1-Phenyl-1,2-diaminoethane derivatives as modulators of the chemokine receptor activity

FIELD OF THE INVENTION

[0002] This invention relates generally to the use of 1-phenyl-1,2-diaminoethanes as modulators of chemokine receptor activity, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment and prevention of inflammatory diseases such as asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis.

BACKGROUND OF THE INVENTION

[0003] Chemokines are chemotactic cytokines, of molecular weight 6-15 kDa, that are released by a wide variety of cells to attract and activate, among other cell types, macrophages, T and B lymphocytes, eosinophils, basophils and neutrophils (reviewed in Luster, New Eng. J. Med., 338, 436-445 (1998) and Rollins, Blood, 90,909-928 (1997)). There are two major classes of chemokines, CXC and CC, depending on whether the first two cysteines in the amino acid sequence are separated by a single amino acid (CXC) or are adjacent (CC). The CXC chemokines, such as interleukin-8 (IL-8), neutrophil-activating protein-2 (NAP2) and melanoma growth stimulatory activity protein (MGSA) are chemotactic primarily for neutrophils and T lymphocytes, whereas the CC chemokines, such as RANTES, MIP-1a, MIP-1 (3, the monocyte chemotactic proteins (MCP-1, MCP-2, MCP-3, MCP-4, and MCP-5) and the eotaxins (-1,-2, and-3) are chemotactic for, among other cell types, macrophages, T lymphocytes, eosinophils, dendritic cells, and basophils. There also exist the chemokines lymphotactin-1, lymphotactin-2 (both C chemokines), and fractalkine (a CXXXC chemokine) that do not fall into either of the major chemokine subfamilies.

[0004] The chemokines bind to specific cell-surface receptors belonging to the family of G-protein-coupled seventransmembrane-domain proteins (reviewed in Horuk, Trends Pharm. Sci., 15,159-165 (1994)) which are termed “chemokine receptors.” On binding their cognate ligands, chemokine receptors transduce an intracellular signal through the associated trimeric G proteins, resulting in, among other responses, a rapid increase in intracellular calcium concentration, changes in cell shape, increased expression of cellular adhesion molecules, degranulation, and promotion of cell migration. There are at least ten human chemokine receptors that bind or respond to CC chemokines with the following characteristic patterns: CCR1 (or “CKR-1” or “CC-CKR-1”) [MIP-1a, MCP-3, MCP-4, RANTES] (Ben-Barruch, et al., Cell, 72,415-425 (1993), Luster, New Eng. J. Med., 338,436-445 (1998)); CCR-2A and CCR-2B (or “CKR-2A”/“CKR-2B” or “CC-CKR-2A”/“CC-CKR-2B”) [MCP-1, MCP2, MCP-3, MCP-4, MCP-5] (Charo et al., Proc. Natl. Acad. Sci. USA, 91,2752-2756 (1994), Luster, New Eng. J. Med., 338,436-445 (1998)); CCR-3 (or “CKR-3” or “CC-CKR-3”) [eotaxin-1, eotaxin-2, RANTES, MCP-3, MCP-4] (Combadiere, et al., J. Biol. Chem., 270,16491-16494 (1995), Luster, New Eng. J. Med., 338,436-445 (1998)); CCR-4 (or “CKR-4” or “CC-CKR-4”) [TARC, MIP-1a, RANTES, MCP-1] (Power et al., J. Biol. Chem., 270,19495-19500 (1995), Luster, New Eng. J. Med., 338,436-445.(1998)); CCR-5 (or “CKR-5” OR “CCCKR-5”) [MIP-1a, RANTES, MIP-1p] (Sanson, et al., Biochemistry, 35,3362-3367 (1996)); CCR-6 (or “CKR-6” or “CC-CKR-6”) [LARC] (Baba et al., J. Biol. Chem., 272, 14893-14898 (1997)); CCR-7 (or “CKR-7” or “CC-CKR-7”) [ELC] (Yoshie et al., J. Leukoc. Biol. 62,634-644 (1997)); CCR-8 (or “CKR-8” or “CC-CKR-8”) [1−309, TARC, MIP-1p] (Napolitano et al., J. Immunol., 157,2759-2763 (1996), Bernardini et al., Eur. J. Immunol., 28,582-588 (1998)); and CCR-10 (or “CKR-10” or “CC-CKR-10”) [MCP-1, MCP-3] (Bonini et al, DNA and Cell Biol., 16,1249-1256 (1997)).

[0005] In addition to the mammalian chemokine receptors, mammalian cytomegaloviruses, herpesviruses and poxviruses have been shown to express, in infected cells, proteins with the binding properties of chemokine receptors (reviewed by Wells and Schwartz, Curr. Opin. Biotech., 8, 741-748 (1997)). Human CC chemokines, such as RANTES and MCP-3, can cause rapid mobilization of calcium via these virally encoded receptors. Receptor expression may be permissive for infection by allowing for the subversion of normal immune system surveillance and response to infection. Additionally, human chemokine receptors, such as CXCR4, CCR2, CCR3, CCR5 and CCR8, can act as coreceptors for the infection of mammalian cells by microbes as with, for example, the human immunodeficiency viruses (HIV).

[0006] Chemokine receptors have been implicated as being important mediators of inflammatory, infectious, and immunoregulatory disorders and diseases, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. For example, the chemokine receptor CCR-3 plays a pivotal role in attracting eosinophils to sites of allergic inflammation and in subsequently activating these cells. The chemokine ligands for CCR-3 induce a rapid increase in intracellular calcium concentration, increased expression of cellular adhesion molecules, cellular degranulation, and the promotion of eosinophil migration. Accordingly, agents which modulate chemokine receptors would be useful in such disorders and diseases. In addition, agents which modulate chemokine receptors would also be useful in infectious diseases such as by blocking infection of CCR3 expressing cells by HIV or in preventing the manipulation of immune cellular responses by viruses such as cytomegaloviruses.

[0007] A substantial body of art has accumulated over the past several decades with respect to substituted 1-phenyl-1,2-diaminoethanes. These compounds have implicated in the treatment of a variety of disorders, in particular as neurokinin antagonists, as for example in the US patent U.S. Pat. No. 6,235,732. However, this patent is completely silent about any activity as modulators of chemokine receptors.

[0008] WO 00/35452 describes N-ureidoalkyl-piperidines which are useful as modulators of chemokine receptors.

[0009] These reference compounds are readily distinguished structurally by either the nature of the substitution pattern of the piperidine moiety, the attachment chain, or the possible substitution of the present invention. The prior art does not disclose nor suggest the unique combination of structural fragments which embody these novel 1-phenyl-1,2-diaminoethanes as having activity toward the chemokine receptors.

SUMMARY OF THE INVENTION

[0010] Accordingly, one object of the present invention is to provide agonists or antagonists of CCR-3, or pharmaceutically acceptable salts thereof.

[0011] It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt thereof.

[0012] It is another object of the present invention to provide a method for treating inflammatory diseases and allergic disorders comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt thereof.

