CZ20014490A3 - Antagonists of IL-8 receptor - Google Patents

Abstract

This invention relates to novel compounds of Formula (I), pharmaceutical compositions and their use in the treatment of disease states mediated by the chemokine, Interleukin-8 (IL-8).

Description

IL-8 receptor antagonists

Technical field

The present invention relates to a novel class of guanidine-containing compounds, to pharmaceutical compositions containing these compounds, to a process for their preparation, and to the use of these compounds in the treatment of diseases mediated by IL-8, GRO10, GROP, GROy ENA-78 and NAP-2.

BACKGROUND OF THE INVENTION

Interleukinin-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. Biol. Chem. 1989, 264, 10621 (Strieter and coworkers), and · · ··· ············· · · ··· J. Immunol. 1992, 148, 3216 (Cassatella et al.).

It belongs to the chemokinin family as well as GROα, GRO3, GROγ and NAP-2. Like IL-8, these chemokinins are referred to by different names. For example, GROo1, 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, ββ, 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 protein re-synthesis. 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, GROβ, 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, 97 (Baggiolini et al.), Crit. Roar. Immunol. 1992, 12, 17 (Miller et al.), Ann. Roar. Immunol.

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) are associated 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. Therefore, the IL-8 receptor represents a potential target for the development of novel anti-inflammatory agents.

Characterization of two high affinity human IL-8 receptors (with 77 percent homology) has been reported: IL-8Rα, which only binds IL-8 with high affinity, and IL-8RP, • fcfcfc ··· · fc · · · ·· Fc which has a high affinity for IL-8 as well as for GROo1, GROp, GROy and NAP-2 (see Science 1991, 253, 1278 (Holmes et al.), Science 1991) , 253, 1280 (Murphy et al.), J. Biol. Chem. 1992, 26Ί, 16283 (Lee et al.), J. Biol. Chem. 1992, 267, 25402 (LaRosa et al.), And J. Biol. Chem., 1993, 268, 7283 (Gayle et al.).

In this field of treatment, there is still a need for compounds capable of binding to the IL-8α 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:

W - NH N - (CR ₁₃ R ₁₄ ) v - W,

H (I) wherein

Z is cyano, OR _U, C (O) NR ₅ R _16, R _i8, C (O) R, C (O) ORU or S (O) ₂ Ri7;

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 (CR ₈ R ₈ ) _q S (O) _t R ₄ group, a hydroxyl group, a hydroxyalkyl group containing from 1 to 4 carbon atoms, aryl, arylalkyl containing from 1 to 4 carbon atoms, aryloxy, arylalkyloxy containing from 1 to 4 carbon atoms, heteroaryl, heteroarylalkyl, • ······! 9,999,999,999,999,999,999,999,999,999,999,999,999,999,999,999,999,999,999,999,999,999,999,999,999,999,999,999,999,999,999,999,999,999,999,999,999,999,999,999,999,999,999,999,999,999,999,999,999,999,999,999,999,999,999,999,999,999 (C 2 -C 10) alkenyl moiety, (C 2 -C 10) heteroarylalkenyl, C 2 -C 10 heterocyclic-substituted alkenyl moiety, (CR ₈ R ₈ ) _q NR ₄ R 5, alkenyl-C (O) NR ₄ R ₅ , containing from 2 to 10 carbon atoms in the alkenyl moiety, (CR ₈ R ₈ ) _q C (O) NR ₄ R ₅ , (CR ₈ R ₈ ) _q C (O) NR ₄ R ₁₀ , S (O) ₃ H, S (O) 3 R ₈ , (CR ₈ R ₈ ) _q C (O) R 11, alkenyl-C (O) R 11 containing from 2 to 10 alkenyl moieties carbon atoms, alkenyl-C (O) ORu group containing in the alkenyl moiety from 2 d about 10 carbon atoms, (CR ₈ R _{8) q} C (O) OR _I2 group (CRgRg) _q OC (O) R group, (CRgRg) _q NR ₄ C (O) R group (CRgR _{8) q} NHS (O) ₂ R 19, (CR ₈ R ₈ ) _q S (O) ₂ NR ₄ R ₅ , or two R _x groups together form O- (CH ₂ ) _S O or a 5- to 6-membered saturated or unsaturated ring ;

q is 0, or an integer from 1 to 10;

s is an integer from 1 to 3;

t is 0, or an integer of 1 or 2;

v is 0, or an integer from 1 to 4;

• 9

9

9

9

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 the nitrogen atom to which are bound to form a 5- to 7-membered ring which may optionally contain an additional heteroatom selected from the group consisting of 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 (CR ₈ R 5) _q S (O) _t Ro hydroxyl group, a hydroxyalkyl group containing from 1 to 4 carbon atoms, an aryl group arylalkyl having 1 to 4 carbon atoms in the alkyl moiety, aryloxy, arylalkyloxy having 1 to 4 carbon atoms in the alkyloxy moiety, heteroaryl, heteroarylalkyl, · • ·

a heteroarylalkyloxy group containing from 1 to 4 carbon atoms in the alkyloxy moiety, a heterocyclic group, a heterocyclic 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 from 2 to 10 carbon atoms, a heterocyclic-substituted alkenyl group containing from 2 to 10 carbon atoms in the alkenyl moiety, a (CR ₈ R ₈ ) _q NR ₄ R _{5 group} , an alkenyl-C (O) NR ₄ R ₅ group which the alkenyl portion contains 2 to 10 carbon atoms, (CR ₈ R _{8) q} C (O) NR ₄ R _5, (CR ₈ R _{8) q} C (O) NR4R3.0, S (O) 3H ,. S (O) 3 R _8, (CR ₈ R _{8) q} C (O) R, alkenyl-C (O) R group in the alkenyl moiety contains from 2 to 10 carbon atoms, alkenyl-C (O) ORU a group containing from 2 to 10 carbon atoms in the alkenyl moiety, a C (O) R 11 group, a (CR ₈ R ₈ ) _q C (O) OR ₁₂ group, a (CR ₈ R ₈ ) _q OC (O) R 11 group, a group (CR ₈ R ₈ ) _q NR ₄ C (O) R 11, (CR ₈ R ₈ ) _q NHS (O) ₂ R 6, (CR ₈ R ₈ ) _q S (O) 2NR ₄ R ₅ , or two Y groups may together form a group -O- (CH _{2) s} O ^- or a five- to six-membered saturated or unsaturated ring;

n is an integer from 1 to 3;

m is an integer from 1 to 3;

R ₆ and R ₇ are independently selected from the group consisting of hydrogen, alkyl of 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, φ který který který který který který který který který který který který který který který který který který který který který který který který který který který který který který který který který který který který který který který selected from the group consisting of oxygen, nitrogen or sulfur;

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;

R ₁₃ and R ₁₄ are independently selected from the group consisting of hydrogen, optionally substituted alkyl of 1 to 4 carbon atoms, or one of R 13 and R 14 may be an optionally substituted aryl group;

• · · · · · · · ·

9 ···· ·

9 9

9

9 9

999 ·

99 • 9 9 • • 9 9 • 99

9 9 • 9 9999

R 18 and R 16 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 optionally substituted heteroarylalkyl group the alkyl portion contains 1 to 4 carbon atoms, optionally substituted heterocyclic group, optionally substituted heterocyclic group-substituted alkyl group the alkyl portion contains 1 to 4 carbon atoms or the groups R ₅ and R ₆ together with the nitrogen to which they are attached form a five to seven membered ring, which may optionally contain another heteroatom selected from oxygen, nitrogen or sulfur;

R 11 is an alkyl group containing from 1 to 4 carbon atoms, an NR ₁₅ R ₁₆ group, an OR ₁₁ group, an optionally substituted aryl group, an optionally substituted arylalkyl group containing from 1 to 4 carbon atoms, an optionally substituted heteroaryl group, an optionally substituted heteroarylalkyl group having from 1 to 4 carbon atoms in the alkyl moiety, an optionally substituted heterocyclic group, an optionally substituted heterocyclic group, an alkyl group having from 1 to 4 carbon atoms in the alkyl moiety;

R 18 is an optionally substituted alkyl group having from 1 to 4 carbon atoms, an optionally substituted aryl group, or an alkyl group having from 1 to 4 carbon atoms, an optionally substituted aryl group. 4444 444444, optionally substituted arylalkyl group containing from 1 to 4 carbon atoms in the alkyl moiety, optionally substituted heteroaryl group, optionally substituted a heteroarylalkyl group containing from 1 to 4 carbon atoms in the alkyl moiety, an optionally substituted heterocyclic group, an optionally substituted heterocyclic group, a substituted alkyl group having from 1 to 4 carbon atoms;

Ris is an alkyl group containing from 1 to 4 carbon atoms, an aryl group, an arylalkyl group, a heteroaryl group, a heteroarylalkyl group containing from 1 to 4 carbon atoms in the alkyl portion, a heterocyclic group, a heterocyclic substituted alkyl group containing from 1 to 4 atoms in the alkyl portion all of said groups being optionally substituted;

R _d is NR 6 R 7, alkyl, arylalkyl having 1 to 4 carbon atoms in the alkyl moiety, arylalkenyl having 2 to 4 carbon atoms in the alkenyl moiety, heteroaryl, heteroarylalkyl having 1 to 4 carbon atoms in the alkyl moiety , a heteroarylalkenyl group having from 2 to 4 carbon atoms in the alkenyl moiety, a heterocyclic group or a heterocyclic substituted alkyl group having from 1 to 4 carbon atoms in the alkyl moiety, all of said alkyl groups, aryl groups, arylalkyl groups, heteroaryl groups, heteroarylalkyl groups, heterocyclic groups and alkyl-substituted heterocyclic groups may be optionally substituted;

«·

(FQm or group, wherein the ring containing the group

E 'is optionally selected from the group consisting of

wherein the asterisk (*) indicates where the ring is bound to the base ring;

• · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Wi is taking groups

including

is optionally selected from

wherein the asterisk (*) indicates the location bound to the base ring;

wherein said ring or pharmaceutically acceptable salts thereof.

The compounds of formula (I) may also be used in veterinary medicine in the treatment of non-human mammals in need of inhibition of IL-8 or other chemokinins that bind to IL-80 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.

• · ·

4 represents a group W

Suitably in the compounds of formula (I)

Optionally, in these groups, the ring E 'may be present, which is bound at the points indicated by an asterisk (*). If ring E 'is not present in the group W, this group represents a phenyl group which is substituted by the group R _x as defined above. Said group E may be substituted by a group R _x on any ring, whether saturated or unsaturated, and is shown herein only in case of substitution on the unsaturated ring.

In compounds of formula (I) represents the group R suitably any functional moiety having an ionizable hydrogen _{and a} pKa of which 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 formula -NHS (O 12 Rbr -S (O) ₂ NHR _c , NHC (X ₂ ) NHR b, or a tetrazolyl group, wherein X ₂ represents an oxygen or sulfur atom, preferably an oxygen atom, without being limited thereto. 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 group, heteroaryl 9

9 9

9 9

9999 • * 9

9 9 • 9 9

99999 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, 9, 9, 9, 9, 9, 9, 9, 9, 9, and 9 groups. In a more preferred embodiment, R is hydroxyl, thiol or NHS (O) 2 Rb ·

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 8 'and R 7' may suitably represent a hydrogen atom, 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 moiety, an arylalkenyl group containing from 2 to 4 carbon atoms in the alkenyl moiety. , heteroaryl, heteroarylalkyl having 1 to 4 carbon atoms in the alkyl moiety, heteroarylalkenyl having 2 to 4 carbon atoms in the alkenyl moiety, heterocyclic group, heterocyclic-substituted alkyl having 1 to 4 carbon atoms in the alkyl moiety, heterocyclic an alkenyl group having 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, containing from 1 to 4 carbon atoms such as trifluoromethyl (CF ₃ ), an alkyl group containing from 1 to 4 carbon atoms such as a methyl group, an alkoxy group containing from 1 to 4 carbon atoms such as a methoxy group, NR ₉ C (O) R _a , a C (O) NR ₅ R-7 group, an S (O) 3 H group, a C (O) OC-alkyl group containing from 1 to 4 carbon atoms in the alkyl portion, with only one of the R groups ₆ , and R ₇ can be hydrogen.

