independently selected from the group consisting of hydrogen, halogen, nitro, cyano, halogen substituted alkyl of 1 to 10 carbon atoms, alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkoxy a group containing from 1 to 10 carbon atoms, a halogen substituted alkoxy group containing from 1 to 10 carbon atoms, an azide group, a S (O) _t R 4 group, a hydroxyl group, a hydroxyalkyl group containing from 1 to 4 carbon atoms, an aryl group, an arylalkyl group containing from 1 to 4 carbon atoms in the alkyl moiety, aryloxy, arylalkoxy containing from 1 to 4 carbon atoms in the alkoxy moiety, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic-substituted alkyl groups containing from 1 to 4 carbon atoms , a heteroaryl group of subst an itulated alkoxy group containing from 1 to 4 carbon atoms in the alkoxy moiety, an arylalkenyl group containing from 2 to 10 carbon atoms in the alkenyl moiety;

a heteroarylalkenyl group containing from 2 to 10 carbon atoms in the alkenyl moiety, a heterocyclic-substituted alkenyl group containing from 2 to 10 carbon atoms in the alkenyl moiety, an NR4R5 group, an alkenyl-C (O) NR4R5 group containing from 2 to 10 alkenyl moieties carbon atoms, C (O) NR ₄ R _5, C (0) NR ₄ Rio, S (O) ₃ H, S (O) ₃ R _8, alkyl-C (O) R group in the alkyl moiety contains from 1 to 10 carbon atoms, the alkenyl-C (O) Ru group containing from 2 to 10 carbon atoms in the alkenyl moiety, the alkenyl-C (O) ORu group containing from 2 to 10 atoms in the alkenyl moiety alkyl, C (0) R, C (O) oR _2, OC (O) _R, NR ₄ C (O) R, or two R groups together may form O- _{(CH2) s} O - or a 5- to 6-membered unsaturated ring;

t is 0, or an integer whose value is 1 or 2;

s is an integer from 1 to 3;

R ₄ and R ₅ are independently selected from the group consisting of hydrogen, optionally substituted alkyl of 1 to 4 carbon atoms, optionally substituted aryl, optionally substituted arylalkyl of 1 to 4 carbon atoms, optionally substituted a heteroaryl group, an optionally substituted heteroarylalkyl group containing from 1 to 4 carbon atoms, a heterocyclic group, a heterocyclic group substituted alkyl group containing from 1 to 4 carbon atoms, or R ₄ and R ₅ together

AND

with the nitrogen atom to which they are attached form a 5- to 7-membered ring which may optionally contain another heteroatom selected from oxygen, nitrogen and sulfur;

Y is independently selected from the group consisting of hydrogen, halogen, nitro, cyano, halogen substituted alkyl of 1 to 10 carbon atoms, alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkoxy a group containing from 1 to 10 carbon atoms, a halogen substituted alkoxy group containing from 1 to 10 carbon atoms, an azide group, a S (O) _t R 4 group, a hydroxyl group, a hydroxyalkyl group containing from 1 to 4 carbon atoms, an aryl group, an arylalkyl group containing from 1 to 4 carbon atoms in the alkyl moiety, aryloxy, arylalkoxy having 1 to 4 carbon atoms in the alkoxy moiety, heteroaryl, heteroarylalkyl, heteroarylalkoxy having 1 to 4 carbon atoms in the alkoxy moiety, heterocyclic group, heterocyclic group substituted alkyl n, containing from 1 to 4 carbon atoms in the alkyl moiety, an arylalkenyl group containing from 2 to 10 carbon atoms in the alkenyl moiety, a heteroarylalkenyl group containing from 2 to 10 carbon atoms in the alkenyl moiety, a heterocyclic-substituted alkenyl group containing from 2 to 10 alkenyl 10 carbon atoms, an NR ₄ R _{5 group} , an alkenyl-C (O) NR ₄ R ₅ group containing from 2 to 10 carbon atoms in the alkenyl moiety,

9 «» «I

A group C (O) NR ₄ R ₅ , group C (O) NR ₄ R ₁₀ , group S (O) ₃ H, group S (O) ₃ R ₈ , alkyl-C (O) Ru group, which in the the moiety contains from 1 to 10 carbon atoms, the alkenyl-C (O) R 11 group containing from 2 to 10 carbon atoms in the alkenyl moiety, the alkenyl-C (O) OR 11 group containing from 2 to 10 carbon atoms in the alkenyl moiety , C (0) R, C (O) oR _i2, OC (O) R, NR ₄ C (O) R, or two groups Y may together form O- (CH _{2) s} O- or a five to six membered unsaturated ring;

n Yippee whole number from 1 to 3; m Yippee whole number from 1 to 3; r ₈ Yippee atom hydrogen or an alkyl group containing from 1 to 5

carbon atoms;

R ₁₀ is an alkyl-C (O) ₂ R ₈ group containing from 1 to 10 carbon atoms in the alkyl moiety;

R 11 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, optionally substituted aryl, optionally substituted arylalkyl of 1 to 4 carbon atoms, optionally substituted heteroaryl, optionally substituted heteroarylalkyl an alkyl moiety of from 1 to 4 carbon atoms, an optionally substituted heterocyclic group, or an optionally substituted heterocyclic group of a substituted alkyl group containing from 1 to 4 carbon atoms in the alkyl moiety;

R ₁₂ is a hydrogen atom, an alkyl group containing from 1 to carbon atoms, an optionally substituted aryl group or an optionally substituted arylalkyl group;

or a pharmaceutically acceptable salt of said compound.

Another aspect of the present invention is a method of treating a chemokinin-mediated disease that is a chemokinin that binds to the IL-8α or β receptor, the method comprising administering an effective amount of a compound of formula (II) as defined below or a pharmaceutically acceptable salt thereof.

The present invention also relates to a method of inhibiting binding of IL-8 to its receptors in a mammal in need thereof, said method comprising administering to said mammal an effective amount of a compound of formula (II) as defined below.

The present invention also relates to novel compounds of formula (II) as defined below, or pharmaceutically acceptable salts thereof.

Another aspect of the present invention is a method of treating a chemokinin-mediated disease, which is a chemokinin that binds to the IL-8α or β receptor, the method comprising administering an effective amount of a compound of formula (III) as defined below or a pharmaceutically acceptable salt thereof.

The present invention also relates to a method of inhibiting binding of IL-8 to its receptors in a mammal in need thereof, said method comprising administering to said mammal an effective amount of a compound of formula (III) as defined below.

The present invention also relates to novel compounds of formula (III) as defined below, or pharmaceutically acceptable salts thereof.

The compounds of formula (I) may also be used in veterinary medicine for the treatment of non-human mammals in need of inhibition of IL-8 or other chemokinins that bind to IL-8a or β receptors. The group of chemokinin-mediated diseases of mammals to which these compounds exert their effects, whether therapeutic or prophylactic, includes disease states such as those described in the paragraphs below relating to the method of treatment.

In compounds of formula (I) represents the group R suitably any functional moiety having an ionizable hydrogen whose _pKa is 10 or less, preferably from about 3 to about 9, more preferably from about 3 to about 7. The group of such functional groups include hydroxyl, carboxyl, thiol, -SR ₂ , -OR ₂ , -NH-C (O) R _a , -C (O) NR ₆ R 7, substituted sulfonamides of the formula NHS (O) ₂ R _b , -S (O) ₂ NHR _c , NHC (X ₂ ) NHR _b , or tetrazolyl · fc · fcfc · fcfc · fcfc · fcfc · fcfc · fcfc · fcfc · fcfc Wherein the group X ₂ represents an oxygen or sulfur atom, preferably an oxygen atom, without being restricted to the examples given. Preferably, the functional group is not a sulfo group, wherein R is directly or in the form of a substituent, such as SR ₂ or OR ₂ , bonded to an aryl, heteroaryl or heterocyclic group. In a more preferred embodiment, R is hydroxyl, thiol or NHS (O) ₂ R _b . Suitably, R ₂ represents a substituted aryl, heteroaryl or heterocyclic group whose ring contains a functional group containing an ionizable hydrogen atom and whose pK _a is 10 or less.

The groups R ₆ and R ₇ may suitably independently of one another represent a hydrogen atom or an alkyl group containing from 1 to 4 carbon atoms, or the groups R ₆ and R ₇ together with the nitrogen atom to which they are attached form a 5- to 7-membered ring which optionally, it may contain another heteroatom selected from oxygen, nitrogen or sulfur. Said heterocyclic group may be further substituted as described herein.

The group R _a suitably represents an alkyl group, an aryl group, an arylalkyl group containing from 1 to 4 carbon atoms in the alkyl moiety, a heteroaryl group, a heteroarylalkyl group containing from 1 to 4 carbon atoms in the alkyl moiety, a heterocyclic group or alkyl moieties of from 1 to 4 carbon atoms, all of which may be optionally substituted as described below.

• 4 4 44 44 • · 4 4 4 «4 4 4 4 • 4 4 4 4 • 4 4 4 4 4 4 4 4 4 4 4 4 4

R _b can be NR ₆ R ₇ , an alkyl group, an aryl group, an arylalkyl group containing from 1 to 4 carbon atoms in the alkyl moiety, an arylalkenyl group containing from 2 to 4 carbon atoms in the alkenyl moiety, heteroaryl, heteroarylalkyl containing alkyl moieties of from 1 to 4 carbon atoms, heteroarylalkenyl containing from 2 to 4 carbon atoms in the alkenyl moiety, heterocyclic group, heterocyclic-substituted alkyl groups containing from 1 to 4 carbon atoms, or heterocyclic-substituted alkenyl groups containing alkenyl from 2 to 4 carbon atoms, camphor, all of which may be optionally substituted with one to three substituents independently selected from the group consisting of halogen, nitro, halogen substituted alkyl of from 1 to 4 carbon atoms, such as s. Kupina CF _3, alkyl having 1 to 4 carbon atoms such as a methyl group, an alkoxy group having 1 to 4 carbon atoms such as methoxy, NR ₉ C (O) R _a, C (O) NR ₆ R ₇ , S (O) ₃ H or C (O) O-alkyl having from 1 to 4 carbon atoms in the alkyl moiety. Preferably, R _b represents an optionally substituted phenyl, benzyl or styryl group. When R _b is a heteroaryl group, it is preferably an optionally substituted thiazole group, an optionally substituted thienyl group, or an optionally substituted quinolinyl group. When R ₉ represents a hydrogen atom or an alkyl group containing 1 to 4 carbon atoms, but preferably hydrogen, and when said substituent group NRgC (O) R _a, then R _a is preferably an alkyl group such as methyl group.

• φφ ·· · · · · · · · · · · · · · · · · · · ·

The R _{c group} may suitably represent an alkyl group, an aryl group, an arylalkyl group containing from 1 to 4 carbon atoms in the alkyl moiety, an arylalkenyl group containing from 1 to 4 carbon atoms in the alkenyl moiety, a heteroaryl group, a heteroarylalkyl group containing from 1 to 4 alkyl moieties 4-carbon atoms, heteroarylalkenyl having from 1 to 4 carbon atoms in the alkenyl moiety, a heterocyclic group, a heterocyclic-substituted alkyl group containing from 1 to 4 carbon atoms, or a heterocyclic-substituted alkenyl group containing from 1 to 4 alkenyls carbon atoms, all of which may be optionally substituted with one to three substituents independently selected from the group consisting of halogen, nitro, halogen substituted alkyl

containing from 1 to 4 atoms carbon, an alkyl group containing from 1 to 4 atoms carbon, an alkoxy group containing from 1 to 4 atoms carbon, NR ₉ C (O) R _a ,

C (O) NR ₆ R _7, S (O) _3H, or C (0) O-alkyl the alkyl portion contains 1 to 4 carbon atoms, wherein R _g represents a hydrogen atom or an alkyl group containing from 1 up to 4 carbon atoms. Preferably, R _c represents an optionally substituted phenyl group.

When R is in the form of OR ₂ or SR ₂ , it will be apparent to those skilled in the art that the respective aryl ring must contain an ionizable hydrogen atom. Said aryl ring may also be further substituted by one to three substituents which are independently of one another which may also contain another ionizable group and which

Are selected from the group consisting of halogen, nitro, halogen-substituted alkyl of from 1 to 4 carbon atoms, alkyl of from 1 to 4 carbon atoms, alkoxy of from 1 to 4 carbon atoms; 4 carbon atoms, a hydroxyl group, a thiol group, -C (O) NR 6 R _7, -NH-C (0) R _a, -NHS (O) ₂ RBR S (O) ₂ NR ₆ R ₇ group, C (O) OR ₈ or a tetrazolyl ring, without being limited to the examples.

Suitably in the compounds of formula (I), R 1 is independently selected from the group consisting of hydrogen, halogen, nitro, cyano, halogen substituted alkyl of from 1 to 10 carbon atoms, such as CF ₃ , alkyl of from 1 to 10 10 carbon atoms such as methyl, ethyl, isopropyl or n-propyl, alkenyl of 2 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms such as methoxy or ethoxy, halogen substituted alkoxy containing from 1 to 10 carbon atoms such as trifluoromethoxy, azide, S (O) _t R 4 in which t is 0, 1 or 2, hydroxyl, hydroxyalkyl containing from 1 to 4 carbon atoms such as methanol or ethanol, an aryl group such as a phenyl group or a naphthyl group, an arylalkyl group containing an alkyl group from 1 to 4 carbon atoms such as benzyl, aryloxy such as phenoxy, arylalkoxy containing from 1 to 4 carbon atoms in the alkoxy portion such as benzyloxy, heteroaryl, heteroarylalkyl, heteroarylalkyloxy containing from 1 to 4 alkoxy up to 4 atoms

• ·· • fc · • fc · • · · • · · fc • · fc · «· • * • fc • · · • « • · · • · • · • · • fc fc ·

carbon, arylalkenyl having 2 to 10 carbon atoms in the alkenyl moiety, heteroarylalkenyl having 2 to 10 carbon atoms in the alkenyl moiety, NR4R5, alkenyl-C (O) NR4R5 having from 2 to 10 carbon atoms in the alkenyl moiety C (O) NR ₄ R ₅ , C (O) NR ₄ R ₁₀ / S (O) ₃ H, S (O) ₃ R ₈ , an alkyl-C (O) R 11 group containing from the alkyl moiety 1 to 10 carbon atoms, alkenyl-C (O) Rn group containing from 2 to 10 carbon atoms in the alkenyl moiety, alkenyl-C (O) ORn group containing 2 to 10 carbon atoms in the alkenyl moiety, C group (0) R 11, C (O) OR ₁₂ , such as carboxy, methyl carboxylate or phenylbenzoate, OC (O) Rh, NR ₄ C (O) R 11, azido, or two R _x together may form O- _{(CH2) S} O-- or pětiaž six membered unsaturated ring; wherein s is an integer from 1 to 3. Said aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heterocyclic, alkylheterocyclic and alkenylheterocyclic groups may be optionally substituted as described below. In a preferred embodiment of the present invention, R 1 is not an azido or S (O) ₃ R _{8 group} .

If R 1 forms a dioxy bridge, it is preferably equal to 1. If R 1 forms another unsaturated ring, the ring is preferably a six membered ring, resulting in the formation of a naphthylene system. The naphthylene system may be substituted independently with 1 to 3 substituents, which are R 1 as defined above.

R4 and R5 independently represent a hydrogen atom or an optionally substituted alkyl group containing from 1 to 5

4 44 4 * 4 • 4 4 4 4 4 4 «4,444 • 4 4 · · · 4

43 4 4 4 4 4 4

4 4 4

4 »4444 444 4« 44 44 444 carbon atoms, optionally substituted aryl group, optionally substituted arylalkyl group containing from 1 to 4 carbon atoms in the alkyl moiety, optionally substituted heteroaryl group, optionally substituted heteroarylalkyl groups containing from 1 to 4 in the alkyl moiety carbon atoms, a heterocyclic group, a heterocyclic group, a substituted alkyl group containing from 1 to 4 carbon atoms in the alkyl portion, or R ₄ and R ₅ together with the nitrogen atom to which they are attached form a 5- to 7-membered ring which may optionally contain an additional heteroatom selected from oxygen, nitrogen and sulfur.

The group R ₁₀ represents an alkyl-C (O) ₂ R 5 group containing from 1 to 10 carbon atoms in the alkyl moiety, such as CH ₂ C (O) ₂ H or CH ₂ C (O) ₂ CH 3.

R _u represents hydrogen, alkyl having 1 to 4 carbon atoms, aryl, arylalkyl the alkyl portion contains 1 to 4 carbon atoms, a heteroaryl group, a heteroarylalkyl group, the alkyl portion contains 1 to 4 carbon atoms, a heterocyclic or a heterocyclic-substituted alkyl group having from 1 to 4 carbon atoms in the alkyl moiety.

R ₁₂ represents a hydrogen atom, an alkyl group containing from 1 to 10 carbon atoms, an optionally substituted aryl group or an optionally substituted arylalkyl group.

··············· · 9

9 99 9 9 9

In a preferred embodiment, 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 A -C (O) OR ₁₂ group, a heteroaryl group, a heteroarylalkyl group, a heteroarylalkenyl group or a S (O) NR ₄ R _{5 group} , preferably both R ₄ and R ₅ represent hydrogen atoms or phenyl groups. The preferred ring substitution for R 1 is the 4-position of the phenyl ring.

When R is a hydroxyl group, a thiol group, or an NSO ₂ R _b group, then preferably R _{x is} one substituent at the 3-position, the 4-position, or the ring is substituted by two R groups at the 3-position and 4. electronceptor group. When R is a hydroxyl group, a thiol group or an NSO ₂ R _b group, then R 1 is preferably a nitro group, an atom. halogen, cyano, trifluoromethyl and C (O) NR ₄ R ₅ .

When R is a carboxylic acid residue, then R 1 preferably represents a hydrogen atom, or R 1 is preferably substituted at the 4-position, more preferably it is substituted with trifluoromethyl or chlorine.

In the compounds of formula (I), Y is suitably independently selected from the group consisting of hydrogen, halogen, nitro, cyano, halogen substituted alkyl of 1 to 10 carbon atoms, alkyl of 1 to 10 carbon atoms, alkenyl a group containing from 2 to 10 carbon atoms,

an alkoxy group containing from 1 to 10 carbon atoms, a halogen substituted alkoxy group containing from 1 to 10 carbon atoms, an azide group, a S (O) _t -OH hydroxyl group, a hydroxyalkyl group containing from 1 to 4 carbon atoms, an aryl group, an arylalkyl group containing from 1 to 4 carbon atoms in the alkyl moiety, aryloxy, arylalkoxy containing from 1 to 4 carbon atoms in the alkoxy moiety, from 2 to 10 carbon atoms in the alkenyl moiety, heteroaryl, heteroarylalkyl, heteroarylalkoxy containing alkoxy parts of from 1 to 4 carbon atoms, heteroarylalkenyl containing from 2 to 10 carbon atoms in the alkenyl moiety, heterocyclic group, heterocyclic-substituted alkyl group containing from 1 to 4 carbon atoms in the alkyl moiety, heterocyclic-substituted alkenyl group containing CI alkenyl moieties of 2 to 10 carbon atoms, NR ₄ R _5, alkenyl-C (O) NR ₄ R ₅ group in the alkenyl moiety contains from 2 to 10 carbon atoms, C (O) NR ₄ R ₅ , C (0) NR ₄ Rio, S (O) ₃ H, S (O) ₃ R _8, alkyl-C (O) _R group in the alkyl portion contains from 1 to 10 carbon atoms, alkenyl -C (O) R group in the alkenyl moiety contains from 2 to 10 carbon atoms, alkenyl-C (O) ORN group in the alkenyl moiety contains from 2 to 10 carbon atoms, C _(O) R group, C (O) OR ₁₂ , OC (O) R 11, NR ₄ C (O) R 11, azido, or two Y groups together may form O- (CH ₂ ) _S O- or a 5- to 6-membered unsaturated ring. If the group Y forms a dioxy bridge, it is preferably equal to 1. If the group Y forms another unsaturated ring, this ring is preferably a six-membered ring, resulting in the formation of a naphthylene system. The naphthylene system may be substituted independently with 1 to 3 substituents as defined above. Said aryl, heteroaryl and heterocyclic group may be optionally substituted as described below. In a preferred embodiment of the invention, R 1 is not an azido or S (O) 3 R 8 group.

In a preferred embodiment of the present invention, Y is a halogen atom, an alkoxy group having from 1 to 4 carbon atoms, an optionally substituted aryl group, an optionally substituted aryloxy group, an arylalkoxy group, methylenedioxy group, NR ₄ R ₅ , a thioalkyl group having 1 to 4 carbon atoms , a thioaryl group, a halogen substituted alkoxy group, an optionally substituted alkyl group having from 1 to 4 carbon atoms, or a hydroxyalkyl group. More preferably, Y represents one substituent which is a halogen atom, two substituents which are halogen atoms, one substituent which is an alkoxy group, two substituents which are alkoxy groups, a methylenedioxy group, an aryl group or an alkyl group, more preferably said substituents are found in position 2 ', respectively in the case of two substituents at position 2' and 3 '.

Although Y may be substituted at any position of the five ring positions, when R is a hydroxyl group, the thiol group or the NSO ₂ R b group is preferably a monosubstituted at the 2 'or 3' position, wherein the 4 'position of said ring is in this case preferably unsubstituted. When said ring is disubstituted, substituents are found when R is a hydroxyl group, a thiol group or an NSO ₂ R _{b group} preferably in the 2 'or 3' position.

999 9 999 9 · 999 * 9 9 9 9 9 • 99 9 9 «9 9 9 • 9 9 9 9 9 9

9999999 9999999 «9 999 monocyclic ring. Although both R 1 and Y groups can be hydrogen atoms, it is preferred that at least one of the rings be substituted, preferably both rings are substituted.

In the compounds of formula (I), X represents an oxygen or sulfur atom, preferably an oxygen atom.

Although not explicitly described by the structures represented by the general formulas (Ia-c), (II) or (III), yet another aspect of the present invention are symmetrical bis-compounds of each of said structures.

An example of such a bis-compound may be:

N- (bis- (2-hydroxy-4-nitrophenyl) -N '- (dianisdin) diurea; and 4-methylene-bis (N- (2-chlorophenyl) -N' - (2-hydroxy-4-nitrophenyl) urea) .

An example of a compound of formula (I) may be:

N- [2-hydroxy-4- (methoxycarbonyl) phenyl] -N'-phenyl urea;

N- [5-nitro-2-hydroxyphenyl] -1'-phenylurea;

3-hydroxy-4 - {[(phenylamino) carbonyl] amino} benzamide;

N- (2-hydroxy-4-fluorophenyl) -1'-phenylurea;

2 - {[(phenylamino) carbonyl] amino} thiophenol-N- (2-carboxy-4-hydroxyphenyl) -1'-phenylurea;

N- [2-hydroxy-4- (trifluoromethyl) phenyl] -1'-phenyl urea;

N- (2-hydroxy-4-nitrophenyl) -1 '- (2-hydroxy-4-nitrophenyl) urea;

N- (2-hydroxy-4-nitrophenyl) -N'-phenylthiourea;

N- (4-nitro-2- (phenylsulfonylamino) phenyl) -1'-phenylurea;

• 9 9 99 9 9 9 9 9 9 9 9 9 9 9

9 9 9 9 9 9 9 9 9 9

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) -1 '- (3-methoxyphenyl) urea;

N- (2-hydroxy-4-nitrophenyl) -1 '- (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-nitrophenyl) -N '- (3-bromophenyl) urea;

N- (2-hydroxy-4-nitrophenyl) -4- (4-bromophenyl) urea;

N- (2-hydroxy-4-nitrophenyl) -1 '- (2-phenylphenyl) urea;

N- (2-hydroxy-4-nitrophenyl) -1 '- (1-naphthyl) urea;

N- (2-hydroxy-4-nitrophenyl) -N '- (2-nitrophenyl) urea;

N- (2-hydroxy-4-nitrophenyl) -1 '- (2-fluorophenyl) urea;

N- (2-hydroxy-4-nitrophenyl) -1 '- (2'-difluorophenyl) urea;

N- (2-hydroxy-4-nitrophenyl) -1 '- (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) -1 '- (2-methylthiophenyl) urea;

N- (2-hydroxy-4-nitrophenyl) -1 '- (2-chloro-6-methylphenyl) urea; N- (2-hydroxy-4-nitrophenyl) -N '- (2-sulfoxymethylphenyl) urea; N- (4-Trifluoromethyl-2-hydroxyphenyl) -N '- (2-bromophenyl) urea; N- (4-carbomethoxy-2-hydroxyphenyl) -N '- (2-bromophenyl) urea;

N- (4-trifluoromethyl-2-hydroxyphenyl) -1 '- (2-phenylphenyl) urea; N- (4-carbomethoxy-2-hydroxyphenyl) -N '- (2-phenylphenyl) urea;

N- (2-hydroxy-4-nitrophenyl) -N '- (2,3-dichlorophenyl) urea;

N- (2-hydroxy-4-nitrophenyl) -N '- (2,4-dichlorophenyl) urea;

N- (2-hydroxy-4-nitrophenyl) -N '- (2-chlorophenyl) urea;

N- (2-hydroxy-4-nitrophenyl) -1 '- (2,4-dibromophenyl) urea;

N- (2-hydroxy-1-naphthyl) -N '- (2-bromophenyl) urea;

»♦

N- (2-hydroxy-4-nitrophenyl) -1 '- (2,3-methylenedioxyphenyl) urea;

N- (2-hydroxy-4-nitrophenyl) -1 '- (3-chloro-2-methoxyphenyl) urea;

N- (2-hydroxy-4-nitrophenyl) -1 '- (2-methylphenyl) urea;

N- [4- (benzylamino) carbonyl-2-hydroxyphenyl] -1 '- (2-bromophenyl) urea;

N- (2-hydroxy-4-nitrophenyl) -1 '- (2-phenoxyphenyl) urea;

N- (2-hydroxy-4-fluorophenyl) -N '-( 2-bromophenyl) urea;

N- (2-hydroxy-3-naphthyl) -N '- (2-bromophenyl) urea;

N- (3,4-difluoro-2-hydroxyphenyl) -1 '- (2-bromophenyl) urea;

N- (2-hydroxy-4-phenylphenyl) -1 '- (2-bromophenyl) urea;

N- (2-hydroxy-4-methylphenyl) -1 '- (2-bromophenyl) urea;

N- (2-hydroxy-4-nitrophenyl) -N '- (2-phenylaminophenyl) urea;

N- (2-hydroxy-3-carboxyphenyl) -N '- (2-bromophenyl) urea;

N- (2-sulfhydryl-4-bromophenyl) -N '- (2-bromophenyl) urea;

N- (2-hydroxy-4-nitrophenyl) -N '- (2-iodophenyl) urea;

N- (2-hydroxy-4-nitrophenyl) -N '- (2-bromophenyl) thiourea;

N - [(2-phenylsulfamido) -4-cyanophenyl] -N '- (2-bromophenyl) urea; N- (2- (aminosulfonamidophenyl) phenyl) -N '- (2-bromophenyl) urea; N- (2- (aminosulfonylstyryl) phenyl) -1 '- (2-bromophenyl) urea; 2 - ((3,4-dimethoxyphenylsulfonyl) amino] phenyl) -N '- (2-bromophenyl) urea;

N- (2 - ((4-acetamidophenylsulfonyl) amino] phenyl) -N '- (2-bromophenyl) urea;

N- (2- (aminosulfonyl (2-thiophene) phenyl) -N '- (2-bromophenyl) urea N- (2- (aminosulfonyl (3-tolyl) phenyl) -N' - (2-bromophenyl) urea; N - (2- (aminosulfonyl (8-quinolinyl)) phenyl) -N '- (2-bromophenyl) urea;

N- (2- (aminosulfonylbenzyl) phenyl) -N '- (2-bromophenyl) urea;

N- (2-hydroxy-4-azidophenyl) -N '-( 2-methoxyphenyl) urea;

··· »· ··

Ν- [2-hydroxy-5-cyanophenyl] -1 '- [2-bromophenyl] urea;

N- [2-hydroxy-3-fluorophenyl] -1 '- [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-diphenylphenyl] -N '- [2-bromophenyl] urea;

N- [2-hydroxy-3-glycine-methyl-ester-carbonylphenyl] -N '- [2-bromophenyl] urea;

N- [2-hydroxy-3-glycinecarbonylphenyl] -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 '- [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-trifluoromethylphenyl] urea;

N- [2-hydroxy-3-n-propylphenyl] -N '- [2-bromophenyl] urea;

SN- [2-hydroxy-4-ethylphenyl] -N '- [2-bromophenyl] urea;

N- [2-hydroxy-3-phenylaminocarbonylphenyl] -N '- [2-bromophenyl] urea;

N- [2-hydroxy-3-cyano-4-methylphenyl] -N '- [2-bromophenyl] urea; N- [2-hydroxy-4-carbophenylphenyl] -N '- [2-bromophenyl] urea;

N- [2-hydroxy-3-carbophenylphenyl] -N '- [2-bromophenyl] urea;

N- [3-benzyloxy-2-hydroxyphenyl] -N '- [2-bromophenyl] urea;

(E) -N- [4- [2- (methoxycarbonyl) ethenyl] -2-hydroxyphenyl] -N '- [2-bromophenyl] urea;

(E) -N- [3- [2- (methoxycarbonyl) ethenyl] -2-hydroxyphenyl] N '- [2-bromophenyl] 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-benzamidophenyl] -N '- [2-bromophenyl] urea;

N- [4-aminocarbonyl-2-hydroxyphenyl] -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 - [[[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-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;

• A * AA

AAAA A A A A A A A

A A A A A A A A A A

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-trifluoromethylphenyl] urea;

N- [2-hydroxy-3-naphthyl] -1 '- [2,3-dichlorophenyl] 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] -4 '- (2-bromophenyl) urea;

N - [[2- (1S) -10-Camphorsulfonylamino] phenyl] -1 '- (2-bromophenyl) urea;

N - [[2- (1R) -10-Camphorsulfonylamino] phenyl] -N '- (2-bromophenyl) urea;

N- [2- [2- (2-nitro- (4-trifluoromethyl) phenyl) sulfonylamino] phenyl] - (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] -1 '- [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- (aminosulfonylphenyl) -3-aminophenyl] -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-trifluoromethylphenyl] urea;

N- [2-hydroxy-3-naphthyl] -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'-phenyl urea;

N- (2-hydroxy-4-nitrophenyl) -1'-phenylurea;

1- (2-carboxyphenyl) -3- (4-chlorophenyl) urea;

2- (3,4-dichlorophenylcarbonyldiimino) -5-trifluoromethyl benzoic 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-carboxyphenyl) 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; and N- (2-hydroxy-4-nitrophenyl) -N '- (4-nitrophenyl) urea.

A group of preferred compounds of formula (I) includes:

N- (2-hydroxy-4-nitrophenyl) -1 '- (2-methoxyphenyl) urea;

N- (2-hydroxy-4-nitrophenyl) -N '- (2-bromophenyl) urea;

N- (2-hydroxy-4-nitrophenyl) -1 '- (2-phenylphenyl) urea;

N- (2-hydroxy-4-nitrophenyl) -1 '- (2-methylthiophenyl) urea; N- (2-Hydroxy-4-nitrophenyl) -N ^'- (2,3-dichlorophenyl) urea; N- (2-hydroxy-4-nitrophenyl) -1 '- (2-chlorophenyl) urea;

N- (2-hydroxy-4-nitrophenyl) -1 '- (2,3-methylenedioxyphenyl) urea;

N- (2-hydroxy-4-nitrophenyl) -N '- (2-methoxy-3-chlorophenyl) urea;

N- (2-hydroxy-4-nitrophenyl) -N '- (2-phenyloxyphenyl) urea;

N- (3-chloro-2-hydroxyphenyl) -N '- (bromophenyl) urea;

N- (2-hydroxy-3-glycine-methyl ester-carbonylphenyl) -1 '- (2-bromophenyl) urea;

N- (3-nitro-2-hydroxyphenyl) -1 '- (2-bromophenyl) urea;

N- (2-hydroxy-4-cyanophenyl) -N '-( 2-bromophenyl) urea;

N- (2-hydroxy-3,4-dichlorophenyl) -1 '- (2-bromophenyl) urea;

N- (3-cyano-2-hydroxyphenyl) -N '- (2-bromophenyl) urea;

N- (2-Hydroxy-4-cyanophenyl) -N- ^f - (2-methoxyphenyl) urea;

N- (2-hydroxy-4-cyanophenyl) -1 '- (2-phenylphenyl) urea;

N- (2-hydroxy-4-cyanophenyl) -1 '- (2,3-dichlorophenyl) urea;

N- (2-hydroxy-4-cyanophenyl) -1 '- (2-methylphenyl) urea;

N- (2-hydroxy-3-cyano-4-methylphenyl) -N '-( 2-bromophenyl) urea; N- (4-cyano-2-hydroxyphenyl) -1 '- (2-trifluoromethylphenyl) urea; N- (3-trifluoromethyl-2-hydroxyphenyl) -N '- (2-bromophenyl) urea; N- (3-phenylaminocarbonyl-2-hydroxyphenyl) -1 '- (2-bromophenyl) urea;

N- (2-hydroxy-4-nitrophenyl) -1 '- (2-iodophenyl) urea;

N- (2-hydroxy-4-nitrophenyl) -N '- (2-bromophenyl) thiourea;

N- (2-phenylsulfonamido) -4-cyanophenyl-N '-( 2-bromophenyl) 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) -1 '- (2,3-dichlorophenyl) urea; and N- (2-hydroxy-3-cyanophenyl) -1 '- (2,3-dichlorophenyl) urea.

The term "optionally substituted" as used herein includes, unless otherwise indicated, such groups as halogen, such as fluorine, chlorine, bromine or iodine, hydroxyl, hydroxyalkyl containing from 1 to 10 carbon atoms, an alkoxy group containing from 1 to 10 carbon atoms, such as a methoxy or ethoxy group, an S (O) alkyl group containing from 1 to 10 carbon atoms in the alkyl moiety, wherein m 'is 0, 1 or 2, such as methylthio, methylsulfinyl or methylsulfonyl, amino, mono- and disubstituted amino such as NR ₄ R ₅ , NHC (O) R ₄ , C (O) NR ₄ R 5, C (O) OH, S (O) ₁₂ NR ₄ R 5, NHS (O) ₂ R 11, an alkyl group containing from 1 to 2

carbon atoms such as a methyl group, an ethyl group, a propyl group, an isopropyl group, or a tert. butyl, halogen substituted alkyl having from 1 to 10 carbon atoms such as trifluoromethyl (CF ₃ ), optionally substituted aryl such as phenyl, optionally substituted arylalkyl such as benzyl or phenethyl, optionally substituted heterocyclic an optionally substituted alkylheterocyclic group, an optionally substituted heteroaryl group, an optionally substituted heteroarylalkyl group, wherein said aryl, heteroaryl or heterocyclic groups may be substituted with one or two substituents selected from the group consisting of halogen, hydroxyl, hydroxyalkyl, alkoxy containing from 1 up to 10 carbon atoms, S (O) _m 'alkyl group containing from 1 to 10 carbon atoms in the alkyl moiety, amino, mono- and disubstituted amino groups such as NR ₄ R ₅ , alkyl an alkyl group having from 1 to 10 carbon atoms or a halogen substituted alkyl group having from 1 to 10 carbon atoms, such as a trifluoromethyl group (CF ₃ ).

R ₁₃ represents an alkyl group containing from 1 to 4 carbon atoms, an aryl group, an arylalkyl group containing from 1 to 4 carbon atoms in the alkyl portion, a heteroaryl group, a heteroarylalkyl group containing from 1 to 4 carbon atoms, a heterocyclic group or an alkylheterocyclic a group containing from 1 to 4 carbon atoms in the alkyl moiety.

• 44 44 44 4 • · 4 4 4 • · 4 4 4 4 4 4 4 • 4 4 • 4 4 4 • * 4 4 • 4 ♦ 4 4 4 4 4

Another aspect of the present invention are the novel compounds of formula (II) described below, or pharmaceutically acceptable salts thereof, which are also useful for inhibiting binding of IL-8 to its receptors in mammals in need of such inhibition. The present invention also relates to pharmaceutical compositions comprising a compound of formula (II) and a pharmaceutically acceptable diluent or carrier. Compounds of formula (II) are also useful in the treatment of chemokinin mediated diseases, wherein the chemokinin is an IL-8a or β receptor-binding chemokinin, the treatment comprising administering an effective amount of a compound of formula (II) or a pharmaceutically acceptable salt thereof. According to this aspect of the present invention, compounds of formula (II) may suitably be used:

where

X is an oxygen or sulfur atom;

R is any ionizable group having an ionizable hydrogen _{and a} pKa of which is 10 or less;

R 1 is independently selected from the group consisting of hydrogen, halogen, nitro, cyano, halogen substituted alkyl of 1 to 10 carbon atoms, alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms carbon atoms, an alkoxy group containing from 1 to 10 carbon atoms, a halogen-substituted alkoxy group containing from 1 to 10 carbon atoms, azide, S (O) _t R _4, hydroxy, hydroxyalkyl having 1 to 4 carbon atoms, aryl, arylalkyl the alkyl portion contains 1 to 4 carbon atoms, aryloxy, arylalkoxy containing -alkoxy from 1 to 4 carbon atoms, heteroaryl, heteroarylalkyl, heterocyclic, alkyl-substituted heterocyclic C 1 -C 4 alkyl, C 1 -C 4 heteroaryl substituted alkoxy C 2 -C 10 arylalkenyl, C 2 -C 10 arylalkenyl, C 2 -C 10 heteroarylalkenyl 10 carbon atoms, a heterocyclic-substituted alkenyl group containing from 2 to 10 carbon atoms in the alkenyl moiety, an NR ₄ R ₅ group, an alkenyl-C (O) NR ₄ R ₅ group containing from 2 to 10 carbon atoms in the alkenyl moiety, a C group O) NR ₄ R _5, C (0) NR ₄ Rio, S (O) ₃ H, S (O) ₃ R g, alkyl-C (O) R group in the alkyl portion contains 1 to 10 carbon atoms, alkenyl-C (O) _Rn group containing from 2 to 10 carbon atoms in the alkenyl moiety, alkenyl-C (O) ORn group containing from 2 to 10 carbon atoms in the alkenyl moiety, C (O) R 11, C (O) OR 12, OC (O) R 11, groups in NR ₄ C (O) R 11, or two R 1 groups together may form an O- (CH ₂ ) _S O- group or a five to six membered unsaturated ring;

Fcfc fc fc

fc · fc · fc t is 0, or an integer whose value is 1 or 2;

s is an integer from 1 to 3;

R ₄ and R ₅ are independently selected from the group consisting of hydrogen, optionally substituted alkyl of 1 to 4 carbon atoms, optionally substituted aryl, optionally substituted arylalkyl of 1 to 4 carbon atoms, optionally substituted a heteroaryl group, an optionally substituted heteroarylalkyl group containing from 1 to 4 carbon atoms, a heterocyclic group, a heterocyclic group substituted alkyl group containing from 1 to 4 carbon atoms, or R ₄ and R ₅ together with a nitrogen atom; to which they are attached, form a five to seven membered ring which may optionally contain another heteroatom selected from the group consisting of oxygen, nitrogen and sulfur;

Y is independently selected from the group consisting of hydrogen, halogen, nitro, cyano, halogen substituted alkyl of 1 to 10 carbon atoms, alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkoxy a group containing from 1 to 10 carbon atoms, a halogen substituted alkoxy group containing from 1 to 10 carbon atoms, an azide group, a S (O) _t R 4 group, a hydroxyl group, a hydroxyalkyl group containing from 1 to 4 carbon atoms, an aryl group, an arylalkyl group • 4 44 44 ♦ 4 4 · 494 «4 4 4 • 4 9 4 4

44 4 4 4 9 4 • 4 4 4 4 4 containing from 1 to 4 carbon atoms, aryloxy, arylalkoxy containing from 1 to 4 carbon atoms, heteroaryl, heteroarylalkyl, heteroarylalkoxy containing alkoxy from 1 to 4 carbon atoms, heterocyclic group, heterocyclic-substituted alkyl group containing from 1 to 4 carbon atoms in the alkyl moiety, arylalkenyl group containing from 2 to 10 carbon atoms in the alkenyl moiety, heteroarylalkenyl group containing from 2 to 10 atoms in the alkenyl moiety alkenyl-C (O) NR ₄ R ₅ group containing from 2 to 10 carbon atoms in the alkenyl moiety, C ₄ -C ₅ alkenyl-C (O) NR ₄ R ₅ (O) NR ₄ R 8, C (O) NR ₄ R ₁₀ , S (O) ₃ H, S (O) ₃ R ₈ , alkyl-C (O) R 11 v. an alkyl moiety containing from 1 to 10 carbon atoms, an alkenyl-C (O) R 11 group having from 2 to 10 carbon atoms in the alkenyl moiety, an alkenyl-C (O) OR 11 group having from 2 to 10 alkenyl moieties 10 carbon atoms, C (0) R, C (O) _R groups ORi2 0C (0) R, NR ₄ C (O) R, or two Y groups together may form O- (CH2) _s O- or a five to six membered unsaturated ring;

n is an integer from 1 to 3;

m is an integer from 1 to 3;

R ₈ is a hydrogen atom or an alkyl group containing from 1 to 4 carbon atoms;

• ·

R ₁₀ is an alkyl-C (O) ₂ R ₈ group containing from 1 to 10 carbon atoms in the alkyl moiety;

R 11 is selected from the group consisting of hydrogen, alkyl of 1 to 4 carbon atoms, optionally substituted aryl, optionally substituted arylalkyl of 1 to 4 carbon atoms, optionally substituted heteroaryl, optionally substituted heteroarylalkyl an alkyl moiety of from 1 to 4 carbon atoms, an optionally substituted heterocyclic group, or an optionally substituted heterocyclic group substituted with an alkyl group containing from 1 to 4 carbon atoms in the alkyl moiety;

R 12 is a hydrogen atom, an alkyl group containing from 1 to carbon atoms, an optionally substituted aryl group or an optionally substituted arylalkyl group;

E is optionally selected from the group consisting of

wherein the asterisk (*) indicates where the ring is bound to the backbone of the compound of formula (II) and the compound contains at least one E group;

or a pharmaceutically acceptable salt of said compound.