[0013] These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors' discovery that compounds of formula (I):

[0014] or stereoisomers or pharmaceutically acceptable salts thereof, wherein the groups A, R1, R2 and Ra through Rj are defined below, are effective modulators of chemokine activity.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

[0015] In one embodiment, the present invention provides the use of compounds of formula (I):

[0016] wherein

[0017] Ra through Re each independently represent a hydrogen or halogen atom or a group selected from C1-C6-alkyl, C1-C4-alkoxy, C1-C4-alkylthio, C2-C6-alkenyl C2-C6-alkinyl, C3-C8-cycloalkyl —NH2, —NH(C1-C4-alkyl), —N(C1-C4-alkyl)2 and phenyl, wherein any of these groups may optionally substituted by one or more of the groups hydroxy, halogen, CF3, or

[0018] two adjacent groups Ra and Rb or Rb and Rc together form a group —(CH2)m—O—, —(CH2)n— or —CH═CH—CH═CH—, in which m is 1 or 2, and n is 3, 4 or 5;

[0019] Rf through Rj each independently represent a hydrogen or halogen atom or a group selected from C1-C6-alkyl, C1-C4-alkoxy, C1-C4-alkylthio, C2-C6-alkenyl C2-C6-alkinyl, C3-C8-cycloalkyl, cyano, —NH2, —NH(C1-C4-alkyl), —N(C1-C4-alkyl)2, wherein any of these groups may optionally be substituted by one or more hydroxy or halogen groups,

[0020] R1 and R2 each independently represent a hydrogen atom or a group selected from C1-C6-alkyl, C2-C6-alkenyl C2-C6-alkinyl, C3-C8-cycloalkyl, piperidinyl and phenyl, wherein any of these groups optionally may be substituted by one or more of the groups C1-C6-alkyl, C1-C4-alkoxy, C1-C4-alkylthio, hydroxy, halogen, C3-C8-cycloalkyl, pyridyl, piperidyl, pyrrolidinyl, oxopyrrolidinyl, tetrahydrofuranyl, furanyl, phenyl, hydroxyphenyl, alkoxyphenyl, dialkoxyphenyl, methylendioxyphenyl, CF3, or —NR3R4, in which R3 and R4 each independently represent hydrogen, C1-C6-alkyl, C1-C4-alkanoyl, C3-C6-cycloalkylmethyl, omega-hydroxy-C2-C4-alkyl, 1,3-dihydroxyprop-2-yl

[0021] R1 and R2 together with the interjacent nitrogen atom form a a 5- to 7-membered, saturated or unsaturated heterocyclic group, which may contain one or two hetero atoms selected from among oxygen, nitrogen or sulphur, wherein said heterocyclic group may be substituted by hydroxy, C1-C4-alkyl, C3-C8-cycloalkyl, C3-C6-cycloalkylmethyl, hydroxy-C3-C8-cycloalkyl, C1-C4-alkoxy, C1-C4-alkoxycarbonyl, 2-oxobenzimidazolyl, piperidyl, benzyl 9-H-fluorenyl, di-(C1-C4-alkyl)-amino-C1-C4-alkyl or —NR3R4, in which R3 and R4 each independently represent hydrogen, C1-C6-alkyl, C1-C4-alkanoyl, C3-C6-cycloalkylmethyl, omega-hydroxy-C2-C4-alkyl, 1,3-dihydroxyprop-2-yl, or a group of formula

—(CH2)n-phenyl,

[0022] in which n is 0 or an integer from 1 to 3, and

[0023] the phenyl group may be substituted by one to three substituents selected from the group the group consisting of C1-C6-alkyl, C1-C4-alkoxy, C1-C4-alkylthio, C2-C6-alkenyl C2-C6-alkinyl, C3-C8-cycloalkyl, —NH2, —NH(C1-C4-alkyl), —N(C1-C4-alkyl)2,

[0024] wherein any of said substituents may optionally be substituted by one or more hydroxy or halogen groups), and

[0025] wherein said heterocyclic group may optionally be fused with one or two benzene rings; and

[0026] A represents —CH2CH2—, —C(═O)—NH— or —C(═O)—CH2—;

[0027] optionally in the form of their tautomers, racemates, enantiomers, diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof;

[0028] for the preparation of a medicament for the treatment and/or prevention of a disease, wherein the activity of a CCR3 receptor is involved.

[0029] In another embodiment, the present invention provides a pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of the present invention.

[0030] In another embodiment, the present invention provides a method for modulation of chemokine receptor activity comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention.

[0031] Another aspect of the present invention are the novel 1-phenyl-1,2-diaminoethane derivatives of formula (IA)

[0032] wherein

[0033] Ra through Re each independently represent a hydrogen or halogen atom or a group selected from C1-C6-alkyl, C1-C4-alkoxy, C1-C4-alkylthio, C2-C6-alkenyl C2-C6-alkinyl, C3-C8-cycloalkyl —NH2, —NH(C1-C4-alkyl), —N(C1-C4-alkyl)2 and phenyl, wherein any of these groups may optionally substituted by one or more of the groups hydroxy, halogen, CF3, or

[0034] two adjacent groups Ra and Rb or Rb and Rc together form a group —O—(CH2)m—O—, —(CH2)n— or —CH═CH—CH═CH—, in which m is 1 or 2, and n is 3, 4 or 5;

[0035] Rf through Rj each independently represent a hydrogen or halogen atom or a group selected from C1-C6-alkyl, C1-C4-alkoxy, C1-C4-alkylthio, C2-C6-alkenyl C2-C6-alkinyl, C3-C8-cycloalkyl, cyano, —NH2, —NH(C1-C4-alkyl), —N(C1-C4-alkyl)2, wherein any of these groups may optionally be substituted by one or more hydroxy or halogen groups,

[0036] R1 and R2 each independently represent a hydrogen atom or a group selected from C1-C6-alkyl, C2-C6-alkenyl C2-C6-alkinyl, C3-Cg-cycloalkyl, and phenyl, wherein any of these groups optionally may be substituted by one or more of the groups C1-C6-alkyl, C1-C4-alkoxy, C1-C4-alkylthio, hydroxy, halogen, C3-C8-cycloalkyl, —NH2, —NH(C1-C4-alkyl), —N(C1-C4-alkyl)2, —N(C1-C4-alkanoyl)(C1-C4-alkyl), pyridyl, piperidyl, pyrrolidinyl, oxopyrrolidinyl, tetrahydrofuranyl, furanyl, phenyl, hydroxyphenyl, alkoxyphenyl, dialkoxyphenyl, methylendioxyphenyl, CF3, or

[0037] R1 and R2 together with the interjacent nitrogen atom form a a 5- to 7-membered, saturated or unsaturated heterocyclic group, which may contain one or two hetero atoms selected from among oxygen, nitrogen or sulphur, wherein said heterocyclic group may be substituted by hydroxy, C1-C4-alkyl, C3-Cg-cycloalkyl, C3-C6-cycloalkylmethyl, hydroxy-C3-C8-cycloalkyl, C1-C4-alkoxy, C1-C4-alkoxycarbonyl, 2-oxobenzimidazolyl, piperidyl, benzyl 9-H-fluorenyl, di-(C1-C4-alkyl)-amino-C1-C4-alkyl or —NR3R4, in which R3 and R4 each independently represent hydrogen, C1-C6-alkyl, C1-C4-alkanoyl, C3-C6-cycloalkylmethyl, omega-hydroxy-C2-C4-alkyl, 1,3-dihydroxyprop-2-yl, or a group of formula

—(CH2)n-phenyl,

[0038] in which n is 0 or an integer from 1 to 3, and

[0039] the phenyl group may be substituted by one to three substituents selected from the group the group consisting of C1-C6-alkyl, C1-C4-alkoxy, C1-C4-alkylthio, C2-C6-alkenyl C2-C6-alkinyl, C3-C8-cycloalkyl, —NH2, —NH(C1-C4-alkyl), —N(C1-C4-alkyl)2,

[0040] wherein any of said substituents may optionally be substituted by one or more hydroxy or halogen groups), and

[0041] wherein said heterocyclic group may optionally be fused with one or two benzene rings;

[0042] optionally in the form of their tautomers, racemates, enantiomers, diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.