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 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 another heteroatom selected from oxygen, nitrogen or sulfur. Said heterocyclic group may be further substituted as described herein.

R _and suitably represents 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, heterocyclic group or heterocyclic group, substituted alkyl group containing in the alkyl moiety by All of these groups may be optionally substituted as described below.

R b can be 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 C 1 -C 4 heteroarylalkenyl, C 2 -C 4 alkenyl, heterocyclic, heterocyclic-substituted C 1 -C 4 alkyl or heterocyclic 9 9 999 ···· substituted alkenyl having 2 to 4 carbon atoms in the alkenyl moiety, camphor, all of which may be optionally substituted with one to three substituents independently selected from halogen, nitro, halogen-substituted alkyl having from 1 to 4 carbon atoms such as CF ₃ , an alkyl group containing from 1 to 4 carbon atoms such as methyl, an alkoxy group containing from 1 to 4 carbon atoms such as methoxy, NR 8 C (O) R, _and , a C (O) NR ₆ R 7 group, an S (O) ₃ H group, or a C (O) O-alkyl group containing from 1 to 4 carbon atoms in the alkyl portion. 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.

R 8 represents a hydrogen atom or an alkyl group containing from 1 to 4 carbon atoms, but preferably a hydrogen atom. When said substituent is NR 8 C (O) R _a , then R _a preferably represents an alkyl group such as a methyl group.

The R _{c group} may suitably represent a hydrogen atom, 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, heteroaryl, heteroarylalkyl group containing in the alkyl moiety from 1 to 4 carbon atoms, a heteroarylalkenyl group containing from 1 to 4 carbon atoms in the alkenyl moiety, and from 1 to 4 carbon atoms; It is a heterocyclic group, a heterocyclic-substituted alkyl group containing from 1 to 4 atoms in the alkyl moiety. or a heterocyclic-substituted alkenyl group containing from 1 to 4 carbon atoms in the alkenyl moiety, all of which may be optionally substituted with one to two carbon atoms. three substituents independently selected from the group consisting of halogen, nitro, halogen-substituted alkyl of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, NR ₉ C (O R _a , a group

C (O) NR ₆ R _7, S (O) 3H, or C (0) O-alkyl the alkyl portion contains 1 to 4 carbon atoms, wherein Rg represents hydrogen or an alkyl group containing 1 to 4 carbon carbon. 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 one skilled in the art that the respective aryl ring must contain an ionizable hydrogen atom. Said aryl ring may also be further substituted with 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 1 to 4 carbon atoms , (C 1 -C 4) alkyl, (C 1 -C 4) alkoxy, hydroxyl, thiol, -C (O) NR 5 R 7, -NH-C (O) R _a , -NHS ( O) 2Rb, S (O) 2 NR 5 R 7, C (O) OR 5, 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 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 a trifluoromethoxy group, an azide group, a (CR 9 R ₅ ) q S (O) _t R _{4 group} wherein t is 0, 1 or 2, a hydroxyl group, a hydroxyalkyl group containing from 1 to 4 carbon atoms such as is methanol or ethanol, an aryl group such as a phenyl group or a naphthyl group, an arylalkyl group containing alkyl moieties of from 1 to 4 carbon atoms such as benzyl, aryloxy such as phenoxy, arylalkoxy containing from 1 to 4 carbon atoms in the alkoxy moiety such as benzyloxy, heteroaryl, heteroarylalkyl, heteroarylalkyloxy containing from the alkyloxy moiety of from 1 to 4 carbon atoms; (1 to 4 carbon atoms), 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; (CR ₈ R ₈ ) _q NR ₄ R ₅ , alkenyl-C (O) NR ₄ R 8 group containing from 2 to 10 carbon atoms in the alkenyl moiety, (CR ₈ R ₈ ) _q C (O) NR ₄ R 8, (CR ₈ R 8) group _q C (O) NR ₄ R _{X is} O, S (O) ₃ H, S (O) ₃ R ₈ group (CRsRs) _q C (O) _R, alkenyl-C (O) R group in the alkenyl moiety contains from 2 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 (CR ₈ R ₈ ) _q C (O) OR ₁₂ group, a group (CR ₈ R ₈ ) _q OC (O) R 11, (CR ₈ R ₈ ) _q NR ₄ C (O) R 11, (CR ₈ R ₈ ) _q NHS (O) ₂ R ₉ , (CR ₈ R _{8) 8} ) _q S (O) ₂ NR ₄ R ₅ , or two R _x groups together may form an O- (CH ₂ ) _S O- group or a five to six membered unsaturated ring; wherein δ is an integer from 1 to 3. The aryl, heteroaryl and heterocyclic groups may be optionally substituted as described below.

Suitably, index 3 is equal to 0, or takes integer values from 1 to 10.

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

R ₄ and R 5 independently represent a hydrogen atom, an optionally substituted alkyl group containing from 1 to carbon atoms, an optionally substituted aryl group, an optionally substituted arylalkyl group containing from 1 to 4 carbon atoms, an optionally substituted heteroaryl group, optionally substituted a 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 five- to seven-membered ring, which may optionally contain another heteroatom selected from the group consisting of oxygen, nitrogen and sulfur.

R 8 is independently selected from the group consisting of hydrogen and alkyl of from 1 to 4 carbon atoms.

The group R 10 represents an alkyl-C (O) ₂ R ₈ 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 .

Rn represents a hydrogen atom, 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 moiety, a heteroaryl group, a heteroarylalkyl group containing from 1 to 4 carbon atoms in the alkyl moiety, a heterocyclic group or a heterocyclic-substituted alkyl group having from 1 to 4 carbon atoms in the alkyl moiety.

The group R ₂₂ 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.

R19 represents an alkyl group containing from 1 to 4 carbon atoms, an aryl group, an arylalkyl group, a heteroaryl group, a heteroarylalkyl group containing from 1 to 4 carbon atoms, a heterocyclic group;

9 9

or a heterocyclic group substituted by an alkyl group having from 1 to 4 carbon atoms, all of which may be optionally substituted.

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 one of them represents a phenyl group. 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 the R ₃ group is preferably 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, a halogen atom, a cyano group, a trifluoromethyl group and a C (O) NR ₄ R _{5 group} .

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), R 13 and R _{14 are} independently selected from hydrogen;

optionally substituted alkyl group containing 1 to 4 carbon atoms which may be linear or branched as defined herein, or may be one of the groups R _i3 and _R14 represent optionally substituted aryl.

The index v is equal to 0, or is an integer value from 1 to 4

When R ₁₃ or R ₁₄ is an optionally substituted alkyl group, the alkyl group may be substituted with one to three substituents independently selected from the group consisting of a halogen atom, a halogen substituted alkyl group containing from 1 to 4 carbon atoms, such as trifluoromethyl , a hydroxyl group, a hydroxyalkyl group having from 1 to 4 carbon atoms, an alkoxy group having from 1 to 4 carbon atoms, such as a methoxy or ethoxy group, a halogen substituted alkoxy group having from 1 to 10 carbon atoms, a S (O) _t R 4 group, aryl, NR ₄ R ₅ , NHC (O) R ₄ , C (O) NR ₄ R 5 or C (O) OR ₆ .

In the compounds of formula (I), W 1 suitably represents a group or a group

’) N

I · «· · ·

Optionally, ring E may be present in these groups, which is bound at the points indicated by an asterisk (*). In the absence of ring E in the group W _x , this group represents a phenyl group which is substituted by a group Y as defined above. Said group E may be substituted with a group Y on any ring, whether saturated or unsaturated, and is shown herein only in case of substitution on the unsaturated ring.

Suitably, Y is independently selected from the group consisting of hydrogen, halogen, nitro, cyano, halogen substituted alkyl

containing from 1 to 10 atoms carbon, an alkyl group containing from 1 to 10 atoms carbon, alkenyl containing from 2 to 10 atoms carbon, an alkoxy group containing from 1 to 10 atoms carbon, halogen substituted

an alkoxy group containing from 1 to 10 carbon atoms, an azide group, a group (CR _g R g) _q S (O) _t R 4, a hydroxyl group, a hydroxyalkyl group containing from 1 to 4 carbon atoms, an aryl group, an arylalkyl group containing from 1 to 10 4 carbon atoms, aryloxy, arylalkyloxy containing from 1 to 4 carbon atoms, heteroaryl, heteroarylalkyl, heteroarylalkyloxy containing from 1 to 4 carbon atoms, heterocyclic group, heterocyclic-substituted alkyl group containing alkyl 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. v ·· · 4 · 4 · 4 · 4 · 4 · 4 · 4 ·

444 «alkenyl moieties of from 2 to 10 carbon atoms, (CR ₈ R ₈ ) q NR ₄ R ₅ , alkenyl-C (O) NR ₄ R ₅ group containing from 2 to 10 carbon atoms in the alkenyl moiety, (CR ₈ R ₈₎ ) _q C (O) NR4R5, (CR ₈ R _{8) q} C (O) NR4R10, S (O) ₃ H, S (O) ₃ R _8, (CR ₈ R _{8) q} C (O ) Ru, alkenyl-C (O) _R group in the alkenyl moiety contains from 2 to 10 carbon atoms, alkenyl-C (Ό) ORU group in the alkenyl portion contains 2 to 10 carbon atoms, (CR ₈ R ₈ ) _q C (O) OR ₁₂ , (CR ₈ R ₈ ) _q OC (O) Ru, (CR ₈ R ₈ ) _q NR ₄ C (O) Ru, (CR ₈ R ₈ ) _q NHS (O) ZR d, (CR ₈ R _{8) q} s (O) 2NR4R5, or two Y groups together may form O- (CH2) _s O ^_ or a five- to six-membered saturated or unsaturated ring, wherein any of the groups containing aryl, heteroaryl and heterocyclic groups may be optionally substituted.

If group Y forms a dioxy bridge, it is preferably 1. If group Y forms another unsaturated ring, this ring is preferably six-membered, resulting in the formation of a naphthylene system. These ring systems can be independently substituted with one to three additional Y groups as defined above. The above-mentioned aryl groups, arylalkyl groups, arylalkenyl groups, heteroaryl groups, heteroarylalkyl groups, heteroarylalkenyl groups, heterocyclic groups, heterocyclic-substituted alkyl groups and heterocyclic-substituted alkenyl groups may be optionally substituted as described herein.

The Rd group is suitably NR6R7 / alkyl, an arylalkyl group containing from 1 to 4 carbon atoms in the alkyl moiety, an arylalkenyl group containing alkenyl in the alkenyl moiety. C 2 -C 4 moieties, heteroaryl group, C 1 -C 4 heteroarylalkyl group, C 2 -C 4 heteroarylalkenyl group, heterocyclic group, heterocyclic-substituted alkyl group in the alkyl moiety of 1 to 4 carbon atoms or a heterocyclic-substituted alkenyl group containing in the alkenyl moiety of 1 to 4 carbon atoms, all of the above aryl groups, arylalkyl groups, arylalkenyl groups, heteroaryl groups, heteroarylalkyl groups, heteroarylalkenyl groups, heterocyclic groups , hérerocyklických sk up-substituted alkyl groups and heterocyclic-substituted alkenyl groups may be optionally substituted as described herein.

The group Y is preferably a halogen atom, an alkoxy group having from 1 to 4 carbon atoms, an optionally substituted aryl group, an optionally substituted aryloxy group or an arylalkoxy group, methylenedioxy, NR ₄ R ₅ , a thioalkyl group having from 1 to 4 carbon atoms, 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, the group Y represents a single substituent which is a halogen atom, two substituents which are halogen atoms, a single substituent which is an alkoxy group, two substituents which are alkoxy groups, a methylenedioxy group, an aryl group or an alkyl group; 99 99 9999 9 99 ⁹ 9 9 9

9 9

Groups having one or two substituents at the 2 'and 2' and 3 'positions, respectively.