Suitable variations of the compounds of formula (II), as the various meanings of the groups X, R, R, R _4, R 5, R _6, R a GCC R9, Yr Rar ^R b _R R _c, and n, m, and etc. have been described above in connection with the general formula (I). Optionally, said ring E may be present in the compound of formula (II), which is bonded to the backbone of the compound of formula (II) at the locations indicated by an asterisk (*). When ring E is not present in the compound of formula (II), a phenyl group is substituted in its place, which is substituted by the groups R and R 1 as _defined above. However, the compound of formula (II) must contain at least one ring E. Said group E may be substituted with R 1 on any ring, whether saturated or unsaturated, and is shown herein only in the case of substitution on the unsaturated ring.

An example of a compound of formula (II) is:

N- (2-hydroxy-5-indanone) -1 '- (2-bromophenyl) urea;

N- (1-hydroxyfluorene) -1 '- (2-bromophenyl) urea;

N- (3-hydroxy-9,10-anthraquinon-2-yl) -1- (2-bromophenyl) urea.

Another aspect of the present invention are the novel compounds of formula (III) below, or pharmaceutically acceptable salts thereof, which are also useful for inhibiting the binding of IL-8 to its receptors in mammals in need of such inhibition. The present invention also relates to pharmaceutical compositions comprising a compound of formula (III) and a pharmaceutically acceptable diluent or carrier.

• «·

Compounds of formula (III) are also useful in the treatment of chemokinin mediated diseases, wherein the chemokinin is an IL-8α or β receptor-binding chemokinin. the treatment comprising administering an effective amount of a compound of formula (III) or a pharmaceutically acceptable salt thereof. According to this aspect of the present invention, compounds of formula (III) may suitably be used:

where

X is an oxygen or sulfur atom;

R is any functional moiety having an ionizable hydrogen _{and a} pKa of which is 10 or less;

R 1 is independently selected from the group consisting of hydrogen, halogen, nitro, cyano, halogen substituted alkyl of 1 to 10 carbon atoms, alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkoxy a group containing from 1 to 10 carbon atoms, a halogen substituted alkoxy group containing from 1 to 10 carbon atoms, an azide group, a S (O) _t R 4 group, a hydroxyl group, a hydroxyalkyl group containing from 1 to 4 carbon atoms, an aryl group, an arylalkyl group containing from 1 to 4 carbon atoms in the alkyl moiety,

• 4 « • · • 4 4 '4 4 « 4 4 4 4 • • · • • • 4 4 • 4 4 4 4 4 4 • 4 4 4 44

aryloxy, arylalkoxy having from 1 to 4 carbon atoms in the alkoxy moiety, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic substituted alkyl having from 1 to 4 carbon atoms, heteroaryl substituted alkoxy having from the alkoxy moiety from (C 1 -C 4) arylalkenyl group having from 2 to 10 carbon atoms in the alkenyl moiety, heteroarylalkenyl group containing from 2 to 10 carbon atoms in the alkenyl moiety, a heterocyclic-substituted alkenyl group having from 2 to 10 carbon atoms in the alkenyl moiety, NR ₄ R ₅ , alkenyl-C (O) NR ₄ R ₅ , which contains from 2 to 10 carbon atoms in the alkenyl moiety, C (O) NR ₄ R ₅ , C (O) NR ₄ R ₁₀ , S (O) ₃ H, an S (O) ₃ R _{8 group} , an alkyl-C (O) R 11 group containing from 1 to 10 carbon atoms in the alkyl moiety u, an alkenyl-C (O) Ru group containing from 2 to 10 carbon atoms in the alkenyl moiety, an alkenyl-C (O) ORn group containing from 2 to 10 carbon atoms in the alkenyl moiety, a C (O) Ru group , C (O) oR group _2z 0C (0) R, NR ₄ C (O) R, or two R groups together may form O- (CH _{2) s} O- or a five- to six-membered unsaturated ring;

t is 0, or an integer whose value is 1 or 2;

s is an integer from 1 to 3;

R ₄ and R ₅ are independently selected from the group consisting of hydrogen or optionally substituted alkyl

4 90 • · 0 94 · 9 9 4 • · 4 4 «« 00 4 4 4 4 • 0 9 4 9 9 4 • 0 0 4 4 9 9 • · 9 9 494 4944 00 • 0

having from 1 to 4 carbon atoms, an optionally substituted aryl group, an optionally substituted arylalkyl group containing from 1 to 4 carbon atoms in the alkyl moiety, an optionally substituted heteroaryl group, an optionally substituted heteroarylalkyl group having from 1 to 4 carbon atoms, heterocyclic group a heterocyclic-substituted alkyl group having from 1 to 4 carbon atoms in the alkyl moiety, or the groups R ₄ and R 5 together with the nitrogen atom to which they are attached form a 5- to 7-membered ring which may optionally contain another heteroatom selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom;

Y is independently selected from the group consisting of hydrogen, halogen, nitro, cyano, halogen substituted alkyl of 1 to 10 carbon atoms, alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkoxy a group containing from 1 to 10 carbon atoms, a halogen substituted alkoxy group containing from 1 to 10 carbon atoms, an azide group, a S (O) _t R ₄ group, a hydroxyl group, a hydroxyalkyl group containing from 1 to 4 carbon atoms, an aryl group, arylalkyl C 1 -C 4 alkyl, aryloxy, arylalkoxy C 1 -C 4 alkoxy, heteroaryl, heteroarylalkyl, C 1 -C 4 heteroarylalkoxy, heterocyclic, heterocyclic }, · *, ·· · ° ** ”” group with a substituted alkyl group containing from 1 to 4 carbon atoms, an arylalkenyl group containing from 2 to 10 carbon atoms in the alkenyl moiety, a heteroarylalkenyl group containing from 2 to 10 carbon atoms in the alkenyl moiety, a heterocyclic-substituted alkenyl group containing from 2 to 10 carbon atoms 2 to 10 carbon atoms, NR ₄ R ₅ , alkenyl-C (O) NR ₄ R ₅ group containing from 2 to 10 carbon atoms in the alkenyl moiety, C (O) NR ₄ R 5, C (O) NR ₄ R ₁₀ , S (O) ₃ H group, S (O) ₃ R _{8 group} , alkyl-C (O) R 11 group containing from 1 to 10 carbon atoms in the alkyl moiety, alkenyl-C (O) Ru group having from 2 to 10 carbon atoms in the alkenyl moiety, an alkenyl-C (O) ORu group having from 2 to 10 carbon atoms in the alkenyl moiety, a C (O) R 11 group, a C (O) OR 12, C group (0) R 11, NR ₄ C (O) R 11, or two Y groups together may form an O- (CH ₂ ) group _with O- or five i- to 6-membered unsaturated ring;

n is an integer from 1 to 3;

m is an integer from 1 to 3;

R ₈ is a hydrogen atom or an alkyl group containing from 1 to 4 carbon atoms;

R ₁₀ is an alkyl-C (O) ₂ R e group containing from 1 to 10 carbon atoms in the alkyl moiety;

R 11 is selected from the group consisting of hydrogen, alkyl of from 1 to 4 carbon atoms, optionally

a substituted aryl group, an optionally substituted arylalkyl group containing from 1 to 4 carbon atoms in the alkyl moiety, an optionally substituted heteroaryl group, an optionally substituted heteroarylalkyl group containing from 1 to 4 carbon atoms in the alkyl moiety, an optionally substituted heterocyclic group, or an optionally substituted heterocyclic group substituted an alkyl group containing from 1 to 4 carbon atoms in the alkyl moiety;

R 12 is a hydrogen atom, an alkyl group containing from 1 to carbon atoms, an optionally substituted aryl group or an optionally substituted arylalkyl group;

or a pharmaceutically acceptable salt thereof.

Suitable variants of the compound of formula (III), such as the different meanings of R, etc., have been described above in connection with the foregoing compounds of the present invention.

An example of a compound of formula (III) is:

N- (2-hydroxy-4-nitrophenyl) -1 '- (3-methoxy-2-thienyl) urea; and N- (2-hydroxy-5-nitrophenyl) -N '- (3-methoxy-2-thienyl) urea.

Another aspect of the present invention are the novel compounds of formula (Ia) described below which form a subset of compounds of formula (I) and which are also useful for the treatment of chemokinin mediated diseases. The present invention also relates to pharmaceutical compositions comprising

a compound of formula (Ia) and a pharmaceutically acceptable diluent or carrier. According to this aspect of the present invention, compounds of formula (Ia) may suitably be used:

- H

(la) where

X is an oxygen or sulfur atom;

R _a is an alkyl group, an aryl group, an arylalkyl group containing from 1 to 4 carbon atoms, a heteroaryl group, a heteroarylalkyl group containing from 1 to 4 carbon atoms, a heterocyclic group or a heterocyclic-substituted alkyl group containing an alkyl moiety from 1 to 4 carbon atoms, all of which may be optionally substituted;

R _b is NR ₆ R ₇ , alkyl, aryl, arylalkyl having 1 to 4 carbon atoms in the alkyl moiety, arylalkenyl having 2 to 4 carbon atoms in the alkenyl moiety, heteroaryl, heteroarylalkyl containing in the alkyl moiety from 1 to 4 carbon atoms, a heteroarylalkenyl group containing from 2 to 4 carbon atoms in the alkenyl moiety, a heterocyclic group or a heterocyclic group substituted by an alkyl group containing from 1 to 4 carbon atoms or a heterocyclic-substituted alkenyl group;

Containing from 2 to 4 carbon atoms in the alkenyl moiety, all of which may optionally be substituted with one to three substituents selected from the group consisting of halogen, nitro, halogen substituted alkyl of from 1 to 4 carbon atoms, alkyl containing from 1 to 4 carbon atoms, alkoxy group containing from 1 to 4 carbon atoms, NR _g C (O) R _a , C (O) NR ₆ R 7, S (O) 3 H or C (O) O- an alkyl group containing from 1 to 4 carbon atoms in the alkyl moiety;

R 8 and R 7 are independently selected from the group consisting of hydrogen and alkyl having from 1 to 4 carbon atoms, or R 8 and R ₇ together with the nitrogen atom to which they are attached form a 5- to 7-membered ring which may optionally contain further a heteroatom selected from oxygen, nitrogen or sulfur, and the ring may be optionally substituted;

R ₉ is a hydrogen atom or an alkyl group containing from 1 to 4 carbon atoms, preferably a hydrogen atom;

R 1 is independently selected from the group consisting of hydrogen, halogen, nitro, cyano, halogen. substituted alkyl of 1 to 10 carbon atoms, alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, halogen substituted alkoxy of 1 to 10 carbon atoms carbon atoms, azide group, S (O) _t R 4 <hydroxyl group, 9 9 9 9 999 999 9999 99 999 hydroxyalkyl group containing from 1 to 4 carbon atoms , aryl, arylalkyl having 1 to 4 carbon atoms in the alkyl moiety, aryloxy, arylalkoxy having 1 to 4 carbon atoms in the alkoxy moiety, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic-substituted alkyl moieties containing alkyl moieties from 1 to 4 carbon atoms, a heteroaryl substituted alkoxy group containing va alkoxy of 1 to 4 carbon atoms, arylalkenyl of 2 to 10 carbon atoms in the alkenyl moiety, heteroarylalkenyl of 2 to 10 carbon atoms in the alkenyl moiety, a heterocyclic-substituted alkenyl group of 2 to 10 carbon atoms in the alkenyl moiety , NR ₄ R ₅ , alkenyl-C (O) NR ₄ R ₅ , which contains from 2 to 10 carbon atoms in the alkenyl moiety, C (O) NR ₄ R ₅ , C (O) NR ₄ R ₁₀ , a S (O) 3 H group, an SfO 4 R 8 group, an alkyl-C (O) R 11 group containing from 1 to 10 carbon atoms in the alkyl moiety, an alkenyl-C (O) R 11 group containing from 2 up to 10 carbon atoms, an alkenyl-C (O) OR n group containing from 2 to 10 carbon atoms in the alkenyl moiety, a C (O) R n group, a C (O) OR _{L 2} group from a 0C (O) R n group, a NR group ₄ C _(O) R, or two R _X taken together may form O- (CH _{2) s} O- or a five- to six-membered unsaturated ring;

t is 0, or an integer whose value is 1 or 2;

s is an integer from 1 to 3;

· * * * * «« «

R 4 and R 5 are independently selected from the group consisting of hydrogen, optionally substituted alkyl of 1 to 4 carbon atoms, optionally substituted aryl, optionally substituted arylalkyl of 1 to 4 carbon atoms, optionally substituted heteroaryl , an optionally substituted heteroarylalkyl group containing from 1 to 4 carbon atoms, a heterocyclic group, a heterocyclic group substituted alkyl group containing from 1 to 4 carbon atoms, or R ₄ and R ₅ together with the nitrogen atom to which they are attached linked to form a 5- to 7-membered ring which may optionally contain another heteroatom selected from the group consisting of oxygen, nitrogen and sulfur;

Y is independently selected from the group consisting of hydrogen, halogen, nitro, cyano, halogen substituted alkyl of 1 to 10 carbon atoms, alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkoxy a group containing from 1 to 10 carbon atoms, a halogen substituted alkoxy group containing from 1 to 10 carbon atoms, an azide group, a S (O) _t R 4 group, a hydroxyl group, a hydroxy group containing from 1 to 4 carbon atoms, an aryl group, an arylalkyl group containing from 1 to 4 carbon atoms in the alkyl moiety, aryloxy, arylalkoxy containing from 1 to 4 carbon atoms in the alkoxy moiety, heteroaryl, heteroarylalkyl, heteroaryl groups 9

an alkoxy group containing from 1 to 4 carbon atoms, a heterocyclic group, a heterocyclic-substituted alkyl group containing from 1 to 4 carbon atoms in the alkyl portion, an arylalkenyl group containing from 2 to 10 carbon atoms in the alkenyl portion, a heteroarylalkenyl group containing in alkenyl from 2 to 10 carbon atoms, a heterocyclic-substituted alkenyl group containing from 2 to 10 carbon atoms in the alkenyl moiety, NR 4 R 5, alkenyl-C (O) NR 4 R 5 group containing from 2 to 10 carbon atoms in the alkenyl moiety, C group (O) NR ₄ R _5, C (0) NR ₄ Rio, S (O) ₃ H, S (O) ₃ R _8, alkyl-C (O) R group in the alkyl portion contains from 1 up to 10 carbon atoms, alkenyl-C (O) Rn group containing from 2 to 10 carbon atoms in the alkenyl moiety, alkenyl-C (O) ORn group containing from 2 to 10 carbon atoms in the alkenyl moiety, C ( 0) Rn, Gr nu C (O) OR 12, OC (O) R 11, NR ₄ C (O) R 11, or two Y groups together may form a group

O- (CH _{2) s} O- or a five- to six-membered unsaturated ring;

n is an integer from 1 to 3;

m is an integer from 1 to 3;

R 8 is a hydrogen atom or an alkyl group containing from 1 to 4 carbon atoms;

R 10 is an alkyl-C (O) ₂ R ₈ group containing from 1 to 10 carbon atoms in the alkyl moiety;

• 9 9 9 9 9 9 9

R 11 is selected from the group consisting of hydrogen, alkyl of 1 to 4 carbon atoms, optionally substituted aryl, optionally substituted arylalkyl of 1 to 4 carbon atoms, optionally substituted heteroaryl, optionally substituted heteroarylalkyl an alkyl moiety of from 1 to 4 carbon atoms, an optionally substituted heterocyclic group, or an optionally substituted heterocyclic group substituted with an alkyl group containing from 1 to 4 carbon atoms in the alkyl moiety;

R ₁₂ is a hydrogen atom, an alkyl group containing from 1 to carbon atoms, an optionally substituted aryl group or an optionally substituted arylalkyl group;

or a pharmaceutically acceptable salt thereof.

In a preferred embodiment, the group R _{x is} present on the ring once in position 3 or 4, or twice in position 3 and 4.

Suitably said substituent is an electron acceptor group.

In a preferred embodiment, R _{x is} nitro, halogen, cyano, trifluoromethyl or C (O) NR ₄ R ₅ .

Although the group Y may be substituted at any position of the five ring positions, the group is preferably a monosubstituted ring of said ring at position 2 or 3, wherein position 4 of said ring is preferably unsubstituted. When said ring is disubstituted, the substituents are located at the 2 'or 3' position of the monocyclic ring. Although both • fc

R 1 and Y groups may be hydrogen atoms, it is preferred that at least one of the rings is substituted, preferably both rings are substituted with at least one substituent, ie n and m are 1 or more.

More preferably, Y represents one substituent which is a halogen atom, two substituents which are halogen atoms, one substituent which is an alkoxy group, two substituents which are alkoxy groups, a methylenedioxy group, an aryl group or an alkyl group, more preferably said substituents are found in position 2 ', respectively in the case of two substituents at position 2' and 3 '.

An example of a compound of formula (Ia) is:

N- (4-nitro-2- (phenylsulfonylamino) phenyl) -N'-phenyl urea;

N - [(2-phenylsulfamido) -4-cyanophenyl] -N '- (2-bromophenyl) urea;

N- (2- (aminosulfonamidofenyl) phenyl) -N ^'- (2-bromophenyl) urea;

N- (2- (aminosulfonylstyryl) phenyl) -1 '- (2-bromophenyl) urea;

2 - [(3,4-dimethoxyphenylsulfonyl) amino] phenyl) -4- (2-bromophenyl) urea;

N- (2 - [(4-acetamidophenylsulfonyl) amino] phenyl) -N '- (2-bromophenyl) urea;

N- (2- (aminosulfonyl (2-thiophene) phenyl) -1 '- (2-bromophenyl) urea);

N- (2- (aminosulfonyl (3-tolyl) phenyl) -N '- (2-bromophenyl) urea);

N- (2- (aminosulfonyl (8-quinolinyl)) phenyl) -N- (2-bromophenyl) urea;

N- (2- (aminosulfonylbenzyl) phenyl) -N '- (2-bromophenyl) urea;

N- [2 - [[[2- (trifluoromethyl) phenyl] sulfonyl] amino] phenyl] N '- (2-bromophenyl) urea;

• 9 • 9

9 [N- (2-bromophenyl) -1 '- [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 - [(2,3-dichlorothien-5-yl)] sulfonylamino] phenyl] -4 '- (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] -4 '- (2-bromophenyl) urea;

N - [[2- (1S) -10-Camphorsulfonylamino] phenyl] -N '- (2-bromophenyl) urea;

N - [[2- (1R) -10-Camphorsulfonylamino] phenyl] -1 '- (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 are the novel compounds of formula (Ib) described below which form a subset of compounds of formula (I) and which are also useful for the treatment of chemokinin mediated diseases. The present invention also relates to pharmaceutical compositions comprising

a compound of formula (Ib) and a pharmaceutically acceptable diluent or carrier. According to this aspect of the present invention, compounds of formula (Ib) may be suitably used:

(Ib) where

X

X 1 is an oxygen or sulfur atom;

is an oxygen or sulfur atom;

R _x is independently selected from the group consisting of hydrogen, halogen, nitro, cyano, halogen substituted alkyl of 1 to 10 carbon atoms, alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, an alkoxy group containing from 1 to 10 carbon atoms, a halogen substituted alkoxy group containing from 1 to 10 carbon atoms, an azide group, a S (O) _t -OH hydroxyl group, a hydroxyalkyl group containing from 1 to 4 carbon atoms, an aryl group, an arylalkyl group containing from 1 to 4 carbon atoms in the alkyl moiety, aryloxy, arylalkoxy containing from 1 to 4 carbon atoms in the alkoxy moiety, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic-substituted alkyl groups containing from 1 to 4

carbon atoms, a heteroaryl-substituted alkoxy group containing from 1 to 4 carbon atoms, an arylalkenyl group containing from 2 to 10 carbon atoms in the alkenyl moiety, a heteroarylalkenyl group containing from 2 to 10 carbon atoms in the alkenyl moiety, a heterocyclic-substituted alkenyl group having from 2 to 10 carbon atoms in the alkenyl moiety, the group NR ₄ R ₅ , the alkenyl-C (O) NR ₄ R ₅ group having from 2 to 10 carbon atoms in the alkenyl moiety, the C (O) NR ₄ R _{5 group} , a C (O) NR ₄ R ₁₀ group, an S (O) ₃ H group, an S (O) ₃ R 8 group, an alkyl-C (O) Ru group containing from 1 to 10 carbon atoms in the alkyl moiety, alkenyl- A C (O) Ru group having from 2 to 10 carbon atoms in the alkenyl moiety, an alkenyl-C (O) ORu group having from 2 to 10 carbon atoms in the alkenyl moiety, a C (O) Ru group, a C ( O) ORi2 _R OC (O) R, NR ₄ C (O) R, or two R ₄ together They may form a group -O- (CH ₂₎ O ^- or a five- to six-membered unsaturated ring;

t is 0, or an integer whose value is 1 or 2;

s is an integer from 1 to 3;

R ₂ is a substituted aryl, heteroaryl or heterocyclic ring containing a functional group having an ionizable hydrogen _{and a} pKa of which is 10 or less;

R ₄ and R ₅ are independently selected from the group consisting of hydrogen or optionally substituted alkyl

·· ·· ·

having from 1 to 4 carbon atoms, an optionally substituted aryl group, an optionally substituted arylalkyl group containing from 1 to 4 carbon atoms in the alkyl moiety, an optionally substituted heteroaryl group, an optionally substituted heteroarylalkyl group having from 1 to 4 carbon atoms, heterocyclic group , a heterocyclic-substituted alkyl group having from 1 to 4 carbon atoms in the alkyl moiety, or R ₄ and R ₅ together with the nitrogen atom to which they are attached form a 5- to 7-membered ring which may optionally contain another heteroatom selected from the group including oxygen, nitrogen and sulfur;

is independently selected from the group consisting of hydrogen, halogen, nitro, cyano, halogen substituted alkyl of 1 to 10 carbon atoms, alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkoxy containing from 1 to 10 carbon atoms, a halogen substituted alkoxy group containing from 1 to 10 carbon atoms, an azide group, a S (O) _t R 4 group, a hydroxyl group, a hydroxy group containing from 1 to 4 carbon atoms, an aryl group, an arylalkyl group containing in the alkyl moiety of from 1 to 4 carbon atoms, aryloxy, arylalkoxy having from 1 to 4 carbon atoms in the alkoxy moiety, heteroaryl, heteroarylalkyl, heteroarylalkoxy having from 1 to 4 carbon atoms in the alkoxy moiety, heterocyclic group, heterocyclic This this this • 9 An alkyl-substituted alkyl group containing from 1 to 4 carbon atoms in the alkyl moiety, an arylalkenyl group containing from 2 to 10 carbon atoms in the alkenyl moiety, and a heteroarylalkenyl group containing from 2 to 2 alkenyl moieties. up to 10 carbon atoms, a heterocyclic-substituted alkenyl group containing from 2 to 10 carbon atoms in the alkenyl moiety, an NR ₄ R _{5 group} , an alkenyl-C (O) NR ₄ R ₅ group containing from 2 to 10 carbon atoms in the alkenyl moiety , C (O) NR ₄ R _5, C (0) NR ₄ Rio, S (O) ₃ H, S (O) ₃ R g, alkyl-C (O) R group in the alkyl moiety contains from 1 to 10 carbon atoms, alkenyl-C (O) Ru group containing from 2 to 10 carbon atoms in the alkenyl moiety, alkenyl-C (O) ORn group containing from 2 to 10 carbon atoms in the alkenyl moiety, C (O) R 11, C (O) OR 12, OC (O) R 11, NR ₄ C (O) R 11, or two Y groups together they may form an O- (CH ₂ ) group _{with an} O- or 5- to 6-membered unsaturated ring;

n is an integer from 1 to 3;

m is an integer from 1 to 3;

R ₈ is a hydrogen atom or an alkyl group containing from 1 to 4 carbon atoms;

R 10 is an alkyl-C (O) ₂ R 8 group containing from 1 to 10 carbon atoms in the alkyl moiety;

R 11 is selected from the group consisting of hydrogen, alkyl of from 1 to 4 carbon atoms, optionally

a substituted aryl group, an optionally substituted arylalkyl group containing from 1 to 4 carbon atoms in the alkyl moiety, an optionally substituted heteroaryl group, an optionally substituted heteroarylalkyl group containing from 1 to 4 carbon atoms in the alkyl moiety, an optionally substituted heterocyclic group, or an optionally substituted heterocyclic group substituted an alkyl group containing from 1 to 4 carbon atoms in the alkyl moiety;

R 12 is a hydrogen atom, an alkyl group containing from 1 to carbon atoms, an optionally substituted aryl group or an optionally substituted arylalkyl group;

or a pharmaceutically acceptable salt thereof.

Suitable variants of compounds of formula (1b) are the same as those described above in relation to compounds of formula (I). Such a suitable variant is, for example, a functional group containing an ionizable hydrogen atom whose pK _a is 10 or less and which is present in the group R ₂ . Such functional groups include hydroxyl, carboxyl, thiol, -NH-C (O) R _a , -C (O) NR ₆ R ₇ , substituted sulfonamides of the formula -NHS (O) ₂ R _b , -S ( O) ₂ NHR _C , NHC (X ₂ ) NHRb, or the tetrazolyl group described above in relation to compounds of Formula (I), without being limited thereto.

In a preferred embodiment, the group R ₇ in the compound of formula (1b) is present on the ring once in the 3 or 4 position, or twice in the 3 and 4 position. The substituent is suitably present. An electron-acceptor group. In a preferred embodiment, R 1 is nitro, halogen, cyano, trifluoromethyl or C (O) NR ₄ R ₅ .

Although the group Y may be substituted at any position of the five ring positions, this group is preferably a monosubstituted ring of said ring at position 2 or 3, wherein position 4 of said ring is preferably unsubstituted. When said ring is disubstituted, the substituents are located at the 2 'or 3' position of the monocyclic ring. Although both R 1 and Y may represent hydrogen atoms, it is preferred that at least one of the rings be substituted, preferably both rings are substituted with at least one substituent, i.e., n and m are 1 or more.

More preferably, Y represents one substituent which is a halogen atom, two substituents which are halogen atoms, one substituent which is an alkoxy group, two substituents which are alkoxy groups, a methylenedioxy group, an aryl group or an alkyl group, more preferably said substituents are found in position 2 ', respectively in the case of two substituents at position 2' and 3 '.

Another aspect of the present invention are the novel compounds of formula (Ic) described below which form a subset of compounds of formula (I) and which are also useful for the treatment of chemokinin mediated diseases. The present invention also relates to pharmaceutical compositions comprising a compound of formula (Ic) and a pharmaceutically acceptable diluent or carrier. According to this aspect of the present invention, compounds of formula (Ic) may suitably be used:

• 4

I · • · where

X

Xi

R 1 ^(Y) k k..A

(Ic) i is an oxygen or sulfur atom;

is an oxygen or sulfur atom;

is independently selected from the group consisting of hydrogen, halogen, nitro, cyano, halogen substituted alkyl of 1 to 10 carbon atoms, alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkoxy containing from 1 to 10 carbon atoms, a halogen substituted alkoxy group containing from 1 to 10 carbon atoms, an azide group, a S (O) _t R ₄ group, a hydroxyl group, a hydroxyalkyl group containing from 1 to 4 carbon atoms, an aryl group, an arylalkyl group containing from 1 to 4 carbon atoms in the alkyl moiety, aryloxy, arylalkoxy containing from 1 to 4 carbon atoms in the alkoxy moiety, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic-substituted alkyl groups containing from 1 to 4 carbon atoms , a heteroaryl group of substi a fatty alkoxy group having from 1 to 4 carbon atoms in the alkoxy moiety, an arylalkenyl group having from 2 to 10 carbon atoms in the alkenyl moiety,

A heteroarylalkenyl group containing from 2 to 10 carbon atoms in the alkenyl moiety, a heterocyclic-substituted alkenyl group containing from 2 to 10 alkenyl moieties carbon atoms, NR ₄ R _5, alkenyl-C (O) NR ₄ R 5 group in the alkenyl moiety contains from 2 to 10 carbon atoms, C (O) NR ₄ R _5, C (0) NR ₄ Rio , an S (O) ₃ H group, an S (O) ₃ R 8 group, an alkyl-C (O) R 11 group containing from 1 to 10 carbon atoms in the alkyl moiety, an alkenyl-C (O) R 11 group which is present in alkenyl the moiety contains from 2 to 10 carbon atoms, the alkenyl-C (O) OR n group which in the alkenyl moiety contains from 2 to 10 carbon atoms, the C (O) R 11 group, the C (O) OR 12 group, the OC (O) R n group , NR ₄ C _(O) R, or two R groups together may form O- (CH2) _s-O or a five- to six-membered unsaturated ring;

t is 0, or an integer whose value is 1 or 2;

s is an integer from 1 to 3;

R ₄ and R 5 are independently selected from hydrogen, optionally substituted alkyl of 1 to 4 carbon atoms, optionally substituted aryl, optionally substituted arylalkyl of 1 to 4 carbon atoms, optionally substituted heteroaryl an optionally substituted heteroarylalkyl group containing from 1 to 4 carbon atoms, a heterocyclic group, a heterocyclic substituted alkyl group containing from 1 to 4 carbon atoms, or R ₄ and R ₅ together »

with the nitrogen atom to which they are attached, form a 5- to 7-membered ring which may optionally contain another heteroatom selected from the group consisting of oxygen, nitrogen and sulfur;

Y is independently selected from the group consisting of halogen, nitro, cyano, halogen substituted alkyl of 1 to 10 carbon atoms, alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkoxy of From 1 to 10 carbon atoms, a halogen-substituted alkoxy group containing from 1 to 10 carbon atoms, an azide group, a S (O) _t R ₄ group, a hydroxyl group, a hydroxyalkyl group containing from 1 to 4 carbon atoms, an aryl group, an arylalkyl group containing alkyl moieties of from 1 to 4 carbon atoms, aryloxy, arylalkoxy containing from 1 to 4 carbon atoms in the alkoxy moiety, heteroaryl, heteroarylalkyl, heteroarylalkoxy groups containing from 1 to 4 carbon atoms in the alkoxy moiety, heterocyclic groups, heterocyclic substituted alkyl groups group containing in the alkyl moiety of from 1 to 4 carbon atoms, an arylalkenyl group containing from 2 to 10 carbon atoms in the alkenyl moiety, a heteroarylalkenyl group containing from 2 to 10 carbon atoms in the alkenyl moiety, a heterocyclic substituted alkenyl group containing from 2 to 10 alkenyl moieties carbon atoms, NR ₄ R _{5 group} , alkenyl-C (O) NR ₄ R ₅ group containing from 2 to 10 carbon atoms in the alkenyl moiety, C (O) NR ₄ R ₅ group, C (O) NR _{4 group} R ₁₀ , group S (O) 3H,

an S (O) ₃ R _{8 group} , an alkyl-C (O) R 11 group having from 1 to 10 carbon atoms in the alkyl portion, an alkenyl-C (O) R 11 group having from 2 to 10 carbon atoms in the alkenyl portion alkenyl-C (0) orn which the alkenyl moiety contains from 2 to 10 carbon atoms, C (0) R, C (O) OR ₂ radical, 0C (0) R, NR ₄ C (0 ) R 11, or two Y groups together, may form an O- (CH ₂ ) _S- group or a 5- to 6-membered unsaturated ring;

n is an integer from 1 to 3;

m is an integer from 1 to 3;

R 8 is a hydrogen atom or an alkyl group containing from 1 to 4 carbon atoms;

R ₁₀ is an alkyl-C (O) ₂ R ₈ group containing from 1 to 10 carbon atoms in the alkyl moiety;

R 11 is selected from the group consisting of hydrogen, alkyl of 1 to 4 carbon atoms, optionally substituted aryl, optionally substituted arylalkyl of 1 to 4 carbon atoms, optionally substituted heteroaryl, optionally substituted heteroarylalkyl an alkyl moiety of from 1 to 4 carbon atoms, an optionally substituted heterocyclic group, or an optionally substituted heterocyclic group substituted with an alkyl group containing from 1 to 4 carbon atoms in the alkyl moiety;

R 12 is a hydrogen atom, an alkyl group containing from 1 to carbon atoms, an optionally substituted aryl group or an optionally substituted arylalkyl group; provided that if n = 1, then n = 2, then at positions 2 'or at positions Y is in position 2 or 3 of the ring;

group Y is located in the 2 'and 3' positions,

5 ', at positions 2' and 6 ', at positions 3' and 5 '3' and 6 'of a given ring;

n = 3, then the Y group is in the 2 ', 3' and 5 'positions, or in the 2', 3 'and 6' positions; whereby

X 1 is an oxygen atom, m = 2, R 1 is 2-tert. butyl, 4-methyl and n = 3, then Y is not 2'-OH,

3'-target butyl, 5'-methyl;

X 1 is an oxygen atom, m = 1, R _x is a 4-methyl group and n = 2, then Y is not a 2'-OH, 5'-methyl group;

Xx is oxygen, m = 1, R1 is hydrogen and n = 2, then Y is not 2 ', 6'-diethyl;

X 1 is an oxygen atom, m = 1, R 1 is 2-OH and n = 2, then Y is not a 2 ', 5'-methyl group;

X 1 is sulfur, m = 1, R 1 is 4-ethyl and n = 1, then Y is not 2-methoxy;

or a pharmaceutically acceptable salt thereof.

• 9 ♦ »

Unless otherwise indicated, suitable variants of the compounds of formula (Ic) are the same as those described above for compounds of formula (I).

In a preferred embodiment, R 1 in the compound of formula (Ic) is present on the ring once in the 3 or 4 position, or twice in the 3 and 4 position. Preferably, R 1 is not a hydrogen atom. Suitably said substituent is an electron acceptor group. In a preferred embodiment, R 1 is nitro, halogen, cyano, trifluoromethyl or C (O) NR ₄ R ₅ .

Although the group Y may be substituted at any position of the five ring positions, this group is preferably a monosubstitute of said ring at position 2 or 3, wherein position 4 of said ring is preferably unsubstituted. When said ring is disubstituted, the substituents are located at the 2 'or 3' position of the monocyclic ring. Although both R 1 and Y may represent hydrogen atoms, it is preferred that at least one of the rings be substituted, preferably both rings are substituted with at least one substituent, i.e., n and m are 1 or more.

More preferably, Y represents one substituent which is a halogen atom, two substituents which are halogen atoms, one substituent which is an alkoxy group, two substituents which are alkoxy groups, a methylenedioxy group, an aryl group or an alkyl group, more preferably said substituents are found in position 2 ', respectively in the case of two substituents at position 2' and 3 '.

An example of a compound of formula (Ic) may be

N- [2-hydroxy-4- (methoxycarbonyl) phenyl] -1'-phenylurea;

N- [2-hydroxy-5-nitro-phenyl] -1'-phenylurea;

N- (2-hydroxy-4-fluorophenyl) -1'-phenylurea;

N- [2-hydroxy-4- (trifluoromethyl) phenyl] -N'-phenyl urea;

N- (2-hydroxy-4-nitrophenyl) urea;

N- (2-hydroxy-4-nitrophenyl) -N- (2-hydroxy-5-nitrophenyl) -N- (2-hydroxy-4-nitrophenyl) -N- (2-hydroxy-4) -nitrophenyl) -N '- (2-hydroxy-4-nitrophenyl) -N' - (2-hydroxy-4-nitrophenyl) - N '- N- (2-hydroxy-4-nitrophenyl) - N' N- (2-hydroxy-4-nitrophenyl) -N '- (2-hydroxy-4-nitrophenyl) -N' N- (2-hydroxy-4-nitrophenyl) - N '- (2-hydroxy-4-nitrophenyl) ) -N 'N- (2-hydroxy-4-nitrophenyl) -N' - (2-hydroxy-4-nitrophenyl) -N 'N- (2-hydroxy-4-nitrophenyl) -N' N- (2) -hydroxy-4-nitrophenyl) -N '- (2-hydroxy-4-nitrophenyl) -N' N- (2-hydroxy-4-nitrophenyl) -N 'N- (2-hydroxy-4-nitrophenyl) - N 'urea;

N- (2-hydroxy-4-nitrophenyl) -N '- (2-hydroxy-4-nitrophenyl) -N' urea;

N- (2-hydroxy-4-nitro-phenyl) -1 '- (2-hydroxy-4-nitrophenyl) phenyl-thiourea;

(3-methoxy-2-thienyl) urea; (3-methoxy-2-thienyl) urea;

(3-methoxyphenyl) urea;

(2-methoxyphenyl) urea;

(3-trifluoromethylphenyl) urea; (2-trifluoromethylphenyl) urea; (4-trifluoromethylphenyl) urea; (2-bromophenyl) urea;

(3-bromophenyl) urea;

(4-bromophenyl) urea; (2-phenylphenyl) urea; (2-nitrophenyl) urea;

(2-fluorophenyl) urea;

(2,6-difluorophenyl) urea;

(2-ethoxyphenyl) urea; (2-ethylphenyl) urea; (2-Trifluoromethoxyphenyl) (2-methylthiophenyl) urea;

- (2-chloro-6-methylphenyl) - (2-sulfoxymethylphenyl) urea;

• · · ♦

#.