[0043] Another aspect of the present invention are the novel 1-phenyl-1,2-diaminoethane derivatives of formula (IB)

[0044] wherein

[0045] Ra through Re each independently represent a hydrogen or halogen atom or a group selected from C1-C6-alkyl, C1-C4-alkoxy, C1-C4-alkylthio, C2-C6-alkenyl C2-C6-alkinyl, C3-C8-cycloalkyl —NH2, —NH(C1-C4-alkyl), —N(C1-C4-alkyl)2 and phenyl, wherein any of these groups may optionally substituted by one or more of the groups hydroxy, halogen, CF3, or

[0046] two adjacent groups Ra and Rb or Rb and Rc together form a group —O—(CH2)m—O—, —(CH2)n— or —CH═CH—CH═CH—, in which m is 1 or 2, and n is 3, 4 or 5;

[0047] Rf through Rj each independently represent a hydrogen or halogen atom or a group selected from C1-C6-alkyl, C1-C4-alkoxy, C1-C4-alkylthio, C2-C6-alkenyl C2-C6-alkinyl, C3-C8-cycloalkyl, cyano, amino, —N(C1-C4-alkyl)2, wherein any of these groups may optionally be substituted by one or more hydroxy groups,

[0048] provided that at least one of the groups Rb, Rc, Rd, Rg, Rh and Rj is different from hydrogen;

[0049] R1 and R2 each independently represent a hydrogen atom or a group selected from C1-C6-alkyl, C2-C6-alkenyl C2-C6-alkinyl, C3-C8-cycloalkyl, and phenyl, wherein any of these groups optionally may be substituted by one or more of the groups C1-C6-alkyl, C1-C4-alkoxy, C1-C4-alkylthio, hydroxy, halogen, C3-C8-cycloalkyl, —NH2, —NH(C1-C4-alkyl), —N(C1-C4-alkyl)2, —N(C1-C4-alkanoyl)(C1-C4-alkyl), pyridyl, piperidyl, pyrrolidinyl, oxopyrrolidinyl, tetrahydrofuranyl, furanyl, phenyl, hydroxyphenyl, alkoxyphenyl, dialkoxyphenyl, methylendioxyphenyl, CF3, or

[0050] R1 and R2 together with the interjacent nitrogen atom form a a 5- to 7-membered, saturated or unsaturated heterocyclic group, which may contain one or two hetero atoms selected from among oxygen, nitrogen or sulphur, wherein said heterocyclic group may be substituted by hydroxy, C1-C4-alkyl, C3-C8-cycloalkyl, C3-C6-cycloalkylmethyl, hydroxy-C3-C8-cycloalkyl, C1-C4-alkoxy, C1-C4-alkoxycarbonyl, 2-oxobenzimidazolyl, piperidyl, benzyl 9-H-fluorenyl, di-(C1-C4-alkyl)-amino-C1-C4-alkyl or —NR3R4, in which R3 and R4 each independently represent hydrogen, C1-C6-alkyl, C1-C4-alkanoyl, C3-C6-cycloalkylmethyl, omega-hydroxy-C2-C4-alkyl, 1,3-dihydroxyprop-2-yl, or a group of formula

—(CH2)n-phenyl,

[0051] in which n is 0 or an integer from 1 to 3, and

[0052] the phenyl group may be substituted by one to three substituents selected from the group the group consisting of C1-C6-alkyl, C1-C4-alkoxy, C1-C4-alkylthio, C2-C6-alkenyl C2-C6-alkinyl, C3-C8-cycloalkyl, —NH2, —NH(C1-C4-alkyl), —N(C1-C4-alkyl)2,

[0053] wherein any of said substituents may optionally be substituted by one or more hydroxy or halogen groups), and

[0054] wherein said heterocyclic group may optionally be fused with one or two benzene rings; optionally in the form of their tautomers, racemates, enantiomers, diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.

[0055] In a preferred embodiment, the present invention provides a method for modulation of chemokine receptor activity comprising contacting a CCR3 receptor with an effective inhibitory amount of a compound of the present invention.

[0056] In another embodiment, the present invention provides a method for treating inflammatory disorders comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention

[0057] In another embodiment, the present invention provides a method for treating or preventing disorders selected from asthma, allergic rhinitis, atopic dermatitis, inflammatory bowel diseases, idiopathic pulmonary fibrosis, bullous pemphigoid, helminthic parasitic infections, allergic colitis, eczema, conjunctivitis, transplantation, familial eosinophilia, eosinophilic cellulitis, eosinophilic pneumonias, eosinophilic fasciitis, eosinophilic gastroenteritis, drug induced eosinophilia, HIV infection, cystic fibrosis, Churg-Strauss syndrome, lymphoma,

[0058] Hodgkin's disease, and colonic carcinoma.

[0059] In a preferred embodiment, the present invention provides a method for treating or preventing disorders selected from asthma, allergic rhinitis, atopic dermatitis, and inflammatory bowel diseases.

[0060] In a more preferred embodiment, the present invention provides a method for treating or preventing disorders wherein the disorder is asthma.

[0061] Definitions

[0062] The compounds herein described may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Many geometric isomers of olefins, C═N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated.

[0063] The term “substituted” as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substitent is keto (i.e., ═O), then 2 hydrogens on the atom are replaced.

[0064] When any substituent occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 substituents, then said group may optionally be substituted with up to two such substituents which at each occurrence is selected independently from the definitions of said substituents. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

[0065] When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

[0066] As used herein, “alkyl” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, examples of which include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, and hexyl. C1-6 alkyl, is intended to include C1, C2, C3, C4, C5, and C6 alkyl groups.

[0067] “Alkenyl” is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl, and the like. “Alkynyl” is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl, propynyl, and the like. “C3-8 cycloalkyl” is intended to include saturated ring groups having the specified number of carbon atoms in the ring, including mono-, bi-, or poly-cyclic ring systems, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl in the case of C7 cycloalkyl. C3-8 cycloalkyl, is intended to include C3, C4, C5, and C6 cycloalkyl groups.

[0068] “Halo” or “halogen” as used herein refers to fluoro, chloro, bromo, and iodo; and “haloalkyl” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups, for example CF3, having the specified number of carbon atoms, substituted with 1 or more halogen (for example-CVFw where v=1 to 3 and w=1 to (2v+1)).

[0069] The compounds of Formula I can also be quaternized by standard techniques such as alkylation of the amino group NR1R2 with an alkyl halide to yield quaternary piperidinium salt products of formula I. Such quaternary ammonium salts would include a counterion. As used herein, “counterion” is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate, and the like.

[0070] As used herein, the term “heterocyclic group” is intended to mean a stable 5,6, or 7-membered monocyclic or 7, 8, 9, or 10-membered bicyclic heterocyclic ring which is saturated or partially unsaturated, and which consists of carbon atoms and 1,2, or 3heteroatoms independently selected from the group consisting of N, O and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring is attached to its pendant group at the nitrogen atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If specifically noted, a nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another.

[0071] Examples of heterocycles include, but are not limited to, 1H-indazole, 2-pyrrolidonyl, 2H, 6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 1-piperidinyl, 1-piperazinyl, 1-morpholinyl.