Although the group Y may be substituted at any position of the five ring positions, this group is preferably the only substituent at the 2 'or 3' position. wherein the 4 'position of said ring is preferably unsubstituted in this case. In a preferred embodiment, R represents a hydroxyl group, a thiol group or an NSO ₂ Rb group. When said ring is disubstituted, preferably when R is a hydroxyl group, a thiol group or an NSO ₂ Rb group, the substituents are preferably in 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.

When Z is cyano, W is phenyl, R is hydroxyl, v is 0 and W 1 is phenyl, then (Y) _n in which n is 1 or 2 preferably does not represent a single substituent at the 3-position or two substituents at the 3'-5 'position of said phenyl ring which are selected from the group consisting of halogen, trifluoromethyl, OCF 3, C (O) ₂ H, C (O) ₂ alkyl, C (O) ) ₂ aryl,

C (O) amino, cyano, alkyl, alkoxy, hydroxyl, nitro, hydroxymethyl, sulfamoyl, amino, aryloxy, alkylcarbonyl, arylcarbonyl, alkylcarbonyloxy and arylcarbonyloxy.

I '. I

It is further preferred that when Z is cyano, v is 0, W is phenyl, R is hydroxyl, Wi is phenyl, (Y) _n in which n is 1, other than 2-substituted arylalkyl or arylalkenyl (which may be optionally substituted with alkyl).

In compounds of formula (I) represents the moiety Z suitably cyano, ORU, C (O) NR ₅ R ₆ group, Ris, C (O) R, C (O) ORU or S (O) 2Ri7 ·

R 15 and R 16 are suitably 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 a heteroaryl group, an optionally substituted heteroarylalkyl group having from 1 to 4 carbon atoms in the alkyl moiety, an optionally substituted heterocyclic group, an optionally substituted heterocyclic group substituted with an alkyl group of 1 to 4 carbon atoms, or R 15 and R ₁₆ together with an atom The nitrogen to which they are attached forms a 5- to 7-membered ring, which may optionally contain another heteroatom selected from oxygen, nitrogen or sulfur.

Suitably, R 17 is an alkyl group having from 1 to 4 carbon atoms, NR 15 R 16, OR 11, optionally substituted aryl, optionally substituted.

an 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, an optionally substituted heterocyclic group substituted alkyl group, it contains from 1 to 4 carbon atoms.

The group R 18 is suitably an optionally substituted alkyl group having from 1 to 4 carbon atoms, an optionally substituted aryl group, an optionally substituted arylalkyl group containing from 1 to 4 carbon atoms, an optionally substituted heteroaryl group, an optionally substituted heteroarylalkyl group containing from 1 to 4 carbon atoms. C 1-4 alkyl, optionally substituted heterocyclic, optionally substituted heterocyclic substituted alkyl having from 1 to 4 carbon atoms.

The term "optionally substituted," as used herein, unless otherwise indicated, includes groups such as a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, a hydroxyl group, a hydroxyalkyl group containing from 1 up 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, m 'being 0, 1 or 2, such as is 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) 2NR ₄ R 5, NHS (O) ₂ R ₂₁ , an alkyl group containing from 1 to 10 carbon atoms, such as methyl, ethyl, propyl, isopropyl or t erč. 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) -alkyl having from 1 to 10 carbon atoms in the alkyl moiety, amino, mono- and disubstituted amino groups such as NR ₄ R ₅ , alkyl for a 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 ₂ i represents an alkyl group having from 1 to 4 carbon atoms, an aryl group, an arylalkyl group having from 1 to 4 carbon atoms in the alkyl moiety, a heteroaryl group, a heteroarylalkyl group having from 1 to 4 carbon atoms in the alkyl moiety, a heterocyclic group or an alkylheterocyclic group containing from 1 to 4 carbon atoms in the alkyl moiety.

9 • 9 ·

9999 9 9 9

9 9 9 • 9 9

999 «·· 99 • 9 9 • 9

9 9 »» 9 ·· 999

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,

··. 9 9 Z • 9999999 '9 U * 4 isobutyl group, tert. butyl, n-pentyl, and the like, without being limited thereto.

The term "cycloalkyl" as used herein refers to a cyclic moiety preferably containing 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.

The term "heterocyclic group (alone or in any association, 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, but not limited to, 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, which is 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 saturated or unsaturated ring" as used herein refers to the formation of an aromatic ring system such as a naphthylene system or a phenyl group to which is attached a 6-membered, partially saturated or unsaturated a ring such as cycloalkenyl of 6 carbon atoms, i.e. cyclohexene, or cycloalkenyl of 5 carbon atoms, i.e. cyclopentene.

* «

· · ·.

** *

An example of a compound of formula (I) is

N- (2-hydroxy-4-nitrophenyl) -Ν '- (2-chlorophenyl) -1'-cyanoguanidine,

N- (2-hydroxy-4-nitrophenyl) -Ν '- (2-chlorophenyl) -1'-cyanoguanidine,

N- (4-cyano-2-hydroxyphenyl) -1 '- (phenyl) cyanoguanidine,

N- (2-bromophenyl) -N '- (4-cyano-2-hydroxyphenyl) -1'-cyanoguanidine, N- (4-cyano-2-hydroxyphenyl) -1' - (2,3-dichlorophenyl) - Ν''kyanoguanidin,

N- (2-bromophenyl) -1 '- (4-cyano-2-hydroxy-3-propylphenyl) -1'-cyanoguanidine,

N- (2-bromophenyl) -1- (4-cyano-2-hydroxy-3-isobutylphenyl) -1'-cyanoguanidine,

N- (2-bromophenyl) -N '- (3-bromo-4-cyano-2-hydroxyphenyl) -1'-cyanoguanidine,

N- (4-cyano-2-hydroxy-3-propylphenyl) -1 '- (2,3-dichlorophenyl) -1'-cyanoguanidine; and.

N- (3-bromo-4-cyano-2-hydroxyphenyl) -N- (2,3-methylenedioxyphenyl) -1'-cyanoguanidine,

N- (2-chlorophenyl) -1 '- (4-cyano-2-hydroxy-3-propylphenyl) -N'-cyanoguanidine, and

N- (2-bromophenyl) -1 '- (4-cyano-2-hydroxy-3-methoxycarbonylphenyl) -N' - cyanoguanidine.

It will be appreciated that the compounds of the present invention may exist in the form of stereoisomers, regioisomers or diastereoisomers. These compounds may contain one or more asymmetric carbon atoms and may exist in the form of a racemate or in an optically active form. All such forms of the compound of formula (I) are within the scope of the present invention.

Compounds of formula (I) may 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 formula (I) containing various R, R _x and aryl groups which are subject to chemical reactions, said groups also optionally containing additional substituents which are suitably protected for compatibility with 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.

The compounds of the invention can be synthesized from thiouronium salt 2 (Scheme 1). In these compounds, R 1 is a linking group of formula - (R 13 R 14) v -Wi, the meaning of each group being as defined above in connection with the definition of the compound of formula (I). By way of illustration, the schemes below depict compounds wherein W is a substituted phenyl group.

4

a) Na, EtOH, cyanamide; b) EDC.HCl

The thiourinium salt 2 (Scheme 1) can be synthesized by reacting sodium cyanamide with commercially available isothiocyanate 1 (if this isothiocyanate is not commercially available, it can be prepared by reacting the corresponding amine with thiophosgene in the presence of a base such as sodium bicarbonate). The resulting thiouronium salt 2 may be condensed with a suitably substituted aniline in the next step in the presence of an addition agent such as EDC.HCl, or the acid may be acidified to form cyanothiourea, which may be used in the next reaction.

Alternatively, compound (6) can be synthesized by reacting commercially available (e.g., Aldrich Chemical Company) diphenylcyanocarboimidate 5 (Scheme 2) with an amine to produce an intermediate, O-phenylisourea 6, which subsequently reacts with a suitably substituted aniline in the presence of trimethyl aluminum, and as described in Atwal, KS Tetrahedron Lett., 1994, 35, 8085. Compounds in which R 'represents an alkyl group can be prepared by heating an appropriately substituted alkylamine, but in the absence of a catalyst.

Scheme 2

a) acetonitrile, heating; (b) AlMe ₃

Alternatively, the compounds of the present invention can be synthesized using protected ortho-substituted aniline 8. (Scheme 3). For more information see. the syntheses described in U.S. Provisional Patent Application Serial No. USSN 60/020655 filed June 27, 1996; International Publication No. WO 96/25157 filed August 22, 1996; and U.S. Patent Application Serial No. USSN 08/701299 filed August 21, 1996, the contents of which are incorporated herein by reference. The ortho-substituted aniline] (Scheme 3) is first protected (e.g. with a tert-butyldimethylsilyl group,

99 ♦ ♦ 9 ·

9 • 9 · 9 • 9 * 9 * * 9 * 9 ·

9 by an allyl, benzyl, MOM or other suitable protecting group) by reacting said ortho-substituted aniline with the appropriate alkyl or silyl halide in the presence of a suitable base (e.g., in the presence of cesium carbonate, potassium carbonate or imidazole) in an aprotic solvent. Said protected ortho-substituted aniline can also be synthesized from ortho-substituted nitrobenzene 9 by reaction with a preservative under commonly known conditions (see Greene, T. Protecting Groups in Organic Synthesis, Wiley & Sons, New York, 1981). . The resulting protected ortho-substituted nitro compound is then reduced with SnCl 2 in ethanol, or with H ₂ / Pd or with LiAlH ₄ in an aprotic solvent to give the corresponding aniline.

Scheme 3

X = N, O, S

a) an alkyl or silyl halide, base; b) reducing agent • 9 · * * »

* 9 • 99

The protected ortho-substituted aniline 8 thus obtained can be converted into an isothiocyanate by thiophosgene in the subsequent reaction, which can be further reacted with the ZNH anion (formed by reaction of ZNH ₂ with a base such as NaH). The meaning of Z is defined above in connection with the description of the compound of formula (I). The resulting thioanion can be alkylated with a suitable alkylating agent, such as methyl iodide, to give a thioamidate, such as compound 10 (Scheme 4).

Scheme 4

NH 2 a, b, c

N '

N SCH,

H ³

a) C1CSC1, NaHCO _3; b) WMD; c) Mel

The thioamidate 10 (Scheme 5) can be converted to the compound (6) by reaction with an amine of formula R ₁ NH ₂ . This reaction can be accelerated by adding a metal salt with high affinity to sulfur, such as mercury oxide or silver acetate, or by oxidizing sulfur with dimethyl oxirane to form a better leaving group. In the final step, the phenolic group is deprotected to give Compound 6 of the present invention.

·· ·· · · ·

Scheme 5

Alternatively, the compound of the invention can be synthesized by reacting the protected carbodiimide 11 (Scheme 6) with a ZNH anion (formed by reacting ZNH ₂ with a base such as NaH) or with neutral NH ₂ Z compounds (Z is CN) and a tertiary base an amine such as Hiinig base (diisopropylethylamine), triethylamine, triisopropylethylamine,

N, N-dimethylbenzylamine or N, N-dimethylisopropylamine, under conditions where the nucleophile is present in the reaction mixture in large excess and the reaction time is minimized by careful monitoring of the completion of said reaction followed by deprotection. Other suitable bases which may be used in this reaction include secondary amines such as pyridine and amino substituted pyridine derivatives. When Z is cyano, various aprotic solvents such as acetonitrile, halogenated solvents such as chloroform and dichloromethane, ethylene glycol dimethyl ether (GLYM), dioxane,

N, N-dimethylformamide (DMF) and dimethylsulfoxide (DMSO) or mixtures of these solvents, but preferably acetonitrile is used in the reaction. One skilled in the art will recognize that the solubility of the cyano derivative is a limiting factor for the use of said solvents. Although aprotic solvents are also preferred when Z is not cyano, it will be apparent to those skilled in the art that other solvents, such as protic solvents, such as alcohols, may be used.