N- (2-hydroxy-4-trifluoromethylphenyl) -N '- (2-bromophenyl) urea; N- (2-hydroxy-4-trifluoromethylphenyl) -1 '- (2-phenylphenyl) urea; N- (2-hydroxy-4-carbomethoxyphenyl) -1 '- (2-phenylphenyl) urea;

N- (2-hydroxy-4-nitrophenyl) -1 '- (2,3-dichlorophenyl) urea;

N- (2-hydroxy-4-nitrophenyl) -N '- (2,4-dichlorophenyl) urea;

N- (2-hydroxy-4-nitrophenyl) -N '- (2-chlorophenyl) urea;

N- (2-hydroxy-4-nitrophenyl) -N '- (2,4-dibromophenyl) urea;

N- (2-hydroxy-1-naphthyl) -N '- (2-bromophenyl) urea;

N- (2-hydroxy-4-nitrophenyl) -N '- (2,3-methylenedioxyphenyl) urea;

N- (2-hydroxy-4-nitrophenyl) -1 '- (3-chloro-2-methoxyphenyl) urea;

N- [2-hydroxy-4- (benzylamino) carbonylphenyl] -N '- (2-bromophenyl) urea;

N- (2-hydroxy-4-nitrophenyl) -N '- (2-phenoxyphenyl) urea;

N- (2-hydroxy-4-fluorophenyl) -N '-( 2-bromophenyl) urea;

N- (2-hydroxy-3,4-difluorophenyl) -N '- (2-bromophenyl) urea;

N- (2-hydroxy-4-phenylphenyl) -N '- (2-bromophenyl) urea;

N- (2-hydroxy-4-methylphenyl) -N '- (2-bromophenyl) urea;

N- (2-hydroxy-4-nitrophenyl) -N '- (2-phenylaminophenyl) urea;

N- (2-hydroxy-3-carboxyphenyl) -1 '- (2-bromophenyl) urea;

N- (2-sulfhydryl-4-bromophenyl) -1 '- (2-bromophenyl) urea;

N- (2-hydroxy-4-nitrophenyl) -1 '- (2-iodophenyl) urea;

N- (2-hydroxy-4-nitrophenyl) -1 '- (2-bromophenyl) thiourea;

N- (2-hydroxy-4-azidophenyl) -1 '- (2-methoxyphenyl) urea;

N- [2-hydroxy-5-cyanophenyl] -1 '- [2-bromophenyl] urea;

N- [2-hydroxy-3-fluorophenyl] -1 '- [2-bromophenyl] urea;

N- [2-hydroxy-3-fluoro-5-bromophenyl] -1 '- [2-bromophenyl] urea;

N- [2-hydroxy-3-chlorophenyl] -1 '- [2-bromophenyl] urea;

N- [2-hydroxy-3-trifluoromethylphenyl] -1 '- [2-bromophenyl] urea; N- [2-hydroxy-3,4-diphenylphenyl] -N '- [2-bromophenyl] urea;

N- [2-hydroxy-3-glycinomethyl-ester-carbonylphenyl] -1 '- [2-bromophenyl] urea;

N- [2-hydroxy-3-glycinecarbonylphenyl] -1 '- [2-bromophenyl] urea; N- [2-hydroxy-3,5-dichlorophenyl] -N '- [2-bromophenyl] urea;

N- [2-hydroxy-3-nitrophenyl] -1 '- [2-bromophenyl] urea;

N- [2-hydroxy-3,4-dichlorophenyl] -4- [2-bromophenyl] urea;

N- [2-hydroxy-3-cyanophenyl] -1 '- [2-bromophenyl] urea;

N- [2-hydroxy-4-cyanophenyl] -N '- [2-bromophenyl] urea;

N- [2-hydroxy-4-cyanophenyl] -4- [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] -1 '- [3-trifluoromethylphenyl] urea; N- [2-hydroxy-4-cyanophenyl] -4- [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-phenylaminocarbonylphenyl] -1 '- [2-bromophenyl] urea;

N- [2-hydroxy-3-cyano-4-methylphenyl] -4- [2-bromophenyl] urea; N- [2-hydroxy-4-carbophenylphenyl] -1 '- [2-bromophenyl] urea;

N- [2-hydroxy-3-carbophenylphenyl] -1 '- [2-bromophenyl] urea;

N- [2-hydroxy-3-benzyloxyphenyl] -N '- [2-bromophenyl] urea;

(E) -N- [4- [2- (methoxycarbonyl) ethenyl] -2-hydroxyphenyl) -N '- [2-bromophenyl] urea;

(E) -N- [3- [2- (methoxycarbonyl) ethenyl] -2-hydroxyphenyl] N '- [2-bromophenyl] 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-benzamidophenyl] -N '- [2-bromophenyl] urea;

4

N- [2-hydroxy-4-aminocarbonylphenyl] -1 '- [2-bromophenyl] urea;

Ν- (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] -1 '- [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-trifluoromethylphenyl] urea;

N- [2-hydroxy-3-naphthyl] -N '- [2,3-dichlorophenyl] 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] -1 '- [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-trifluoromethylphenyl] urea;

N- [2-hydroxy-3,4-dichlorophenyl] -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 '- [benzoyl] 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-naphthalenesulfonic acid] -N '- [2-bromophenyl] urea;

N- (2-hydroxy-3-naphthyl) -N '- (2-bromophenyl) urea;

N- (2-hydroxy-1-naphthyl) -N '- (2-bromophenyl) urea; and

N- (2-hydroxy-4-nitrophenyl) -N '- (1-naphthyl) urea.

Φ φ φ

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, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, acetic acid, malic acid, acid tartaric, citric, lactic, oxalic, succinic, fumaric, maleic, benzoic, salycilic, phenylacetic and mandelic acids. In addition, the pharmaceutically acceptable salts of the compound of formula (I) may also form a pharmaceutically acceptable cation, for example when the substituent group contains a carboxyl group. Suitable pharmaceutically acceptable cations are well known to those skilled in the art and include alkali cations, alkaline earth metal cations, ammonium cations and quaternary ammonium cations.

The following explains the meaning of the terms used herein.

The term "halogen atom" or "halo" as used herein means all halogens, i.e., chlorine, fluorine, bromine and iodine.

The term "C 1 -C 10 alkyl" or "alkyl" as used herein refers to a linear or branched C 1 -C 10 radical unless the chain length is otherwise limited, and such radicals include methyl, ethyl , n-propyl, isopropyl, n-butyl, sec-butyl, • 4

isobutyl, tert. butyl, n-pentyl, and the like, without being limited thereto.

The term "cycloalkyl" as used herein refers to a cyclic moiety preferably having from 3 to 8 carbon atoms, the moiety of such moieties including cyclopropyl, cyclopentyl, cyclohexyl, and the like, without being limited thereto.

The term "alkenyl" as used herein refers in each case to a linear or branched radical having from 2 to 10 carbon atoms, unless the chain length is otherwise limited, and such radicals include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl and the like, without being limited thereto.

The term "aryl" or "aryl" as used herein refers to phenyl or naphthyl.

The term "heteroaryl group (alone or in any combination such as" heteroaryloxy or "heteroarylalkyl)" as used herein refers to a 5- to 10-membered aromatic ring system in which one or more rings contain one or more heteroatoms selected from the group consisting of nitrogen, oxygen or sulfur such as pyrrole, pyrazole, furan, thiophene, quinoline, isoquinoline, quinazolinyl, pyridine, pyrimidine, oxazole, thiazole, thiadiazole, triazole, imidazole or benzimidazole, without being limited to the examples.

9 99 9 9 9 9 9 9 9 9

The term "heterocyclic group (alone or in any combination, such as a" heterocyclic-substituted alkyl group) "as used herein refers to a saturated or partially unsaturated four to ten membered ring system in which one or more rings contain one or more heteroatoms selected from the group including a nitrogen atom, an oxygen atom or a sulfur atom such as pyrrolidine, piperidine, piperazine, morpholine, tetrahydropyran or imidazolidine.

The term "arylalkyl or" heteroarylalkyl or "heterocyclic-substituted alkyl" as used herein refers to an alkyl group having from 1 to 10 carbon atoms as defined above, attached to an aryl, heteroaryl or heterocyclic group, as defined above, if not otherwise stated.

The term "sulfinyl group" as used herein refers to the group S (O), ie, the oxide of the corresponding sulfide; The term "thio" as used herein refers to a given sulfide, and "sulfonyl" or "sulfonyl" as used herein refers to a fully oxidized S (O) _{2 group} .

The term "two R 1 groups (or two Y groups) may form together a 5- to 6-membered ring herein refers to the formation of a naphthylene ring system or a phenyl group to which is attached a 6-membered, partially unsaturated ring such as 6-carbon cycloalkenyl, ie. cyclohexene, or cycloalkenyl containing 5 carbon atoms, i.e. cyclopentene.

• ·

Compounds of formulas (I), (Ia), (Ib), (Ic), (II) and (III) can be obtained using various synthetic processes, some of which are illustrated in the schemes below. The synthesis procedures depicted in these schemes are useful for the preparation of compounds of formulas (I), (Ia), (II) and (III) containing various R, Rx and Ar groups which are subject to chemical reactions, said groups also optionally having additional substituents which are suitably protected for compatibility with the reaction conditions. In these cases, subsequent deprotection of these groups yields compounds whose nature is generally described herein. Once the basic urea moiety is formed, other compounds of the above formulas can be obtained using standard functional group conversion procedures known to those skilled in the art. Since the following schemes illustrate only the preparation of compounds of formula (I), these schemes are for illustrative purposes only and are not intended to limit the scope of the invention in any way.

Scheme 1

R = NH _2, OH. CO ₂ H, SH (a) PhNCO NHSO ₂ R

Ortho substituted phenyl ureas (Scheme 1) can be prepared under standard conditions which include condensation of commercially available ortho substituted aniline (Aldrich).

9 9 9 9 9 9 9

9

9 9 9 9 9 9 9 • 9 9 9

Chemical Co., Milwaukee, WI, USA) with a commercially available, optionally substituted arylisocyanate (Aldrich Chemical Co., Milwaukee, WI, USA) in an aprotic solvent (DMF, toluene). If compound 1- (RSO ₂ -NH) ₂ - (NH) ₂ Ph is not commercially available, it can be prepared by reacting commercially available RSO ₂ C1 with the corresponding 2-phenylenediamine in the presence of a base such as triethylamine or sodium hydride (NaH) , in an aprotic solvent (such as dichloromethane or DMF).

Scheme 2

R

R = OH, NH 2, NHSO ₂ R;

a) HNO ₃ , 23 ° C b) SnCl ₂ , EtOH

If the desired 2-substituted aniline 5 (Scheme 2) is not commercially available, the corresponding nitro compound can be prepared from compound 3 (Scheme 2) under standard conditions (using HNO 3 or BF 4 NO 3) at 23 ° C. The resulting nitro compound is then reduced to the corresponding aniline with SnCl ₂ in ethanol (EtOH) (or with H ₂ / Pd or with L 1 AlH 4).

Scheme 3

7.

a) _NH4 SCN, Br ₂

b) NaOH EtOH

If the desired 2-aminobenzenethiol δ (Scheme 3) is not commercially available, it can be synthesized by reacting phenylaniline with a thiocyanate anion in the presence of an oxidizing agent (such as bromine) to give 2-aminobenzothiazole δ (Scheme 3). This thiazole can be hydrolyzed to give the desired 2-aminobenzenethiol 8 (Scheme 3) using a strong base such as sodium hydroxide (NaOH) in a protic solvent (i.e., ethanol).

Scheme 4 o ₂ n • OH x = s, o nh ₂ g

₃ , ii) PhNH ₂ c) Et ₃ N-HF, CH ₃ CN

a) TBSCl, imide, DMF b) i) C 1 CXCl, NaHCO

In the event that said thioisocyanate or phenylisocyanate is not commercially available, thiourea 11 (Scheme 4) can be prepared from commercially available ortho substituted aniline. This compound is first protected with a protecting group (tert-butyldimethylsilyl or benzyl) under known conditions (Greene, T. Protecting Groups in Organic Synthesis, Wiley & Sons, New York, 1981). The thus protected aniline subsequently reacts in the presence of a base (such as triethylamine or sodium bicarbonate) first with either thiophosgene or a solution of phosgene in an aprotic solvent

(i.e. in DMF, toluene) and then with aniline to form the protected thiourea and urea, respectively. The resulting urea or thiourea is then deprotected under standard conditions to give the desired urea or thiourea 11 (Scheme 4).

Scheme 5

a) (PhO) ₂ PON ₃ , Et ₃ Nb) PhXNH ₂ I

X = OH. NHSO ₂ P. SH |

Alternatively, the urea may be prepared by a Curtius rearrangement from the corresponding aromatic carboxylic acid or thiophenecarboxylic acid 12 (Scheme 5). Said carboxylic acid is subjected to standard Curtius conditions (i.e., treatment (PhO) _{2 with} PON ₃ , Et ₃ N or C 1 COCOCl and then NaN ₃ ) and the isocyanate formed as an intermediate in this reaction is captured with an appropriately substituted aniline.

Pharmaceutically acceptable salts of the compounds of formula (I) may be obtained by a known method, such as by reacting a compound of formula (I) with an appropriate amount of an acid or base in the presence of a suitable solvent.

Another aspect of the present invention is a novel process for the synthesis of cyanonitrophenol intermediates. Many methods of converting aryl halides to arylcyanoderivatives using copper (I) cyanide have been described in the past. However, to date an example where a hydroxyl group was present on the aryl ring was not described. Several attempts to obtain a cyanophenol group with published results failed completely. The use of known conditions, which include elevated temperature, i.e. a temperature above 170 ° C, such as a temperature in the range of 180 ° C to 210 ° C, has not resulted in the exchange of the halogen atom for a cyano group. The use of standard bases, such as DMF or pyridine, further resulted in the formation of an undesirable product. Experiments were carried out with various intermediates such as 2-amino-5-fluorophenol, 2-nitro-5-fluorophenol, 2-nitro-5-methyl-6-bromophenol, with halogen changes from fluorine to chlorine and chlorine to bromine, and all the compounds thus prepared were reacted with cuprous cyanide. It has been found that the use of a bromo derivative such as 2-nitro-5-methyl-6-bromophenol with dimethylformamide and triethylamine together with a catalytic amount of dimethylaminopyridine and cuprous cyanide at a reduced temperature, i.e. below 100 ° C, preferably at a temperature in the range of from 60 to about 80 ° C, for less than the reaction time under standard conditions, i.e. less than 18 hours, preferably for a period of from about 4 to 6 hours, gave the desired products.

Thus, another aspect of the present invention is a process for preparing a cyanophenol derivative of the general formula

OH

wherein R 1 has the same meaning as in formula (I), the method comprising reacting a compound of formula

R,

OH

wherein X is a halogen atom, with cuprous cyanide, dimethylformamide, triethylamine and a catalytic amount of dimethylaminopyridine. Preferably, the method is carried out at a reduced temperature in the range of about 60 to 80 ° C. In a preferred embodiment of the invention, X is a bromine atom.

The compounds of formulas (I), (Ia), (II) and (III), or a pharmaceutically acceptable salt thereof, can be used for the manufacture of a medicament for the prophylactic or therapeutic treatment of a disease state in humans or other mammals which is induced or or unregulated, IL-8 cytokinin production by such mammalian cells, such as monocytes and / or macrophages, without being limited thereto, or by other chemokinins that bind to the IL-8a or β receptor, also referred to as the type I receptor, or Type II.

For the purposes of this invention, the dosage sizes and dosage forms of all the compounds of formulas (I), (Ia), (1b), (1c), (II) and (III) are the same as those of the compound of formula (I) and said compound. is interchangeable.

Accordingly, another aspect of the present invention is a method of treating a chemokinin-mediated disease wherein: 9 9 · 9 · 9 · 9 · 9 · 9 · 9 · 9

9 9 9 ·

Said chemokinin is one that binds to IL-8a or β receptors, said method comprising administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Specifically, said chemokinins are IL-8, GROα, GROβ, GROγ or NAP-2.

The compounds of formula (I) are administered in an amount sufficient to inhibit cytokinin function, particularly IL-8, GROα, GROβ, GROγ or NAP-2, such that their content is biologically reduced to normal physiological levels, or in some cases to a level below normal to improve said disease state. Abnormal levels of IL-8, GROα, GROβ, GROγ or NAP-2 include, in the context of the present invention, for example: (i) a level of free IL-8 equal to or greater than 1 picogram / ml; (ii) a content of any cells associated with IL-8, GROα, GROβ, GROγ or NAP-2 above normal physiological level; or (III) the presence of basal levels of IL-8, GROα, GROβ, GROγ, or NAP-2 in cells or tissues that produce IL-8, GROα, GROP, GROγ, and NAP-2, respectively.

There are many disease states in which excessive or unregulated production of IL-8 is associated with the induction and / or causation thereof. Chemokinin-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, syndromic sepsis, syndrome cardiac and renal reperfusion injury, glomeluronephritis, thrombosis, graft-versus-host reaction, Alzheimer's disease, this to · this · to · this ·· · Transplant rejection, malaria, restinosis, angiogenesis, unwanted release of stem hematopoietic cells.

These diseases are primarily characterized by massive neutrophil infiltration, T-cell infiltration, or neovascular growth and are associated with increased production of IL-8, GROα,

GROP, GROγ, or NAP-2, which are responsible for chemotaxis of neutrophils to the site of inflammation or directional growth of endothelial cells. Unlike other inflammatory chemokinins (IL-1, TNF and IL-6), IL-8, GROα, GROP, GROγ or NAP-2 has a unique property of promoting neutrophil chemotaxis, promoting enzyme release, such as promoting elastase release , and the production and activation of peroxide. Said α-chemokinins, but specifically GROα, GROP, GROγ or NAP-2, which function through the IL-8 receptor of type I or II, can promote neovascularization of tumors by promoting the directional growth of endothelial cells. Therefore, inhibition of chemotaxis or activation induced by IL-8 could lead to a direct reduction in neutrophil infiltration.

The compounds of formula (I) of the present invention are administered in an amount sufficient to inhibit IL-8 which binds to the IL-8a or β receptor by inhibiting the binding of the compound of formula I to said receptors. (I) according to the invention, as evidenced by a reduction in chemotaxis and neutrophil activation. The finding that the compounds of formula (I) of the present invention are inhibitors of IL-8 binding is based on the effect of said compounds of formula (I) in in vitro binding studies of said compounds to said receptor, these studies also being described herein. . The compounds of formula (I) of the present invention have been shown to be dual inhibitors of both recombinant receptors. IL-8 types I and II. Preferably, the compounds of the present invention are inhibitors of only one receptor, which is preferably a type II receptor.

The term "IL-8-mediated disease or condition" means all and any disease states in which IL-8, GROα, GROβ, GROγ, or NAP-2 plays a role, which may consist in IL-8 production alone, GROα, GROα, GROγ or NAP-2, or wherein IL-8, GROα, GROγ, GROγ or NAP-2 is the cause of the release of another chemokinin, such as IL-1, IL-β or TNF, without being limited to the examples given. Therefore, a disease state in which IL-1 is a major agent whose production or effect is due to IL-8 action can be considered a disease state mediated by IL-8.

Diseases that can be treated with the compounds of the present invention 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, glomeluronephritis, thrombosis, graft-versus-host disease, Alzheimer's disease, transplant rejection, malaria, restinosis, angiogenesis, unwanted release of stem hematopoietic cells.

The compounds of the present invention are also useful for the treatment of diseases caused by respiratory viruses comprising rhinovirus, influenza virus, herpesviruses including herpes simplex virus I and herpes simplex virus II, and hepatitis viruses whose group includes hepatitis B-inducing virus; hepatitis C-inducing virus, without being limited to the examples given.

The term "chemokinin-mediated disease or condition" as used herein refers to all and any disease states in which any chemokinin that binds to IL-8α or β receptors plays a role, such as IL-8, GROα, GROα, GROγ or NAP-2, without being limited thereto. For example, a group of such disease states may include a condition in which IL-8 plays a role, which may be in the production of IL-8 itself, or in that IL-8 is responsible for the release of another chemokinin such as IL-1. , 11-6 or TNF, without being limited thereto. Therefore, a disease state in which IL-1 is a major agent whose production or effect is due to IL-8 action can be considered a disease state mediated by IL-8.

The term "cytokinin" as used herein refers to any secreted polypeptide that affects cellular functions and which is a compound that modulates cell-cell interactions in an immunological, inflammatory or hematopoietic response. The family of cytokinins includes monokinins and lymphokines, without being limited to the examples given, regardless of which cells produce them. For example, it is usually stated that monokinin is

It is produced and secreted by a cell containing a single nucleus, such as a macrophage and / or monocyte. However, many other cells also produce monokinins, including natural killer cells, fibroblasts, basophils, neutrophils, endothelial cells, brain astrocytes, bone marrow cells, epideral keratinocytes and B-lymphocytes. It is generally reported that lymphokines are produced by lymphocyte cells. An example of a cytokinin is

Interleukinin-1 (IL-1), Interleukinin-β (IL-6),

Interleukinin-8 (IL-8), tumor necrosis factor α (TNF-α) and tumor necrosis factor β (TNF-β), without being limited thereto.

The term "chemokinin" as used herein refers to any secreted polypeptide that affects cellular functions and which is a compound that modulates cell-cell interactions in an immunological, inflammatory or hematopoietic response, the meaning of which is similar to "cytokinin" as defined above. . Chemokinin is primarily secreted through cellular transmembranes and causes chemotaxis and activation of specific white blood cells and leukocytes, neutrophils, monocytes, macrophages, T-cells, B-cells, endothelial cells and smooth muscle cells. The class of chemokinins includes IL-8, GRO-α, GRO-β, GRO-γ, NAP-2, IP-10,,-β, ΜΙΡ-β, PF-4 and MCP 1, 2 and 3. examples.

In order for a compound of formula (I) of the invention or a pharmaceutically acceptable salt thereof to be used in therapy, it is usually necessary to formulate the compound or a pharmaceutically acceptable salt thereof in the form of a pharmaceutical composition in accordance with standard

44 4 44 ·· 4

444 4 444 4 · · 4 4 · 4 · 4 · · · 4 4 44444

4 4 4 4 4 4 • 44 4444 444 · 44 · 44 444 pharmaceutical practice. ' Thus, another aspect of the invention is a pharmaceutical composition comprising an effective, non-toxic amount of a compound of formula (I) and a pharmaceutically acceptable carrier or diluent.

The compounds of formula (I), the pharmaceutically acceptable salts thereof and the pharmaceutical compositions comprising the compounds and / or the pharmaceutically acceptable salts thereof according to the invention can be administered without any difficulty by any conventional route of administration such as orally, topically, parenterally or by inhalation. Said compounds of formula (I) may be administered in conventional dosage forms prepared by standard procedures involving admixing a compound of formula (I) with standard pharmaceutical carriers. The compounds of formula (I) may also be administered in conventional doses in combination with a known, second therapeutically active agent.

The above processes may include mixing, granulating and compressing or dissolving said components, depending on the desired form of the resulting formulation. It will be appreciated that the form and nature of the pharmaceutically acceptable carrier or diluent is determined by the amount of active ingredient with which the carrier or diluent is to be combined, the route of administration of the resulting pharmaceutical composition and other generally known factors. The carriers must be "acceptable" in the sense of being compatible with the other ingredients of the pharmaceutical composition and not deleterious to the recipient thereof.

Said pharmaceutical carrier may be, for example, a solid or a liquid. An example of a solid carrier is lactose, 9 9 9 9 9 9 9 9

9 9 9 9 9

Gypsum, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. As the liquid carrier, syrup, peanut oil, olive oil, water and the like can be mentioned. Similarly, the carrier or diluent may comprise a delayed release material, such materials are well known in the art and exemplified by glyceryl monostearate or glyceryl stearate, alone or in combination with a wax.

A wide variety of pharmaceutical forms can be used according to the invention. Thus, when a solid carrier is used, the pharmaceutical composition may be in the form of a tablet or may be in the form of a hard gelatin capsule, powder, pellet, pill or lozenge. The amount of solid carrier may vary within wide limits, but is preferably from about 25 milligrams to about 1 gram. When a liquid carrier is used, the composition of the invention may take the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid, such as an ampoule or a non-aqueous liquid suspension.

The compounds of formula (I) of the present invention may be administered topically, i.e. non-systemically. By non-systemic administration in the context of the present invention is meant external administration of a compound of formula (I) to the skin or cheek cavity and instillation of said compound into the ear, eye or nose such that the compound of the present invention does not significantly enter the bloodstream. On the other hand, systemic administration means oral, intravenous, intraperitoneal and intramuscular administration.

Fc · ·· ·

The group of pharmaceutical compositions of the present invention suitable for topical administration includes liquid or semi-liquid formulations suitable for penetration through the skin into the site of inflammation, such as liquid ointments, solutions, creams, ointments and pastes, and drops which are suitable. for administration to the eyes, ears and nose. In the case of a topical pharmaceutical composition, the active ingredient may comprise from 0.001 weight percent to 10 weight percent, for example from 1 weight percent to 2 weight percent, of the total weight of the pharmaceutical composition. However, the active ingredient may comprise up to 10 weight percent, but preferably less than 5 weight percent, more preferably from 0.1 weight percent to 1 weight percent of the total weight of said pharmaceutical composition.

The group of solutions of the present invention includes those suitable for application to the skin or eye. The ophthalmic solution may comprise a sterile aqueous solution, which may optionally contain a bactericide, and which may be prepared in a similar manner as drops. Solutions or liquid ointments for application to the skin may also include an agent to accelerate drying and to cool the skin, such as alcohol or acetone, and / or a humectant, such as glycerol or an oil, such as castor oil or peanut oil.

The creams, ointments or pastes of the present invention are semi-liquid pharmaceutical formulations for external use that comprise the active ingredient of the present invention. The pharmaceutical compositions may be prepared by mixing the active ingredient of the present invention in finely divided or finely divided form

powder form, either alone or in solution or suspension in an aqueous or non-aqueous liquid with a greasy or non-greasy base, which mixing is effected by means of a suitable device. Said base may include hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax, metal-containing soap; glue; a natural oil such as almond oil, corn oil, peanut oil, castor oil or olive oil; wool wool or derivatives thereof or fatty acids such as stearic or oleic acid together with an alcohol such as propylene glycol or macrogel. Said pharmaceutical composition may comprise any suitable surfactant, such as an anionic, cationic or nonionic surfactant, such as a sorbitan ester or a polyoxyethylene derivative thereof. Said pharmaceutical composition may also include suspending agents such as natural rubbers, cellulose derivatives, or inorganic materials such as various forms of silica, and other ingredients such as lanolin.

The drops of the present invention may comprise sterile aqueous or oily solutions or suspensions and may be prepared by dissolving the active ingredient of the invention in a suitable aqueous solution of a bactericidal and / or fungicidal agent and / or other suitable preservative, the solution preferably containing a surfactant. . The resulting solution can then be clarified by filtration, transferred to a suitable container, which is then sealed and sterilized for half an hour in an autoclave at a temperature of from 98 ° C to 100 ° C. Alternatively, the solution may be sterilized by filtration and transferred to the container aseptically. As an example of bactericidal and 9

999 9 9 999

9

. 9 9999 9

9

The fingicidal agent that may be included in the droplets of the present invention include phenylmercury nitrate or acetate (0.002 weight percent), benzalkonium chloride (0.01 weight percent) and chlorhexidine acetate (0.01 weight percent). Suitable reagents for preparing an oily solution include glycerol, dilute alcohol, and propylene glycol.

The compounds of formula (I) may be administered parenterally, i.e., intravenously, intramuscularly, subcutaneously, intranasally, intrarectally, intravaginally, or intraperitoneally. Subcutaneous and intramuscular forms of parenteral administration are generally preferred. Appropriate dosage forms for these types of administration may be prepared by conventional methods. The compounds of formula (I) may also be administered by inhalation, i.e. by intranasal or oral inhalation. Appropriate dosage forms for this type of administration, such as an aerosol or a single dose inhaler, may be prepared by conventional methods.

For all of the above-described uses of the compound of formula (I), the daily dose of said compound for oral administration preferably ranges from about 0.01 milligrams / kilogram of total body weight to about 80 milligrams / kilogram of total body weight. For parenteral administration, the daily dose of a compound of the invention ranges from about 0.001 milligrams / kilogram of total body weight to about 80 milligrams / kilogram of total body weight. In the case of topical administration of said compound, the daily dose is preferably in the range of 0.1 milligram to 150 milligrams, said daily dose

• • 0 0 00 • 0 • 0 0 0 0 0 0 0 0 0 • 0 0 0 0 0 • 0 0 0 0 0 0 0 • 0 0 0 0 0 • 0

the dose is administered one to four times, preferably two to three times daily. For administration by inhalation of the compound, the daily dose is preferably in the range of about 0.01 milligrams / kilogram of total body weight to about 1 milligrams / kilogram of total body weight. One of ordinary skill in the art will recognize that the optimum amount and timing of single doses of a compound of Formula (I) or a pharmaceutically acceptable compound thereof is determined by the nature and extent of the condition being treated, the pharmaceutical form, route and site of administration, and the particular patient to be treated. said optima being determined by conventional methods. Further, one of skill in the art will recognize that the optimal course of treatment, i.e., the number of doses of a compound of Formula (I) or a pharmaceutically acceptable salt thereof administered over a given day for a given number of days, can be determined by a person skilled in the art using routine tests .

DETAILED DESCRIPTION OF THE INVENTION

In the examples below, all temperatures are given in degrees Celsius (° C). Unless otherwise noted, mass spectra were measured on a VG Zab mass spectrometer using fast atom bombardment (FAB) ionization. ¹ H NMR spectra (hereinafter referred to as "NMR") were measured on a Bruker AM 250 or Bruker AM 400 spectrometer at 250 megahertz and 400 megahertz respectively. The following abbreviations have been used to denote multiplicity of signals: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, and br indicates a broad signal.

Flash chromatography was performed on Merck Silica gel 60 (230-400 mesh).

Synthetic examples

The present invention will now be further described by way of the following examples, which are provided by way of illustration and not by way of limitation. All temperatures reported herein are in degrees Celsius, all solvents used were of the highest purity possible, and unless otherwise noted, all reactions were carried out under anhydrous conditions in an argon atmosphere.

General Procedure A: Synthesis of Ν, Ν'-phenylurea

To a solution of 1.0 equivalent of substituted phenylisocyanate in 5 mL of toluene was added 1.0 equivalent of the corresponding aniline. The reaction mixture was stirred at about 80 ° C until the reaction was complete (i.e., for 24-48 hours) and then cooled to room temperature. The purification methods, yields and spectral characteristics of the individual compounds are shown below.

General procedure B: synthesis of Ν, N'-phenylurea

To a solution of 1.0 equivalent of phenyl isocyanate in 1 mL of dimethylformamide was added 1.0 equivalent of the corresponding aniline. The reaction mixture was stirred at about 80 ° C until the reaction was complete (i.e., for 24-48 hours) and the solvent was then removed in vacuo. The purification methods, yields and spectral characteristics of the individual compounds are shown below.

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General Procedure C: Sulfonamide Synthesis.

1.0 equivalents of ortho substituted aniline, 1.0 equivalents of triethylamine and 1.0 equivalents of the desired sulfonyl chloride were mixed in dichloromethane, and the resulting mixture was allowed to stir at about 23 ° C until completion of the reaction (i.e., for 12 to 36 hours). . The reaction mixture was partitioned between water and dichloromethane. The organic layer was separated and dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Methods for purifying the individual compounds are described below.

Example 1

Preparation of N- [2-hydroxy-4- (methoxycarbonyl) phenyl] -N'-phenylurea

N- [2-Hydroxy-4- (methoxycarbonyl) phenyl] -4'-phenylurea was prepared from 200 mg (1.19 mmol) of methyl 4-amino-3-hydroxybenzoate and 1.19 mmol of phenyl isocyanate by the general procedure described above. The product was purified by precipitation from toluene and filtered to give 309 mg (90 percent) of the desired product.

melting point: 188.4 to 188.8 ° C ^{Χ Η} NMR (CD ₃ OD / CDC1 _3): δ 8.15 (d, IH, J = 8.25 Hz), 7.70 (s, IH)

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, Δ (t, 1H, J = 8.25 Hz), 3.87 (s, 3H); EI-MS m / z 286 (M + H) ^&lt; ^{+ &gt};;

Anal. (C15H14N2O4) C, Η, N.

Example 2

Preparation of N- [5-nitro-2-hydroxyphenyl] -N'-phenylurea

N- [5-Nitro-2-hydroxyphenyl] -N'-phenylurea was prepared from 5-nitro-2-hydroxyaniline and phenyisocyanate according to general procedure A. The product was purified by precipitation from toluene and filtered to give 100 mg (30 mg) of the title compound. percent) of the desired product.

¹ H NMR (CD ₃ OD): δ 9.48 (s, 1H, NH), 9.07 (d, J = 1.56 Hz, NH), 8.55 (s, 1H), 7.80 (s) dd, 1H, 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) &lt; + & gt ^; .

Example 3

Preparation of 3-hydroxy-4 - {[(phenylamino) carbonyl] amino] benzamide

a) Preparation of a 0.67 molar stock solution of aluminum amide reagent

To a suspension of 0.02 mole of the corresponding hydrochloride in 20 ml of dry toluene at about 0 ° C was slowly added 10 ml of a 2 molar solution of trimethyl aluminum in toluene. After all the solution was added, the reaction mixture was allowed to warm to room temperature and stirred for 1-2 hours until gas evolution ceased.

b) Preparation of 3-hydroxy-4 - {[(phenylamino) carbonyl] amino] benzamide

To 60 mg (0.2 mmol) of N- [2-hydroxy-4- (methoxycarbonyl) phenyl] -N'-phenylurea in 2 mL of toluene was added 0.9 mL of a 0.67 molar solution of an aluminum amide reagent. The reaction mixture was heated to reflux for about 12 hours, cooled to room temperature and carefully quenched with 5% hydrochloric acid. The organic layer was separated and the aqueous layer was extracted three times with ethyl acetate. The organic extracts were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Chromatography of the obtained solid on silica gel (eluting with ethyl acetate) afforded 28 mg (49 percent) of the desired amide.

mp 106.8 - 107.1 ° C

NMR (CD 3 OD / CDCl 3): δ 7.98 (d, 1H, J = 8.25 Hz), 7.35 (d, 2H,

J = 8.25 Hz), 7.30 (d, 2H, J = 8.25 Hz), 7.17 (t, 2H, J = 8.25 Hz), 6.91 (t, 1H, J = 8.25 Hz);

EI-MS m / z 272 (M + H) &lt; + & gt ^;.

Anal. (C ₁₄ H ₁₃ N ₃ O ₃ ) C, Η, N.

Example 4

Preparation of N- (2-hydroxy-4-fluorophenyl) -1'-phenylurea

a) Preparation of 2-amino-5-fluorophenol

A mixture of 500 milligrams (3.18 millimoles) of 5-fluoro-2-nitrophenol a

1.76 g (9.2 mmol) of stannous chloride in 10 ml of ethanol was heated under argon at 80 ° C. After 30 minutes the starting material disappeared and the solution was allowed to cool to room temperature and poured into ice. Before extraction with ethyl acetate, the pH of the resulting mixture was adjusted to 5% aqueous sodium bicarbonate solution to make it slightly basic (7-8). The organic phase was washed with brine, dried over anhydrous magnesium sulfate, and filtered. Evaporation of the solvent gave

335 mg (83 percent) of the desired product.

NMR (CD ₃ OD / CDCl ₃ ): δ 6.6 (m, 1H), 6.38 dd, 1H, J = 8.3 Hz and

J = 2.8 Hz), 6.29 (m, 1H).

b) Preparation of N- (2-hydroxy-4-fluorophenyl) -4'-phenylurea N- (2-Hydroxy-4-fluorophenyl) -4'-phenylurea was prepared from 200 mg (1.57 mmol) of 2-amino- 5-fluorophenol and phenyl isocyanate according to general procedure A.

The product was purified by precipitation from toluene and filtered to give 352 mg (91 percent) of the desired product.

melting point: 195.5 to 195.7 ° C ^X H NMR (CD ₃ OD / CDC1 _3): δ 7.70 (m, 1H), 7.3 (d, 2H, J = 8.25 Hz) 7.15 (t, 2H, J = 8.25 Hz), 6.89 (t, 1H, J = 8.25 Hz), 6.50 6.38 (m, 2H);

EI-MS m / z 246 (M + H) &lt; + & gt ^;.

Anal. (C ₁₃ HuN ₂ O ₂ F) C, Η, N.

Example 5

Preparation of 2 - {[(phenylamino) carbonyl] amino] thiophenol

2 - {[(Phenylamino) carbonyl] amino} thiophenol was prepared from 200 mg (1.6 mmol) of 2-aminothiophenol and phenyl isocyanate according to general procedure A. The product was purified by precipitation from toluene and filtered to give 330 mg (85 mg). mp: 194.5 ° C)

^{Χ Η} NMR (CD3OD / CDCl3): δ 7.48 to 7.26 (m, 4Η), 7.25 to 7.10 (m,

3Η), 7.04-6.79 (m, 2Η);

EI-MS m / z 244 (M + H) &lt; + & gt ^;.

Anal. (C ₁₃ H ₁₂ N ₂ OS) C, Η, N.

Example 6

Preparation of N- (2-carboxy-4-hydroxyphenyl) -N'-phenylurea

N- (2-Carboxy-4-hydroxyphenyl) -N'-phenylurea was prepared from 1 gram (6.53 mmol) of 2-amino-5-hydroxybenzoic acid according to general procedure B. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, and filtered. Removal of the solvent under reduced pressure and chromatography of the resulting solid on silica gel (eluting with hexane / ethyl acetate (1: 1 to 100 percent ethyl acetate)) gave 1.5 g (84 percent) of the desired product.

¹ H NMR (CD 3 OD / CDCl 3): δ 8.36 (d, 1H, J = 8.25 Hz), 7.63 (m, 4H), 7.48 (t, 2H, J = 8.25 Hz) 7.20 (m, IH).

EI-MS m / z 272 (M + H) &lt; + & gt ^;.

Anal. (Ci ₂ H ₂ N ₂ O ₄ ) C, Η, N.