[0072] The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

[0073] As used herein, “pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from nontoxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.

[0074] The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remingto which release an active parent drug of the present invention in vivo when such prodrug is administered to a mammalian subject. Prodrugs the present invention are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of the present invention wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug of the present invention is administered to a mammalian subject, it cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the present invention.

[0075] “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

[0076] R1 and R2 together with the interjacent nitrogen atom form a 5- to 7-membered, saturated or unsaturated heterocyclic group, which may contain one or two hetero atoms selected from among oxygen, nitrogen or sulphur, wherein said heterocyclic group may be substituted by hydroxy, C1-C4-alkyl, C3-C8-cycloalkyl, hydroxy-C3-C8-cycloalkyl, C1-C4-alkoxycarbonyl, phenyl, alkoxyphenyl, halophenyl, trifluoromethylphenyl, 2-oxobenzimidazolyl, piperidyl, benzyl 9-H-fluorenyl or di-(C1-C4-alkyl)-amino-C1-C4-alkyl, and which may optionally be fused with one or two benzene rings.

[0077] Particularly preferred are those compounds of formulae IA and IB, wherein

[0078] Ra Rb, Rd and Re each represent a hydrogen atom;

[0079] Rc represents a hydrogen or halogen atom or a group selected from C1-C6-alkyl, C1-C4-alkoxy, C1-C4-alkylthio, C2-C6-alkenyl C2-C6-alkinyl, C3-C8-cycloalkyl —NH2, —NH(C1-C4-alkyl), —N(C1-C4-alkyl)2 and phenyl, wherein any of these groups may optionally substituted by one or more of the groups hydroxy, halogen, CF3, or

[0080] Rf represents a hydrogen atom or a C1-C4-alkoxy group,

[0081] Rg and Rj each independently represent a hydrogen or halogen atom or a C1-C6-alkyl group optionally substituted by halogen,

[0082] Rh represents a hydrogen or halogen atom or a group selected from C1-C6-alkyl, C1-C4-alkoxy, C1-C4-alkylthio, C2-C6-alkenyl C2-C6-alkinyl, C3-C8-cycloalkyl, cyano,

[0083] —NH2, —NH(C1-C4-alkyl), —N(C1-C4-alkyl)2, wherein any of these groups may optionally be substituted by one or more of the groups hydroxy or halogen,

[0084] Rj represents a hydrogen atom,

[0085] R1 and R2 together with the interjacent nitrogen atom form a piperidine or piperazine group, which may be substituted by hydroxy, C1-C4-alkyl, C3-C8-cycloalkyl, hydroxy-C3-C8-cycloalkyl, C1-C4-alkoxycarbonyl, phenyl, alkoxyphenyl, halophenyl, trifluoromethylphenyl, 2-oxobenzimidazolyl, piperidyl, benzyl 9-H-fluorenyl or di-(C1-C4-alkyl)-amino-C1-C4-alkyl, and which may optionally be fused with one or two benzene rings;

[0086] optionally in the form of their tautomers, racemates, enantiomers, diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.

[0087] Most preferred are those compounds of formulae IA and IB, wherein

[0088] Ra Rb, Rd and Re each represent a hydrogen atom;

[0089] Rc represents a halogen atom or a group selected from C1-C6-alkyl, C1-C4-alkoxy, C3-C8-cycloalkyl and phenyl, wherein any of these groups may optionally substituted by one or more of the groups hydroxy, halogen, CF3,

[0090] Rf represents a hydrogen atom or a methoxy group,

[0091] Rg and Rj each independently represent a hydrogen or chlorine atom or a methyl group,

[0092] Rh represents a hydrogen or chlorine atom or a group selected from methyl, tert-butyl, trifluoromethyl, methoxy, cyano, amino and dimethylamine;

[0093] Rj represents a hydrogen atom,

[0094] R1 and R2 together with the interjacent nitrogen atom form a piperidine or piperazine group, which may be substituted by cyclohexyl or phenyl,

[0095] optionally in the form of their tautomers, racemates, enantiomers, diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.

[0096] Synthesis

[0097] The compounds of formula I can be prepared using the reactions and techniques described below. The reactions are performed in a solvent appropriate to the reagents and materials employed and suitable for the transformations being effected. It will be understood by those skilled in the art of organic synthesis that the functionality present on the molecule should be consistent with the transformations proposed. This will sometimes require a judgment to modify the order of the synthetic steps or to select one particular process scheme over another in order to obtain a desired compound of the invention. It will also be recognized that another major consideration in the planning of any synthetic route in this field is the judicious choice of the protecting group used for protection of the reactive functional groups present in the compounds described in this invention. An authoritative account describing the many alternatives to the trained practitioner is Greene and Wuts (Protective Groups In Organic Synthesis, Wiley and Sons, 1991).

[0098] The compounds of formula IA are preferably prepared by the reaction of a compound of formula (IIA)

[0099] wherein the groups R1, R3 and Ra through Re have the meanings given hereinabove and hereinbelow, with a compound of formula (IIIA)

[0100] wherein the groups Rf through Rj have the meanings given hereinabove and hereinbelow, and

[0101] (a) X represents hydroxy or a leaving group and Y represents two hydrogen atoms an oxygen atom, or

[0102] (b) X represents a hydrogen atom and Y represents an oxygen atom, in a nucleophilic substitution for type (a) optionally followed by reduction for X═OH or a leaving group, or

[0103] in a reductive amination for type (b).

[0104] The compounds of formula IB are preferably prepared by the reaction of a compound of formula (IIA) with a compound of formula (IIIB)

[0105] wherein the groups Rf through Rj have the meanings given hereinabove and hereinbelow.

[0106] Utility

[0107] The utility of the compounds in accordance with the present invention as modulators of chemokine receptor activity may be demonstrated by methodology known in the art, such as the assays for CCR-2 and CCR-3 ligand binding, as disclosed by Ponath et al., J. Exp. Med., 183,2437-2448 (1996) and Uguccioni et al., J. Clin. Invest., 100,11371143 (1997). Cell lines for expressing the receptor of interest include those naturally expressing the chemokine receptor, such as EOL-3 or THP-1, those induced to express the chemokine receptor by the addition of chemical or protein agents, such as HL-60 or AML14.3D10 cells treated with, for example, butyric acid with interleukin-5 present, or a cell engineered to express a recombinant chemokine receptor, such as CHO or HEK-293. Finally, blood or tissue cells, for example human peripheral blood eosinophils, isolated using methods as described by Hansel et al., J. Immunol. Methods, 145,105-110 (1991), can be utilized in such assays. In particular, the compound of the present invention have activity in binding to the CCR-3 receptor in the aforementioned assays. As used herein, “activity” is intended to mean a compound demonstrating an IC50 of 10 MM or lower in concentration when measured in the aforementioned assays. Such a result is indicative of the intrinsic activity of the compounds as modulators of chemokine receptor activity. A general binding protocol is described below.

[0108] CCR3-Receptor Binding Protocol

[0109] The CCR3 receptor binding test is based on a K562 cell line (leukemia myelogenic blast cells) transfected with the human chemokine receptor CCR3 (hCCR3-C1). The cell membranes were prepared by disrupting the hCCR3 transfected K562 cells by nitrogen decomposition and centrifugation at 40000 g, 4° C. for 1 h. The membranes were resuspendet in the SPA incubation buffer (see below) without bovine serum albumin for storage in aliquots at −80 degrees C.