Preferably, said reaction (wherein Z is cyano) is at a temperature in the range of about -10 ° C to about 100 ° C, preferably at a temperature in the range of about 10 ° C to about 50 ° C, even more preferably at a temperature of about at room temperature, i.e. at a temperature of from 20 ° C to 30 ° C.

The protected R '' group can be deprotected by a suitable method known to those skilled in the art. When the protecting group is an allyl derivative, this deprotection preferably comprises deallylation with palladium.

Scheme 6

R1

a) ZNH (ZNH ₂ + NaH) for Z = OR, COOEt, CHO, RNHSO ₂ , ArNHSO ₂ ; b) ZNH ₂ · HCl for Z = OH; c) ZNH ₂ and NR 3 for Z = CN; (d) deprotection

Said carbodiimide 11 is prepared from thiourea 12a (scheme 7) by reaction with or with phosgene and a tertiary amine. thiourea 12a or urea 12b by reaction with triphenylphosphine, carbon tetrachloride and triethylamine.

The carbodiimide can also be prepared by reacting thiourea 12b with an excess such as 2 or more equivalents of methanesulfonyl chloride and a tertiary amine base such as Hunig's base (diisopropylethylamine), triethylamine, triisopropylethylamine, N, N-dimethylbenzylamine, or Ν, preferably triethylamine is used. A halogenated solvent such as dichloromethane, chloroform or tetrachlorethylene, etc. may be used in the reaction. Suitably the reaction proceeds at a temperature in the range of about -30 ° C to about 80 ° C, preferably in the range of about -10 ° C to about 50 ° C. ° C, more preferably at a temperature in the range of about 0 ° C to a temperature corresponding to about room temperature. For more details see. Fell, J. B., Coppola, J. B., Syn. Coiamunications, 1995, 25, 43.

Scheme 7

X

12a. X = S 12b. X = O a or b or c ->

R

R1

(a) phosgene, Et ₃ N; (b)

Ph ₃ P, CCl ₄ , Et ₃ N;

c) MsCl, Et ₃ N

Said urea or thiourea is synthesized as described in U.S. Provisional Patent Application Serial No. USSN 60/020655 filed June 27, 1996, the contents of which are incorporated herein by reference. Thiourea 12a (Scheme 8) can also be prepared by reacting said protected ortho-substituted aniline and two equivalents of the appropriate base, such as NaH, KH, calcium hydride, and reacting the anion with a commercially available isothiocyanate of the formula Wy-NCS as defined in connection with the description of the compound of formula (I)). The reaction is carried out in a suitable aprotic solvent or halogenated solvent at a temperature in the range of about -10 ° C to about 50 ° C.

If the desired isothiocyanate is not commercially available, it can be prepared by reacting the corresponding aniline with thiophosgene and a suitable base, such as sodium bicarbonate.

Scheme 8

(a) bases; b) R'NCS

Another aspect of the present invention of formula (II) are novel compounds

Wi-N = C = N-W

4 fc 4 fc 4

4 4 · 4

«· · Fc where

W and WI have the same meaning as in the compound of formula (I), wherein W contains a protected or unprotected R (R ^{, z} ) group, the meaning of which is also the same as that of the compound of formula (I).

Another aspect of the present invention are novel compounds of formula (III)

Wi-NH-C (S) -NH-W (III) wherein

W and W 1 have the same meaning as in the compound of formula (I), wherein the group W contains a protected or unprotected group R (R ^2z ), the meaning of which is also the same as for the compound of formula (I).

The present invention also includes protected (i.e. a group ^of R 'containing) versions of compounds of formula (I).

One skilled in the art will appreciate that the guanidine group may take the form of many different tautomers, such as Wi-NC (= NZ) -NW; ZN = C (NWJ -NW; W _x -NC (= NW) -NZ, all such tautomeric forms also being within the scope of the present invention.

The compounds of formula (I) or pharmaceutically acceptable salts thereof may be used for the manufacture of a medicament for the prophylactic or therapeutic treatment of any disease state in humans or other mammals caused by, or caused by, excessive or unregulated production of IL-8 by cytokinin by such mammalian cells. , such as monocytes and / or macrophages, without being limited thereto, or other chemokinins that bind to the IL-8a or β receptor, also referred to as the Type I or Type II receptor.

Accordingly, another aspect of the present invention is a method of treating a chemokinin-mediated disease, wherein said chemokinin is a chemokinin that binds to the IL-8a or β receptor, said method comprising administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salts. Specifically, said chemokinins are IL-8, GROα, 6ββ, GROγ, ENA-78 or NAP-2.

The compounds of formula (I) are administered in an amount sufficient to inhibit cytokinin function, particularly IL-8, GROα, β, GROγ, ENA-78 or NAP-2, such that their content is biologically reduced to normal physiological levels, or in some cases below a normal level to improve said disease state. Abnormal levels of IL-8, GROα, β, GROγ, NAP-2 or ENA-78 include, in the context of the present invention, for example: (i) a level of free IL-8 equal to or greater than picogram / milliliter; (ii) content of any cells associated with IL-8, GROα, β, GROγ, NAP-2 or ENA-78 higher than normal physiological level; or (III) the presence of basal levels of IL-8, GROα, ββ, GROγ, NAP-2 or ENA-78 in cells or tissues producing IL-8, GROα, σΡΟβ, GROγ, NAP-2, and ENA-78, respectively.

• * • ·

There are many disease states in which excessive or unregulated IL-8 production 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 disease, Alzheimer's disease, transplant rejection, malaria, restinosis, angiogenesis, atherosclerosis, osteoporosis, gingivitis, unwanted stem hematopoietic cell release.

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.

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,

GROβ, 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, GROβ, GROγ or NAP-2 has a unique property of promoting neutrophil chemotaxis;

• 4 · · · · · · · · · · · · · · · · ·

enzyme release, such as promoting the release of elastase, and peroxide production and activation. Said α-chemokinins, but specifically GROα, GROβ, GROγ or NAP-2, which function through IL-8 receptors of type I or II, can promote neovascularization of tumors by promoting directional growth of endothelial cells. Therefore, inhibition of chemotaxis or activation induced by IL-8 could lead to a direct reduction in neutrophil infiltration.

Recent scientific results have also shown the role of chemokinins in the treatment of HIV infections, see Littleman et al., Nature, 1996, 381, 661 and Koup et al., Nature, 1996, 381, 667.

The present invention also provides a tool for the treatment, in the event of a sudden occurrence, and prevention of CNS injury in individuals deemed susceptible to such injury, using chemokinin receptor antagonists which are compounds of formula (I).

CNS injury as used herein refers to both an open or penetrating head injury, such as a surgical injury, and a closed head injury, such as a head injury. This definition also includes ischemic stroke, especially in the brain area.

Ischemic stroke can be defined as a focal neurological disorder that results from insufficient blood supply to a particular area of the brain, usually due to embolism, thrombosis, or local atheromatous obstruction of the vessel. The role played by inflammatory cytokinins in these events has recently been elucidated and fcfc fcfc fcfcfc fcfcfc fcfcfc fcfcfc fcfcfcfcfcfcfcfcfcfcfcfcfcfcfcfcfcfcfcfcfc the present invention provides a means for potentially treating such injuries. Relatively few treatments are available for acute injuries, such as those described above.

TNF-α is a pro-inflammatory cytokinin, including expression of adhering endothelial leukocyte molecules. Leukocytes infiltrate into ischemic brain lesions and therefore compounds that inhibit or decrease TNF levels would be useful for the treatment of ischemic brain injury. For more details see. See Liu et al., Stoke, 1994, 25, 1481-1488, the contents of which are incorporated herein by reference.

Models of closed head injury and treatment with mixed 5-LO / CO reagents have been discussed in Shohami et al., J. of Vaisc and Clinical Physiology and Pharmacology, 1992, 3, 99-107, the contents of which are incorporated herein by reference. Treatment to reduce edema has been found to improve functional termination in the animals treated.

The compounds of formula (I) of the present invention are administered in an amount sufficient to inhibit IL-8 that binds to the IL-8a or β receptors by inhibiting the binding of the IL-8a or β receptors to said receptors. of formula (I) according to the invention, as evidenced by a reduction in chemotaxis and neutrophil activation. The finding that 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. These compounds to the receptor are also described, and these studies are also described herein. The compounds of formula (I) of the present invention have been shown to be inhibitors of the type II IL-8 receptor.

As used herein, the term "IL-8 mediated disease or condition" refers to all and any disease states in which IL-8, GROα, GROβ, GROγ, NAP-2 or ENA-78 plays a role, which may consist in production itself IL — 8, GROα,

GROβ, GROγ, NAP-2 or ENA-78, or in that IL-8, GROα,

GROP, GROγ, NAP-2 or ENA-78 is the cause of the release of another chemokinin, such as IL-1, IL-6 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.

The term "chemokinin-mediated disease or condition" as used herein refers to all and any disease states in which any chemokinin that binds to the IL-8α or β receptor plays a role, such as IL-8, GROα, GROP, GROγ , NAP-2, or ENA-78, 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. , IL-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.

99 99

9 9 9 9 9 9 • 9 9 9 9

9999999 9 9 • 9 9 9 9 9 ·· 9 99 9999

• 9

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 restricted to the examples given, regardless of which cells produce them. For example, it is generally reported that monokinin is produced and secreted by a single core cell, 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. Examples of cytokinins include

Interleukinin-1 (IL-1), Interleukinin-6 (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 chemokinin class includes IL-8,

0 • 0 0 • 0 0 0 <0909 «00

0

00

9 0 9

9 9

0 9 9

9 9

GRO-α, GRO-β, GRO-γ, NAP-2, ENA-78, IP-10, MIP-1β, ΜΙΡ-β, PF-4, and MCP 1, 2, and 3.

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 according to standard 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 understood 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.

9 • ·

9 9 • 99 99 99

9 9 9 9 9 9 9 9 9 9 9 9

9 9 9 9 9 • 9 9999 99 9 99 9 by 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. Examples of solid carriers include lactose, 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. Nonsystemic

9 9 9 9 9 9 9 9 9 9 9

By administration in the context of the present invention is meant the external administration of a compound of formula (I) to the skin or cheek cavity and dripping said compound into the ear, eye or nose, such that the compound of the present invention it does not significantly enter the bloodstream. On the other hand, systemic administration means oral, intravenous, intraperitoneal and intramuscular administration.

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 of the present invention 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,

4 · · 4

4 4

4

4444 *

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 powdered form, either alone or in a solution or suspension in an aqueous or non-aqueous liquid, with a greasy or non-greasy base, by means of suitable equipment. 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 include 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

and / or other suitable preservative, said solution preferably comprising a surfactant. The resulting solution can then be clarified by filtration, transferred to a suitable container, which is then sealed and sterilized in an autoclave at a temperature of from 98 ° C to 100 ° C for half an hour. Alternatively, the solution may be sterilized by filtration and transferred to the container aseptically. Examples of bactericidal and fungicidal agents that may be included in the drops 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 dosage of said compound for oral administration is preferably in the range of about

I • β · · »

0.01 milligrams / kilogram total body weight to about 80 milligrams / kilogram 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 dosage being administered one to four times, preferably two to three times daily. For administration by inhalation of said 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 .

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

• - »* • · · 9 · 9 • • 9 9 · · · · φ I

DETAILED DESCRIPTION OF THE INVENTION

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.

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).