Example 7

Preparation of N- [2-hydroxy-4- (trifluoromethyl) phenyl] -N'-phenylurea

a) Preparation of 2-nitro-5-trifluoromethylphenol 2-Nitro-5-trifluoromethylphenol was prepared by dropwise addition of milliliters of concentrated HNO ₃ to 5 grams (30.8 millimoles) of α, α, α-trifluoro-m-cresol at room temperature. After completion of the dropwise addition, the reaction mixture was quenched with saturated ammonium acetate and extracted with ethyl acetate (EtOAc). The organic layer was separated, dried over anhydrous sodium sulfate, and filtered. Concentration of the resulting solution under reduced pressure gave an oil which was purified by column chromatography (gradient elution from 100 percent hexane to 50 percent ethyl acetate (EtOAc) in hexanes) to afford 1.7 g (27 percent) of the desired product.

1 H NMR (CDCl ₃ ): δ 10.6 (s, 1H, OH), 8.26 (d, 1H, J = 7.8 Hz), 7.45 (s, 1H, arom), 7.26 (d, 1H, J = 7.8Hz).

b) Preparation of 2-Amino-5-trifluoromethylphenol 2-Amino-5-trifluoromethylphenol was prepared by reaction

500 mg (2.41 mmol) of 2-nitro-5-trifluoromethylphenol with a solution of 3.5 g of stannous chloride (SnCl2) in ethanol at 23 DEG C. for 12 hours. The reaction mixture was concentrated to 50 mL and adjusted to pH 7 with saturated sodium bicarbonate solution. The reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was separated and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. 370 milligrams (87 percent)

The resulting colorless oil was used in the next step without further purification.

^{Χ Η} NMR (CDC1 _3): δ 7.6 (s, 1H), 7.39 (d, 1H, J = 8.5 Hz), 7.08 (d, 1H, J = 8.5 Hz).

c) Preparation of N- [2-hydroxy-4- (trifluoromethyl) phenyl] -N'-phenylurea

N- [2-Hydroxy-4- (trifluoromethyl) phenyl] -4'-phenylurea was prepared from 150 mg (1.09 mmol) of 2-amino-5-trifluoromethylphenol and 1.09 mmol of phenyl isocyanate according to general procedure A. Product obtained was purified by precipitation from dichloromethane and filtered to give 230 mg (87 percent) of the desired product.

¹ H NMR (DMSO-d 6): δ 9.45 (s, 1H, NH), 8.50 (s, 1H, NH), 8.31.

(d, 1H, J = 10.0Hz), 7.45 (d, 2H, J = 10.0Hz), 7.29 (t, 2H,

J = 6.67 Hz), 7.10 (m, 2H), 6.9 (t, 1H, J = 6.67 Hz).

EI-MS m / z 296 (M ^& lt ^{; +} & gt ^; ).

Anal. (C14H11N2O2F3) C, Η, N.

Example 8

Preparation of N- (2-hydroxy-4-nitrophenyl) -4- (2-hydroxy-4-nitrophenyl) urea

a) Preparation of 2- (tert-butyldimethylsilyloxy) -4-nitroaniline

To a solution of 1 gram (6.49 millimoles) of 2-amino-5-nitrophenol a

0.88 g (12.3 mmol) of imidazole in 15 ml of dimethylformamide (DMF) was added 11.2 ml (64.9 mmol) of the target. butyldimethylsilyl chloride. The resulting mixture was allowed to stir at 23 ° C for 48 hours. Reaction

the mixture was partitioned between 0.1% hydrochloric acid (HCl) and ethyl acetate. The combined organic phase was washed with brine, dried over anhydrous magnesium sulfate, and filtered. Removal of the solvent under reduced pressure and chromatography of the obtained oil on silica gel (eluting with hexane / ethyl acetate (5: 1)) gave 1.7 g (98 percent) of the desired product.

¹ H NMR (CDCl 3): δ 7.78 (dd, 1H, J = 6.7 Hz and J = 2.7 Hz), 7.61 (d, 1H, J = 2.7 Hz), 6.7 (d, 1H, J = 8.8Hz), 1.0 (s, 9H),

0.28 (s, 6 H).

b) Preparation of N - [(2-tert-butyldimethylsilyloxy) -4-nitrophenyl] - N - [(2-tert-butyldimethylsiloxy) -4-nitrophenyl] urea

To a solution of 200 milligrams (0.75 millimoles) of 2-tert. butyldimethylsilyloxy) -4-nitroaniline in 10 mL of toluene was added 0.13 mL (1.64 mmol) of triethylamine and 88.4 mg (0.3 mmol) of triphosgene. The reaction mixture was stirred at 70 ° C for 2 hours and then allowed to cool to room temperature. A further 200 mg (0.75 mmol) of 2- (tert-butyldimethylsilyloxy) -4-nitroaniline was then added to the reaction mixture. The resulting mixture was allowed to stir at 70 ° C for 48 hours and cooled to room temperature. The reaction mixture was partitioned between water and ethyl acetate. The combined organic phase was washed with brine, dried over anhydrous magnesium sulfate, and filtered. Removal of the solvent under reduced pressure and chromatography of the resulting colorless oil on silica gel (eluting with hexane / ethyl acetate (10: 1)) gave 130 mg (31 percent) of the product.

¹ H NMR (CDCl ₃ ): 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 = 2.8Hz), 7.22 (s, 2H), 1.02 (s, 18H), 0.35 (s, 12H).

c) Preparation of N- (2-hydroxy-4-nitrophenyl) -N '- (2-hydroxy-4-nitrophenyl) urea

To a solution of 50 mg (0.089 mmol) of N - [(2-tert-butyldimethylsilyloxy) -4-nitrophenyl] -4 '- [(2-tert-butyldimethylsiloxy) -4-nitrophenyl] urea in 2 mL of tetrahydrofuran (THF) at 0 0.09 mL (1 molar, 0.89 mmol) of tetrabutylammonium fluoride was added. The reaction mixture was stirred at 23 ° C and disappeared after 1 hour. The reaction mixture was partitioned between water and ethyl acetate. The combined organic phase was dried over anhydrous magnesium sulfate and filtered. Removal of the solvent under reduced pressure and chromatography of the resulting colorless oil on silica gel (eluting with hexane / ethyl acetate (1: 1 to 100 percent ethyl acetate)) gave 24 mg (81 percent) of the desired product.

^{Χ Η} 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 7.7 (d, 2H, J = 2.06 Hz).

EI-MS m / z 334 (M + H) &lt; + & gt ^; .

Anal. (C ₃ Hi ₀ N ₄ O ₇₎ C Η N.

· · · · · · · · · · · · · · · · · · · · ·.

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Example 9

Preparation of N- (2-hydroxy-4-nitrophenyl) -N'-phenylthiourea

a) Preparation of N- (2-tert-butyldimethylsilyloxy-4-nitrophenyl) -Nthioureas

N- (2-tert-Butyldimethylsilyloxy-4-nitrophenyl) -N'-phenylthiourea was prepared by adding thiophosgene at 0 ° C to a biphasic solution of 80 mg (0.308 mmol) of 2-tert. butyldimethylsilyloxy-4-nitroaniline and sodium bicarbonate in 7 mL of chloroform (CHCl ₃ ) / water (2.5: 1). The solution was allowed to warm to 23 ° C and the reaction continued overnight. The chloroform layer was separated and dried over anhydrous sodium sulfate. The solution was concentrated in vacuo and the residue was dissolved in toluene. To the resulting solution was added 100 microliters of aniline and allowed to react for 12 hours at 23 ° C. The reaction mixture was concentrated and the residue was purified by flash chromatography (eluting with 10% ethyl acetate in hexane) to give 120.8 mg (98 percent) of the desired product as a yellow solid.

mp 144- 145 ° C ^X H NMR (CD ₃ OD / CDC1 _3): δ 8.65 (d, IH, J = 10.0 Hz), 7.58 (d, IH,

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'-phenylthiourea

N- (2-Hydroxy-4-nitrophenyl) -4'-phenyl-2-thiourea was prepared by reacting a solution of 100 mg (0.248 mmol) of N- (2-tert-butyldimethylsilyloxy-4-nitrophenyl) -N'-phenylthiourea in 1 ml of acetonitrile (CH ₃ CN) with 100 microlitres • »·

4 · 4 • 4 · 4 4 4 4 4 4 4 44 44

4 • 4

4 &apos; (0.62 mmol) of Et2N.HF in acetonitrile at 23 [deg.] C. for 10 minutes. The solution was concentrated and poured through a pad of silica gel with ethyl acetate to give 55 mg (77 percent) of the desired product as an orange solid.

mp 144-145 ° C ^{ς Η} NMR (CD3OD / CDCl3): δ 8.65 (d, 1H, J = 10.0 Hz), 7.58 (d, 1H, J = 10.0 Hz), 7 47 (d, 1H, J = 1.25Hz), 7.26 (m, 4H), 7.10 (m, 1H).

Example 10

Preparation of N- (4-nitro-2- (phenylsulfonylamino) phenyl) -N'-phenylurea

a) Preparation of 4-nitro-2- (phenylsulfonylamino) aniline

To a solution of 1.53 grams (10.0 millimoles) of 4-nitro-1,2-phenylenediamine in dimethylformamide (DMF) was added

1.76 g (10.0 mmol) of sulfonyl chloride and 1.01 g of triethylamine in dimethylformamide (DMF) were allowed to react at 23 ° C for 12 hours. The mixture was partitioned between saturated ammonium chloride solution and dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The solid obtained was recrystallized from ethanol to give 0.275 g (9 percent) of product.

¹ H NMR (DMSO) 9.5 (s, 1H, br), 7.83 (dd, 1H, J = 10Hz, 2Hz), 7.74 (d, 2H, J = 8Hz), 7, 76 (t, 1H, J = 8Hz), 7.56 (t, 2H,

J = 8Hz), 7.55 (d, 1H, J = 2Hz), 6.79 (d, 1H, 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) -4'-phenylurea was prepared from 82 mg of 4-nitro-2- (phenylsulfonylamino) aniline and 33 mg of phenylisocyanate by general procedure A. The reaction mixture was cooled and partitioned between saturated ammonium chloride solution and dichloromethane / methanol (9: 1). The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The obtained residue was purified by column chromatography (eluting with ethyl acetate / hexane) to give 30.8 mg (26 percent) of the desired product.

EI-MS m / z 413 (M + H) &lt; + & gt ^; .

Example 11

Preparation of N- (2-hydroxy-5-nitrophenyl) -N '- (3-methoxy-2-thienyl) urea

a) Preparation of 3-methoxy-2-thienylcarboxylic acid

To a solution of 4.81 g (42.1 mmol) of 3-methoxythiophene in 20 mL of ether was added 17 mL (47.6 mmol) of butyllithium at -78 ° C. The reaction mixture was stirred at -78 ° C for 1 hour, allowed to warm to 0 ° C and stirred at this temperature for 3 hours. The reaction mixture was then recooled to -78 ° C, poured into a beaker filled with 14.5 grams of crushed dry ice and allowed to stand until the excess dry ice had fully sublimated. The reaction mixture was then poured into a mixture of 10 grams of ice to which 24 ml of concentrated hydrochloric acid had been added. The product was purified by precipitation from • 9 9 99

9 9 9 ·

999.9999 999.9999 ether and filtered to give 6.42 g (96 percent) of product.

EI-MS m / z 159 (M + H) &lt; + & gt ^; .

b) Preparation of N- (2-hydroxy-5-nitrophenyl) -N '- (3-methoxy-2-thienyl) urea

To a solution of 200 mg (1.27 mmol) of acid

3-methoxy-2-thiophenecarboxylic acid in benzene was added

0.33 milliliters (PhO) _{2 of} PON ₃ , 195.7 milligrams (1.27 millimoles) of 2-amino-4-nitrophenol and 0.25 milliliters (1.1 equivalents) of triethylamine. The reaction mixture was stirred overnight at boiling point and then partitioned 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 anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Chromatography of the obtained solid on silica gel (eluting with hexane / ethyl acetate (1: 1)) afforded 160 mg (41 percent) of a solid.

mp 172.6-173.0 ° C;

¹ H NMR (CD ₃ OD / CDCl ₃ ): δ 8.96 (d, 1H, J = 2.5 Hz), 7.74 (dd, 1H,

J = 5.0 Hz and J = 1.25 Hz), 6.82 (d, 1H, J = 7.5 Hz), 6.76 (s, 2H), 3.80 (s, 3H);

EI-MS m / z 309 (M + H) &lt; + & gt ^; .

Anal. (C ₁₂ HuN ₃ O ₅ S) C, Η, N.

100 • · ♦ ·

Example 12

Preparation of N- (2-hydroxy-4-nitrophenyl) -N '- (3-methoxy-2-thienyl) urea

To a solution of 200 mg (1.27 mmol) of 3-methoxy-2-thiophenecarboxylic acid prepared in Example 11a in toluene was added 0.33 ml (PhO) ₂ PON ₃ and 0.25 ml (1.1 equivalents) triethylamine. The reaction mixture was stirred at 70 ° C for 2 hours and cooled to room temperature. Then 2-amino-5-nitrophenol was added to the mixture. The reaction mixture was stirred overnight at 70 ° C and then partitioned 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 anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Chromatography of the obtained solid on silica gel (eluting with hexane / ethyl acetate (1: 1)) afforded 190 mg (48 percent) of a solid.

¹ H NMR (CD 3 OD / CDCl 3): δ 8.38 (d, 1H, J = 5.0 Hz), 7.85 (dd, 1H,

J = 5.0 Hz and J = 1.25 Hz), 7.76 (d, 1H, J = 2.5 Hz), 6.9 (s, 2H), 3.95 (s, 3H);

EI-MS m / z 309 (M + H) &lt; + & gt ^; .

Anal. (C ₁₂ H _U N ₃ O ₅ S) C, Η, N.

101 • · ·

Example 13

Preparation of N- (2-hydroxy-4-nitro phenyl) -1 '- (3-methoxyphenyl) urea

N- (2-Hydroxy-4-nitrophenyl) -N '- (3-methoxyphenyl) urea was prepared from 154 mg (1.0 mmol) of 2-hydroxy-4-nitroaniline and 1.0 mmol of 3-methoxyphenylisocyanate according to the general procedure B. Product was purified by dissolving in dichloromethane and precipitating with hexane. Filtration gave 140 mg (46 percent) of the desired product.

EI-MS m / z 302 (MH +).

Example 14

Preparation of N- (2-hydroxy-4-nitrophenyl) -1 '- (2-methoxyphenyl) urea

N- (2-Hydroxy-4-nitrophenyl) -4 '- (2-methoxyphenyl) urea was prepared from 154 mg (1.0 mmol) of 2-hydroxy-4-nitroaniline and 1.0 mmol of 2-methoxyphenylisocyanate according to the general procedure B. Product was purified by dissolving in dichloromethane and precipitating with hexane. Filtration gave 82 mg (27 percent) of the desired product.

EI-MS m / z 302 (M-H) &lt; - &gt;.

Example 15

Preparation of N- (2-hydroxy-4-nitrophenyl) -N '- (3-trifluoromethylphenyl) urea

102

N- (2-Hydroxy-4-nitrophenyl) -4 '- (3-trifluoromethylphenyl) urea was prepared from 154 mg (1.0 mmol) of 2-hydroxy-4-nitroaniline and 1.0 mmol of 3-trifluoromethylphenylisocyanate by general procedure B The product was purified by dissolving in dichloromethane and precipitating with hexane. Filtration yielded 180 mg (52 percent) of the desired product. EI-MS m / z 342 (M + H) &lt; + & gt ^; .

Example 16

Preparation of N- (2-hydroxy-4-nitrophenyl) -N '- (2-trifluoromethylphenyl) urea

N- (2-Hydroxy-4-nitrophenyl) -N '- (2-trifluoromethylphenyl) urea was prepared from 154 mg (1.0 mmol) of 2-hydroxy-4-nitroaniline and 1.0 mmol of 2-trifluoromethylphenylisocyanate according to the general procedure B. Product was purified by dissolving in dichloromethane and precipitating with hexane. Filtration yielded 180 mg (52 percent) of the desired product. EI-MS m / z 342 (M + H) &lt; + & gt ^; .

Example 17

Preparation of N- (2-hydroxy-4-nitrophenyl) -N'- (4-trifluoromethylphenyl) urea

N- (2-Hydroxy-4-nitrophenyl) -4 '- (4-trifluoromethylphenyl) urea was prepared from 154 mg (1.0 mmol) of 2-hydroxy-4-nitroaniline and 1.0 mmol of 4-trifluoromethylphenylisocyanate by general procedure B The product has been purified

103 by dissolution in dichloromethane and precipitation with hexane. Filtration gave 111 mg (32 percent) of the desired product. EI-MS m / z 340 (MH).

Example 18

Preparation of N- (2-hydroxy-4-nitrophenyl) -1 '- (2-bromophenyl) urea

N- (2-Hydroxy-4-nitrophenyl) -4 '- (2-bromophenyl) urea was prepared from 500 mg (3.24 mmol) of 2-hydroxy-4-nitroaniline and 3.24 mmol of 2-bromophenylisocyanate according to the general procedure B. Product was purified by dissolving in dichloromethane and precipitating with hexane. Filtration gave 530 mg (47 percent) of the desired product.

EI-MS m / z 350 (M-H) &lt; - &gt;.

Example 19

Preparation of N- (2-hydroxy-4-nitrophenyl) -N '- (3-bromophenyl) urea

N- (2-Hydroxy-4-nitrophenyl) -N '- (3-bromophenyl) urea was prepared from 500 mg (3.24 mmol) of 2-hydroxy-4-nitroaniline and 3.24 mmol of 3-bromophenylisocyanate by the general procedure B. Product was purified by dissolving in dichloromethane and precipitating with hexane. Filtration gave 0.96 g (87 percent) of the desired product.

EI-MS m / z 350 (MH +).

104

Example 20

Preparation of N- (2-hydroxy-4-nitro phenyl) -N'- (4-bromophenyl) urea

N- (2-Hydroxy-4-nitrophenyl) -4 '- (4-bromophenyl) urea was prepared from 500 mg (3.24 mmol) of 2-hydroxy-4-nitroaniline and 3.24 mmol of 4-bromophenylisocyanate by the general procedure B. The product was purified by dissolution in dichloromethane and precipitation with hexane. Filtration gave 0.41 g (37 percent) of the desired product.

EI-MS m / z 352 (M + H) &lt; + & gt ^; .

Example 21

Preparation of N- (2-hydroxy-4-nitrophenyl) -N '- (2-phenylphenyl) urea

N- (2-Hydroxy-4-nitrophenyl) -4 '- (2-phenylphenyl) urea was prepared from 500 mg (3.24 mmol) of 2-hydroxy-4-nitroaniline and 3.24 mmol of 2-phenylphenylisocyanate according to the general procedure B. Product was purified by dissolving in dichloromethane and precipitating with hexane. Filtration gave 0.22 g (19 percent) of the desired product.

EI-MS m / z 350 (M + H) &lt; + & gt ^; .

Example 22

Preparation of N- (2-hydroxy-4-nitrophenyl) -1 '- (1-naphthyl) urea

N- (2-Hydroxy-4-nitrophenyl) -1 '- (1-naphthyl) urea was prepared from 500 mg (3.24 millimoles) of 2-hydroxy-4-nitroaniline and 3.24 millimoles of 1-naphthylisocyanate

105 by the procedure B. The product was precipitated from dichloromethane and filtered off. The solid obtained was triturated with triethylamine / dichloromethane (1: 3). The filtrate was concentrated in vacuo and the residue dissolved in dichloromethane and then triturated with normal hydrochloric acid. The desired product precipitated out of solution and filtered to give 0.11 g (10 percent) of product.

EI-MS m / z 324 (M + H) &lt; + & gt ^; .

Example 23

Preparation of N- (2-hydroxy-4-nitrophenyl) -1 '- (2-nitrophenyl) urea

N- (2-Hydroxy-4-nitrophenyl) -4- (2-nitrophenyl) urea was prepared from 500 mg (3.24 millimoles) of 2-hydroxy-4-nitroaniline and 3.24 millimoles of 2-nitrophenylisocyanate according to the general procedure B. Product was purified by dissolving in dichloromethane and precipitating with hexane. Filtration gave 0.44 g (44 percent) of the desired product.

EI-MS m / z 319 (M + H) &lt; + & gt ^; .

Example 24

Preparation of N- (2-hydroxy-4-nitrophenyl) -N '- (2-fluorophenyl) urea

N- (2-Hydroxy-4-nitrophenyl) -4 '- (2-fluorophenyl) urea was prepared from 500 mg (3.24 mmol) of 2-hydroxy-4-nitroaniline and 3.24 mmol of 2-fluorophenylisocyanate by the general procedure B. Product was purified by dissolving in dichloromethane and precipitating with hexane. Filtration gave 0.59 g (31 percent) of the desired product.

106

EI-MS m / z 292 (M + H) &lt; + & gt ^; .

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 from 500 mg (3.24 mmol) of 2-hydroxy-4-nitroaniline and 3.24 mmol of 2,6-difluorophenyl isocyanate in general The product was purified by dissolving in dichloromethane and precipitating with hexane. Filtration gave 0.91 g (91 percent) of the desired product.

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) -4 '- (2-ethoxyphenyl) urea was prepared from 500 mg (3.24 mmol) of 2-hydroxy-4-nitroaniline and 3.24 mmol of 2-ethoxyphenylisocyanate according to the general procedure B. The product was purified by dissolution in dichloromethane and precipitation with hexane. Filtration gave 0.84 g (81 percent) of the desired product.

EI-MS m / z 318 (M + H) &lt; + & gt ^; .

107 • 9 «

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 500 mg (3.24 mmol) of 2-hydroxy-4-nitroaniline and 3.24 mmol of 2-ethylphenylisocyanate by the general procedure B. Product was purified by dissolving in dichloromethane and precipitating with hexane. Filtration gave 0.44 g (43 percent) of the desired product.

EI-MS m / z 302 (M + H) &lt; + & gt ^; .

Example 28

Preparation of N- (2-hydroxy-4-nitrophenyl) -1 '- (2-trifluoromethoxyphenyl) urea

N- (2-Hydroxy-4-nitrophenyl) -N '- (2-trifluoromethoxyphenyl) urea was prepared from 500 mg (3.24 mmol) of 2-hydroxy-4-nitroaniline and 3.24 mmol of 2-trifluoromethoxyphenyl isocyanate by general procedure B The product was purified by dissolving in dichloromethane and precipitating with hexane. Filtration gave 0.69 g (60 percent) of the desired product. EI-MS m / z 358 (M + H) &lt; + & gt ^; .

108

9 99 9 • * ·· 9 9 9 9 9 · 9 • 9 9 9 · 9 · φ 9 9 • 9 ·

Example 29

Synthesis of N- (2-hydroxy-4-nitrophenyl) -N '- (2-methylthiophenyl) urea

The urea derivative was prepared from 500 mg (3.24 mmol) of 2-hydroxy-4-nitroaniline and 3.24 mmol of 2-methylthiophenyl isocyanate according to the general procedure B. The product was purified by dissolution in dichloromethane and precipitation with hexane. Filtration gave 0.63 g (61 percent) of the desired product.

EI-MS m / z 320 (M + H) &lt; + & gt ^; .

Example 30

Synthesis of N- (2-hydroxy-4-nitrophenyl) -N '- (2-chloro-6-methylphenyl) urea

The urea derivative was prepared from 500 mg (3.24 mmol) of 2-hydroxy-4-nitroaniline and 2-chloro-6-methylphenylisocyanate according to the general procedure B. The product was purified by dissolving in dichloromethane and precipitating with hexane. Filtration gave 0.31 g (29 percent) of the desired product.

EI-MS m / z 322 (M + H) &lt; + & gt ^; .

109 • 4

Example 31

Synthesis of N- (2-hydroxy-4-nitrophenyl) -N '- (2-methylsulfoxyphenyl) urea

The urea derivative was prepared by reacting 100 milligrams of N- (2-hydroxy-4-nitrophenyl) -N '- (2-methylthiophenyl) urea (prepared in Example 29) with 100 milligrams of sodium perorate in a target mixture. button / water at 23 ° C for 12 hours. The product precipitated from the reaction mixture and was 30 mg (29 percent).

EI-MS m / z 336 (M + H) &lt; + & gt ^; .

Example 32

Synthesis of N- (2-hydroxy-4-trifluoromethylphenyl) -1 '- (2-bromophenyl) urea

The urea derivative was prepared from 0.171 g (1 mmol) of 2-hydroxy-4-trifluoromethylaniline (prepared in Example 7a) and 1 mmol of 2-bromophenylisocyanate according to general procedure B. The product was purified by dissolving in dichloromethane and precipitating with hexane. Filtration gave 0.25 g (54 percent) of the desired product.

EI-MS m / z 375 (M + H) &lt; + & gt ^; .

110

··

Example 33

Synthesis of N- (2-hydroxy-4-carbomethoxyphenyl) -N '- (2-bromophenyl) urea

The urea derivative was prepared from 0.167 g (1 mmol) of 2-hydroxy-4-carbomethoxyaniline and 1 mmol of 2-bromophenylisocyanate according to general procedure B. The product was purified by dissolving in dichloromethane and precipitating with hexane. Filtration gave 0.12 g (33 percent) of the desired product.

EI-MS m / z 363 (M-H) &lt; - &gt;.

Example 34

Synthesis of N- (2-hydroxy-4-trifluoromethylphenyl) -N '- (2-phenylphenyl) urea

The urea derivative was prepared from 0.171 grams (1 millimole) of 2-hydroxy-4-trifluoromethylaniline (prepared in Example 7a) of 2-phenylphenyl isocyanate according to the general procedure B.

The product was purified by dissolution in dichloromethane and precipitation with hexane. Filtration gave 0.24 g (64 percent) of the desired product.

EI-MS m / z 373 (M + H) &lt; + & gt ^; .

111

Example 35

Synthesis of N- (2-hydroxy-4-carbomethoxyphenyl) -N '- (2-phenylphenyl) urea

The urea derivative was prepared from 0.167 g (1 mmol) of 2-hydroxy-4-carbomethoxyaniline and 1 mmol of 2-phenylphenylisocyanate according to general procedure B. The product was purified by dissolving in dichloromethane and precipitating with hexane. Filtration gave 0.185 g (50 percent) of the desired product.

EI-MS m / z 363 (M-H) &lt; - &gt;.

Example 36

Synthesis of N- (2-hydroxy-4-nitrophenyl) -N '- (2,3-dichlorophenyl) urea

The urea derivative was prepared from 308 mg (2 millimoles) of 2-hydroxy-4-nitroaniline and 2 millimoles of 2,3-dichlorophenyl isocyanate according to the general procedure B. The product was purified by dissolving in dichloromethane and precipitating with hexane. Filtration gave 0.5 g (73 percent) of the desired product.

EI-MS m / z 342 (M + H) &lt; + & gt ^; .

112

Example 37

Synthesis of N- (2-hydroxy-4-nitrophenyl) -N '- (2,4-dichlorophenyl) urea

The urea derivative was prepared from 308 mg (2 millimoles) of 2-hydroxy-4-nitroaniline and 2 millimoles of 2,4-dichlorophenyl isocyanate according to the general procedure B. The product was purified by dissolving in dichloromethane and precipitating with hexane. Filtration gave 0.26 g (38 percent) of the desired product.

EI-MS m / z 342 (M + H) &lt; + & gt ^; .

Example 38

Synthesis of N- (2-hydroxy-4-nitrophenyl) -1 '- (2-chlorophenyl) urea

The urea derivative was prepared from 308 mg (2 millimoles) of 2-hydroxy-4-nitroaniline and 2 millimoles of 2-chlorophenyl isocyanate according to general procedure B. The product was purified by dissolving in dichloromethane and precipitating with hexane. Filtration gave 0.29 g (47 percent) of the desired product.

EI-MS m / z 308 (M + H) &lt; + & gt ^; .

113

Example 39

• · · • fc

Synthesis of N- (2-hydroxy-4-nitrophenyl)-) '- (2,4-dibromophenyl) urea

The urea derivative was prepared from 308 mg (2 millimoles) of 2-hydroxy-4-nitroaniline and 2 millimoles of 2,4-dibromophenyl isocyanate according to the general procedure B. The product was purified by dissolving in dichloromethane and precipitating with hexane. Filtration gave 0.34 g (39 percent) of the desired product.

EI-MS m / z 430 (M + H) &lt; + & gt ^; .

Example 40

Synthesis of N- (2-hydroxynaphthyl) -N '- (2-bromophenyl) urea

The urea derivative was prepared from 195 mg (1 mmol) of 1-amino-2-hydroxynaphthalene and 1 mmol of 2-bromophenylisocyanate according to the general procedure B. The product was purified by dissolution in dichloromethane and precipitation with hexane. Filtration gave 0.030 g (8 percent) of the desired product.

EI-MS m / z 357 (M + H) &lt; + & gt ^; .

··

114 • ·· f · fc ·

Example 41

Synthesis of N- (2-hydroxy-4-nitro phenyl) -N '- (2,3-methylenedioxyphenyl) urea

a) Preparation of 2,3-methylenedioxyphenylcarboxylic acid

To a solution of 3.09 g (32 mmol) of 1,3-benzodioxole in 50 mL of dry ether was added dropwise at -10 ° C 15 mL of n-butyllithium in hexane (2.5 molar, 35 mmol). After all the butyllithium was added, the mixture was stirred at reflux for one hour, cooled to room temperature, and then crushed solid carbon dioxide was added to the reaction mixture. After 24 hours, a 10% aqueous sodium bicarbonate solution and ether were added to the remainder of the reaction mixture. The alkaline layer was separated, washed with ether, acidified with cold concentrated hydrochloric acid and extracted with chloroform. The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give 1.1 g (20 percent) of the desired product. EI-MS m / z 167 (M + H) &lt; + & gt ^; .

b) Preparation of N- (2-hydroxy-4-nitrophenyl) -N '- (2,3-methylenedioxyphenyl) urea

To a solution of 2,3-methylenedioxyphenylcarboxylic acid in toluene was added 0.27 mL (1.95 mmol) of triethylamine and 0.32 mL (1.5 mmol) of diphenylphosphoryl azide (DPPA). The reaction mixture was stirred at 60 ° C for 2 hours and then 250 mg (1.5 mmol) of 2-amino-5-nitrophenol was added. The mixture was stirred at 100 ° C for 18 hours. After cooling the reaction

115.

a. At room temperature, the mixture was partitioned 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 anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Chromatography of the solid residue on silica gel (eluting with hexane-ethyl acetate (5: 1)) afforded 200 mg (42 percent) of the desired product.

EI-MS m / z 318 (M + H) &lt; - &gt;

Example 42

Synthesis of N- (2-hydroxy-4-nitrophenyl) -N '- (2-methoxy-3-chlorophenyl) urea

The urea derivative was prepared from 308 mg (2 millimoles) of 2-hydroxy-4-nitroaniline and 2 millimoles of 2-chloro-3-methoxyphenyl isocyanate according to general procedure B. The product was purified by dissolving in dichloromethane and precipitating with hexane. Filtration gave 0.48 g (63 percent) of the desired product.

EI-MS m / z 338 (M + H) &lt; + & gt ^; .

Example 43

Synthesis of N- (2-hydroxy-4-nitrophenyl) -1 '- (2-methylphenyl) urea

The urea derivative was prepared from 308 mg (2 millimoles) of 2-hydroxy-4-nitroaniline and 2 millimoles of 2-methylphenylisocyanate according to general procedure B. The product was purified by dissolving in dichloromethane and precipitating with hexane.

Φ · ··

Φ · Φ φ · ·>

• Φ Φ | · · »Φ

116 • Φ • »fr • Φ • • Φ

Φ Φ

) · · Μ • 9) φ ♦ φ

Φ <

Φ '>

Φ ·

ΦΦ Φ · · ·

Filtration gave 0.38 g (53 percent) of the desired product.

EI-MS m / z 288 (M + H) &lt; + & gt ^; .

Example 44

Synthesis of N- (bis- (2-hydroxy-4-nitrophenyl) -N '- (dianisdin) dimurea

The urea derivative was prepared from 616 milligrams (4 millimoles) of 2-hydroxy-4-nitroaniline and 2 millimoles of dianidine diisocyanate according to general procedure B (except that equivalents 2 were used instead of 1 equivalent of 4-nitro-2-hydroxyaniline). The product was purified by dissolution in dichloromethane and precipitation with hexane. Filtration gave 0.08 g (6 percent) of the desired product.

EI-MS m / z 605 (M + H) &lt; + & gt ^; .

Example 45

Synthesis of 4-methylene bis- (N- (2-chlorophenyl) -N '- (2-hydroxy-4-nitrophenyl) urea)

The urea derivative was prepared from 616 milligrams (4 millimoles) of 2-hydroxy-4-nitroaniline and 2 millimoles of 4-methylenebis (N- (2-chlorophenyl) diisocyanate) by general procedure B (except that instead of 1 equivalent of 4- nitro-2-hydroxyaniline was used with equivalents 2. The product was purified by dissolving in dichloromethane and precipitating with hexane to give 0.10 g (8 percent) of the desired product.

9

S 9 • ·

117

EI-MS m / z 627 (M + H) &lt; + & gt ^; .

Example 46

Synthesis of N- [2-hydroxy-4- (benzylamino) carbonylphenyl] -N'- (2-bromophenyl) urea

a) Synthesis of N- (2-hydroxy-4-carboxylate phenyl) -4 '- (2-bromophenyl) urea

The urea derivative was prepared from 3.69 g (24 mmol) of 3-hydroxy-4-aminobenzoic acid and 24 mmol of 2-bromophenyl diisocyanate according to the general procedure B. The product was purified by dissolution in dichloromethane and precipitation with hexane. Filtration gave 4.0 grams (48 percent) of the desired product.

EI-MS m / z 351 (M + H) &lt; + & gt ^; .

b) Preparation of N- [4- (benzylamino) carbonyl-2-hydroxyphenyl] -N '- (2-bromophenyl) urea

To a solution of 200 mg (0.58 mmol) of N- (2-hydroxy-4-carboxylate phenyl) -N '- (2-bromophenyl) urea in 15 mL of dimethylformamide (DMF) was added 121.9 mg (0.58 mmol) of EDC and 156.6 milligrams (11.6 millimoles) of HOBT. The reaction mixture was stirred at room temperature for 16 hours, then 123 mg (11.6 mmol) of benzylamine was added. The mixture was stirred at the same temperature for an additional 24 hours and then partitioned between water 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 anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Silica gel solid residue chromatography (s • »» »

A · · · · A · A · A · A ·

118 eluting with hexane / ethyl acetate (1: 1)) yielded 500 mg (65 percent) of the benzylamine product. EI-MS m / z 441 (M + H) &lt; + & gt ^; .

Example 47

Synthesis of N- (2-hydroxy-4-nitrophenyl) -N '- (2-phenoxyphenyl) urea

The urea derivative was prepared by reaction (2 millimoles) of 2-phenoxyphenylcarboxylic acid with 0.475 milliliters of diphenylphosphoryl azide and 0.14 milliliters of triethylamine in dimethylformamide (DMF) at 80 ° C. After 24 hours, 1 equivalent of 2-amino-5-nitrophenol was added to the reaction mixture. The mixture was heated at 80 ° C for an additional 24 hours and then the product was isolated in hexane as an oil, which was first dissolved in methanol and after adding water to this solution, 180 mg (24 percent) of the desired product precipitated.

EI-MS m / z 364 (M-H) &lt; - &gt;.

Example 48

Synthesis of N- (2-hydroxy-4-fluorophenyl) -N '- (2-bromophenyl) urea

a) Synthesis of 2-hydroxy-4-fluoroaniline

To 2 grams (11 millimoles) of 3-fluoro-6-nitrophenol was added 1 gram of 10% Pd / C at 23 ° C. The reaction mixture was purged with hydrogen, allowed to stir for 12 hours and filtered through celite. Concentration of the filtrate in vacuo afforded 1.4 g (77 percent) of product.

EI-MS m / z 169 (M + H) &lt; + & gt ^; .

• ·

119

b) Synthesis of N- (2-hydroxy-4-fluorophenyl) -Ν '- (2-bromophenyl) urea

The urea derivative was prepared from 254 mg (2 mmol) of 2-hydroxy-4-fluoroaniline and 2-bromophenylisocyanate according to the general procedure B. The product was purified by dissolving in dichloromethane and precipitating with hexane. Filtration gave 173 mg (26 percent) of the desired product.

EI-MS m / z 325 (M + H) &lt; + & gt ^; .

Example 49

Synthesis of N- (2-hydroxy-3,4-difluorophenyl) -N '- (2-bromophenyl) urea

a) Synthesis of 2-hydroxy-3,4-difluoroaniline

To 2 grams (11 millimoles) of 2,3-difluoro-6-nitrophenol was added 1 gram of 10% Pd / C at 23 ° C. The reaction mixture was purged with hydrogen, allowed to stir for 12 hours and filtered through celite. Concentration of the filtrate in vacuo afforded 1.6 g (97 percent) of the product.

EI-MS m / z 146 (M + H) &lt; + & gt ^; .

b) Synthesis of N- (2-hydroxy-3,4-difluorophenyl) -N'- (2-bromophenyl) urea

The urea derivative was prepared from 0.290 grams (2 millimoles) of 2-hydroxy-3,4-difluoroaniline and 0.4 grams of 2-bromophenyl isocyanate according to general procedure B. The product was purified by dissolving in dichloromethane and precipitating with hexane. Filtration gave 0.254 g (37 percent) of the desired product.

EI-MS m / z 343 (M + H) &lt; + & gt ^; .

• φ »

120

Example 50

Synthesis of N- (2-hydroxy-3-naphthyl) -N '- (2-bromophenyl) urea

The urea derivative was prepared from 0.320 grams (2 millimoles) of 3-amino-2-hydroxynaphthalene and 0.4 grams of 2-bromophenyl isocyanate according to general procedure B. The product was purified by dissolving in dichloromethane and precipitating with hexane. Filtration gave 0.339 g (47 percent) of the desired product EI-MS m / z 357 (M + H) ⁺ .

Example 51

Synthesis of N- (2-hydroxy-4-phenylphenyl) -N '- (2-bromophenyl) urea

a) Synthesis of 2-nitro-5-phenylphenol

To a solution of 2 grams (11 millimoles) of 3-phenylphenol in acetic acid, concentrated nitric acid was added dropwise until complete consumption of the starting compound. The solution was partitioned between water and dichloromethane. The organic phase was separated and the aqueous phase was washed once more with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (eluting with ethyl acetate / hexane) to give 1.2 g (50 percent) of the product.

¹ H NMR (CDCl ₃ ): δ 10.65 (s, 1H), 8.18 (d, 1H, J = 10.0 Hz),

7.65 (d, 2H, J = 6.0 Hz), 7.49 (m, 3H), 7.34 (s, 1H), 7.10 (d, 1H, J = 10.0 Hz).

120 • · «

b) Synthesis of 2-amino-5-phenylphenol

To a solution of 1.2 g (5.5 mmol) of 2-nitro-5-phenylphenol in methanol was added 1.2 g of 10% Pd / C. The reaction mixture was purged with hydrogen and allowed to stir overnight. The mixture was filtered through celite and the filtrate was concentrated in vacuo to give 1.01 g (98 percent) of the desired product.