[0110] The CCR3 receptor binding assay with the radioligand 125Jodine-eotaxin-1 was performed in a Scintillation Proximity Assay (SPA) design. Cell membranes of hCCR3 C1 cells were diluted in suitable concentrations (0.5-5 ug protein/well) in 96 well microtiter plates (1450401, Wallac).

[0111] The test incubation mixture comprising 60 μl of the membrane suspension, 80 μl of the Wheat Germ Agglutinin coated PVT beads (organic scintillator, Amersham Pharmacia biotech) in a concentration of 0,4 mg and 40 μl of radiolabelled 125J rhEotaxin (Amersham, IM290) were incubated with 20 μl of the test compound (dissolved in DMSO dilutions) for 2 hours. The SPA incubation buffer contained 25 mM HEPES, 25 mM MgCl2 6×H2O, 1 mM CaCl2 2×H2O and 0,1% bovine serum albumin. Included were controls for specific binding (no displacer added) and non-specific binding by adding unlabelled rhEotaxin (R&D Systems) or a test compound. Bound radioactivity was determined by scintillation counter (Micro Beta “Trilux”, Wallac).

[0112] Determination of affinity of test compounds (dissociation constant Ki) was calculated by iterative fitting of experimental data using the law of mass action based program “easy sys” (Schittkowski, Num Math 68, 129-142 (1994)).

[0113] The utility of the compounds in accordance with the present invention as inhibitors of the migration of eosinophils or cell lines expressing the chemokine receptors may be demonstrated by methodology known in the art, such as the chemotaxis assay disclosed by Bacon et al., Brit. J. Pharmacol., 95,966-974 (1988). In particular, the compound of the present invention have activity in inhibition of the migration of eosinophils in the aforementioned assays. As used herein, “activity” is intended to mean a compound demonstrating an Ki of 10 μM or lower in concentration when measured in the aforementioned assays. Such a result is indicative of the intrinsic activity of the compounds as modulators of chemokine receptor activity.

[0114] Mammalian chemokine receptors provide a target for interfering with or promoting immune cell function in a mammal, such as a human. Compounds that inhibit or promote chemokine receptor function are particularly useful for modulating immune cell function for therapeutic purposes.

[0115] Accordingly, the present invention is directed to compounds which are useful in the prevention and/or treatment of a wide variety of inflammatory, infectious, and immunoregulatory disorders and diseases, including asthma and allergic diseases, infection by pathogenic microbes (which, by definition, includes viruses), as well as autoimmune pathologies such as the rheumatoid arthritis and atherosclerosis.

[0116] For example, an instant compound which inhibits one or more functions of a mammalian chemokine receptor (e.g., a human chemokine receptor) may be administered to inhibit (i.e., reduce or prevent) inflammation or infectious disease. As a result, one or more inflammatory process, such as leukocyte emigration, adhesion, chemotaxis, exocytosis (e.g., of enzymes, histamine) or inflammatory mediator release, is inhibited. For example, eosinophilic infiltration to inflammatory sites (e.g., in asthma or allergic rhinitis) can be inhibited according to the present method. In particular, the compound of the following examples has activity in blocking the migration of cells expressing the CCR-3 receptor using the appropriate chemokines in the aforementioned assays.

[0117] Similarly, an instant compound which promotes one or more functions of the mammalian chemokine receptor (e.g., a human chemokine) as administered to stimulate (induce or enhance) an immune or inflammatory response, such as leukocyte emigration, adhesion, chemotaxis, exocytosis (e.g., of enzymes, histamine) or inflammatory mediator release, resulting in the beneficial stimulation of inflammatory processes. For example, eosinophils can be recruited to combat parasitic infections. In addition, treatment of the aforementioned inflammatory, allergic and autoimmune diseases can also be contemplated for an instant compound which promotes one or more functions of the mammalian chemokine receptor if one contemplates the delivery of sufficient compound to cause the loss of receptor expression on cells through the induction of chemokine receptor internalization or the delivery of compound in a manner that results in the misdirection of the migration of cells.

[0118] In addition to primates, such as humans, a variety of other mammals can be treated according to the method of the present invention. For instance, mammals, including but not limited to, cows, sheep, goats, horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine, canine, feline, rodent or murine species can be treated. However, the method can also be practiced in other species, such as avian species. The subject treated in the methods above is a mammal, male or female, in whom modulation of chemokine receptor activity is desired. “Modulation” as used herein is intended to encompass antagonism, agonism, partial antagonism and/or partial agonism. Diseases or conditions of human or other species which can be treated with inhibitors of chemokine receptor function, include, but are not limited to: inflammatory or allergic diseases and conditions, including respiratory allergic diseases such as asthma, allergic rhinitis, hypersensitivity lung diseases, hypersensitivity pneumonitis, eosinophilic cellulitis (e.g., Well's syndrome), eosinophilic pneumonias (e.g., Loeffler's syndrome, chronic eosinophilic pneumonia), eosinophilic fasciitis (e.g., Shulman's syndrome), delayed-type hypersensitivity, interstitial lung diseases (ILD) (e.g., idiopathic pulmonary fibrosis, or ILD associated with rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, systemic sclerosis, Sjogren's syndrome, polymyositis or dermatomyositis); systemic anaphylaxis or hypersensitivity responses, drug allergies (e.g., to penicillin, cephalosporins), eosinophilia-myalgia syndrome due to the ingestion of contaminated tryptophan, insect sting allergies; autoimmune diseases, such as rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, systemic lupus erythematosus, myasthenia gravis, juvenile onset diabetes; glomerulonephritis, autoimmune thyroiditis, Behcet's disease; graft rejection (e.g., in transplantation), including allograft rejection or graftversus-host disease; inflammatory bowel diseases, such as Crohn's disease and ulcerative colitis; spondyloarthropathies; scleroderma; psoriasis (including Tcell mediated psoriasis) and inflammatory dermatoses such as an dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria; vasculitis (e.g., necrotizing, cutaneous, and hypersensitivity vasculitis); eosinophilic myositis, eosinophilic fasciitis; cancers with leukocyte infiltration of the skin or organs. Other diseases or conditions in which undesirable inflammatory responses are to be inhibited can be treated, including, but not limited to, reperfusion injury, atherosclerosis, certain hematologic malignancies, cytokine-induced toxicity (e.g., septic shock, endotoxic shock), polymyositis, dermatomyositis. Infectious diseases or conditions of human or other species which can be treated with inhibitors of chemokine receptor function, include, but are not limited to, HIV.

[0119] Diseases or conditions of humans or other species which can be treated with promoters of chemokine receptor function, include, but are not limited to: immunosuppression, such as that in individuals with immunodeficiency syndromes such as AIDS or other viral infections, individuals undergoing radiation therapy, chemotherapy, therapy for autoimmune disease or drug therapy (e.g., corticosteroid therapy), which causes immunosuppression; immunosuppression due to congenital deficiency in receptor function or other causes; and infections diseases, such as parasitic diseases, including, but not limited to helminth infections, such as nematodes (round worms); (Trichuriasis, Enterobiasis, Ascariasis, Hookworm, Strongyloidiasis, Trichinosis, filariasis); trematodes (flukes) (Schistosomiasis, Clonorchiasis), cestodes (tape worms) (Echinococcosis, Taeniasis saginata, Cysticercosis); visceral worms, visceral larva migraines (e.g., Toxocara), eosinophilic gastroenteritis (e.g., Anisaki sp., Phocanema sp.), cutaneous larva migraines (Ancylostona braziliense, Ancylostoma caninum). The compounds of the present invention are accordingly useful in the prevention and treatment of a wide variety of inflammatory, infectious and immunoregulatory disorders and diseases. In addition, treatment of the aforementioned inflammatory, allergic and autoimmune diseases can also be contemplated for promoters of chemokine receptor function if one contemplates the delivery of sufficient compound to cause the loss of receptor expression on cells through the induction of chemokine receptor internalization or delivery of compound in a manner that results in the misdirection of the migration of cells.