♦ 9 9 • 9 9 · i * ···· · · * · 9 · * · φ 9 · · · 9 · · 9 »*> 9 ti« * ·

4 * 9 9 · 9 · 9999

Example 1

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

(a) N- (2-chlorophenyl) -N '- cyanothiourea sodium

1.64 grams (71.3 millimoles) of sodium was dissolved in ethanol until gas evolution ceased. To the solution was added 1.685 g (40 millimoles) of cyanamide. The reaction mixture was stirred for 15 minutes, 7.21 g (42.66 mmol) of 2-chlorophenylisothiocyanate was added thereto, and the resulting mixture was heated to reflux for 6 hours. The mixture was cooled and diluted with dichloromethane. A white solid precipitated, which was filtered off and dried, yielding 8.26 g (87.5 percent) of N- (2-chlorophenyl) -N'-cyanothiourea sodium.

MS (ES ⁺ ) mlz 210.212 [M + H] ⁺ .

b) N- (2-Hydroxy-3-nitrophenyl) -N '- (2-chlorophenyl) -1'-cyanoguanidine

To a stirred solution of 234 mg (1 mmol) of N- (2-chlorophenyl) -N'-cyanothiourea sodium salt and 156 mg (1 mmol) of 2-hydroxy-3-nitroaniline in 2 ml of dry N, N-dimethylformamide (DMF) under argon atmosphere, 384 mg (2 mmol) of EDC hydrochloride was added and the reaction mixture was stirred at room temperature for 4 days. The mixture was partitioned between ethyl acetate and normal hydrochloric acid and the organic extracts were washed with water and brine. After drying over anhydrous sodium sulfate and evaporating the solvent under reduced pressure, a red oil was isolated. Silica gel chromatography (eluting with 3% acetone in chloroform) 9

9 9

9

9 98 9 9

9 9 9

9 · · · · · · ·

9 9 9 9 yielded 30 mg (9 percent) of a pale yellow solid, which was recrystallized from tert-butyl methyl ether to give the desired product.

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.93 (s, 1H), 8.53 (s, 1H), 7.92 (d, J = 7.8 Hz, 1H), 7.61 (d J = 7.8 Hz, 2H), 7.38-7.50 (m,

2H), 7.22 (s, 1H), 7.08 (t, 1H).

IR (KBr) 2181 cm ^-1 .

MS (ES) mle 330 [M-H].

mp: 163-164 ° C.

Example 2

Preparation of N- (2-hydroxy-4-cyanophenyl) -N '- (2-bromophenyl) -N' 'cyanoguanidine

a) 1-Allyloxy-5-cyano-2-nitrobenzene

A mixture of 3,0 grams (18,9 millimoles) of 5-cyano-2-nitrophenol,

1.82 ml (21.0 mmol) of allyl bromide and 7.39 g (22.7 mmol) of cesium carbonate in 20 ml of Ν, Ν-dimethylformamide (DMF) were stirred under argon at room temperature for 18 hours. The reaction mixture was partitioned between tert. butyl methyl ether and water. The layers were separated and the aqueous layer was extracted three more times. The combined organic layers were washed successively twice with water, brine, dried over anhydrous magnesium sulfate, and filtered. Removal of the solvent under reduced pressure gave 3.89 g (100 percent) of the desired product. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.87 (d, J = 8.5 Hz, 1H), 7.35 (dd, J = 8.4 Hz, J = 1.2 Hz, 1H), 7.35 (d, J = 1.5 Hz, 1H), 6.02 • 4 *

4.t (m, 1H), 5.52 (d, 1H), 5.43 (d, 1H), 4.73 (dd, J = 3.6 Hz),

J = 1.2Hz, 2H).

b) 2-Allyloxy-4-cyanoaniline

A mixture of 3.6 g (17.46 mmol) of 1-allyloxy-5-cyano-2-nitrobenzene and 19.7 g (87.3 mmol) of stannous chloride in 100 ml of ethanol was stirred overnight at room temperature. The solvent was evaporated under reduced pressure and the reaction mixture was partitioned between 5% sodium bicarbonate solution and ethyl acetate. The tin salts were filtered off and the aqueous layer was extracted four more times with ethyl acetate. The combined organic layers were washed successively with water, brine, dried over anhydrous magnesium sulfate, and filtered. After removal of the solvent under reduced pressure, 2.82 g of a brown solid was obtained, which was recrystallized from a target mixture. butyl methyl ether / hexane to give 2.63 g (93 percent) of the desired product as a light brown solid.

MS (ES ⁺ ) mlz 175 [M + H] ⁺ .

MS (ES) mlz 173 [M-H].

c) N- (2-Allyloxy-4-cyanophenyl) -1 '- (2-bromophenyl) -thiourea

240 mg of sodium hydride as a 60 percent dispersion in mineral oil (6.0 mg) was washed with hexanes and stirred in 10 ml of N, N-dimethylformamide (DMF). To this mixture was added at 0 ° C

522 mg (3 mmol) of 2-allyloxy-4-cyanoaniline in 1.5 mL of N, N-dimethylformamide (DMF). The reaction mixture was stirred at 0 ° C for 15 minutes under argon, 2-bromophenylisocyanate was added dropwise at 0 ° C, and the resulting mixture was stirred at room temperature for 1 hour. The mixture was quenched by addition of 0.5 molar sodium phosphate monobasic solution, extracted with ethyl acetate, washed with water and dried over anhydrous sodium sulfate. The crude solid was recrystallized from methanol to yield 911 mg (78 mg). percent) of the desired product as a white solid.

MS (ES ⁺ ) mlz 388, 390 [M + H] ⁺ .

d) N- (2-Allyloxy-4-cyanophenyl) -N '- (2-bromophenyl) carbodiimide

To a stirred solution of 900 milligrams (2.32 millimoles)

N- (2-allyloxy-4-cyanophenyl) -N '- (2-bromophenyl) thiourea and 1 ml (6.95 mmol) of triethylamine in dichloromethane were added dropwise at 0 ° C under argon atmosphere (360 microliters) (4.64 milimol) methanesulfonyl chloride. The reaction mixture was stirred at room temperature for 15 minutes and TLC showed no starting material. The mixture was chromatographed on silica gel eluting with dichloromethane to give 1.2 g (&gt; 100 percent) of the desired product which was used in the next reaction without purification.

e) N- (2-Allyloxy-4-cyanophenyl) -N '- (2-bromophenyl) -N'-cyanoguanidine

To a stirred mixture of 560 mg (13.33 mmol) of cyanamide and 2.6 ml of Hunig's base in acetonitrile was added dropwise a solution of 600 mg (1.69 mmol) of N- (2-allyloxy-4-cyanophenyl) -N '(2-bromophenyl) -carbodiimide in 30 ml of acetonitrile.

The mixture was stirred at room temperature for 15 minutes, the solvent was removed under reduced pressure, and the residue was hydrolyzed with 0.5 molar sodium dihydrogen phosphate solution. The ethyl acetate extracts of the aqueous mixture were washed with 0.5 molar sodium dihydrogen phosphate solution and brine. After drying over anhydrous magnesium sulfate and evaporating the solvent under reduced pressure, 500 mg of crude product was obtained as a tan solid which was chromatographed on silica gel eluting with ethyl acetate / hexane (50:50) to give 455 mg (95 percent). of the desired product.

MS (ES) m / e 394, 396 [M-H] -.

f) N- (4-Cyano-2-hydroxyphenyl) -N '- (2-bromophenyl) -N'-cyanoguanidine

To a mixture of 100 mg (0.25 mmol) of N- (2-allyloxy-4-cyanophenyl) -N '- (2-bromophenyl) -N' - cyanoguanidine and 20 mg (0.52 mmol) of sodium borohydride in 3 ml of tetrahydrofuran ( 21 mg (7 mole percent) of tetrakis (triphenylphosphine) palladium was added at room temperature. The mixture was stirred at room temperature until TLC showed no starting material. Subsequently, the mixture was partitioned between ethyl acetate and 0.5 molar sodium dihydrogen phosphate solution. After drying over anhydrous magnesium sulfate and evaporating the solvent under reduced pressure, 100 mg of crude product was obtained as a tan solid which was chromatographed on a silica gel column eluting with 5% methanol in chloroform to give 64 mg of the desired product as a pale yellow solid. solids. Recrystallization from chloroform gave 42 mg (74 percent) of the product.

¹ H NMR (400 MHz, DMSO) δ 10.93 (s, 1H), 9.57 (s, 1H), 8.74 (s, 1H), 7.84 (d, J = 8.3 Hz, 1H), 7.71 (d, J = 7.8Hz, 2H),

7.50-7.42 (m, 2H), 7.30-7.26 (m, 2H), 7.17 (s, 1H),

7.08 (t, 1 H).

· + + * * * * * 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9

IR (KBr) 2224, 2193 cm ^-1 . MS (ES) m / e 354, 356 [M-H] -. MS (ES ⁺ ) m / e 356, 358 [M + H] &lt; + ^&gt; . temperature mp: 175-176 ° C. Example 3

Preparation of N- (4-cyano-2-hydroxyphenyl) -N '- (phenyl) -N' 'cyanoguanidine

(a) 5-Cyano-1-methoxymethyloxy-2-nitrobenzene

260 mg of sodium hydride as a 60% dispersion in mineral oil (6.5 mmol) was washed with a mixture of hexanes and stirred in 5 ml of tetrahydrofuran (THF). To this mixture was added dropwise 978 mg (5.96 mmol) of 5-cyano-2-nitrophenol in 10 mL of tetrahydrofuran (THF) at room temperature. The reaction mixture turned light orange and a large amount of precipitate was formed. After stirring at room temperature for one minute, bromomethyl methyl ether was added dropwise to the suspension, and the reaction mixture was stirred at room temperature for 18 hours. The yellow-colored mixture was then distributed between the target. butyl methyl ether and water and the aqueous layer was extracted three times and washed four times

5% sodium bicarbonate solution and brine. Drying over anhydrous magnesium sulfate, filtration and evaporation under reduced pressure gave 1.05 g (85 percent) of the desired product as a pale yellow solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.84 (d, J = 8.4 Hz, 1H),

7.66 (d, J = 1.4Hz, 1H), 7.35 (dd, J = 8.4Hz, J = 1.5Hz,

1H), 5.34 (s, 2H), 3.55 (s, 3H).

9 · · 9 9 99 β 4 9 4

9 9 9 9 9 • · · 9 9 9 • 9 9 9 · 9 · 99

4 »9

9

9- 9

9990

b) 4-Cyano-2-methoxymethyloxyaniline

A mixture of 0.5 g (2.4 mmol) of 5-cyano-1-methoxymethyloxy-2-nitrobenzene and 0.05 g of 10 percent palladium on charcoal in 50 ml of ethyl acetate was stirred at room temperature and hydrogen pressure for 101.325 kilopascal (i.e. atmosphere). Palladium was removed by filtration through Celite and the residue was chromatographed on silica gel eluting with 25 percent ethyl acetate in hexane to give 250 mg (58 percent) of the desired product.

MS (ES ⁺ ) mlz 179 [M + H] ⁺ .

c) N- (4-Cyano-2-methoxymethyloxyphenyl) -N '- (2-phenyl) -N'-cyanoguanidine

In the same manner as in Example 1 (c) -1 (e), except that 2-bromophenyl isocyanate was replaced with phenyl isocyanate and 2-allyloxy-4-cyanoaniline was replaced with 2-methoxymethyloxy-4-cyanoaniline to give the title compound in a total yield of 24 percent.

IR (KBr) 2226, 2198 cm &^lt; -1 &gt;.

MS (ES) mlz 320 [M-H].

d) N- (4-Cyano-2-hydroxyphenyl) - N '- (phenyl) -N'-cyanoguanidine milligrams (0.146 millimoles) of the compound prepared in Example 2 (b) was dissolved in 20 mL of ethyl acetate. 10 ml of 6N hydrochloric acid were added to the obtained solution, and they were stirred at room temperature for 3 hours. Then an additional 5 ml of 6N hydrochloric acid was added and stirring was continued for a further 2 hours. The mixture was diluted with ethyl acetate and brine, and the aqueous layer was extracted five more times with ethyl acetate. United · »4 • ·

V 4 4 4 4 4

9 4 4

The organic layers were dried over anhydrous sodium sulfate and evaporated in vacuo to give 64 mg of the desired product after recrystallization from tert. butyl methyl ether yielded 2 mg (5 percent) of product.