EI-MS m / z 186 (M + H) &lt; + & gt ^; .

c) Synthesis of N- (2-hydroxy-4-phenylphenyl) -N ^'- (2-bromophenyl) urea

The urea derivative was prepared from 0.185 g (1 mmol) of 2-hydroxy-4-phenylaniline and 0.198 g of 2-bromophenylisocyanate according to the general procedure B. The product was purified by dissolving in dichloromethane and precipitating with hexane. Filtration yielded 215 mg (56 percent) of the desired product. EI-MS m / z 383 (M + H) &lt; + & gt ^; .

Example 52

Synthesis of N- (2-hydroxy-4-methylphenyl) -1 '- (2-bromophenyl) urea

The urea derivative was prepared from 0.274 g (2 mmol) of 2-hydroxy-4-methylaniline and 0.40 g (2 mmol) of 2-bromophenyl isocyanate according to the general procedure B. The product was purified by dissolving in dichloromethane and precipitating with hexane. Filtration gave 249 mg (39 percent) of the desired product.

EI-MS m / z 319 (MH).

122 • · *

·· ·

Example 53

Synthesis of N- (2-hydroxy-4-nitrophenyl) -N '- (2-phenylaminophenyl) urea

The urea derivative was prepared by reacting 0.419 grams (1.5 equivalents) of 2-tert. butyldimethylsilyloxy-4-nitrophenylisocyanate (prepared in Example 9a) with 0.184 g (1 equivalent) of 2-anilinoaniline in tetrahydrofuran (THF) at 40 ° C overnight. The desired product precipitated from the reaction mixture at 30 mg (8 percent). EI-MS m / z 365 (M + H) &lt; + & gt ^; .

Example 54

Synthesis of N- (2-hydroxy-3-carboxylate phenyl) -N '- (2-bromophenyl) urea

The urea derivative was prepared from 300 mg (2 mmol) of 2-hydroxy-3-aminobenzoic acid and 2-bromophenyl isocyanate according to the general procedure B. The product was purified by diluting dimethylformaldehyde (DMF) solution with dichloromethane and precipitating with hexane. Filtration gave 0.287 g (41 percent) of the desired product.

EI-MS m / z 351 (M + H) &lt; + & gt ^; .

123

Example 55

Synthesis of N- (2-sulfhydryl-4-bromophenyl) -N '- (2-bromophenyl) urea

a) Synthesis of 2-amino-6-bromothiazole

4.3 grams (25 millimoles, 1 equivalent) of 4-bromoaniline and 5.7 grams (3 equivalents) of ammonium thiocyanate were dissolved in acetic acid and 4 grams (1 equivalent) of bromine was added at room temperature. After complete disappearance of the starting material, the reaction mixture was poured into water and a solid was isolated, which was used in the next step without further purification.

EI-MS m / z 229 (M + H) &lt; + & gt ^; .

b) Synthesis of bis (3-bromo-6-aminophenyl) disulfide

To a solution of 500 milligrams (1.6 millimoles) of hydrobromide

2-Amino-6-bromothiazole in 5 ml of water was added 2.5 g of potassium hydroxide and the mixture was heated to reflux for 8 hours. The reaction mixture was then acidified to pH 4 with acetic acid and extracted with dichloromethane. The resulting dichloromethane mixture was concentrated in vacuo and the residue was dissolved in dimethylsulfoxide (DMSO). To the solution was added iodine, the mixture was stirred overnight at room temperature and then partitioned between dichloromethane and saturated sodium bicarbonate solution. The dichloromethane layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The obtained solid residue was purified by flash chromatography (eluting with ethyl acetate / hexane) to give 230 mg (34 percent) of the desired product.

EI-MS m / z 405 (M + H) &lt; + & gt ^; .

124

c) Synthesis of N- (2-sulfhydryl-4-bromophenyl) -N '- (2-bromophenyl) urea

To a solution of 201 mg (0.5 mmol) of (3-bromo-6-aminophenyl) disulfide in dimethylformamide (DMF) was added 1 mmol of 2-bromophenyl isocyanate and the mixture was allowed to react overnight at 80 ° C. The reaction mixture was then diluted with dichloromethane and a solid precipitated out of solution with hexane. The solution was diluted with methanol and NaBH ₄ was added. After gas evolution had ceased, the reaction mixture was carefully acidified with normal hydrochloric acid and the resulting solid was filtered off to give 52 mg (13 percent) of product.

EI-MS m / z 399 (MH).

Example 56

Synthesis of N- (2-hydroxy-4-nitrophenyl) -N '- (2-iphenyl) urea

The urea derivative was prepared by reacting 5 grams (20 millimoles) of 2-iodobenzoic acid with 1 equivalent of diphenylphosphoryl azide and 1 equivalent of triethylamine in dimethylformamide (DMF) at 80 ° C. After gas evolution had ceased, 3 grams (1 equivalent) of 5-nitro-2-aminophenol was added to the reaction mixture and heated to 80 ° C overnight. The reaction mixture was purified by filtration through celite, which was rinsed with dichloromethane. Subsequently, the desired product was precipitated from the reaction mixture with hexane. Filtration gave 1.08 g (13 percent) of product.

EI-MS m / z 398 (M-H) &lt; + &gt;.

125

Example 57

Synthesis of N- (2-hydroxy-4-nitrophenyl) -N '- (2-bromophenyl) thiourea

The thiourea derivative was prepared by reaction of 3.73 millimoles of 2-tert. butyldimethylsilyloxy-4-nitrophenylthioisocyanate (see Example 9a) with 2-bromoaniline, the reaction was heated in toluene at 88 ° C for 36 hours. The resulting solution was concentrated and the residue purified by flash chromatography (eluting with ethyl acetate / hexane). The fraction whose R _f was slightly less than the starting material R _f contained the desired product. This fraction was concentrated and then allowed to react at 23 ° C for 15 minutes with a solution of triethylamine hydrofluoride in acetonitrile. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography (eluting with ethyl acetate / hexanes) to give 52 mg (4 percent) of N- (2-hydroxy-4-nitrophenyl) -N '- (2- bromophenyl) thiourea.

EI-MS m / z 369 (M + H) &lt; + & gt ^; .

Example 58

Synthesis of N- (2-phenylsulfamido) -4-cyanophenyl-N '- (2-bromophenyl) urea

a) Synthesis of 3- (phenylsulfamido) benzonitrile

3- (Phenylsulfamido) benzonitrile was synthesized from

23.9 g (0.2 mol) of 3-cyanoaniline according to the general procedure C.

• 9 9

9

126

The product was purified by recrystallization from ethanol to yield 15.8 g (31 percent).

¹ H NMR (CDCl ₃ ): δ 7.95 (s, 1H), 7.84 (d, 2H, J = 8.0 Hz), 7.59 (t, 1H, J = 8.0 Hz), 7.45 (m, 2H); 7.35 (m, 4H).

b) Synthesis of 3- (phenylsulfamido) -4-nitrobenzonitrile grams (39 millimoles) of 3- (phenylsulfamido) benzonitrile was dissolved in acetic anhydride and concentrated nitric acid was added dropwise at room temperature until the starting material was consumed. The reaction mixture was then quenched by carefully pouring into sodium bicarbonate solution and allowed to stand until gas evolution. The reaction mixture was partitioned between dichloromethane and water. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo, absorbed onto silica gel and purified by column chromatography (eluting with dichloromethane / hexane) to give 1.7 g (15 percent) of product.

EI-MS m / z 302 (M + H) &lt; + & gt ^; .

c) Synthesis of 3- (phenylsulfamido) -4-aminobenzonitrile

1.5 g (4.9 millimoles) of 3- (phenylsulfamido) -4-nitrobenzonitrile was treated with stannous chloride dihydrate by heating to 80 ° C for 12 hours in ethanol. The mixture was concentrated and washed through a pad of silica gel, which was rinsed with 5% methanol in dichloromethane. The filtrate was absorbed onto silica gel and purified by column chromatography (eluting with dichloromethane / hexane) to give 0.9 g (60 percent) of product.

EI-MS m / z 274 (M + H) &lt; + & gt ^; .

127

d) Synthesis of N- (2-phenylsulfamido) -4-cyanophenyl-N '- (2-bromophenyl) urea

The urea derivative was prepared from 77 mg (0.28 mmol) of 2- (phenylsulfamido) -4-aminobenzonitrile and 2-bromophenyl isocyanate according to general procedure C. The product was purified by column chromatography (eluting with ethyl acetate / hexane) to give 30 mg. (22 percent) of the desired product.

EI-MS m / z 469 (M-H &lt; + &gt;).

Example 59

Synthesis of N- (2- (phenylsulfamido) phenyl) -N'- (2-bromophenyl) urea

a) Synthesis of 2- (phenylsulfamido) aniline

The sulfonamide was synthesized from 0.01 millimoles of phenylsulfonyl chloride and 1.08 grams (0.01 millimoles) of o-phenylenediamine according to general procedure C. The product was purified by recrystallization from ethanol to give 1.0 grams (40 percent).

EI-MS m / z 249 (M + H) &lt; + & gt ^; .

b) Synthesis of N- (2- (phenylsulfamido) phenyl) -N '- (2-bromophenyl) urea

The urea derivative was prepared from 1 millimole of 2- (phenylsulfamido) aniline and 2-bromophenyl isocyanate according to general procedure B. The product was purified by dissolving in dichloromethane and precipitating with hexane. Filtration gave 0.234 g (52 percent) of the desired product.

EI-MS m / z 446 (M + H) &lt; + & gt ^; .

• · · · · · · · · • * *

128

Example 60

Synthesis of N- (2- (styrylsulfamido) phenyl) -N- (2-bromophenyl) urea

a) Synthesis of 2- (styrylsulfamido) aniline

The sulfonamide was synthesized from 0.01 mole of styrylsulfonyl chloride and 0.01 mole of o-phenylenediamine according to general procedure C. The product was purified by recrystallization from ethanol to give 1.2 g (60 percent).

EI-MS m / z 199 (M + H) &lt; + & gt ^; .

b) Synthesis of N- (2- (styrylsulfamido) phenyl) -N '- (2-bromophenyl) urea

The urea derivative was prepared from 1 millimole of 2- (styrylsulfamido) aniline and 1 millimole of 2-bromophenylisocyanate according to the general procedure B. The product was purified by dissolving in dichloromethane and precipitating with hexane. Filtration gave 0.309 g (65 percent) of the desired product.

EI-MS m / z 472 (M + H) &lt; + & gt ^; .

Example 61

Synthesis of 2 - _[(3-f 4-dimethoxyphenyl) sulfonylamino] phenyl) -N '(2-bromophenyl) urea

a) Synthesis of 2 - [(3,4-dimethoxyphenyl) sulfonylamino] phenylaniline The sulfonamide was synthesized from 0.01 mol.

3,4-dimethoxyphenylsulfonyl chloride and o-phenylenediamine according to general procedure C. The product was purified by recrystallization from ethanol to give 0.65 g (21 percent).

EI-MS m / z 309 (M + H) &lt; + & gt ^; .

129

·· ··

• · · · · · ·

b) Synthesis of 2 - [(3,4-dimethoxyphenyl) sulfonylamino] phenyl) N '- (2-bromophenyl) urea

The urea derivative was prepared from 1 millimole of 2 - [(3,4-dimethoxyphenyl) sulfonylamino] phenylaniline and 2-bromophenyl isocyanate by the general procedure B. The product was purified by dissolving in dichloromethane and precipitating with hexane. Filtration gave 0.062 g (12 percent) of the desired product.

EI-MS m / z 504 (M-H) &lt; + &gt;.

Example 62

Synthesis of N- (2 - [(4-acetamidophenyl) sulfonylamino] phenyl) N '- (2-bromophenyl) urea

a) Synthesis of 2 - [(4-acetamidophenyl) sulfonylamino] phenylaniline

The sulfonamide was synthesized from 0.01 mol

4-acetamidophenylsulfonyl chloride and 0.01 mole of o-phenylenediamine according to general procedure C. The product was purified by recrystallization from ethanol to give 1.27 g (40 percent).

EI-MS m / z 304 (MH +).

b) Synthesis of N- (2 - [(4-acetamidophenylsulfonyl) amino] phenyl) N '- (2-bromophenyl) urea

The urea derivative was prepared from 1 millimole of 2 - [(4-acetamidophenyl) sulfonylamino] phenylaniline and 1 millimole of 2-bromophenylisocyanate according to general procedure B. The product was purified by dissolving in dichloromethane and precipitating with hexane. Filtration gave 0.12 g (24 percent) of the desired product.

EI-MS m / z 501 (MH).

··

130

Example 63

Synthesis of N- (2- (2-thiophenesulfamidophenyl) -1 '- (2-bromophenyl) urea

a) Synthesis of 2- (2-thiophenesulfamido) aniline

The sulfonamide was synthesized from 0.01 mol

2-thiophenesulfonyl chloride and 0.01 mole of o-phenylenediamine according to general procedure C. The product was purified by recrystallization from ethanol to give 0.77 g (30 percent).

EI-MS m / z 255 (M + H) &lt; + & gt ^; .

b) Synthesis of N- (2- (2-thiophenesulfonylaminophenyl) -N '- (2-bromophenyl) urea

The urea derivative was prepared from 1 millimole of 2- (2-thiophenesulfonylamino) aniline and 1 millimole of 2-bromophenylisocyanate according to general procedure B. The product was purified by dissolving in dichloromethane and precipitating with hexane. Filtration gave 0.29 g (64 percent) of the desired product. EI-MS m / z 450 (M-H) &lt; - &gt;.

Example 64

Synthesis of N- (2- (3-tolylsulfonylaminophenyl) -N '- (2-bromophenyl) urea

a) Synthesis of 2- (3-tolylsulfonylamino) aniline

The sulfonamide was synthesized from 0.01 mol

3-tolylsulfonyl chloride and 0.01 mole of o-phenylenediamine according to general procedure C. The product was purified by recrystallization from ethanol to give 0.73 g (28 percent).

131

β 44 • ·· 44 4 4 4 * 44 4 4 4 4 4 4 4 • 4 4 4 4 4 4 4 4 4 4 4 4 44 4 4 4 4

EI-MS m / z 263 (M + H) &lt; + & gt ^; .

b) Synthesis of N- (2 - ((3-tolylsulfonylamino) phenyl) -N '- (2-bromophenyl) urea

The urea derivative was prepared from 1 millimole of 2- (3-tolylsulfonylamino) aniline and 1 millimole of 2-bromophenylisocyanate according to the general procedure B. The product was purified by dissolving in dichloromethane and precipitating with hexane. The product was recrystallized twice from ethanol to give 25 mg (5 percent) of the desired product.

EI-MS m / z 458 (M-H) &lt; - &gt;.

Example 65

Synthesis of N- (2- (8-quinolinylsulfonylamino) phenyl) -N '- (2-bromophenyl) urea

a) Synthesis of 2- (8-quinolinylsulfonylamino) aniline

The sulfonamide was synthesized from 0.01 mol

8-quinolinylsulfonyl chloride and 0.01 mole of o-phenylenediamine according to general procedure C. The product was purified by recrystallization from ethanol to give 0.82 g (27 percent).

EI-MS m / z 300 (M + H) &lt; + & gt ^; .

b) Synthesis of N- (2 - ((8-quinolinyl) sulfonylamino) phenyl) -N- (2-bromophenyl) urea

The urea derivative was prepared from 1 millimole of 2 - ((8-quinolinyl) sulfonylamino) aniline and 1 millimole of 2-bromophenylisocyanate according to the general procedure B. The product was purified

132 44 by dissolving in dichloromethane and precipitating with hexane. Filtration gave 0.23 g (46 percent) of the desired product. EI-MS m / z 495 (M-H &lt; + &gt;).

Example 66

Synthesis of N- (2- (benzylsulfonylamino) phenyl) -N '- (2-bromophenyl) urea

a) Synthesis of 2- (benzylsulfonylamino) aniline

The sulfonamide was synthesized from 0.01 mole of benzylsulfonyl chloride and 0.01 mole of o-phenylenediamine according to general procedure C. The product was purified by recrystallization from ethanol to give 0.87 g (33 percent).

EI-MS m / z 263 (M + H) &lt; + & gt ^; .

b) Synthesis of N- (2- (benzylsulfonylamino) phenyl) -N '- (2-bromophenyl) urea

The urea derivative was prepared from 1 millimole of 2- (benzylsulfonylamino) aniline and 1 millimole of 2-bromophenylisocyanate according to the general procedure B. The product was purified by dissolution in dichloromethane and precipitation with hexane. Filtration gave 0.11 g (23 percent) of the desired product. EI-MS m / z 460 (M + H) &lt; + & gt ^; .

133

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 1.0 g of N- (2-hydroxy-4-nitrophenyl) -N '- (2-methoxyphenyl) urea (from Example 15) was added 100 mg of 10% Pd / C. The reaction mixture was hydrogenated under a hydrogen balloon pressure for 18 hours. The solid was filtered through celite and washed three times with methanol. The filtrate was concentrated under reduced pressure to give 0.8 g (89 percent) of the amine. EI-MS m / z 274 (M + H) &lt; + & gt ^; .

b) Synthesis of N- (2-hydroxy-4-azidophenyl) -N '- (2-methoxyphenyl) urea

To 300 mg (1.17 mmol) of N- (2-hydroxy-4-aminophenyl) -4 '- (2-methoxyphenyl) urea was added a mixture

1.17 ml HCl and 2.34 ml water and the reaction mixture was cooled to 0 ° C. To the reaction mixture was added 80.7 mg (1.17 mmol) of sodium nitrite, and the resulting mixture was stirred at 0 ° C for 30 minutes. Then, 76 mg (1.17 mmol) of sodium azide was added to the reaction mixture, which was allowed to warm to room temperature and stirred at this temperature for 18 hours. Subsequently, the reaction mixture was extracted three times with ethyl acetate. The organic extracts were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Chromatography of the solid obtained on silica gel (eluting with

134

hexane / ethyl acetate (5: 1)) yielded 125 mg (38 percent) of the desired product.

EI-MS m / z 300 (M + H) &lt; + & gt ^; .

Example 68

Preparation of N- [2-hydroxy-5-cyano phenyl] -N ^'- [2-bromophenyl] urea

a) Preparation of 2-amino-4-cyanophenol

To a solution of 10 grams (61 millimoles) of 2-nitro-4-cyanophenol in 250 mL of methanol was added 1 gram of 10% Pd / C. The mixture was purged with argon. Subsequently, hydrogen was bubbled through the solution for 10 minutes and the reaction mixture was left under hydrogen pressure over a hydrogen-filled balloon overnight. The mixture was filtered through celite, which was then rinsed with methanol. The filtrate was concentrated and chromatographed on silica gel (eluting with 5% methanol in dichloromethane) to give 8.0 g (97%) of the desired product.

¹ H NMR (CD ₃ OD): δ 6.96 (d, 1H), 6.90 (dd, 1H), 6.77 (d, 1H).

b) Preparation of N- [2-hydroxy-5-cyanophenyl] -N '- [2-bromophenyl] urea

N- [2-Hydroxy-5-cyanophenyl] -4 '- [2-bromophenyl] urea was prepared from 268 mg (2 mmol) of 2-amino-4-cyanophenol by general procedure B. The product was purified by precipitation from dichloromethane / hexane. (1:20). Filtration was obtained

540 mg (81 percent) of the desired product.

¹ H NMR (CD 3 OD): δ 8.10 (d, 1H), 7.87 (d, 1H), 7.43 (d, 1H),

7.20 (t, 1H), 7.09 (d, 1H), 6.86 (t, 1H), 6.77 (d, 1H).

• ·

135

Example 69

Preparation of N- [2-hydroxy-3-fluorophenyl] -N '- [2-bromophenyl] Urea

a) Preparation of 2-amino-3-fluorophenol

To a solution of 1 gram (6.4 millimoles) of 2-nitro-3-fluorophenol in 250 ml of methanol was added 1 gram of 10% Pd / C. The mixture was purged with argon. Subsequently, hydrogen was bubbled through the solution for 10 minutes and the reaction mixture was left under hydrogen pressure over a hydrogen-filled balloon overnight. The mixture was filtered through celite, which was then rinsed with methanol. The filtrate was concentrated and chromatographed on silica gel (eluting with 5% methanol in dichloromethane) to give 650 mg (80.2%) of the desired product.

¹ H NMR (CD ₃ OD): δ 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-bromophenyl] urea was prepared from 254 mg (2 millimoles) of 2-amino-4-fluorophenol by general procedure B. The product was purified by precipitation from: dichloromethane / hexane (1:20). Filtration was obtained

500 mg (77 percent) of the desired product.

^λ Η NMR (CD 3 OD): δ 8.05 (d, 1H), 7.50 (d, 1H), 7.26 (t, 1H),

7.18 (d, 1H), 6.92 (t, 1H), 6.86-6.68 (m, 2H).

136

Example 70

Preparation of N-2- [1-hydroxyfluorene] -N-N '- [2-bromophenyl] urea

a) Preparation of 2-amino-1-hydroxyfluorene

To a solution of 250 mg (1.23 mmol) of 1-hydroxy-2-nitrofluorene in 250 mL of methanol was added 1 gram of 10% Pd / C. The mixture was purged with argon. Subsequently, hydrogen was bubbled through the solution for 10 minutes and the reaction mixture was left under hydrogen pressure over a hydrogen-filled balloon overnight. The mixture was filtered through celite, which was then rinsed with methanol. The filtrate was concentrated and chromatographed on silica gel (eluting with 5% methanol in dichloromethane) to give 171 mg (81.2%) of the desired product.

⁴ H NMR (CD ₃ OD): δ 7.60 (d, 1H), 7.47 (d, 1H), 7.28 (t, 1H),

7.18 (m, 2H), 6.82 (d, 1H), 3.76 (s, 2H).

b) Preparation of N-2- [1-hydroxyfluorene] -1 '- [2-bromophenyl] urea

N-2- [1-Hydroxyfluorene] -4 '- [2-bromophenyl] urea was prepared from 170 mg (0.86 mmol) of 2-amino-1-hydroxyfluorene by General Procedure B. The product was purified by chromatography of the obtained solid on silica gel ( eluting with 30% ethyl acetate in hexane) to give 300 mg (84.5 percent) of the desired product.

NMR (CD ₃ Cl): 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, 1H).

137

Example 71

Preparation of N-3- [2-hydroxy-9,10-anthraquinonyl] -1 '- [2-bromophenyl] urea

N-3- [2-Hydroxy-9,10-anthraquinonyl] -4 '- [2-bromophenyl] urea was prepared from 480 mg (2 millimoles) of 2-hydroxy-3-aminoanthraquinone by general procedure B. The product was purified by precipitation from dichloromethane / hexane (1:20). Filtration yielded 610 mg (70 percent) of the desired product.

¹ H NMR (CD ₃ OD): δ 8.93 (s, 1H), 8.12 (m, 2H), 8.02 (d, 1H),

7.77 (m, 2H), 7.61 (d, 1H), 7.52 (s, 1H), 7.38 (t, 1H), 7.05 (t, 1H).

Example 72

Preparation of N- [2-hydroxy-3-fluoro-5-bromophenyl] -N '- [2-bromophenyl] urea

a) Preparation of 2-amino-6-fluoro-4-bromophenol

A mixture of 1 gram (4.2 millimoles) of 4-bromo-2-fluoro-6-nitrophenol a

4.78 grams (21.2 millimoles) of stannous chloride in 50 milliliters of ethanol were heated to 80 ° C under an argon atmosphere. After 2 hours the starting material disappeared, the solution was allowed to cool to room temperature and poured into ice. Before extraction with ethyl acetate, the pH of the resulting mixture was adjusted to slightly basic (7-8) by addition of solid sodium hydroxide. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, and filtered. Evaporation of the solvent and chromatography of the residue on silica gel (eluting with 4%

138

710 mg (82%) of the desired product was obtained.

¹ H NMR (CD ₃ OD): δ 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] -4 '- [2-bromophenyl] urea was prepared from 254 mg (2.00 mmol) of 2-amino-6-fluoro-4-bromophenol by general procedure B The product was purified by precipitation from dichloromethane / hexane (1:20) to give 500 mg (77 percent) of the desired product. ¹ H NMR (CD 3 OD): δ 7.98 (s, 1H), 7.91 (d, 1H), 7.60 (d, 1H),

7.33 (t, 1H), 7.00 (t, 1H), 6.94 (d, 1H).

Example 73

Preparation of N- [2-hydroxy-3-chlorophenyl] -N '- [2-bromophenyl] urea

a) Preparation of 2-amino-3-chlorophenol

A mixture of 250 mg (1.4 mmol) of 3-chloro-2-nitrophenol a

1.2 g (5.3 mmol) of stannous chloride in 50 ml of ethanol were heated to 80 ° C under an argon atmosphere. After 2 hours the starting material disappeared, the solution was allowed to cool to room temperature and poured into ice. Before extraction with ethyl acetate, the pH of the resulting mixture was adjusted to slightly basic (7-8) by addition of solid sodium hydroxide. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, and filtered. Evaporation of the solvent and chromatography of the residue on silica gel (eluting with 4%

(139% methanol in dichloromethane) gave 143 mg (69 percent) of the desired product.

NMR (CD ₃ OD): δ 6.75 (t, 1H), 6.70 (d, 1H), 6.65 (d, 1H).

b) Preparation of N- [2-hydroxy-3-chlorophenyl] -N '- [2-bromophenyl] urea

N- [2-Hydroxy-3-chlorophenyl] -4 '- [2-bromophenyl] urea was prepared from 143 mg (1.00 mmol) of 2-amino-3-chlorophenol by the general procedure B. The product was purified by chromatography of the solid obtained on silica gel. (eluting with 30 percent ethyl acetate in hexane) to yield 195 mg (57 percent) of the desired product.

NMR (CD 3 OD): δ 7.81 (d, 1H), 7.68 (d, 1H), 7.47 (d, 1H), 7.20 (t, 1H), 6.90 (m, 2H) 6.70 (t, 1H).

Example 74

Preparation of N- [2-hydroxy-3-trifluoromethylphenyl] -N '- [2-bromophenyl] urea

a) Preparation of 2-nitro-6-trifluoromethylphenol

3.00 g (18.5 mmol) of 2-trifluoromethylphenol was dissolved in 40 ml of dichloromethane and 1.73 g (20.4 mmol) of sodium nitrate was added. Then 23 milliliters of 3 molar sulfuric acid and a catalytic amount of sodium nitrite were added sequentially to the reaction mixture. The reaction mixture was allowed to stir for 24 hours, diluted with dichloromethane and extracted with water. The organic layer was dried over anhydrous magnesium sulfate and filtered. After evaporation of the solvent and chromatography of the residue obtained, the residue is chromatographed on

9 ··

140 silica gel (eluting with 4% methanol in dichloromethane) gave 1.84 g (47 percent) of the desired product.

¹ H NMR (CD 3 COCD 3): δ 8.35 (d, 1H), 7.95 (d, 1H), 7.13 (t, 1H).

b) Preparation of 2-amino-6-trifluoromethylphenol

A mixture of 1.84 g (8.67 mmol) of 6-trifluoro-2-nitrophenol, 6.0 g (26.2 mmol) of stannous chloride in 150 ml of ethanol was heated under argon at 80 ° C. After 2 hours the starting material disappeared, the solution was allowed to cool to room temperature and poured into ice. Before extraction with ethyl acetate, the pH of the resulting mixture was adjusted to slightly basic (7-8) by addition of solid sodium hydroxide. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, and filtered. Evaporation of the solvent and chromatography of the residue on silica gel (eluting with 4% ¹ methanol in dichloromethane) gave 1.35 g (88 percent) of the desired product.

NMR (CD 3 OD): δ 6.93 (d, 1H), 6.82 (t, 1H), 6.78 (d, 1H).

c) Preparation of N- [2-hydroxy-3-trifluoromethylphenyl] -1 '- [2-bromophenyl] urea

N- [2-Hydroxy-3-trifluoromethylphenyl] -4 '- [2-bromophenyl] urea was prepared from 280 mg (1.60 mmol) of 2-amino-6-trifluoromethylphenol by general procedure B. The product was purified by precipitation from dichloromethane hexane (1:20) and filtered to give 390 mg (65 percent) of the desired product.

¹ H NMR (CD 3 OD): δ 7.99 (d, 1H), 7.60 (d, 1H), 7.58 (d, 1H),

7.34 (t, 1H), 7.30 (d, 1H), 7.00 (t, 1H), 6.96 (d, 1H).

141

Example 75

Preparation of N- [3,4-diphenyl-2-hydroxyphenyl] -N '- [2-bromophenyl] urea

N- [3,4-Diphenyl-2-hydroxyphenyl] -4 '- [2-bromophenyl] urea was prepared from 50 mg (0.19 mmol) of 2-amino-5,6-diphenylphenol by general procedure B. The product was purified by precipitation from dichloromethane / hexane (1:20) and filtration to give 51 mg (69 percent) of the desired product.

¹ H NMR (CD ₃ OD): δ 7.97 (d, 1H), 7.66 (d, 1H), 7.58 (d, 1H),

7.31 (t, 1H); 7.25-7.00 (m, 11H); 6.91 (d, 1H).

Example 76

Preparation of N- [2-hydroxy-3-glycinomethyl-ester-carbonylphenyl] -N '[2-bromophenyl] urea

N- [2-Hydroxy-3-glycinomethyl-ester-carbonylphenyl] -Ν '[2-bromophenyl] urea was prepared from 50 milligrams (0.22 millimoles) of 6-glycinomethyl-ester-carbonyl-2-aminophenol obtained from the University of New Hampshire by a general procedure B. The product was purified by precipitation from dichloromethane / hexane (1:20) and filtered to give 65 mg (69 percent) of the desired product.

^{Χ Η} NMR (CD3OD): δ 8.14 (d, 1H), 7.96 (d, 1H), 7.49 (d, 1H)

7.24 (t, 2H), 6.89 (dd, 1H), 6.81 (t, 1H), 4.10 (s, 2H), 3.74 (s, 3H).

142 4 4

Example 77

Preparation of N- [2-hydroxy-3-glycinecarbonylphenyl] -N '- [2-bromophenyl] urea

N- [2-Hydroxy-3-glycinecarbonylphenyl] -N '- [2-bromophenyl] urea was prepared by mixing 50 milligrams (0.12 millimoles) of N- [2-hydroxy-3-glycinomethyl-ester-carbonylphenyl] -1' - [2-bromophenyl] urea in 10 ml methanol / water (3: 1). To this mixture was added 1 equivalent of lithium hydroxide and stirring was continued until the starting material disappeared. 45 mg (92 percent) of a solid was obtained, which was purified by silica gel chromatography (eluting with dichloromethane / methanol / acetone (9: 1: 0.1)) to give 195 mg (57 percent) of the desired product.

¹ H NMR (CD ₃ OD): δ 8.14 (d, 1H), 7.92 (d, 1H), 7.60 (d, 1H),

7.46 (d, 1H), 7.34 (t, 1H), 7.04 (t, 1H), 6.82 (t, 1H), 3.96 (2H).

Example 78

Preparation of N- [2-hydroxy-3,5-dichlorophenyl] -N '- [2-bromophenyl] urea

a) Preparation of 2-amino-4,6-dichlorophenol

A mixture of 1.0 g (4.8 millimoles) of 4,6-dichloro-2-nitrophenol and a

3.2 grams (14.4 millimoles) of stannous chloride in 50 ml of ethanol were heated under argon at 80 ° C. After 2 hours the starting material disappeared, the solution was allowed to cool to room temperature and poured into ice. The pH of the resulting mixture was adjusted by addition before extraction with ethyl acetate

143

9 9 9 solid sodium hydroxide to make it slightly alkaline (7-8). The organic phase was washed with brine, dried over anhydrous magnesium sulfate, and filtered. Evaporation of the solvent and chromatography of the residue on silica gel (eluting with 4% methanol in dichloromethane) gave 685 mg (80 percent) of the desired product.

NMR (CD ₃ OD): δ 6.75 (s, 1H), 6.61 (s, 1H).

b) Preparation of N- [2-hydroxy-3,5-dichlorophenyl] -1 '- [2-bromophenyl] urea

N- [2-Hydroxy-3,5-dichlorophenyl] -4 '- [2-bromophenyl] urea was prepared from 143 mg (1.00 mmol) of 2-amino-4,6-dichlorophenol by the general procedure B. The product was purified by precipitation from dichloromethane / hexane (1:20) and filtered to give 660 mg (88 percent) of the desired product.

¹ H NMR (CD ₃ OD): δ 7.96 (s, 1H), 7.89 (d, 1H), 7.60 (d, 1H),

7.35 (t, 1H); 7.00 (t, 1H); 6.95 (dd, 1H).

Example 79

Preparation of N- [2-hydroxy-3-nitrophenyl] -N '- [2-bromophenyl] urea

N- [2-Hydroxy-3-nitrophenyl] -4 '- [2-bromophenyl] urea was prepared from 1.25 grams (8.1 millimoles) of 2-hydroxy-3-nitroaniline by the general procedure B. The product was purified by precipitation from dichloromethane hexane (1:20) and filtered to give 2.4 g (84 percent) of the desired product.

9

9

144

¹ H NMR (CD ₃ OD): δ 8.45 (d, 1H), 7.94 (d, 1H), 7.78 (d, 1H),

7.60 (d, 1 H), 7.35 (t, 1 H), 7.01 (m, 2 H).

Example 80

Preparation of N- [2-hydroxy-4-naphthalenesulfonic acid] -N '- [2-bromophenyl] urea

N- [2-Hydroxy-4-naphthalenesulfonic acid] -4 '- [2-bromophenyl] urea was prepared from 0.48 grams (2.00 millimoles) of 1-amino-2-hydroxy-4-naphthalenesulfonic acid by general procedure B and adding 1 mL of triethylamine. The product was purified by precipitation from dichloromethane / hexane (1:20) and filtered to give 690 mg (79 percent) of the desired product.

¹ H NMR (CD 3 OD): δ 8.14 (s, 1H), 8.04 (d, 1H), 7.98 (m, 2H),

7.61-7.55 (m, 3H), 7.43 (t, 1H), 6.98 (t, 1H).

Example 81

Preparation of N- [2-hydroxy-5-naphthalenesulfonic acid]-] '- (2-bromophenyl) urea

N- [2-Hydroxy-5-naphthalenesulfonic acid] -4 '- [2-bromophenyl] urea was prepared from 0.48 grams (2.0 millimoles) of 2-amino-3-hydroxy-6-naphthalenesulfonic acid by general procedure B and adding 1 mL of tiethylamine. The product was purified by precipitation from dichloromethane / hexane (1:20) and filtered to give 715 mg (82 percent) of the desired product.

• 9 ··.

• · · ·

145

NMR (CD 3 OD): δ 8.09 (s, 1H), 7.96 (d, 1H), 7.65-7.48 (m, 3H), 7.36 (t, 1H), 7.25 ( s, 1H), 7.04 (m, 2H).

Example 82

Preparation of N- [2-hydroxy-3,4-dichlorophenyl] -N '- [2-bromophenyl] urea

a) Preparation of 2-nitro-5, β-dichlorophenol

3.26 grams (20 millimoles) of 2,3-dichlorophenol was dissolved in 40 milliliters of dichloromethane, and 1.88 grams (22 millimoles) of sodium nitrate was added. Then 20 milliliters of 3 molar sulfuric acid and a catalytic amount of sodium nitrite were added sequentially to the reaction mixture.

The reaction mixture was allowed to stir for 24 hours, diluted with dichloromethane and extracted with water. The organic layer was dried over anhydrous magnesium sulfate and filtered. Evaporation of the solvent and chromatography of the residue on silica gel (eluting with 4% methanol in dichloromethane) gave 1.8 g (44%) of the desired product.

^{Χ Η} NMR (CD3COCD3): δ 8.04 (d, 1H), 7.15 (d, 1H).

b) Preparation of 2-amino-5, β-dichlorophenol

A mixture of 1.8 grams (8.7 millimoles) of 5,6-dichloro-2-nitrophenol and 5.8 grams (26.1 millimoles) of tin (II) chloride in 50 ml of ethanol was heated under argon at 80 ° C. After 2 hours the starting material disappeared, the solution was allowed to cool to room temperature and poured into ice. The pH of the resulting mixture was adjusted by addition before extraction with ethyl acetate

146

solid sodium hydroxide until slightly alkaline (7-8). The organic phase was washed with brine, dried over anhydrous magnesium sulfate, and filtered. Evaporation of the solvent and chromatography of the residue on silica gel (eluting with 4% methanol in dichloromethane) gave 1.4 g (90 percent) of the desired product.

¹ H NMR (CD ₃ OD): δ 6.71 (d, 1H), 6.45 (d, 1H).

c) Preparation of N- [2-hydroxy-3,4-dichlorophenyl] -N '- [2-bromophenyl] urea

N- [2-Hydroxy-3,4-dichlorophenyl] -4 '- [2-bromophenyl] urea was prepared from 350 mg (2.00 mmol) of 2-amino-5,6-dichlorophenol by the general procedure B. The product was purified by precipitation from of dichloromethane / hexane (1:20) and filtration to give 670 mg (89 percent) of the desired product.

¹ H NMR (CD 3 OD): δ 7.90 (d, 1H), 7.85 (d, 1H), 7.59 (d, 1H),

7.31 (t, 1H), 6.99 (t, 1H), 6.96 (d, 1H).

Example 83

Preparation of N- [2-hydroxy-3-cyano phenyl] -N '- [2-bromophenyl] urea

a) Preparation of 2-nitro-6-cyanophenol

2.38 grams (20 millimoles) of 2-cyanophenol was dissolved in 40 milliliters of dichloromethane and 1.88 grams (22 millimoles) of sodium nitrate was added. Then 20 milliliters of 3 molar sulfuric acid and a catalytic amount of sodium nitrite were added sequentially to the reaction mixture. The reaction mixture was allowed to stir for 24 hours, diluted

147

♦ • «· • 4 9 · 44 4 4 • 4 • * 4 • 4 4 · • 4 4 4

4 with dichloromethane and extracted with water. The organic layer was dried over anhydrous magnesium sulfate and filtered. Evaporation of the solvent and chromatography of the residue on silica gel (eluting with 4% methanol in dichloromethane) gave 1.4 g (42%) of the desired product.

^{Τ Η} NMR (CD ₃ COCD _3): δ 8.47 (d, 1H), 8.15 (d, 1H), 7.30 (t, 1H).

b) Preparation of 2-amino-6-cyanophenol

A mixture of 600 mg (1.0 mmol) of 6-cyano-2-nitrophenol and 3.2 g (14.4 mmol) of stannous chloride in 50 ml of acetic acid was heated to 80 ° C under argon. After 2 hours the starting material disappeared, the solution was allowed to cool to room temperature and poured into ice. Before extraction with ethyl acetate, the pH of the resulting mixture was adjusted to slightly basic (7-8) by addition of solid sodium hydroxide. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, and filtered. Evaporation of the solvent and chromatography of the residue on silica gel (eluting with 4% methanol in dichloromethane) afforded

365 mg (75 percent) of the desired product.

¹ H NMR (CD ₃ OD): δ 6.92 (d, 1H), 6.85-6.69 (m, 2H).

c) Preparation of N- [2-hydroxy-3-cyanophenyl] -1 '- [2-bromophenyl] urea

N- [2-Hydroxy-3-cyanophenyl] -4 '- [2-bromophenyl] urea was prepared from 134 mg (1.0 mmol) of 2-amino-6-cyanophenol by General Procedure B. The product was purified by precipitation from dichloromethane / hexane. (1:20) a

148 «9 9 · 9 9 · 9 9 * * * 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 Filtration gave 260 mg (78 percent) of the desired product.