[0120] In another aspect, the instant invention may be used to evaluate the putative specific agonists or antagonists of a G protein coupled receptor. The present invention is directed to the use of these compounds in the preparation and execution of screening assays for compounds that modulate the activity of chemokine receptors. Furthermore, the compounds of this invention are useful in establishing or determining the binding site of other compounds to chemokine receptors, e.g., by competitive inhibition or as a reference in an assay to compare its known activity to a compound with an unknown activity. When developing new assays or protocols, compounds according to the present invention could be used to test their effectiveness.

[0121] Specifically, such compounds may be provided in a commercial kit, for example, for use in pharmaceutical research involving the aforementioned diseases. The compounds of the instant invention are also useful for the evaluation of putative specific modulators of the chemokine receptors. In addition, one could utilize compounds of this invention to examine the specificity of G protein coupled receptors that are not thought to be chemokine receptors, either by serving as examples of compounds which do not bind or as structural variants of compounds active on these receptors which may help define specific sites of interaction.

[0122] Combined therapy to prevent and treat inflammatory, infectious and immunoregulatory disorders and diseases, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis, and those pathologies noted above is illustrated by the combination of the compounds of this invention and other compounds which are known for such utilities. For example, in the treatment or prevention of inflammation, the present compounds may be used in conjunction with an anti-inflammatory or analgesic agent such as an opiate agonist, a lipoxygenase inhibitor, a cyclooxygenase-2 inhibitor, an interleukin inhibitor, such as an interleukin-1 inhibitor, a tumor necrosis factor inhibitor, an NMDA antagonist, an inhibitor or nitric oxide or an inhibitor of the synthesis of nitric oxide, a nonsteroidal anti-inflammatory agent, a phosphodiesterase inhibitor, or a cytokine-suppressing anti-inflammatory agent, for example with a compound such as acetaminophen, aspirin, codeine, fentaynl, ibuprofen, indomethacin, ketorolac, morphine, naproxen, phenacetin, piroxicam, a steroidal analgesic, sufentanyl, sunlindac, interferon alpha and the like. Similarly, the instant compounds may be administered with a pain reliever; a potentiator such as caffeine, an H2-antagonist, simethicone, aluminum or magnesium hydroxide; a decongestant such as phenylephrine, phenylpropanolamine, pseudophedrine, oxymetazoline, ephinephrine, naphazoline, xylometazoline, propylhexedrine, or levodesoxy-ephedrine; and antitussive such as codeine, hydrocodone, caramiphen, carbetapentane, or dextramethorphan; a diuretic; and a sedating or nonsedating antihistamine. Likewise, compounds of the present invention may be used in combination with other drugs that are used in the treatment/prevention/suppression or amelioration of the diseases or conditions for which compound of the present invention are useful. Such other drugs may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of the present invention. When a compound of the present invention is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound of the present invention is preferred. Accordingly, the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of the present invention. Examples of other active ingredients that may be combined with a compound of the present invention, either administered separately or in the same pharmaceutical compositions, include, but are not limited to: (a) integrin antagonists such as those for selectins, ICAMs and VLA-4; (b) steroids such as beclomethasone, methylprednisolone, betamethasone, prednisone, dexamethasone, and hydrocortisone; (c) immunosuppressants such as cyclosporin, tacrolimus, rapamycin and other FK-506 type immunosuppressants; (d) antihistamines (H1-histamine antagonists) such as bromopheniramine, chlorpheniramine, dexchlorpheniramine, triprolidine, clemastine, diphenhydramine, diphenylpyraline, tripelennamine, hydroxyzine, methdilazine, promethazine, trimeprazine, azatadine, cyproheptadine, antazoline, pheniramine pyrilamine, astemizole, terfenadine, loratadine, cetirizine, fexofenadine, descarboethoxyloratadine, and the like; (e) non-steroidal anti-asthmatics such as b2-agonists (terbutaline, metaproterenol, fenoterol, isoetharine, albuteral, bitolterol, and pirbuterol), theophylline, cromolyn sodium, atropine, ipratropium bromide, leukotriene antagonists (zafirlukast, montelukast, pranlukast, iralukast, pobilukast, SKB-102,203), leukotriene biosynthesis inhibitors (zileuton, BAY-1005); (f) nonsteroidal antiinflammatory agents (NSAIDs) such as propionic acid derivatives (alminoprofen, benxaprofen, bucloxic acid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin, pirprofen, pranoprofen, suprofen, tiaprofenic acid, and tioxaprofen), acetic acid derivatives (indomethacin, acemetacin, alclofenac, clidanac, diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac, isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidometacin, and zomepirac), fenamic acid derivatives (flufenamic acid, meclofenamic acid, mefenamic acid, niflumic acid and tolfenamic acid), biphenylcarboxylic acid derivatives (diflunisal and flufenisal), oxicams (isoxicam, piroxicam, sudoxicam and tenoxican), salicylates (acetyl salicylic acid, sulfasalazine) and the pyrazolones (apazone, bezpiperylon, feprazone, mofebutazone, oxyphenbutazone, phenylbutazone); (g) cyclooxygenase-2 (COX-2) inhibitors; (h) inhibitors of phosphodiesterase type IV (PDE-IV); (I) other antagonists of the chemokine receptors; (j) cholesterol lowering agents such as HMG-COA reductase inhibitors (lovastatin, simvastatin and pravastatin, fluvastatin, atorvsatatin, and other statins), sequestrants (cholestyramine and colestipol), nicotonic acid, fenofibric acid derivatives (gemfibrozil, clofibrat, fenofibrate and benzafibrate), and probucol; (k) anti-diabetic agents such as insulin, sulfonylureas, biguanides (metformin), a-glucosidase inhibitors (acarbose) and glitazones (troglitazone ad pioglitazone); (1) preparations of interferons (interferon alpha-2a, interferon-2B, interferon alpha-N3, interferon beta-1a, interferon beta-1b, interferon gamma-1b); (m) antiviral compounds such as efavirenz, nevirapine, indinavir, ganciclovir, lamivudine, famciclovir, and zalcitabine; (o) other compound such as 5-aminosalicylic acid an prodrugs thereof, antimetabolites such as azathioprine and 6-mercaptopurine, and cytotoxic cancer chemotherapeutic agents. The weight ratio of the compound of the present invention to the second active ingredient may be varied and will depend upon the effective doses of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the present invention is combined with an NSAID the weight ratio of the compound of the present invention to the NSAID will generally range from about 1000: 1 to about 1: 1000, preferably about 200: 1 to about 1: 200. Combinations of a compound of the present invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.

[0123] The compounds are administered to a mammal in a therapeutically effective amount. By “therapeutically effective amount” it is meant an amount of a compound of formula I that, when administered alone or in combination with an additional therapeutic agent to a mammal, is effective to prevent or ameliorate the thromboembolic disease condition or the progression of the disease.

[0124] Dosage and Formulation

[0125] The compounds of this invention can be administered in such oral dosage forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. They may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts. They can be administered alone, but generally will be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

[0126] The dosage regimen for the compounds of the present invention will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient, and the effect desired. A physician or veterinarian can determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the thromboembolic disorder.