¹ H NMR (400 MHz, DMSO d ₆ ) δ 9.70 (s, 1H), 9.12 (s, 1H),

7.62 (d, J = 8.3 Hz, 1H), 7.55 (d, J = 1.2 Hz, 1H), 7.49 (dd, J = 1.2 Hz, J = 8.1 Hz, 1H), 7.36 (m, 4H), 7.18 (m, 1H).

IR (KBr) 2233, 2192 cm ^-1 .

MS (ES ⁺ ) mlz 278 [M + H] ⁺ .

MS (ES) mlz 276 [M-H] -.

mp: 270-271 ° C.

Example 4

Preparation of N- (4-cyano-2-hydroxyphenyl) -N- (2,3-dichlorophenyl) -N-cyanoguanidine

In the same manner as in Example 1 (a) - 1 (e), except that 2-bromophenyl isocyanate was replaced with 2,3-dichlorophenyl isocyanate, the title compound was obtained in a total yield of 17 percent.

IR (KBr) 2231, 2197 cm &^lt; -1 &gt;.

MS (ES ⁺ ) mlz 346, 348, 350 [M + H] ⁺ .

MS (ES) mlz 344, 346, 347, 348 [M-H].

mp 155-156 ° C.

fc fcfc fc fc fc fc fcfc fcfc fcfc fcfc fcfc fcfc · · Fcfc · · fcfcfc • fc «fcfcfc

Example 5

Preparation of N- (2-bromophenyl) -N '- (4-cyano-2-hydroxy-3-propylphenyl) -N' - cyanoguanidine

a) 2-Amino-5-cyano-6-prop-1-en-3-yl-phenol

To 1.88 g (1.29 mmol) of the compound prepared in Example 2 (b) was added 20 ml of N, N-dimethylaniline under argon and heated at 175 ° C (oil bath temperature) for 3.5 hours. . Then the solvent was removed from the reaction mixture in vacuo and the residue was recrystallized from the mixture containing the target. butyl methyl ether, up to 20 percent dichloromethane and 10 to 20 percent hexane to give 1.67 g (89 percent) of the desired product as a colorless solid.

MS (ES ⁺ ) mlz 175 [M + H] ⁺ .

MS (ES) m / e 173 (M-H &lt; - &gt;).

b) 2-Amino-5-cyano-6-propyl-phenol

A mixture of 0.5 g (2.4 mmoles) of 2-amino-5-cyano-6-prop-1-en-3-ylphenol and 0.05 g of 10 percent palladium on charcoal in 50 ml of ethyl acetate was stirred at room temperature for 2 hours. a hydrogen pressure of 101.325 kilopascals (i.e., 1 atmosphere). Palladium was removed by filtration through Celite and the residue was concentrated under reduced pressure to give 1.2 g (78 percent) of the desired product as a pinkish solid.

MS (ES ⁺ ) mlz 177 [M + H] ⁺ .

MS (ES) mlz 175 [M-H] -.

9 9 9 9 9 9 9

9 9 9 9

9 9 9

9 9 • 9 9

9 9

9 9 · 9 9

c) N- (2-Bromophenyl) -N '- (4-cyano-2-hydroxy-3-propylphenyl) -N'-cyanoguanidine

In the same manner as in Example 2 (a) - 1 (e) except that 5-cyano-2-nitrophenol was replaced with 5-cyano-6-propylphenol, the title compound was obtained in a total yield of 37 percent.

¹ H NMR (400 MHz, DMSO d ₆ ) δ 9.72 (s, 1H), 9.45 (s, 1H),

8.66 (s, 1H), 7.71 (d, J = 7.0 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.45 (m, 2H), 7.28 (d, J = 8.4Hz, 1H); 7.26 (t, 1H);

2.76 (t, J = 7.5, 2H), 1.55 (hextet, J = 7.6 Hz, 2H), 0.93 (t, J = 7.3 Hz, 3H).

IR (KBr) 2224, 2184 cir i “ ¹ . MS (ES ⁺ ) m / e 398, 400 [M + H] &lt; + ^&gt; . MS (ES ') m / e 396,398 [M-H] '

Example 6

Preparation of N- (4-cyano-2-hydroxy-3-propylphenyl) -1 '- (2,3-dichlorophenyl) -N' - cyanoguanidine

In the same manner as in Example 1 (b) -1 (e), except that 2-bromophenyl isocyanate was replaced by 2,3-dichlorophenyl isocyanate and 2-allyloxy-4-cyanoaniline was replaced by 2-allyloxy-4-cyano-3-propylaniline in total yield of 7 percent prepared the desired compound.

IR (KBr) 2236, 2182 cm ^-1 . MS (ES ⁺ ) m / e 388,390,391 [M + H] &lt; + ^&gt; . MS (ES ') m / e 386,388,390 [M-H]. temperature m.p .: 143-147 ° C.

ft * ♦

Example 7

Preparation of N- (2-chlorophenyl) -1 '- (4-cyano-2-hydroxy-3-propylphenyl) -1'-cyanoguanidine

In the same manner as in Example 1 (b) -1 (e), except that 2-bromophenyl isocyanate was replaced with 2-chlorophenyl isocyanate and 2-allyloxy-4-cyanoaniline was replaced with 2-allyloxy-4-cyano-3-propylaniline in total yield. 26 percent of the title compound prepared.

IR (KBr) 2225, 2187 cm ¹ . MS (ES ⁺ ) me 354, 356 [M + H] &lt; + ^&gt; . MS (ES ') me 352, 354 [M-H] -. temperature thaw : 159 - 160 ° C.

Example 8

Preparation of N- (2-bromophenyl) -N '- (4-cyano-2-hydroxy-3-isobutylphenyl) -N''-cyanoguanidine

In the same manner as in Example 4 (a) -1 (c) except that the allyl bromide was replaced with 3-bromo-2-methyl-1-propene, the title compound was obtained in a total yield of 16 percent. IR (KBr) 2231, 2189 cm ^-1 .

MS (ES ⁺ ) mlz 412, 414 [M + H] ⁺ .

MS (ES &lt; ^{- &gt;} ) m / e 410, 412 [MH].

To • to to to to to........

• it to this to it to it * * *

Example 9

Preparation of N- (2-bromophenyl) -1 '- (3-bromo-4-cyano-2-hydroxyphenyl) -N' - cyanoguanidine

(a) 2-Bromo-3-hydroxy-4-nitrobenzonitrile

To a solution of 3.03 g (18.4 mmol) of 3-hydroxy-4-nitrobenzonitrile in 660 mL of dichloromethane was added 9.91 g (26.0 mmol) of hexamethylenetetramine / HBr ₃ (1: 1). The resulting solution was allowed to stir at room temperature for 1 week. The reaction mixture was acidified with normal hydrochloric acid and then extracted with ethyl acetate / hexane (1: 1). The organic layers were combined, dried over anhydrous magnesium sulfate, and filtered. After evaporation of the solvent, the residue was chromatographed on silica gel eluting with hexane / ethyl acetate (50:50) to give 1.47 g (35.0 percent) of the desired product.

MS (ES) mlz 241, 243 [M-H].

b) N- (2-Bromophenyl) -N '- (3-bromo-4-cyano-2-hydroxyphenyl) -N' - cyanoguanidine

In the same manner as in Example 2 (a) - 1 (e) except that 5-cyano-2-nitrophenol was replaced by 2-bromo-3-hydroxy-4-nitrobenzonitrile, the title compound was obtained as a white solid in 44% overall yield. substances.

¹ H NMR (400 MHz, DMSO d ₆ ) δ 10.66 (s, 1H), 9.56 (s, IH),

8.92 (s, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 8.5 Hz, IH), 7.48-7.41 (m) 3H, 7.26 (t, 1H).

IR (KBr) 2228, 2186 cm ^-1 .

• 9

9 9 9 1 »98 9 <

99 · 99

MS (ES ⁺ ) me 434, 436, 438 [M + H] &lt; + &gt; ^. MS (ES) me 432, 434, 436 [M-H] temperature thaw : 142 Deň: 32 ° C. Example 10

Preparation of N- (3-bromo-4-cyano-2-hydroxyphenyl) -N '- (2,3-methylenedioxyphenyl) -N' - cyanoguanidine

In the same manner as in Example 8 (a) -1 (b), except that the 2-bromophenyl isocyanate was replaced with methylenedioxyphenyl isocyanate, the title compound was obtained in a total yield of 14 percent.

IR (KBr) 2230, 2196 cm ^-1 . MS (ES ⁺ ) m / e 400, 402 [M + H] &lt; + ^&gt; . MS (ES ^- ) m / e 398.400 [M-H]. temperature mp: 164-165 ° C. Example 11

Preparation of N- (2-bromophenyl) -N '- (4-cyano-2-hydroxy-3-methoxycarbonylphenyl) -N''-cyanoguanidine

a) Methyl 2,6-dihydroxybenzoate

A solution of 10.00 grams (333.3 millimoles) of 80 percent NaH in milliliters of N, N-dimethylformamide (DMF) was cooled to 0 ° C under argon. 48.88 g (317.1 mmol) of 2,6-dihydroxybenzoic acid in 50 ml of N, N-dimethylformamide (DMF) was slowly added over 45 minutes. The solution was allowed to stir for 45 minutes and then 21.0 ml (337 millimoles) was added over 20 minutes. · Methyl iodide (Mel) · · · · · · · · · · · · · · · · · · · · · · · · ·. The resulting mixture was allowed to stir at room temperature for 70 hours, diluted with dichloromethane and filtered through a pad of silica gel, which was then washed with dichloromethane. Evaporation of the solvent gave 35.22 g (66.1 percent) of the desired product.

1 H NMR (250 MHz, DMSO d ₆ ) δ 9.91 (s, 2H), 7.09 (t, J = 1.2 Hz, J = 2.5 Hz, 1H), 6.37 (d, J = 1.1 Hz, 2H), 3.78 (s, 3H).

b) Methyl 2-benzyloxy-6-hydroxybenzoate

To a mixture of 20.00 grams (118.9 millimoles) of methyl 2,6-dihydroxybenzoate in 100 milliliters of Ν, N, -dimethylformamide (DMF) was gradually added 3.9144 grams (130.5 millimoles) of 80 percent NaH and 25, 5 ml (214.5 mmol) of benzyl bromide. The solution was warmed to room temperature for 20 hours. The reaction mixture was cooled, saturated sodium bicarbonate solution was added thereto, and extracted with ethyl acetate. The organic layers were dried over anhydrous magnesium sulfate and filtered. Evaporation of the solvent followed by chromatography of the residue on silica gel (eluting with hexane / ethyl acetate (95: 5)) gave 16.71 g (54.4 percent) of the desired product.

MS (ES) mlz 257 [M-H].

c) Methyl 2-benzyloxy-6-cyanobenzoate

To a solution of methyl 2-benzyloxy-6-hydroxybenzoate (2.730 g, 10.6 mmol) in dichloromethane (28.5 ml) was added N-phenyltrifluoromethanesulfonimide (4.5424 g, 12.7 mmol) under argon at 0 ° C. ml (11.6 mmoles) of triethylamine. The reaction mixture was allowed to warm to room temperature and stirred for an additional 14 hours. The solution was diluted with diethyl ether, washed with water,

44 44 * 4 4 4 * * 4 4 4

4 4 4 4

4 4 4

444 44 4444

5% sodium hydroxide solution and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated to give 4.462 grams (108 percent) of the crude triflate.

¹ H NMR (250 MHz, CDCl ₃ ) δ 7.35 (m, 6H), 6.95 (m, 2H), 5.16 (s, 2H), 3.94 (s, 3H).