¹ H NMR (CD ₃ OD): δ 7.98 (d, 1H), 7.74 (d, IH), 7.57 (d, IH),

7.30 (t, 1H), 7.22 (d, 1H), 6.98 (t, 1H), 6.94 (t, 1H).

Example 84

Preparation of N- [2-hydroxy-4-cyanophenyl] -N '- [2-bromophenyl] urea

a) Preparation of 2-nitro-5-cyanophenol

2.38 g (20 millimoles) of 3-cyanophenol was dissolved in 40 ml of dichloromethane and 1.88 g (22 millimoles) of sodium nitrate was added. Then 20 milliliters of 3 molar sulfuric acid and a catalytic amount of sodium nitrite were gradually added to the reaction mixture. The reaction mixture was allowed to stir for 24 hours, diluted with dichloromethane and extracted with water. The organic layer was dried over anhydrous magnesium sulfate and filtered. Evaporation of the solvent and chromatography of the residue on silica gel (eluting with 4% methanol in dichloromethane) gave 910 mg (28%) of the desired product.

¹ H NMR (CD 3 COCD 3): δ 8.30 (d, 1H), 7.67 (s, 1H), 7.49 (d, 1H).

b) Preparation of 2-amino-5-cyanophenol

A mixture of 250 mg (1.5 mmoles) of 5-cyano-2-nitrophenol and 3.2 g (14.4 mmoles) of stannous chloride in 50 ml of ethanol was heated to 80 ° C under an argon atmosphere. After 2 hours the starting material disappeared, the solution was allowed to cool to room temperature and poured into ice. Before

By extraction with ethyl acetate, the pH of the resulting mixture was adjusted to slightly basic (7-8) by addition of solid sodium hydroxide. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, and filtered. Evaporation of the solvent and chromatography of the residue on silica gel (eluting with 4% methanol in dichloromethane) gave 175 mg (86%) of the desired product.

¹ H NMR (CD ₃ OD): δ 7.00 (d, 1H), 6.88 (s, 1H), 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 170 mg (1.27 mmol) of 2-amino-5kyanofenolu procedure in General Method B. The product was purified by precipitation from methylene chloride / hexane (1:20) and filtering to give 310 mg (74 percent) of the desired product.

¹ H NMR (CD 3 OD): δ 8.25 (d, 1H), 7.91 (d, 1H), 7.59 (d, 1H),

7.33 (t, 1H), 7.17 (d, 1H), 7.07 (s, 1H), 7.01 (t, 1H).

Example 85

Preparation of N- [2-hydroxy-4-cyanophenyl] -N'- [4-methoxyphenyl] urea

N- [2-Hydroxy-4-cyanophenyl] -4 '- [4-methoxyphenyl] urea was prepared from 60 mg (0.45 mmol) of 2-amino-5-cyanophenol by general procedure B. The product was purified by precipitation from dichloromethane / hexane (1:20) a

150

• · ’· • · • 9 9 9 9 • 9 • • · · • · · • 9 9 ·· • 9 • • 9 9 9 9

filtration to give the desired product.

NMR (CD ₃ OD): δ 8.23 (d, 1H), 7.20 (d, 1H), 7.15 (d obtained 110 milligrams)

1H), 7.61-7.51 (m, 1H), 7.03 (s, 1H).

(86

2H), percent)

7.32 (d,

Example 86

Preparation of N- [2-hydroxy-4-cyanophenyl] -N- [2-phenylphenyl] urea

N- [2-Hydroxy-4-cyanophenyl] -4 '- [2-phenylphenyl] urea was prepared from 170 mg (1.27 mmol) of 2-amino-5-cyanophenol by General Procedure B. The product was purified by precipitation from dichloromethane / hexane. (1:20) and filtering to give 150 mg (85 percent) of the desired product.

NMR (CD ₃ OD): δ 8.20 (d, 1H), 7.73 (d, 1H), 7.51-7.20 (m, 8H), 7.13 (d, 1H), 7, 01 (s, 1 H).

Example 87

Preparation of N- [2-hydroxy-4-cyano phenyl] -N '- [2-methylphenyl] urea

N- [2-Hydroxy-4-cyanophenyl] -N '- [2-methylphenyl] urea was prepared from 60 mg (0.45 mmol) of 2-amino-5-cyanophenol by general procedure B. The product was purified by precipitation from dichloromethane / hexane. (1:20) and filtering to give 90 mg (75 percent) of the desired product.

¹ H NMR (CD 3 OD): δ 8.25 (d, 1H), 7.59 (d, 1H), 7.26-7.00 (m,

5H), 2.30 (s, 3H).

151

44 4 44 44 ·

4 4 f 4 4 4 · · * 44

4 4 · · 4 4

4 4 4 4 4

4 4 4 4 4 5

4444444 4444444 «· 444

Example 88

Preparation of N- [2-hydroxy-4-cyanophenyl] -N '- [2-trifluoromethylphenyl] urea

N- [2-Hydroxy-4-cyanophenyl] -4 '- [2-trifluoromethylphenyl] urea was prepared from 60 mg (0.45 mmol) of 2-amino-5-cyanophenol by general procedure B. The product was purified by precipitation from dichloromethane hexane (1:20) and filtered to give 110 mg (76 percent) of the desired product.

NMR (CD ₃ OD): δ 8.25 (d, 1H), 7.81 (d, 1H), 7.68 (d, 1H),

7.61 (t, 1H), 7.32 (t, 1H), 7.15 (dd, 1H), 7.09 (s, 1H).

Example 89

Preparation of N- [2-hydroxy-4-cyanophenyl] -N '- [3-trifluoromethylphenyl] urea

N- [2-Hydroxy-4-cyanophenyl] -4 '- [3-trifluoromethylphenyl] urea was prepared from 60 mg (0.45 mmol) of 2-amino-5-cyanophenol by the general procedure B. The product was purified by precipitation from dichloromethane hexane (1:20) and filtered to give 114 mg (79 percent) of the desired product.

¹ H NMR (CD 3 OD): δ 8.30 (d, 1H), 7.92 (s, 1H), 7.60 (d, 1H),

7.47 (t, 1H), 7.29 (d, 1H), 7.18 (dd, 1H), 7.06 (s, IR).

• ·

152

Example 90

Preparation of N- [2-hydroxy-4-cyanophenyl] -N '- [4-trifluoromethylphenyl] urea

N- [2-Hydroxy-4-cyanophenyl] -N '- [4-trifluoromethylphenyl] urea was prepared from 60 mg (0.45 mmol) of 2-amino-5-cyanophenol by the general procedure B. The product was purified by precipitation from dichloromethane hexane (1:20) and filtered to give 108 mg (75 percent) of the desired product.

^{Χ Η} NMR (CD ₃ OD): δ 8.31 (d, 1H), 7.68 (d, 2H), 7.59 (d, 2H);

7.20 (dd, 1H); 7.07 (s, 1H).

Example 91

Preparation of N- [2-hydroxy-3-n-propyl phenyl] -N '- [2-bromophenyl] urea

a) Preparation of 2-nitro-6-n-propylphenol

5.00 g (36.8 mmol) of 2-n-propylphenol was dissolved in 40 ml of dichloromethane and 3.43 g (40.5 mmol) of sodium nitrate was added. Then, 45 milliliters of 3 molar sulfuric acid and a catalytic amount of sodium nitrite were added sequentially to the reaction mixture. The reaction mixture was allowed to stir for 24 hours, diluted with dichloromethane and extracted with water. The organic layer was dried over anhydrous magnesium sulfate and filtered. After evaporation of the solvent and chromatography of the residue obtained on silica gel (eluting with 4% methanol in methanol)

153 g (48%) of the desired product was obtained.

¹ H NMR (CD 3 COCD 3): δ 7.99 (d, 1H), 7.46 (dd, 1H), 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 grams (11 millimoles) of 2-nitro-6-n-propylphenol in 100 milliliters of methanol was added 200 milligrams of 10% Pd / C. The mixture was purged with argon. Subsequently, hydrogen was bubbled through the solution for 10 minutes and the reaction mixture was left under hydrogen pressure over a hydrogen-filled balloon overnight. The mixture was filtered through celite, which was then rinsed with methanol. The filtrate was concentrated and chromatography of the obtained solid residue on silica gel (eluting with 5% methanol in dichloromethane) afforded 1.5 g (80.2 percent) of the desired product.

¹ H NMR (CD 3 OD): δ 6.65 (m, 2H), 6.55 (t, 1H), 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-propylphenyl] -4 '- [2-bromophenyl] urea was prepared from 302 mg (2.00 mmol) of 2-amino-6-n-propylphenol by general procedure B. The product was purified by precipitation from dichloromethane / hexane (1:20) and filtration to give 640 mg (92 percent) of the desired product.

³ H NMR (CD ³ OD): δ 8.00 (d, 1H), 7.58 (d, 1H), 7.32 (t, 1H),

7.26 (t, 1H), 6.96 (dd, 1H), 6.89 (t, 1H), 6.78 (d, 1H).

154

Example 92

Preparation of N- [2-hydroxy-4-ethylphenyl] -N '- [2-bromophenyl] urea

a) Preparation of 2-nitro-5-ethylphenol

5.00 grams (41 millimoles) of 3-ethylphenol was dissolved in 40 milliliters of dichloromethane, and 3.83 grams (45 millimoles) of sodium nitrate was added. Then 50 milliliters of 3 molar sulfuric acid and a catalytic amount of sodium nitrite were added sequentially to the reaction mixture. The reaction mixture was allowed to stir for 24 hours, diluted with dichloromethane and extracted with water. The organic layer was dried over anhydrous magnesium sulfate and filtered. Evaporation of the solvent and chromatography of the residue on silica gel (eluting with 4% methanol in dichloromethane) gave 1.7 g (25%) of the desired product.

¹ H NMR (CD 3 COCD 3): δ 8.02 (d, 1H), 6.99 (s, 1H), 6.85 (d, 1H), 2.69 (q, 2H), 1.30 (t, 3H).

b) Preparation of 2-amino-5-ethylphenol

To a solution of 1 gram (6.4 mmol) of 2-nitro-5-ethylphenol in 250 ml of methanol was added 100 mg of 10% Pd / C. The mixture was purged with argon. Subsequently, hydrogen was bubbled through the solution for 10 minutes and the reaction mixture was left under hydrogen pressure over a hydrogen-filled balloon overnight. The mixture was filtered through celite, which was then rinsed with methanol. The filtrate was concentrated and chromatography of the obtained solid residue on silica gel (eluting with 5% methanol in dichloromethane) afforded 750 mg (91%) of the desired product.

• · · · · · · · · · · · · · · · ·

155 ^X H NMR (CD ₃ OD): δ 6.41 to 6.17 (m, 3Η).

c) Preparation of N- [2-hydroxy-4-ethylphenyl] -N '- [2-bromophenyl] urea

N- [2-Hydroxy-4-ethylphenyl] -N '- [2-bromophenyl] urea was prepared from 274 mg (2.00 mmol) of 2-amino-5-ethylphenol by general procedure B. The product was purified by precipitation from dichloromethane / hexane. (1:20) and filtering to give 520 mg (77 percent) of the desired product.

¹ H NMR (CD 3 OD): δ 7.96 (d, 1H), 7.62 (s, 1H), 7.56 (d, 1H),

7.30 (t, 1H), 6.96 (t, 1H), 6.82 (d, 1H), 6.76 (d, 1H).

Example 93

Preparation of N- [2-hydroxy-3-phenylaminocarbonylphenyl] -N '- [2-bromophenyl] urea

a) Preparation of 2-nitro-6-phenylaminocarbonylphenol

5.00 grams (23 millimoles) of 2-phenylaminocarbonylphenol was dissolved in 40 milliliters of dichloromethane and 2.20 grams (25.5 millimoles) of sodium nitrate was added. Then 30 milliliters of 3 molar sulfuric acid and a catalytic amount of sodium nitrite were added sequentially to the reaction mixture. The reaction mixture was allowed to stir for 24 hours, diluted with dichloromethane and extracted with water. The organic layer was dried over anhydrous magnesium sulfate and filtered after evaporation of the solvent and chromatography of the residue on silica gel (eluting with 4% methanol in methanol).

156 2.50 g (42 percent) of the desired product were obtained. M.p. 156-2 (H + CH 2 Cl 2 / CH 2 Cl 2 / CH 2 Cl 2).

NMR (CD 3 COCD 3): δ 8.15 (d, 1H), 8.09 (d, 1H), 7.51 (d, 1H),

7.30 (d, 1H); 7.10 (t, 1H); 7.01 (t, 1H).

b) Preparation of 2-amino-6-phenylaminocarbonylphenol

To a solution of 1 gram (4.0 millimoles) of 2-nitro-6-phenylaminocarbonylphenol in 250 mL of methanol was added 100 mg of 10% Pd / C. The mixture was purged with argon. Subsequently, hydrogen was bubbled through the solution for 10 minutes and the reaction mixture was left under hydrogen pressure over a hydrogen-filled balloon overnight. The mixture was filtered through celite, which was then rinsed with methanol. The filtrate was concentrated and chromatography of the obtained solid residue on silica gel (eluting with 5% methanol in dichloromethane) gave 800 mg (91%) of the desired product.

^τ Η NMR (CD 3 OD): δ 7.73 - 7.57 (m, 2H), 7.43 - 7.27 (m, 3H),

7.25-7.10 (m, 1H), 6.94 (t, 1H), 6.74 (t, 1H).

c) Preparation of N- [2-hydroxy-3-phenylaminocarbonylphenyl] N '- [2-bromophenyl] urea

N- [2-Hydroxy-3-phenylaminocarbonylphenyl] -4 '- [2-bromophenyl] urea was prepared from 456 mg (2.00 mmol) of 2-amino-6-phenylaminocarbonylphenol by general procedure B. The product was purified by precipitation from dichloromethane hexane (1:20) and filtered to give 800 mg (94 percent) of the desired product.

• · • ·

157 ^X H NMR (CD ₃ OD) δ 25 (d, 1H), 7.94 (d, 1H), 7.75 - 7.57 (m, 4H), 7.48 - 7.30 (m, 3H), 7.21 (t, 1H), 7.02 (dd, 1H), 6.92 (t, 1H).

Example 94

Preparation of N- [2-hydroxy-3-cyano-4-methylphenyl] -N '- [2-bromophenyl] urea

a) Preparation of 2-nitro-5-methyl-6-bromophenol

To 6.88 mL (4.79 grams, 2 equivalents) of tert. of butylamine in dichloromethane was added 1.67 ml (5.2 g, 1 equivalent) of bromine at -20 ° C. The flask was cooled to -78 ° C and 5 grams (1 equivalent) of 2-nitro-5-methylphenol in dichloromethane was added dropwise with vigorous stirring. The reaction mixture was allowed to warm slowly to -30 ° C, stirred at this temperature for 1 hour, then the temperature was raised to -10 ° C and the mixture was stirred at this temperature for 2 hours. The reaction mixture was partitioned between dichloromethane and 5% aqueous acetic acid. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The reaction mixture was then purified by flash chromatography (eluting with ethyl acetate / hexane) to separate the dibrominated compounds. Subsequently, 2-nitro-4-bromo-5-methylphenol was selectively crystallized from dichloromethane. Final silica gel column chromatography (eluting with 5% ethyl acetate in hexane) afforded 1.05 g (14 percent) of the desired isomer in 90% purity.

158 • · ·· ·· ·· ·· ·· · · · · · · · · · • fc • · · · · · · · · · • · · · · · ^X 1 HNMR (CDCl _3): δ 7 95 (d, 1H, J = 10.0 Hz), 6.91 (d, 1H, J = 10.0 Hz), 2.52 (s, 3H).

b) Preparation of 2-nitro-5-methyl-6-cyanophenol

100 mg (0.433 mmol) of 2-nitro-5-methyl-6-bromophenol was dissolved in 2 ml of dimethylformamide and 0.175 g (1.73 mmol) of triethylamine was added. A catalytic amount of dimethylaminopyridine and 155 mg (1.73 mmol) of copper (I) cyanide were then gradually added to the reaction mixture. The reaction mixture was allowed to stir at 80 ° C for 4 hours. Evaporation of the solvent and chromatography of the residue on silica gel (eluting with 2% methanol in dichloromethane) gave 70 mg (91%) of the desired product.

¹ H NMR (CD 3 COCD 3): δ 8.30 (d, 1H), 7.15 (d, 1H), 2.61 (s, 3H).

c) Preparation of 2-amino-5-methyl-6-cyanophenol

A mixture of 70 milligrams (0.39 millimoles) of 5-cyano-2-nitrophenol and 265 milligrams (1.18 millimoles) of stannous chloride in 20 milliliters of ethanol was heated under argon at 80 ° C. After 2 hours the starting material disappeared, the solution was allowed to cool to room temperature and poured into ice. Before extraction with ethyl acetate, the pH of the resulting mixture was adjusted to slightly basic (7-8) by addition of solid sodium hydroxide. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, and filtered. Evaporation of the solvent and chromatography of the residue on silica gel (eluting with 4% methanol in dichloromethane) gave 175 mg (86%) of the desired product.

¹ H NMR (CD ₃ OD): δ 6.87 (d, 1H), 6.75 (d, 1H), 6.32 (s, 3H).

• · · fc · ·

159

d) Preparation of N- [2-hydroxy-3-cyano-4-methylphenyl] -N '- [2-bromophenyl] urea

N- [2-Hydroxy-3-cyano-4-methylphenyl] -4 '- [2-bromophenyl] urea was prepared from 50 mg (0.34 mmol) of 2-amino-5-methyl-6-cyanophenol by general procedure B The product was purified by precipitation from dichloromethane / hexane (1:20) and filtered to give 70 mg (60 percent) of the desired product.

NMR (CD ₃ OD): δ 7.92 (d, 1H), 7.68 (d, 1H), 7.59 (d, 1H),

7.31 (t, 1H), 7.00 (t, 1H), 6.62 (t, 1H), 2.49 (s, 3H).

Example 95

Preparation of N- [2-hydroxy-4-carboxyphenylphenyl] -N '- [2-bromophenyl] urea

a) Preparation of 4-nitro-3-hydroxybenzophenone

3.00 g (15.1 mmol) of 3-hydroxybenzophenone was dissolved in 40 ml of dichloromethane and 1.42 g (16.7 mmol) of sodium nitrate was added. Then 25 milliliters of 3 molar sulfuric acid and a catalytic amount of sodium nitrite were added sequentially to the reaction mixture. The reaction mixture was allowed to stir for 24 hours, diluted with dichloromethane and extracted with water. The organic layer was dried over anhydrous magnesium sulfate and filtered. Evaporation of the solvent and chromatography of the residue on silica gel (eluting with 4% methanol in dichloromethane) gave 1.10 g (30%) of the desired product.

160

• · » «99 ·· · • · 4 ·· · · • 9 • 4 • 9 • · • 4 • · · • · • · • • · • · 9 9 9 • 4 4

¹ H NMR (CD 3 COCD 3): δ 8.25 (d, 1H), 7.86 (d, 1H), 7.71 (m, 1H), 7.59 (d, 1H), 7.48 (s, 1H), 7.39 (dd, IH).

b) Preparation of 4-amino-3-hydroxybenzophenone

A mixture of 900 mg (3.7 mmol) of 4-nitro-3-hydroxybenzophenone and 2.5 g (11.1 mmol) of stannous chloride in 50 ml of ethanol was heated under argon at 80 ° C. After 2 hours the starting material disappeared, the solution was allowed to cool to room temperature and poured into ice. Before extraction with ethyl acetate, the pH of the resulting mixture was adjusted to slightly basic (7-8) by addition of solid sodium hydroxide. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, and filtered. Evaporation of the solvent and silica gel chromatography of the residue (eluting with 4% methanol in dichloromethane) gave 685 mg (87 percent) of the desired product.

NMR (CD 3 OD): δ 7.65 (d, 2H), 7.55 (d, 1H), 7.49 (t, 2H),

7.26 (s, 1H); 7.16 (dd, 1H); 6.68 (d, 1H).

c) Preparation of N- [4-carboxyphenyl-2-hydroxyphenyl] -4 '- [2-bromophenyl] urea

N- [4-Carboxyphenyl-2-hydroxyphenyl] -N '- [2-bromophenyl] urea was prepared from 330 mg (1.5 mmol) of 4-amino-3-hydroxybenzophenone according to the general procedure B. The product was purified by precipitation from dichloromethane hexane (1:20) and filtered to give 490 mg (79 percent) of the desired product.

¹ H NMR (CD 3 OD): δ 8.40 (d, 1H), 8.09 (d, 1H), 7.83 (d, 2H),

7.65-7.60 (m, 4H), 7.48 (s, 1H), 7.43 (d, 1H), 7.35 (d, 1H), 7.10 (t, 1H).

»*)

99 »9 * 99

9 Φ ««

9-99 9

9

99 »9» 99 49 999

161 <* 4

9 9

9

9 9

9

Example 96

Preparation of Ν- [2-hydroxy- 3 3-carboxyphenyl phenyl] -N '- [2-bromophenyl] urea

a) Preparation of 3-nitro-2-hydroxybenzophenone

3.00 g (15.1 mmol) of 2-hydroxybenzophenone was dissolved in 40 ml of dichloromethane and 1.42 g (16.7 mmol) of sodium nitrate was added. Then 25 milliliters of 3 molar sulfuric acid and a catalytic amount of sodium nitrite were added sequentially to the reaction mixture. The reaction mixture was allowed to stir for 24 hours, diluted with dichloromethane and extracted with water. The organic layer was dried over anhydrous magnesium sulfate and filtered. Evaporation of the solvent and chromatography of the residue on silica gel (eluting with 4% methanol in dichloromethane) gave 1.60 g (44%) of the desired product.

¹ H NMR (CD ₃ COCD ₃ ): δ 8.30 (d, 1H), 7.86 (m, 3H), 7.71 (m, 1H), 7.78 (d, 1H), 7.56 (dd, 2H), 7.24 (t, 1 H).

b) Preparation of 3-amino-2-hydroxybenzophenone

A mixture of 600 mg (2.5 mmol) of 3-nitro-2-hydroxybenzophenone and 1.7 g (7.5 mmol) of stannous chloride in 50 ml of ethanol was heated under argon at 80 ° C. After 2 hours the starting material disappeared, the solution was allowed to cool to room temperature and poured into ice. Before extraction with ethyl acetate, the pH of the resulting mixture was adjusted to slightly basic (7-8) by addition of solid sodium hydroxide. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, and filtered.

162

Evaporation of the solvent and chromatography of the residue on silica gel (eluting with 4% methanol in dichloromethane) gave 490 mg (92%) of the desired product.

1 H NMR (CD ₃ OD): δ 7.65-7.40 (m, 5H), 6.98 (d, 1H), 6.86 (d, 1H), 6.67 (t, 1H).

c) Preparation of N- [2-hydroxy-3-carboxyphenylphenyl] -N '- [2-bromophenyl] urea

N- [2-Hydroxy-3-carboxyphenylphenyl] -4 '- [2-bromophenyl] urea was prepared from 250 mg (1.20 mmol) of 3-amino-2-hydroxybenzophenone according to the general procedure B. The product was purified by precipitation from dichloromethane hexane (1:20) and filtered to give 200 mg (78 percent) of the desired product.

^{Χ Η} NMR (CD3OD): δ 8.35 (d, 1H), 7.96 (d, 1H), 7.72 (d, 2H);

7.65-7.50 (m, 4H), 7.35 (d, 1H), 7.30 (d, 1H), 7.01 (dd,

1H), 6.92 (t, 1H).

Example 97

Preparation of N- [2-hydroxy-3-benzyloxyphenyl] -N '- [2-bromophenyl] urea

a) Preparation of 2-nitro-6-benzyloxyphenol

5.00 grams (25.0 millimoles) of 2-benzyloxyphenol was dissolved in 40 milliliters of dichloromethane and 2.30 grams (27.5 millimoles) of sodium nitrate was added. Thereafter, 31 milliliters of 3 molar sulfuric acid and a catalytic amount of sodium nitrite were added to the reaction mixture. The reaction mixture was allowed to stir for 24 hours,

163

• ·

Dilute with dichloromethane and extract with water. The organic layer was dried over anhydrous magnesium sulfate and filtered. Evaporation of the solvent and chromatography of the residue on silica gel (eluting with 4% methanol in dichloromethane) gave 2.6 g (43 percent) of the desired product.

NMR (CD3COCD3): δ 7.70 (d, 1H), 7.50-7.28 (m, 5H), 7.14 (d, 1H), 6.92 (t, 1H), 5.21 ( s, 2H).

b) Preparation of 2-amino-6-benzyloxyphenol

A mixture of 1.0 grams (4.10 millimoles) of 2-nitro-6-benzyloxyphenol and 2.75 grams (12.2 millimoles) of tin (II) chloride in 150 milliliters of ethanol was heated under argon at 80 ° C. After 2 hours the starting material disappeared, the solution was allowed to cool to room temperature and poured into ice. Prior to extraction with ethyl acetate, the pH of the mixture was adjusted to slightly basic (7-8) by addition of solid sodium hydroxide. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, and filtered. Evaporation of the solvent and chromatography of the residue on silica gel (eluting with 4% methanol in dichloromethane) gave 1.35 g (88 percent) of the desired product.

¹ H NMR (CD 3 OD): δ 7.46 (d, 2H), 7.40-7.35 (m, 5H), 6.55 (d, 1H), 6.40 (d, 1H), 10 (s, 2H).

c) Preparation of N- [2-hydroxy-3-benzyloxyphenyl] -N '- [2-bromophenyl] urea

N - [2-Hydroxy-3-benzyloxyphenyl] -N '- [2-bromophenyl] urea was prepared from 430 mg (2.00 mmol) of 2-nitro-6-benzyloxyphenol by the general procedure B. The product was purified

164 was precipitated from dichloromethane / hexane (1:20) and filtered to give 630 mg (76 percent) of the desired product.

¹ H NMR (CD ₃ OD): δ 7.93 (d, 1H), 7.58 (d, 1H), 7.54 - 7.42 (m, 3H), 7.40 - 7.25 (m 4H), 7.00 (t, 1H), 6.69 (d, 2H), 5.16 (s, 2H).

Example 98

Preparation of N-3- [2-hydroxy-5-indanone] -N '- [2-bromophenyl] urea

a) Preparation of 2-hydroxy-3-nitro-5-indanone

3.00 g (20.0 mmoles) of 2-hydroxy-5-indanone was dissolved in 40 ml of dichloromethane and 1.95 g (21.0 mmoles) of sodium nitrate was added. Then 25 milliliters of 3 molar sulfuric acid and a catalytic amount of sodium nitrite were added sequentially to the reaction mixture. The reaction mixture was allowed to stir for 24 hours, diluted with dichloromethane and extracted with water. The organic layer was dried over anhydrous magnesium sulfate and filtered. Evaporation of the solvent and chromatography of the residue on silica gel (eluting with 4% methanol in dichloromethane) gave 1.5 g (39%) of the desired product.

¹ H NMR (CD 3 COCD 3): δ 7.70 (d, 1H), 7.04 (d, 1H), 3.04 (d, 2H), 2.74 (d, 2H).

b) Preparation of 3-amino-2-hydroxy-5-indanone

A mixture of 1.50 grams (7.80 millimoles) of 2-hydroxy-3-nitro-5-indanone and 5.25 grams (23.2 millimoles) of tin (II) chloride in t.

165

150 mL of ethanol was heated to 80 ° C under an argon atmosphere. After 2 hours the starting material disappeared, the solution was allowed to cool to room temperature and poured into ice. Before extraction with ethyl acetate, the pH of the resulting mixture was adjusted to slightly basic (7-8) by addition of solid sodium hydroxide. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, and filtered. Evaporation of the solvent and chromatography of the residue on silica gel (eluting with 4% methanol in dichloromethane) gave 1.0 g (79 percent) of the desired product.

^{Χ Η} NMR (CD ₃ OD): δ 6.85 (d, 1H), 6.45 (d, 1H), 2.95 (d, 2H), 2.60 (d, 2H).

c) Preparation of N-3- [2-hydroxy-5-indanone] -N '- [2-bromophenyl] urea

N-3- [2-Hydroxy-5-indanone] -4 '- [2-bromophenyl] urea was prepared from 326 mg (2.00 mmol) of 3-amino-2-hydroxy-5-indanone by general procedure B. The product was purified precipitation from dichloromethane / hexane (1:20) and filtering to give 610 mg (85 percent) of the desired product.

NMR (CD 3 OD): δ 7.92 (d, 1H), 7.65 (m, 2H), 7.45 (t, 1H),

7.09 (t, 1 H), 7.00 (d, 1 H), 2.90 (d, 2 H), 2.66 (d, 2 H).

166

Example 99

Preparation of (E) -N- [4- [2- (methoxycarbonyl) ethenyl] -2-hydroxyphenyl] -N '- [2-bromophenyl] urea

a) Preparation of 4-nitro-3-hydroxycinnamic acid

3.00 g (18.3 mmol) of 3-hydroxy cinnamic acid was dissolved in 40 ml of dichloromethane and 1.70 g (26.1 mmol) of sodium nitrate was added. Then 25 milliliters of 3 molar sulfuric acid and a catalytic amount of sodium nitrite were added sequentially to the reaction mixture. The reaction mixture was allowed to stir for 24 hours, diluted with dichloromethane and extracted with water. The organic layer was dried over anhydrous magnesium sulfate and filtered. Evaporation of the solvent and chromatography of the residue on silica gel (eluting with 4% methanol in dichloromethane) gave 1.0 g (26%) of the desired product.

NMR (CD 3 COCD 3): δ 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-hydroxymethylcinamate

4-Nitro-3-hydroxycinnamic acid was stirred in excess methanol with a catalytic amount of sulfuric acid.

Evaporation of the solvents and chromatography of the solid residue on silica gel (eluting with 4% methanol in dichloromethane) gave 1.0 g (94%) of the desired product.

NMR (CD 3 COCD 3): δ 8.17 (d, 1H), 7.69 (d, 1H), 7.52 (s, 1H), 7.45 (d, 2H), 6.75 (d, 1H) 3.80 (s, 3H).

• · ♦ · ·

167

c) Preparation of 4-amino-3-hydroxymethylcinamate

A mixture of 1.0 grams (4.50 millimoles) of 4-nitro-3-hydroxymethylcinnamate and 3.0 grams (13.4 millimoles) of stannous chloride in 50 milliliters of ethanol was heated under argon at 80 ° C. After 2 hours the starting material disappeared, the solution was allowed to cool to room temperature and poured into ice. Before extraction with ethyl acetate, the pH of the resulting mixture was adjusted to slightly basic (7-8) by addition of solid sodium hydroxide. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, and filtered. Evaporation of the solvent and chromatography of the residue on silica gel (eluting with 4% methanol in dichloromethane) gave 650 mg (75 percent) of the desired product. ¹ HNMR (CD ₃ OD): δ 7.50 (d, 1H), 6.94 (s, 1H), 6.89 (d, 1H),

6.68 (d, 1H); 6.18 (d, 1H); 3.74 (s, 3H).

d) Preparation of (E) -N- [4- [2- (methoxycarbonyl) ethenyl] -2-hydroxyphenyl] -1 '- [2-bromophenyl] urea (E) -N- [4- [2- (methoxycarbonyl)] ethenyl] -2-hydroxyphenyl] -2 '- [2-bromophenyl] urea was prepared from 250 mg (1.30 mmol) of 4-amino-3-hydroxymethylcinnamate according to the general procedure B. The product was purified by precipitation from dichloromethane / hexane ( 1:20) and filtered to give 300 mg (59 percent) of the desired product.

Η NMR (CD 3 OD): δ 8.24 (d, 1H), 8.05 (d, 1H), 7.69 (d, 1H),

7.65 (d, 1 H), 7.42 (t, 1 H), 7.21 (s, 1 H), 7.19 (d, 1 H), 7.10 (t, 1 H), 6.45 (d) 1 H, 3.81 (s, 3H).

I • ·

9

9

168

Example 100

Preparation of (E) -N- [3- [2- (methoxycarbonyl) ethenyl] -2-hydroxyphenyl] -N '- [2-bromophenyl] urea -N' - [2-bromophenyl] urea

a) Preparation of 3-nitro-2-hydroxycinnamic acid

2.00 g (18.3 mmol) of 2-hydroxycinnamic acid was dissolved in 40 ml of dichloromethane and 2.21 g (26.1 mmol) of sodium nitrate was added. Then 30 milliliters of 3 molar sulfuric acid and a catalytic amount of sodium nitrite were added sequentially to the reaction mixture. The reaction mixture was allowed to stir for 24 hours, diluted with dichloromethane and extracted with water. The organic layer was dried over anhydrous magnesium sulfate and filtered. Evaporation of the solvent and chromatography of the residue on silica gel (eluting with 4% methanol in dichloromethane) gave 2.0 g (52%) of the desired product.

² H NMR (CD ₃ COCD ₃ ): δ 8.21 (d, 1H), 8.16 (d, 1H), 8.05 (d, 1H),

7.19 (t, 1 H), 6.72 (d, 1 H).

b) Preparation of 3-nitro-2-hydroxymethylcinamate

3-Nitro-2-hydroxycinnamic acid was stirred in excess methanol with a catalytic amount of sulfuric acid.

Evaporation of the solvents and chromatography of the solid residue on silica gel (eluting with 4% methanol in dichloromethane) gave 1.0 g (94%) of the desired product.

¹ H NMR (CD 3 COCD 3): δ 8.25 (d, 1H), 7.8.15 (d, 1H), 8.06 (s, 1H),

7.20 (t, 2H); 6.76 (d, 1H); 3.80 (s, 3H).

169 ··· · · fc · fc · · · · · · · · · · · · · ·

c) Preparation of 3-amino-2-hydroxymethylcinamate

A mixture of 1.0 grams (4.5 millimoles) of 3-nitro-2-hydroxymethylcinnamate and 3.0 grams (13.4 millimoles) of stannous chloride in 50 milliliters of ethanol was heated under argon at 80 ° C. After 2 hours the starting material disappeared, the solution was allowed to cool to room temperature and poured into ice. Before extraction with ethyl acetate, the pH of the resulting mixture was adjusted to slightly basic (7-8) by addition of solid sodium hydroxide. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, and filtered. Evaporation of the solvent and chromatography of the residue on silica gel (eluting with 4% methanol in dichloromethane) gave 700 mg (81%) of the desired product.

¹ H NMR (CD ₃ OD): δ 8.04 (d, 1H), 6.93 (d, 1H), 6.79 (d, 1H),

6.71 (t, 1H), 6.43 (d, 1H), 3.72 (s, 3H).

d) Preparation of (E) -N- [3- [2- (methoxycarbonyl) ethenyl] -2-hydroxyphenyl] -N '- [2-bromophenyl] urea (E) -N- [3- [2- (methoxycarbonyl)] ethenyl] -2-hydroxyphenyl] -2 '- [2-bromophenyl] urea was prepared from 100 mg (0.52 mmol) of 3-amino-2-hydroxymethylcinamate according to general procedure B. The product was purified by precipitation from dichloromethane / hexane ( 1:20) and filtered to give 150 mg (74 percent) of the desired product.

¹ H NMR (CD 3 OD): δ 8.10 (d, 1H), 8.00 (d, 1H), 7.69 (d, 1H),

7.65 (d, 1 H), 7.42 (t, 1 H), 7.38 (t, 1 H), 7.32 (d, 1 H), 7.05 (t, 1 H), 6.55 (d) 1 H, 3.81 (s, 3H).

• · ♦

Example 101

170

Preparation of (E) -N- [3- [2- (aminocarbonyl) ethenyl] -2-hydroxyphenyl] N '- [2-bromophenyl] urea-N' - [2-bromophenyl] urea

a) Preparation of 2-hydroxycinamide

2.00 grams (12.3 millimoles) of 2-hydroxy cinnamic acid were dissolved in 10 milliliters of dimethylformamide and 5.4 grams (12.3 millimoles) of benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate were added, and 7 ml (12.3 mmol) of triethylamine. Ammonia gas was introduced into the reaction mixture for 30 minutes. The reaction mixture was allowed to stir for 24 hours, diluted with dichloromethane and extracted with water. The organic layer was dried over anhydrous magnesium sulfate and filtered. Evaporation of the solvent and chromatography of the solid residue on silica gel (eluting with 4% methanol in dichloromethane) gave 1.5 g (75%) of the desired product.

b) Preparation of 3-nitro-2-hydroxycinamide

750 mg (4.6 mmol) of 2-hydroxycinamide was dissolved in 40 ml of dichloromethane and 430 mg (5.1 mmol) of sodium nitrate was added. Then 7 milliliters of 3 molar sulfuric acid and a catalytic amount of sodium nitrite were gradually added to the reaction mixture. The reaction mixture was allowed to stir for 24 hours, diluted with dichloromethane and extracted with water. The organic layer was dried over anhydrous magnesium sulfate and filtered. After evaporation of the solvent and chromatography of the residue obtained on silica gel (eluting with a 4% methanol / hexane mixture).

171 dichloromethane), 350 mg (36 percent) of the desired product was obtained.

NMR (CD 3 COCD 3): δ 8.19 (d, 1H), 8.02 (d, 1H), 7.88 (d, 1H),

7.15 (t, 1H); 6.84 (d, 1H).

c) Preparation of 3-amino-2-hydroxycinamide

A mixture of 350 mg (1.70 mmol) of 3-nitro-2-hydroxymethyltinate and 3.0 g (13.4 mmol) of stannous chloride in 50 ml of ethanol was heated under argon at 80 ° C. After 2 hours the starting material disappeared, the solution was allowed to cool to room temperature and poured into ice. Before extraction with ethyl acetate, the pH of the resulting mixture was adjusted to slightly basic (7-8) by addition of solid sodium hydroxide. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, and filtered. Evaporation of the solvent and chromatography of the residue on silica gel (eluting with 4% methanol in dichloromethane) gave 244 mg (80 percent) of the desired product.

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 100 mg (0.56 mmol) of 3-amino-2-hydroxycinamide according to the general procedure B. The product was purified by precipitation from dichloromethane / hexane ( 1:20) and filtered to give 110 mg (52 percent) of the desired product.

¹ H NMR (CD ₃ OD): δ 8.00 (d, 1H), 7.90 (d, 1H), 7.63 (d, 1H),

7.55 (d, 1H), 7.35 (m, 2H), 7.05 (t, 1H), 6.95 (t, 1H), 6.70 (d, 1H).

• A

A A A

AAA ·

172

Example 102

Preparation of (E) -N- [4- [2- (aminocarbonyl) ethenyl] -2-hydroxyphenyl] N '- [2-bromophenyl] urea-N' - [2-bromophenyl] urea

a) Preparation of 3-hydroxycinamide

2.00 grams (12.3 millimoles) of 3-hydroxy cinnamic acid was dissolved in 10 milliliters of dimethylformamide, and 5.4 grams (12.3 millimoles) of benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate were added to the resulting solution. 7 ml (12.3 mmol) of triethylamine. Ammonia gas was introduced into the reaction mixture for 30 minutes. The reaction mixture was allowed to stir for 24 hours, diluted with dichloromethane and extracted with water. The organic layer was dried over anhydrous magnesium sulfate and filtered. Evaporation of the solvent and chromatography of the solid residue on silica gel (eluting with 4% methanol in dichloromethane) gave 1.3 g (65%) of the desired product.

b) Preparation of 4-nitro-3-hydroxycinamide

750 mg (4.6 mmol) of 3-hydroxycinamide was dissolved in 40 ml of dichloromethane and 430 mg (5.1 mmol) of sodium nitrate was added. Then 7 milliliters of 3 molar sulfuric acid and a catalytic amount of sodium nitrite were gradually added to the reaction mixture. The reaction mixture was allowed to stir for 24 hours, diluted with dichloromethane and extracted with water. The organic layer was dried over anhydrous magnesium sulfate and filtered. After evaporation of the solvent and chromatography of the residue obtained on silica gel (eluting with 4% methanol in methanol)

173

240 mg (25 percent) of the desired product was obtained.