[0127] By way of general guidance, the daily oral dosage of each active ingredient, when used for the indicated effects, will range between about 0.001 to 1000 mg/kg of body weight, preferably between about 0.01 to 100 mg/kg of body weight per day, and most preferably between about 1.0 to 20 mg/kg/day. Intravenously, the most preferred doses will range from about 1 to about 10 mg/kg/minute during a constant rate infusion. Compounds of this invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily.

[0128] Compounds of this invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using transdermal skin patches. When administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.

[0129] The compounds are typically administered in admixture with suitable pharmaceutical diluents, excipients, or carriers (collectively referred to herein as pharmaceutical carriers) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.

[0130] For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl callulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.

[0131] The compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.

[0132] Compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues.

[0133] Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels.

[0134] Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 milligram to about 100 milligrams of active ingredient per dosage unit.

[0135] In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about 0.5-95% by weight based on the total weight of the composition.

[0136] Gelatin capsules may contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.

[0137] Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.

[0138] In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl-or propyl-paraben, and chlorobutanol.

[0139] Suitable pharmaceutical carriers are described in Reminqton's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field.

[0140] Representative useful pharmaceutical dosage-forms for administration of the compounds of this invention can be illustrated as follows:

[0141] Capsules

[0142] A large number of unit capsules can be prepared by filling standard two-piece hard gelatin capsules each with 100 milligrams of powdered active ingredient, 150 milligrams of lactose, 50 milligrams of cellulose, and 6 milligrams magnesium stearate.

[0143] Soft Gelatin Capsules

[0144] A mixture of active ingredient in a digestable oil such as soybean oil, cottonseed oil or olive oil may be prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 100 milligrams of the active ingredient. The capsules should be washed and dried.

[0145] Tablets

[0146] Tablets may be prepared by conventional procedures so that the dosage unit is 100 milligrams of active ingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams of microcrystalline cellulose, 11 milligrams of starch and 98.8 milligrams of lactose. Appropriate coatings may be applied to increase palatability or delay absorption.

[0147] Injectable

[0148] A parenteral composition suitable for administration by injection may be prepared by stirring 1.5% by weight of active ingredient in 10% by volume propylene glycol and water. The solution should be made isotonic with sodium chloride and sterilized.

[0149] Suspension

[0150] An aqueous suspension can be prepared for oral administration so that each 5 mL contain 100 mg of finely divided active ingredient, 200 mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution, U.S. P., and 0.025 mL of vanillin.

[0151] Where the compounds of this invention are combined with other anticoagulant agents, for example, a daily dosage may be about 0.1 to 100 milligrams of the compound of Formula I and about 1 to 7.5 milligrams of the second anticoagulant, per kilogram of patient body weight. For a tablet dosage form, the compounds of this invention generally may be present in an amount of about 5 to 10 milligrams per dosage unit, and the second anti-coagulant in an amount of about 1 to 5 milligrams per dosage unit.

[0152] Where two or more of the foregoing second therapeutic agents are administered with the compound of Formula I, generally the amount of each component in a typical daily dosage and typical dosage form may be reduced relative to the usual dosage of the agent when administered alone, in view of the additive or synergistic effect of the therapeutic agents when administered in combination.

[0153] Particularly when provided as a single dosage unit, the potential exists for a chemical interaction between the combined active ingredients. For this reason, when the compound of Formula I and a second therapeutic agent are combined in a single dosage unit they are formulated such that although the active ingredients are combined in a single dosage unit, the physical contact between the active ingredients is minimized (that is, reduced). For example, one active ingredient may be enteric coated. By enteric coating one of the active ingredients, it is possible not only to minimize the contact between the combined active ingredients, but also, it is possible to control the release of one of these components in the gastrointestinal tract such that one of these components is not released in the stomach but rather is released in the intestines. One of the active ingredients may also be coated with a material which effects a sustained-release throughout the gastrointestinal tract and also serves to minimize physical contact between the combined active ingredients.

[0154] Furthermore, the sustained-released component can be additionally enteric coated such that the release of this component occurs only in the intestine. Still another approach would involve the formulation of a combination product in which the one component is coated with a sustained and/or enteric release polymer, and the other component is also coated with a polymer such as a lowviscosity grade of hydroxypropyl methylcellulose (HPMC) or other appropriate materials as known in the art, in order to further separate the active components. The polymer coating serves to form an additional barrier to interaction with the other component.

[0155] These as well as other ways of minimizing contact between the components of combination products of the present invention, whether administered in a single dosage form or administered in separate forms but at the same time by the same manner, will be readily apparent to those skilled in the art, once armed with the present disclosure.

[0156] As will be appreciated by one of skill in the art, numerous modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described herein.

EXAMPLE 1

[0157] 1A 2-(4-Cyclohexyl-piperazin-1-yl)-2-(4-methoxy-phenyl)-acetonitril 60 ml of 1 molar hydrochloric acid are added to a mixture of 7.2 ml (0.059 mol) of 4-methoxy-benzaldehyde, 9.93 g (0.059 mol) of 1-cyclohexylpiperazine and 60 ml of diethylether at ambient temperature under nitrogen. Subsequently, a solution of 3.91 g (0.06 mol) potassium cyanide in 6 ml water is added at 0° C., the resulting mixture is stirred for 48 hours at ambient temperature. Upon addition of diethylether and tetrahydrofuran the phases are separated and the aqueous phase is extracted with diethylether. The combined organic phases are dried over sodium sulfate and concentrated in vacuo. A white residue is obtained, which is filtered and dried.

[0158] Yield: 14.02 g (=76%)

[0159] 1B 2-(4-Cyclohexyl-piperazin-1-yl)-2-(4-methoxy-phenyl)-ethylamine-hydrochloride

[0160] 4.80 ml (0.09 mol) of conc. sulfuric acid are added to a mixture of 6.83 g (0.18 mol) lithium aluminiumhydride and 180 ml diethylether at −40° C. under nitrogen. The mixture is srtirref for 1 hour at ambient temperature. Subsequently, a mixture of 14.02 g (0.045 mol) 1A and 200 ml diethylether are added. The resulting mixture is stirred for 3 hours under reflux.

[0161] Ethyl acetate is added under cooling. Then 338 ml of hydrochloric acid (2 molar) are added. The phases are separated and the aqueous phase is extracted with diethylether. Subsequently, 76.2 g of potassium sodium tartrate are added to the aqueous phase followed by 86 ml of sodium hydroxide. The resulting mixture is stirred for two hours at 60° C. and extracted with diethylether. The combined organic phases obtained in the final extraction step are dried over sodium sulfate and concentrated in vacuo and the hydro chloride is precipitated.

[0162] Yield: 15.83 g (=83%)

[0163] 1C N-[2-(4-Cyclohexyl-piperazin-1-yl)-2-(4-methoxy-phenyl)-ethyl]-2-(3,5-dimethyl-phenyl)-acetamide:

[0164] A mixture of 2.0 g (0.006 mol) of 1B and 50 ml dichloromethane is treated with 2.44 g (0.024 mol) of N-methylmorpholine. Subsequently, a mixture of 2.89 g (0.009 mol) TBTU (═O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-tetrafluoroborate) and 0.99 g (0.006 mol) 3,5-dimethylphenylacetic acid is added. The mixture is stirred for 24 hours at ambient temperature. The mixture is washed with an aqueous solution of sodium hydrogencarbonate (10%) and with a saturated solution of sodium chloride. The organic phase is dried over magnesium sulfate and concentrated in vacuo.