This crude triflate was dissolved in 23 mL of N, N-dimethylformamide (DMF) and treated with 0.3036 g (0.260 millimoles) of tetrakis (triphenylphosphine) palladium and

1.1027 grams (9.39 millimoles) of zinc cyanide. The mixture was heated at 80 ° C for 10 hours, cooled to room temperature and poured into saturated sodium bicarbonate solution. The resulting mixture was extracted with ethyl acetate and the organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated. The solid residue was purified by silica gel chromatography eluting with hexane / ethyl acetate (80:20) to give 2.20 g (78 percent for both steps) of the desired product.

1 H NMR (250 MHz, CDCl ₃ ) δ 7.5-7.2 (m, 8H), 5.19 (s, 2H),

4.00 (s, 3H).

d) Preparation of methyl 6-cyano-2-hydroxybenzoate

To a solution of 10.0 grams (37.4 millimoles) of methyl 2-benzyloxy-6-cyanobenzoate in 330 milliliters of ethyl acetate was added 4.72 grams of 10 percent palladium on charcoal under argon. The reaction vessel was purged with hydrogen and the mixture was allowed to stir at room temperature under the pressure of hydrogen formed by the inflated balloon. After 3 hours, the reaction mixture was purged with argon and the solution was filtered through

Face. Evaporation of the solvent gave 6.12 g (92.2 percent) of the desired product.

Analysis for C9H7NO3:

Calculated: C 61.02; H, 3.98; N, 7.91

Found: C, 60.74; H, 3.99; N, 7.65

e) Preparation of methyl 6-cyano-2-hydroxy-3-nitrobenzoate

To a suspension of 1.1428 g (6.45 mmol) of methyl 6-cyano-2-hydroxybenzoate in 21 mL of acetic anhydride was added dropwise 0.41 mL (6.44 mmol) of concentrated nitric acid at 0 ° C. The mixture was allowed to warm to room temperature during which time all of the starting material dissolved. The solution was stirred for an additional 36 hours and then poured into water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated and chromatography of the obtained solid residue on silica gel eluting with hexane / ethyl acetate / acetic acid (70: 30: 1) afforded 0.50 g (35.7 percent) of the desired product.

MS (ES ^- ) m / e 221 [MH] -.

f) Methyl 3-amino-6-cyano-2-hydroxybenzoate

To a solution of 402 mg (1.81 mmol) of 6-cyano-2-hydroxy-3-nitrobenzoate in 40 mL of ethyl acetate was added 0.23 g of 10 percent palladium on carbon under argon. The reaction vessel was purged with hydrogen and the mixture was allowed to stir at room temperature under the pressure of hydrogen formed by the inflated balloon. After 2 hours the reaction mixture was fcfc fcfc fcfc fcfc fcfc fcfc fcfc fcfcfc fcfcfc Fc fc fcfc flushed with argon and the solution was filtered through Celite. Evaporation of the solvent gave 334 mg (96 percent) of the desired product.

MS (ES &lt; ^{- &gt;} ) m / e 192 [MH].

g) N- (2-Bromophenyl) -1 '- (4-cyano-2-hydroxy-3-methoxycarbonylphenyl) -N' - cyanoguanidine

In the same manner as in Example 2 (a) -1 (e), except that 5-cyano-2-nitrophenol was replaced with methyl 3-amino-6-cyano-2-hydroxybenzoate, the title compound was obtained in a total yield of 19 percent.

1 H NMR (400 MHz, DMSO d ₆ ) δ 11.08 (s, 1H), 9.69 (s, 1H),

8.89 (s, 1H); 7.99 (d, J = 8.40 Hz, 1H); 7.73 (d,

J = 7.9 Hz, 1H), 7.50-7.42 (m, 3H), 7.28 (t, 1H).

IR (KBr) 2228, 2186 cm &^lt; -1 &gt;.

IR (KBr) 2225, 2177 cm ^1st

MS (ES -) m / e 412, 414 [M-H] -.

mp: 210-211 ° C.

Biological examples

The inhibitory effects of the compounds of the present invention on the chemokinin IL-8 and GROα 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 NEN - New England Nuclear. All other chemicals had • 4

4 · · 4 4 4 4

4 · · · ·

4 4 4

4 4 4 4 4 ·· 4444 44 4444 analytical purity. High levels of recombinant human IL-8 receptors of α and β types 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 millimoles of ethylenediaminetetraacetic acid (EDTA), millimoles of α-toluenesulfonylfluoride (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 IL-8Rα or 1.0 microgram / ml IL-8R ® membrane in a mixture of 20 millimoles of bis (trispropanoic) and 0.4 millimoles of a pH of 8.0 containing 1 2 millimoles MgSO ₄ , 0.1 millimoles EDTA, 25 millimoles 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 1 percent polyethyleneimine / 0.5 percent BSA, washed three times with 25 millimole NaCl, 10 millimoles Tris-HCl, ··

4 <

· • ·

4 1 millimole of MgSO ₄ , 0.5 millimole of 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.

Representatives of the compounds of formula (I), which were the compounds prepared in Examples 1 to 11, showed IC50 values in the range of about 5 nanomolar / liter to about 100 nanomolar / liter for the IL-δβ inhibition models . A compound lacking an ionizable hydrogen atom at the 2-position, which was N- (2-allyloxy-4-cyanophenyl) -N '- (2-bromophenyl) -1'-cyanoguanidine, showed no activity in this assay.

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

4

4

4 4

4 4

4

4 4 polycarbonate filter with a thickness of 5 micrometers. To test the compounds of the present invention, the compounds were mixed with said cells (at a concentration of 0.001 nanomolar to 1000 nanomolar) just prior to the addition of said cells to the upper chamber. Incubation was allowed to proceed in a humidified incubator with an atmosphere containing 5 percent CO ₂ at about 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,

> · ·

9 9 »«> ··· · ·

9 9

9499

Suppl 1, Unit 7.23.1. To each well of a 96-well plate was placed 0.88 χ 10 ⁶ PMN cells suspended in Ringer's solution (containing NaCl 118, KCl 4.56, NaHCCb 25,

KH 2 PO 4 1.03, glucose 11.1, HEPES 5 micromoles and having a pH of 7.4), each well containing 50 microliters of said 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 cells so treated 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, GROP, 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.

· 9 «<* * * * * * * * * * * * * * * * * * * *

TNF-α in a traumatic brain injury test

This assay was used to test the expression of tumor necrosis factor mRNA in certain areas of the brain following experimentally induced traumatic brain injury (TBI) in rats, caused by lateral fluid and tapping. Adult SpragueDawley rats (n = 42) were anesthetized with sodium pentobarbital (60 milligrams / kilogram, intraperitoneally) and were injured with moderate brain injury (243.18 kilopascal pressure, ie 2.4 atmospheres) by lateral fluid, with the center of this was above the left temporaparietal cortex (n = 18), or was caused by "false injury" (ie, animals were anesthetized and operated without causing injury, n = 18). At 1, 6 and 24 hours after the injury, the animals were sacrificed by decapitation, their brains removed, and tissue samples were prepared from the left (injured) parietal cortex (LC), corresponding opposite right cortex (RC), from the cortex adjacent to the injured parietal cortex. (LA), a corresponding cortex adjacent to said right cortex (RA), left hippocampus (LH) and right hippocampus (RH). Total RNA was isolated, Northern blot hybridization was performed, which was quantified relative to the TNF-α positive control RNA (macrophage = 100 percent). In the injured hemisphere, a significant increase in TNF-α mRNA expression was observed in LH (104 ± 17% of positive control sample, p <0.05 vs. mock injury), 1 hour after injury, in LC (105 ± 21%, p <0, 05) and in LA (69 ± 8%, p <0.01). TNF-α mRNA overexpression was also observed 6 hours after injury in LH (46 ± 8%, p <0.05), in e · • ·

Fc · 4 4 · fc · in fc f «fc · · · · · ··· fcfc ····

LC (30 ± 3%, p <0.01) and LA (32 ± 3%, p <0.01), with this overexpression disappearing within 24 hours of injury. In the opposite hemisphere, overexpression of TNF-α mRNA was observed 1 hour after injury in RH (46 ± 2%, p <0.01), RC (4 ± 3%) and RA (22 ± 8%) and 6 hours after injury in RH (28 + 11%), RC (7 + 5%) and RA (26 + 6%, p <0.05). Consistently changes in TNF-α mRNA expression were observed in any of the 6 brain regions and in all the above 6 time intervals in mock-injured animals (i.e., animals that were operated without brain injury) or in non-operated animals. . These results have shown that after parasagital brain injury, caused by lateral fluid and percussion, there are temporary changes in TNF-α mRNA expression in certain areas of the brain, including areas of the brain belonging to the uninjured hemisphere. Since TNF-α is able to induce nerve growth factor (NGF) and stimulate the release of other cytokinins from activated astrocytes, this post-traumatic change in TNF-α gene expression plays an important role in both acute and regenerative responses to CNS injury.

CNS injury model for IL-β mRNA

This assay was used to characterize the regional expression of interleukinin-β (mRNA) in certain areas of the brain following experimentally induced traumatic brain injury (TBI) in rats, caused by lateral fluid and tapping. Adult Sprague-Dawley rats (n = 42) were anesthetized with sodium pentobarbital (60 milligrams / kilogram, intraperitoneally) and were injured with moderate brain injury by lateral fluid • 4 • 4 · 4 · O

4 4 · »· · 4

4 ··· 4 ···

4,444 4 4 4 4 4 4 · 4

444 444 44 »

4,444,444,444,444 (243.18 kilopascal pressure, i.e. 2.4 atmospheres), with the center of the midline of this swelling above the left temporaparietic cortex (n = 18), or caused by "false injury (i.e., animals were anesthetized) and operated without causing injury). At 1, 6 and 24 hours after the injury, the animals were sacrificed by decapitation, their brains removed, and tissue samples were prepared from the left (injured) parietal cortex (LC), corresponding opposite right cortex (RC), from the cortex adjacent to the injured parietal cortex. (LA), a corresponding cortex adjacent to said right cortex (RA), left hippocampus (LH), and right hippocampus (RH). Whole RNA was isolated, Northern blot hybridization was performed, and the amount of IL-β mRNA present in brain tissue was expressed as relative radioactivity in percent relative to a positive control sample of IL-ββ macrophages that was loaded on the same gel. In the injured hemisphere, a significant increase in IL-β mRNA expression was observed in LC (20.0 ± 0.7% of the positive control sample, n = 6, p <0.05 vs. false injury) 1 hour after injury, in LH (24 , 5 ± 0.9%, p <0.05) and in LA (21.5 ± 3.1%, p <0.05), which expression remained up to 6 hours post LC injury (4.0 ± 0.4%, n = 6, p <0.05) and in LH (5.0 ± 1.3%, p <0.05). IL-ILβ mRNA expression was not observed in any of the 6 brain regions in mock-injured animals (ie animals that were operated without brain injury) or in non-operated animals. The results of these tests show that, after traumatic brain injury (TBI), IL-ββ mRNA expression is temporarily stimulated in certain areas of the brain. These regional changes in cytokinins such as

· · · »4 9 · · 9 9 ·

44 4 * 44 4 · 444 is IL-Ιβ, they play a role in the post-traumatic pathological or regenerative response to CNS injuries.

The contents of all publications, including patent literature, cited herein are also incorporated herein by reference.

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. On the basis of the above description, one of ordinary skill in the art should be able to utilize the present invention to its fullest extent without the need for further specification. 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.