NMR (CD 3 COCD 3): δ 8.09 (d, 1H), 7.49 (d, 1H), 7.26 (s, 1H), 7.16 (d, 1H), 6.71 (d, 1H) .

c) Preparation of 4-amino-2-hydroxycinamide

A mixture of 300 mg (1.40 mmol) of 4-nitro-3-hydroxymethylcinnamate and 980 mg (4.30 mmol) of stannous chloride in 50 ml of ethanol was heated to 80 ° C under argon. After 2 hours the starting material disappeared, the solution was allowed to cool to room temperature and poured into ice. Before extraction with ethyl acetate, the pH of the resulting mixture was adjusted to slightly basic (7-8) by addition of solid sodium hydroxide. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, and filtered. Evaporation of the solvent and chromatography of the residue on silica gel (eluting with 4% methanol in dichloromethane) gave 200 mg (74 percent) of the desired product.

d) Preparation of (E) -N- [3- [2- (aminocarbonyl) ethenyl] -2-hydroxyphenyl] -N '- [2-bromophenyl] urea (E) -N- [3- [2- (Aminocarbonyl)] ethenyl] -2-hydroxyphenyl] -2 '- [2-bromophenyl] urea was prepared from 100 mg (0.56 mmol) of 4-amino-2-hydroxycinamide according to the general procedure B. The product was purified by precipitation from dichloromethane / hexane ( 1:20) and filtered to give 125 mg (54 percent) of the desired product.

¹ H NMR (CD 3 OD): δ 8.05 (d, 1H), 7.92 (d, 1H), 7.60 (d, 1H),

7.45 (d, 1H), 7.35 (t, 1H), 7.05 (m, 2H), 6.50 (d, 1H).

174 «· to to toto toto toto toto toto toto toto toto toto toto toto toto toto toto toto toto toto

Example 103

Preparation of N- [2-hydroxy-4- (phenylaminocarboxy) phenyl] -N '- [2-bromophenyl] urea

N- [2-Hydroxy-4- (phenylaminocarboxy) phenyl] -4 '- [2-bromophenyl] urea was prepared using 0.50 mmol of 5- (phenylaminocarboxy) -2-aminophenol according to the general procedure B. The product was purified by precipitation from dichloromethane hexane (1:20) and filtered to give 150 mg (70 percent) of the desired product.

¹ H NMR (CD ₃ OD): δ 8.25 (d, 1H), 8.00 (d, 1H), 7.75 (d, 2H),

7.64 (d, 1H), 7.50 (d, 2H), 7.41 (m, 3H), 7.16 (t, 1H), 7.05 (t, 1H).

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 304 mg (0.50 mmol) of 5-aminocarbonyl-2-aminophenol by general procedure B. The product was purified by precipitation from dichloromethane hexane (1:20) and filtered to give 440 mg (62 percent) of the desired product.

¹ H NMR (CD ₃ OD): δ 8.09 (d, 1H), 7.91 (d, IH), 7.60 (d, IH),

7.45 (m, 3H), 7.00 (d, 1H).

175 • · ·· ·

Example 105

Preparation of N- (2-hydroxy-3,5,6-trifluorophenyl) -4- (2-bromophenyl) urea

N- (2-Hydroxy-3,5,6-trifluorophenyl) -N '- (2-bromophenyl) urea was prepared from 83 mg (0.51 mmol)

3,5,6-trifluoro-2-hydroxyaniline and 100 mg (0.53 mmol) of 2- (bromophenyl) isocyanate according to the general procedure B.

The product was purified by thin layer chromatography.

EI-MS m / z 359 (M-H) &lt; + &gt;.

Example 106

Preparation of N- (2-hydroxy-3-fluoro-4-trifluoromethylphenyl) -N '(2-bromophenyl) urea

N- (2-Hydroxy-3-fluoro-4-trifluoromethylphenyl) -1 '(2-bromophenyl) urea was prepared from 239 mg (1.2 mmol) of 4-trifluoromethyl-3-fluoro-2-hydroxyaniline and 243 mg ( (Removal of solvent and chromatography of the solid residue on silica gel (eluting with hexane / ethyl acetate)) gave 20 mg (4 percent) of the desired product.

EI-MS m / z 391 (M-H) &lt; - &gt;.

Example 107

Preparation of N- (2-hydroxy-3-iodophenyl) -N '- (2-bromophenyl) urea

N- (2-Hydroxy-3-iodophenyl) -1 '- (2-bromophenyl) urea was

9

9

176

prepared from 200 mg (0.85 mmol) of 3-iodo-2-hydroxyaniline and 169 mg (0.85 mmol) of 2- (bromophenyl) isocyanate by General Procedure B. Removal of solvent and chromatography of the solid residue on silica gel (eluting with hexane / ether), 40 mg (11 percent) of the desired product was obtained.

NMR (DMSO): δ 9.45 (s, 1H), 9.15 (s, 1H), 8.8 (s, 1H), 7.95 (d, 1H), 7.8 (d, 1H) 7.65 (d, 1H); 7.4 (d, 1H); 7.3 (t, 1H); 7.0 (t, 1H); 6.65 (t, 1H).

Example 108

Preparation of N- [2 - [[[2- (trifluoromethyl) phenyl] sulfonyl] amino] phenyl] -N '- (2-bromophenyl) urea

a) Preparation of 2- [2- (trifluoromethyl) phenyl] (sulfonamido) aniline

The title compound was prepared according to the general procedure C from the equivalent of 2- (trifluoromethyl) benzenesulfonyl chloride. Purification of the crude product by silica gel chromatography (eluting with dichloromethane / methanol) gave 1.04 g (33 percent) of pure product.

EI-MS m / z 317 (M + H) &lt; + & gt ^; .

b) Preparation of N- [2 - [[[2- (trifluoromethyl) phenyl] sulfonyl] amino] phenyl] -1 '- (2-bromophenyl) urea

The title compound was prepared from 1.04 g (3.2 millimoles) of 2- [2- (trifluoromethyl) phenyl] (sulfonamido) aniline and 652 mg (3.2 millimoles) of 2- (bromophenyl) isocyanate by general procedure B. Removal of the solvent 1.03 g (61 percent) of the desired urea derivative was obtained.

EI-MS m / z 514 (M + H) &lt; + & gt ^; .

177 • 9

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 procedure C from dimethylsulfamoyl chloride equivalent. The product was purified by silica gel chromatography (eluting with dichloromethane / methanol).

EI-MS m / z 216 (M + H) &lt; + & gt ^; .

b) Preparation of N- (2-bromophenyl) -N '- [2-dimethylaminosulfonylamino] -phenyl] urea

The title compound was prepared from 137 mg (0.6 mmol) of 2- [1,1- (trifluoromethyl) phenyl] (sulfonamido)] aniline and 126 mg (0.6 mmol) of 2- (bromophenyl) isocyanate according to the general procedure B. Removal the desired urea derivative was obtained.

EI-MS m / z 413 (M + H) &lt; + & gt ^; .

Example 110

Preparation of N- [2- (phenethylsulfonylamino) phenyl] -N '- (2-bromophenyl) urea

300 milligrams (1.09 millimoles) of 2- (phenethylsulfonamido) aniline (from Example 60) was placed in a Parr mixing bottle containing 180 milligrams of palladium under argon flow. 150 mL of methanol was added to the mixture, and the vessel (pressurized to a pressure of 379.2 kilopascals (55 psi) was

178

4 ·

Μ ·

• 4 * ·· • 4 4 4 • • 4 4 4 4 4 · • 4 4 • · • 4 • 4 ··· <r · »

hours placed on a Parr. The reaction mixture was then filtered through celite and the filtrate was evaporated to give 269 mg (90 percent) of the desired aniline derivative. EI-MS m / z 277 (M + H) &lt; + & gt ^; .

b) Preparation of N- [2- (phenethylsulfonylamino) phenyl] N '- (2-bromophenyl) urea

The title compound was prepared from 269 mg (0.97 mmol) of 2- (phenethylsulfonamido) aniline and 193 mg (0.97 mmol) of 2- (bromophenyl) isocyanate according to the general procedure B. Precipitation from toluene / hexane gave 384 mg (78 mg). percent) of the desired urea derivative.

EI-MS m / z 472 (M-H &lt; + &gt;).

Example 111

Preparation of N- [2 - [(2-acetamido-4-methylthiazol-5-yl) sulfonylamino] phenyl] -N '- (2-bromophenyl) urea

a) Preparation of 2 - [(2-acetamido-4-methyl-5-thiazole) sulfonamido] aniline

The title compound was prepared according to the general procedure C from 1 equivalent of 2-acetamido-4-methyl-5-thiazolesulfonyl chloride.

A solid precipitated from the reaction mixture, which was filtered off to give 1.68 g (52 percent) of the desired aniline derivative.

EI-MS m / z 327 (M + H) &lt; + & gt ^; .

b) Preparation of N- [2 - [(2-acetamido-4-methylthiazol-5-yl) sulfonylamino] phenyl] -N '- (2-bromophenyl) urea

The title compound was prepared from 1.68 g

179

(5.14 millimoles) of 2 - [(2-acetamido-4-methylthiazol-5yl) sulfonamido] aniline and 1.02 g (5.14 millimoles)

2- (bromophenyl) isocyanate according to the general procedure B. Precipitation from ethyl acetate / hexane gave 220 mg (8 percent) of the desired urea derivative.

EI-MS m / z 524 (M + H) &lt; + & gt ^;.

Example 112

Preparation of N- [2-hydroxy-4-cyanophenyl] -N '- [4-phenylphenyl] urea

N- [2-Hydroxy-4-cyanophenyl] -4 '- [4-phenylphenyl] urea was prepared from 60 mg (0.45 mmol) of 2-amino-5-cyanophenol by general procedure B. The product was purified by precipitation from ethyl acetate / hexane. and filtering to 135 milligrams (75 percent).

¹ H NMR (CD ₃ OD): δ 8.33 (d, 1H), 7.71-7.29 (m, 9H), 7.25 (d, 1H), 7.12 (s, 1H).

Example 113

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 60 mg (0.45 mmol) of 2-amino-5-cyanophenol by general procedure B. The product was purified by precipitation from ethyl acetate. % hexane and filtration and the amount was 125 milligrams (86 percent).

¹ H NMR (CD ₃ OD): δ 8.27 (d, 1H), 8.15 (m, 1H), 7.39-7.20 (m,

180 »44

4 · * 4 · 4 4 4 4 4 4

4 4 4

4444444 ·· 4

2Η), 7.16 (d, 1Η), 7.06 (s, 1Η).

Example 114

Preparation of N- [2-hydroxy-4-cyanophenyl] -N '- [2-methoxyphenyl] urea

N- [2-Hydroxy-4-cyanophenyl] -4 '- [2-methoxyphenyl] urea was prepared from 60 mg (0.45 mmol) of 2-amino-5-cyanophenol by general procedure B. The product was purified by precipitation from ethyl acetate / hexane and filtering to 105 milligrams (83 percent).

NMR (CD ₃ OD): δ 8.26 (d, 1H), 8.02 (d, 1H), 7.14 (d, 1H), 7.05 (s, 1H), 7. 00-6, 83 (m, 3H), 3.84 (s, 3H).

Example 115

Preparation of N- [2-hydroxy-4-cyanophenyl] -N '- [3-methoxyphenyl] urea

N- [2-Hydroxy-4-cyanophenyl] -4 '- [3-methoxyphenyl] urea was prepared from 60 mg (0.45 mmol) of 2-amino-5-cyanophenol by general procedure B. The product was purified by precipitation from ethyl acetate / hexane and filtered to give 102 milligrams (80 percent).

¹ H NMR (CD ₃ OD): δ 8.25 (d, 1H), 7.25-7.08 (m, 3H), 7.04 (s,

1H), 6.90 (t, 1H), 6.58 (d, 1H).

181 • 9 • 9 9

Example 116

Preparation of N- [2-hydroxy-5-fluorophenyl] -N '- [2-bromophenyl] urea

a) Preparation of 2-amino-4-fluorophenol

A mixture of 1 g (4.64 mmol) of 4-fluoro-2-nitrophenol and 5.4 g (24.2 mmol) of stannous chloride in 50 ml of ethanol was heated under argon at 80 ° C. After 2 hours the starting material disappeared, the solution was allowed to cool to room temperature and poured into ice. Before extraction with ethyl acetate, the pH of the resulting mixture was adjusted to slightly basic (7-8) by addition of solid sodium hydroxide. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, and filtered. Evaporation of the solvent and chromatography of the residue on silica gel (eluting with 4% methanol in dichloromethane) gave 622 mg (85 percent) of the desired product.

¹ H NMR (CD ₃ OD): δ 6.51 (dd, 1H), 6.32 (dd, 1H), 6.17 (ddd, 1H).

b) Preparation of N- [2-hydroxy-5-fluorophenyl] -N '- [2-bromophenyl] urea

N- [2-Hydroxy-5-fluorophenyl] -4 '- [2-bromophenyl] urea was prepared from 254 mg (2.00 mmol) of 2-amino-6-fluorophenol by general procedure B. The product was purified by precipitation from ethyl acetate / hexane and filtering to 520 milligrams (80 percent).

NMR (CD 3 OD): δ 7.88 (d, 1H), 7.79 (dd, 1H), 7.57 (d, 1H),

7.31 (t, 1H), 6.76 (dd, 1H), 6.57 (ddd, 1H).

182

Example 117

Preparation of N- [2-hydroxy-5-trifluoromethylphenyl] -N '- [2-bromophenyl] urea

a) Preparation of 2-amino-4-trifluoromethylphenol

A mixture of 1 g (4.8 mmol) of 4-trifluoromethyl-2-nitrophenol and 5.4 g (24.2 mmol) of stannous chloride in 50 ml of ethanol was heated under argon at 80 ° C. After 2 hours the starting material disappeared, the solution was allowed to cool to room temperature and poured into ice. Before extraction with ethyl acetate, the pH of the resulting mixture was adjusted to slightly basic (7-8) by addition of solid sodium hydroxide. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, and filtered. Evaporation of the solvent and chromatography of the residue on silica gel (eluting with 4% methanol in dichloromethane) gave 708 mg (83%) of the desired product.

¹ H NMR (CD ₃ OD): δ 6.87 (s, 1H), 6.80 (d, 1H), 6.69 (d, 1H).

b) Preparation of N- [2-hydroxy-5-trifluoromethylphenyl] -N '- [2-bromophenyl] urea

N- [2-Hydroxy-5-trifluoromethylphenyl] -N '- [2-bromophenyl] urea was prepared from 354 mg (2.00 mmol) of 2-amino-4-trifluorophenol by general procedure B. The product was purified by precipitation from ethyl acetate / hexane and filtering to 490 milligrams (65 percent).

^{Χ Η} NMR (CD3OD): δ 8.40 (s, 1H), 7.94 (d, 1H), 7.60 (d, 1H)

7.35 (t, 1H), 7.18 (d, 1H), 7.03 (t, 1H), 6.95 (d, 1H).

• ·

4 • 4

4 4

183

Example 118

Preparation of N- [2-hydroxyphenyl] -N '- [2-bromophenyl] urea

N- [2-Hydroxyphenyl] -N '- [2-bromophenyl] urea was prepared from 141 mg (1.30 mmol) of 2-aminophenol by the general procedure B. The product was purified by precipitation from ethyl acetate / hexane and filtering to yield 300 milligrams (75 percent).

¹ H NMR (CD ₃ OD): δ 8.05 (d, 1H), 7.49 (d, 1H), 7.25 (t, 2H), 6.96 (t, 1H), 6.90 ( t, 2H), 6.68 (t, 1H).

Example 119

Preparation of N- [trans-3-styryl-2-hydroxyphenyl] -N '- [2-bromophenyl] urea

a) Preparation of trans-6-styryl-2-nitrophenol

500 mg (2.55 mmol) of trans-2-styrylphenol was dissolved in 40 ml of dichloromethane and 240 mg (2.81 mmol) of sodium nitrate was added. Thereafter, 3 milliliters of 3 molar sulfuric acid and a catalytic amount of sodium nitrite were gradually added to the reaction mixture. The reaction mixture was allowed to stir for 24 hours, stirred, diluted with dichloromethane and extracted with water. The organic layer was dried over anhydrous magnesium sulfate and filtered. Evaporation of the solvent and chromatography of the residue on silica gel (eluting with 4% methanol in dichloromethane) afforded 200 mg (36%) of the desired product.

• 9 • 9

184 ^X H NMR (CD3COCD3): δ 8.05 (d, 1H), 7.90 (d, 2H), 7. 65 - 7.20 (m, 7H), 7.00 (t, 1H).

b) Preparation of trans-6-styryl-2-aminophenol

A mixture of 200 milligrams (0.83 millimoles) of trans-6-styryl-2-nitrophenol and 560 milligrams (2.60 millimoles) of stannous chloride in 50 milliliters of ethanol was heated under argon at 80 ° C. After 2 hours the starting material disappeared, the solution was allowed to cool to room temperature and poured into ice. Before extraction with ethyl acetate, the pH of the resulting mixture was adjusted to slightly basic (7-8) by addition of solid sodium hydroxide. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, and filtered. Evaporation of the solvent and chromatography of the residue on silica gel (eluting with 4% methanol in dichloromethane) gave 50 mg (29 percent) of the desired product. ¹ H NMR (CD ₃ OD): δ 7.51 (m, 3H), 7.29 (m, 3H), 7.11 (t, 1H),

7.00 (m, 2H); 6.69 (m, 2H).

c) Preparation of N- [trans-3-styryl-2-hydroxyphenyl] -N '- [2-bromophenyl] -urea

N- [trans-3-Styryl-2-hydroxyphenyl] -1 '- [2-bromophenyl] urea was prepared from 35 mg (0.17 mmol) of trans-2-styryl-2-aminophenol by general procedure B. The product was purified precipitating from ethyl acetate / hexane and filtering to 36 mg (53 percent).

¹ H NMR (CD 3 OD): δ 7.97 (d, 1H), 7.62-7.48 (m, 4H), 7.45 7.26 (m, 5H), 7.25 (t, 1H) 7.15 (d, 1H); 7.01 (t, 1H); 6.88 (t, 2H).

Example 120

Preparation of N- [2-hydroxy-3,4-dichlorophenyl] -N '- [2-methoxyphenyl] urea

185

N- [2-Hydroxy-3,4-dichlorophenyl] -N '- [2-methoxyphenyl] urea was prepared from 80 mg (0.50 mmol) of 2-amino-5,6-dichlorophenol (from Example 82b) by the general procedure B. The product was purified by precipitation from ethyl acetate / hexane and filtration to give 125 mg (77 percent).

¹ H NMR (CD ₃ OD): δ 8.02 (d, 1H), 7.79 (d, 1H), 7.05-6.86 (m,

4H), 3.92 (s, 3H).

Example 121

Preparation of N- [2-hydroxy-3,4-dichlorophenyl] -N '- [2-methoxyphenyl] urea

N- [2-Hydroxy-3,4-dichlorophenyl] -4 '- [2-methoxyphenyl] urea was prepared from 80 mg (0.50 mmol) of 2-amino-5, β-dichlorophenol (from Example 82b) by a general procedure B. The product was purified by precipitation from ethyl acetate / hexane and filtered to give 120 mg (74 percent).

NMR (CD 3 OD): δ 7.89 (d, 1H), 7.35 (d, 2H), 6.99 (d, 1H),

6.90 (dd, 2H); 3.80 (s, 3H).

186

9 • 9 • 9 ·

9

9 * 9

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 80 mg (0.50 mmol) of 2-amino-5,6-dichlorophenol (from Example 82b) by a general procedure B. The product was purified by precipitation from ethyl acetate / hexane and filtering to 130 mg (71 percent).

¹ H NMR (CD ₃ OD): δ 7.96 (d, 2H), 7.60 (d, 1H), 7.48 (t, 1H),

7.30 (d, 1 H), 7.00 (d, 1 H).

Example 123

Preparation of N- [2-hydroxy-3,4-dichlorophenyl] -N '- [2-phenylphenyl] urea

N- [2-Hydroxy-3,4-dichlorophenyl] -N '- [2-phenylphenyl] urea was prepared from 80 mg (0.50 mmol) of 2-amino-5,6-dichlorophenol (from Example 82b) by the general procedure B. The product was purified by precipitation from ethyl acetate / hexane and filtration to give 110 mg (59%).

¹ H NMR (CD 3 OD): δ 7.77 (d, 1H), 7.73 (d, 1H), 7.53-7.14 (m, 8H), 6.95 (d, 1H).

Example 124

Preparation of N- [2-hydroxy-3,4-dichlorophenyl] -N- [2,3-dichlorophenyl] urea

187

N- [2-Hydroxy-3,4-dichlorophenyl] -N '- [2,3-dichlorophenyl] urea was prepared from 80 mg (0.50 mmol) of 2-amino-5,6-dichlorophenol (from Example 82b) The product was purified by precipitation from ethyl acetate / hexane and filtering to 130 mg (71 percent).

¹ H NMR (CD ₃ OD): δ 8.06 (dd, 1H), 7.91 (d, 1H), 7.25 (m, 2H),

7.00 (d, IH).

Example 125

Preparation of N- [2-hydroxy-4-isopropylphenyl] -N- [3-trifluoromethylphenyl] urea

a) Preparation of 2-nitro-5-isopropylphenol

3.00 grams (22 millimoles) of 3-isopropylphenol was dissolved in 40 milliliters of dichloromethane and 2.06 grams (24 millimoles) of sodium nitrate was added. Then 25 milliliters of 3 molar sulfuric acid and a catalytic amount of sodium nitrite were added sequentially to the reaction mixture.

The reaction mixture was allowed to stir for 24 hours, diluted with dichloromethane and extracted with water. The organic layer was dried over anhydrous magnesium sulfate and filtered. Evaporation of the solvent and chromatography of the residue on silica gel (eluting with 4% methanol in dichloromethane) gave 1.09 g (27%).

188

• · ♦ 9 • 9 * 9 999 • 9 • 9 9 9 • · 9 9 9 9 9 9 9 9 9 • 9 9 9 9 9 9 9 9 9 9 9 9

of the desired product.

¹ H NMR (CD 3 COCD 3): δ 7.95 (d, 1H), 7.62 (d, 1H), 7.11 (d, 1H), 2.95 (m, 1H), 1.24 (d, 6H).

b) Preparation of 2-amino-5-isopropylphenol

To a solution of 1 gram (6.4 millimoles) of 2-nitro-5-isopropylphenol in 50 ml of methanol was added 100 mg of 10%

Pd / C. The mixture was purged with argon. Subsequently, hydrogen was bubbled through the solution for 10 minutes and the reaction mixture was left under hydrogen pressure over a hydrogen-filled balloon overnight. The mixture was filtered through celite, which was then rinsed with methanol. The filtrate was concentrated, and chromatography of the obtained solid residue on silica gel (eluting with 5% methanol in dichloromethane) afforded 775 mg (93%) of the desired product.

^Δ NMR (CD 3 OD): δ 6.71-6.44 (m, 3H), 2.73 (m, 1H), 1.20 (d,

6H).

c) Preparation of N- [2-hydroxy-4-isopropylphenyl] -N ^f - [3-trifluoromethylphenyl] urea

N- [2-Hydroxy-4-isopropylphenyl] -4 '- [3-trifluoromethylphenylurea] was prepared from 75 mg (0.50 mmol) of 2-amino-5-isopropylphenol by general procedure B. The product was purified by precipitation from ethyl acetate / hexane and filtered to 140 milligrams (83 percent).

¹ H NMR (CD 3 OD): δ 7.91 (d, 2H), 7.62 (d, 1H), 7.47 (t, 1H),

7.39 (d, 1H), 6.75 (s, 1H), 6.72 (d, 1H), 2.80 (m, 1H), 1.21 (d, 6H).

· Fc «· · fcfcfc ·

189 fc • fc fc fcfc «fc · · ·

fc fc «fc • fc ·

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 160 mg (1.00 mmol) of 3-amino-2-naphthoi by general procedure B. The product was purified by precipitation from of ethyl acetate / hexane and filtering to 285 mg (82 percent).

¹ H NMR (CD ₃ OD): δ 8.48 (s, 1H), 8.10 (d, 1H), 7.68 (d, 1H),

7.57 (d, 1H); 7.40-7.23 (m, 4H); 7.18 (d, 1H).

Example 127

Preparation of N- [2 - [(2,3-dichlorothien-5-yl)] sulfonylamino] phenyl] N '- (2-bromophenyl) urea

a) Preparation of 2 - [(2,3-dichlorothien-5-yl)] sulfonylaminoaniline

The title compound was prepared via General Procedure C using 1 equivalent of 2,3-dichlorothiophene-5-sulfonyl chloride. The product was purified by flash chromatography on silica gel (eluting with ethyl acetate / hexane (20:80) to dichloromethane / methanol (90:10)) to give 1.25 g (39 percent).

EI-MS m / z 321 (MH).

b) Preparation of N- [2 - [(2,3-dichlorothien-5-yl)] sulfonylamino] phenyl] -N '- (2-bromophenyl) urea

This compound was prepared from 1.25 grams (3.9 millimoles) of 2 - [(2,3-dichlorothien-5-yl)] sulfonylaminoaniline and 768 milligrams (3.9 millimoles) of 2- (bromophenyl) isocyanate in general.

190

Procedure B. The product was purified by flash chromatography on silica gel (eluting with ethyl acetate / hexane (30:70)) to give 272 mg (13 percent).

EI-MS m / z 520 (M-H) &lt; - &gt;.

Example 128

Preparation of N- [2 - [(3,5-bistrifluoromethylphenyl) sulfonylamino] phenyl] -1 '- (2-bromophenyl) urea

a) Preparation of 2- (3,5-bistrifluoromethylphenyl) sulfonylaminoaniline

The title compound was prepared according to the general procedure C using 1.28 g (4.1 millimoles) of 3,5- (bistrifluoromethyl) phenylsulfonyl chloride and 441 mg (4.1 millimoles) of o-phenylenediamine. The product was purified by flash chromatography on silica gel (dichloromethane / methanol (95: 5)) to give 611 mg (39 percent).

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 591 mg (1.5 mmol) of 2 - [(3,5-bistrifluoromethylphenyl) sulfonylaminoaniline and 305 mg (1.5 mmol) of 2-bromophenylisocyanate according to the general procedure B. The product was purified by flash chromatography on silica gel (eluting). ethyl acetate / hexane (30:70)) and the amount was 10 mg (1 percent). EI-MS m / z 580 (MH +).

191

• 4 • 4 • 4 4

4 ♦ · ·

Example 129

Preparation of N- [2 - [(2-benzyl) sulfonylamino] - (5-trifluoromethyl) phenyl] -N '- (2-bromophenyl) urea

a) Preparation of [(4-benzylsulfonylamino) -3-nitrobenztrifluoride 1.0 gram (4.85 mmol) of 4-amino-3-nitrobenztrifluoride was mixed with dimethylformamide (DMF) and the reaction mixture was cooled to 0 ° C. 175 mg (7.28 mmol) of sodium hydride was added to the cooled mixture, and the mixture was stirred for 10 minutes (a change in color of the mixture to a deep red color was noted). Thereafter, 925 mg (4.85 mmol) of toluenesulfonyl chloride was added (the color of the mixture turned yellow) and the reaction mixture was allowed to stir at room temperature for 16 hours. The mixture was then quenched with ammonium chloride and extracted with ethyl acetate / hexane (1: 1). Purification by flash chromatography (eluting with ethyl acetate / hexane (30:70)) gave 878 mg (52 percent) of the product.

EI-MS m / z 359 (M-H) &lt; - &gt;.

b) Preparation of (4-benzylsulfonylamino) -3-aminobenztrifluoride 230 milligrams (0.64 millimoles) of (4-benzylsulfonylamino) -3-nitrobenztrifluoride was mixed with methanium and poured into a Parr bottle. To the mixture was added 15 milligrams of palladium on carbon under a stream of argon. The vessel (pressurized with hydrogen to 379.2 kilopascal (55 psi)) was placed on a Parr shaker for several hours. The reaction mixture was then filtered through celite and the filtrate was evaporated to give 210 mg (99 percent) of the desired product.

EI-MS m / z 329 (M-H) &lt; + &gt;.

** ·· · · · · · φ · · · · · ·

192

c) Preparation of N- [2 - [(2-benzyl) sulfonylamino] - (5-trifluoromethyl) phenyl] -N '- (2-bromophenyl) urea

The title compound was prepared from 210 mg (0.64 mmol) of (4-benzylfulphonylamino) -3-aminobenzotrifluoride and 126 mg (0.64 mmol) of 2-bromophenylisocyanate according to general procedure B. The product was purified by flash chromatography on silica gel (eluting with ethyl acetate). (hexane (30:70)) and amounted to 70 milligrams (21 percent).

EI-MS m / z 526 (M-H) &lt; + &gt;.

Example 130

Preparation of N- [2- [2- (3-triphenyl) sulfonylamino] phenyl] -N '- (2-bromophenyl) urea

a) Preparation of 2 - ((3-nitrophenyl) sulfonylamino) aniline

The title compound was prepared via General Procedure C using 1 equivalent of 3-nitrobenzenesulfonyl chloride.

The product was purified by silica gel flash chromatography (eluting with dichloromethane / methanol (96: 4)) to afford 1.07 g (37 percent) of the desired product.

EI-MS m / z 294 (M + H) &lt; + & gt ^; .

b) Preparation of N- [2 - [(3-nitrophenyl) sulfonylamino] phenyl] -N '- (2-bromophenyl) urea

The title compound was prepared from 590 mg (2.0 mmol) of 2- (3-nitrophenyl) sulfonylaminoaniline and 398 mg (2.0 mmol) of 2- (bromophenyl) isocyanate according to the general procedure B. The product was purified by flash chromatography on silica gel (eluting with mixtures). ethyl acetate / hexane (70:30)) and the amount was 400 mg (40 percent).

193

EI-MS m / z 489 (M-H) &lt; + &gt;.

Example 131

Preparation of N- [2- [2- (4-phenoxyphenyl) sulfonylamino] phenyl] -N '- (2-bromophenyl) urea

a) Preparation of 2 - ((4-phenoxyphenyl) sulfonylamino) aniline

This compound was prepared according to the general procedure C using 969 mg (3.6 mmol) of 4-phenoxyphenylsulfonyl chloride and 300 mg (2.77 mmol) of o-phenylenediamine. The reaction mixture was partitioned between 200 mL of water and toluene / dichloromethane (1: 3). The organic phase was combined. of dichloromethane. Hexane was added to the obtained toluene solution to precipitate the product to give 317 mg (34 percent).

EI-MS m / z 341 (M + H) &lt; + & gt ^; .

b) Preparation of N- [2 - [(4-phenoxyphenyl) sulfonylamino] phenyl] -N '- (2 bromophenyl) urea

The title compound was prepared from 276 mg (0.8 mmol) of 2- (4-phenoxyphenyl) sulfonylaminoaniline and 161 mg (0.8 mmol) of 2- (bromophenyl) isocyanate according to the general procedure B. The product was purified by flash chromatography on silica gel (eluting). ethyl acetate / hexane (70:30)), and the amount was 240 mg (55 percent).

EI-MS m / z 536 (M-H) '.

• · · · · · · · · · ·

194

Example 132

Preparation of N- [[2- (IS) -10-camphorsulfonylamino] phenyl] -N'- (2-bromophenyl) urea

a) Preparation of 2 - ((IS) -10-camphorsulfonylamino) aniline

The title compound was prepared via General Procedure C using 1.16 g (4.6 mmol) of (IS) (+) - 10-camphorsulfonyl chloride and 500 mg (4.6 mmol) of o-phenylenediamine. The reaction mixture was partitioned between 200 mL of water and toluene / dichloromethane (1: 3). The organic phase was combined and dichloromethane was evaporated from the mixture. Hexane was added to the obtained toluene solution to precipitate the product, yielding 130 mg (9 percent).

EI-MS m / z 323 (M + H) &lt; + & gt ^; .

b) Preparation of N- [[2- (IS) -10-camphorsulfonylamino] phenyl] -1 '- (2-bromophenyl) urea

The title compound was prepared from 130 mg (0.4 mmol) of 2- (IS) -10-camphorsulfonylaminoaniline and 80 mg (0.4 mmol) of 2- (bromophenyl) isocyanate according to general procedure B. After evaporation of the solvent, the product was purified by flash chromatography silica gel (eluting with ethyl acetate / hexane (70:30)) and amounted to 200 mg (95 percent).

EI-MS m / z 518 (MH) ^&lt; ^{- &gt};

························

Example 133

Preparation of N- [[2- (IR) -1O-camphorsulfonylamino] phenyl] -N '- (2-bromophenyl) urea

195 • to ·· ·

a) Preparation of 2 - ((IR) -10-camphorsulfonylamino) aniline

This compound was prepared according to the general procedure C using 1.16 g (4.6 mmol) of (IR) (-) - 10-camphorsulfonyl chloride and 500 mg (4.6 mmol) of o-phenylenediamine. The reaction mixture was partitioned between 200 mL of water and toluene / dichloromethane (1: 3). The organic phase was combined and the mixture was evaporated with dichloromethane. Hexane was added to the obtained toluene solution to precipitate 563 mg (38 percent) of the product.

EI-MS m / z 323 (M + H) &lt; + & gt ^; .

b) Preparation of N - [[2- (IR) -10-camphorsulfonylamino] phenyl] -N '- (2-bromophenyl) urea

The title compound was prepared from 5630 mg (1.75 mmol) of 2- (IR) -10-camphorsulfonylaminoaniline and 346 mg (1.75 mmol) of 2- (bromophenyl) isocyanate according to general procedure B. After evaporation of the solvent, the product was purified by flash chromatography silica gel (eluting with ethyl acetate / hexane (70:30)) and amounted to 263 mg (29 percent).

EI-MS m / z 518 (M-H) &lt; - &gt;.

• 9 9

196 # 9

Example 134

Preparation of N- [2- [2- (2-nitro- (4-trifluoromethyl) phenyl) sulfonylamino] phenyl-N '- (2-bromophenyl) urea

a) Preparation of [2 - [(2-nitro) - (4-trifluoromethyl) phenyl] sulfonylamino] aniline

The title compound was prepared via General Procedure C using 1 equivalent of 2-nitro-4- (trifluoromethyl) benzenesulfonyl chloride. The product was purified by flash chromatography (eluting with dichloromethane / methanol (96: 4)) to give 875 mg (25 percent). . bromophenyl) urea EI-MS m / z 362 (M + H) &lt; + & gt ^; .

b) Preparation of N- [2- [2- (2-nitro- (4-trifluoromethyl) phenyl] sulfonylamino] phenyl-N '- (2-bromophenyl) urea

This compound was prepared from 740 mg (2.1 mmol) of 2 - [(2-nitro- (4-trifluoromethyl) phenyl] sulfonylaminoaniline) and 406 mg (2.1 mmol) of 2- (bromophenyl) isocyanate according to the general procedure B. After evaporation The product was further purified by recrystallization from ethyl acetate / hexane to give 320 mg (28 percent).

EI-MS m / z 557 (M-H &lt; - &gt;).

197 4 4 • 4 • 4 · * 4 99 99 4 4 4 4 4 4

4 *>

4 »44» 4 4

4 • 4 «

·· 4

Example 135

Preparation of N- (2-hydroxy-4-azidophenyl) -N '- (2-iodophenyl) urea

a) Preparation of N- (2-hydroxy-4-aminophenyl) -N '- (2jphenyl) urea

To a solution of 220 mg (0.55 mmol) of N- (2-hydroxy-4-nitrophenyl) -N '- (2-iodophenyl) urea in 15 ml of ethanol was added 522 mg (2.75 mmol) of stannous chloride. The mixture was heated to boiling for 16 hours, allowed to cool to room temperature, and basified to pH 8 with aqueous sodium bicarbonate. The reaction mixture was then extracted three times with ethyl acetate. The organic extracts were combined, dried over anhydrous magnesium sulfate, and filtered. Evaporation of the solvent under reduced pressure gave 180 mg (89 percent) of the desired product.

EI-MS m / z 370 (M + H) &lt; + & gt ^; .

b) Preparation of N- (2-hydroxy-4-azidophenyl) -N '- (2jphenyl) urea

To 77 mg (0.21 mmol) of N- (2-hydroxy-4-aminophenyl) -N '- (2-iodophenyl) urea was added a mixture of 0.21 ml HCl and 0.42 ml water and the reaction mixture was cooled to 0 ° C. Deň: 32 ° C. 14.5 mg (0.21 mmol) of sodium nitrate was added to the reaction mixture, and the resulting mixture was stirred at 0 ° C for 30 minutes. 14 mg (0.21 mmol) of sodium azide was then added to the reaction mixture, which was allowed to warm to room temperature and stirred at this temperature for 18 hours. Subsequently, the reaction mixture was extracted three times with ethyl acetate. The organic extracts were combined, dried over anhydrous sulfate

198

magnesium, filtered and concentrated under reduced pressure. Chromatography of the obtained solid on silica gel (eluting with hexane / ethyl acetate (5: 1)) gave 20 mg (24 percent) of the desired product.

EI-MS m / z 396 (M + H) &lt; + & gt ^; .

Example 136

Preparation of N- (2-hydroxy-3-azido phenyl) -1 '- (2-bromophenyl) urea

a) Preparation of N- (2-hydroxy-3-aminophenyl) -N '- (2-bromophenyl) urea

To a solution of 300 mg (0.85 mmol) of N- (2-hydroxy-3-nitrophenyl) -N '- (2-bromophenyl) urea in 20 ml of ethanol was added 958 mg (4.25 mmol) of stannous chloride. The mixture was heated to boiling for 16 hours, allowed to cool to room temperature, and basified to pH 8 with aqueous sodium bicarbonate. The reaction mixture was then extracted three times with ethyl acetate. The organic extracts were combined, dried over anhydrous magnesium sulfate, and filtered. Evaporation of the solvent under reduced pressure gave 274 mg (99 percent) of the desired product.

EI-MS m / z 323 (M + H) &lt; + & gt ^; .

b) Preparation of N- (2-hydroxy-3-azidophenyl) -N '- (2-bromophenyl) urea

To 274 mg (0.85 mmol) of N- (2-hydroxy-3aminophenyl) -N '- (2-bromophenyl) urea was added a mixture of 0.85 ml HCl and 1.7 ml water and the reaction mixture was cooled to 0 ° C. Deň: 32 ° C. To the reaction mixture was added 58.6 mg (0.85 mmol) of sodium nitrate and the resulting

The 199 mixture was stirred at 0 ° C for 30 minutes. Then, 55 mg (0.85 mmol) of sodium azide was added to the reaction mixture, which was allowed to warm to room temperature and stirred at this temperature for 18 hours. Subsequently, the reaction mixture was extracted three times with ethyl acetate. The organic extracts were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Chromatography of the obtained solid on silica gel (eluting with hexane / ethyl acetate (5: 1)) afforded 210 mg (71 percent) of the desired product.