[0165] Yield: 3.12 g Crude product

[0166] 1D [2-(4-Cyclohexyl-piperazin-1-yl)-2-(4-methoxy-phenyl)-ethyl]-[2-(3.5-dimethyl-phenyl)-ethyl]-amin:

[0167] A solution of borandimethylsulfide in tetrahydrofuran (10.50 ml, 0.021 mol, 2 molar) is added to a mixture of 3.12 g (0.007 mol) of 1C and 100 ml tetrahydrofuran at 0° C. under nitrogen and stirred for 15 minutes at this temperature. Subsequently, the mixture is stirred for 2 hours under reflux and 24 hours at ambient temperature. 50 ml of methanol are added and the resulting mixture is concentrated in vacuo. The residue is taken up with ethanol, 3.0 g of potassium carbonate are added. The resulting mixture is stirred under reflux for 5 hours. Upon cooling the mixture is again concentrated in vacuo. The residue is taken up with water and 2 molarer hydrochloric acid (2 molar) and washed with diethylether. The aqueous phase is alkalized and extracted with diethylether. The resulting organic phase is dried over magnesium sulfate. Upon concentration in vacuo the residue is purified by chromatography to yield 0.64 g (=20%) of 1D.

[0168] Analogously the following compounds of formula IA1 are obtained:

1TABLE I(IA1)

Example No.RaRbRcRgRhRiRjR2HHPhenylHCH3HHCyclohexyl3HHCH3OClHClHCyclohexyl4HHHClHClHCyclohexyl5HHCH3OHHHCH3OCyclohexyl6HHCF3HHHCH3OCyclohexyl7HHCF3ClHClHCyclohexyl8HHCH3OHClHHCyclohexyl9HHC(CH3)3HHHCH3OCyclohexyl10HHC(CH3)3ClHClHCyclohexyl11HHC(CH3)3HCF3HHCyclohexyl12HHHHHHCH3OCyclohexyl13HHC(CH3)3HN(CH3)2HHCyclohexyl14CH3OHHClHClHCyclohexyl15HHC(CH3)3HCH3OHHCyclohexyl16HHC(CH3)3HC(CH3)3HHCyclohexyl17HHC(CH3)3HHHHCyclohexyl18HHCF3HCH3OHHPhenyl19HHCH3OHCH3HHCyclohexyl20HHN(CH3)2HCH3HHPhenyl21HHHHClHHCyclohexyl22HHCF3HCH3OHHCyclohexyl23HHCF3HHHHCyclohexyl24HHC(CH3)3HHHCH3OPhenyl25HHPhenylHHHCH3OCyclohexyl26HHPhenylCH3HCH3HCyclohexyl27HHN(CH3)2HHHCH3OPhenyl28HHCF3HCH3HHCyclohexyl29HHCH3OHCH3HHPhenyl30HHCF3HN(CH3)2HHPhenyl31CH3OHHHC(CH3)3HHCyclohexyl32HHCH3OClHClHPhenyl33CH3OHHHCH3HHPhenyl34CH3OHHClHClHPhenyl35HHC(CH3)3HCH3OHHPhenyl36HHCF3HCF3HHCyclohexyl37HHCF3HC(CH3)3HHCyclohexyl38HHCF3HHHCH3OPhenyl39HHHHCH3HHPhenyl40HHCF3HFHHCyclohexyl41HHCH3OHFHHCyclohexyl42HHCH3OHCH3HHCyclohexyl43HHCF3HHHHPhenyl44HHC(CH3)3HFHHPhenyl45HHCH3OHCF3HHCyclohexyl46HHC(CH3)3HHHCH3OCH347HHCH3OCF3HCF3HCyclohexyl48HHCH3OHHHCH3OPhenyl49HHCH3OHHHHCyclohexyl50HHHHFHHPhenyl51HHHHHHCH3OPhenyl52CH3OHHHFHHPhenyl53HHCF3HN(CH3)2HHCyclohexyl54HHC(CH3)3HCF3HHCH355HHC(CH3)3HHHHPhenyl56HHCH3OHC(CH3)3HHCyclohexyl57HHCF3ClHClHPhenyl58HHCH3OHHHHPhenyl59CH3OHHHC(CH3)3HHPhenyl60HHCF3HCH3HHPhenyl61HHCH3OHCF3HHPhenyl62HHHHC(CH3)3HHPhenyl63HHC(CH3)3HFHHCH364HHHHCF3HHCyclohexyl65HHC(CH3)3HC(CH3)3HHPhenyl66HHN(CH3)2HHHHPhenyl67HHHClHClHPhenyl68HHN(CH3)2HFHHPhenyl

EXAMPLE 69

[0169] 1-[2-(4-Cyclohexyl-piperazin-1-yl)-2-(4-methoxy-phenyl)-ethyl]-3-(3,5-dimethyl-phenyl)-harnstoff:

[0170] A mixture of 2.0 g (0.006 mol) 2-(4-cyclohexyl-piperazin-1-yl)-2-(4-methoxy-phenyl)-ethylamine (obtained as described in Example 1B), 0.85 ml (0.006 mol) 3,5-dimethylphenylisocyanate and 25 ml dichloromethane are stirred for 24 hours at ambient temperature under nitrogen. Upon concentration in vacuo the residue is purified by chromatography to yield 0.82 g (==29% d. Th.) of the desired compound.

[0171] Analogously the following compounds of formula IB1 are obtained:

2TABLE II(IB1)

Example No.RaRbRcRgRhRiRjR70HHPhenylHCH3HHCyclohexyl71HHPhenylCH3HCH3HCyclohexyl72HHCF3HHHHCyclohexyl73HHHClHClH3,4-Di-Cl-Benzyl74HHCH3OClHClHCyclohexyl75HHHCH3HCH3H3,4-Di-Cl-Benzyl76CH3OHHHClHH3,4-Di-Cl-Benzyl77CH3OHHClHClHCyclohexyl78HHCH3OHC(CH3)3HHCyclohexyl79HHCF3ClHClHCyclohexyl80HHPhenylClHClHCyclohexyl81HHC(CH3)3HCF3HHCyclohexyl82CH3OHHHCH3HH3,4-Di-Cl-Benzyl83HHN(CH3)2ClHClHCyclohexyl84HHCH3OHFHHCyclohexyl85CH3OHHHCH3HHCyclohexyl86HHC(CH3)3HCH3HHCyclohexyl87CH3OHHHC(CH3)3HHCyclohexyl88HHCF3HCH3HHCyclohexyl89HHCF3HFHHCyclohexyl90HHC(CH3)3HFHHCyclohexyl91HHC(CH3)3HHHHCyclohexyl92HHHHCH3HH3,4-Di-Cl-Benzyl93CH3OHHCF3HCF3HCycloheptyl94HFHClHClHCyclohexyl95HHHClHClHCyclohexyl96HHHHClHH3,4-Di-Cl-Benzyl97HHCF3HCF3HHCyclohexyl98HHHHCF3HHCyclohexyl99HHCF3HC(CH3)3HHCyclohexyl

[0172] All the compounds of the examples 1 to 99 show dissociation constants Ki from 0.05 to 1.5 μM in the above mentioned CCR3-Receptor Binding Protocol.

1-Phenyl-1,2-diaminoethane derivatives as modulators of the chemokine receptor activity

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