• * · «9 • • · • 9 * « • · • 9 · • • • « • • • 9 9 ♦ 9 • • 9 · 9 • 9 9 • · «9 • 9 • • · • ·

W & 004 ~

Claims (8)

PATENT CLAIMS 1. A compound of formula (I): W - NH _(C R ₁₃ R _{14) V - Wi} (I) wherein Z is cyano, Orn, C (O) NR ₅ R _6, R _18, a group 0 (0) Rn, C (0) 0Rn or S (0) 2Rn; 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 (CR ₈ R 5) q 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, an aryloxy group, an arylalkyloxy group • · · 4 · • • · • * «· * * • • * • • · • · · • • • · • • « • · «· • • · · · • · • • • · «· · • « • • * ·· · · (C 1 -C 4) alkyloxy group, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic-substituted (C 1 -C 4) alkyl, (C 1 -C 4) heteroarylalkyloxy, arylalkenyl (C 2 -C 10) alkenyl group, (C 2 -C 10) heteroarylalkenyl, (C 2 -C 10) heterocyclic-substituted alkenyl group (CR ₈ R ₈ ) _q NR ₄ R ₅ , alkenyl-C (O) NR ₄ R ₅ group containing from 2 to 10 carbon atoms in the alkenyl moiety, (CR ₈ R ₈ ) _q C (O) NR ₄ R ₅ , (CR ₈ R ₈ ) _q C (O) NR ₄ R ₁₀ , S (O) ₃ H, S (O) ₃ R ₈ , (CR ₈ R ₈ ) _q C (O) R 11, alkenyl-C (O) Ru in the alkenyl moiety from 2 to 10 at carbon atoms, alkenyl-C (O) ORn group containing from 2 to 10 carbon atoms in the alkenyl moiety, (CR ₈ R ₈ ) _q C (O) OR ₁₂ , (CR ₈ R ₈ ) _q OC (O) R _n, (CR ₈ R _{8) q} NR ₄ C (0) _R, (CR ₈ R _{8) q} NHS (O) ₂ Ri9, (CR ₈ R _{8) q} S (O) ₂ NR ₄ R ₅ , or two R _x groups together form an O- (CH ₂ ) _S O group or a 5- to 6-membered saturated or unsaturated ring, wherein all aryl, heteroaryl, and heterocyclic groups may be optionally substituted; q is 0, or an integer from 1 to 10; v * · 9 * V ·· 9 4 • 4 4 4 999 · 9 4 9 • 4 94 9499 · 4 9 49,444 4,4999 449 4 444 44 · ·> 4 4 · 4444 s is an integer from 1 to 3; t is 0, or an integer of 1 or 2; v is 0, or an integer from 1 to 4; 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 a substituted 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 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, by halogen, by a halogen atom; Substituted alkoxy group containing from 1 to 10 carbon atoms, azide group, (CR _g R g) _q S (O) _t R ₄ , hydroxyl group, hydroxyalkyl from 1 to 4 carbon atoms, aryl, arylalkyl from 1 to 4 carbon atoms, aryloxy, arylalkyloxy from 1 to 4 carbon atoms, heteroaryl, heteroarylalkyl a heteroarylalkyloxy group containing from 1 to 4 carbon atoms in the alkyloxy moiety, a heterocyclic group, a heterocyclic 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, a heteroarylalkenyl group containing in the alkenyl moiety of from 2 to 10 carbon atoms, a heterocyclic-substituted alkenyl group containing in the alkenyl moiety of from 2 to 10 carbon atoms, a (CR ₉ R ₈ ) _q NR ₄ R _{5 group} , an alkenyl-C (O) NR ₄ R ₅ group containing 2 to 10 carbon atoms, (CRgRg) _q C (O) NR4R5, (CRgRg) q C (O) NR4R10, S (O) ₃ H, S (O) ₃ R _3, (CRgRg) q C (O) Rn, 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) Rn, group ( CRgRg) qC (O) OR12, (CRgRg) qOC (O) Rn, (CRgRg) qNR ₄ C (O) Rn, (CRgRg) _q NHS (O) ₂ Rd / (CRgRg) _q S (O ) ₂ NR ₄ R ₅ , or two Y groups together · fcfcfc fcfcfc fcfcfc fcfcfc fcfcfc fcfcfc may form an O- (CH ₂ ) _S -O- group or a 5- to 6-membered saturated or unsaturated ring, wherein all aryl, heteroaryl and heterocyclic groups may be optionally substituted; n is an integer from 1 to 3; m is an integer from 1 to 3; R ₆ and R ₇ are independently selected from the group consisting of hydrogen, alkyl of 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 an additional heteroatom selected from oxygen, nitrogen or sulfur; 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 containing · · · · · · · · · · · · · · · · · · · · · · 9999999 · 9 in the alkyl moiety of 1 to 4 carbon atoms, an optionally substituted heterocyclic group, or an optionally substituted heterocyclic group a substituted alkyl group containing in the alkyl moiety of 1 to 4 carbon atoms; 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; R ₁₃ and R ₁₄ are independently selected from the group consisting of hydrogen, optionally substituted alkyl of from 1 to 4 carbon atoms, or one of R ₁₃ and R ₁₄ may be an optionally substituted aryl group; R 18 and R 16 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 having from 1 to 4 carbon atoms, an optionally substituted heterocyclic group, an optionally substituted heterocyclic group substituted with an alkyl group having from 1 to 4 carbon atoms, or R 18 and R 16 together with the nitrogen atom, to to which they are attached, form a five to seven membered ring which may optionally contain another heteroatom selected from oxygen, nitrogen or sulfur; R 17 is an alkyl group containing from 1 to 4 carbon atoms, an NR 15 R 16 group, an OR 11 group, an optionally substituted aryl group, an optionally substituted arylalkyl group containing from 1 to 4 carbon atoms, an optionally substituted heteroaryl group, an optionally substituted heteroarylalkyl group containing a C 1 -C 4 moiety, an optionally substituted heterocyclic group, an optionally substituted heterocyclic group substituted alkyl group containing from 1 to 4 carbon atoms in the alkyl moiety; R 18 is an optionally substituted alkyl group 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 portion, an optionally substituted heteroaryl group, an optionally substituted heteroarylalkyl group containing from 1 up to 4 carbon atoms, an optionally substituted heterocyclic group, an optionally substituted heterocyclic group, an alkyl group containing from 1 to 4 carbon atoms; R 19 is an alkyl group having from 1 to 4 carbon atoms, an aryl group, an arylalkyl group, or an alkyl group having 1 to 4 carbon atoms; Heteroaryl, heteroarylalkyl having 1 to 4 carbon atoms in the alkyl moiety, heterocyclic group, heterocyclic-substituted alkyl having 1 to 4 alkyl moieties All of said groups may be optionally substituted; Rd is NR 8 R 7 alkyl, arylalkyl having 1 to 4 carbon atoms in the alkyl moiety, arylaalkenyl having 2 to 4 carbon atoms in the alkenyl moiety, heteroaryl, heteroarylalkyl having 1 to 4 carbon atoms in the alkyl moiety, a heteroarylalkenyl group containing from 2 to 4 carbon atoms in the alkenyl moiety, a heterocyclic group or a heterocyclic substituted alkyl group containing from 1 to 4 carbon atoms in the alkyl moiety, all of said alkyl groups, aryl groups, arylalkyl groups, heteroaryl groups, heteroarylalkyl groups, heterocyclic groups and substituted alkyl substituted; heterocyclic groups of the group may optionally be ¥ is a group selected from the group consisting of wherein the asterisk (*) indicates where the ring is bound to the parent ring; from the group comprising the group consisting of the group consisting of: - - - - - - - - - - - - - - - - - the asterisk (*) indicates where the ring is bound to the base ring; or a pharmaceutically acceptable salt thereof for said mammal for use in treating a chemokinin-mediated disease in a mammal, wherein said chemokinin binds to IL-8a or β receptors and said disease is selected from malaria, restinosis, angiogenesis, atherosclerosis, osteoporosis, gingivitis, undesirable stem cell haematopoietic cell release and diseases caused by respiratory viruses, herpesviruses and hepatitis-causing viruses, including but not limited to hepatitis B-causing virus and hepatitis C-virus. The compound of claim 1, wherein the ionizable hydrogen atom has a pK _and in the range of from 3 to 10. A compound according to claim 2, wherein the R group is selected from the group consisting of a hydroxyl group, a carboxylic acid moiety, a thiolic acid. 4 44 4 · 4 · 44 4 4 44 * 4444444 443 44 4 44 44444 ·· · ··, -SR ₂ , -OR ₂ , -NH-C (O) R _a , -C (O) NR ₆ -R 7 -, -NHS (O) ₂ R bz -S (O) ₂ NHR _c, NHC _(X2) NHR _b, or tetrazolyl, wherein R ₂ is substituted aryl, heteroaryl or heterocyclic group, which ring contains the functional moiety having an ionizable hydrogen whose _pKa is 10 or less; R ₆ , and R ₇ - are selected from the group consisting of hydrogen, alkyl of from 1 to 4 carbon atoms, aryl, aralkyl of from 1 to 4 carbon atoms, arylalkenyl of from 2 to 4 alkenyl; up to 4 carbon atoms, heteroaryl, heteroarylalkyl having 1 to 4 carbon atoms in the alkyl moiety, heteroarylalkenyl having 2 to 4 carbon atoms in the alkenyl moiety, heterocyclic group, heterocyclic group substituted alkyl having 1 to 4 alkyl moieties carbon atoms, a heterocyclic-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 for a group containing from 1 to 4 carbon atoms such as trifluoromethyl (CF3), an alkyl group containing from 1 to 4 carbon atoms such as » • 9 99 0 0 9 9 9 9 0 9 9 9 09 9909 a methyl group, an alkoxy group having from 1 to 4 carbon atoms such as a methoxy group, a NR _g group C (O) R _a , a C (O) NR ₆ R ₇ group, a S (O) ₃ H group, C (0) OC-alkyl the alkyl portion contains 1 to 4 carbon atoms, wherein only one of Rg and R ₇ may be hydrogen; R _a represents 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 group substituted with an alkyl group containing from 1 to 4 carbon atoms up to 4 carbon atoms, all of which may be optionally substituted; R b represents 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, a heterocyclic group substituted alkenyl group containing from 2 to 4 alkenyl groups up to 4 carbon atoms, camphor, all of which may be 4 4> 4 4 44 445 4 44 to 4444 44 4 optionally substituted with one to three substituents independently selected from the group consisting of halogen, nitro, halogen substituted alkyl of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 alkoxy, NRgC _(O) Ra, C (O) NR ₆ R _7, S (O) 3H, or C (0) O-alkyl the alkyl portion contains 1 to 4 carbon atoms; R 8 represents a hydrogen atom or an alkyl group containing from 1 to 4 carbon atoms; 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 1 to 4 carbon atoms, alkyl containing 9 99 94 44 9 «4 9 9 • 99 9 9 · 4 99 · · 9 4449 . 4 9 4 9 4 9 995 99 99 4 4 9 9 9 9 9 9 9 9 9 49 9949 of from 1 to 4 carbon atoms, alkoxy of 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-alkyl having from 1 to 4 carbon atoms in the alkyl moiety; and X ₂ represents an oxygen or sulfur atom. 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, (C 1 -C 10) alkoxy, hydroxyl, thio, -C (O) NR ₅ , 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. A compound according to claim 3, wherein the R group represents a hydroxyl group, an -NHS (O) ₂ R _b group, or a carboxyl group. The compound of claim 1, wherein R 1 is halogen, cyano, nitro, trifluoromethyl, C (O) NR ₄ R ₅ , alkenyl-C (O) NR ₄ R 5, C (O) R ₄ R 10, alkenyl-C (O) OR ₁₂ , heteroaryl, 99 * 9 • 9 9 99 99 • 99 9 9 ·· ♦ 9 9 9 9 »* 9 9 «9 9 9 9 9 999 t 9 9 · X 9 9 9 « 9 9 9 9 99 9999 heteroarylalkyl, heteroarylalkenyl or S (O) NR ₄ R ₅ . 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. A compound according to claim 1, wherein the + R group represents a hydroxyl group, a thio group or an NHS (O) group _with R _b and the R ₄ group is monosubstituted at the 3-position or at the 4-position or is disubstituted at the 3,4-positions, namely by an electron-acceptor group.