EI-MS m / z 349 (M + H) &lt; + & gt ^; .

Example 137

Preparation of N- [2-hydroxy-3-cyanophenyl] -N '- [2-methoxyphenyl] urea

N- [2-Hydroxy-3-cyanophenyl] -1 '- [2-methoxyphenyl] urea was prepared from 134 mg (1.00 mmol) of 2-amino-6-cyanophenol by General Procedure B. The product was purified by precipitation from dichloromethane / hexane. (1:20). Filtration gave 230 mg (81 percent) of the desired product.

¹ H NMR (CD ₃ OD): δ 8.06 (d, 1H), 7.79 (d, 1H), 7.49-7.35 (m, 2H), 7.05-6.77 (m 3H), 3.95 (s, 3H).

Example 138

Preparation of N- [2-hydroxy-3-cyanophenyl] -N '- [3-trifluoromethylphenyl] urea

N- [2-Hydroxy-3-cyanophenyl] -4 '- [3-trifluoromethyl200-phenyl] urea was prepared from 134 mg (1.00 mmol) of 2-amino-6-cyanophenol (from Example 83a) by the general procedure B. Product was purified by precipitation from dichloromethane / hexane (1:20). Filtration gave 280 mg (87 percent) of the desired product.

NMR (CD ₃ OD): δ 8.10 (d, 1H), 7.96 (s, 1H), 7.54 (d, 1H),

7.55-7.25 (m, 3H), 7.01 (t, 1H).

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 134 mg (1.00 mmol) of 2-amino-6-cyanophenol (from Example 83a) by general procedure B. The product was purified by precipitation from dichloromethane / hexane (1:20). Filtration yielded 270 mg (82 percent) of the desired product.

NMR (CD ₃ OD): δ 7.81 (d, 1H), 7.75 (d, 1H), 7.56-7.15 (m, 9H), 6.91 (t, 1H).

Example 140

Preparation of N- [2-hydroxy-3-cyanophenyl] -N '- [2,3-dichlorophenyl] urea

N- [2-Hydroxy-3-cyanophenyl] -1 '- [2,3-dichlorophenyl] urea was prepared from 134 mg (1.00 mmol) of 2-amino-6-cyanophenol (from Example 83a) by the general procedure B. The product was purified by precipitation from dichloromethane / hexane (1:20).

201

Filtration yielded 300 mg (93 percent) of the desired product.

¹ H NMR (CD 3 OD): 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-dichlorophenyl] urea was prepared from 150 mg (1.00 mmol) of 2-amino-5-isopropylphenol (from Example 128a) by the general procedure B. The product was purified by precipitation from dichloromethane / hexane (1:20). Filtration gave 285 mg (84 percent) of the desired product.

¹ H NMR (CD 3 OD): δ 8.05 (d, 2H), 7.77 (s, 1H), 7.26 (m, 2H),

6.88 (m, 2H), 2.82 (m, 1H), 1.25 (d, ^J 6H).

Example 142

Preparation of N- [2-hydroxy-4-isopropylphenyl) -N '- [2-chloro-5-trifluoromethylphenyl] urea

N- [2-Hydroxy-4-isopropylphenyl] -4 '- [2-chloro-5-trifluoromethylphenyl] urea was prepared from 150 mg (1.00 mmol) of 2-amino-5-isopropylphenol (from Example 128a) by general Procedure B. The product was purified by precipitation from dichloromethane / hexane (1:20). Filtration yielded 275 mg (82 percent) of the desired product.

202 • 9 · 9 9 9 9 · 9 I 9 O • 9 9 9 * 9 * 99 9 9 9 9 ··

9 · 9 · 9 ··· ···· · 9 999 · 9 Η ^Χ NMR (CD ₃ OD): δ 8.50 (s, 1Η), 7.70 (s, 1H), 7.51 (d, 1 H), 7.22 (d, 1 H), 6.70 (m, 2 H), 6.62 (dd, 1 H), 2.76 (m, 1 H), 1.16 (d) , 6H).

Example 143

Preparation of N- [2-hydroxy-3-phenylphenyl] -N '- [2,3-dichlorophenyl] urea

a) Preparation of 2-nitro-6-phenylphenol

3.00 grams (17.6 millimoles) of 2-phenylphenol was dissolved in 40 milliliters of dichloromethane and 1.65 g (19.4 millimoles) of sodium nitrate was added. Then 25 milliliters of 3 molar sulfuric acid and a catalytic amount of sodium nitrite were added sequentially to the reaction mixture. The reaction mixture was allowed to stir for 24 hours, diluted with dichloromethane and extracted with water. The organic layer was dried over anhydrous magnesium sulfate and filtered. Evaporation of the solvent and chromatography of the residue on silica gel (eluting with 4% methanol in dichloromethane) gave 900 mg (24%) of the desired product.

^{Χ Η} NMR (CD ₃ COCD _3): δ 8.19 (d, 1H), 7.79 (d, 1H), 7.64 (d, 2H), 7.50 (t, 2H), 7.45 (t, 1 H), 7.22 (t, 1 H).

b) Preparation of 2-amino-6-phenylphenol

To a solution of 900 mg (4.2 mmol) of 2-nitro-6-phenylphenol in 50 mL of methanol was added 100 mg of 10% Pd / C. Hydrogen was then bubbled through the solution for 10 minutes and the reaction mixture was left under overnight

203

«· •»

9 *

· Hydrogen pressure created by a balloon filled with hydrogen. The mixture was filtered through celite, which was then rinsed with methanol. The filtrate was concentrated and chromatographed on silica gel (eluting with 5% methanol in dichloromethane) to give 700 mg (90%) of the desired product.

^{Τ Η} NMR (CD ₃ OD): δ 7.55 to 7.27 (m, 5H), 6.77 to 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 92.5 mg (0.50 mmol) of 2-amino-6-phenylphenol by general procedure B. The product was purified by precipitation from dichloromethane / hexane (1:20). Filtration gave 150 mg (81 percent) of the desired product.

NMR (CD ₃ OD): 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 40 (t, 2H), 7.32 (d, 1H), 7.22 (m, 2H), 7.04-6, 88 (m, 2 H).

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 154 mg (1.00 mmol) of 2-amino-4-nitrophenol by the general procedure B. The product was purified by precipitation from dichloromethane / hexane. (1:20). Filtration yielded 270 mg (89 percent) of the desired product.

NMR (CD 3 OD): δ 9.10 (s, 1H), 8.10 (d, 1H), 7.85 (d, 1H),

204

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] -4 '- [3-trifluoromethylphenyl] urea was prepared from 154 mg (1.00 mmol) of 2-amino-4-nitrophenol by general procedure B. The product was purified by precipitation from dichloromethane / hexane (1:20). Filtration yielded 290 mg (85 percent) of the desired product.

¹ H NMR (CD ₃ OD): 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-nitrophenyl] -N '- [2-phenylphenyl] urea

N- [2-Hydroxy-5-nitrophenyl] -4 '- [2-phenylphenyl] urea was prepared from 154 mg (1.00 mmol) of 2-amino-4-nitrophenol by general procedure B. The product was purified by precipitation from dichloromethane / hexane. (1:20). Filtration yielded 285 mg (81 percent) of the desired product.

¹ H NMR (CD 3 OD): δ 8.09 (s, 1H), 7.86 (d, 1H), 7.58-7.20 (m, 9H), 6.95 (d, 1H).

205

Example 147

Preparation of N- [2-hydroxy-5-nitro-phenyl] -N-N- [2,3-dichlorophenyl] -urea

N- [2-Hydroxy-5-nitrophenyl] -4 '- [2,3-dichlorophenyl] urea was prepared from 154 mg (1.00 mmol) of 2-amino-4-nitrophenol by the general procedure B. The product was purified by precipitation from dichloromethane / hexane (1:20). Filtration yielded 290 mg (85 percent) of the desired product.

¹ H NMR (CD ₃ OD): δ 9.11 (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] -1 '- [2,3-dichlorophenyl] urea was prepared from 185 mg (1.00 mmol) of 2-amino-4- (ethylsulfonyl) phenol by the general procedure B. The product was purified by precipitation from dichloromethane / hexane (1:20). Filtration gave 310 mg (84 percent) of the desired product.

¹ H NMR (CD 3 OD): 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).

206

Example 149

N- [2- (2-Amino- (4-trifluoromethyl) phenyl) sulfonylamino] phenyl] -N '- (2-bromophenyl) urea was prepared according to the schemes and examples described above.

EI-MS m / z 527 (M-H) &lt; + &gt;.

Example 150

N- [2- (Aminosulfonylphenyl) -3-aminophenyl] -1 '- (2-bromophenyl) urea was prepared according to the schemes and examples described above.

EI-MS m / z 426 (M + H) &lt; + & gt ^; .

The following compounds of formula (I) may be prepared according to the examples and schemes described above, or may be obtained commercially from well known sources. For example, Aldrich Chemical Company can be obtained commercially

N- (2-hydroxy-4-nitrophenyl) -N'-phenylurea.

For example, 1- (2-carboxyphenyl) -3- (3-fluorophenyl) urea and 1- (2-carboxyphenyl) -3- (3-chlorophenyl) urea may be obtained from the Alfred Bader Collection of Aldrich Chemical.

1- (2-Carboxyphenyl) -3- (4-chlorophenyl) urea and 1- (p-anisyl) -3- (2-carboxyphenyl) urea may be obtained from Gallard Schlesinger Company and / or Sigma Aldrich Library of Rare Compounds. .

207 ·· · 9 9 99

9 9 9 9999 fc ·· • fc · fcfc · fc ·· · fcfc ·· · ··· · fcfcfcfcfcfcfc fc fc fc fc · fc fc fcfc «

2- (3,4-Dichlorophenylcarbonyldiimino) -5-trifluoromethylbenzoic acid, 2- (4-chlorophenylcarbonyldiimino) -5-trifluoromethylbenzoic acid, can be obtained from Gallard Schlesinger Company and

N-phenyl-N '- (2-carboxyphenyl) urea.

It is available from Maybridge Chemical Company, Cambridge England

1,1 '- (4-methyl-2-phenylene) bis [3-tolyl] thiourea a

N- (5-chloro-2-hydroxy-4-nitrophenyl) -N'-phenylurea.

1- (m-Anisyl) -3- (2-carboxyphenyl) urea

1- (o-anisyl) -3- (2-carboxyphenyl) urea

1- (2-Carboxyphenyl) -3- (3,4-dichlorophenyl) urea a

1- (2-carboxyphenyl) -3- (2,4-dichlorophenyl) urea, which are also compounds of formula (I), may be prepared according to the examples and schemes described above or as described in the relevant publications cited in Chemical Abstracts.

Biological examples

The inhibitory effects of the compounds of the present invention on chemokinin IL-8 and GROoc were determined by the following in vitro assay:

[ ¹²⁵ I] Receptor Binding Assays IL-8 (recombinant human) was obtained from Amersham Corp., Arlington Heights, IL, USA and its specific activity was 2000 Ci / millimole. GROa was obtained from the company

208

NEN - New England Nuclear. All other chemicals were of analytical purity. High levels of recombinant human α-β and IL-8 receptors were individually expressed in Chinese hamster ovary cells as previously described (Holmes et al., Science, 1991, 253, 1278). Chinese hamster ovary cell membranes were also homogenized as previously described (Haour et al., J. Biol. Chem., 1974, 249, 2195-2205) except that a mixture of 10 millimoles of Tris-HCl was used as homogenization buffer. , 1 millimole MgSO ₄ ,

0,5 millimole of ethylenediaminetetraacetic acid (EDTA), millimole of t-toluenesulfonyl fluoride (MPMSF),

0.5 milligrams / liter of leupeptin having a pH of 7.5. The membrane protein concentration was determined by a Pierce Co. microassay kit using bovine serum albumin as the standard. All assays were performed on 96-well microplates. Each reaction mixture contained 0.25 nanomolar of ¹²⁵ L IL-8 or ¹²⁵ L GROa a

0.5 microgram / ml of IL-8Rα or 1.0 microgram / ml of IL-8Rβ membrane in a mixture of 20 millimoles of bis (trispropane) and 0.4 millimoles of a pH of 8.0 containing 1, 2 millimoles of MgSO ₄ , 0.1 millimoles of EDTA, 25 millimoles of NaCl and 0.03 percent CHAPS. Next, a test drug or test compound was added to the mixture, which drug was previously dissolved in DMSO to achieve a final drug concentration ranging from 0.01 nanomolar to 100 micromolar. The assay was initiated by the addition of ¹²⁵ L of IL-8. After one hour at room temperature, the plate described above was harvested with a dedicated Tomtec device onto a glass fiber filter plate which was blocked with a 1 percent polyethyleneimine / 0.5 percent BSA plate.

209 • A A ♦ • 9 9 9 9 9 ♦ ♦ ♦ ♦ ♦ ♦

9 9 9 9 · thrice washed with 25 mmol NaCl, 10 millimoles of Tris-HCl, millimoles of MgSO _4, 0.5 millimoles EDTA, 0.03 percent CHAPS, whose pH was 7.4. The filter was then dried and evaluated on a Betaplate liquid scintillation counter. The recombinant IL-8Rα receptor, or type I receptor, has also been referred to herein as an unacceptable receptor, and the recombinant IL-8Rβ, or type II receptor, has also been referred to as an acceptable receptor in this context.

All compounds of formulas (I) to (III), both those prepared as described in Examples 1 to 150 above and others that were purchased, showed IC50 values ranging from about 45 micrograms / milliliter to about <1 micrograms / milliliter. All of these compounds were also found to inhibit approximately the same potency of GROα binding. In the case of 1- (2-carboxyphenyl) -3- (4-chloro-2-methylphenyl) urea, an activity of about 75 micrograms / ml was found.

For some compounds that were generally tested at a concentration of up to 45 micrograms / milliliter, antagonism to IL-8 receptors was not found to an extent that would meet the above criteria at the concentrations tested. These compounds include:

1- (4-chloro-α, α, α-trifluoro-3-tolyl) -3- [2- (4-chlorophenyl) thio] -5-chlorophenyl urea;

1- (6-chloro-α, α, α-trifluoro-3-tolyl) -3- [2- (4-chlorophenoxy) -5-chlorophenyl] urea;

1- (2-mercaptophenyl) -3-phenyl-2-thiourea;

1- (2-hydroxyphenyl) -3-phenyl-2-thiourea;

3,3 '- (carbonthioyldiimino) bis [4-hydroxybenzoic acid];

210 m, m '- (1,3-thioureylene) di (4-hydroxybenzoic acid);

1- (2-tolyl) -3- (3-chloro-6-hydroxyphenyl) -2-thiourea;

1 - [(2-hydroxy-4-aminophenyl)] - (3-phenyl) -urea;

N- (2-carboxy-4-trifluoromethylphenyl) -1 '- (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] benzoic acid; 2- [2- [3- (4-chloro-3- (trifluoromethyl) phenyl) ureido] phenoxy] benzoic acid;

N- (2-hydroxyphenyl) -N'-phenyl urea;

N- [2-hydroxy-5- (methoxycarbonyl) phenyl] -N'-phenyl urea;

N- [4-carboxy-2-hydroxyphenyl] -N'-phenylurea;

N- (2-hydroxy-4-nitrophenyl) -N '- (4-nitrophenyl) 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-methylphenyl) urea;

1 - [(2-hydroxyphenyl) -3- (2-methyl) -5-nitrophenyl] urea;

1- (2,5-dichlorophenyl) -3- (2-hydroxy-4-nitrophenyl) urea;

1- (2-carboxyphenyl) -3- (4-chloro-2-methylphenyl) urea;

N- (2-phenylsulfonylaminophenyl) -N'-phenyl urea;

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;

211 «4

N- (4-Trifluoromethyl-2- (4-nitrobenzenesulfonyl) amino) N'-phenylurea;

N- (3-carboxyphenyl) -N '- (2-hydroxy-4-nitrophenyl) urea;

N- (4-trifluoromethyl-2- (methylsulfonyl) amino] -1'-phenyl urea; N- (2-hydroxy-4-nitrophenyl) -N '- [2- (isopropyl) phenyl] urea;

N- (2-hydroxy-4-nitrophenyl) -1 '- (2,6-dimethylphenyl) urea;

N- (2-hydroxy-4-nitrophenyl) -N '- (2-fluoro-5-nitrophenyl) urea; N- (2-hydroxy-4-nitrophenyl) -N '- (2-chloro-5-trifluoromethylphenyl) urea;

N- (2-hydroxy-4-nitrophenyl) -1 '- (2-methoxy-4-nitrophenyl) urea;

N- (2-hydroxy-1-naphthyl) -N '- (2-phenylphenyl) urea;

N- (2-hydroxy-5-ethylsulfonylphenyl) -1 '- (2-bromophenyl) urea;

N- (2-hydroxy-3,4-dichlorophenyl) -4- (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) -4- (4-methoxyphenyl) urea;

N- (2-hydroxy-3-naphthyl) -N '- (3-trifluoromethylphenyl) urea;

N- (2-hydroxy-3-naphthyl) -4- (4-phenylphenyl) urea;

N- [2- (2-carboxyphenylsulfonylamino) phenyl] -N '- (2-bromophenyl) urea;

N- (2-hydroxy-3-phenylphenyl) -1 '- (2-methoxyphenyl) urea;

N- (2-hydroxy-3-phenylphenyl) -N '- (4-methoxyphenyl) urea;

N- (2-hydroxy-3-phenylphenyl) -N '- (3-trifluoromethylphenyl) urea; N- (2-hydroxy-3-phenylphenyl) -1 '- (2-phenylphenyl) urea;

N- (2-hydroxy-3-phenylphenyl) -1 '- (4-phenylphenyl) urea;

N- [2 - [(2,5-dichlorothien-3-yl) sulfonylamino] phenyl] -N '- (2-bromophenyl) urea;

N- (2-hydroxy-3,4-dichlorophenyl) -1 '- (2,4-dimethoxyphenyl) urea;

212 • fc

• · # ··

N- (2-hydroxy-3,4-dichlorophenyl) -N '- (2-chloro-5-trifluoromethylphenyl) urea;

N- (2-hydroxy-3-naphthyl) -4- (2,4-dimethoxyphenyl) urea;

N- (2-hydroxy-3-naphthyl) -1 '- (2-chloro-5-trifluoromethylphenyl) urea;

N- (2-hydroxy-3-phenylphenyl) -1 '- (2,4-dimethoxyphenyl) urea;

N- (2-hydroxy-4-isopropylphenyl) -N '- (2,4-dimethoxyphenyl) urea;

N- (2-hydroxy-3-phenylphenyl) -1 '- (2-chloro-5-trifluoromethylphenyl) urea;

N- (2-hydroxy-5-nitrophenyl) -N ^'- (2,4-dimethoxyphenyl) urea;

N- (2-hydroxy-5-nitrophenyl) -1 '- (2-chloro-5-trifluoromethylphenyl) 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) -1 '- (2-chloro-5-trifluoromethylphenyl) urea;

N- (2-hydroxy-5-phenylphenyl) -1 '- (2-methoxyphenyl) urea;

N- (2-hydroxy-5-phenylphenyl) -4- (4-methoxyphenyl) urea;

N- (2-hydroxy-5-phenylphenyl) -N '- (3-trifluoromethylphenyl) urea; N- (2-hydroxy-5-phenylphenyl) -N ^'- (2-phenylphenyl) urea N- (2-hydroxy-5-phenylphenyl) -Ν' - (4-phenylphenyl) urea;

N- (2-hydroxy-5-phenylphenyl) -1 '- (2,3-dichlorophenyl) urea;

N- (2-hydroxy-5-phenylphenyl) -1 '- (2,4-dimethoxyphenyl) urea;

N- (2-hydroxy-5-phenylphenyl) -1 '- (2-chloro-5-trifluoromethylphenyl) urea;

N- (2-hydroxy-5-ethylsulfonylphenyl) -1 '- (4-methoxyphenyl) urea;

N- (2-hydroxy-5-ethylsulfonylphenyl) -N '- (3-trifluoromethylphenyl) urea;

213 • to • this •· this •• to ·· ·

N- (2-hydroxy-5-ethylsulfonylphenyl) -1 '- (2-phenylphenyl) urea; N- (2-hydroxy-5-ethylsulfonylphenyl) -1 '- (4-phenylphenyl) urea; N- (2-hydroxy-5-ethylsulfonylphenyl) -1 '- (2,4-dimethoxyphenyl) urea;

N- (2-hydroxy-5-ethylsulfonylphenyl) -N '- (2-chloro-5-trifluoromethylphenyl) urea;

N- [2-hydroxy-3,4-dichlorophenyl] -1 '- [2,4-dimethoxyphenyl] urea;

N- [2-hydroxy-3,4-dichlorophenyl] -N- [2-chloro-5-trifluoromethylphenyl] urea; and

N- [2-hydroxy-3-naphthyl] -4 '- [3-trifluoromethylphenyl] urea.

Chemotaxis test

The in vitro inhibitory properties of the above compounds were determined in a neutrophil chemotaxis assay as described in Current Protocols in Immunology, vol. I, Suppl 1, Unit 6.12.3, the contents of which are incorporated herein by reference. . Neutrophils were isolated from human blood as described in Current Protocols in Immunology, Vol. I, Suppl 1, Unit 7.23.1, the contents of which are incorporated herein by reference. Chemoattractants, IL-8, GROα, GROβ, GROγ and NAP-2, were placed in the lower chamber of a 48-well chamber (Neuro Probe, at concentrations ranging from 0.1 nanomolar to 100 nanomolar).

Cabin John, MD). The two chambers were separated from each other by a 5 micrometer thick polycarbonate filter. To test the compounds of the present invention, the compounds were mixed with said cells (at a concentration of from 0.001 nanomolar to 1000 nanomolar) just prior to the addition of said cells to the upper chamber. The incubation was allowed to proceed at

214 9 9 9 9 9 9 9 9 9

999 9999 999 9999 99 9 humidified incubator with atmosphere containing 5 percent CO ₂ at approximately 37 ° C for 45 to 90 minutes. At the end of the incubation, the polycarbonate membrane was removed, the top side was washed, and the membrane was stained using Diff Quick staining (Baxter Products, McGaw Park, IL). Cells that were chemotaxed into a given chemokinin were visually read using a microscope. Typically, four fields were counted for each sample and the count was averaged to obtain the average number of cells that migrated. Each sample was tested in triplicate and each compound was tested at least four times. No compound was added to some cells (which served as positive comparator cells) and these cells thus represented the maximal chemotactic response of said cells. When it was desired to use a negative comparison (unstimulated cells), no chemokinin was added to the lower chamber. The difference between the activity of the positive reference cells and the activity of the negative reference cells represented the chemotactic activity of said cells.

Elastase release test

The compounds of the present invention were tested for their ability to prevent elastase release from human neutrophils. Neutrophils were isolated from human blood as described in Current Protocols in Immunology, vol. I, Suppl 1, Unit 7.23.1. 0.88 x 10 ⁶ PMN cells suspended in Ringer's solution (containing NaCl 118, KCl 4.56, NaHCCU 25) were placed in each well of a 96-well plate.

KH ₂ PO ₄ 1.03, glucose 11.1, HEPES 5 micromoles and whose pH was

7.4), each well containing 50 microliters of said

215

suspension. 50 microliters of test compound (from 0.001 nanomolar to 1000 nanomolar), microlitres of cytochalasin B solution (20 micrograms / ml) and 50 microliters of Ringer's solution were added to the plate. The treated cells were heated at 37 ° C for 5 minutes in an atmosphere containing 5 percent CO ₂ and 95 percent relative humidity, followed by addition of IL-8, GROα, GROγ, GROγ or NAP-2 at a final concentration of 0, 01 nanomolar to 1000 nanomolar. The reaction was allowed to run for 45 minutes, then the plate was centrifuged (800 x G, 5 minutes) and 100 microliters of supernatant was collected. This supernatant was first added to a second 96-well plate, followed by the addition of an artificial elastase substrate (specifically MeOSuc-Ala-Ala-Pro-ValAMC, purchased from Nova Biochem, La Jolla, CA, USA). the substrate was dissolved in phosphate buffered saline to a final concentration of 6 micrograms / ml. Immediately after the addition of said substrate, the plate was placed in a fluorescent counter of a 96-well plate (Cytofluor 2350, Millipore, Bedford, MA) and as described by Nakajima et al., J. Biol.

Chem., 1979, 254, 4027, data were read at 3 minute intervals. The amount of elastase released from PMN cells was calculated by measuring the rate of degradation of MeOSuc-Ala-Ala-Pro-ValAMC.

The foregoing fully describes the nature of the present invention, including preferred embodiments thereof. Modifications and improvements to the specifically described embodiments of the present invention are also within the scope of the following claims. Based on the above description, one of ordinary skill in the art should be able to utilize the subject matter

216 of the invention in its entirety, without the need for detailed information. For this reason, all of the examples described above are for the purpose of illustration and better understanding of the nature of the present invention and are not intended to limit the scope thereof.

Claims (12)

PATENT CLAIMS 1. A compound of formula (I): where X is an oxygen or sulfur atom; is any hydrogen atom a functional group containing pK _a is 10 or less; ionizovatelný R 1 is independently selected from the group consisting of hydrogen, halogen, nitro, cyano, halogen substituted alkyl of 1 to 10 carbon atoms, alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkoxy a group containing from 1 to 10 carbon atoms, a halogen substituted alkoxy group containing from 1 to 10 carbon atoms, an azide group, a S (O) _t Ro hydroxyl group, a hydroxyalkyl group containing from 1 to 4 carbon atoms, an aryl group, an arylalkyl group containing (C 1 -C 4) alkyl, aryloxy, arylalkoxy of (C 1 -C 4) alkoxy, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic-substituted (C 1 -C 4) alkyl, 218 • 9 9 • 9 • 999 9 9 9 9 9 9 * 9 9 9 9 9 9 • · 9 9 9 • 9 9 9 9 * 9 9 9 · 9 9 9 a heteroaryl-substituted alkoxy group containing from 1 to 4 carbon atoms, an arylalkenyl group containing from 2 to 10 carbon atoms in the alkenyl portion, a heteroarylalkenyl group containing from 2 to 10 carbon atoms in the alkenyl portion, a heterocyclic-substituted alkenyl group containing in alkenyl from 2 to 10 carbon atoms, NR ₄ R ₅ , alkenyl-C (O) NR ₄ R ₅ group containing from 2 to 10 carbon atoms in the alkenyl portion, C (O) NR ₄ R 5, C ( 0) _NR4 Rior S (O) ₃ H, S (O) ₃ R _8, alkyl-C (O) _R group in the alkyl portion contains from 1 to 10 carbon atoms, alkenyl-C (O) R group in the alkenyl moiety contains from 2 to 10 carbon atoms, alkenyl-C (O) ORU group in the alkenyl moiety contains from 2 to 10 carbon atoms, C (0) R, C (0) OR ₂ group, 0C (0) R, NR ₄ C (O) R, or two R groups together can form et O- (CH2) _s O ^- pětiaž or six-membered unsaturated ring; t is 0, or an integer whose value is 1 or 2; s is an integer from 1 to 3; R ₄ and R ₅ are independently selected from the group consisting of hydrogen, optionally substituted alkyl of from 1 to 4 carbon atoms, optionally substituted aryl, optionally substituted arylalkyl of from 1 to 4 carbon atoms, optionally 219 4 · · 4 4 4 ··· 44 44 • 44 4 · 4 · · · 4444 4 4444 4 5 · 444 44 44 4 44 · ♦ 4444 substituted heteroaryl, optionally substituted heteroarylalkyl containing from 1 to 4 carbon atoms, heterocyclic, heterocyclic substituted alkyl having 1 to 4 carbon atoms, or R ₄ and R ₅ together with the nitrogen atom to which they are attached form a five to seven membered ring, which may optionally contain another heteroatom selected from the group consisting of oxygen, nitrogen and sulfur; Y is independently selected from the group consisting of hydrogen, halogen, nitro, cyano, halogen substituted alkyl of 1 to 10 carbon atoms, alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, an alkoxy group containing from 1 to 10 carbon atoms, a halogen substituted alkoxy group containing from 1 to 10 carbon atoms, an azide group, a S (O) _t R 4 group, a hydroxyl group, a hydroxyalkyl group containing from 1 to 4 carbon atoms, an aryl group, arylalkyl (C 1 -C 4) alkyl, aryloxy, arylalkoxy (C 1 -C 4) alkoxy, heteroaryl, heteroarylalkyl, (C 1 -C 4) heteroarylalkoxy, heterocyclic, heterocyclic an alkyl-substituted group u containing v 220 alkyl moieties of from 1 to 4 carbon atoms, arylalkenyl group containing from 2 to 10 carbon atoms in the alkenyl moiety, heteroarylalkenyl groups containing from 2 to 10 carbon atoms in the alkenyl moiety, heterocyclic-substituted alkenyl groups containing from 2 to 10 alkenyl moieties alkyl, NR4R5, alkenyl-C (O) NR4R5 group in the alkenyl moiety contains from 2 to 10 carbon atoms, C (O) NR ₄ R _5, C (0) NR ₄ Rio, S (O) 3H, an S (O) ₃ R 8 group, an alkyl-C (O) R 11 group having from 1 to 10 carbon atoms in the alkyl portion, an alkenyl-C (O) R 11 group having from 2 to 10 atoms in the alkenyl portion carbon, alkenyl-C (O) OR n group containing from 2 to 10 carbon atoms in the alkenyl moiety, C (O) R n group, C (O) OR ₁₂ group, OC (O) R n group, NR ₄ C group ( O) R 11, or two Y groups together, may form an O- (CH ₂ ) _S- group or a 5- to 6-membered unsaturated ring; n is an integer from 1 to 3; m is an integer from 1 to 3; R ₈ is a hydrogen atom or an alkyl group containing from 1 to 4 carbon atoms; R 10 is an alkyl-C (O) ₂ R 8 group containing from 1 to 10 carbon atoms in the alkyl moiety; • · 4 · 221 Λ 4 • 44 R 11 is selected from the group consisting of hydrogen, alkyl of 1 to 4 carbon atoms, optionally substituted aryl, optionally substituted arylalkyl of 1 to 4 carbon atoms, optionally substituted heteroaryl, optionally substituted heteroarylalkyl an alkyl moiety of from 1 to 4 carbon atoms, an optionally substituted heterocyclic group, or an optionally substituted heterocyclic group substituted with an alkyl group containing from 1 to 4 carbon atoms in the alkyl moiety; R ₁₂ is a hydrogen atom, an alkyl group containing from 1 to 10 carbon atoms, an optionally substituted aryl group or an optionally substituted arylalkyl group; or a pharmaceutically acceptable salt of said compound for use in treating a chemokinin-mediated disease state in a mammal in need thereof, wherein said chemokinin binds to IL-8a or β receptors and said disease state is selected from malaria, restinosis, angiogenesis, atherosclerosis , osteoporosis, gingivitis, unwanted stem cell hematopoietic cell release, and diseases caused by respiratory viruses, herpesviruses and hepatitis-causing viruses, which include, but are not limited to, hepatitis B virus and hepatitis C virus. 222 9 9 999 · 99 99 9 · 9 9 9 9 9 «9 9 9 9 The compound of claim 1, wherein said ionizable hydrogen atom has a pK _and in the range of from 3 to 10. The compound of claim 2, wherein R is selected from the group consisting of hydroxyl, carboxylic acid, thiol, -SR ₂ , -OR ₂ , -NH-C (O) R _a , -C (O) NR _S R ₇ , -NHS (O) ₂ R b, -S (O) ₂ NHR _C , NHC (X) NHR _b , or tetrazolyl, wherein R ₂ is substituted aryl, heteroaryl or a heterocyclic group, which ring contains the functional moiety having an ionizable hydrogen _{and a} pKa of which is 10 or less; R 1 and R ₇ independently represent a hydrogen atom or an alkyl group containing from 1 to 4 carbon atoms, or R 6 and R ₇ together with the nitrogen atom to which they are attached form a 5- to 7-membered ring which may optionally contain further a heteroatom selected from the group consisting of oxygen, nitrogen or sulfur; R _a represents an alkyl group, an aryl group, an arylalkyl group containing from 1 to 4 carbon atoms in the alkyl moiety, a heteroaryl group, a heteroarylalkyl group containing from 1 to 4 carbon atoms in the alkyl moiety, a heterocyclic group or a heterocyclic group substituted 223 • 99 • · 9 9 9 9 · 9 · 9 99 · 9 9 9 9 9 »99 9 · 9 9 · • 9 9 9 ·· 9 9 9 9 · 9 9 9 an alkyl group containing from 1 to 4 carbon atoms in the alkyl moiety, all of which may be optionally substituted; R _b is NR ₆ R _{7 -} alkyl, aryl, arylalkyl having 1 to 4 carbon atoms in the alkyl moiety, arylalkenyl having 2 to 4 carbon atoms in the alkenyl moiety, heteroaryl, heteroarylalkyl containing in the alkyl moiety from 1 to 4 carbon atoms, a heteroarylalkenyl group containing from 2 to 4 carbon atoms in the alkenyl moiety, a heterocyclic group, a heterocyclic group substituted by an alkyl group containing from 1 to 4 carbon atoms, or a heterocyclic group substituted alkenyl group containing from 1 to 4 carbon atoms; 2 to 4 carbon atoms, camphor, all of which may be optionally substituted with one to three substituents independently selected from the group consisting of halogen, nitro, halogen substituted alkyl of from 1 to 4 carbon atoms, alkyl containing from 1 to 4 carbon atoms, alkoxy group containing from 1 to 4 carbon atoms, NR ₉ C (O) R _a , C (O) NR ₆ R ₇ , S (O) 3 H or C (O) O an alkyl group containing from 1 to 4 carbon atoms in the alkyl moiety; R 8 represents a hydrogen atom or an alkyl group containing from 1 to 4 carbon atoms; 224 fc fcfc • · fc fc ·· • fc • fc • · • · «· • • · · • fc fcfc • fcfc · • fc · • · fcfc fc * fc · fc • ♦ fc fc · fc R _c represents an alkyl group, an aryl group, an arylalkyl group containing from 1 to 4 carbon atoms in the alkyl moiety, an arylalkenyl group containing from 2 to 4 carbon atoms in the alkenyl moiety, a heteroaryl group, a heteroarylalkyl group containing from 1 to 4 atoms in the alkyl moiety a heteroarylalkenyl group containing from 2 to 4 carbon atoms in the alkenyl moiety, a heterocyclic group, a heterocyclic substituted alkyl group containing from 1 to 4 carbon atoms in the alkyl moiety, or a heterocyclic group substituted alkenyl group containing from 2 to 4 carbon atoms in the alkenyl moiety all of which may be optionally substituted with one to three substituents independently selected from the group consisting of halogen, nitro, halogen substituted alkyl of from 1 to 4 carbon atoms, alkyl of from 1 to 4, and toms atoms, alkoxy containing 1 to 4 carbon atoms, NRgC _(O) Ra, C (O) NR ₆ R _7, S (O) _3H, or C (0) O-alkyl group containing alkyl moieties of from 1 to 4 carbon atoms. The compound of claim 3, wherein R 2 is optionally substituted with one to three substituents selected from the group consisting of halogen, nitro, halogen substituted alkyl of from 1 to 10 carbon atoms, alkyl of from 1 to 10 carbon atoms, 225 • · • · · · 9 fc • » • fc • fcfc · fc • ·· • fc fcfc • fcfc fc · • · · · fc · fc · fc 9 9 C 1 -C 10 alkoxy, hydroxyl, thio, -C (O) NR ₆ R 7, -NH-C (O) R _a , -NHS (O) R _b , S (O) NR ₆ R 7, C (O) OR _8, or a tetrazolyl ring. The compound of claim 3, wherein R is hydroxyl, -NHS (O) ₂ Rb, or carboxyl. A compound according to claim 1, wherein R 1 represents a halogen atom, a cyano group, a nitro group, a trifluoromethyl group, a C (O) NR ₄ R _{5 group} , an alkenyl-C (O) NR ₄ R ₅ group, a C (O) R group ₄ R _0, alkenyl-C (O) OR12, heteroaryl, heteroarylalkyl, heteroarylalkenyl group, or a group S (O) NR ₄ R _5th The compound of claim 1, wherein Y is halogen, alkoxy of from 1 to 4 carbon atoms, optionally substituted aryl, optionally substituted arylalkoxy, methylenedioxy, NR ₄ R ₅ , thioalkyl of from 1 to 4 carbon atoms, a thioaryl group, a halogen substituted alkoxy group, an optionally substituted alkyl group containing from 1 to 4 carbon atoms, a hydroxyalkyl group. 226 • ·· φ · φ φ · · ♦ • • • • • • φ φ φ φ φ φ φ φ φ φ φ · · · A compound according to claim 1, wherein R is hydroxyl, thio or NHS (O) _with R _b and R 1 is monosubstituted at the 3-position or at the 4-position, or is disubstituted at the 3,4-positions, by an electron acceptor group . The compound of claim 1 or 8, wherein the Y group is monosubstituted at the 2 'or 3' position or is disubstituted at the 2 ', 3' positions of the monocyclic ring. A compound according to claims 1, 8 or 9, wherein n and m are equal to or greater than 1. The compound of claim 1, wherein R is carboxylic acid and R 1 is hydrogen, or R _{x is} substituted at the 4-position. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of 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; • 0 0000 227 • 0 0 0 0 0 0 00 00 N- (2-hydroxy-4-nitrophenyl) -1 '- (2-methylthiophenyl) urea; N - (2-hydroxy-4-nitrophenyl) - N - (2,3-dichlorophenyl) urea N- (2-hydroxy-4-nitrophenyl) - N - (2-chlorophenyl) urea; N- (2-hydroxy-4-nitrophenyl) -N '- (2,3-methylenedioxyphenyl) urea; N- (2-hydroxy-4-nitrophenyl) -N '- (2-methoxy-3-chlorophenyl) urea; N- (2-hydroxy-4-nitrophenyl) -N '- (2-phenyloxyphenyl) urea; N- (3-chloro-2-hydroxyphenyl) -N '- (bromophenyl) urea; N- (2-hydroxy-3-glycine-methyl-ester-carbonylphenyl) -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-hydroxy-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-nitrophenyl) -N '- (2-iodophenyl) urea; N- (2-hydroxy-4-nitrophenyl) -N '- (2-bromophenyl) thiourea; N- (2-phenylsulfonamido) -4-cyanophenyl-N '-( 2-bromophenyl) urea; (E) -N- [3 - [(2-aminocarbonyl) ethenyl] 2-hydroxyphenyl] -N '- (2-bromophenyl) urea; ························· << Back Page 9 999 9 9 9 9 · · «· 228 999 9 · 9 999 • 99 99 ·· 9 ·· 9 · · Μ · N- (2-hydroxy-3,4-dichlorophenyl) -1- (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) -1 '(2,3-dichlorophenyl) urea; and N- (2-hydroxy-3-cyanophenyl) -N '- (2,3-dichlorophenyl) urea or pharmaceutically acceptable salts thereof. Represented by: